CA2681110A1 - Synthesis of chirally purified substituted benzothiazole diamines - Google Patents

Abstract

Methods for preparing chirally purified substituted 4,5,6,7-tetrahydro-benzotiazole diamines such as, for example, (6R)2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and purifying a dominant enantiomer of substituted 4,5,6,7-tetrahydro-benzotiazole diamines from entantiomerically enriched mixtures of substituted 4,5,6,7-tetrahydro-benzotiazole diamines are provided herein.

Description

A. Title:
SYNTHESIS OF CHIRALLY PURIFIED
SUBSTITUTED BENZOTHIAZOLE DIAMINES
B. Cross-Reference to ]telated Applications:
[0001] '1'his application claims priority to and benefit of U.S. Provisional Application No. 60/894,829 entitled "Methods of Synthesizing and Purifying and S(-) Pramipexole", filed on March 14, 2007 and U.S. Provisional Application No. 60/894,814 entitled "Methods of Enantiornerically Purifying Chiral Compounds", filed on March 14, 2007, the entire contents of which are hereby incorporated by reference in their entireties.
C. Government Interests: Not applicable D. Parties to a Joint Research Agreement: Not applicable E. Incorporation by Reference of Material submitted on a Compact Disc: Not applicable F. Background 1. Field of Invention: Not applicable 2. Description of Related Art:
[0002] 1'he compound 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is a synthetic aminobenzothiazole derivative whose (6S) enantiomer, commonly known as pramipexole and conunercially available under the Mirapex name, is a potent dopamine a,onist, and thus, miniics the effects of the neurotransmitter dopamine.
Pramipexole has also been shown to have both neuroprotective and dopaminergic activities, presumably throuah inhibition of lipid peroxidation, normalization of mitochondrial metabolism and/or detoxification of oxygen radicals. Tfierefore, pramipexole may have utility as an inhibitor of the cell death cascades and loss of cell viability observed in neurodegencrative diseases and is indicated for treating Parkinson's disease, cluster headaches, restless legs syndrome and bipolar disorder with only small daily doses required and tolerated by patients activates dopamine receptors. Additionally, oxidative stress inay be caused by an incrcase in oxygen and other free radicals, and has been associated with the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegencrative disorder involving the motor neurons of the cortex, brain stem, and spinal cord. About 10% of all ALS patients are familial cases, of which 20% have niutations in the superoxide dismutase I
(SOD-1) gene. The SOD-1 enzyme may play a pivotal role in the pathogenesis and progression of familial amyotrophic lateral sclerosis (FALS). Recent studies also link the premature neuronal death associated with ALS to mutated mitochondrial genes which lead to abnormalities in functioning of the energy production pathways in mitochondria.

[0003j The neuroprotectant activity of both enantiomers of pramipexole have typical therapeutic doses expected to be in the range of about 10 mg/day to about 1,500 mg/day.
However, the pramipexole's agonistic effect on of the D2 family of dopamine receptors only requires therapeutic doses that range between 0.5 and 5.0 mg/day, and even these relatively low doses adverse side effects have been reported. For example, the Boehringer Ingelheim product insert for Mirapex sets the maximally tolerated dose for humans at 4.5 tng/day, and a dose of pramipexole as low as 1.5 mg has been shown to cause somnolence in humans.
Single dose toxicity of pramipexole after oral administration lias been studied in rodents, dogs, monkeys and humans. In rodents, death occurred at doses of 70-105 nig/kg and above which is equivalent to a human dose of 7-12 mg/kg/ or approximately 500-850 mg for a 70 kg (-150 lb) individual. In dogs, vomiting occurred at 0.0007 mg/kg and above, while rnonkeys displayed major excitation at 3.5 mg/kg. In human subjects, an initial single dose of praniipcxole of greater than 0.20 mg was not tolerated. All species showed signs of toxicity related to exaggerated pharmaeodynamic responses to the pramipexole related to dopaminergic agonism.
[0004] Thus, a clinical use of pramipexole as a mitochondria-targeted antioxidant is unlikely, as the high doses needed for the neuroprotective or anti-oxidative/rnitochondrial normalization action are not accessible due to high dopamine receptor affinity associated with the (6S) enantiomer. In contrast, (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine is an effective mitochondria-targeted neuroprotectant that exhibits excellent anti-oxidative properties when administered without adverse side effects. Thus, higher doses of' (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine can be tolerated by patients and will allow greater brain, spinal cord and mitochondrial concentrations increasing the degree to which oxidative stress and/or mitochondrial dysfunction may be reduced. The neuroprotective effect of the compositions of this disclosure may also be derived at least in part from the ability of the (6R) enantiomer of pramipexole to prevent neural cell death by at least one of three mechanisms. First, the (6R) enantiomer of praniipexole may be capable of reducing the formation of reactive oxygen species in cells with impaired mitochondrial energy production. Second, the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine niay partially restore the reduced mitochondrial membrane potential that is correlated with Alzheimer's, Parkinson's, Huntington's and amyotrophic lateral sclerosis diseases. Third, the (6R) enantiomer of pramipexole may block the apoptotic cell death pathways which are produced by pharmacological models of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis diseases and mitochondrial impairment. High doses of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine required to elicit these neuroprotective effects generally require highly pure preparations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine which take into account the upper limit of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine contamination (0.5 mg to 5.0 mg).
100051 Processes for the preparation of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole using a simple alkylation reaction were iirst described in [J.S.
Patent Nos. 4,843,086 and 4,886,812. Other preparations of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole have been described that involve reductive amination rather than simple alkylation and, thus, produce a mixture of the R and S optical isoniers with no direct means for further purification of the optical isomers. These knoNvn processes for the production of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole are expensive, labor intensive, and utilize hydride reducing agents that pose safety risks.
Furthermore, there are currently no known processes for the direct synthesis of the pure (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine froni a diamine. Therefore, the R isomer must be synthesized as a mixture of the optical isomers that is purified by expensive and time consuming methods that may utilize other problematic substances. Moreover, know-n processes involving deamination result in a loss of enantiomeric purity, and methods useful for resolution of the optical isomers from mixtures fall short of producing chirally and chemically pure preparations of the R enantiomer or the S enantiomer.
G. Brief summary of the invention:
[00061 Embodiments of the invention presented herein are directed to a process for preparing a chirally purified substituted 4,5,6,7,-tetrahydro-benzothaizole diamine including the steps of: heating a solution comprising entantiomerically enrichcd 4,5,6,7-tetrahydro-benzothiazole diamine of general formula (1):
Ri N R4 I
/ \
R2 R3 (1) wherein:
Ri represents a hydrogen atom, an alkyl group having I to 6 carbon atoms, an alkenvl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having I
to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atonis in the alkyl part, whilst the above-mentioned phenyl nuclei inay be substituted by I or 2 halogen atoms;

R2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms;
R3 represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoins, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, R4 represents a hydrogen atom, an alkyl group with I to 4 carbon atoms, an alkenyl or alkynyl group llaving 3 to 6 carbon atoms; and at least one or Ri, R,,, R3 or R4 is a hydrogen in an organic solvent; and an alkyl sulfonate or an alkyl halide in a solvent to form a reaction mixture reacting the reaction mixture; and recovering a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine.
100071 In various embodiments, the alkyl sulfonate may be of general formula (11):

R, Z~
0 (11) wherein:
R' is an alkyl group having 1 to 6 carbons, or a cycloalkyl, alkenyl, alkynyl, allyl, having I to 10 carbon atoms, or a benzyl, chlorobenzvl, phenyl or phenyl alkyl; and Z is an alkyl group having I to 6 carbons, or a cycloalkyl, alkenyl, alkynyl, allyl, having 1 to 10 carbon atoms, or a benzyl, chlorobenzyl, phenyl or phenyl alkyl. In particular embodiments, X may be a propyl and, in sonie embodiments, the alkyl sulfonate may be a propyl sulfonate selected from n-propyl tosylate, n-propyl niethoxysulfonate and combinations thereof. In other einbodiments, the alkyl halide may be of general formula (12):
R' X (12) wherein:
R' is an alkyl group having I to 6 carbons, or a cycloalkyl, alkenyl, alkynyl, allyl, having 1 to 10 carbon atoms, or a benzyl, chlorobenzyl, phenyl or phenyl alkyl; and X is any halide including, for example, fluorine, chlorine, bromine or iodide.
In particular embodiments, X may be a propyl, and in sonie embodiments, the alkyl halide may be a propyl halide selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thcrcof.

[0008] The chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine of various embodiments may be at least greater than about 97% chirally pure. In some embodiments, the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine may be at least greater than about 99% chirally pure, and in other embodiments, chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least about 99.9%
chirally pure.
[0009] I'he chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine of various embodiments may be greater than about 99%. In some embodiments, the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine may be greater than about 99.9%, and in other embodiments, the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole dianiine is greater than about 99.99%.
[0010] In some embodiments, the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine inay be entantiomerically enriched for an (6R) entantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally purified for an (6R) entantiomer, and in particular embodiments, the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine may be entantiomerically enriched for (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole may be (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In other embodiments, the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine may be entantiomerically enriched for an (6S)-entantiomer and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is chirally puritied for an (6S) entantiomer, and in certain embodiments, the entantiomerically enriched 4,5,6,7-tetrahydio-benzothiazole diamine may be entantiomerically enriched for (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole is (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazale-diamine.
In still other embodiments, the entantiomerically enriched 4,5,6,7-tetrahydrobenzothiazole diamine may be a ratio of greater than about 1:4 (6R)-entantiomer to (6S)-entantiomer to about 4:1 (6R)-entantiomer to (6S)-entantiomer.
100111 '1`he solvent of various embodiments may be selected from an organic solvent and an organic solvent mixed with water, and in some embodiments, the solvent may selected from, but not limited to, ethanol, 1-propanol, n-butanol, dihydrofuran, diniethylformamide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.
100121 In soine embodiments, the steps of heating, reacting and recovering each independently include stirring. In other embodiments, the steps of heating and reacting may each independently be carried out at a temperature of from about 50 C to about 125 C. In yet other embodiments, the step of heating may further include adding the alkyl sulfonate or alkyl halide to the heated 4,5,6,7-tetrahydro-benzothiazole diamine. In still other embodiments, the step of adding may be carried out for about 0.5 liours to about 2 hours, and in certain embodiments, about 1.0 to about 2.0 molar equivalents of the alkly sulfonate or alkyl halide may be added. In particular embodiments, the step of reacting may be carried out for up to about 12 hours. In yet other embodiments, the step of recovering may include one or more steps selected from, but not limited to, filtering the reaction mixture to isolate a precipitate, washing a precipitate, and drying a precipitate, and the process of certain embodiments may include the step of cooling the reaction niixture to a temperature of about 25 C after the step of reacting.
[0013] Other embodinients of the invention include a process for preparing a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine including the steps of heating a solution comprising an entantiomerically enriched 4,5,6,7-tetrahydro-benzoihiazole diaminc of general formula (1):
R \ N /Ra N I N
~
R2 S R3 (1) wherein:
Ri represents a hydrogen atom, an alkyl group having 1 to 6 carbon atonis, an alkenyl or alkynyl group each having 3 to 6 carbon atoins, an alkanoyl group having I to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having I to 3 carbon atoms in the alkyl part, whilst the above-mentioned phenyl nuclei may be substituted by I
or 2 halogen atoms:
R2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms;
R3 represents a hydrogen atom, an alkyl group witli I to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, R4 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; and at least one or Ri, R2, R3 or R4 is a hydrogen in an organic solvent;

adding to the heated solution propyl sulfonate or a propyl halide to form a reaction mixturc; and reacting the reaction mixture.
[00141 In some embodiments, the propyl sulfonate may be selected from n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof, and in other embodinients, the propyl halide is selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thereof.
[00151 The chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine of various embodinients may be at least greater than about 97% chirally pure. In some embodiments, the chirally purified substituted 4,5,6,7-tetrahydro-bcnzothiazole diamine is at least greater than about 99% chirally pure, and in other embodiments, the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least about 99.9%
chirally pure.
[00161 The chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine of various embodiments may be greater than about 99%. In some embodiments, the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazolc diamine is greater than about 99.9%, and in other embodiments, the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than about 99.99%.
[0017) In certain embodiments, the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole may be enriched for (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diainine may be (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In certain other embodiments, the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine may be enriched for (6S) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine may be (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diaminc. In some embodiments, the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine may include a mixture of (6R) 4,5,6,7-tetrahydro-benzothia=r_olc diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine may include a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diainine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In particular embodiments, the mixture may be a racemic mixture. In other embodiments, the enantiomerically enriched mixture may be a ratio of greater than about 1:4 (6R) 4,5,6,7-tetrahydro-benzothiazole dianiine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine to about 4:1 (6R) 4,5,6,7-tetrahydro-benzothia-r.ole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine.

[0018] In some embodiments, the solvent may be selected from a polar or organic solvent and a polar or organic solvent mixed with water, and in certain embodiments, the solvent may be selected from ethanol, 1-propanol, n-butanol, dihydrofuran, dimethylformainide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof. In other embodiments, the steps of heating and reacting each independently may include stirring. In still other embodiments, the steps of heating, adding and reacting may each independently be carried out at a temperature of from about 50 C to about 125 C. In yet other embodiments, the process may further include the step of cooling the reaction niixture to a teniperature of about 25 C after the step of reacting. In particular embodiments, the step of adding may be carried out for up to about 2 hours.
Various embodiments may further include the step of recovering the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine, and in some embodiments, recovering may include one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate. In particular embodiments, about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide may be added.
[00191 Various embodiments of the invention also include chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process including the steps of: heating a solution comprising entantiomerically enriched 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and a propyl halide or a propyl sulfonate to form a reaction mixture; reacting the reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole. ln some embodiments, the propyl sulfonate may be selected from, but not limited to, n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof, and in other embodiments, the propyl halide may be selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thereof.
[00201 In various embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be at least greater than about 97% chirally pure. ln some enibodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be at least greater than about 99% chirally pure, and in other embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)bcncothiazolc is at least about 99.9%
chirally pure.
[00211 "I'he cliemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of various embodiments may be greater than about 99%. In some embodinients, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylaniino)benzothiacole is greater than about 99.9%, and in other entbodiments, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.99%.
100221 In particular embodiments, the entantiomerically enriched 2,6 diamino-4,5,6,7-tctrahydro-benzothiazole may be a ratio of greater than about 2:1 (6R)-2,6 diamino-4,5,6,7-tetrahvdro-benzothiazole to (6S) 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.
100231 In some embodiments, the solvent may be selected from an organic solvent and an organic solvent mixed with water, and in certain embodiments, the solvent may be selected from ethanol, I-propanol, n-butanol, dihydrofuran, dimethvlformamide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.
[00241 In various embodiments, the steps of heating and reacting may each independently include stirring, and in some embodiments, the steps of heating and reacting may each be independently carried out at a temperature of from about 50 C to about 125 C.
In other embodiments, the process may further include cooling the reaction mixture to a temperature of about 25 C after the step of reacting. In yet other embodiments, the process may further include the step of adding the propyl halide or propyl sulfunate to heated entantiomerically enriched 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, and in certain embodiments, the step of adding may be carried out for up to about 2 hours. In particular embodiments, about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide may be added. In still other embodiments, the step of reacting may be carried out for up to about 12 hours. In further embodiments, the step of recovering may include one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.
[00251 Various other embodiments of the invention include a process for preparing a chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole including the steps of heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-bcnzothiazole in an organic solvent; adding to the heated solution propyl sulfonate or a propyl halide to form a reaction mixture; and reacting the reaction mixture for up to about 12 hours.
In some embodiments, the propyl sulfonate may bc selected from n-propyl tosylate, n-propyl mcthoxysulfonate and combinations thereof, and in othcr embodiments, the propyl halide is selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thereof:
100261 The process of embodiments may result in chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole that is at least greater than about 97% chirally pure.
In some embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)bcnzothiazole may be at least greater than about 99% chirally pure, and in other embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be at least about 99.9% chirally pure.
[0027] The chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of some embodiments may be greater than about 99%.
In certain embodiments, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazolc may be greater than about 99.9%, and in certain other embodiments, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)becizothiazole may be greater than about 99.99%.
100281 In some embodiments, the 2,6 diamino-4,5,6,7-tetrahydro-bcnzothiazole inay be (6R) 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In other embodiments, the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole may be (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In still other embodiments, the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole may be a mixture of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be a mixture of (6R)-4,5,6,7-tetrahvdro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In certain embodiments, the mixture is a racemic mixture. In other embodiments, the mixture may be a ratio of greater than about 1:4 (6R)-2,6 diamino-4,5,6,7-tetrahydro-ben-r..othiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole to about 4:1 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-bcnzothiazole.
100291 7'he organic solvent of embodiments may be selected from an organic solvent and an organic solvent is mixed with water, and in some embodiments, the organic solvent may be selected from ethanol, 1-propanol, n-butanol, dihydrofuran, dimethylformanlide, dimetlivl, dimethylacetamide, hexamethylphosphoric triamide or miXtures or hydrates thereof:
[0030] In various enibodiments, the steps of heating, adding and reacting each independently may include stirring, and in some embodiments, the steps of heating, adding and reacting may each independently bc carried out at a temperature of from about 50 C to about 125 C. In certain embodiment, the process may further include the step of cooling the reaction mixture to a temperature of about 25 C after the step of reacting.
In some embodiments, about 1.0 to about 2.0 molar equivalents of the propyl sulfonatc or propyl halide may be added, and the step of adding in particular enibodinients niay be carried out for up to about 2 hours. In still other embodiments, the process may include the step of recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, and in some embodiments, recovering may include one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.
[0031] Embodiments of the invention furtlier include a process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole including the steps of heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole;
adding a propyl halide or a propyl sulfonate to the heated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture; reacting the reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.
[0032] In some embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be at least greater than about 97% chirally pure. In other embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be at least greater than about 99% chirally pure, and in certain embodiments, the chirally purified 2-amino-4,5,6,7-tetra.hydro-6-(propylamino)benzothiazole is at least about 99.9%
chirally pure.
100331'The chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of various embodiments may be greater than about 99%. In some embodiments, the chemical purity of the 2-amino-4,5,6,7-tctrahydro-6-(propylamino)benzothiazole may be greater than about 99.9%, and in particular embodiments, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.99%.
100341 In some embodiments, the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole may be (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In other embodiments, the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole is (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In certain embodiments, the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole may be a mixture of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diainine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In some such embodiments, the mixture may be a racemic mixture. In other such embodiments, the mixture may be a ratio of greater than about 1:4 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 dianiino-4,5,6,7-tctrahydro-benzothiazole to about 4:1 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.
[0035] In particular embodiments, the steps of heating, reacting and cooling each independently may include stirring. In other embodiments, the step of recovering may include cooling the mixture to a temperature of about 25 C, and in still other embodiments, the step of recovering may include stirring the reaction mixture for at least about 2 hours. In yet other embodiments, the step of recovering may further include one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate. In various embodiments, the steps of heating, adding and reacting may each independently be carried out at a temperature of from about 50 C to about 125 C. and in certain embodiments, the step of reacting may include stirring the reaction mixture for up to about 12 hours at from about 50 C to about 125 C.
[0036J Some embodiments of the invention include a chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process including the steps of heating a solution comprising 2,6 diamino-4,5,6,7-tetrahydro-benzothia~r_ole;
adding a propyl halide or a propyl sulfonate to the hcated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture; reacting the reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.
[0037] In some embodiments, the propyl sulfonate is selected from n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof, and in otlier embodiments, the propyl halide is selected from n-propyl bromide, n-propyl chloride, n-propyl lluoride, n-propyl iodide and combinations thereof.
100381 In various embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may at least greater than about 97% chirally pure.
In some embodi.mcnts, fhe chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be at least greater than about 99% chirally pure, and in other embodiments, the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least about 99.9%
chirally pure.

[0039] In various other embodiments, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be greater than about 99%. In some cmbodiments, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazolc may be greater than about 99.9%, and in other embodiments, the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than about 99.99%.
[0040] In some embodiments, the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole may be a mixture of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diainine and S(+) 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.
In certain embodiments, the mixture may be a racemic mixture. In other embodiments, the mixture may be a ratio of greater than about 4:1 (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole.
100411 The organic solvent of various embodiments may be selected from a organic solvent and aii organic solvent is mixed with water, and the organic solvent of some embodiments may be selected from ethanol, 1-propanol, n-butanol, dihydrofuran, dimethylformamide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.
100421 In particular embodiments, the steps of heating, reacting and cooling each independently may include stirring, and in some embodiments, the steps of heating, adding and reacting are each independently carried out at a temperature of from about 50 C to about 125 C. In other embodiments, the process may further include cooling the reaction mixturc to a temperature of about 25 C after the step of reacting, and in still other embodiments, the step of adding is carried out for up to about 2 hours. In certain embodiments, the step of recovering may include one or niore steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate. In various embodiments, about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide inay be added.
[0043] Yet other embodinlents of the invention include a process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzot.hiazole including the steps of dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution; heating the solution to from about 50 C to about 125 C; adding an acid to the solution to form a reaction mixture;

and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.
[00441 In some embodiments, about I molar equivalent to about 4 molar equivalents of the acid may be added. In other embodiments, recovering may include one or more steps including cooling the reaction mixture to a temperature of about 25 C;
stirring the reaction mixture for at least about 2 hours; filtering the mixture to isolate a precipitate; washing a precipitate; and drying a precipitate.
[00451 Further embodiments of the invention include a chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by such a process. 100461 Still other embodiments of the invention include a process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole including the steps of dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution; heating the solution to from about 50 C to about 125 C; adding an achiral salt to the solution to form a reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole .
100471 In some embodiments, about I molar equivalent to about 4 molar equivalents of the achiral salt is added. In other embodiments, the step of recovering may include one or more steps selected from cooling the reaction mixture to a temperature of about 25 C;
stirring the reaction mixture for at least about 2 hours; filtering the mixture to isolate a precipitate; washing a precipitate; and drying a precipitate.
[0048[ Further embodiments of the invention include a chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a such a process.
[00491 Still further embodiments of the invention include a process for preparing a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride comprising dissolving a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt in an organic solvent to form a solution; cooling the solution to a temperature of from about 0 C to about C; adding concentrated HCI and an organic solvent to the cooled solution; and stirring the solution at a temperature of about 0 C to about 5 C.
H. Description of Drawings:
[00501 For a fuller understanding of the nature and advantages of the present invention, reference should be made to the following detailed description taken in connection with the accompanying drawings, in which:

[0051] FIG. 1A shows a reaction scheme illustrating the alkylation of 4,5,6,7-tetrahvdro-benzothiazole diamine.
[0052] FIG. 1B shows a reaction scheme illustrating the entantiomeric purification of one 4,5,6,7-tetrahydro-benzothiazole diamine from an entantiomeric mixture of 4,5,6,7-tetrahydro-benzothiazole diamines.
[0053] FIG. 2 shows a reaction scheme illustrating the preparation of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine-dihydrochloride and (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-di am i ne-difumerate.
100541 FIG. 3A shows an exemplary HPLC trace of a mixture of (6R) and (6S)-4,5,6,7-tetrahydro-N6-propyI-2,6-benzothiazole-diamine that is entantiomerically enriched for (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and a corresponding data table.
[0055] FIG. 3B shows an exemplary HPLC trace of chirally purified (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and a corresponding data table.
100561 F. IG. 4A shows an exemplary HPLC trace of Sample 118.
[0057] FIG. 4B shows an exemplary I-IPLC trace of Sample 105.
10058] FIG. 4C shows an exemplary HPLC trace of Sample 061.
100591 FIG. 4D show an exemplary HPLC trace of Sample 326A.
[00601 FIG. 5 shows an exemplary UV spectrum of a propyl tosylate peak cluted from an SPE column.
[006.1] FIG. 6A shows an exemplary HPLC trace of a propyl tosylate standard.
[0062[ FIG. 6B shows an exemplary HPLC trace of a (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine sample.
[0063] FIG. 7A shows an exemplary HPLC trace of a standard (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diami ne.
100641 FIG. 7I3 shows an exemplary HPLC trace of a sample (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.
1. Detailed Description:
[0065] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or einbodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0066] It must be noted that, as used herein, and in the appended claiins, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientifc terms uscd herein have the same nieanings as commonly understood by onc of ordinary skill in the art.
Although any methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods are now described. All publications and references mentioned herein are incorporated by reference.
Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
100671 As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. '1'herefore, about 50% means in the range of 45%-55%.
[0068] "Optional" or "optionally" may be taken to mean that the subscquently described structure, event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
[0069] "Administering" when used in conjunction with a therapeutic means to administer a therapeutic directl_v into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
"Administering" a composition may be accomplished by oral administration, injection, infusion, absorption or by any method in combination with other known techniques. Such combination techniques include heating, radiation and ultrasound.
[0070] The term "target", as used herein, refers to the material for which either deactivation, rupture, disruption or destruction or preservation, maintenance, restoration or improvenient of function or state is desired. For example, diseased cells, pathogens, or infectious material may be considered undesirable material in a diseased subject and may be a target for therapy.
[0071] Generally speaking, the tenn "tissue" refers to any aggregation of similarly specialized cells which are united in the performance of a particular fiinction.
[0072] The tenn "improves" is used to convey that the present invention changes either the appearance, form, characteristics and/or physical attributes of the tissue to which it is being provided, applied or administered. "Improves" may also refer to the overall physical state of an individual to whom an active agent has been administered. For example, the overall physical state of an individual may "improve" if one or more symptoms of a neurodegenerative disorder are alleviated by administration of an active agent.

[0073] As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate or prevcnt an unwanted condition or disease of a patient.
[00741 The tcrms "therapeutically effective amount" or "therapeutic dose" as used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. A biological or medicinal response may include, for example, one or more of the following: (1) preventiiig a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and/or symptoms of the disease, condition or disorder, and (3) ameliorating a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or syniptonis of the disease, condition or disorder or reversing the pathology and/or symptoms experienced or exhibited by the individual.
[0075] As used herein, the term "neuroprotectant" refers to any agent that may prevent, ameliorate or slow the progression of neuronal degeneration and/or neuronal cell death.
[0076] The term "treating" may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and/or prevention of the symptoms associated with a specific disorder, disease or condition.
[0077] The term "patient" generally refers to any living organism to which to compounds described herein are administered and may include, but is not limited to, any non-human mammal, primate or human. Such "patients" may or my not be exhibiting the signs, syinptoms or pathology of the particular diseased state.
100781 As used herein, the terms "enantiomers", "stereoisomers" and "optical isomers" may be used interchangeably and refer to molecules which contain an asyinmetric or chiral center and are mirror images of one another. Further, the terms "enantiomers", "stereoisomers" or "optical isomers" describe a molecule which, in a given configuration, cannot be superimposed on its mirror image.
100791 As used herein, the terms "optically pure" or "cntantiomerically pure"
may be taken to indicate that a composition contains at least 99.95% of a single optical isomer of a compound. The term "entantiomerically enriched" may be taken to indicate that at least 51 %
of a composition is a single optical isomer or enantiomer. 1'he term "entantiomeric enrichment" as used herein refers to an increase in the amount of one entantiomer as compared to the other. A "racemic" mixture is a mixture of equal amounts of (6R) and (6S) enantiomers of a chiral molecule.
100801 Throughout this disclosure, the word "pramipexole" will refer to (6S) enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole unless otherwise specified.
1008,11 yt'he term "trituration" may be taken to indicate a method of solidifying a chemical compound. Trituration involves agitating the compound by stirring, beating or a method of the like until the chemical compound forms a crystalline solid or precipitate. This solid may act to seed the remaining chemical compound in solution, causing it to precipitate or crystallize from solution.
[0082] The term "pharmaceutical composition" shall mean a composition including at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mainmal (for example, without limitation, a human).
Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. A pharmaceutical composition may, for example, contain (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or a pharmaceutically acceptable salt of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine as the active ingredient.
Alternatively, a pharmaceutical composition may contain (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-dianline or a pharmaceutically acceptable salt of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine as the active ingredient.
[0083] For the purposes of this disclosure, a "salt" is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including but not limited to, halogenic acid salts such as hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic, etlianesulfonic, benienesuli:onic orp-toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, niandelic, mucic, pamoic, pantothenic, oxalic and inaleic acid salts;
and an amino acid salt such as aspartic or glutamic acid salt. Thc acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogenic, di-sulfuric, di-phosphoric or di-organic acid salt. In all cases, the acid addition salt is used as an achiral reagent which is not selected on the basis of any expected or knoxvn preference for interaction with or precipitation of a specific optical isomer of the products of this disclosure.
[0084] "Pharmaceutically acceptable salt" is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (1977) J. Pharm. Sciences, Vol 6.
1-19, describes pharmaceutically acceptable salts in detail.
[0085] Embodiments of the invention described herein are generally directed to processes for the production of an entantiomerically and/or cheniically pure compound.
More specifically, embodiments of the invention are directed to production of an entantiomerically and/or chemically pure compound using a trituration step where one enantiomer of an entantionieric mixture of R and S stereoisomers of a compound is precipitated out of solution and can be isolated by, for example, simple filtering or other mcans for separating a solid or crystalline compound from a solution.
[0086] For example, embodiments of the invention include a method for preparation of an entantiomerically and chemically pure compound using an one-pot bi-molecular nucleophilic substitution (SN2) reaction synthesis method as illustrated in the reaction scheme provided in FIG. 1A. In FIG. IA, a 4,5,6,7-tetrahydro-benzothiazole diamine (1) is reacted with an alkyl sulfonate (11) or a alkyl halide (12), exemplified by n-propyl sulfonate or propyl halide, to generate an aminoalkyl containing compound of a 4,5,6,7-tetrahydro-benzothiazole diamine (2), and a sulfonate or halide salt. In a trituration step, one enantiomer of the 4,5,6,7-tetrahydro-benzothiazole diamine, for example, (R)(+)-4,5,6,7-tetrahydro-benzothiazole diamine (3), is precipitated based on insolubility of the enantiomers in the achiral halide or sulfonate salts produced as a result of the reaction and can be isolated. "I'he other enantiomer remains in solution.
[0087] In another exemplary embodiment illustrated in FIG. 1I3, chirally pure coinpounds, such as, (6R) 4,5,6,7-tetrahydro-benzothiazole diamine (3), may be prepared from a mixture of R and S enantiomers of a compound, such as, for example, (6R) 4,5,6,7-tetraliydro-benzothiazole diainine (4) and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine (5).
In this process, trituration may result from the addition of an organic solvent and an achiral salt or acid to the mixture which may cause the formation of an acid addition salt of one enantiomer. The salt, (6R) 4,5,6,7-tetrahydro-benzothiazole dianiine (3), precipitates out of the solution based on insolubility of the enantiomers in the resulting solution while the other enantiomer remains in solution. The precipitated crystalline enantiomer may then be isolated.
100881 The reaction illustrated in FIG. 1A is not limited to a particular 4,5,6,7-tetrahydro-benzothiazole diamine. For example, the 4,5,6,7-tetrahydro-benzothiazole diamine may be any 4,5,6,7-tetrahydro-benzothiazole diamine of formula (1):
R, N Ra \N /

/ \R2 s R3 (1) wherein:
R, represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having I
to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the above-mentioned phenyl nuclei may be substituted by 1 or 2 halogen atoms;
R2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms;
R, represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having I
to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, Ra represents a hydrogen atom, an alkyl group with I to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms;
and at least one or Ri, R2, R3 or R4 is a hydrogen.
"I'he 4,5,6,7-tetrahydro-benzothiazole diamine of formula 1 encompasses all enantiomers at any chiral center on the molecule.
100891 '1'he reaction illustrated in FIG. 1A is not limited by the type of alkyl halide or alkyl sulfonate utilized in the reaction. For example, the alkyl sulfonates may be any alkyl sulfonate of formula (11):

O
1-11, O____ R
Z\

(11) wherein:

R' is an alkyl group having 1 to 6 carbons, or a cycloalkyl, alkenvl, alkynyl, allyl, having I to 10 carbon atoms, or a benzyl, chlorobenzyl, phenyl, phenyl alkyl and the like; and Z is an alkyl group having 1 to 6 carbons, or a cycloalkyl, alkenyl, alkynyl, allyl, having I to 10 carbon atoms, or a benzyl, chlorobenzyl, phenyl, phenyl alkyl and the like;
and the alkyl halide may be any alkyl halide of formula (12):
R' x (12) wherein R' is an alkyl group having 1 to 6 carbons, or a cycloalkyl, alkenyl, alkynyl, allyl, having 1 to 10 carbon atoms, or a benzyl, chlorobenzyl, phenyl, phenyl alkyl and the like; and X is any halide including, for example, chlorine, bromine or iodide.
In various embodiments, R' is an alkyl and, in particular embodiments, an n-propyl. In certain embodiments where alkyl sulfonate, the Z moiety may be toluenesulfonate (tosylate) or methoxysui fonate. For examplc, in various embodiments, the alkyl sulfonate may be n-propyl tosylate. In embodiments in which an alkyl halide is used, the alkyl halide may be n-propyl bromide or n-propyl chloride. In general, the alkyl sulfonate or alkyl halidc may be added in a quantity corresponding to about 1.0 to about 4.0 molar equivalents of the diamine.
[0090] Advantages of embodiments such as those described above may include, for example, (1) the use of simple reagents for the synthesis and purification of one enantioinei-enantiomeric conipounds, (2) the surprising improvement of the optical and chemical purity achieved by simple trituration, and (3) such processes may be performed as a one-pot synthesis and purification reactions. Vi/hen taken as a whole, the processes described above may be simpler, safer, and more efficient for the production of chirally and cheinically pure compounds. Additionally, the compounds may be sufficiently chirally and chemically pure to makc such compounds safe an effective for use in pharmaceutical coinpounds and in the treatnient of disease.
[00911 While the methods provided above may be used to purify any enantiomeric compound known in the art, particular embodiments of the invention are directed to the production and optical purification of 2-amino-4,5,6,7-tetrahydro-6-(propylaniino)benzothiazole and, in particular, (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. "hhe extremely high chiral and chemical purity of the compound produced by methods of the present invention allow for pharmaceutical compositions that niay have a wide individual and daily dose range. For example, in some enibodiments, (6R)-4,5,6,7-tctrahydro-N6-propyl-2,6-benzothiazole-diamine produced using methods embodied herein may be nearly 100% chirally pure. Such compositions include little to no (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine contamination and may be administered at high doses without the risk of the dopaminergic side effects associated with administration of high dose (6S)-4.5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. The compositions of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may therefore be used to treat neurodegenerative diseases, or those associated with mitochondrial dysfunction or increased oxidative stress such as, for example, neurodegenerative dementias, neurodegenerative movement disorders and ataxias, seizure disorders, motor neuron disorders or diseases, inflammatory deinyelinating disorders and the like in adults and children. The compositions of this disclosure may also be useful in the treatinent of other disorders not listed herein, and any listing provided in this disclosure is for exemplary purposes only and is non-liiniting.

100921 Compositions and pharmaceutical compositions comprising entantiomerically pure (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine, such as those discussed above, are further disclosed in U.S. Application No. 11/773,642 cntitled "7'etrahydrobenzothiazoles and Uses Thereof" filed April 10, 2007, U.S.
Application 1~To.
11/957,157 entitled "'Compositions and Methods of Using R(+) Pramipexole", filed December 14, 2007 and U.S. Application No. 11/749,497 entitled "Prarnipexolc Fonnulations for the Treatment of Parkinson's Disease", filed on May 16, 2007, each of which are hereby incorporated by reference in their entireties. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are described in detail herein.
[00931 Production of either enantiomer, (6R) or (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may be carried using the bi-molecular nucleophilic substitution (SN2) reaction described above and optical purification based on insolubility of the compound product in achiral reagents. More specifically, FIG. 2 scheniatically illustrates an embodiment of the process for the production of entantionierically and chemically pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothia7ole using a bi-molecular nucleophilic substitution (SN2) reaction. In a first step, 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole (7) is nlixed propyl p-toluenesulfonate (propyl tosylate), and reacted to produce 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (8) and 4-methylbenzenesulfonic acid (p-toluenesulfonic acid, p-TSA). Without wishing to be bound by theory, the diamine, 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole (7), in the reaction scheme of FIG. 2 may act as the nucleophile in a nucleophilic attack on the substrate, a propyl tosylate, and the tosvlate group may provide a good leaving group as depicted below:
,---N
~
~
S
~ -~ ~W5 HZN ?~O \1 ~
S NHZ

//JJ o HZN-{' ji ws + "
S N-1`1/ Ho' "t'hus, an embodiinent of the invention is a process for preparing a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt (8) by a bimolecular nucleophilic substitution reaction. In a second step, the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)ben-r_othiazole (8) may be entantiomerically purified by allowing the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (8) to precipitate out of the reaction solution without the addition of any secondary agcnts, such as, for example, additional salt. Thus, entantiomerically pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be isolated in a third step by simply filtering out the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)ben-r_othiazole crystals.
100941 Some embodiments of methods of the invention may include additional steps.
For example, in some embodiments, p-TSA may be removed to form the entantiomerically purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (8) to form a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole free base (9) and hydrochloric acid or fumaric acid may be added to the free base to form 2-amino-4,5,6,7-tetrahydro-(propylamino)benzothiazole-dihydrochloride (14) or 2-amino-4,5,6,7-tetrahydro-(propylamino)benzothiazole-difumerate (15). In other embodiments, 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazolc-dihydrochloride (14) may be produced by adding hydrochloric acid to the entantiomerically purified 2-amino-4,5,6,7-tetrahydro-(propylamino)benzothiazole (8).
100951 While the reaction scheme illustrated in FIG. 2, shows the production of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine from (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, in some embodiments, the same reaction may be carried out using (6S)- 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole to produce (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In other embodiments, a mixture of (6R) and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may be used as starting material which nZay result in a mixture of (6R) and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. In particular embodiments, a mixture of (6R) and (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole that is entantiomcrically enriched for one entantiomer may be used as starting material. Additionally, the reaction illustrated in F1G. 2 may be carried out is an n-propyl halide or a mixture of n-propyl halide and n-propyl sulfonate.
[00961 In some embodiments, step one of the process niay include the additional steps of heating a diamine to form a solution or melt in a heating step and adding the n-propyl halide or n-propyl sulfonate slowly over a period of time from, for cxaniple, about 0.5 hours to about 5 hours, in an additional step. In other embodiments, after the n-propyl halide or n-propyl sulfonate has been completely added to the 2,6 diamino-4,5,6,7-tctrahydro-benzothiazole, the reaction may continue under heating for an additional period of time ranging from, for example, about 1 hour to about 12 hours, in a reaction step.
In certain embodiments, the reaction mixture may be mixed by, for example, stirring for one or nlore of the steps above or the reaction mixture may be continually stirred from the heating step to the reaction step. Following the reaction step, the reaction mixture may be cooled and the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be isolated and purified.
[0097) In embodiments such as those exemplified above, the diamine, 2,6 diamino-4,5,6,7-tctrahydro-benzothiazole, may be a racemic mixture or entantiomerically enriched for either the S or R enantiomer, and the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole produced may be generally optically enriched for the dominant enantiomer. For example, (6R) 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole may be the dominant enantiomer in mixtures used as a starting material in reaction that produces (6R)-4,5,6,7-tctrahydro-N6-propyl-2,6-benzothiazole-diamine. In various embodiments, any R to S ratio of diamine may be used. For example, in some embodiments, the diamine may bc in a racemic mixture (i.e., R:S is about 50:50), and in such embodiments, the yield of the reaction would be expected to be a racemic mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-dianiine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine (i.e., about 50:50). In other embodiments, the diamine may be provided in a mixture in which one stereoisomer is in excess over the other, for example, R:S may be about 60:40. In such embodiments, the reaction would be expected to yield a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-bemr.othiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine that is about 60:40 R to S.
[00981 The reaction niay be carried out in a melt or in a solvent or mixture of solvents, and the methods embodied herein are not limited by the type or number of solvents present during the reaction. Any solvent or mixture of solvents known in the art in which the diamine and alkyl halide or alkyl sulfonate can dissolved may be used. For example, in various embodiments, the solvents may be, for exainple, tetrahydrofuran, dimethylformamide, dimethly sulfoxide, dimethylacetamide, hexainethylohosphoric triamide, glacial acetic acid, pyridine, dioxan, ethanol, 1-propanol, i-propanol, n-butanol, i-butanol, or combinations thereof, for example, dioxan/water, ethanol/water, tetrahydrofuran/water and the like. In embodiments in which a combination of an organic solvent and water are used, the organic solvent may have a water content of from about 0 to about 10 volume percent.
Preferably, the solvents used in the practice of this invention are standard ACS grade solvents. The selection of a solvent may enhance the reaction rate of the SN2 reaction. In some embodiments, one or niore base such as, for example, sodium hydroxide, sodiuni hydride, potassium carbonate, sodium acetate, potassium-tertbutyloxide, triethylamine, di-isoproplyethylamine and the like, may be additionally added to the reaction inixture which may further enhance the efficiency of the reaction. When added, a base may be present in a concentration of about 0.5 to about 3.0 equivalents based on the solvent. In still other embodiments, an alkylating agent may be provided in the melt or solvent.
Alkylating agents are well known in the art and may be useful in embodiments of the invention.
For example, alkylating agents may include, but not limited to, methyliodide, dimethylsulfatc, ethylbromide, diethylsulfate, allyliodide, benzylbromide, 2-phenylethylbromide and methyl-p-toluenesulfonate.
[0099] In general, the reaction may be carried out under ambient conditions.
Fiowevcr, the reaction temperature may vary aniong embodiments from between about -10 C
to about 50 C and, in particular embodiments, from 0 C to 30 C.
[00100] In further embodiments, dissolved diamine may be heated and mixed or stirred during the reaction. For example, various embodiinents include the step of heating a dissolved diamine, adding a n-propyl sulfonate or n-propyl halide which may, in some embodiments, be dissolved in a solvent to form a mixture, and stirring the mixture. In other embodiments, a base such as di-isoproplyethylamine may be added to a solution including a diamine. N-propyl sulfonate or n-propyl halide may be dissolved in a solvent, and then added to the diamine/di-isoproplyethylamine solution and this reaction mixture may be stirred. The temperature of reactions of such embodiments may, generally, be below the boiling temperaturc of the reaction mixture, more specifically, below the boiling temperature of the solvent(s) of the reaction mixture. For example, in some embodiments, an elevated tempcraturc niay be lower than about 125 C. In others, an elevated temperature may be lower than about 100 C, and in yet another enibodiment lower than about 95 C, and in still others less than about 75 C. Therefore, the reaction temperature may range from about 500 C
to about 125 C in some embodiments, about 55 C to about 100 C in other embodiments, about 60 C to about 95 C in still other embodiments, about 60 C to about 75 C in yet other embodiments and in certain embodiments, froin about 55 C to about 65 C.
(00101] The reaction time may vary within embodiments, and may depend upon, for example, the identities of the reactants, the solvent system and the chosen temperature. For example, in some enibodiments, the reaction time may be f.rom about 0.5 hours to about 12 hours. In other embodiments, the reaction time may be from about I hour to about 8 hours, and in certain embodiments, the reaction time may be about 4 hours. In general, the reaction time is chosen to provide sufficient time for substantially all of the diamine to undergo alkylation. In particular embodiments, the reaction tiune further provides sufficient tinle for the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole formed to precipitate out of the reaction solution and from visible crystals.
1001021 Embodiments of the invention may further include the step of cooling the reaction to a temperature about room temperature (25 C) following the reaction. In such embodiments, the reaction may be cooled for any amount of time with or without continued stirring. For example, in some embodiments, the reaction may be cooled with stirring for about 0.5 to about 4 hours or more, and in other embodiments, the reaction may be cooled with stirring for about 2 hours.
[00103] More specific embodiments may include the steps of: dissolving a diamine in dimethylformamide; heating the dissolved diamine to an elevated temperature;
adding the n-propyl sulfonate or n-propyl halide dissolved in dimethylformamide to form a reaction mixture; and stirring the reaction mixture for about 4 hours. In another embodiment, the steps may include dissolving a diamine in dimethylformamide, heating the dissolved diamine to an elevated temperature, slowly adding to the heated dissolved diarnine 1.25 molar equivalents of n-propyl sulfonate or n-propyl halide dissolved in 10 volumes of dimethylformamide and 1.25 molar equivalents of di-isoproplyethylamine with stirring the reaction over a period of about 4 hours. In yet another embodiment, 1.25 molar equivalents of di-isoproplyethylamine may be added to a diamine dissolved in dimethylformamide and the n-propyl sulfonate or n-propyl lialide dissolved in dimethylformamide may be added to this mixture with stirring for about 4 hours.
1001041 Following synthesis, entantiomerically pure isomers of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be recovered using a trituration step in which the major isomer is isolated as a precipitated crystals, while the minor stercoisomcr remains in solution. Without wishing to be bound by theory, insolubility of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product in achiral reagents, such as p-TSA, may be independent of the R or S cnantiomer, such that purity of the recovered isomer may depend only on the volume of the reaction solution and starting percentage of the major isomer.
Thus, in an embodiment such as is described above, an entantiomerically pure (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine (R:S equals 100:0) yield may be produced from a reaction in which diamine is provided in an R to S ratio of 60:40.
1001051 An unexpected advantage of the process for preparing 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole described above is the limited solubility of the sulfonate or halide salt of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in polar organic solvents which causes the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product to precipitate once formed thereby purifying the final synthesis product, 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, from the reaction mixture. In further embodiments, the substitution reaction such as that illustrated in FIG. 2 may result in a sufficient achiral salt, p-TSA, concentration to cause the 2-amino-4,5,6,7-tetrahydro-6-(propylainino)benzothiazole to become insoluble and crystallize in the reaction solution without adding additional agents, such as, for example, additional achiral salts.
1001061 The reaction embodied above and described in FIG. 2 may provide highly purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in a one-pot synthesis method. For example, in embodiments of the process, the chemical purity of the final 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazolc prepared may be at least 97%, 98%, and up to 100% without additional purification steps, and in particular embodiments, the chemical purity may be from 99.90% to 100% without any additional purification steps. In still other embodiments, the final 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be substantially free of achiral salts such as, for example, p-TSA. For example, in some embodiments, the achiral salt concentration of the final synthesis product may be less than 3%, and in others the achiral salt concentration of the final synthesis product may be less than 1%. 0.5%, 0.1%, 0.01%, 0.001% and so on. In certain cmbodinients, the achiral salt concentration niay be less than 1.5 ppm to less than 25 ppb or less than 0.00015% to less than 0.0000025%. Without wishing to be bound by theory, the ability to produce highly chemically pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in a one-pot method may demonstrate a significant advancement in the production of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole. Morcover, such purity may provide pharmaceutical grade 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole more efficiently than previous methods.
1001071 In various embodiments, the chiral purity for the R enantiomer prepared and purified may be greater than 99.6% about when a starting material that is entantiomerically enriched for R diamine is used. Similarly, in various other embodiments, the chiral purity for the S enantiomer produced and purified may be greater than 99.6% when a starting material that is entantiomerically enriched for S diamine is used. In some embodiments, the chiral purity for the R enantiomer prepared and purified may be greater than 99.8%
about when a starting material that is entantiomerically enriched for R diamine is used.
Similarly, in some other embodiments, the chiral purity for the S enantiomer produced and purified may be greater than 99.8% when a starting material that is entantiomerically enriched for S dianiine is used. In particular embodiments, the chiral purity for the R enantiomer prepared and purified may be greater than 99.9% about when a starting material that is entantiornerically enriched for R diaminc is used. Similarly, in particular other embodiments, the chiral purity for the S enantiomer produced and purified may be greater than 99.9% when a starting material that is entantiomerically enriched for S diamine is used.
(00108) Not wishing to be bound by theory, the solubility of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may be the same in the trituration step of the synthesis and purification processes. For example, if a synthesis process is carried out with 90 grams of the (6R) diamine and 10 grams of the (6S)diamine, and the solubility of the final 2-amino-4.5,6,7-tetrahydro-6-(propylamino)benzothiazole product is 10 grams for either enantiomer, then 80 gratns of the (6R)-4,5.6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine product and 0 grams of the (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine product would precipitate (assuniing a 100% cheniical conversion from the diamine and no change in molecular weight in going to the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product). That is, 10 grams of each enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be expected to go into solution. This would lead to a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product witli a 100%
chiral purity for the (6R) enantiomer. The opposite ratio of starting materials f:or the synthesis process (90 grams of the (6S) diamine and 10 grams of the (6R) diamine) may generate a reaction product of 90 grams of the (6S)-4,5,6,7-tctrahydro-N6-propyl-2,6-benzothiazole-diamine and granis of the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.
Froin this reaction product mixture, 80 grams of the (6S) enantiomer and 0 grams of the (6R) enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole would be expected to precipitate, leading to a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product with a 100% chiral purity for the (6S) enantiomer. "I'hus, the volumes which are used for a reaction may have a large potential effect on the final yield and chiral purity. 'l'hat is, too large a volume will reduce the yield as more of the 2-amino-4,5,6,7-tctrahydro-(propylamino)benzothiazole enantiomer products will go into solution (but increase the chiral purity) and too small a volume will increase the yield as less of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole products will go into solution (but reduce the chiral purity).
1001091 Other embodiments of the invention are directed to a process for the purification of entantiomerically pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole from a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine including a trituration step. In some embodiments, the mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-bcnzothiazole-diamine used in the purification methods may be prepared as described herein above. In other embodiments, the mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-dianiine and (6S)-4,5,6,7-tctrahydro-N6-propyl-2,6-benzothiazolc-diamine may be obtained using another method or form a commercially available mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.
1001101 In soine embodiments, the trituration step may include the addition of an achiral salt to a solution containing a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.
As described above, the addition of an achiral salt to a solution containing ainixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may cause the enantiomer having a greater concentration to become insoluble and form crystals in the solution. In some embodiments, the solution containing a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may be lieated to an elevated temperature such as, for example, about 50 C to about 125 C, about 55 C to about 100 C, about 60 C to about 95 C or about 60 C to about 750 C and an achiral salt may be added to the solution. This solution may than be cooled from the elevated temperature to about room teniperature slowly. For example in one embodiment, the reaction may be cooled at a rate of about less than 25 C/hour. In another embodiment, the reaction may be slowly cooled and the reaction solution may be stirrcd for at least about an additional 2 hours.
The rates of cooling and the time required for the additional stirring may vary with the choice of achiral salt and may be easily appreciated by one skilled in the art.
1001111 The crystalline (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or (6S)-4,5,6,7-tetralrydro-N6-propyl-2,6-benzothiazole-diamine may then be isolated, washed and dried, and in various embodiments, may result in entantiomerically pure (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine having a chemical purity of at least 97% and, in some embodiments, 98% to 100%. In such embodiments, the achiral salt may be any achiral salt listed hereinabove or any other achiral salt known in the art. Similarly, the solvent of the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine solution may be any solvent described above in relation to the method for preparing 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole. Either (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine or (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may be purified using the process of such embodiments. Flowever, in certain embodiments, (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may be purified.
(00112) In other embodiments, entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be triturated from an acid addition solution based on the insolubility of the enantiomers in the achiral reagents. Various embodiments of this method may include the steps of dissolving an entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in a solvent at an elevated temperature such as, for example, about 50 C to about 125 C, about 55 C to about 100 C, about 60 C to about 95 C or about 60 C to about 75 C, adding an acid to the dissolved 2-amino-4,5,6,7-tctrahydro-6-(prop),lamino)benzothiazolc, cooling the reaction to about room temperature (25 C) with stirring, stirring the cooled reaction mixturc for an extended time at room temperature to allow formation of entantiomerically pure crystals and recovering entantiomerically purc (6R) or (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine (rom the reaction mixture. In other embodiments, entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be dissolved in a solvent at an elevated temperature, about 0.5 equivalents to about 2.05 equivalents of an acid may be added to the solution and the solution may be cooled to room temperature. The cooled solution may then be stirred for an extended period of time and entantiomerically pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be recovered. In particular embodiments, the selccted acid may be p-toluenesulfonic acid (p-TSA) and the solvent may be ethanol. In other embodiments, the temperature of the solution when the acid is added may be lower than about 125 C, lower than about ] 00 C or lower than about 75 C, and in certain embodiments, the temperature may be from about 65 C to about 85 C. The cooling may generally occur slowly at, for example, a rate of about 25 C per hour and the solution may be stirred for at least about 2 hours after 25 C temperature has been reached. The times necessary for the reaction may vary with the identities of the reactants, the solvent system and witli the choscn temperature, and may be easily appreciated by one of skill in the art.
Reaction volunies may additionally dictate the degree of optical purification and the overall yield of the optically pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole. These volumes would be understood and appreciated by one of skill in the art. Examples of specific times, temperatures and volumes which enable the practice of this invention are given in the Examples.
[00113] The solvent utilized may vary in embodiments and may generally be an organic solvent such as, for example, acetonitrile, acetone, ethanol, ethyl acetate, methyl tert-butyl ether, methyl ethyl ketone, isopropyl acetate, isopropyl alcohol and combinations thereof. In a particular embodiment, the organic solvent may be ethanol.
100114J The acid of various embodiments may include: halogenic acids such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid;
inorganic acids such as, for cxample, nitric, perchloric, sulfuric and phosphoric acid; organic acids such as, for example, sulfonic acids (methanesulfonic, trifluoromethane sulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid; and amino acids such as aspartic or glutamic acid. The acid may be a mono- or di-acid, such as, for example, a di-hydrohalogenic, di-sulfuric, di-phosphoric or di-organic acid.
The acid of embodiments may be used as an achiral reagent which is, generally, not selected on the basis of any expected or known preference for interaction with, or precipitation of, a specific optical isomer of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole to be isolated. For example, in one embodiment, the selected acid may be p-toluenesulfonic acid.
"I'he amount of acid added may vary and is generally provided at about 1 molar equivalent to about 4 molar equivalents of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.
[00115J Insoluble 2-amino-4,5,6,7-tctrahydro-6-(propylamino)benzothiazole inay be separated from the reaction solution by any method known in the art. For example, in some embodiments, the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be collected by simple filtering. There are numerous methods for filtering a solid froni a solution, and any such method may by useful in embodimeiits of ttie invention.
In other enibodirnents, insoluble 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothia-r.ole may be isolated by centrifugation. Again, such methods are well known in the art and any such method may be used in various embodiments of the invention. The insoluble crystalline 2-amino-4,5,6,7=tetrahydro-6-(propylamino)benzothiazole may then be washed to remove any contaminating solvent, sulfonate or halide salt, or soluble enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole from the crystals using any method available. For example, in one embodiment, the precipitated material may be washed in a volatile solvent such as an alcohol or heptane followed by vacuum drying.
[00116] The 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole enantiorners prepared using methods above may be purified from a starting (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine mixture that is enriched for one or the other enantiomers. For example, in some embodiments, the starting mixture may contain at least 55% or greater of either the R or S
enantionier, and in others the starting mixture may contain about 70% or greater of either the R or the S enantiomer. In still other embodiments, the starting material may contain greater than about 90% of either the R or S enantiomer. In particular embodiments, the starting mixture is enriched for (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.
[00117] Without wishing to be bound by theory, the relative solubility of the optical isomers of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in the achiral salt or acid solutions allows for chiral and chemical purification that is unexpected by using a relatively easy recovery method via a simple trituration step. The enhanced enrichment resulting from the purilication methods described above result in that may reach optical purity. For example, in various embodiments, the final 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product may be enriched to 99% optical purity or greater, 99.5%
optical purity or greater, 99.8% optical purity or greater, and in certain embodiments, 99.9%
optical purity or greater. In still other embodiments, the optical purity of the final 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole may be 99.95% or greater, or even 99.99%
or greater. ln particular embodiments, the optical purity may be 100%.
1001181 The processes disclosed herein have several advantages. First, the processes avoid the use of borane reagents such as sodiuni borohydride, common in the reductive amination schemes used in the prior art, which decoinposes rapidly to borane and hydrogen upon acidification. Second, reductive amination schemes involve the use of a two-step procedure in which the amide is formed first, followed by a reduction step.
The methods of this disclosure are one-pot synthesis and purification procedures, and therefore provide a safer, easier and more economical synthesis. '1'hird, there is no loss of chirality during the alkylation processes of the SN2 reaction mechanism of this disclosure, as opposed to previous synthesis schemes where chiral purity is often reduced or lost altogether during synthesis.
Finally, the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product of the nucleophilic substitution reaction precipitates from the reaction mixture.
"Fhis may be especially true for the p-TSA salt fonn of 2-aniino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole . This is an unexpected advantage of the methods of the instant disclosure and provides unique methods for chiral and chemical enrichment or purification of the final 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product.
[00.1191 Additional embodiments of the invention include the conversion of either sulfonate or halide salts of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole or free base 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole into an hydrochloric acid (I-ICl) salt as illustrated in FIG. 2. For example, in some embodiments, solid 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole sulfonate or halide salt (8) may be re-dissolved in an alcohol, such as ethanol, and the niixturc may be cooled to between about 0 and about 5 C with continuous stirring. Concentrated 1-ICl may then be added, followed by a solvent such as methyl tert-butyl ether (MTBE), and the mixture may be stirred for about 0.5 to about 3 hours at between about 0 and about 5 C until or until insoluble 2-amino-4,5,6,7-tctrahydro-6-(propylamino)benzothiazole dihydrochloride crystals (10) have formed. "l'he reaction mixture may then be filtered, washed in an inert solvent such as MTBE/alcohol solution and dried under vacuum. A detailed example of this synthesis may be found in Example 12.
[00120J In another embodiment, of 2-amino-4,5,6,7-tetrahydro-6-(propylarnino)benzothiazole sulfonate or halide salts (8) may be converted to an I-ICI salt using a concentrated solution of HC1 and isopropyl acetate (IPAC). In such embodiments, 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole sulfonate or halide salt (8) may be dissolved in IPAC and cooled to about 15 C. HCI (gas) may then be bubbled into the slurry for from about 0.5 hours to 3 hours to produce 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride (10), after which the mixture may be filtered, washed with an inert solvent, such as, for exaanple, IPAC and dried under vacuum at rooni temperature. A detailed example of this synthesis may be found in Example 13.

[001211 '1'he sulfonate or halide salts of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)bcnzothiazole may alternatively be converted to the free base form of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole as illustrated in FIG. 2. For example, in one embodiment, a p-'I'SA 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt (8) rnay be dissolved in dichloromethane (DCM) and water. The solution may then by brought to a pH of about 11-12 using NaOH and resulting in the formation of two phases. The aqueous phase contains 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole that may be extracted with DCM, dried over magnesium sulfate (MgSO4), filtercd over Celite and concentrated. The concentrated residue may be re-dissolved in M1'BE and stirred as a slurry for several hours. The solids may then be filtered, washed with MTBE, and dried under vacuum at a temperature of about 35 C. The final product is 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole free base (9). A detailed example of this synthesis may be found in Example 14.
1001221 In another embodiment, the sulfonate or halide salts of 2-ami.no-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (8) may be converted to the free base form of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (9) by dissolving p-TSA
salt of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in water and cooling the solution to a temperature of about 10 C. NaOH may be added to the solution to increase the pH, the solution may be diluted and extracted several times in DCM. 1'he combined organic phases are then washed, dried over MgSO4, filtered and concentrated to dryness. A
detailed example of this synthesis may be found in Example 15.
1001231 In some embodiments, the free base form of 2-amino-4,5,6,7-tetrahydro-(propylamino)benzothiazole may be converted to 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride (9) by bubbling HCI gas into a cooled solution of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole free base in IPAC.
Alternatively, in other embodiments, the free base form of 2-amino-4,5,6,7-tetrahvdro-6-(propylamino)benzothiazole (9) may be converted to 2-amino-4,5,6,7-tctrahydro-(propylaniino)benzothiazole dihydrochloride (10) by mixing with concentrated HCI at room temperature overnight. Detailed examples of such schemes may be found in Examples 16 and 17, respectively. In still other embodiments, the free base form of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (9) niay be converted to 2-amino-4,5,6,7-tetrahydro-6-(propy)amino)benzothiazole fumarate (11) by the addition of about 1 to about 4 molar equivalents of fumaric acid.

[001241 The methods of the present disclosure require little time, utilize readily available starting materials and do not involve the use of hazardous or difticult to handle reagents. Each of the several steps of the methods disclosed as part of the present invention are high yielding and afford products with very high chemical and chiral purity. Further, the processes disclosed herein may be scaled for industrial scale manufacturing.
As such, entantiomerically pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzot.hiazole may be manufactured in batches of greater than 1 kg or more, 10 kg or more, or even 25 kg or more as may be required to meet the needs of a large scale pharmaceutical use.
1001251 Embodiments of the invention also relate to a pure enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, either (6R) or (6S), produced by processes disclosed herein. Thus, an embodiment of the invention is a chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt prepared by a process which comprises dissolving 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole in an organic solvent, reacting the 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole with a n-propyl sulfonate or a n-propyl halide under conditions sufficient to generate the 2-arnino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt and recovering the chirally pure 2-arnino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt.
[00126] The present invention should not be considered limited to the particular embodiments described above, but rather should be understood to cover all aspects of the invention as fairly set out in the attached clainis. Various modifications, equivalent processes, as well as numerous structures to which the present invention may be applicable, will be readily apparent to those skilled in the art to which the present invention is directed upon review of the present specification. The claims are intended to cover such modifications and devices. "1'he invention and embodiments thereof illustrating the method and materials used may be further understood by reference to the following non-limiting examples.
EXAMPLES
[001.27] 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole was prepared using the SN2 substitution reaction described above. Reactions were carried out under exemplary reactions conditions A, B and C described below. Results of example syntheses using each of the several conditions which are embodiments of the present disclosure are listed in Table 1. Several example syntheses of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole using conditions A, B and C of the present disclosure are detailed in Examples 1-5, the results are presented in Table 1.
[001281 A: diainine dissolved in an organic solvent was heated to a reaction temperature of less than about 125 C with continuous stining. A solution of n-propyl sulfonatc or n-propyl halide dissolved in di-isoproplyethylamine and an organic solvent was added to the dissolved, heated diamine slowly over a period of up to several hours to form a mixture, and this reaction mixture was stirred at the reaction temperature for an additional period of time of up to about 4 hours.
[00129] B: diamine dissolved in an organic solvent was heated to a reaction temperature of less than about 125 CArith continuous stirring. A solution of n-propyl sulfonate or n-propyl halide dissolved in dimethylformamide was added slowly over a period of up to several hours to form a reaction mixture, and this reaction mixture was stirred at the reaction temperature for an additional amount of time up to about 4 hours.
[00130] C: diamine was dissolved in dimethylformamide and heated to less than about 125 C with continuous stirring. A solution of n-propyl sulfonate or n-propyl halide dissolved in dimethylformamide and di-isopropylethylamine was added to the heated diamine slowly over a period of up to several hours to form a reaction mixture. This reaction mixture was then stirred at the reaction temperature for up to about 4 hours.
1001311 Alternatively, di-isoproplyethylaminc may be added to the heated diamine dissolved in an organic solvent prior to the addition of a solution including n-propyl sulfonate or n-propyl halide dissolved in dimethylformamide. As above, the n-propyl sulfonate or propyl halide/dimethlyformamide solution may be added slowly for a time period up to several hours with continuous stirring and the reaction mixture formed may be stirred at the reaction temperature for up to about 4 hours.
1001321 These products were analyzed by high pressure liquid chromatography (HPI,C) for chemical and chiral purity. 'H NMR and 13C NMR was also used to confirm the structure of the product is 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole Preparation of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-"1'SA salt:
Condition A
1001331 A 2.0 liter, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a reflux condenser, aild a 500 ml addition I'unnel. The flask was charged with 45 gratns of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine, followed by 750 ml of n-propanol. Under continuous stirring, the mixture was heated to 95 C over 15 minutes generating a clear solution. The addition funnel was charged with a solution of 74 grams propyl tosylate and 60 ml diisopropylethyleamine in 250 mi n-propanol. This solution was added dropwise to the 2.0 liter flask with continuous stirring over a period of 4 hours. The reaction was continued with stirring for an additional 8 hours at 95 C, after which the solution was brought to room temperature, and stirring was continued for an additional 4 hours.
[00134] The precipitated material was collected by filtration and washed three tiines using 100 ml reagent grade alcohol each time. The alcohol washed precipitated cake was then washed with 100 ml heptane and dried under high vacuum for 2 hours.
[001351 'fhe final weight of the dried product was 53.2 grams, representing a 52.2%
yield. HPLC was used to determine the chemical purity of the (6R)-2,6-diamino-4,5,6,7-tetrahvdro-benzothiazole as 98.2% and the chiral purity as greater than 99.5%.
IH NMR and 13C NMR were used to confirm the structure.

Preparation of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt:
Condition A
[00136] A 250 ml, three necked flask was equipped with a magnetic stirrer, a temperature probe, a heating mantle, a claisen joint, a reflux condenser, and a 50 ml addition funnel. The flask was charged with 5 grams of (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 45 ml of n-propanol. Under continuous stirring, the mixture was heated to a temperature of 95 C over 15 minutes generating a clear solution.
1'he addition funnel was charged with a solution of 8.2 grams propyl tosylate and 6.7 ml diisopropylethyleamine in 16 mi n-propanol. 'fhis solution was added dropwise to the 250 ml flask with continuous stirring over a period of 2 hours. The reaction was continued with stirring for an additional 6 hours at 95 C, after which the solution was brought to room temperature, and stirring was continued for an additional 4 hours.
[00137] '1'he precipitatcd material was collected by filtration and washed three tinies using 10 ml reagent grade alcohol each time. The alcohol washed precipitated cake was then washed witli 10 ml heptane and dried under high vacuum for 2 liours.
1001381 The final weight of the dried product was 4.99 grams, representing a 44.2%
yield. I-1PLC was used to determine the chemical purity of the (6S)-2,6-diamino-4,5,6,7-tetrahydro-benzothiazole as 98.0% and the chiral purity as greater than 99.6%.
'I-1 NMR was used to confirm the structure.

Preparation of racemic 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole p-TSA salt:
Condition A
[001391 A 250 ml, three necked flask was equipped with a magnetic stirrer, a tcmperature probe, a heating mantle, a claisen joint, a reflux condenser, and a 100 ml addition funnel. The flask was charged with 5 grams of racemic 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 80 ml of n-propanol. Under continuous stirring, the niixture was heated to a temperature of 95 C over 15 minutes gencrating a clear solution.
The addition funnel was charged with a solution of 10.1 grams propyl tosylate and 8.2 nil diisopropylethyleamine in 28 ml n-propanol. This solution was added dropwise to the 250 ml flask with continuous stirring over a period of 2 hours. The reaction was continued with stirring for an additional 6 hours at 95 C, after which the solution was brought to room temperature, and stirring was continued for an additional 6 hours.
1001401 The precipitated material was collected by filtration and washed two times using 25 ml reagent grade alcohol each time. 171e alcohol washed precipitated cake was then washed with 25 ml heptane and dried under high vacuum for 1 hour.
1001411 The final weight of the dried product was 5.12 grams, representing a 45%
yield. HPLC was used to determine the chemical purity of the racemic 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole as 97.1%, and the chiral purity showed a 1:1 mixture of the (6R) and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine . 'H NMR was used to confirm the structure.
EXAMPLI? 4 Preparation of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt:
Condition B
[00142J A 250 ml, three necked flask was equipped with a nlagnetic stirrer, a temperature probe, a heating mantle, a claisen joint, a reflux condenser, and a 50 inl addition funnel. The flask was charged with 5 grams of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 50 ml of DMF. Under continuous stirring, the mixture was heatcd to a temperature of 75 C. 6.3 grams propyl tosylate was added dropwise to the 250 ml flask with continuous stirring over a period of 6 hours. Progress of the reaction was monitored by analysis on HPLC.
1001431 "l'he reaction was continued with stirring for an additional 12 hours at room temperature. The solution was diluted with 20 ml M1'BE and stirred for an additional hour.
The precipitated material was collected by filtration and washed with 20 ml M"I'BE, followed by 2 washes of 20 ml each ethanol. The washed precipitated cake was dried under high vacuum.
[00144] '1'he final weight of the dried product was 4.6 grams, representing a 40%
yield. HPLC was used to determine the chemical purity of the (6R)-4,5,6,7-tetrahydro-1`T6-propyl-2,6-benzothiazole-diamine as 94.9% and the chiral purity as greater than 99.6%. 'H
NMR was used to confirin the structure.

Preparation of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine P-TSA salt:
Condition B
[00145] A 250 ml, three necked flask was equipped with a magnetic stirrer, a temperature probe, a heating mantle, a claisen joint, a reflux condenser, and a 50 ml addition funnel. The flask was charged with 10 grams of (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 100 ml of DMF. Under continuous stirring, the mixture was heated to a temperature of 75 C. The addition funnel was charged with a solution of 16.4 grams propyl tosylate in 20 ml DMF. This solution was added dropwise to the 250 ml flask with continuous stirring over a period of 1.5 hours. Progress of the reaction was monitored by analysis on HPLC.
[00146] The reaction was continued with stirring for an additional 12 hours at 75 C, after which the solution was brought to room temperature, and stirring was continued for an additional 7 hours. The solution was diluted with 100 ml MTBE and stirred for an additional hour. The precipitated material was collected by filtration and washed with 100 ml MTBE, followed by 2 washes of 50 ml each ethanol, and a wash with 50 ml heptane. The washed precipitated cake was dried under high vacuum.
[00147] The final weight of the dried product was 9.81 grams, representing a 43.3%
yield. 1-IPLC was used to determine the cheniical purity of the (6S)-4,5,6,7-ietrahydro-N6-propyl-2,6-benzothiazole-diamine as 99.4% and the chiral purity as greater than 99.8%. 'H
NMR was used to confirm the structure.

Preparation of racemic 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazolep-TSA salt:
Condition B
[001481 A 250 ml, thrce necked flask was equipped with a magnetic stirrer, a temperature probe, a heating mantle, a claisen joint, a reflur condenser, and a 50 ml addition funnel. The flask was charged with 5 grams of racemic-2,6 diainino-4,5,6,7-tetrahydro-benzothiazole, followed by 50 ml of DMF. Under continuous stirring, the mixture was heated to a temperature of 75 C. 9.5 grams was added to the 250 ml flask with continuous stirring. Progress of the reaction was monitored by analysis on HPLC.
[00149] The reaction was continued with stirring for an additional 4 hours at 75 C, after which the solution was brought to room temperature, and stirring was continued for an additional 12 hours. The solution was diluted with 20 ml MTBE and stirred for an additional hour. 'I'he precipitated material was collected by filtration and washed with 50 ml MTBE, followed by 3 washes of 25 ml each ethanol, and the precipitated cake was dried under high vacuum.
[00150] The final weight of the dried product was 2.9 grams, representing a 25.6%
yield. I-IPLC was used to determine the chemical purity of the racemic 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole as 98.3%, and the chiral purity showed a 1:1 mixture of the (6R) and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine . 'H NMR was used to conlirm the structure.

Preparation of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt:
Condition C
100151] A 12 L, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 500 ml addition funnel. The flask was charged with 250 grams of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 2 L of dimcthyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of 65 C. The addition funnel was charged with a solution of 386.6 grains propyl tosylate and 322 ml diisopropylethyleamine in 500 ml DMF.
This solution was added to the 12 L flask dropwise over a period of 2.0 hours.
The reaction was monitored by analysis on I-IPLC.

[00152] The reaction was continued at 65 C for an additional 5 hours, after which the solution was gradually cooled to room temperature and stirred overnight. The solution was diluted with 2 L MTBE and stirred for an additional 0.5 hours. The precipitated material was collected by filtration and washed with 500 ml MTBE, followed by 3 washes of 500 ml each reagent alcohol. The washed precipitated cake was dried under high vacuum.
[00153] The final weight of the dried product was 317.6 grams, representing a 56%
yield. HPLC was used to determine the chemical purity of the (6R)-2,6-diamino-4,5,6,7-tetrahydro-benzothiazolc as 98.4% and the chiral purity as greater than 99.8%.
11-I NMR and 13C NMR was used to confirm the structure: 'H NMR (300 MHz, DMSO-d6) 6 8.5 (br.s, 2H), 7.5 (d, 2H), 71.2 (d, 1 H), 6.8 (s, 21-I), 3.4 (m, 1 H), 2.95 (m, 3H), 2.6 (m, 2H, nlerged with DMSO peak), 2.3 (s, 3H), 2.15 (m, 11=I), 1.8 (m, 1 H), 1.55 (m, 2H), 0.9 (t, 3I-I); 1 'C NMR
(300 MHz, DMSO-d6) S 167.0, 145.5, 144.6, 138.4, 128.6, 125.8, 110.7, 53.9, 46.5, 25.8, 25.6, 24.5, 21.2, 19.6, 11.3.

Preparation of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt:
Condition C
1001541 A 500 ml, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 100 ml addition funnel. The flask was charged with 20 grams of (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 180 ml of dimethyl formamide (DMF). Under continuous stirring, the mixture was lieated to a temperature of 65 C. The addition funnel was charged with a solution of 35.5 grams propyl tosylate and 32.8 ml diisopropylethylamine in 40 ml DMF. This solution was added to the 500 ml flask dropwise over a period of 2.0 hours. The reaction was monitored by analysis on HPLC.
[00155] The reaction was continued at 65 C for an additional 10 hours, after which the solution was gradually cooled to room temperature and stirred for 6 hours.
The solution was diluted with 220 ml MTBC and stirred for an additional 0.5 hours. The precipitated material was collected by filtration and washed with 50 ml MTBE, followed by 3 washes of 50 ml each reagent alcohol and a wash with 75 ml of heptane. The washed precipitated cake was dried under high vacuum.
[00156) The final weiglit of the dried product was 25.4 grams, representing a 56%
yield. HPLC was used to determine the chemical purity of the (6S)-2,6-diamino-4,5,6,7-tetrahydro-benzothiazole as 99.4% and the chiral purity as greater than 99.7%.
'H NMR and 13C NMR was used to confirm the structure: 'H NMR (300 MHz, DMSO-d6) S 8.5 (br.s, 2H), 7.5 (d, 2H), 71.2 (d, 1H), 6.8 (s, 21-I), 3.4 (m, IH), 2.95 (ni, 3H), 2.6 (m, 2H, merged with DMSO peak), 2.3 (s, 3H), 2.15 (m, 1H), 1.8 (m, 1H), 1.55 (m, 2H), 0.9 (t, 3H).

Preparation of racemic 2-alnino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazolep-TSA salt:
Condition C
[001571 A 250 ml, three necked flask was equipped with a. magnetic stirrer, a temperature probe, a heating mantle, a claisen joint, a rcflux condenser, and a 50 ml addition funnel. The flask was charged with 5 grams of racemic-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 45 ml of DMF. Under continuous stirring, the mixture was heated to a temperature of 65 C. The addition funnel was charged with a solution of 8.86 grams propyl tosylate and 8.2 ml of diisopropylethylainine in 10 ml DMF.
This solution was added dropwise to the 250 ml flask with continuous stirring over a period of 2 hours.
Progress of the reaction was monitored by analysis on HPLC.
[001581 The reaction was continued with stirring for an additional 6 hours at 65 C, after which the solution was brought to room temperature. The solution was diluted with 70 ml MTBE and stirred for an additional hour. The precipitated material was collected by filtration and washed with 15 ml M"1`BE, followed by 2 washes of 15 ml each ethanol, and a wash with 15 ml heptane. The washed precipitated cake was dried under high vacuum.
[001591 The final weight of the dried product was 6.02 grams, representing a 53.1%
yield. HPLC was used to deterniine the chemical purity of the racemic 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole as 99.2%, and the chiral purity showed a 1:1 inixture of the (6R) and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-ben=r.othiazole-diamine . 'H NMR was used to confirm the structure.

Preparation of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine n TSA salt:
Condition E
1001601 A 1000 ml, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 250 nil addition funnel. 'I'he flask was charged with 25 grams of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 200 ml of dimethyl formamide (DMF). Under continuous stirring, the niixture was heated to a temperature of 75 C. The addition funnel was charged with a solution of 39.5 granls propyl tosylate and 32.5 ml diisopropylethyleamine in 50 ml DMF. This solution was added to the 1000 ml flask dropwise over a period of 1.0 hours.
1'he reaction was monitored by analysis on HPLC.
100161] The reaction was continued at 75 C for an additional 5 hours, after which the solution was gradually cooled to room temperature and stirred overnight. `I'he precipitated material was collected by filtration and washed with 2 waslzes with 100 ml M"IBE, followed by 3 washes of 75 ml each reagent alcohol and one wash with 125 ml of heptane.
The washed precipitated cake was dried under high vacuum.
[00162] The reaction resulted in a 47% yield. HPLC was used to deternline the chiral purity as 99.8%. 'H NMR and 13C NMR was used to confirm the structure.

Preparation of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt:
Condition E [001631 A 1000 ml, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 250 ml addition funnel. 'I`he flask was charged with 25 grams of (6S)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 200 ml of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of 75 C. The addition funnel was charged with a solution of 39.5 grams propyl tosylate and 32.5 ml diisopropylethyleamine in 50 ml DMF. This solution was added to the 1000 ml flask dropwise over a period of 2.0 hours.
'1'he reaction was monitored by analysis on HPLC.
[00164) The reaction was continued at 65 C for an additional 5 hours, after which the solution was gradually cooled to room temperature and stirred overnight. The precipitated material was collected by filtration and washed with twice with 10 ml M'I'BE;, followed by 3 washes of 75 ml each reagent alcohol and one wash with 125 ml oi' heptruie.
The washed precipitated cake was dried under high vacuum.
1001651 "I'he reaction resulted in a 47% yield. HPLC was used to determine the chiral purity as 99.8%. 1H NMR and 13 C NMR was used to confirm the structure.

'1'able 1: Experiments for S1,2 preparation of 2-ainino-4,5,6,7-tetrahydro-6-(propylamino)bcnzothiazole pTSA salt Condition Isomer Batch Size Results Ex. 1 (6R) 45 grams Yield = 53.2 grams (52%) Chemical Purity = 98.2% AUC by HPLC
Chiral Purity > 99.5% AUC by HPLC
Ex. 2 (6S) 5 grams Yield = 4.99 grams (44.2%) Cheinical Purity = 98.0% AUC by HPLC
Chiral Purity => 99.6% AUC by HPLC
Ex. 3 Raceniic 5 gram Yield = 5.12 grams (45%) Chemical Purity = 97.1 % AUC by HPLC
Chiral Purity = I:1 (6R):(6S) by HPLC
Ex. 4 (6R) 5 gram Yield = 4.6 grains (40%) Chemical Purity = 94.9% AUC by HPLC
Chiral Purity = 99.6% AUC by HPLC
Ex. 5 (6S) 10 gram Yield = 9.81 grams (43.3%) Cheinical Purity = 94.9% AUC by HPLC
Chiral Purity = 99.7% AUC by HPLC
Ex. 6 Racemic 5 gram Yield = 2.9 grams (25.6%) Chemical Purity = 98.3% AUC by HPLC
Chiral Purity = 1:1 (6R):(6S) by HPLC
Ex. 7 (6R) 250 gram Yield = 317.6 grams (56%) Chemical Purity = 99.4% AUC by I IPLC
Chiral Purity = 99.8% AUC by HPLC
Ex. 8 (6S) 20 gram Yield = 25.41 grams (56%) Chemical Purity = 99.4% AUC by HPLC
Chiral Purity = 99.7% AUC by 1-[PLC
Ex. 9 Racemic 5 gram Yield = 6.02 grams (53.1%) Chemical Purity = 99.2% AUC by HPLC
Chiral Purity = 1:1 (6R):(6S) by HPLC
Ex. 10 (6R) 25 gram Yield = 47%
Chiral Purity = 99.8% AUC by HPLC
Ex. 11 (6S) 25 gram Yield = 47%
Chiral Purity = 99.8% AUC by HPLC

1001661 Various ratios of entantiomerically enriched mixtures of (6R)2,6 diamino-4,5,6,7-tetrahydro-benzothiazole and (6S)2,6 diamino-4,5,6,7-tetrahydro-benzothiazole liaving (6R) to (6S) ratios of: 80:20, 20:80, 85:15, 15:85, 90:10, 10:90, 95:5 and 5:95, were used to prepare (6R) or (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine based on the enriched species in the starting material. The following reaction conditions were used:
F: 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole mixtures were dissolved in 10 volumes of DMF and 1.25 equivalents of propyl tosylate at 65-67 C. The reaction is then cooled to room temperature, insoluble species were collected and washed with 8 voluines of MTBE.
G: 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole mixtures were dissolvcd in 18 volumes of DMF and 1.25 equivalents of propyl tosylate at 65-67 C. The reaction is then cooled to room tenlperature, insoluble species were collected and washed with 8 volumes of MTF3E.
E1: 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole mixtures were dissolved in 10 volumes of DMF and 1.25 equivalents of propyl tosylate at 65-67 C. '1'he reaction is then cooled to room temperature and insoluble species were collected. No washing step was performed.
[001671 Results are compiled in Table 2:

Table 2: Experiments for SN2 preparation of pure enantiomers of 2-amino-4,5,6,7-tetrahydro-6-(propylarnino)benzothiazole Ratio of Condition F Condition G Condition H
starting diamines icld/chiral uri ietd/chiral uri ield/chira) urit 6R : 6S (Y P tY) (Y P tY) (yield/chiral Y) 80:20 29% / 99% 34% / .98.2%
20:80 - 30% / 99.4% 35% / 95.7%
85:15 43% / 86.8% 36% / 99.8% 39% / 99.9%
15:85 52% / 88.9% 27% / 99.6% 37% / 99.9%
90:10 47% / 95.9% - -10:90 58% / 93.6% - -95:5 50% / 99.6% - -5:95 47% / 99.6% -[001681 The data in 'I'able 2 demonstrates that both enantiomers of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazolc have similar, if not the sanie, solubility. I"urther, the data shows that the synthesis is equally efficient for eitlier enantiomer of 2-arnino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole . These data also demonstrate that the enantiorners behave independently of one another, in that the solubility of one enantiomer appears to be unaffected by the concentration in solution of the other. For example, the various synthesis reactions carried out using condition F all have chemical yields of about 50%, independent of the perccntage of predominant diamine enantiomer of the starting material.
When the volume of the organic solvent used in the synthesis reaction is increased, the chemical yield is reduced, but the chiral yield is increased. This is apparent by comparison of the reaction carried out in conditions F and G, where an 85:15 ratio of (6R):(6S) diaminc produced a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product having an 86.8%
chiral purity for the (6R) enantiomer when the reaction used 10 volumes of the organic solvent and a 99.8% chiral purity for the (6R) enantiomer when the reaction used 18 volumes of the organic solvent. Note also that the chemical yield was reduced in the reaction using a larger volume of organic solvent (43% yield in condition F and 36% yield in condition G).
[001691 In Table 3, condition H is the same as condition F, cxcept that the recovery step does not incorporate dilution in MTBE. 'Che M'I'BE is observed to increase 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole recovery (yield) from the synthesis reaction, but may reduce the overall chiral purity. This is born out by a comparison of the results for trials carried out in an 85:15 ratio of (6R):(6S) diamine, which produced a 2-a.mino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product having a 86.8%
chiral purity for the (6R) enantiomer when the reaction included the MTBE organic solvent and a 99.9%
chiral purity for the (6R) enantiomer when the reaction did not include the M"IBE organic solvent. 1'he chemical yield was reduced by exclusion of the MI'BE dilution in the recovery step; a 43% yield in condition C as opposed to a 39% yield in condition E.

Conversion of (6R)-4,5,6,7-tctrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt to (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride 1001701 (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt (50 grams; 0.13 mol) was taken into 150 ml absolute ethanol and cooled to between 0 and 50 C with continuous stirring. Concentrated HCl (33 ml) was slowly added to the reaction while maintaining the temperature at betwecn 0 and 5 C, and the mixture was stirred for an additional 15 minutes. MTBE (200 ml) was added to the mixture, and stirring was continued for an additional 1.5 hours at temperature. The reaction mixture was then filtered, washed twice with an M'I'BE/ethanol solution (2:1, 2 x 50 ml wash volumes), and dried under vacuum at 30 C overnight. The final product was 34 grams of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, indicative of 92% yield, and a 97.3%
chemical purity as determined by I-113LC.

Conversion of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt to (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diainine dihydrocliloride [001711 (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt (10 grams; 0.026 mol) was dissolved in 200 ml IPAC and cooled to 15 C with continuous stirring. HCI gas was bubbled into the slurry for 1 hour. The mixture was then filtered, washed with IPAC, and dried overnight under vacuum at room temperature. The final product was 6.8 grams of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, indicative of 92% yield, and a 97% chemical purity as determined by HPLC.

Conversion of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-1'SA salt to (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine free base 1001721 (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt (25 grams; 0.065 mol) was dissolved in 200 ml DCM and mixed into a slurry. 10 ml of water was added and the mixture was basified with 12 ml of 6N NaOI-I to a pH of 11-12. The two phases were split, and the aqueous was extracted with 200 ml of DCM. The combined organic phases were dried over MgSO4, filtered over Celite and concentrated.
"l'he residue was dissolved in 100 ml M"IBE and slurricd for several hours. The solids were then filtered, washed with MTBE and dried under vacuum at 35 C. The final product was 9.1 grams of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, indicative a of 66% yield, and a 98% chemical purity as determined by HPLC.

Conversion of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazolc-diaminep-TSA
salt to (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine free base 1001731 Freebasc formation was performed on a 200 gram scale. A 5 L, three necked, round-bottomed flask, equipped with an over head stirrer, thermometer, and addition fumlel was charged with 200 g (0.522 mol) of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-dianiine p-TSA salt and I L of water. The mixture was stirred and cooled to C. The slurry was basified to a pH of about 11-12 by the slow addition of 200 ml of 6 N
NaOH over a period of 15 min. The reaction mixture was diluted with 500 ml of brine (sodium chloride dissolved in water) aiid extracted with 3 x 1 L of dichloromethane. The combined organic phases were washed with 1.0 L of brine, dried over MgSO4, filtered and concentrated to dryness. The residue was triturated with I L of 1:1 IPAC:Heptane, the resulting slurry was stirred for 1 hour, filtered and the filter cake was washed with 2 x 250 mi of 1:1 mixture of IPAC:Heptane. The filter cake was collected and dried at 40 C under high vacuum for 24 hours to give 94.1 grams (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine (85.5%) as a white solid. The chemical purity was 100%
AUC as tested by HPLC, and the chiral purity was 100% AUC as tested by HPLC. 'H NMR
and '3C
NMR was used to confirm the structure: 'H NMR (300 MHz, DMSO-86) 6 6.6 (s, 2H), 2.8 (m, 2H), 2.5 (m, 21-1, merged with DMSO peak), 2.2 (m, IH), 1.9 (ni, 11-1), 1.5-1.3 (m, 41-I), 0.85 (t, 3H); 13 C NMR (300 MHz, DMSO-d6) S 166.2, 144.8, 113.6, 54.2, 49.1, 30.0, 29.6, 25.2, 23.5, 12.3.

Conversion of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine free base to (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride 1001741 The freebase of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-bcnzothiazole-diamine (4.8 gralns; 0.022 mol) was dissolved in 200 ml of IPAC and cooled to 15 C. I-ICl gas was bubbled into the slurry for 1 hour. The mixture was then filtered, washed with IPAC
and dried under vacuuni at room temperature overnight. `1'he final product was 6.4 grams of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-dia.mine dihydrochloride, indicative of 100% yield, and a 97% chemical purity as determined by HPLC.

Conversion ol' (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine free base to (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride 1001751 The freebase of (6R)-4,5,6,7-tetrahydro-i`'6-propy1-2,6-benzothiazole-dianiine (50 grams; 0.13 mol) was dissolved in 500 ml of IPAC. Under continuous stirring, the mixture was slowly charged with 78 ml of concentrated HCI at a temperature of 25 C.
`fhe mixture was stirred overnight at ambient conditions (-25 C), filtered and dried under vacuum at 40 C. 'I'he final product was 68 grams of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, indicative of 95% yield.

Optical purification of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine using achiral acid addition (001761 2-ainino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole entantioenriched for the (6R) enantiomer (-300 mg) was dissolved in 10 ml of the choscn solvent at 75 C.
Complete dissolution was observed in all samples. Acid addition was made at 1.05 inolar equivalents for the p-TSA (solvent is ethanol; 2.97 ml of 0.5 M acid) and MSA
(solvent is acetonitrile; 1.49 ml of 1.0 M acid), and 2.05 molar equivalents for the fumaric (solvent is acetonitrile; 5.84 ml of 0.5 M acid) and phosphoric (solvent is acetonitrile;
2.90 ml of 1.0 M
acid). The reaction mixtures were cooled to room temperature at a rate of 25 C/hour and stirred at room temperature for an additional 19 hours.
1001771 '1'he products of purification processes were then analyzed by I-1PLC
for chemical and chiral purity. FIG. 3A shows an exemplary 14PLC trace starting material. In FIG. 4A, a large (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine peak can be observed at about 6 minutes and a much smaller (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine peak can be seen at about 9 minutes. The area of these peaks provides an estimated coniposition for the mixture which is shown in the table below the trace, and shows the mixture as containing about 90.2% (6R) and 8.8% (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. FIG. 3B shows an exemplary trace of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product following purification. In FIG. 3B, a large (6R)2-amino-4,5,6,7-tetrahvdro-6-(propylamino)benzothiazole peak is observed at about 6 minutes, and no (6S)2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole peak is observed. It is additionally of note that several other minor peaks are also reduced or eliminated in the product trace, and the table below the trace indicates that (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine makes up 99.9% of the product solution which is within the limits of analytical detectability. Results for each exemplary reaction are provided in Table 3:

Table 3: Experiments for preparation of the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diam ine Salt/Acid Solvent Batch Size Results Yield = 489.5 nig (90.3%) p=fSA ethanol 298.7 mg Start Chiral Purity = 91% AUC (6R) by I-1PLC
Final Chiral Purity = 100% AUC by HPLC
Yield = 431.8 ing (98.9%) MSA acetonitrile 300.0 mg Start Chiral Purity = 91 % AUC (6R) by HPLC
Final Chiral Purity = 99.23% AUC by HPLC
Yield = 532 mg (84.2%) fumaric acetonitrile 301.0 mg Start Chiral Purity = 91 % AUC (6R) by H.PLC
(hot ethanol) Final Chiral Purity = 99.26% AUC by HPLC.
Yield = 592 mg (-100%) phosphoric acetonitrile 299.4 nlg Start Chiral Purity = 91 % AUC (6R) by HPLC
Final Chiral Purity = 100% AUC by HPLC

1001781 The solids obtained by this trituration step were isolated by filtration and dried under high vacuum at room temperature. These products were analyzed by HPLC, IH
NMR, thermal gravinletric analysis, differential scanning calorimetry, X-ray powder diffraction (XPRD), Fourier transform infrared spectroscopy and moister-sorption analysis.
The XPRD patterns showed that the p-TSA, MSA and fumarate salt forms of the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine were crystalline, whilc the phosphate salt form of the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine was amorphous.

Industrial scale resolution of racemic diamine 1001791 A 72 L, unjacketed reactor was charged with racemic 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole (4.5 kg; 26.6 mol) and 58.5 L water, and heated as a suspension to a temperature of about 60 C to 65 C. Resolution of the enantiomers was achieved by addition of one equivalent oP (D)-(-)=1'artaric acid (3991 grams; 26.6 mol) in 4.5 L of water, after whicli the resulting solution was lieated to a temperature of about 70 C to 75 C and maintained at this temperature for about 1 hour. '1.'he mixture was allowed to cool to a temperature of about 20 C to 25 C and stirred for an additional 15 hours, after which the mixture was f'iltered and the solids were washed 3 X with water (6.3 L each wash).

[001801 The wet solids, which contain the (6R) enantiomer of the diamine, were charged to the reactor followed by 54 L of water, and the mixture was heated to a teinperature of about 700 C to 75 C for 2 hours. The mixture was allowed to cool to a tcniperature of' about 20 C to 25 C and stirred for 17 hours. The mixture was then filtered and the solids were washed 2 X with water (4.5 L each wash). The wet solids were transferred to a jacketed reactor and the reactor was charged with 8.1 L of water. The mixture was cooled to a temperature of about 0 C to 5 C and cautiously charged with concentrated 1.6 L of FIC1, followed by 1.2 L of 50% NaOH to achieve a pH of about 9-10. During the addition, the temperature was maintained at about 0 C to 5 C, and stirred for an additional hour at temperature. The resulting mixture was then filtered and the solids were washed 2 X with cold (0 C to 5 C) water (1.1 L each wash). The solids were transferred to a jacketed reactor and were reslurried once more with 4.5 L of water at 0 C to 5 C. The solids 'were filtered and dried under warm air (40 C to 45 C) to give 1940 grams of the product ((6R) diaminc) as a white solid, with an 86% yield for the (6R) enantiomer.
[00181] The mother liquors of the initial resolution step, which contain the (6S) enantiomer of the diamine, were concentrated to afford diamine with a 95.5%
yield for the (6S) enantiomer. Results of reactions performed using 1000, 4500 and 4100 grams of starting material are provided in Table 4 Table 4: Experinients for industrial scale resolution of the (6R) enantiomer of diamine Input (grams) Yield (%) of Chemical Purity Chiral Purity (6R cnantionier (AUC % by HPLC (AUC % by HPLC) 1000 76 >99 98.3 4500 86 >99 98.5 4100 54 >99 98.5 Industrial scale preparation of propyl tosylate 1001821 A 100 L glass, jacketed reactor was charged with 1-propanol (2.098 kg;
34.9 mol), tricthylamine (4.585 kg; 45.3 mol; 1.3 equivalents) and DCM (20.1 L). 't'he mixture was cooled to a temperature of about 5 C to 15 C and cautiously charged with a solution of p-toluenesulfonyl chloride (6 kg; 31.47 mol; 0.9 equivalents) in DCM (10.5 L) over 30 minutes. Once the addition was complete, the mixture was warmed to a temperature of about 18 C to 22 C and stirred for 12 hours. The reaction mixture was assayed by 'H

NMR (in CDCl3) and dcemed complete. HCl (6 N; 2.98 L) was cautiously charged while maintaining the temperature below 25 C. The aqueous phase was removed, and the organic phase was washed 2 X with water (21 L each wash), dried with MgSO:4, and filtered over CeliteO. 'I'he filtered solids were then washed with DCM (4 L) and concentrated to a residue.
'fhe residue was dissolved in heptane and concentrated again to afford a final propyl tosylate product (6.385 kg, 95% yicld).

Industrial scale preparation of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine p-TSA salt: Condition C
1001831 A 72 liter unjacketed reactor was charged with 1.84 kg (10.87 mol) of (6R)-2,6 diarnino-4,5,6,7-tctrahydro-benzothiazole ((6R) diamine), followed by 14.7 L of dimethyl formamide (DMr). Under continuous stirring, the mixture was heated to a temperature of between 65 C and 68 C. A solution of 2926 grams propyl tosylate and 1761 grams diisopropylethyleamine in 3.5 L DMF was added slowly over a period of 2 hours.
The reaction was continued at 67 C for an additional 4 hours, afler which the solution was gradually cooled to room temperature (18 C to 22 C) and stirred for an additional 15 hours.
111e solution was diluted with 14.7 L of MTBE over a time period of 30 minutes, and stirred for an additional 1 hour. The precipitated material was collected by filtration and washed with 7.3 L M'TBE, followed by 3 washes of 3.7 I. each of ethanol, and a wash with 9.2 l..
heptane. 'I'he washed precipitated cake was dried under high vacuum at 30 C
to 35 C. The final weight of the dried product was 2090 grams, representing a 50% yield.

Purity of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.
1001841 The Limit of Quantitation (LOQ) to 0.05% precision was determined from six replicate preparations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothia=r.ole-diamine.
The RSD was measured to be 6.3% and the S/N (signal to noise ratio) was measured to be 61:1. The pre-defined acceptance criteria at LOQ was to have a S/N > 10:1 and for the RSD
to be < 20.0%. These results exceeded the acceptance criteria by a wide margin.
(001851 Signal-to-noise levels can vary for numerous reasons, including punip behavior, air in lines, extent of mobile phase degassing, system-to-system variations and electronic fluctuations. The LOD had previously been estiniated to be 0.03%
based upon the 0.1% preparation which produced a S/N of 30:1. Although the recent 0.05%
levels produced a S/N of 61:1, based upon the overall history of the method, the estimated LOD
will remain at the stated 0.03%.
1001861 Linearity was determined over the range 0.05%-150% of nominal (0.2 g/mL-600 g/mL). The correlation coefficient over this expanded range was determined to be 0.9999. This exceeded the pre-defined linearity acceptance criterion of >
0.995.
1001871 The weight percent assay is on an as-is basis versus the current standard which has a purity of 94.0%. Each sample was prepared in duplicate with single injections.
Purity data is provided in the Table 5:

Table 5: (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine Purity Data Sample %area ave wtiwt ave Sample 118 100.0 95.1 Sample 118 100.0 100.0 95.0 95.1 Sample 105 100.0 94.7 Sample 105 100.0 100.0 94.7 94.7 Sample 061 100.0 94.5 Sample 061 100.0 100.0 94.6 94.5 Sample 326A 100.0 95.0 Sample 326A 100.0 100.0 94.7 94.8 1001881 Example chromatographs are provided in FIG. 4A-D. Specifically, FIG.

is an HPLC Chromatograph of Sample 118; FIG. 4B is an HPLC Chromatograph of Saniple 105; FIG 4C is an HPLC Chromatograph of Sample 061; and FIG. 4 D is an HPLC
Chromatograph of Sample 326A. These data show preparation of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine at 100% purity.

Propyl tosylate concentration of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine 1001891 A solid phase extraction (SPE) procedure was developed to remove the high levels of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine prior to analysis wliile niaintaining recovery of propyl tosylate spiked at 1.5 ppni. The SPE
cartridges (Supelco Discovery DSC- l 8, 6 nil.., 1 g) are pre-activated and washed with 6 mL acetonitrile (MeCN) followed by 6 mL of water. Five milliliters of 100mg/mL solutions of prepared in 5:95, MeCN/water with 0.5% phosphoric acid are then introduced into the SPE
cartridges. The acid sufficiently maintains the polarity of the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine so that it can be readily washed from the SPE
cartridge with an additional 5 mL of 5:95, MeCN/water with 0.5% phosphoric acid while retaining any propyl tosylate. Any propyl tosyate is then eluted from the SPE cartridges using 5 mL of 95:5 MeCN/water. Fortunately, due to the sensitivity gained from method development experiments, no further sample enrichment is needed and the samples are analyzed as-is. The samples are compared to a standard of 1.5 ppm (0.15 pg/mL) propyl tosylate prepared in 95:5 MeCNfhvater.
[00190] An examplary UV spectrum of propyl tosylate eluted from the SPE
cartridgcs is shown in FIG. 5.
[00191] Exemplary HPLC data from of the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine eluted from the SPE cartridge is provided in FIG. 6A and 6B. FIG.
6A shows an HPLC chromatograph of a propyl tosylate standard prepared from 100 mg of propyl tosylate. FIG. 6B shows an HPLC chromatograph of a 1 g sample of (6R)-4,5,6,7-tctrahydro-N6-propyl-2,6-benzothiazole-diamine prepared by the method of embodiments of the invention. No propyl tosylate is evident based on the data provided in FIG. 6B as indicated by the absence of a peak corresponding to propyl tosylate (right).

Chiral purity of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine 1001921 The chirality of the (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazolc-diamine prepared as described above was tested using a Chiralpak IA column under HPLC
conditions. About 25 mg of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine were applied to the column. Exemplary HPLC traces of a(6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-dianline standard are provided in FIG. 7A and an HPLC trace of a sample (6S)-4,5,6,7-tctrahydro-N6-propyl-2,6-benzothiazole-diamine is provided in FIG. 7B. Test data is provided in Table 6.

Table 6: % Recovery of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine Level Preparation % Recovery 1 91.13 100% 2 91.18 3 97.61 Average 93.3 % RSD 4.0 1001931 Although the present invcntion has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible.
Therefore the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification.

Claims (76)

1. A process for preparing a chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine comprising:
heating a solution comprising an entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine of general formula (1):

wherein:
R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the above-mentioned phenyl nuclei may be substituted by 1 or 2 halogen atoms;
R2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms;
R3 represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, R4 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; and at least one or R1, R2, R3 or R4 is a hydrogen in an organic solvent;
adding to the heated solution propyl sulfonate or a propyl halide to form a reaction mixture; and reacting the reaction mixture.

2. The process of claim 1, wherein the propyl sulfonate is selected from n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof.

3. The process of claim 1, wherein the propyl halide is selected from n-propyl bromide, n-propyl chloride, n-propyl iodide and combinations thereof.

4. The process of claim 1, wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than 97% chirally pure.

5. The process of claim 1, wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least greater than 99% chirally pure.

6. The process of claim 1, wherein the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is at least 99.9% chirally pure.

7. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than 98%.

8. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than 99%.

9. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is greater than 99.99%.

10. The process of claim 1, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.

11. The process of claim 1, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is substantially free of achiral salts.

12. The process of claim 1, wherein the substituted 4,5,6.7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.

13. The process of claim 1, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.

14. The process of claim 1, wherein the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole is enriched for (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

15. The process of claim 1, wherein the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine is enriched for (6S) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine is (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

16. The process of claim 1, wherein the entantiomerically enriched 4,5,6,7-tetrahydro-benzothiazole diamine comprises a mixture of (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine comprises a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

17. The process of claim 16, wherein the mixture is a racemic mixture.

18. The process of claim 16, wherein the enantiomerically enriched mixture comprises a ratio of greater than about 1:4 (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine to about 4:1 (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine.

19. The process of claim 1, wherein the solvent is selected from a organic solvent and a organic solvent mixed with water.

20. The process of claim 1, wherein the solvent is selected from ethanol, 1-propanol, i-propanol, n-butanol, i-butanol, dihydrofuran, dimethylformamide, dimethyl, dimethylacetamide, hexamethylphosphoric triamide or mixtures or hydrates thereof.

21. The process of claim 1, wherein the steps of heating and reacting each independently comprise stirring.

22. The process of claim 1, wherein the steps of heating, adding and reacting are each independently carried out at a temperature of from about 50° C to about 125° C.

23. The process of claim 1, further comprising cooling the reaction mixture to a temperature of about 25°C after the step of reacting.

24. The process of claim 1, wherein the step of adding is carried out for up to about 2 hours.

25. The process of claim 1, further comprising recovering the chirally purified substituted 4,5,6,7-tetrahydro-benzothiazole diamine.

26. The process of claim 25, wherein recovering comprises one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

27. The process of claim 1, wherein about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide is added.

28. A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:
heating a solution comprising 4,5,6,7-tetrahydro-benzothiazole diamine;
adding a propyl halide or a propyl sulfonate to the heated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture;
reacting the reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

29. The process of claim 28, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than 97% chirally pure.

30. The process of claim 28, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than 99% chirally pure.

31. The process of claim 28, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least 99.9% chirally pure.

32. The process of claim 28, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than 99%.

33. The process of claim 28, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than 99.9%.

34. The process of claim 28, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than 99.99%.

35. The process of claim 28, wherein the chemical purity of the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is 100%.

36. The process of claim 28, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine is substantially free of achiral salts.

37. The process of claim 28, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 1.5 ppm of achiral salts.

38. The process of claim 28, wherein the substituted 4,5,6,7-tetrahydro-benzothiazole diamine contains less than 2.5 ppb of achiral salts.

39. The process of claim 28, wherein the 4,5,6,7-tetrahydro-benzothiazole diamine is (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

40. The process of claim 28, wherein the 4,5,6,7-tetrahydro-benzothiazole diamine is (6S) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

41. The process of claim 28, wherein the 4,5,6,7-tetrahydro-benzothiazole diamine comprises a mixture of (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprises a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine.

42. The process of claim 41, wherein the mixture is a racemic mixture.

43. The process of claim 41, wherein the mixture comprises a ratio of greater than about 1:4 (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine to about 4:1 (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine.

44. The process of claim 28, wherein reacting comprises stirring the reaction mixture for up to about 12 hours at from about 50° C to about 125° C.

45. The process of claim 28, wherein the steps of heating, adding and reacting are each independently carried out at a temperature of from about 50° C to about 125° C.

46. The process of claim 28, wherein the steps of heating, adding and reacting each independently comprise stirring.

47. The process of claim 28, wherein recovering comprises stirring the reaction mixture for at least about 2 hours.

48. The process of claim 28, wherein recovering comprises one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

49. Chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process comprising:
heating a solution comprising 4,5,6,7-tetrahydro-benzothiazole diamine;
adding a propyl halide or a propyl sulfonate to the heated solution slowly over from about 0.5 hours to about 2 hours to form a reaction mixture;
reacting the reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

50. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the propyl sulfonate is selected from n-propyl tosylate, n-propyl methoxysulfonate and combinations thereof.

51. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the propyl halide is selected from n-propyl bromide, n-propyl chloride, n-propyl fluoride, n-propyl iodide and combinations thereof.

52. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than 97% chirally pure.

53. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least greater than 99% chirally pure.

54. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is at least 99.9% chirally pure.

55. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than 99%.

56. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than 99.9%.

57. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the chemical purity of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is greater than 99.99%.

58. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the 4,5,6,7-tetrahydro-benzothiazole diamine comprises a mixture of (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine and the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprises a mixture of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and S(+) 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

59. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 58, wherein the mixture is a racemic mixture.

60. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 58, wherein the mixture comprises a ratio of greater than about 4:1 (6R) 4,5,6,7-tetrahydro-benzothiazole diamine and (6S) 4,5,6,7-tetrahydro-benzothiazole diamine.

61. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the solvent is selected from an organic solvent and an organic solvent mixed with water.

62 62. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 61, wherein the organic solvent is selected from ethanol, 1-propanol, n-butanol, dihydrofuran, dimethylformamide, dimethyl, dimethylacetamide, hcxamethylphosphoric triamide or mixtures or hydrates thereof.

63. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the steps of heating, reacting and cooling each independently comprise stirring.

64. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein the steps of heating, adding and reacting are each independently carried out at a temperature of from about 50° C
to about 125° C.

65. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, further comprising cooling the reaction mixture to a temperature of about 25° C after the step of reacting.

66. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein recovering comprises one or more steps selected from filtering the mixture to isolate a precipitate, washing a precipitate, and drying a precipitate.

67. The chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole of claim 49, wherein about 1.0 to about 2.0 molar equivalents of the propyl sulfonate or propyl halide is added.

68. A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:
dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution;
heating the solution to from about 50° C to about 125° C;
adding an acid to the solution to form a reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

69. The process of claim 68, wherein about 1 molar equivalent to about 4 molar equivalents of the acid is added.

70. The process of claim 68, wherein recovering comprises one or more steps selected from:
cooling the reaction mixture to a temperature of about 25° C;
stirring the reaction mixture for at least about 2 hours;

filtering the mixture to isolate a precipitate;
washing a precipitate; and drying a precipitate.

71. A chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process of claim 70.

72. A process for preparing chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole comprising:
dissolving entantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in an organic solvent to form a solution;
heating the solution to from about 50° C to about 125° C;
adding an achiral salt to the solution to form a reaction mixture; and recovering the chirally purified 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.

73. The process of claim 72, wherein about 1 molar equivalent to about 4 molar equivalents of the achiral salt is added.

74. The process of claim 72, wherein recovering comprises one or more steps selected from:
cooling the reaction mixture to a temperature of about 25° C;
stirring the reaction mixture for at least about 2 hours;
filtering the mixture to isolate a precipitate;
washing a precipitate; and drying a precipitate.

75. A chirally pure 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole prepared by a process of claim 72.

76. A process for preparing a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride comprising:
dissolving a 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt in an organic solvent to form a solution;
cooling the solution to a temperature of from about 0° C to about 5° C;
adding concentrated HCl and an organic solvent to the cooled solution; and stirring the solution at a temperature of about 0° C to about 5°
C.