CN100430405C - Processes for preparing calcium salt forms of statins - Google Patents

Processes for preparing calcium salt forms of statins Download PDF

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CN100430405C
CN100430405C CNB028159993A CN02815999A CN100430405C CN 100430405 C CN100430405 C CN 100430405C CN B028159993 A CNB028159993 A CN B028159993A CN 02815999 A CN02815999 A CN 02815999A CN 100430405 C CN100430405 C CN 100430405C
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fland
spit
calcium
atorvastatin
ester derivative
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CN1543468A (en
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V·尼达姆-希尔德希姆
R·里斯茨-里伦
R·里多尔-哈达斯
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Teva Pharmaceutical Industries Ltd
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—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
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Processes for preparing a calcium salt of a statin from an ester derivative or protected ester derivative of the statin by using calcium hydroxide are provided. The ester or protected ester derivative is contacted with calcium hydroxide to obtain the calcium salt. Preferred statins are rosuvastatin, pitavastatin and atorvastatin, simvastatin and lovastatin. In processes beginning with a protected satin ester derivative, the protecting group is hydrolyzed during salt formation by contact with calcium hydroxide, or is contacted with an acid catalyst followed by contact with calcium hydroxide.

Description

The method of the calcium salt forms of preparation Statins
The cross-reference of related application
The application requires the provisional application 60/312 of proposition on August 16 calendar year 2001, the u.s. patent application serial number 10/037 that No. 812 and October 24 calendar year 2001 propose, No. 412 (it has required the provisional application 60/249 of proposition on November 16th, 2000, No. 319 rights and interests) rights and interests, this paper is all incorporated in all these applications by reference into.
Invention field
The present invention relates to prepare the method for the Statins of calcium salt forms.
Background of invention
A class medicine that is called his spit of fland is to have the most effective medicine in the treatment of low-density lipoprotein (LDL) granule density in patient's blood flow of cardiovascular diseases danger for reduction at present, so Statins can be used for treating hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.LDL level high in the blood flow also can cause angiorrhexis and impel the formation of thrombotic crown infringement (coronary lesions) relevant with plug flow.Referring to " the Pharmacological Basis of Therapeutics " of Goodman and Gilman, 879 pages (the 9th edition, 1996).
Statins suppresses the biosynthesizing of cholesterol in the human body by competitive inhibition 3-hydroxy-3-methyl-glutaryl coenzyme A (" HMG-CoA ") reductase enzyme.HMG-CoA reductase enzyme catalysis HMG is to the conversion of mevalonic acid, and that this is a rate determining step in the cholesterol biosynthesizing is rapid.The generation that reduces cholesterol causes the increase of ldl receptor number in the blood flow and the reduction of corresponding LDL concentration.The reduction of LDL level has alleviated the danger of coronary artery disease in the blood flow.Referring to J.A.M.A.1984,251,351-74.
The available Statins comprises lovastatin, Simvastatin, Pravastatin, fluvastatin, Cerivastatin and atorvastatin at present.Lovastatin (being disclosed in United States Patent (USP) 4,231,938) and Simvastatin (ZOCOR; Be disclosed in United States Patent (USP) 4,444,784 and WO00/53566) with the lactone form administration.After the absorption, lactonic ring is opened by chemical hydrolysis or enzymatic hydrolysis in liver, and produces active hydroxy acid.Pravastatin (PRAVACHOL; Be disclosed in United States Patent (USP) 4,346, No. 227) as the sodium salt administration.Fluvastatin (LESCOL; Be disclosed in United States Patent (USP) 4,739, No. 073) and Cerivastatin (be disclosed in United States Patent (USP) 5,006,530 and 5,177, No. 080) also with the sodium-salt form administration, it is synthetic compound fully, and is different with the such epiphyte product part that contains a hexahydro naphthalene ring on the structure." super he spit of fland (superstatin) " superstatin that atorvastatin and two kinds are new and pitavastatin are with the calcium salt forms administration.These his structural formulas in spit of fland are as follows:
Figure C0281599900071
Lovastatin Simvastatin Pravastatin
Figure C0281599900072
The fluvastatin Cerivastatin
Figure C0281599900073
Atorvastatin superstatin pitavastatin
Atorvastatin is [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dihydroxyl-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-the universalization formal name used at school of 1H-pyrroles-1-enanthic acid.The atorvastatin free acid is easy to lactonize.The cycle chemistry of atorvastatin lactone is called (2R-is anti-)-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-phenylbenzene-1-[2-tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl] ethyl]-the 1H-pyrrole-3-carboxamide.Atorvastatin and its corresponding racemize lactone are disclosed in United States Patent (USP) 4,681,893.
Described lactone form is disclosed in United States Patent (USP) 5,273, No. 995.In the embodiment 4 and 5 of ' 995 patents, described lactone is prepared as follows: with (R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-yl]-5-hydroxyl-3-oxo-1-enanthic acid 1,1-dimethyl ethyl ester is dissolved in tetrahydrofuran (THF) and the triethylborane, then adds tertiary butyl formic acid.After the cooling, add methyl alcohol and then add sodium borohydride.Mixture is poured in ice/hydrogen peroxide/water mixture.Add trichloromethane and mixture is distributed.Organic layer is through dried over mgso, filtration and solvent evaporated.Be dissolved in product in tetrahydrofuran (THF) and the methyl alcohol and join in the sodium hydroxide solution.Mixture concentrated remove organic solvent, be added to the water and use extracted with diethyl ether.Water layer is with hcl acidifying and use ethyl acetate extraction.Organic layer is through anhydrous magnesium sulfate drying, filtration and solvent evaporated.Be dissolved in the toluene residue also concentrated.With product from ethyl acetate and hexane recrystallization and produce lactone.
Described lactone also can be according to being disclosed in United States Patent (USP) 5,003, the method preparation in No. 080.For example, in embodiment 2 method A, with suitable-2-(4-fluorophenyl)-β, δ-dihydroxyl-5-(1-methylethyl)-3-phenyl-4-(phenyl amino) carbonyl-1H-pyrroles-1-Methylheptanoate sodium-hydroxide treatment, and dilute with water with separate after, with rest layers with the washing of hexane and ethyl acetate and then wash with concentrated hydrochloric acid solution.After the separation, the upper strata also concentrates with the salt acid elution.Residue is dissolved in the toluene.
In ' 080 patent disclosed, lactone also can pass through (±)-suitable-6-(2-amino-ethyl)-2,2-dimethyl-1,3-diox-4-acetate (embodiment 2, method B); (±)-(2 α, 4 α, 6 α) or (±)-(2 α, 4 β, 6 β)-6-(2-amino-ethyl)-2-phenyl-1,3-diox-4-acetate (embodiment 2, method C); (±)-suitable-9-(2-amino-ethyl)-6,10-dioxo spiro [4.5] decane-7-acetate (embodiment 2, method D); (±)-suitable-(4-(2-amino-ethyl)-1,5-dioxo spiro [5.5] undecane-2-acetate (embodiment 2, method E); Or (±)-(2 α, 4 α, 6 α) or (±)-(2 α, 4 β, 6 β)-6-(2-amino-ethyl)-2-methyl isophthalic acid, 3-diox-4-acetate (embodiment 2, method F or G) and (±)-4-fluoro-α-[2-methyl isophthalic acid-oxopropyl]-γ-oxo-N, β-diphenyl benzene butyramide mixes in dimethyl sulfoxide (DMSO) and prepares.After the heating, solution is poured in the mixture of ether and saturated aqueous ammonium chloride.After the separation, organic layer water and sodium hydroxide washing.Water layer is with the dilute hydrochloric acid acidifying and use ethyl acetate extraction, to wherein adding hydrochloric acid and with solution concentration.Residue is dissolved in the toluene.
According to ' 080 patent, the another kind of method for preparing lactone comprises (±)-suitable-1,1-dimethyl ethyl-6-(2-amino-ethyl)-2,2-dimethyl-1,3-diox-4-acetic ester (embodiment 2, method H); (±)-(2 α, 4 α, 6 α) or (±)-(2 α, 4 β, 6 β)-1,1-dimethyl-6-(2-amino-ethyl)-2-phenyl-1,3-diox-4-acetic ester (embodiment 2, method I); Or (±)-suitable-1,1-dimethyl ethyl-(4-(2-amino-ethyl)-1,5-dioxo spiro [5.5] undecane-(embodiment 2 for the 2-acetic ester, method J) with (±)-4-fluoro-α-[2-methyl isophthalic acid-oxopropyl]-γ-oxo-N, β-diphenyl benzene butyramide is at heptane: mixing in toluene (9: 1).After the heating, solution is poured in the mixture of tetrahydrofuran (THF) and aqueous ammonium chloride solution.After the separation, organic layer salt water washing then adds hydrochloric acid.After the stirring, sodium hydroxide is joined in the organic layer.By adding the mixture stopped reaction of entry and hexane.After the separation, water layer dilute hydrochloric acid acidifying is with ethyl acetate extraction and concentrated.Residue is dissolved in the toluene.
Described lactone or free acid can be used for preparing pharmaceutically acceptable calcium salt [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dihydroxyl-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-Calcium salt enanthate (2: 1) trihydrate.In animal model, the atorvastatin calcium salt demonstrates by suppressing HMG-CoA reductase enzyme and synthetic plasma cholesterol and the lipoprotein levels of reducing of cholesterol in the liver.Atorvastatin with half calcium salt trihydrate forms by PFIZER with the trade(brand)name of LIPITOR with 10,20,40 and the 80mg tablet introduce to the market.Atorvastatin hemi-calcium salt has following structure:
Figure C0281599900091
Atorvastatin hemi-calcium salt
Described half calcium salt is disclosed in United States Patent (USP) 5,273, No. 995, described patent point out calcium salt can by with the transposition of calcium chloride and sodium salt from salt brine solution crystallization and be further purified through recrystallization from 5: 3 ethyl acetate and hexanes mixtures obtain.
United States Patent (USP) 5,298 also discloses the method for preparing half calcium salt No. 627.In the embodiment 1 of this patent, with (4R-is suitable)-1-[2-[6-[2-(diphenyl amino)-2-oxoethyl]-2,2-dimethyl-1,3-diox-4-yl] ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-phenylbenzene-1H-pyrrole-3-carboxamide is dissolved in the methyl alcohol and with hydrochloric acid reaction and forms [R-(R *, R *)]-5-(4-fluorophenyl)-β, δ-dihydroxyl-2-(1-methylethyl)-N, N, 4-triphenyl-3-[(phenyl amino) carbonyl]-1H-pyrroles-1-heptamide, it mixes with methyl alcohol and sodium hydroxide.Filtrate is washed with tertiary butyl methyl ester, and water layer forms [R-(R with the aqueous hydrochloric acid acidifying and with the extraction of tertiary butyl methyl ester *, R *)]-2-(4-fluorophenyl)-β, δ-dihydroxyl-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-sodium salt of 1H-pyrroles-1-enanthic acid.By adding the lime acetate aqueous solution sodium salt is changed into half calcium salt.
In a kind of similar approach, (4R-is suitable)-6-(2-amino-ethyl)-2,2-dimethyl-N, N-two (phenyl methyl)-1,3-diox-4-ethanamide is converted to [R-(R *, R *)]-5-(4-fluorophenyl)-β, δ-dihydroxyl-2-(1-methylethyl)-4-phenyl-3-[(phenyl amino) carbonyl]-N, N-two (phenyl methyl)-1H-pyrroles-1-heptamide, it further is converted to half calcium salt (embodiment 2); (4R-is suitable)-6-(2-amino-ethyl)-N, N-diethyl-2,2-dimethyl-1,3-diox-4-ethanamide is converted to [R-(R *, R *)]-N, N-diethyl-5-(4-fluorophenyl)-β, δ-dihydroxyl-2-(1-methylethyl)-4-phenyl-3-[(phenyl amino) carbonyl]-1H-pyrroles-1-heptamide, it further is converted to half calcium salt (embodiment 3); (4R-is suitable)-6-(2-amino-ethyl)-N-butyl-N, 2,2-trimethylammonium-1,3-diox-4-ethanamide is converted to [R-(R *, R *)]-N-butyl-5-(4-fluorophenyl)-β, δ-dihydroxyl-N-methyl-2-(1-methylethyl)-4-phenyl-3-[(phenyl amino) carbonyl]-1H-pyrroles-1-heptamide, it further is converted to half calcium salt (embodiment 4); (4R-is suitable)-6-(2-amino-ethyl)-N-(1, the 1-dimethyl ethyl)-2,2-dimethyl-N-(phenyl methyl)-1,3-diox-4-ethanamide is converted to [R-(R *, R *)]-N-(1,1-(dimethyl ethyl)-5-(4-fluorophenyl)-β, δ-dihydroxyl-2-(1-methylethyl)-4-phenyl-3-[(phenyl amino) carbonyl]-N-(phenyl methyl)-1H-pyrroles-1-heptamide, it further is converted to half calcium salt (embodiment 5); And (4R-is suitable)-1-[[6-(2-amino-ethyl)-2,2-dimethyl-1,3-diox-4-yl]-ethanoyl] piperidines is converted to [R-(R *, R *)]-1-[3,5-dihydroxyl-7-oxo-7-(piperidino) heptyl]-(4-fluorophenyl-2-(1-methylethyl)-N-4-xenyl-1H-pyrrole-3-carboxamide, it further is converted to half calcium salt (embodiment 6) to 5-.
Superstatin is [S-[R *, S *-(E)]]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl (methyl sulphonyl) amino]-the 5-pyrimidyl]-3, the formal name used at school that routinizes of 5-dihydroxyl-6-heptenoic acid.Superstatin is with examining in the process that the trade(brand)name (containing ZD-4522) of CRESTOR is introduced to the market.Superstatin, its calcium salt (2: 1) and lactone form thereof be at United States Patent (USP) 5,260, and be open and require to obtain patent protection in No. 440.The method of ' 440 patents by under refluxing, make 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methyl sulphonyl amino)-5-pyrimidine formaldehyde with (3R)-3-(t-butyldimethylsilyloxy base)-5-oxo-6-triphenyl phosphoranediyl (phosphoranylidene) methyl caproate prepared in reaction superstatin in acetonitrile.With the hydrogen fluoride silyl that dissociates, use NaBH subsequently then 4Also obtained the methyl esters of superstatin originally.
Then described ester is at room temperature used sodium hydroxide hydrolysis in ethanol, subsequent removal ethanol also adds ether and obtains the sodium salt of superstatin.With a rapid method of multistep sodium salt is transformed into calcium salt then.Sodium salt is dissolved in the water and remains under the nitrogen atmosphere.Then calcium chloride is joined in the solution, obtain the precipitation of ZD-4522 (2: 1).So the method for ' 440 patents is by sodium salt intermediate preparation ZD-4522.
United States Patent (USP) 6,316, the medicinal compositions that discloses a kind of superstatin No. 460.Described medicinal compositions comprises superstatin or its salt and multivalence ternary phosphates.The method of the calcium salt of described ' 460 patents and unexposed any preparation superstatin.
Pitavastatin is (E)-3,5-dihydroxyl-7-[4 '-(4 " fluorophenyl)-2 '-cyclopropyl-quinoline-3 '-yl]-heptan-the universalization formal name used at school of 6-olefin(e) acid.Pitavastatin, its calcium salt (2: 1) and its lactone are disclosed in three relevant United States Patent (USP)s 5,011,930,5,856,336 and 5,872, in No. 130.
Described ' 930 patents are according to embodiment 1 preparation pitavastatin ethyl ester.At first by make 2-amino-4 '-fluorine benzophenone and ethyl isobutyryl prepared in reaction 4-(4 '-fluorophenyl)-2 '-(1 '-cyclopropyl) quinoline-3 '-the yl carboxylic acid ester, change into 4-(4 '-fluorophenyl)-3-methylol-2-(1 '-cyclopropyl) quinoline again, its change into again 4-4 '-fluorophenyl-2-(1 '-cyclopropyl)-quinoline-3 '-Ji formaldehyde, its change into again 3-(3 '-oxyethyl group-1 '-hydroxyl-2 '-propenyl)-4-(4 '-fluorophenyl)-2-(1 '-cyclopropyl) quinoline, its change into again (e)-3-[4 '-(4 " fluorophenyl)-2 '-(1-cyclopropyl)-quinoline-3 '-yl] propenal; its change into again (E)-7-[4-(4 " fluorophenyls-2 '-(1 "-cyclopropyl)-quinoline-3 '-yl)]-5-hydroxyl-3-oxo heptan-6-olefin(e) acid ethyl ester; it changes into (E)-3 again, 5-dihydroxyl-7-[4 '-(4 " fluorophenyl)-2 '-(1 "-cyclopropyl)-quinoline-3 '-yl]-heptan-6-olefin(e) acid ethyl ester.
According to embodiment 2, by using aqueous sodium hydroxide solution with the ester that obtains---(E)-3,5-dihydroxyl-7-[4 '-(4 " fluorophenyl)-2 '-(1 "-cyclopropyl)-quinoline-3 '-yl]-heptan-6-olefin(e) acid ethyl ester changes into sodium salt.With compound dissolution in ethanol, to wherein adding aqueous sodium hydroxide solution.Ethanol is removed in mixture that stirring obtains and decompression.After adding entry, mixture is extracted with ether again.Then the water layer freeze-drying is obtained end product, perhaps with water layer dilute hydrochloric acid solution weak acidization.Then with ether extraction acidifying water layer.After the extraction, with the ether layer through dried over mgso.Decompression is removed ether and is obtained sodium salt then.The preparation of the relevant patent of described ' 930 patents and unexposed any compound calcium salt with it.
These patents are prepared as follows lactone: the sodium salt of preparation is dissolved in the dry toluene, and toluene is removed in reflux solution and decompression.Then rough solid recrystallization from diisopropyl ether is obtained lactone [4 '-(4 " fluorophenyl)-2 '-(1 "-methylethyl) quinoline-3 '-the ethyl-acetylene base]-4-hydroxyl-3,4,5,6-tetrahydrochysene-2H-pyran-2-one.Under nitrogen atmosphere, further reduce described lactone with palladium/carbon.
United States Patent (USP) 6,335 has improved the art methods of preparation pitavastatin for No. 449, and it obtains to synthesize the nitrile intermediate that pitavastatin is used by aldehyde quinoline and cyanogen methyl acid phosphate diethyl ester are reacted.United States Patent (USP) 6,335,449 and unexposed calcium salt or other salt that how to prepare pitavastatin.
Simvastatin is a compound butyric acid 2,2-dimethyl-1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-[2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl)-ethyl]-1-naphthalene ester [1S *-[1a, 3a, 7b, 8b (2S *, 4S) ,-8ab]] general chemical name.(CAS number of registration 79902-63-9).Simvastatin is introduced to the market with the title of ZOCOR, and is disclosed in United States Patent (USP) 4,444, and 784 and 6,002,021 and WO00/53566 number.These bibliographys disclose the preparation of the Simvastatin of lactone and open loop form.
In these bibliographys, have only WO00/53566 to disclose the preparation of open loop form Simvastatin calcium salt.In a typical embodiment, the method for WO00/53566 then adds calcium source such as lime acetate hydrate with the lactone of sodium hydroxide hydrolysis Simvastatin.
Prepare how the above-mentioned art methods of calcium salt of his spit of fland such as atorvastatin, pitavastatin, superstatin and Simvastatin is all unexposed prepares calcium salt or by sodium salt intermediate preparation calcium salt.In addition, certain methods is extremely sensitive and can not repeat all the time, for scale operation, has undesirable filtration and drying step.Therefore need can repeat easily and the method for suitable scale operation to obtain stable product than art methods step still less.
The present invention's summary
The invention provides the novel method that a kind of preparation has his spit of fland calcium salt of following formula:
Figure C0281599900131
R represents organic group in the formula,
This method comprises makes the ester derivative that is selected from his following spit of fland:
Figure C0281599900132
With
Figure C0281599900133
With the calcium hydroxide reaction of capacity,
R wherein 1Be C 1-C 8Alkyl,
R 2, R 3And R 4Each represents hydrogen or identical or different hydrolyzable protecting group, perhaps R independently 2And R 3Form hydrolyzable ring protection base with its Sauerstoffatom that connects separately.
Described reaction can be with or without phase-transfer catalyst in the presence of carry out.Preferred phase-transfer catalyst is quaternary ammonium salt such as Tetrabutyl amonium bromide (TBAB) and triethyl benzyl ammonia chloride (TEBA).Described reaction is preferably heated and is promoted to transform.
Preferably his spit of fland is atorvastatin, superstatin, pitavastatin and Simvastatin.In preferred embodiments, R 2, R 3And R 4Be hydrogen.Each R 2, R 3Or R 4Also can be identical or different protecting group, it can be-COOR by using calcium hydroxide and ester group 1Hydrolysis one one-step hydrolysis, or after using the acid catalyst hydrolysis, carry out ester group-COOR 1Hydrolysis.Preferred protecting group is silyl such as trialkylsilkl (its can by the calcium hydroxide hydrolysis) and acetonide (it can pass through the acid catalyst hydrolysis).Acetonide forms ring-type hydrolyzable protecting group Ji diox.
On the other hand, the invention provides the method for calcium salt that a kind of preparation has his spit of fland of following formula:
Figure C0281599900141
R represents organic group in the formula,
This method comprises the steps:
The ester derivative in calcium hydroxide and aforesaid his spit of fland is joined water and C 1-C 4In the mixture of alcohol, heated mixt is settled out the calcium salt in his spit of fland and separates calcium salt.
The present invention describes in detail
Forming ester is people's protection carboxylic acid group who is familiar with and methods of covering its sour proton.Referring to Green, T.W.; Wuts, the P.G.M.Protective Groups in Organic Synthesis third edition, the 5th chapter (John Wiley﹠amp; Sons:New York 1999) (" Greene﹠amp; Wuts ").People also know usually can be by coming deprotection with the highly basic ester hydrolysis as the protected carboxylic acid of ester.Referring to above-mentioned document 377-378 page or leaf.
Sodium hydroxide is a kind of dissociation constant (pK of 6.37 of having b=-0.80) highly basic, (CRC press: Boca Raton 2000-01), it is as purposes existing people's explanation in this area of the deprotecting regent of the carboxylic acid of being protected by ester referring to chemical and 81 editions 8-45 pages or leaves of physics handbook.Referring to described Green﹠amp; The 377th page of Wuts.Have 3.74 * 10 -3(pK b=2.43) first dissociation constant and 4.0 * 10 -2(pK bThe calcium hydroxide of second dissociation constant=1.40) (Ca (OH) 2) be than a little less than the sodium hydroxide the alkali of Duoing.Referring to 63 editions chemistry and physics handbook D-170 (CRC press: Boca raton 1983).
In the organic synthesis field in functional group that people are familiar with conversion summary calcium hydroxide be not listed among the reagent that is used for ester hydrolysis.Referring to the ComprehensiveOrganic Transformations of the 2nd edition Larock R.C., nitrile, carboxylic acid and derivative part, the 1959-1968 page or leaf (Wiley-VCH:New York 1999) of 9.17 joints.In known reference, its application as the general deprotecting regent of the carboxylic acid of being protected by ester is not described about protection and deprotection organo-functional group.Referring to described Greene﹠amp; The 377-379 page or leaf of Wuts.In fact, United States Patent (USP) 5,273 remind to oppose uses for No. 995 excessive sodium hydrate to prepare sodium salt and forms calcium hydroxide when preventing to join calcium chloride in the sodium salt solution afterwards.As if it does not recognize that his spit of fland such as atorvastatin of ester protection form can directly change into separately half calcium salt such as atorvastatin hemi-calcium salt; at first do not resemble the sodium-hydroxide treatment ester and make its hydrolysis, replace sodium ion by sodium salt is contacted with calcium salt such as calcium chloride or lime acetate then with highly basic.
Used term " ester derivative " is meant to use by carbon bond and is incorporated into the compound that the hydroxyl proton of carboxylic acid group in the substituting group displacement open loop of hydroxyl oxygen atom or his spit of fland of dihydroxylated acid form obtains in this.This ester derivative comprises that the substituting group of the hydroxyl oxygen that for example is bonded to described carboxylic acid is C 1-C 8The compound of alkyl.The ester derivative that is used to transform can be the mixture that contains the derivative of various esters.For example methyl ester derivation can join in the ethanol, makes some methyl esters be transformed into ethyl ester.The ester derivative in described his spit of fland can maybe can be purchased by the method preparation that this area people are familiar with.Described ester derivative also comprises the lactone or the closed loop in his spit of fland.Described lactone form is a kind of cyclic ester, and wherein his ester group in spit of fland is incorporated in the ring.The mixture of ester derivative also comprises the mixture in open loop and his spit of fland of closed loop.
The present invention relates to have his spit of fland of following general formula:
Figure C0281599900151
One of them organic group R is connected on dihydroxyl-valeric acid base.These his spits of fland comprise for example Pravastatin, fluvastatin, Cerivastatin, atorvastatin, superstatin, pitavastatin, lovastatin and Simvastatin.Wherein preferred atorvastatin, superstatin, pitavastatin and Simvastatin.
R is meant the organic group that is bonded to the dihydroxy-acid base.
According to the kind in his spit of fland, described R group can be:
Pravastatin: 1,2,6,7,8,8a-six hydrogen-6-hydroxy-2-methyl-8-(2-methyl isophthalic acid-oxo butoxy)-1-naphthalene ethyl.
Fluvastatin: 3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl]-vinyl.
Cerivastatin: 4-(4-fluorophenyl)-5-methoxymethyl)-2,6-two (1-methylethyl)-3-pyridine-vinyl.
Atorvastatin: 2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles's ethyl.
Superstatin: [4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl (methyl sulphonyl) amino]-5-pyrimidyl]-vinyl.
Pitavastatin: [4 '-(4 " fluorophenyl)-2 '-cyclopropyl-quinoline-3 '-yl] vinyl.
Described R base also can be open loop form, the i.e. dihydroxylated acid of Simvastatin or lovastatin.These open loop forms also have the dihydroxy-acid base.Term Simvastatin and lovastatin used in this comprise lactone form and open loop form.When described his spit of fland was Simvastatin or lovastatin, described R group was;
Simvastatin: 1,2,6,7,8,8a-six hydrogen-2,6-dimethyl-8-(2,2-dimethyl-1-oxo butoxy)-1-naphthalene ethyl.
Lovastatin: 1,2,6,7,8,8a-six hydrogen-2,6-dimethyl-8-(2-methyl isophthalic acid-oxo butoxy)-1-naphthalene ethyl.
The calcium salt in all his spits of fland can be by method of the present invention preparation, and the organic group that is attached to dihydroxy-acid base or corresponding lactone has defined the compound as his spit of fland, promptly suppresses the compound of 3-hydroxy-3-methylglutaryl-coenzyme A (" HMG-CoA ") reductase enzyme.Referring to for example WO00/53566.Therefore, R should be interpreted as to be limited to and be bonded to disclosed or the dihydroxy-acid base in his spit of fland that exemplifies or the organic group of corresponding lactone in this.All hydrates, solvate and the non-hydrate of the calcium salt in these his spit of fland and other polymorphic, crystal or amorphous substance are all within the scope of the invention.
The present invention illustrates the preparation of the calcium salt in these his spit of fland as an example by the preparation of using atorvastatin hemi-calcium.With regard to the preparation that the preparation of atorvastatin hemi-calcium is different from another kind of his spit of fland in some aspects, it will be understood by those skilled in the art that atorvastatin just is used as explanation; The all respects that can easily revise the preparation atorvastatin hemi-calcium prepare other his spit of fland, and it is still in aim of the present invention and scope.
The invention provides a kind of method for preparing his spit of fland half calcium salt, this method is by making his spit of fland ester derivative of following formula:
Figure C0281599900171
Or
(R represents organic group in the formula, R 1Be C 1-C 8Alkyl) contacts with the calcium hydroxide of capacity, described ester derivative is transformed into has following formula
Figure C0281599900173
Corresponding half calcium salt.Used term " capacity " is meant the amount that described ester derivative can be transformed into corresponding half calcium salt basically of calcium hydroxide in this.Used term in this " transform basically " be meant with greater than about 50% (mole), be preferably greater than about 70% (mole), change into such amount of half calcium salt more preferably greater than his spit of fland ester derivative of about 90% (mole).Most preferably will be transformed into corresponding half calcium salt greater than about 95% his spit of fland ester derivative.
Amazing advantage of present method is that calcium hydroxide has played two kinds of effects.It has played as being used for the effect of esterolytic basic catalyst and the effect that forms the required calcium ion of half calcium salt being provided.The amount that another tangible real advantage of the present invention is a calcium hydroxide does not need careful control as the amount of the sodium hydroxide that is used for other method different with the present invention and calcium chloride/lime acetate, and described other method relates to NaOH ester hydrolysis derivative and follows the successive processes of replacing sodium ion with calcium ion.
Described his spit of fland ester derivative can pure form or so that his form of mixtures of spit of fland ester derivative provides with other.With his spit of fland ester derivative preferred dissolution of optional form of mixtures with his spit of fland ester derivative or be suspended in and comprise C with other 1-C 4In the mixed solvent of alcohol and water.Preferred alcohol is ethanol and Virahol (" IPA "), and preferred solvent mixture more preferably contains about 10% water and about 90% ethanol (v/v) or IPA for to comprise about 5-15% water in ethanol or IPA.Whether his spit of fland ester derivative is dissolved in depends on various factors such as C in the mixed solvent 1-C 4The purity of the selection of alcohol, ratio, temperature and the Ta Ting ester derivative of water.Then calcium hydroxide is suspended in the solvent, keeps the macromolecule alkali for hydrolysis mixture to be exhausted up to his spit of fland ester derivative.The consumption of his spit of fland ester derivative can be by method such as TLC, HPLC and the NMR monitoring of any routine.After his spit of fland ester derivative consumes, reclaim his spit of fland half calcium from described macromolecule alkali for hydrolysis mixture by ordinary method.For atorvastatin hemi-calcium salt, not needing to add another kind of calcium source provides Ca 2+Ion.
According to the preferred steps of implementing the basic hydrolysis method, described his spit of fland ester derivative adds to the amount of about 1 mol mixed solvent to be enough to provide about 10 mmoles/rise mixed solvent.
With respect to ester derivative, preferably use about 1 to about 6 normal calcium hydroxides.More preferably use about 1 to about 2 equivalents.
Calcium hydroxide just is slightly soluble in C 1-C 4Alcohol: in the water mixed solvent, and have only small proportion can be suitable for the time in office with solution form catalytic hydrolysis.In order to quicken basic hydrolysis, can add the solvability that phase-transfer catalyst improves calcium hydroxide.Phase-transfer catalyst is familiar with by this area people, comprises for example tetra-n-butyl ammonium bromide (" TBAB "), benzyltriethylammoinium chloride (" TEBA "), tetrabutylammonium chloride, tetrabutylammonium iodide, etamon chloride, benzyl tributyl ammonium chloride, benzyl tributyl brometo de amonio, benzyl triethyl ammonium bromide, tetramethyl ammonium chloride and polyoxyethylene glycol.A kind of most preferred phase-transfer catalyst is TBAB.During use, phase-transfer catalyst should be to use corresponding to the substoichiometric amount of his spit of fland ester derivative, preferably with corresponding to the about 0.05-0.25 equivalent of his spit of fland ester derivative, more preferably from about 0.1 normal amount use.
Can be with described mixture heating up to the reflux temperature that is up to mixed solvent with accelerated reaction.Preferred temperature range is about 40-70 ℃ a high temperature.
After consuming his spit of fland ester derivative, reclaim his spit of fland half calcium or its solvate from the macromolecule alkali for hydrolysis mixture.As a part that reclaims his spit of fland half calcium, preferably reaction mixture is filtered to remove the calcium hydroxide of excessive suspension.Preferably with the reaction mixture filtered while hot to prevent that his spit of fland half calcium deposit is on the calcium hydroxide filter cake.
After removing by filter the calcium hydroxide of suspension, can reclaim his spit of fland half calcium from filtrate by precipitation.According to a kind of preferred recovery technology, his spit of fland half calcium is precipitated from filtrate by slowly adding entry.The water that is substantially equal to filtrate volume was added with about 1 hour time.The slow adding of preferably water is also carried out under 40-65 ℃ the temperature according to appointment at high temperature.Obtain his spit of fland half calcium of crystallized form and prevented the formation of gelatinous precipitate by his spit of fland half calcium of slow adding water precipitation.Perhaps, his spit of fland half calcium can reclaim by any ordinary method.Behind required purification step, his spit of fland half calcium of recovery can be used as the active Cheng Zhong for preparing medicines.
The filtering feature of his spit of fland half calcium and purity can be dissolved in described crystallized product again and form clear solution in the aqueous alcohol reaction mixture and further improve by being heated to the temperature that is enough to make whole resolution of precipitates.Described solution preferably slowly cools off with several hrs and preferred the maintenance forms up to no longer observing crystallization at ambient temperature.Filter and dry and any other optional purification step after, his spit of fland half calcium or its solvate can be used as the activeconstituents of medicine.
As mentioned above, he passes through intermediate preparation in the spit of fland sometimes, and wherein the hydroxyl of one or two hydroxyl of valeric acid glycol-based (open loop form) or lactone (closed loop) is through the protection of hydrolyzable protecting group, and carboxyl is protected through ester derivative.For example, No. 5,260,440, United States Patent (USP) incorporating this paper by reference into uses the silyl protecting group when superstatin synthetic.The United States Patent (USP) 6,002,021 and 4,444 of incorporating this paper by reference into, No. 784 use silyl protecting groups when Simvastatin is synthetic.The Brower that incorporates this paper by reference into, people such as P.L. be at Tet.Lett.1992, and 33, the article of 2279-82 and Baumann, people such as K.L. be at Tet.Lett.1992, and 33, the article of 2283-2284 is by having acetonide protecting group, i.e. R 2And R 3Form hydrolyzable ring protection base De diox intermediate preparation atorvastatin with the Sauerstoffatom that links to each other separately.
The compound that these are called hereinto " protected he spit of fland ester derivative " can change into corresponding half calcium salt according to the present invention.Therefore, in another embodiment, the present invention relates to the method for calcium salt that a kind of preparation has his spit of fland of following formula:
Figure C0281599900201
(R represents organic group in the formula), this method comprise making and are selected from following ester derivative:
With
Figure C0281599900203
Contact with the calcium hydroxide of capacity, wherein R 1Be C 1-C 8Alkyl, R 2, R 3And R 4Each represents hydrogen or identical or different hydrolyzable protecting group, perhaps R independently 2And R 3The Sauerstoffatom that links to each other separately with them forms hydrolyzable ring protection base.Used protecting group preferably can hydrolysis under acidity or alkaline condition.Preferred protecting group R according to embodiment of the present invention 2, R 3And R 4Comprise for example silyl (more preferably trialkylsilkl and alkyl diaryl silyl, most preferably t-butyldimethylsilyl) and ring protection base (thereby R 2And R 3Form for example diox).
The United States Patent (USP) of incorporating this paper by reference into discloses for 6,294, No. 680 and has been used for the synthetic particularly other protecting group of Simvastatin synthetic in his spit of fland.Disclosed ring protection base comprises diox, cyclic sulfates, annular phosphate or borylene (borylidene), and these protecting groups are optional to be replaced by alkyl and aryl.Other protecting group comprises disclosed boric acid among the WO95/13283 that incorporates this paper by reference into, and as disclosed such diacetyl oxide esterification of using in No. 5,159,104, the United States Patent (USP) of incorporating this paper by reference into.The United States Patent (USP) of incorporating this paper by reference into discloses other protecting group 6,100, No. 407.Disclosed protecting group can be used according to the present invention in these reference.
Find unexpectedly now that silyl can be hydrolyzed and can be by contact removal with calcium hydroxide.So the use of silyl can allow to remove protecting group and ester is changed into calcium salt with a step in same solvent.Use calcium hydroxide not need the silicomethane protecting group with hydrogen halide such as hydrogen fluoride acidolysis for example with the independent step of removing protecting group (as United States Patent (USP) 5,260,440 and the needs of the method for No. 4,444,784, United States Patent (USP)).Therefore, the inventive method is applicable to and has silyl or other protecting group R that can pass through the calcium hydroxide hydrolysis 2, R 3And R 4Ta Tingshi.For example can use to be disclosed in United States Patent (USP) 5,260, be protected superstatin in No. 440, and have ketone was also obtained as R originally 2The modification of hydrogen.Also can use to be disclosed in United States Patent (USP) 4,444, No. 784 and 6,002, the Simvastatin of the silyl protection in No. 021.
Some protecting groups obtain optimum hydrolysis under acidic conditions.Therefore, before being protected his spit of fland ester derivative and calcium hydroxide contacts, add acid catalyst hydrolysising protection base.The example of this acid catalyst comprises acetate, trifluoroacetic acid, to toluene yellow, zinc bromide and spirit of salt or other halogen hydracid, preferred acetate and hydrochloric acid.Then the diol ester that obtains is transformed into calcium salt by contacting with calcium hydroxide.Described method also can be carried out by a pot process.Form diol ester as mentioned above, make it in identical jar, form atorvastatin hemi-calcium and not change solvent then with calcium hydroxide reaction.A kind of preferred solvent is water and C 1-C 4The mixture of alcohol is preferably ethanol.The preferred pH of described reaction be lower than about 3, more preferably less than about 1.
A kind of preferred protecting group of removing with acid catalyst is an acetone solvate, and promptly glycol forms the compound Ji diox of ring-type hydrolyzable protecting group.Preferably pass through for example acetone of evaporation under reduced pressure removed formation when acetone solvate and acid catalyst reaction.
Use a pot process example of acid catalyst to be described as follows:
Figure C0281599900221
Medicinal compositions can be prepared into the medicament that can supply per os, parenteral, rectum, subcutaneous, cheek or nasal administration.Be fit to peroral administration formulation and comprise tablet, concentrated pill or coated pill, drageeing, folliculus, hard capsule or gelatine capsule, lozenge, syrup and suspension.The formulation of the administered parenterally that is fit to comprises the aqueous solution or non-aqueous solution or emulsion, and the formulation that is fit to rectal administration comprises the suppository of the hydrophilic or hydrophobic carrier of tool.For the formulation of topical, the invention provides that this area people are familiar be fit to through the skin delivery system, deliver for intranasal, the invention provides the aerosol delivery system that is fit to that this area people are familiar with.
Medicinal compositions of the present invention comprises his spit of fland half calcium, particularly atorvastatin hemi-calcium, superstatin half calcium, pitavastatin half calcium, Simvastatin half calcium and lovastatin half calcium.Except activeconstituents, medicinal compositions of the present invention can comprise one or more vehicle.The selection of vehicle and consumption thereof can easily be determined with this field reference based on experience and reference standard program by the preparation teacher.The medicament vehicle handbook of incorporating the American Pharmaceutical Association of No. 6,316,460, the United States Patent (USP) of this paper and latest edition by reference into can be used as guide.
Figure C0281599900222
The formulation of (atorvastatin hemi-calcium) and other medicament and preparation also can be used as guide.
Embodiment
General rule
Unless add explanation in addition, what reagent was purchased promptly uses.Form pyrrole ring preparation [R-(R by the condensation reaction between corresponding diketone and the corresponding Chiral Amine *, R *)]-2-(4-fluorophenyl)-β, δ-dioxs-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-tertiary butyl heptanoate (diox 2, R 1=the tertiary butyl).Also can prepare by currently known methods.Referring to Brower, people such as P.L. are at Tet.Lett.1992, and 33,2279-82; Baumann, people such as K.L be at Tet.Lett.1992, and 33, described among the 2283-84.Below the HPLC condition be used for measuring in an embodiment the composition of the mixture that the acid hydrolysis of report obtains: Waters Spherisorb S3 ODS1 (7.6 * 100mm), 70: 30 acetonitriles: water, 0.6mL/min, 20 μ L samples, UV-light detects γ=254.
Embodiment 1
You diox ester derivative prepares atorvastatincalcuim
In being furnished with the flask of magnetic stirring apparatus, with [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dioxs-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-tertiary butyl heptanoate (2.0g) is suspended in 80% acetic acid aqueous solution (50mL).With mixture at ambient temperature stir about 20 hours up to obtaining clear solution.Clear solution is evaporated to dry doubling by (3 * 50mL) component distillations are removed trace acetate and obtained powder with toluene.
With powder (200mg, 0.32 * 10 that obtains above -3Mole) is dissolved in the ethanol (8mL), to wherein adding the calcium hydroxide saturated solution (8mL) that contains Tetrabutyl amonium bromide (10mg).Stir described mixture and under about 45 ℃ temperature the heating about 24 hours.The saturated solution (4mL) that adds calcium hydroxide more in addition.Stir about is after 20 minutes at ambient temperature, and reaction is finished.Obtaining degree of purity of production analyzes by HPLC.Vacuum filtration white depositions and under about 65 ℃ temperature dry about 18 hours.After the drying, obtain the atorvastatin calcium salt (142mg) of 77% yield.
Embodiment 2
Cong diox ester derivative prepares atorvastatincalcuim
In being furnished with the flask of magnetic stirring apparatus, with [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dioxs-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-tertiary butyl heptanoate (10.0g, 15.29 * 10 -3Mmol) be suspended in 80% acetic acid aqueous solution (150mL).Mixture stirred at ambient temperature spend the night up to obtaining clear solution.Clear solution is evaporated to dry doubling by (3 * 100mL) component distillations are removed the oily product that trace acetate obtains to contain toluene with toluene.
The oily product is placed ethanol (100mL) and the water (mixture of 20mL.Add calcium hydroxide (5.5 equivalents, 6.22g, 84.0 * 10 -3Mmol) and the mixture of 5% (w/w diox ester derivative) Tetrabutyl amonium bromide (0.46g).Mixture heating up was finished up to reaction to about 45 ℃ temperature in about 3 hours.While hot the excessive hydrogen calcium oxide is removed in the mixture vacuum filtration.Then mixture is cooled to envrionment temperature, under agitation adds entry (200mL) afterwards.Stir about is after 20 minutes at ambient temperature, and reaction is finished.The degree of purity of production that obtains is analyzed by HPLC.With white depositions vacuum filtration and under about 65 ℃ temperature dry about 18 hours.After the drying, obtain the atorvastatin calcium salt (7.44g) of 84% yield.
Embodiment 3
You diox ester derivative prepares the atorvastatin lactone
In being furnished with the flask of magnetic stirring apparatus, in the presence of the water of catalytic amount, with [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dioxs-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-tertiary butyl heptanoate (0.5g, 0.76 * 10 -3Mmol) be dissolved in 1: 1 trifluoroacetic acid: in the mixture of tetrahydrofuran (THF) (4mL).With reaction mixture stir about 24 hours at ambient temperature.With the solution evaporation of acquisition and by (3 * 10mL) component distillations are removed the trace trifluoroacetic acid with ether.Obtain white solid (0.3g).Analyze based on HPLC, described white solid is that ratio is respectively 40: 60 the atorvastatin and the mixture of atorvastatin lactone.
Embodiment 4
You diox ester derivative prepares the atorvastatin lactone
In being furnished with the flask of magnetic stirring apparatus, with [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dioxs-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-tertiary butyl heptanoate (0.2g, 0.30 * 10 -3Mmol) and zinc bromide (3.5 equivalents, 1.07 * 10 -3Mole) is dissolved in the methylene dichloride (5mL).With reaction mixture stir about 24 hours at ambient temperature.Add entry (30mL) and with mixture stir about 3 hours.(3 * 10mL) extract water layer, and organic layer also filters with dried over sodium sulfate with methylene dichloride.The product that the organic layer reduction vaporization is obtained forming (150mg) then.Analyze based on HPLC, the product that obtains is is that ratio is respectively 57: 43 the atorvastatin and the mixture of atorvastatin lactone.
Embodiment 5
You diox ester derivative prepares the atorvastatin lactone
In being furnished with the flask of magnetic stirring apparatus, with [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dioxs-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-tertiary butyl heptanoate (0.2g) is suspended in 90% acetic acid aqueous solution (4mL).With this mixture stir about 5 days under about 50 ℃ of temperature.With the solution evaporation that obtains to dry doubling by (3 * 15mL) component distillations are removed trace acetate and obtained a kind of powder with toluene.Analyze based on HPLC, the product that obtains is that ratio is respectively 54: 46 the atorvastatin and the mixture of atorvastatin lactone.
Embodiment 6
You diox ester derivative prepares the atorvastatin lactone
In being furnished with the flask of magnetic stirring apparatus, with hydrochloric acid (1mL) and [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dioxs-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-3% aqueous solution of 1H-pyrroles-1-tertiary butyl heptanoate (0.2g) is dissolved in the methyl alcohol (2mL).With mixture stir about 4 hours under about 110 ℃ temperature, stir at ambient temperature then and spend the night.The solution evaporation that obtains is obtained a kind of powder to doing.Analyze based on HPLC, this powder is that ratio is respectively 54: 46 the atorvastatin and the mixture of atorvastatin lactone.
Embodiment 7
Prepare ZD-4522 by ester derivative
In being furnished with the flask of magnetic stirring apparatus; with 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methyl sulphonyl amino) pyrimidine-5-yl]-(3R; 5S)-dihydroxyl-(E)-6-Methylheptanoate is dissolved in the ethanol, and to wherein adding the calcium hydroxide saturated solution that contains 5% (accounting for the weight ratio of ester derivative) Tetrabutyl amonium bromide.Mixture stirred and about 24 hours of heating under about 45 ℃ temperature.Add the calcium hydroxide saturated solution again.Stir about is after 20 minutes at ambient temperature, and reaction is finished, and obtains ZD-4522.
Embodiment 8
Prepare ZD-4522 by ester derivative
In being furnished with the flask of magnetic stirring apparatus, with 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methyl sulphonyl amino) pyrimidine-5-yl]-(3R, 5S)-dihydroxyl-(E)-6-heptenoic acid methyl esters places the mixture of second alcohol and water.To the mixture that wherein adds calcium hydroxide and 5% (accounting for the weight ratio of ester derivative) Tetrabutyl amonium bromide.Mixture heated under about 45 ℃ temperature finished up to reaction in about 3 hours.The excessive hydrogen calcium oxide is removed in mixture vacuum filtration while hot.Then mixture is cooled to room temperature, when stirring, adds entry afterwards.Stir about is after 20 minutes at ambient temperature, and reaction is finished, and obtains ZD-4522.
Embodiment 9
Prepare Pitavastatin Calcium by ester derivative
In being furnished with the flask of magnetic stirring apparatus, with (E)-3,5-dihydroxyl-7-[4 '-(4 " fluorophenyl) 1-2 '-cyclopropyl-quinoline-3 '-yl]-heptan-6-olefin(e) acid ethyl ester is dissolved in the ethanol, and to wherein adding the calcium hydroxide saturated solution that contains 5% (accounting for the weight ratio of ester derivative) Tetrabutyl amonium bromide.Mixture stirred and about 24 hours of heating under about 45 ℃ temperature.Add the calcium hydroxide saturated solution again.Stir about is after 20 minutes at ambient temperature, and reaction is finished, and obtains Pitavastatin Calcium.
Embodiment 10
Prepare Pitavastatin Calcium by ester derivative
In being furnished with the flask of magnetic stirring apparatus, with (E)-3,5-dihydroxyl-7-[4 '-(4 " fluorophenyl)-2 '-cyclopropyl-quinoline-3 '-yl]-heptan-6-olefin(e) acid ethyl ester places the mixture of second alcohol and water.To the mixture that wherein adds calcium hydroxide and 5% (accounting for the weight ratio of ester derivative) Tetrabutyl amonium bromide.Mixture heated under about 45 ℃ temperature finished up to reaction in about 3 hours.The excessive hydrogen calcium oxide is removed in mixture vacuum filtration while hot.Mixture is cooled to envrionment temperature, under agitation adds entry then.Stir about is after 20 minutes at ambient temperature, and reaction is finished, and obtains Pitavastatin Calcium.
With reference to concrete embodiment preferred the present invention is described like this and with after the explanation of embodiment example, those skilled in the art know various do not deviate from as disclosed aim of the present invention and scope in the patent specification as mentioned above with example to modification of the present invention.Described embodiment is used for helping to understand the present invention, but does not intend also should not regarding as by any way limiting the scope of the invention.Described embodiment does not comprise the description of ordinary method.This method is familiar with by those skilled in the art and is disclosed in the various documents.Reference described in all this is incorporated this paper in full into.

Claims (41)

1. method for preparing the calcium salt in his spit of fland with following formula:
R represents organic group in the formula,
This method comprises makes the ester derivative that is selected from his following spit of fland
Figure C028159990002C2
With
With the calcium hydroxide reaction of capacity,
R wherein 1Be C 1-C 8Alkyl, R 2, R 3And R 4Each represents hydrogen or identical or different hydrolyzable protecting group, perhaps R independently 2And R 3Form hydrolyzable ring protection base with its Sauerstoffatom that links to each other separately.
2. the process of claim 1 wherein that R is the organic group that is selected from his spit of fland of Pravastatin, fluvastatin, Cerivastatin, atorvastatin, superstatin, pitavastatin, Simvastatin and lovastatin.
3. the method for claim 2, wherein said his spit of fland is selected from atorvastatin, superstatin, pitavastatin and Simvastatin.
4. the method for claim 3, wherein said his spit of fland is a superstatin.
5. the method for claim 3, wherein said his spit of fland is a pitavastatin.
6. the method for claim 3, wherein said his spit of fland is a Simvastatin.
7. the method for claim 3, wherein said his spit of fland is an atorvastatin.
8. the process of claim 1 wherein that described method is at water and C 1-C 4Carry out in the mixture of alcohol.
9. the process of claim 1 wherein that described contact carries out at elevated temperatures.
10. the process of claim 1 wherein that described contact carries out in the presence of phase-transfer catalyst.
11. the method for claim 1 also comprises the step of the calcium salt that reclaims his spit of fland.
12. the process of claim 1 wherein R 2And R 3Be hydrogen.
13. the process of claim 1 wherein R 4Be hydrogen.
14. the process of claim 1 wherein R 2Or R 3In at least one is the trialkylsilkl protecting group.
15. the process of claim 1 wherein R 4Be the trialkylsilkl protecting group.
16. the method for claim 1 comprises also making ester derivative contact preliminary step with the hydrolysising protection base with acid catalyst that wherein said ester derivative has at least one protecting group.
17. the method for claim 16, wherein said ester derivative has following formula:
Figure C028159990003C1
18. the method for claim 17, wherein R is the organic group of atorvastatin.
19. the method for claim 1; his wherein prepared spit of fland salt is calcium salt of rosuvastatin; this method comprises makes 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methyl sulphonyl amino) pyrimidine-5-yl]-(3R, 5S)-dihydroxyl-(E)-C of 6-heptenoic acid 1-C 8Ester contacts with the calcium hydroxide of capacity.
20. the process of claim 1 wherein that his prepared spit of fland salt is calcium salt of rosuvastatin, this method comprises that the superstatin that makes lactone form contacts with the calcium hydroxide of capacity.
21. the process of claim 1 wherein that his prepared spit of fland salt is the pitavastatin calcium salt, this method comprises makes (E)-3,5-dihydroxyl-7-[4 '-(4 " fluorophenyl)-2 '-(1 "-cyclopropyl)-quinoline-3 '-yl]-heptan-C of 6-olefin(e) acid 1-C 8Ester contacts with the calcium hydroxide of capacity.
22. the process of claim 1 wherein that his prepared spit of fland salt is the pitavastatin calcium salt, this method comprises that the pitavastatin that makes lactone form contacts with the calcium hydroxide of capacity.
23. the process of claim 1 wherein that his the prepared calcium salt in spit of fland has following formula:
Figure C028159990004C1
Wherein R represents organic group,
This method comprises following step:
A) to water and C 1-C 4Add calcium hydroxide and the ester derivative that is selected from his following spit of fland in the mixture of alcohol:
Figure C028159990004C2
With
Figure C028159990004C3
R wherein 1Be C 1-C 8Alkyl, R 2, R 3And R 4Each represents hydrogen or identical or different hydrolyzable protecting group, perhaps R independently 2And R 3Form hydrolyzable ring protection base with its Sauerstoffatom that links to each other separately;
B) heat described mixture;
C) precipitate the calcium salt in his spit of fland; With
D) separate calcium salt.
24. the method for claim 23, wherein R is the organic group that is selected from his spit of fland of Pravastatin, fluvastatin, Cerivastatin, atorvastatin, superstatin, pitavastatin, Simvastatin and lovastatin.
25. the method for claim 24, wherein said his spit of fland is selected from atorvastatin, superstatin, pitavastatin and Simvastatin.
26. the method for claim 25, wherein said his spit of fland is a superstatin.
27. the method for claim 25, wherein said his spit of fland is a pitavastatin.
28. the method for claim 25, wherein said his spit of fland is a Simvastatin.
29. the method for claim 25, wherein said his spit of fland is an atorvastatin.
30. the method for claim 23, wherein R 2And R 3Be hydrogen.
31. the method for claim 23, wherein R 4Be hydrogen.
32. the method for claim 23, wherein R 2Or R 3In at least one is the trialkylsilkl protecting group.
33. the method for claim 23, wherein R 4Be the trialkylsilkl protecting group.
34. the method for claim 23 comprises also making ester derivative contact preliminary step with the hydrolysising protection base with acid catalyst that wherein said ester derivative has at least one protecting group.
35. the method for claim 34, wherein said ester derivative has following formula:
Figure C028159990005C1
36. the method for claim 35, wherein R is the organic group of atorvastatin.
37. the method for claim 23, the mixture of wherein said water and alcohol are volume ratios is 5% to 20% water and pure mixture.
38. the method for claim 23 also comprises in the mixture of step a) adding phase-transfer catalyst.
39. the method for claim 23 wherein is heated to 70 ℃ with described mixture from 40 ℃.
40. the method for claim 23, also be included in step (b) and (c) between filtration step.
41. the method for claim 23, wherein said precipitation is undertaken by adding entry.
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