WO1998025902A1 - The preparation of enantiomerically-enriched threo-methylphenidate - Google Patents
The preparation of enantiomerically-enriched threo-methylphenidate Download PDFInfo
- Publication number
- WO1998025902A1 WO1998025902A1 PCT/GB1997/003418 GB9703418W WO9825902A1 WO 1998025902 A1 WO1998025902 A1 WO 1998025902A1 GB 9703418 W GB9703418 W GB 9703418W WO 9825902 A1 WO9825902 A1 WO 9825902A1
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- WO
- WIPO (PCT)
- Prior art keywords
- process according
- methylphenidate
- acid
- crystallisation
- threo
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- This invention relates to processes for the preparation of enantiomerically-enriched f ⁇ re ⁇ -methylphenidate, and in particular to bioresolution, to the separation of the enantiomers of acid addition salt forms of tAre ⁇ -methylphenidate, and to the enhancement of enantiomeric excess (ee) of one enantiomer in a mixture.
- Methylphenidate is a therapeutic agent that is widely used in the treatment of attention-deficient hyperactivity disorder. It is a controlled substance.
- Methylphenidate was first prepared as a mixture of the erythro and threo racemates.
- US-A-2957880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo disastereoisomer. It is now considered that it is the d-threo [or (R,R)) enantiomer that has the preferred therapeutic activity. Uses of this enantiomer are disclosed in WO-A-9703671, WO-A-9703672 and WO-A-9703673, the contents of which are incorporated herein by reference.
- WO-A-9727176 and WO-A-9732851 disclose that the resolution of methylphenidate has also been achieved, more economically, using either O,O '- diaroyltartaric acids or menthoxyacetic acid. These resolutions provide d-threo- methylphenidate in high ee and chemical purity, e.g. containing less than 2% w/w of resolving agent and/or ritalinic acid.
- racemate and single enantiomers of a salt of a chiral compound such as t ⁇ reo-methylphenidate have different solid-state crystalline forms.
- Such a salt will have an enantiomeric composition which corresponds to its point of maximum solubility (the eutectic composition), and this is dependent upon the solubility of the racemic salt and the single enantiomer salt.
- the solubility ratio ⁇ is given by the ratio of the solubility of the racemate salt divided by the solubility of the single enantiomer salt.
- One aspect of the present invention is based upon the discovery that certain crystalline salts of t/re ⁇ -methylphenidate, wherein the counterion is achiral, allow for the enhancement of enantiomeric excess (ee) by recrystallisation/crystallisation of partially enriched material in a suitable solvent.
- certain salts of the single enantiomer showed much lower solubility than the corresponding racemate in methanol/TBME (tert-butyl methyl ether).
- a second aspect of the present invention is based on the discovery that (R,R)- methylphenidate (1) can be conveniently obtained by means of biocatalytic resolution of a racemic compound of formula 2 (of which one enantomer is shown, for convenience), using a range of hydrolase enzymes.
- crystallisation can be used to give essentially enantiopure t ⁇ re ⁇ -methylphenidate.
- the starting material should be enantiomerically enriched above the eutectic point of the t ⁇ reo-methylphenidate salt.
- the eutectic point has been measured to be 25% ee by solubility. That is to say, t//reo-methylphenidate.HCl salt with a composition of enantiomers greater than 25% ee will, by crystallisation, yield enriched material.
- tAre ⁇ -methylphenidate salts of significantly lower enantiomeric purity in the range 25-95%, preferably 50-95%, and more preferably 70-95%, can be usefully enriched by direct crystallisation.
- the process of the invention is therefore of considerable utility with a feedstock of t ireo-methylphenidate of moderate enantiomeric purity, for example following classical resolution.
- Any resolving agent that may be present can be removed, e.g. to a level of 2% w/w or below, e.g. no more than 0.5 or 1% w/w.
- the novel crystallisation process can be used in combination with the novel biocatalytic resolution.
- the novel bioresolution encompasses the following embodiments:
- bioresolution process of the present invention provides a number of benefits, including mild reaction conditions (ambient temperature, low environmental impact), cost savings by avoidance of stoichiometric resolving agents, and easier processing (e.g. simple solvent partitioning in selected cases instead of salt cracking).
- suitable biocatalysts can readily be identified. It is preferred that the biocatalyst provides a sufficient degree of optical enrichment that the desired product can be used effectively, e.g. at least 20%, preferably at least 40% , and more preferably at least 50% , ee, up to substantially single enantiomer product, e.g. at least 80% or 90% ee.
- novel crystallisation process is also useful to enhance the ee of material of high ee, e.g. at least 95% ee, if that has been produced in chemically-pure form, using a more efficient resolving agent for this purpose than l, -binaphthyl-2,2'-diyl hydrogen phosphate.
- a more efficient resolving agent for this purpose than l, -binaphthyl-2,2'-diyl hydrogen phosphate.
- the solvent that is used in the invention can readily be chosen by those of ordinary skill in the art.
- the solvent should be sufficiently polar, e.g. an alcohol, optionally together with another solvent such as an ether.
- An aprotic solvent such as acetonitrile or acetone can also be used.
- a mixture of methanol and TBME is preferred.
- the salt used in the invention may have the formula
- HX is any achiral acid that forms a suitable salt.
- the suitability of any salt for use in the invention is readily tested in a crystallisation procedure by one of ordinary skill in the art.
- HX is preferably a hydrohalide, and X is more preferably Br or Cl.
- racemic £ /-t »reo-methylphenidate.HCl (1.0 g) was suspended in 10 ml of 1 : 1 methanol:TBME (7.4 g) and stirred at 25°C for 16 hours. The solid material was collected by filtration, washing the reaction vessel with 10 ml TMBE. This gave 0.640 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.340 g of a white solid. i//-t ⁇ reo-methylphenidate.HCl therefore has a solubility of 34 mg per ml of 1 : 1 MeOH:TBME at 25°C.
- the enrichment procedure may also be effected by simply treating a solution of //weo-methylphenidate free base above the eutectic point (>25% ee) with hydrogen chloride in methanol, and isolating the resultant precipitate.
- Table 2 The results of a series of experiments are given in Table 2.
- Example 1 95% - d-threo 99.0% (90%) 36.5% (6%) The following Examples illustrate the present invention more specifically.
- Example 1 95% - d-threo 99.0% (90%) 36.5% (6%)
- Suitable enzymes for the bioresolution were identified by the following screening protocol: 100 mg of racemic tftre ⁇ -methylphenidate (free base) was dissolved in 100 mM phosphate buffer adjusted to pH 7. Approximately 50 mg (or equivalent ml) of each candidate enzyme was added and the reactions incubated at 30 °C for 24 hours with gentle agitation. For assaying purposes, 40 ⁇ l of the reaction mixture was dispensed into a vial and allowed to evaporate over KOH in a desiccator overnight. The residue was then dissolved in 1 ml IPA/2% diethylamine solution and undissolved material removed by centrifugation.
- the reaction mixture was then heated at reflux for 5 minutes. After this 30 ml TMBE was added to the reaction mixture which was cooled over one hour to room temperature, and finally at 0°C for 1 hour. The solid material was collected by filtration, washing the reaction vessel with 30 ml TMBE. This gave 13.50 g (77.8%) of solid precipitate, with an enantiomeric excess of 97.8%. The mother liquors were evaporated to dryness to give 3.60 g of a yellow/orange solid (20.7%), with an enantiomeric excess of 32.1%.
- Example 7 ⁇ i-t 7reo-methylphenidate enriched in the ./-enantiomer (91.3% ee) 11.50 g was taken up in 23 ml of methanol, and stirred at 40-50°C whilst bubbling hydrogen chloride gas through the reaction mixture for 10 minutes. The reaction mixture was then heated at reflux for 5 minutes. After this 23 ml TMBE was added to the reaction mixture which was cooled over one hour to room temperature, and finally at 0°C for 1 hour. The solid material was collected by filtration, washing the reaction vessel with 23 ml TMBE. This gave 10.60 g (79.7%) of solid precipitate, with an enantiomeric excess of 99.2%. The mother liquors were evaporated to dryness to give 2.50 g of a white solid (18.8%), with an enantiomeric excess of 43.6%.
- the resultant racemic i//-tAre ⁇ -methylphenidate.HBr (0.500 g) was suspended in 5 ml of 1: 1 methanol:TBME (3.80 g) and stirred at 25°C for 16 hours. The solid material was collected by filtration. This gave 0.355 g of solid precipitate. The mother liquors were evaporated to dryness to give 0.140 g of a white solid. /-t/7re ⁇ -methylphenidate.HBr therefore has a solubility of 28 mg per ml of 1 : 1 MeOH:TBME at 25°C.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0001604A HUP0001604A3 (en) | 1996-12-13 | 1997-12-11 | The preparation of an enantiomerically-enriched threo-methylphenidate |
AU78470/98A AU7847098A (en) | 1996-12-13 | 1997-12-11 | The preparation of enantiomerically-enriched threo- methylphenidate |
PL97334136A PL334136A1 (en) | 1996-12-13 | 1997-12-11 | Method of obtaining enantiomerically enriched methyl threophenidate |
JP52637898A JP2001506621A (en) | 1996-12-13 | 1997-12-11 | Preparation of enantiomerically enriched threo-methylphenidate |
CA002272373A CA2272373A1 (en) | 1996-12-13 | 1997-12-11 | The preparation of enantiomerically-enriched threo-methylphenidate |
EP97949034A EP0948484A1 (en) | 1996-12-13 | 1997-12-11 | The preparation of enantiomerically-enriched threo-methylphenidate |
NO992875A NO992875L (en) | 1996-12-13 | 1999-06-11 | Preparation of enantiomerically enriched threo-methylphenidate |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9625972.6A GB9625972D0 (en) | 1996-12-13 | 1996-12-13 | Bioresolution |
GB9625972.6 | 1996-12-13 | ||
GB9712298.0 | 1997-06-12 | ||
GBGB9712298.0A GB9712298D0 (en) | 1997-06-12 | 1997-06-12 | Crystallisation |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998025902A1 true WO1998025902A1 (en) | 1998-06-18 |
Family
ID=26310627
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1997/003418 WO1998025902A1 (en) | 1996-12-13 | 1997-12-11 | The preparation of enantiomerically-enriched threo-methylphenidate |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0948484A1 (en) |
JP (1) | JP2001506621A (en) |
AU (1) | AU7847098A (en) |
CA (1) | CA2272373A1 (en) |
CZ (1) | CZ206299A3 (en) |
HU (1) | HUP0001604A3 (en) |
NO (1) | NO992875L (en) |
PL (1) | PL334136A1 (en) |
WO (1) | WO1998025902A1 (en) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6025502A (en) * | 1999-03-19 | 2000-02-15 | The Trustees Of The University Of Pennsylvania | Enantopselective synthesis of methyl phenidate |
US6100401A (en) * | 1998-04-20 | 2000-08-08 | Novartris Ag | Process for preparing the d-threo isomer of methylphenidate hydrochloride |
US6127385A (en) * | 1999-03-04 | 2000-10-03 | Pharmaquest Limited | Method of treating depression using l-threo-methylphenidate |
US6162919A (en) * | 1998-12-03 | 2000-12-19 | Novartis Ag | Process for preparing the d-threo isomer of methylphenidate hydrochloride |
EP1163907A1 (en) * | 2000-06-17 | 2001-12-19 | Pharmaquest Limited | Use of l-threo-methylphenidate for the treatment of depression |
US6395752B1 (en) * | 1999-03-04 | 2002-05-28 | Pharmaquest Limited | Method of treating depression using 1-threo-methylphenidate |
EP1292305A1 (en) * | 2000-04-12 | 2003-03-19 | THE McLEAN HOSPITAL CORPORATION | METHOD OF DOPAMINE INHIBITION USING i L-THREO /i -METHYLPHENIDATE |
WO2004080959A2 (en) * | 2003-03-07 | 2004-09-23 | Isp Investments Inc. | Process for the preparation of dexmethylphenidate hydrochloride |
US7115631B2 (en) | 1995-12-04 | 2006-10-03 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
US7897777B2 (en) | 2007-01-05 | 2011-03-01 | Archimica, Inc. | Process of enantiomeric resolution of D,L-(±)-threo-methylphenidate |
WO2012080834A1 (en) | 2010-12-17 | 2012-06-21 | Rhodes Technologies | Low-temperature synthesis of methylphenidate hydrochloride |
US8552030B2 (en) | 2009-05-07 | 2013-10-08 | Malladi Drugs & Pharmaceuticals Ltd. | Process for the preparation of d-threo-ritalinic acid hydrochloride by resolution of dl-threo-ritalinic acid using chiral carboxylic acid |
US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9028868B2 (en) | 2011-03-23 | 2015-05-12 | Ironshore Pharmaceuticals & Development, Inc. | Methods and compositions for treatment of attention deficit disorder |
US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9233924B2 (en) | 2014-03-11 | 2016-01-12 | Ampac Fine Chemicals Llc | Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof |
US9283214B2 (en) | 2011-03-23 | 2016-03-15 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US10081597B2 (en) | 2014-06-27 | 2018-09-25 | Embio Limited | Process for preparation of dexmethylphenidate hydrochloride |
US10292937B2 (en) | 2011-03-23 | 2019-05-21 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US10905652B2 (en) | 2011-03-23 | 2021-02-02 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US11241392B2 (en) | 2011-03-23 | 2022-02-08 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02190195A (en) * | 1989-01-19 | 1990-07-26 | Rikagaku Kenkyusho | Production of optically active propionic acid ester compound |
EP0387068A1 (en) * | 1989-03-08 | 1990-09-12 | Wisconsin Alumni Research Foundation | Improving the enantioselectivity of biocatalytic resolution of racemic compounds |
EP0623678A2 (en) * | 1993-04-22 | 1994-11-09 | Shionogi & Co., Ltd. | Norbornane type ester hydrolase |
WO1995003421A1 (en) * | 1993-07-19 | 1995-02-02 | Dsm N.V. | Process for the enzymatic preparation of optically active n-substituted-3-pyrrolidinol |
EP0687736A1 (en) * | 1994-06-15 | 1995-12-20 | Basf Aktiengesellschaft | Method for the preparation of enantiomerically pure lactams |
-
1997
- 1997-12-11 AU AU78470/98A patent/AU7847098A/en not_active Abandoned
- 1997-12-11 CA CA002272373A patent/CA2272373A1/en not_active Abandoned
- 1997-12-11 JP JP52637898A patent/JP2001506621A/en active Pending
- 1997-12-11 HU HU0001604A patent/HUP0001604A3/en unknown
- 1997-12-11 EP EP97949034A patent/EP0948484A1/en not_active Withdrawn
- 1997-12-11 WO PCT/GB1997/003418 patent/WO1998025902A1/en not_active Application Discontinuation
- 1997-12-11 CZ CZ992062A patent/CZ206299A3/en unknown
- 1997-12-11 PL PL97334136A patent/PL334136A1/en unknown
-
1999
- 1999-06-11 NO NO992875A patent/NO992875L/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02190195A (en) * | 1989-01-19 | 1990-07-26 | Rikagaku Kenkyusho | Production of optically active propionic acid ester compound |
EP0387068A1 (en) * | 1989-03-08 | 1990-09-12 | Wisconsin Alumni Research Foundation | Improving the enantioselectivity of biocatalytic resolution of racemic compounds |
EP0623678A2 (en) * | 1993-04-22 | 1994-11-09 | Shionogi & Co., Ltd. | Norbornane type ester hydrolase |
WO1995003421A1 (en) * | 1993-07-19 | 1995-02-02 | Dsm N.V. | Process for the enzymatic preparation of optically active n-substituted-3-pyrrolidinol |
EP0687736A1 (en) * | 1994-06-15 | 1995-12-20 | Basf Aktiengesellschaft | Method for the preparation of enantiomerically pure lactams |
Non-Patent Citations (3)
Title |
---|
DATABASE WPI Section Ch Week 9036, Derwent World Patents Index; Class B05, AN 90-271113, XP002059042 * |
PATRICK K S ET AL: "PHARMACOLOGY OF THE ENANTIOMERS OF THREO-METHYLPHENIDATE", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 241, no. 1, April 1987 (1987-04-01), pages 152 - 158, XP000602302 * |
SHIEH W -C ET AL: "ASYMMETRIC TRANSFORMATION OF EITHER ENANTIOMER OF NARWEDINE VIA TOTAL SPONTANEOUS RESOLUTION PROCESS A CONCISE SOLUTION TO THE SYNTHESIS OF (-)-GALANTHAMINE", JOURNAL OF ORGANIC CHEMISTRY, vol. 59, no. 18, 9 September 1994 (1994-09-09), pages 5463 - 5465, XP000562837 * |
Cited By (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7115631B2 (en) | 1995-12-04 | 2006-10-03 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
US6100401A (en) * | 1998-04-20 | 2000-08-08 | Novartris Ag | Process for preparing the d-threo isomer of methylphenidate hydrochloride |
US6162919A (en) * | 1998-12-03 | 2000-12-19 | Novartis Ag | Process for preparing the d-threo isomer of methylphenidate hydrochloride |
US6127385A (en) * | 1999-03-04 | 2000-10-03 | Pharmaquest Limited | Method of treating depression using l-threo-methylphenidate |
US6395752B1 (en) * | 1999-03-04 | 2002-05-28 | Pharmaquest Limited | Method of treating depression using 1-threo-methylphenidate |
US6025502A (en) * | 1999-03-19 | 2000-02-15 | The Trustees Of The University Of Pennsylvania | Enantopselective synthesis of methyl phenidate |
EP1292305A1 (en) * | 2000-04-12 | 2003-03-19 | THE McLEAN HOSPITAL CORPORATION | METHOD OF DOPAMINE INHIBITION USING i L-THREO /i -METHYLPHENIDATE |
EP1292305A4 (en) * | 2000-04-12 | 2004-04-07 | Mclean Hospital Corp | METHOD OF DOPAMINE INHIBITION USING i L-THREO /i -METHYLPHENIDATE |
EP1163907A1 (en) * | 2000-06-17 | 2001-12-19 | Pharmaquest Limited | Use of l-threo-methylphenidate for the treatment of depression |
WO2004080959A2 (en) * | 2003-03-07 | 2004-09-23 | Isp Investments Inc. | Process for the preparation of dexmethylphenidate hydrochloride |
WO2004080959A3 (en) * | 2003-03-07 | 2004-11-25 | Isp Investments Inc | Process for the preparation of dexmethylphenidate hydrochloride |
US7897777B2 (en) | 2007-01-05 | 2011-03-01 | Archimica, Inc. | Process of enantiomeric resolution of D,L-(±)-threo-methylphenidate |
US8552030B2 (en) | 2009-05-07 | 2013-10-08 | Malladi Drugs & Pharmaceuticals Ltd. | Process for the preparation of d-threo-ritalinic acid hydrochloride by resolution of dl-threo-ritalinic acid using chiral carboxylic acid |
EP2937336A1 (en) | 2010-12-17 | 2015-10-28 | Rhodes Technologies | Low-temperature synthesis of methylphenidate hydrochloride |
WO2012080834A1 (en) | 2010-12-17 | 2012-06-21 | Rhodes Technologies | Low-temperature synthesis of methylphenidate hydrochloride |
US9475770B2 (en) | 2010-12-17 | 2016-10-25 | Rhodes Technologies | Low-temperature synthesis of methylphenidate hydrochloride |
US9511032B2 (en) | 2011-03-23 | 2016-12-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
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US9573896B2 (en) | 2014-03-11 | 2017-02-21 | Ampac Fine Chemicals Llc | Methods for preparing d-threo-methylphenidate using diazomethane, and compositions thereof |
US9233924B2 (en) | 2014-03-11 | 2016-01-12 | Ampac Fine Chemicals Llc | Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof |
US10081597B2 (en) | 2014-06-27 | 2018-09-25 | Embio Limited | Process for preparation of dexmethylphenidate hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
AU7847098A (en) | 1998-07-03 |
NO992875D0 (en) | 1999-06-11 |
NO992875L (en) | 1999-06-14 |
HUP0001604A3 (en) | 2003-03-28 |
EP0948484A1 (en) | 1999-10-13 |
CZ206299A3 (en) | 1999-09-15 |
CA2272373A1 (en) | 1998-06-18 |
HUP0001604A2 (en) | 2000-10-28 |
JP2001506621A (en) | 2001-05-22 |
PL334136A1 (en) | 2000-02-14 |
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