Rosuvastatin calcium and process for producing intermediate thereof

Patent metadata

Field	Value
Publication number	US-2016347718-A1
Application number	US-201515116861-A
Country	US
Kind code	A1
Filing date	Feb 6, 2015
Priority date	Feb 6, 2014
Publication date	Dec 1, 2016
Grant date	—

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.

First claim

1 . A production 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, comprising
(i) a step of reducing a compound represented by the following formula (1):

wherein R is as defined for R in said formula (2), —X 1 and —X 2 are each independently —OH or ═O, and —X 1 and/or —X 2 are/is ═O, 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.

2 . The production method according to claim 1 , wherein said enzyme comprises a polypeptide of any of the following (A), (B) or (C):
(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 a compound represented by said formula (1) to a compound represented by said formula (2), (C) a polypeptide comprising an amino acid sequence which is the amino acid sequence shown in SEQ ID NO: 2, wherein 1 or several amino acids are substituted, deleted or added, and having an activity to convert a compound represented by said formula (1) to a compound represented by said formula (2).

3 . The production method according to claim 1 , wherein the gene encoding said enzyme is a DNA comprising the base sequence shown in the following (D), (E) or (F):
(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 act on a compound represented by said formula (1) and convert same to a compound represented by said formula (2), (F) a base sequence having a base sequence which is the base sequence shown in SEQ ID NO: 1 wherein 1 or several bases are substituted, deleted or added, and encodes a polypeptide having an activity to act on a compound represented by said formula (1) and convert same to a compound represented by said formula (2).

4 . (canceled)

5 . A production method of a compound represented by the following formula (1):

wherein R is a primary alkyl group having 1-8 carbon atoms or a secondary alkyl group having 3-6 carbon atoms, —X 1 and —X 2 are each independently —OH or ═O, and —X 1 and/or —X 2 are/is ═O, comprising
(ii) a step of condensing a compound represented by the following formula (3):

and a compound represented by the following formula (4):

wherein R 1 is a linear or branched alkyl group having 1-8 carbon atoms, in the presence of a base.

6 . The production method according to claim 5 , wherein
(iia) a step of condensing a compound represented by the following formula (3):

and a compound represented by the following formula (4a):

wherein R 2 is a branched alkyl group having 3-8 carbon atoms, which is different from said R, in the presence of a base; and
(iib) a step of reacting a compound represented by the following formula (5):

wherein R 2 is as defined for R 2 in said formula (4a), which is obtained in said step (iia)
and 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.

7 . The production method according to claim 5 , comprising
(iia) a step of condensing a compound represented by the following formula (3):

and a compound represented by the following formula (4a):

wherein R 2 is a branched alkyl group having 3-8 carbon atoms, which is different from said R, in the presence of a base;
(iib) a step of reacting a compound represented by the following formula (5):

wherein R 2 is as defined for R 2 in said formula (4a), which is obtained in said step (iia),
and 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; and
(ia) a step of obtaining compound(s) represented by the following formula (1b) and/or (1c):

wherein R is as defined for R in said formula (1a),

wherein R is as defined for R in said formula (1a), comprising acting 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 on 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, to reduce the compound.

8 . The production method according to claim 7 , wherein said enzyme comprises any of the polypeptide shown in the following (A), (B) or (C):
(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 a compound represented by said formula (1) to a compound represented by said formula (2), (C) a polypeptide comprising an amino acid sequence which is the amino acid sequence shown in SEQ ID NO: 2, wherein 1 or several amino acids are substituted, deleted or added, and having an activity to convert a compound represented by said formula (1) to a compound represented by said formula (2).

9 . The production method according to claim 7 , wherein the gene encoding said enzyme is a DNA comprising the base sequence shown in the following (D), (E) or (F):
(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 cond

Assignees

• Api Corp

Inventors

• Watanabe Naoyuki
• Dekishima Yasumasa
• Nagahama Masaki
• Maeda Tomoko
• Ohtani Takashi
• Ito Kosuke
• Kawabata Hiroshi

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C12N9/0006

  acting on CH-OH groups as donors (1.1) · CPC title

• C12Y101/01184

  Carbonyl reductase (NADPH) (1.1.1.184) · CPC title

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title