WO2004113314A1 - Novel boronate esters - Google Patents

Novel boronate esters Download PDF

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Publication number
WO2004113314A1
WO2004113314A1 PCT/IN2004/000175 IN2004000175W WO2004113314A1 WO 2004113314 A1 WO2004113314 A1 WO 2004113314A1 IN 2004000175 W IN2004000175 W IN 2004000175W WO 2004113314 A1 WO2004113314 A1 WO 2004113314A1
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formula
compound
aryl
alkyl
carbons
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PCT/IN2004/000175
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French (fr)
Inventor
Ramakrishan Melarkode
Sanjay Tiwari
Shrikumar Suryanarayan
Anand Khedkar
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Biocon Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila and more particularly to compounds of formula II which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin. BACKGROUND OF THE INVENTION
  • Ri and R 2 are independently chosen alkyl of one to three carbons and R 3 is alkyl of from 1 to 8 carbon atoms, alternatively compounds of formula la,
  • ⁇ and R 2 are independently chosen from alkyl of one to three carbons, phenyl or Ri and R 2 taken together as - (CH2)n- wherein n is 4 or 5 and R 3 is alkyl of from 1 to 8 carbon atoms and also compounds of Formula lb
  • R x and R 2 are alkyl of from 1-5 carbons and R 3 is as defined above is a valuable structural element for synthesizing compounds, which are known as ant hypercholesterolemic agents having an inhibitory effect on HMG-CoA reductase.
  • EP 0 319 847 describes a process for the preparation of compounds of formula 1 starting from L-Malic acid. This process, however, suffers from the fact that the process is not industrially scalable and also possesses purification problems due to the non- crystalline nature of the intermediates.
  • US 5,998,633 describes a process for the preparation of protected esters of 3,4-dihydroxy butyric acid from a carbohydrate moiety which is transformed into the desired 3,4-dihydroxy butanoic acid derivatives in about 4 steps.
  • the 3,4-dihydroxy butanoic acid derivative is then functionalized into compounds of formula I involving a multiple number of steps.
  • Ar ' unsubstituted or substituted aryl or heteroaryl
  • R 3 alkyl from 1 to 8 carbons, aryl or aralkyl
  • the present invention also provides for a process for the manufacture of compounds of formula II
  • Ar unsubstituted or substituted aryl or heteroaryl
  • R 3 alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of:
  • the compound of formula II is oxidized to a compound of formula VIII, where R 3 is alkyl from 1 to 8 carbons, aryl or aralkyl and Ar is unsubstituted or substituted aryl or heteroaryl using pyridinium chloro chromate or DMSO/oxalyl chloride.
  • Formula IX The compound of formula IX is further converted to a compound of formula VII, where R 3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl.
  • Compound of formula II serves as a good intermediate for the synthesis of important substrates, which are useful in the synthesis of statins.
  • Compound of formula II can be converted into a facile leaving group by treating with tosyl chloride, methane sulfonyl chloride and the resulting intermediate can be displaced with cyanide to give compounds of formula VII.
  • Compound of formula II can be converted to formula IX by reacting with aqueous HBr solution or by reaction with triphenyl phosphine and CBr 4 which is then converted to compound of formula VII.
  • Compound of formula II can be oxidized using standard procedures to give a compound of formula VIII.
  • the present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin.
  • Example 4 Synthesis of tert-Butyl 6-triphenylmethyIoxy- 3,5-phenylboranatohexanoate (Formula VI)
  • the crude product from example-3 was dissolved in 100ml of toluene and 5.6g of phenyl boronic acid was added. Water was removed by azeotropic distillation over a period of 3h.
  • the reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give lOg of the title product.
  • Example 5 Synthesis of tert-butyl 6-hydroxy-3,5- (phenylboranato)hexanoate (Formula II)
  • Rl and R2 are alkyl 1 to 3 carbons
  • R3 is alkyl from 1 to 8 carbons
  • Rl and R2 are alkyl from 1 to 5 carbons
  • R 3 is alkyl from 1 to 8 carbons

Abstract

The present invention relates to optically active dihydroxy hexanoate derivatives, boronate esters of formula (IIa) which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin. Ar = unsubstituted or substituted aryl or heteroaryl, R3 = alkyl from 1 to 8 carbons, aryl or aralkyl, R4 = O, OH, CN or a halogen and a = single bond or a double bond.

Description

TITLE OF THE INVENTION Novel Boronate esters FIELD OF THE INVENTION
The present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila and more particularly to compounds of formula II which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin. BACKGROUND OF THE INVENTION
Esters and derivatives of the formula 1,
Figure imgf000003_0001
where Ri and R2 are independently chosen alkyl of one to three carbons and R3 is alkyl of from 1 to 8 carbon atoms, alternatively compounds of formula la,
Figure imgf000003_0002
wherein ^ and R2 are independently chosen from alkyl of one to three carbons, phenyl or Ri and R2 taken together as - (CH2)n- wherein n is 4 or 5 and R3 is alkyl of from 1 to 8 carbon atoms and also compounds of Formula lb
Figure imgf000003_0003
wherein Rx and R2 are alkyl of from 1-5 carbons and R3 is as defined above is a valuable structural element for synthesizing compounds, which are known as ant hypercholesterolemic agents having an inhibitory effect on HMG-CoA reductase.
EP 0 319 847 describes a process for the preparation of compounds of formula 1 starting from L-Malic acid. This process, however, suffers from the fact that the process is not industrially scalable and also possesses purification problems due to the non- crystalline nature of the intermediates.
US 5,399,722 describe a process starting from commercially available ethyl ω-cloroacetoacetate or its benzyloxy derivative. The disadvantages of this process are that a stereo selective reduction using a costly ruthenium-BINAP catalyst in employed and the desired compound of formula 1 is obtained in six steps.
US 5,481,009 describe a process starting from 4-phenyl-3- butenoic acid in about 5 steps. The process uses expensive materials like - N, O-Dimethyl hydroxylamine and hazardous steps (ozonolysis) to obtain the desired product.
US 5,998,633 describes a process for the preparation of protected esters of 3,4-dihydroxy butyric acid from a carbohydrate moiety which is transformed into the desired 3,4-dihydroxy butanoic acid derivatives in about 4 steps. The 3,4-dihydroxy butanoic acid derivative is then functionalized into compounds of formula I involving a multiple number of steps.
US 6,140,527 describes a process for producing butyric acid derivatives starting from a butene derivative followed by reaction with an addition reagent capable of adding across the double bond. However, this procedure does not afford chiral molecules and hence necessitates the need for a resolution step. EP 0 104 750 describes a process for the preparation of 5- hydroxy-3-oxo pentanoic acid derivatives by alkylation of 3- hydroxybutyrate derivatives. The derivatives mentioned in this patent are racemic molecules and thus necessitating a resolution step. The objective of the present is to provide a simple and industrially scalable process for the preparation of derivatives of formula I starting from commercially available and inexpensive malic acid. Summary of the invention To achieve the said object the present invention provides a product of formula Ila and more particularly a compound of formula II
Figure imgf000005_0001
Formula Ila
Figure imgf000005_0002
Formula II wherein
Ar =' unsubstituted or substituted aryl or heteroaryl
R3 = alkyl from 1 to 8 carbons, aryl or aralkyl R4 = 0, OH, CN or a halogen and a = single bond or double bond
The present invention also provides for a process for the manufacture of compounds of formula II
Figure imgf000006_0001
Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of:
(a) reacting compound of formula III with the anion of tertiary butyl acetate to give a compound of formula IV, where G is tetrahydropyranyl, tert-butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyl,
Figure imgf000006_0002
Formula III Formula IV
(b) subjecting compound of formula IV to reduction to give a compound of formula V, where G is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, o o o
Formula V ( c) protecting the compound of formula V with ArB(OH)2 to give a compound of formula VI, where Ar is unsubstituted or substituted aryl or heteroaryl, G is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, and
Figure imgf000007_0001
Formula VI ( f) deprotectϊon of the compound of formula VI using mild acid catalyst to give a compound of formula II. Said ArB(OH)2 is boronic acid.
The compound of formula II is oxidized to a compound of formula VIII, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl and Ar is unsubstituted or substituted aryl or heteroaryl using pyridinium chloro chromate or DMSO/oxalyl chloride.
Figure imgf000007_0002
Formula VIII The compound of formula II is further converted to a compound of formula IX, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl and X is a halogen. rΥY o»
R3
V
Ar
Formula IX The compound of formula IX is further converted to a compound of formula VII, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl.
Figure imgf000008_0001
Formula VII The product of formula Ila and more particularly of formula II are used in the synthesis of atorvastatin, cerivastatin, pitavastatin, fluvastatin or rosuvastatin. Detailed Description of the invention
Compound of formula II serves as a good intermediate for the synthesis of important substrates, which are useful in the synthesis of statins. Compound of formula II can be converted into a facile leaving group by treating with tosyl chloride, methane sulfonyl chloride and the resulting intermediate can be displaced with cyanide to give compounds of formula VII.
Compound of formula II can be converted to formula IX by reacting with aqueous HBr solution or by reaction with triphenyl phosphine and CBr4 which is then converted to compound of formula VII.
Compound of formula II can be oxidized using standard procedures to give a compound of formula VIII. The present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin.
The invention is further illustrated with examples below, which are not intended to be limiting.
Example 1: Synthesis of methyl 4-triphenylmethyloxy-3- hydroxybutyrate (Formula III)
To 25g of methyl 3,4-dihydroxybutanoate was added to 250ml of DCM and stirred to dissolve and 19.8g of pyridine was charged and cooled to 0°C. 41.4g of trityl chloride was dissolved in 50ml of DMC and was added at 0-5°C for 15 min. The temperature was allowed to rise to RT and was stirred at RT for 17h. Water was added and the layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was triturated with 25ml of cyclohexane and the product was purified to give 15g of the pure product.
NMR (CDCI3) : 4.25 (m, 1H), 3.6 (s, 3H), 3.15 (d, 2H), 2.5 (m, 2H), 7.2-7.4 (m, 15H) Example 2: Synthesis of tert-butyl 6-triphenylmethyloxy-5- hydroxy-3-oxohexanoate (Formula IV)
To 125ml of THF, 24g of diisopropylamine were charged and was cooled to -15°C. 168ml of 1.2N n-BuLi was added at -15 to - 5°C and was stirred for 30min. 21.56g of tert-butyl acetate in 45ml of THF which was pre-cooled to -45°C was added maintaining the temperature between -45 to -25°C for 60min. Cool the reaction mixture to -45°C and 30g of example-1 in THF was added over a period of 20min and the stirring was continued at -25°C for 90min. Water was added and the layers were separated. The aqueous layer was extracted using EtOAc and the combined organic layers were washed with brine, water, dried and concentrated to give the title compound which was used as such for the next step. Example 3: Synthesis of tert-butyl 6-triphenylmethyloxy- 3,5-dihydroxhexanaote (Formula V)
To the crude material obtained in example-2, 150ml of THF was added followed by 15ml of MeOH and was chilled to -60°C. 26ml of MDEB (50% solution in THF) was added over a period of 20min and stirring was continued for a further 30min. The reaction mixture was cooled to -80°C and 5g of sodium borohydride was added in portions and the after completion of addition the reaction mixture was stirred for 5h at -78°C. Acetic acid was added to adjust the pH to 7 and water was added. The aqueous layer was extracted using EtOAc, washed with brine, dried and concentrated to give the title compound which was used as such for the next step.
Example 4: Synthesis of tert-Butyl 6-triphenylmethyIoxy- 3,5-phenylboranatohexanoate (Formula VI) The crude product from example-3 was dissolved in 100ml of toluene and 5.6g of phenyl boronic acid was added. Water was removed by azeotropic distillation over a period of 3h. The reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give lOg of the title product. Example 5: Synthesis of tert-butyl 6-hydroxy-3,5- (phenylboranato)hexanoate (Formula II)
To 5g of the product from example-4 20ml of DCM was added and was chilled to 0°C. 5ml of TFA was added and was stirred at 20°C for 6h. Water was separated and the organic layer was washed with bicarbonate, brine, dried and concentrated to give the title product, which was purified by column chromatography.
NMR (CDCI3) : 7.7-7.8 (m, 2H), 7.4-7.5 (m, 1H), 7.3-7.4 (m, 2H), 4.5 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 3.5 (m, 1H), 2.55 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.7 (m, 1H) 1.5 (s, 9H) Example 6: Synthesis of tert-butyl 6-cyano-3,5- (phenylboranato)hexanoate (Formula VII)
5g of the product obtained from example 5 was taken in dichloromethane (50mL) and pyridine (lOmL) was added. The contents were cooled to -10°C and methanesulfonyl chloride (1 eq) was added drop wise. After 5-6 hours of stirring at 0°C, the contents were washed with bicarbonate, water and brine. The solvent was removed under reduced pressure to afford the O- methanesulfonyl derivative, which was used as such for the next step.
The crude mesylate was taken in DMSO (5 vols.) and 1.5 equivalents of potassium cyanide was added. The contents were maintained at reflux for a period of 18-22h. DMSO was removed under reduced pressure and the contents were extracted using ethyl acetate and was washed with bisulfite, brine and solvent was removed under reduced pressure to afford the desired product. Example 7: Synthesis of t-butyl 6-oxo-3,5- phenylboranatohexanoate (Formula VIII)
4.3g of dimethylsulfoxide was added drop wise to a solution of 2.4ml of oxalyl chloride in 100ml of dichloromethane maintained at -78°C. The mixture was stirred at that temperature for a period of 15min and 5g of the compound from example 5 dissolved in dichloromethane was added drop wise. After stirring for 15min, 17ml of triethyl amine was added and the reaction mixture was allowed to warm to ambient temperature in 2h period. Reaction mixture was concentrated and the residue was dissolved in water and extracted using diethyl ether. Removal of solvent affords the title compound.
Formula I Formula lb
Figure imgf000012_0001
Rl and R2 are alkyl 1 to 3 carbons R3 is alkyl from 1 to 8 carbons Rl and R2 are alkyl from 1 to 5 carbons R 3 is alkyl from 1 to 8 carbons
Formula la Formula Ila
Figure imgf000012_0002
Rl and R2 are alkyl 1 to 3 carbons or taken together as • Ar = unsubstituted or substituted aryl or heteroaryl (CH2)n- where n is 4 or 5 R3 = alkyl from 1 to 8 carbons, aryl or aralkyl R3 is alkyl from 1 to 8 carbons R4 = OH, CN or X and a =single bond R4 = O and a = double bond
Formula II Formula III o. o o o
Figure imgf000013_0001
Scheme - 1
Figure imgf000013_0002
III IV
Scheme - 2
Figure imgf000013_0003
IV V
II Scheme - 3
Figure imgf000014_0001
Scheme - 4
Figure imgf000014_0002
VI
Scheme - 5
Figure imgf000014_0003
II IX
Scheme - 6
Figure imgf000014_0004
IX VII
Scheme - 7
Figure imgf000014_0005
II VIII

Claims

We claim:
1. The product of formula Ila
Figure imgf000015_0001
wherein Ar = unsubstituted or substituted aryl or heteroaryl
R3 = alkyl from 1 to 8 carbons, aryl or aralkyl R4 = 0, OH, CN or a halogen and a = single bond or double bond
2. The product as claimed in claim 1 wherein said product is a compound of formula II
Figure imgf000015_0002
B
Ar wherein Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyl
3. A process for the manufacture of compounds of formula II
Figure imgf000016_0001
Ar = unsubstituted or substituted aryl or heteroaryl R3 = alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of:
- (a) reacting compound of formula III with the anion of tertiary butyl acetate to give a compound of formula IV, where G is tetrahydropyranyl, tert-butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyl,
o r IT ^^ ^> ^ 44 IT ^3 o o o o o
Formula III Formula IV
(b) subjecting compound of formula IV to reduction to give a compound of formula V, where G is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyl,
o o o
Formula V ( c) protecting the compound of formula V with ArB(OH)2 to give a compound of formula VI, where Ar is unsubstituted or substituted aryl or heteroaryl, G is tetrahydropyranyl, tert- butyldimethyl silyl or trityl and R3 is alkyl from 1 to 8 carbons, aryl or aralkyl/ and
Figure imgf000017_0001
Formula VI ( f) deprotection of the compound of formula VI using mild acid catalyst to give a compound of formula II.
4. A process as claimed in claim 3 wherein ArB(OH)2 is boronic acid.
5. A process as claimed in claim 3 wherein compound of formula II is oxidized to a compound of formula VIII, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl and Ar is unsubstituted or substituted aryl or heteroaryl using pyridinium chloro chromate or DMSO/oxalyl chloride.
Figure imgf000017_0002
Formula VIII 6.. A process as claimed in claim 3 wherein compound of formula II is further converted to a compound of formula IX, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl and X is a halogen.
Figure imgf000017_0003
Formula IX
7. A process as claimed in claim 6 wherein compound of formula II is converted to compound of formula IX by reacting compound of formula II with aqueous HBr solution or by reaction with triphenyl phosphine and CBr4.
8. A process as claimed in claim 6 or 7 wherein compound of formula IX is further converted to a compound of formula VII, where R3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl.
Figure imgf000018_0001
Formula VII 9. The product as claimed in claim 1, used in the synthesis of atorvastatin, cerivastatin, pitavastatin, fluvastatin or rosuvastatin.
PCT/IN2004/000175 2003-06-23 2004-06-18 Novel boronate esters WO2004113314A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7416865B2 (en) 2000-05-09 2008-08-26 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7442811B2 (en) 2002-06-17 2008-10-28 Astrazeneca Uk Limited Process for the preparation of dioxane acetic acid esters
KR100933172B1 (en) 2007-11-30 2009-12-21 씨제이제일제당 (주) Improved preparation of atorvastatin calcium salt
US7642363B2 (en) 2000-07-19 2010-01-05 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
US7718812B2 (en) 2001-12-27 2010-05-18 Astrazeneca Uk Limited Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates
US7879585B2 (en) 2006-10-02 2011-02-01 Codexis, Inc. Ketoreductase enzymes and uses thereof
JP2015513556A (en) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． Novel statin intermediate and method for producing pitavastatin, rosuvastatin, cerivastatin and fluvastatin using the same

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7416865B2 (en) 2000-05-09 2008-08-26 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7732171B2 (en) 2000-05-09 2010-06-08 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7888083B2 (en) 2000-05-09 2011-02-15 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7642363B2 (en) 2000-07-19 2010-01-05 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
US7989643B2 (en) 2000-07-19 2011-08-02 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US7718812B2 (en) 2001-12-27 2010-05-18 Astrazeneca Uk Limited Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates
US7442811B2 (en) 2002-06-17 2008-10-28 Astrazeneca Uk Limited Process for the preparation of dioxane acetic acid esters
US7879585B2 (en) 2006-10-02 2011-02-01 Codexis, Inc. Ketoreductase enzymes and uses thereof
US8273547B2 (en) 2006-10-02 2012-09-25 Codexis, Inc. Engineered ketoreductases and methods for producing stereoisomerically pure statins
US8617864B2 (en) 2006-10-02 2013-12-31 Codexis, Inc. Polynucleotides encoding ketoreductases for producing stereoisomerically pure statins and synthetic intermediates therefor
KR100933172B1 (en) 2007-11-30 2009-12-21 씨제이제일제당 (주) Improved preparation of atorvastatin calcium salt
JP2015513556A (en) * 2012-05-17 2015-05-14 株式会社エフエヌジーリサーチＦｎｇ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． Novel statin intermediate and method for producing pitavastatin, rosuvastatin, cerivastatin and fluvastatin using the same

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