WO2008059366A2 - Process for the preparation of cis-1, 3-diols from the corresponding beta-hydroxy ketones employing microbial ketone reductases - Google Patents
Process for the preparation of cis-1, 3-diols from the corresponding beta-hydroxy ketones employing microbial ketone reductases Download PDFInfo
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- WO2008059366A2 WO2008059366A2 PCT/IB2007/003530 IB2007003530W WO2008059366A2 WO 2008059366 A2 WO2008059366 A2 WO 2008059366A2 IB 2007003530 W IB2007003530 W IB 2007003530W WO 2008059366 A2 WO2008059366 A2 WO 2008059366A2
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
- C12P7/04—Preparation of oxygen-containing organic compounds containing a hydroxy group acyclic
- C12P7/18—Preparation of oxygen-containing organic compounds containing a hydroxy group acyclic polyhydric
Definitions
- the present invention relates to a process for preparing c;s-1 ,3-d ⁇ ols More particularly, to (3R,5R)-terf-butyl 6-cyano-3,5,d ⁇ hydroxyhexanoate
- c/s-diols are valued as intermediates for the preparation of, for example, HMG-CoA reductase inhibitors containing a c/s-1 ,3-d ⁇ ol moiety
- HMG-CoA reductase inhibitors containing a c/s-1 ,3-d ⁇ ol moiety
- These inhibitors are useful as hypolipidemic and hypocholesterolemic agents
- This is a widely used method of preparation of such agents for example U S Patent Nos 4,645,854, 5,354,772, 5,155,251 , and 4,970,313
- Chemical reduction methods often require hazardous reagents, cryogenic conditions, and complicated workup procedures, and may lack selectivity with respect to producing the desired as diastereomers
- a process using ketone reductase obtained from specific microorganisms to reduce a beta-hydroxy ketone to obtain the corresponding c/s-1 , 3-d ⁇ ol is described in U S patent No 6,001 ,615 However
- a process for producing a c ⁇ s-1 ,3 o-diol comprising the steps of reducing a corresponding beta-hydroxy ketone using a ketone reductase wherein the ketone reductase is obtained from Monosponum, Rhodococcus, Lechevaliena, Fusanum, Spondiobolus, Streptomyces, Absidia, or Rhodotorula and, recovering the desired c/s-1 ,3-diol.
- alkyl means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl, isobutyl, tertiary butyl (t-butyl), n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
- “Purified ketone reductase” or “purified enzyme” means: a preparation derived by removal of some of the materials or the majority of materials not contributing to the desired activity. Obtained from” means that the ketone reductase used is provided from an organism in the form of whole cells, modified whole cells, including but not limited to, dead cells, cell lysates, supernatant from cell lysates, or purified enzyme.
- Halo means halogens such as fluorine, chlorine, and bromine or iodine atoms.
- the compound of formula Il is either known in the art or capable of being prepared by methods known in the art, for example in US patent No. 5,155,251.
- One embodiment of the invention provides a process for producing a c/s-1 ,3-diol comprising the steps of reducing the corresponding beta-hydroxy ketone using a ketone reductase wherein the ketone reductase is obtained from: Monosporium, Rhodococcus, Lechevalie ⁇ a, Fusarium, Sporidiobolus, Streptomyces, Absidia, or Rhodotorula and; recovering the desired cis-1 ,3-diol.
- the invention provides a process for producing a compound of formula (I)
- R is halo or -CN; and R 1 is alkyl of 1 , 2, 3, 4, 5, or 6 carbon atoms; comprising: reducing a compound of formula Il
- R and R 1 are as defined above, with a ketone reductase obtained from Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia or Rhodotorula and recovering the compound of Formula (I).
- ketone reductase that is obtained from: Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia or Rhodotorula.
- the reductase is provided in the form of whole cells of: Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia or Rhodotorula.
- the ketone reductase is obtained from Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusarium solani, Sporidiobolus johnsonii, Streptomyces violascens, Absidia cylindrospora, Rhodotorula sp., Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
- the reductase is in the form of a purified ketone reductase that is obtained from: Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusarium solani, Sporidiobolus johnsonii, Streptomyces violascens, Absidia cylindrospora,
- Rhodotorula sp. Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
- the reductase is provided in the form of whole cells of: Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusarium solani, Sporidiobolus johnsonii, Streptomyces violascens, Absidia cylindrospora, Rhodotorula sp., Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa
- the ketone reductase is obtained from Rhodotorula sp., Rhodotorula minuta, Rhodotorula pilimanae, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
- the reductase is in the form of a purified ketone reductase that is obtained from: Rhodotorula sp., Rhodotorula minuta, Rhodotorula pilimanae, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
- the reductase is provided in the form of whole cells of: Rhodotorula sp., Rhodotorula minuta, Rhodotorula pilimanae, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
- R 1 is tertiary butyl.
- R is -CN.
- R is Chloro or Bromo.
- Suitable methods of mutagenesis are well known in the art, these methods include site-directed mutagenesis or random mutagenesis using Error-prone-PCR. For other methods and a description of their use see, Organic Process Research & Development 2006, 10, 562-571 Cells used in the process of the invention are grown in a suitable nutrient medium. Growth and maintenance conditions for culture of the organisms used in the invention are well known to one of skill in the art.
- the reduction may be carried out using whole cells or with ketone reductase that has been purified from whole cells.
- the conversion of the beta-hydroxy ketone to the corresponding c/s-1 ,3-diol with an isolated ketone reductase must be carried out in the presence of a co-factor, such as nicotinamide adenine dinucleotide (NADH ) or nicotinamide adenine dinucleotide phosphate (NADPH) and components for regenerating the co-factor for example: glucose and glucose dehydrogenase.
- NADH nicotinamide adenine dinucleotide
- NADPH nicotinamide adenine dinucleotide phosphate
- the conversion of the beta-hydroxy ketone to the corresponding c/s-1 ,3-diol may be carried out using whole cells of the organism in a nutrient medium, in which case the cells may provide the co-factor regeneration components.
- the nutrient medium may be that used normally to culture the organism, for example a medium that contains a suitable carbon source. If cell growth during the reaction is desired the medium should contain nitrogen, and phosphorus sources and trace elements.
- a suitable carbon source is, for example, maltose, sucrose, glucose, polyol (e.g.. glycerol, sorbitol), citric acid, or a lower alcohol such as methanol or ethanol.
- a compound of formula (II) is added to a suspension of live cells in a medium that supports growth of the organism in another embodiment the compound of formula (II) is added to a suspension of the live cells that lacks one or more nutrients necessary for growth Dead cells may also be used provided that the necessary enzymes and co-factors are present
- the cells may be immobilized on a support
- the process of the invention may be earned out at a pH between of about 3 5 and about 9, preferably between about 6 and about 9, and more preferably between about 6 and about 8, most preferably about 7 Suitable temperatures for the process of the invention are about 10 to about 50 0 C, preferably about 20 to about 4O 0 C, and more preferably about 25 to about 35°C
- Pu ⁇ fied enzymes may be isolated using methods well known in the art (e g Robert K Scopes, (1994), Protein Purification Principles and Practice, Third Edition, Springer-Verlag, New York) These methods may include cent ⁇ fugation of whole or lysed cells, isolating the enzyme from the supernatant, for example by ion exchange chromatography or by selective precipitation or both
- Fembach flask that contained 500 mL of the same medium The Fembach flask was incubated for 24 hours (for yeast and bacteria) or 48 hours (for fungi and actinomycetes) at 29 0 C on an orbital shaker at 210 rpm
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Abstract
A process for selectively reducing beta-hydroxy ketones, using a ketone reductase obtained from: Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia, or Rhodotorula, to obtain the corresponding cis- 1,3-diol. A purified ketone reductase obtained from an organism of the genera Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia, or Rhodotorula.
Description
PROCESS FOR THE SYNTHESIS OF C/S-1 ,3-DIOLS
FIELD OF THE INVENTION
The present invention relates to a process for preparing c;s-1 ,3-dιols More particularly, to (3R,5R)-terf-butyl 6-cyano-3,5,dιhydroxyhexanoate
BACKGROUND OF THE INVENTION
Processes for selectively reducing a beta-hydroxy ketone to obtain the corresponding c/s-1 ,3-dιol are described in the literature for example US Patent No 6,962,994 also United States Patent No 6,001 ,615 describe reducing a beta- hydroxy ketone to obtain the corresponding c/s-1 ,3-dιol using ketone reductase expressing organisms
These c/s-diols are valued as intermediates for the preparation of, for example, HMG-CoA reductase inhibitors containing a c/s-1 ,3-dιol moiety These inhibitors are useful as hypolipidemic and hypocholesterolemic agents This is a widely used method of preparation of such agents for example U S Patent Nos 4,645,854, 5,354,772, 5,155,251 , and 4,970,313 Chemical reduction methods often require hazardous reagents, cryogenic conditions, and complicated workup procedures, and may lack selectivity with respect to producing the desired as diastereomers A process using ketone reductase obtained from specific microorganisms to reduce a beta-hydroxy ketone to obtain the corresponding c/s-1 , 3-dιol is described in U S patent No 6,001 ,615 However it is desirable to identify other microorganism that are able to carry out this reaction We have found that reduction of hydroxy-ketones to c/s-diols can be carried out with high selectivity and without the use of hazardous reagents using ketone reductases from one or more microorganism of the genera Monosponum, Rhodococcus, Lechevaliena, Fusanum, Spondiobolus, Streptomyces, Absidia, or Rhodotorula
SUMMARY OF THE INVENTION A process for producing a cιs-1 ,3 o-diol comprising the steps of reducing a corresponding beta-hydroxy ketone using a ketone reductase wherein the ketone reductase is obtained from Monosponum, Rhodococcus, Lechevaliena, Fusanum, Spondiobolus, Streptomyces, Absidia, or Rhodotorula and,
recovering the desired c/s-1 ,3-diol.
DETAILED DESCRIPTION
In this invention the term "alkyl" means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl, isobutyl, tertiary butyl (t-butyl), n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
"Purified ketone reductase" or "purified enzyme" means: a preparation derived by removal of some of the materials or the majority of materials not contributing to the desired activity. Obtained from" means that the ketone reductase used is provided from an organism in the form of whole cells, modified whole cells, including but not limited to, dead cells, cell lysates, supernatant from cell lysates, or purified enzyme.
The article "a" or "an" as used herein refers to both the singular and plural form of the object to which it refers. "Halo" means halogens such as fluorine, chlorine, and bromine or iodine atoms.
The compound of formula Il is either known in the art or capable of being prepared by methods known in the art, for example in US patent No. 5,155,251.
One embodiment of the invention provides a process for producing a c/s-1 ,3-diol comprising the steps of reducing the corresponding beta-hydroxy ketone using a ketone reductase wherein the ketone reductase is obtained from: Monosporium, Rhodococcus, Lechevalieήa, Fusarium, Sporidiobolus, Streptomyces, Absidia, or Rhodotorula and; recovering the desired cis-1 ,3-diol.
In one embodiment the invention provides a process for producing a compound of formula (I)
wherein R is halo or -CN; and R1 is alkyl of 1 , 2, 3, 4, 5, or 6 carbon atoms; comprising: reducing a compound of formula Il
wherein R and R1 are as defined above, with a ketone reductase obtained from Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia or Rhodotorula and recovering the compound of Formula (I).
In another embodiment of the invention is purified ketone reductase that is obtained from: Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia or Rhodotorula.
In another embodiment of the invention the reductase is provided in the form of whole cells of: Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia or Rhodotorula.
In another embodiment of the invention the ketone reductase is obtained from Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusarium solani, Sporidiobolus johnsonii, Streptomyces violascens, Absidia cylindrospora, Rhodotorula sp., Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
In another embodiment of the invention the reductase is in the form of a purified ketone reductase that is obtained from: Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusarium solani, Sporidiobolus johnsonii, Streptomyces violascens, Absidia cylindrospora,
Rhodotorula sp., Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
In another embodiment of the invention the reductase is provided in the form of whole cells of: Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusarium solani, Sporidiobolus johnsonii, Streptomyces violascens, Absidia cylindrospora, Rhodotorula sp., Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa
In another embodiment of the invention the ketone reductase is obtained from Rhodotorula sp., Rhodotorula minuta, Rhodotorula pilimanae, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
In another embodiment of the invention the reductase is in the form of a purified ketone reductase that is obtained from: Rhodotorula sp., Rhodotorula minuta,
Rhodotorula pilimanae, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
In another embodiment of the invention the reductase is provided in the form of whole cells of: Rhodotorula sp., Rhodotorula minuta, Rhodotorula pilimanae, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa. In another embodiment of the invention R1 is tertiary butyl. In another embodiment of the invention R is -CN. In another embodiment of the invention R is Chloro or Bromo. One of skill in the art would recognize that the enzymatic activity and stereoselectivity can be increased using mutagenesis of the DNA of the organism listed above. Suitable methods of mutagenesis are well known in the art, these methods include site-directed mutagenesis or random mutagenesis using Error-prone-PCR. For other methods and a description of their use see, Organic Process Research & Development 2006, 10, 562-571 Cells used in the process of the invention are grown in a suitable nutrient medium. Growth and maintenance conditions for culture of the organisms used in the invention are well known to one of skill in the art.
The reduction may be carried out using whole cells or with ketone reductase that has been purified from whole cells. The conversion of the beta-hydroxy ketone to the corresponding c/s-1 ,3-diol with an isolated ketone reductase must be carried out in the presence of a co-factor, such as nicotinamide adenine dinucleotide (NADH ) or nicotinamide adenine dinucleotide phosphate (NADPH) and components for regenerating the co-factor for example: glucose and glucose dehydrogenase. Alternately, the conversion of the beta-hydroxy ketone to the corresponding c/s-1 ,3-diol may be carried out using whole cells of the organism in a nutrient medium, in which case the cells may provide the co-factor regeneration components. The nutrient medium may be that used normally to culture the organism, for example a medium that contains a suitable carbon source. If cell growth during the reaction is desired the medium should contain nitrogen, and phosphorus sources and trace elements. A suitable carbon source is, for example, maltose, sucrose, glucose, polyol (e.g.. glycerol, sorbitol), citric acid, or a lower alcohol such as methanol or ethanol. One of skill in the art would be readily able to select an appropriate growth medium for the maintenance and use of the cells.
In one embodiment of the invention, a compound of formula (II) is added to a suspension of live cells in a medium that supports growth of the organism In another embodiment the compound of formula (II) is added to a suspension of the live cells that lacks one or more nutrients necessary for growth Dead cells may also be used provided that the necessary enzymes and co-factors are present The cells may be immobilized on a support
The process of the invention may be earned out at a pH between of about 3 5 and about 9, preferably between about 6 and about 9, and more preferably between about 6 and about 8, most preferably about 7 Suitable temperatures for the process of the invention are about 10 to about 500C, preferably about 20 to about 4O0C, and more preferably about 25 to about 35°C
When live cells are used, the process is carried out aerobically One skilled in the art would be able to select suitable aeration conditions
Puπfied enzymes may be isolated using methods well known in the art (e g Robert K Scopes, (1994), Protein Purification Principles and Practice, Third Edition, Springer-Verlag, New York) These methods may include centπfugation of whole or lysed cells, isolating the enzyme from the supernatant, for example by ion exchange chromatography or by selective precipitation or both
The following non-limiting example illustrates the inventor's preferred method for obtaining the compound of the invention
EXAMPLE 1 Preparation of (3R,5R)-tert-buty\ 6-cyano-3,5,dιhydroxyhexanoate
Individual cultures of the organisms Monosporium ohvaceum v major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusaπum solani, Sporidiobolus johnsomi, Debaryomyces marama, Streptomyces violascens, Absidia cylindrospora, Rhodotorula sp , Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilagmosa var mucilaginosa were maintained as frozen stocks at -8O0C For each of the frozen stocks, the stock was thawed and used to
inoculate a 300 ml_ Erlenmeyer flask containing 25 mL of a medium of composition (per liter) glucose (20 0 g), NaCI (5 0 g), yeast extract (5 0 g), soy flour (5 0 g), K2HPO4 (5 0 g), PH 7 0
Cultures were incubated at 290C on an orbital shaker at 210 rpm for 48 hours The entire contents of the Erlenmeyer flask seed culture was used to inoculate a 3 L
Fembach flask that contained 500 mL of the same medium The Fembach flask was incubated for 24 hours (for yeast and bacteria) or 48 hours (for fungi and actinomycetes) at 290C on an orbital shaker at 210 rpm
(R)-terf-butyl 6-cyano-5-hydroxy-3-oxohexanoate
was added to the Fembach flask (2 0 mL of a 500 g/L stock in dimethyl sulfoxide) to yield an initial concentration of 2 0 g/L The cultures were incubated for an additional 3 days (bacteria and yeast) or 4 days (fungi and actinomycetes) at 290C on an orbital shaker at 210 rpm
The contents of each culture flask were then extracted two times with 1 L of ethyl acetate The pooled organic extracts were dried over anhydrous MgSO4, filtered through a sintered glass funnel, and concentrated under reduced pressure to yield (3R,5R)-terf-butyl 6-cyano-3,5,dιhydroxyhexanoate The extent of conversion of (R)- tert- 6-cyano-5-hydroxy-3-oxohexanoate (ketoester) to (3R,5R)-fe/f-butyl 6-cyano- 3,5,dιhydroxyhexanoate (c/s-diol) and the diastereomeric excess over (3R, 5S)-tert- butyl 6-cyano-3,5-dιhydroxyhexanoate (frans-diol) was determined using HPLC (high performance liquid chromatography) The conditions for HPLC are described below HPLC Waters 2790 Separations Module
Column lnertsil Cs, 5 micron particle size, 4 6 mm x 250 mm, GL Sciences, lnc Solvent water acetonitnle (80 20, v/v) Flow Rate 1 0 ml_/mιnute Temperature 3O0C Detection Refractive Index (Waters Model 2414 Refractive Index Detector)
The retention times of the trans diol, cis diol, and ketoester were 16.9 minutes, 17.8 minutes, and 27.1 minutes respectively. The results obtained are summarized in Table 1.
Table 1
%
Organism Conversion diastereomeric
Strain No. Organism Name Class (%) excess*
ATCC Monosporium olivaceum v.
36300A major fungi 4.0 90.3
UC7014 Rhodotorula pilimanae yeast 11.9 97.9
ATCC
21766 Rhodococcus rhodochrous bacteria 2.6 67.1
ATCC
39243 Lechevalieria aerocolonigenes bacteria 2.6 71.6
ATCC
12823 Fusarium solani fungi 4.5 94.1
ATCC
16039 Sporidiobolus johnsonii yeast 12.8 95.2
ATCC
11627 Debaryomyces marama yeast 8.6 98.7
ATCC
31560 Streptomyces violascens actinomycete 8.4 66.1
ATCC
1 1516 Absidia cylindrospora fungi 2.6 88.6
UC1271 Rhodotorula sp. yeast 14.2 96.9
ATCC
02776 Rhodotorula minuta yeast 1 1.1 98.0
UC5131 Rhodotorula rubra yeast 1 1.4 97.3
ATCC
36236 Rhodotorula minuta yeast 19.7 98.8
ATCC Rhodotorula mucilaginosa var. yeast 14.5 98.5
32762 mucilaginosa
((amount cis diol - amount trans diol)/(amount cis diol + amount trans diol)) x 100%
Claims
1. A process of making a c/s-1 ,3-diol comprising the steps of reducing a corresponding beta-hydroxy ketone using a ketone reductase wherein the ketone reductase is obtained from: Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus,
Streptomyces, Absidia, or Rhodotorula and; recovering the desired c/s-1 ,3-diol.
2. A process for making a compound of Formula (I);
wherein R is halo or -CN; and R1 is alkyl of 1 , 2, 3, 4, 5, or 6 carbon atoms; comprising: reducing a compound of formula Il
wherein R and R1 are as defined above, with a ketone reductase obtained from:
Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces,
Absidia, or Rhodotorula and; recovering the compound of Formula (I).
3. The process according to claim 2, wherein the ketone reductase is provided in the form of whole cells.
4. The process according to claim 2 wherein the ketone reductase is provided in the form of a purified ketone reductase.
5. The process according to Claim 2 wherein the ketone reductase is obtained from Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieria aerocolonigeses, Fusarium solani, Sporidiobolus johnsonii, Streptomyces violascens, Absidia cylindrospora, Rhodotorula sp., Rhodotorula minuta, Rhodotorula rubra or Rhodotorula mucilaginosa var. mucilaginosa.
6. The process according to claim 5, wherein the ketone reductase is provided in the form of whole cells.
7. The process according to claim 2 wherein R1 is tertiary butyl.
8. The process according to claim 5 wherein R is -CN and R1 is tertiary butyl.
9. The process according to claim 5 wherein the ketone reductase is provided in the form of a purified enzyme.
10. A purified ketone reductase obtained from Monosporium, Rhodococcus, Lechevalieria, Fusarium, Sporidiobolus, Streptomyces, Absidia, or Rhodotorula.
1 1. The purified ketone reductase of Claim 10 wherein the ketone reductase is obtained from Monosporium olivaceum v. major, Rhodotorula pilimanae, Rhodococcus rhodochorous, Lechevalieriaaerocolonigeses, Fusarium solani, Sporidioboluss johnsonii, Streptomyces violascens, Absidia cylindrospora, Rhodotorula sp., Rhodotorula minuta, Rhodotorula rubra and Rhodotorula mucilaginosa var. mucilaginosa.
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| US86633606P | 2006-11-17 | 2006-11-17 | |
| US60/866,336 | 2006-11-17 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7879585B2 (en) | 2006-10-02 | 2011-02-01 | Codexis, Inc. | Ketoreductase enzymes and uses thereof |
| CN104789505A (en) * | 2015-04-23 | 2015-07-22 | 苏州东和盛昌生物科技有限公司 | Method and strain for preparing cis-3,5-dihydroxyhexanoate compound by reduction and strain |
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| CN103146591B (en) * | 2013-01-30 | 2014-08-27 | 浙江工业大学 | Biological reduction for preparing statin side chain 6-cyanogroup-(3R, 5R)- dyhydroxyl caproic acid tert-butyl ester and bacterial strain |
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|---|---|---|---|---|
| US5354772A (en) * | 1982-11-22 | 1994-10-11 | Sandoz Pharm. Corp. | Indole analogs of mevalonolactone and derivatives thereof |
| US4645854A (en) * | 1985-04-25 | 1987-02-24 | Merck & Co., Inc. | Process for preparing HMG-CoA reductase inhibitors with a 3,5-dihydroxypentanoate subunit |
| DE3741509A1 (en) * | 1987-12-08 | 1989-06-22 | Hoechst Ag | METHOD FOR PRODUCING OPTICALLY ACTIVE 3-DESMETHYLMEVALONIC ACID DERIVATIVES AND INTERMEDIATE PRODUCTS |
| US5155251A (en) * | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
| GB9512837D0 (en) * | 1995-06-23 | 1995-08-23 | Zeneca Ltd | reduction of ketone groups |
-
2007
- 2007-11-08 WO PCT/IB2007/003530 patent/WO2008059366A2/en not_active Ceased
- 2007-11-16 US US11/941,485 patent/US20080118962A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104789505A (en) * | 2015-04-23 | 2015-07-22 | 苏州东和盛昌生物科技有限公司 | Method and strain for preparing cis-3,5-dihydroxyhexanoate compound by reduction and strain |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008059366A3 (en) | 2008-11-06 |
| US20080118962A1 (en) | 2008-05-22 |
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