# US 2019/0315696 A1 · Rosuvastatin calcium and process for producing intermediate thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2019/0315696 A1
- Document ID: US20190315696A1
- Status: Published application
- Kind: A1
- Application number: 16/442,770
- Filed: 2019-06-17
- Published: 2019-10-17
- Earliest claimed: 2014-02-06
- Assignees: Api Corporation
- Applicants: Api Corporation
- Inventors: Naoyuki WATANABE; Tomoko MAEDA; Yasumasa DEKISHIMA; Hiroshi KAWABATA; Masaki NAGAHAMA
- Web page: https://patentgrep.com/patent/US20190315696A1

## CPC

- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C12N 9/0006: {acting on CH-OH groups as donors (1.1)}
- C12P 17/12: containing a six-membered hetero ring
- C12Y 101/01184: Carbonyl reductase (NADPH) (1.1.1.184)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C12Y: ENZYMES

## Abstract

An object of the present invention is to provide a novel method capable of producing rosuvastatin calcium and intermediates therefor efficiently, inexpensively and with high purity. The present invention provides a method of efficiently producing rosuvastatin calcium and intermediates therefor having a high purity at an industrial scale, without using an extremely low temperature reaction or a special asymmetric catalyst.

## Claims

### Claim 1

A production method of a compound represented by the following formula (1a):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms, the method comprising:
(ii) condensing a compound represented by the following formula (3):
and a compound represented by the following formula (4):
wherein R1 is a linear or branched alkyl group having 1-8 carbon atoms, in the presence of a base.

### Claim 2

A production method of a compound represented by the following formula (1a):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms, comprising
(iia) condensing a compound represented by the following formula (3):
and a compound represented by the following formula (4a):
wherein R2 is a branched alkyl group having 3-8 carbon atoms, which is different from said R, in the presence of a base to obtain a compound represented by the following formula (5):
wherein R2 is as defined for R2 in said formula (4a); and
(iib) reacting the compound represented by formula (5) with an alcohol represented by R—OH wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms.

### Claim 3 (depends on 2)

A production method of a compound represented by the following formula (1b) or formula (1c):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms,
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms, the method comprising:
obtaining a compound represented by formula (1a) according to the method of claim 2;
reducing the compound of formula (1a) by contacting the compound with:
an enzyme having an activity capable of stereoselectively reducing a carbonyl group,
a microorganism or cell having an ability to produce the enzyme,
a treated product of the microorganism or cell, and/or
a culture solution containing the enzyme obtained by culturing the microorganism or cell,
to obtain the compound represented by formula (1b) or formula (1c).

### Claim 4 (depends on 3)

The production method according to claim 3, wherein said enzyme comprises a polypeptide selected from:
(A) a polypeptide having carbonylreductase (OCR1) (SEQ ID NO: 2) derived from Ogataea minuta var. nonfermentans NBRC1473,
(B) a polypeptide consisting of an amino acid sequence having a homology of 80% or more to the amino acid sequence shown in SEQ ID NO: 2, and having an activity to convert the compound represented by formula (1a) to a compound represented by formula (2),
(C) a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 2, wherein 1 or more amino acids are substituted, deleted or added, and having an activity to convert a compound represented by formula (1a) to a compound represented by formula (2).

### Claim 5 (depends on 3)

The production method according to claim 3, wherein the gene encoding said enzyme is a DNA comprising a base sequence selected from:
(D) the base sequence shown in SEQ ID NO: 1,
(E) a base sequence that hybridizes to a DNA consisting of a sequence complementary to the base sequence shown in SEQ ID NO: 1 under stringent conditions, and encodes a polypeptide having an activity to convert the compound represented by formula (1a) to a compound represented by formula (2), and
(F) a base sequence having a base sequence which is the base sequence shown in SEQ ID NO: 1 wherein 1 or more bases are substituted, deleted or added, and encodes a polypeptide having an activity to convert the compound represented by formula (1a) to a compound represented by formula (2).

### Claim 6

A compound represented by the following formula (1a), (1b) or (1c):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms,
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms,
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms.

### Claim 7

A crystal of a compound represented by the following formula:
which shows a powder X-ray diffraction pattern having characteristic peaks at 2θ=8.4° and 21.1°(±0.2°).

### Claim 8

A production method of rosuvastatin calcium represented by the following formula (6):
the method comprising:
hydrolyzing with a base a compound represented by formula (2):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms, obtained by a method comprising:
reducing a compound represented by the following formula (1a):
wherein R is as defined for R in said formula (2), comprising reacting the compound with an enzyme having an activity capable of stereoselectively reducing a carbonyl group, a microorganism or cell having an ability to produce the enzyme, a treated product of the microorganism or cell, and/or a culture solution containing the enzyme obtained by culturing the microorganism or cell;
wherein said enzyme comprises a polypeptide selected from:
(A) a carbonyl reductase (OCR1) polypeptide of SEQ ID NO: 2 derived from Ogataea minuta var. nonfermentans NBRC1473,
(B) a polypeptide consisting of an amino acid sequence having a homology of 90% or more to the amino acid sequence shown in SEQ ID NO: 2, and having an activity to convert a compound represented by said formula (1a) to a compound represented by said formula (2), and
(C) a polypeptide comprising an amino acid sequence which is the amino acid sequence shown in SEQ ID NO: 2, wherein 20 or less amino acids are substituted, deleted or added, and having an activity to convert a compound represented by said formula (1a) to a compound represented by said formula (2); and
reacting the product thereof with a calcium compound.

### Claim 9

A production method of rosuvastatin calcium represented by the following formula (6):
the method comprising:
hydrolyzing with a base a compound represented by formula (2):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms, obtained by a method comprising:
reducing a compound represented by the following formula (1a):
wherein R is as defined for R in said formula (2), comprising reacting the compound with an enzyme having an activity capable of stereoselectively reducing a carbonyl group, a microorganism or cell having an ability to produce the enzyme, a treated product of the microorganism or cell, and/or a culture solution containing the enzyme obtained by culturing the microorganism or cell;
wherein said enzyme comprises a polypeptide selected from:
(A) a carbonyl reductase (OCR1) polypeptide of SEQ ID NO: 2 derived from Ogataea minuta var. nonfermentans NBRC1473,
(B) a polypeptide consisting of an amino acid sequence having a homology of 90% or more to the amino acid sequence shown in SEQ ID NO: 2, and having an activity to convert a compound represented by said formula (1a) to a compound represented by said formula (2), and
(C) a polypeptide comprising an amino acid sequence which is the amino acid sequence shown in SEQ ID NO: 2, wherein 20 or less amino acids are substituted, deleted or added, and having an activity to convert a compound represented by said formula (1a) to a compound represented by said formula (2); and then
treating with an acid to obtain a compound represented by the following formula (8):
reacting the compound of formula (8) with an amine compound to obtain a compound represented by the following formula (9):
wherein R3 and R4 are each independently a hydrogen atom or an alkyl group having 1-8 carbon atoms,
subjecting the compound of formula (9) to salt-exchange with a base, and then
reacting the reaction product with a calcium compound.

### Claim 10

A production method of rosuvastatin calcium represented by the following formula (6):
the method comprising:
hydrolyzing with a base a compound represented by formula (2):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms, obtained by a method comprising:
reducing a compound represented by the following formula (1a):
wherein R is as defined for R in said formula (2), comprising reacting the compound with an enzyme having an activity capable of stereoselectively reducing a carbonyl group, a microorganism or cell having an ability to produce the enzyme, a treated product of the microorganism or cell, and/or a culture solution containing the enzyme obtained by culturing the microorganism or cell;
wherein said enzyme comprises a polypeptide selected from:
(A) a carbonyl reductase (OCR1) polypeptide of SEQ ID NO: 2 derived from Ogataea minuta var. nonfermentans NBRC1473,
(B) a polypeptide consisting of an amino acid sequence having a homology of 90% or more to the amino acid sequence shown in SEQ ID NO: 2, and having an activity to convert a compound represented by said formula (1a) to a compound represented by said formula (2), and
(C) a polypeptide comprising an amino acid sequence which is the amino acid sequence shown in SEQ ID NO: 2, wherein 20 or less amino acids are substituted, deleted or added, and having an activity to convert a compound represented by said formula (1a) to a compound represented by said formula (2); and then
performing intramolecular dehydration condensation in the presence or absence of an acid catalyst to obtain a compound represented by the following formula (10):
and
reacting the compound of formula (10) with a calcium compound.

### Claim 11

A crystal of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-hydroxy-6-heptenoic acid n-propylamine salt, which shows a powder X-ray diffraction pattern having characteristic peaks at 2θ=19.8°, 22.9°(±0.2°).

### Claim 12

A crystal of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-hydroxy-6-heptenoic acid dimethylamine salt, which shows a powder X-ray diffraction pattern having characteristic peaks at 2θ=6.6°, 17.0°(±0.2°).

### Claim 13

Rosuvastatin calcium comprising not less than 1 ppm and not more than 1500 ppm of a compound represented by the following formula (11):

### Claim 14

A purification method of a compound represented by the following formula (2):
wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms,
the method comprising dissolving the compound in an organic solvent, or a mixed solvent of an organic solvent and water, and cooling same at a cooling rate of 15° C./hr or below to precipitate a crystal of the compound represented by said formula (2).