CN101381356B - Preparation method of simvastatin - Google Patents
Preparation method of simvastatin Download PDFInfo
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- CN101381356B CN101381356B CN2008100796063A CN200810079606A CN101381356B CN 101381356 B CN101381356 B CN 101381356B CN 2008100796063 A CN2008100796063 A CN 2008100796063A CN 200810079606 A CN200810079606 A CN 200810079606A CN 101381356 B CN101381356 B CN 101381356B
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- 0 CCC(C)(C)C(OC1[C@]([C@@](CCC(C[C@](CC(*)=O)O)O)[C@@](C)C=C2)C2=C[C@](C)C1)=O Chemical compound CCC(C)(C)C(OC1[C@]([C@@](CCC(C[C@](CC(*)=O)O)O)[C@@](C)C=C2)C2=C[C@](C)C1)=O 0.000 description 4
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- 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
The invention discloses a method for preparing simvastatin. The method is as follows: a. lovastatin and alkylamine are prepared into lovastatin amide; b. hydroxyl groups in lovastatin amide molecules are protected, and lovastatin amide di-(trimethyl) silyl ether is generated; c. the lovastatin amide dimethyl (trimethyl) silyl ether is subjected to methylation, so as to obtain simvastatin amide di-silyl ether; d. the simvastatin amide di-silyl ether is protected, and simvastatin amide is generated; e. the simvastatin amide is subjected to hydrolysis and is added with ammonia gas, and simvastatin ammonium salt is obtained; and f. the simvastatin ammonium salt is subjected to ring closure to generate the simvastatin. The method takes a composite solvent of tetrahydrofuran and cyclonexane as a solvent for the protective reaction; the lovastatin amide di-(trimethyl) silyl ether can directly perform methylation reaction without alkaline washing and water scrubbing; after water scrubbing of methylate, protective groups are automatically fallen off, thereby the reaction for removing the protective groups is saved and the products can directly perform ammonium salt reaction. The method simplifies the synthesis technique of the simvastatin.
Description
Technical field
The present invention relates to a kind of preparation method of SV.
Background technology
SV is one of most popular in the market blood lipid-lowering medicine as the suppressor factor of hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase enzyme, is widely used in the treatment hyperlipidemia, is used to prevent cardiovascular and cerebrovascular diseases simultaneously.The method for preparing at present SV has:
(1), the lovastatin acid amides, be hydroxyl protection reagent with the TERT-BUTYL DIMETHYL CHLORO SILANE, imidazoles is a catalyzer, methyl iodide is a methylating reagent, and the 2-Methyl Butyric Acid ester side chain is carried out methylated method (U.S. Pat P4820850);
(2), the lovastatin acid amides is without hydroxyl protection, directly carries out methylated method (U.S. Pat P6506929, USP4444784, USP6573385, USP6573392, USP6603022, English Patent EP0864596);
(3), with Pottasium Hydroxide hydrolysis lovastatin; Eliminate the 2-Methyl Butyric Acid ester side chain; Carry out lactonization reaction then and obtain diol ester, with the acetal protection, acidylate, deprotection obtain SV (English Patent EP0033538, EP0511867, U.S. Pat P6384238) again;
(4), utilize the lovastatin hydrolytic enzyme with the lovastatin hydrolysis; Extraction from fermented liquid, separation, purifying obtain hydrolysate; Carry out the selective silicon alkanisation with TERT-BUTYL DIMETHYL CHLORO SILANE then; With 2,2-dimethyl-butyrylchlorine acidylate is taken off the basic SV (U.S. Pat P4965200) that gets of TERT-BUTYL DIMETHYL CHLORO SILANE protection;
(5), can reduce the method (U.S. Pat P6521762, USP6825362, USP6995277) of the purification lovastatin and the SV of dimer impurity level.
In the aforesaid method, method (1) reaction specificity is better, but severe reaction conditions, technical difficulty is high, and used hydroxyl protection reagent TERT-BUTYL DIMETHYL CHLORO SILANE costs an arm and a leg, and deprotection reaction need carry out under strong acidic condition, and operational path is longer; Method (2) operational path is short, but methylated temperature requirement is very harsh, and methylates and possibly take place at other position of molecule, thereby introduces by product, causes the yield of the finished product and purity all undesirable; Method (3) 2-methyl butyl ester is sterically hindered big, and the ester hydrolysis needs high temperature, highly basic and long-time reaction (approximately to need 50h～60h), and with this understanding; Hexa-atomic lactonic ring is prone to open loop; Acyl group is difficult to remove fully, causes product yield not high (about 40%), and influences quality product; Method (4) is utilized high specificity, hyperergy, low cost, the low polluting property of ferment method; Make this semi-synthesis method that utilizes mikrobe, ferment; Become the following direction of tide of producing medicine, but receive the low restriction of fermentation level at present, be difficult to realize large-scale industrial production; The method of dimer content in method (5) the purifying SV product, more complicated needs the number of times of recrystallization more mostly.
Summary of the invention
The technical problem that the present invention will solve provides the new compound method of a kind of SV, to reduce production costs, simplifies production technique.
For solving the problems of the technologies described above, the preparation method of structural formula of the present invention (I) SV is:
A, lovastatin (II) prepare lovastatin acid amides (III) with alkylamine;
Wherein R is hydrogen, ethyl, butyl or cyclopropyl, R
1Be ethyl, butyl or cyclopropyl;
B, use trialkyl silica chlorine are protected the hydroxyl in the above-mentioned lovastatin amide molecule, generate lovastatin acid amides two silicon ethers (IV);
R wherein
2, R
3, R
4Be the tertiary butyl or methyl;
C, use methylating reagent methylate to the alpha-carbon of the side chain 2-Methyl Butyric Acid ester of above-mentioned lovastatin acid amides two silicon ethers, obtain SV acid amides two silicon ethers (V);
D, add the water termination reaction, make above-mentioned SV acid amides two silicon ether deprotections generate SV acid amides (VI);
E, the hydrolysis under alkaline condition of above-mentioned SV acid amides, logical ammonia obtains simvastatin ammonium salt (VII);
F, the cyclization under acidic conditions of above-mentioned simvastatin ammonium salt generate SV (I).
Among the inventive method step b, used hydroxyl protection reagent trialkyl silica chlorine is trimethylchlorosilane, and reaction solvent is THF and the formed double solvents of hexanaphthene, and products therefrom is lovastatin acid amides two (trimethylammonium) silicon ether (VIII).After generating the reacting completely of lovastatin acid amides two (trimethylammonium) silicon ether (VIII) like this; Remove by filter insolubles, can directly carry out methylation reaction, in the pickling and water washing process after methylating; Blocking group comes off automatically; Can be formed directly in SV acid amides (VI), simplified generation technology, reduced production cost;
Among the inventive method step c, methylate (SV acid amides two silicon ethers) is after washing, and blocking group comes off automatically, can be formed directly in the SV acid amides; Among the step f, (damping fluid of strong acid and organic bases) carries out the cyclization esterification under acidic conditions, can obtain the SV bullion of higher degree.
The described alkylamine of the inventive method step a is n-Butyl Amine 99, cyclopropylamine, quadrol; The described methylating reagent of step c is meant n-Butyl Lithium, tetramethyleneimine, methyl iodide; The described basic soln of step e is the sodium hydroxide solution of 2～4M.
Inventive principle of the present invention is to be raw material with the lovastatin, on the 2-Methyl Butyric Acid ester side chain on the 8-position of the hexahydro naphthalene ring system of lovastatin, increases a methyl, forms to have 2, the compound of 2-acid dimethyl ester side chain.1, be starting raw material with lovastatin (II), open loop under the effect of primary amine or secondary amine forms lovastatin acid amides (III); 2, with hydroxy-protective group the hydroxyl in the lovastatin amide molecule is protected; Generate lovastatin acid amides two silicon ethers (IV); Adopt trialkylchlorosilane to replace TERT-BUTYL DIMETHYL CHLORO SILANE in the former technology, have raw material and be easy to get, characteristics with low cost as protection reagent.Technology according to traditional is reacted, and need carry out the operation of alkali cleaning and washing after last protective reaction is accomplished, and this moment, obscission can appear in trialkyl silyl, influenced the carrying out of methylation reaction; And the double solvents of forming with THF and hexanaphthene is the solvent of last protective reaction; Imidazoles is that catalyzer is when going up protective reaction; Reaction is accomplished postcooling to insolubles and is separated out fully, removes by filter insolubles, and solution can directly be used for methylation reaction through drying.3, use lithium alkylide, secondary amine, methyl iodide that it is methylated and form SV acid amides two silicon ethers (V); 4, methylate after, adopt an acidic catalyst deprotections such as methanesulfonic, tetrabutyl fluoride amine and acetate, hydrochloric acid, generate SV acid amides (VI); 5, SV acid amides hydrolysis under alkaline condition, logical ammonia generates simvastatin ammonium salt (VII); 6, simvastatin ammonium salt is dissolved in the aprotic organic solvent; (damping fluid of strong acid and a small amount of organic bases) catalyzed cyclization under acidic conditions; Obtain the SV bullion, then with the SV dissolving crude product in methyl alcohol or ethanol isopolarity solvent, behind activated carbon decolorizing; Add the water recrystallization, obtain the pharmaceutical grade SV.Wherein non-protonic solvent can be acetonitrile, methylene dichloride, ETHYLE ACETATE and toluene etc.; Strong acid can be methanesulfonic, tetrabutyl fluoride amine and acetate, hydrochloric acid etc.; Organic bases can be pyridine, imidazoles and alkylamine etc.
Adopt the beneficial effect that technique scheme produced to be: with the blocking group of trialkylchlorosilane as hydroxyl in the lovastatin amide molecule; With THF and the formed double solvents of hexanaphthene is the solvent of last protective reaction, is that catalyzer is gone up protective reaction with the imidazoles, after reaction finishes; Being cooled to insolubles separates out fully; After removing insolubles, directly carry out methylation reaction, solved the difficult problem that blocking group comes off; After methylation reaction finished, product was in water washing process, and blocking group comes off automatically, has saved deprotection reaction, has simplified synthesis technique.
Embodiment
The preparation method of this SV comprises the steps:
Synthesizing of lovastatin acid amides (III): make lovastatin (II) open loop form the lovastatin acid amides with primary amine or secondary amine; Temperature of reaction is 50～90 ℃, and the reaction times is 2～8 hours, then; Excessive amine is removed in underpressure distillation, obtains heavy-gravity lovastatin acid amides; After perhaps extracting with non-proton organic solvent, excessive amine is removed in pickling, and steaming desolventizes, and obtains thick lovastatin acid amides.
Synthesizing of lovastatin acid amides two (trimethyl silicane) ether (VIII): the lovastatin acid amides is dissolved in the double solvents of THF and hexanaphthene; Wherein the volume ratio of THF and hexanaphthene is (1.0～4.2) in the double solvents: 1, and preferred volume ratio is (2.5～3.5): 1.Then, add 1～8 mole trialkylchlorosilane, 1～6 mole imidazoles was in 40～90 ℃ of reactions 2～10 hours.Technical recipe is 4～8 moles a trialkylchlorosilane preferably, 2～5 moles imidazoles, 40～80 ℃ the reaction 1～6 hour, then, put into refrigerator to insolubles to product and separate out fully, remove insolubles after, solution directly is used for methylation reaction.
SV acid amides (VI) synthetic: secondary amine (tetramethyleneimine, Diisopropylamine etc.) and lithium alkylide (like n-Butyl Lithium, hexyl lithium etc.) are formed the amido lithium between-40～-10 ℃, in the disposable solution that joins lovastatin acid amides two (trimethyl silicane) ether of 2～10 moles amido lithium, insulation reaction is 1～5 hour between-50～-10 ℃; 3～10 moles of disposable adding methyl iodide;-40～-10 ℃ were reacted 2～3 hours again, and methylation reaction generates SV acid amides two silicon ethers (V), adds the water termination reaction; In this process; Blocking group comes off automatically, has directly generated the SV acid amides, has simplified synthesis technique.
Synthesizing of simvastatin ammonium salt (VII): in the methyl alcohol or ethanolic soln of SV acid amides (VI); Slowly add 2～4M sodium hydroxide solution; Hydrolysis reaction is 2～8 hours under 60～90 ℃ condition; Be preferably and between 70～80 ℃, reacted 2～5 hours, carry out stepwise solvent extraction with non-protonic solvents such as ETHYLE ACETATE then, logical ammonia obtains simvastatin ammonium salt (VII).
SV (I) synthetic: the simvastatin ammonium salt that makes (VII) is dissolved in non-protonic solvent such as ETHYLE ACETATE or methylene dichloride or the mixed solvent, under acid (damping fluid of strong acid and a small amount of organic bases) catalysis, the damping fluid of methanesulfonic and pyridine preferably; Cyclization lactonizes and obtains the higher SV bullion of purity, with ethanol with the SV dissolving crude product after, add activated carbon decolorizing; The water that adds 1～5 times of ethanol volume; The water of 1～2 times of ethanol volume preferably, crystallization is filtered; 20～50 ℃ of vacuum-dryings obtain pharmaceutical grade SV product.
Below be the preparing method's of this SV embodiment.
Embodiment 1:
(1), N-butyl-7-[1,2,6,7,8 α (R)-six hydrogen-2 (S), 6 (R)-dimethyl--8-[[2-(S)-methylbutyryl base] oxygen base]-1-(S)-naphthyl]-3 (R), 5 (R)-dihydroxyl enanthic acid acid amides (the positive yulocrotine of lovastatin, III) synthetic:
Under the room temperature 24g (59.6 mmole) lovastatin and 50mL n-Butyl Amine 99 are joined in the exsiccant reactor drum that is connected with nitrogen, be heated to 80 ℃ and refluxed 3～4 hours.Cool to room temperature then, 60 ℃ of following water-baths, n-Butyl Amine 99 is removed in underpressure distillation, and after perhaps extracting with non-proton organic solvent, excessive amine is removed in pickling, obtains the positive yulocrotine of thick lovastatin.
(2), N-butyl-7-[1,2,6; 7,8 α (R)-six hydrogen-2 (S), 6 (R)-dimethyl--8-[[2-(S)-methylbutyryl base] oxygen base]-1-(S)-naphthyl]-3 (R); 5 (R)-two (trimethylsiloxy group) enanthic acid acid amides (the positive yulocrotine two of lovastatin (trimethyl silicane) ether, VIII) synthetic:
100mL THF and 50mL hexanaphthene are joined in the above-mentioned dope, after the dissolving, add imidazoles 225g (3.3 moles) fully; Trimethylchlorosilane 432g (4.0 moles); Be heated to 65 ℃ of down reactions 3 hours, under the cool to room temperature, after putting into refrigerator cold-storage to insolubles and separating out fully; Filter, filtrating directly is used for next step reaction.
(3), N-butyl-7-[1,2,6,7,8 α (R)-six hydrogen-2 (S), 6 (R)-dimethyl--8-[[2-(S)-methylbutyryl base] oxygen base]-1-(S)-naphthyl]-3 (R), 5 (R)-dihydroxyl enanthic acid acid amides (the SV acid amides, VI) synthetic:
Under nitrogen protection, the THF 45ml and the tetramethyleneimine 20ml of molecular sieve drying is cooled under-20 ℃, controlled temperature slowly adds the n-butyllithium solution of 1.6M between-25～-20 ℃, reacted 1.5 hours, is incubated 30 minutes, obtains tetramethyleneimine lithium solution.
The positive yulocrotine two of the lovastatin of last step gained (trimethyl silicane) ethereal solution is cooled to-80～-70 ℃, and nitrogen protection adds the tetramethyleneimine lithium for preparing down fast, reacts 1.5 hours down in-35 ℃; Add methyl iodide 150mL (2.4 moles); When intensification is not obvious extremely naturally, cool to-35～-30 ℃, insulation reaction 1 hour; Be warming up to-10 ℃, insulation reaction 30 minutes.Add the mixed solution that 150mL hexanaphthene and 150mL water are formed, stirred 5 minutes, static 15 minutes, divide to fall water layer; The oil reservoir underpressure distillation removes to desolvate and obtains brown thick SV acid amides, adds 150mL dissolve with methanol, subsequent use.
(4), 7-[1,2,6,7,8 α (R)-six hydrogen-2 (S), 6 (R)-dimethyl--8-[[2-(S)-methylbutyryl base] oxygen base]-1-(S)-naphthyl]-3 (R), 5 (R)-dihydroxyl enanthic acid ammoniums (simvastatin ammonium salt, VII) synthetic:
Under the room temperature, the SV acid amides methanol solution that will go up step (3) preparation adds the sodium hydroxide solution 150mL of 3M under agitation condition, be heated to 70～80 ℃; Back flow reaction 3 hours, underpressure distillation to solution becomes thickness is cooled to 5～10 ℃, and the hydrochloric acid that adds 1.5M is regulated pH to 7.0; Add ETHYLE ACETATE 450mL, stir, continue to regulate pH to 5, stirred 5 minutes; Static 30 minutes, divide water layer, the logical ammonia of oil reservoir to pH be 8.5; Obtain simvastatin ammonium salt, 40 ℃ of decompression oven dry get the white crystals simvastatin ammonium salt.
(5), 7-[1,2,6,7,8 α (R)-six hydrogen-2 (S), 6 (R)-dimethyl--8-[[2-(S)-methylbutyryl base] oxygen base]-1-(S)-naphthyl]-3 (R), 5 (R)-dihydroxy-2-pyrone (SV, I) synthetic:
The simvastatin ammonium salt 7g (14.9 mmole) that step (4) is obtained is dissolved in the methylene dichloride of 70mL, slowly adds solution A (1.25mL methanesulfonic, the methylene dichloride of 0.05mL pyridine and 30mL) 25mL, reacts 30 minutes, adds 25mL water; Stirred 15 minutes, static 30 minutes, divide to fall water layer, oil reservoir adds the sodium hydroxide solution of 2M, stirs static; Divide to fall water layer, the middle mutually 0.5 gram gac that adds of oil reservoir stirs decolouring 1 hour, and filtration is after the oil reservoir underpressure distillation concentrates; Add 50mL ethanol, be heated to 60 ℃, after treating to dissolve fully, add 50 ℃ purified water 50mL, the water-bath cooling; Crystallization after the crystallization fully, in 40 ℃ of decompression oven dry, obtains the SV bullion.
Join bullion SV 12g (28.7 mmole) in the 50ml ethanol, stirring heating, 50～60 ℃ of fully dissolvings stop to stir; Filter.Under 50～60 ℃, in feed liquid slowly, the 45ml purified water of about 5 ℃ of Dropwise 5s at the uniform velocity, the feed liquid stirred crystallization, the room temperature condition held is spent the night.Crystal solution is filtered, and filter cake is with 50ml purified water thorough washing, and filter is done, and weighs; 30～45 ℃ of following vacuum-drying 24h obtain pharmaceutical grade SV (yield 80%), content 99.5%.
Embodiment 2:
Except that step (2), other is with embodiment 1, and the synthesis technique of step (2) is following:
107mL THF and 43mL hexanaphthene are joined in the above-mentioned dope, after the dissolving, add imidazoles 238g (3.5 moles) fully; Trimethylchlorosilane 432g (4.0 moles); Be heated to 60 ℃ of down reactions 3 hours, be cooled to room temperature, after putting into refrigerator cold-storage to insolubles and separating out fully; Filter, filtrating directly is used for next step building-up reactions.
Embodiment 3:
Except that step (2), other is with embodiment 1, and the synthesis technique of step (2) is following:
120mL THF and 30mL hexanaphthene are joined in the above-mentioned dope, after the dissolving, add imidazoles 136g (2.0 moles) fully; Trimethylchlorosilane 432g (4.0 moles); Be heated to 75 ℃ of down reactions 2 hours, be cooled to room temperature, after putting into refrigerator cold-storage to insolubles and separating out fully; Filter, filtrating directly is used for next step building-up reactions.
Embodiment 4:
Except that step (3), other is with embodiment 1, and the synthesis technique of step (3) is following:
Under the nitrogen protection, the THF 40ml and the tetramethyleneimine 25ml of molecular sieve drying is cooled under-20 ℃, controlled temperature slowly adds the n-butyllithium solution of 1.6M between-25～-20 ℃, reacted 1.5 hours, is incubated 30 minutes, obtains tetramethyleneimine lithium solution.
The positive yulocrotine two of the lovastatin of gained of last step (trimethyl silicane) ethereal solution is cooled to-80～-70 ℃, and nitrogen protection adds the tetramethyleneimine lithium for preparing down fast, reacts 1.0 hours down in-25 ℃; Add methyl iodide 188mL (3.0 moles); When intensification is not obvious extremely naturally, cool to-25～-20 ℃, insulation reaction 2 hours; Be warming up to-10 ℃, insulation reaction 30 minutes.Add the mixed solution that 150mL hexanaphthene and 150mL water are formed, stirred 5 minutes, static 15 minutes, divide to fall water layer; The oil reservoir underpressure distillation removes to desolvate and obtains brown thick SV acid amides, adds 150mL dissolve with methanol, subsequent use.
Claims (9)
1. the preparation method of a structural formula (I) SV,
It comprises:
A, lovastatin (II) prepare lovastatin acid amides (III) with alkylamine;
Wherein R is hydrogen, ethyl, butyl or cyclopropyl, R
1Be ethyl, butyl or cyclopropyl;
B, use trialkyl silica chlorine are protected the hydroxyl in the above-mentioned lovastatin amide molecule, generate lovastatin acid amides two silicon ethers (IV);
R wherein
2, R
3, R
4Be the tertiary butyl or methyl;
C, use methylating reagent methylate to the alpha-carbon of the side chain 2-Methyl Butyric Acid ester of above-mentioned lovastatin acid amides two silicon ethers, obtain SV acid amides two silicon ethers (V);
D, add the water termination reaction, make above-mentioned SV acid amides two silicon ether deprotections generate SV acid amides (VI);
E, the hydrolysis under alkaline condition of above-mentioned SV acid amides, logical ammonia obtains simvastatin ammonium salt (VII);
F, the cyclization under acidic conditions of above-mentioned simvastatin ammonium salt generate SV (I).
2. the preparation method of SV according to claim 1; It is characterized in that among the said step b; Used hydroxyl protection reagent trialkyl silica chlorine is trimethylchlorosilane; Reaction solvent is THF and the formed double solvents of hexanaphthene, and products therefrom is lovastatin acid amides two (trimethylammonium) silicon ether (VIII).
3. the preparation method of SV according to claim 1 is characterized in that said steps d is: the methylate SV acid amides two silicon ethers among the step c are after washing, and blocking group comes off automatically, directly forms the SV acid amides.
4. the preparation method of SV according to claim 1 is characterized in that among the said step f, under acidic conditions, carries out the cyclization esterification, obtains the SV bullion of higher degree.
5. the preparation method of SV according to claim 4 is characterized in that the acidic conditions among the said step f is in the damping fluid of strong acid and organic bases, to carry out the cyclization esterification.
6. the preparation method of SV according to claim 1 is characterized in that the described alkylamine of said step a is n-Butyl Amine 99, cyclopropylamine, quadrol.
7. the preparation method of SV according to claim 1 is characterized in that the described methylating reagent of said step c is meant n-Butyl Lithium, tetramethyleneimine, methyl iodide.
8. the preparation method of SV according to claim 1 is characterized in that the described basic soln of said step e is the sodium hydroxide solution of 2～4M.
9. the preparation method of SV according to claim 1 is characterized in that SV (I) that said step f obtains after the proper amount of active carbon decolouring, carries out recrystallization with the second alcohol and water.
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| CN102532185B (en) * | 2010-12-21 | 2015-03-04 | 北大方正集团有限公司 | Preparation methods of lovaamide hexamethyloxy disilane, simvastatin hexamethyloxy disilane and simvastatin |
| CN103787881A (en) * | 2013-11-22 | 2014-05-14 | 成都摩尔生物医药有限公司 | Simvastatin ammonium salt |
| CN104803959B (en) * | 2014-01-24 | 2017-02-08 | 上虞京新药业有限公司 | Simvastatin preparation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031086A (en) * | 1987-07-10 | 1989-02-15 | 麦克公司 | The alkylating method of alpha-carbon of Mai Weinuo element and analogue 8-acyl group thereof |
| WO2006059346A2 (en) * | 2004-12-01 | 2006-06-08 | Morepen Laboratories Limited | An improved process for lactonization to produce highly pure statins |
| US20070129437A1 (en) * | 2005-12-06 | 2007-06-07 | Ferenc Korodi | Process for preparing simvastatin and intermediates thereof |
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2008
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031086A (en) * | 1987-07-10 | 1989-02-15 | 麦克公司 | The alkylating method of alpha-carbon of Mai Weinuo element and analogue 8-acyl group thereof |
| WO2006059346A2 (en) * | 2004-12-01 | 2006-06-08 | Morepen Laboratories Limited | An improved process for lactonization to produce highly pure statins |
| US20070129437A1 (en) * | 2005-12-06 | 2007-06-07 | Ferenc Korodi | Process for preparing simvastatin and intermediates thereof |
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