Rosuvastatin calcium and process for producing intermediate thereof

Patent metadata

Field	Value
Publication number	US-10377722-B2
Application number	US-201715600196-A
Country	US
Kind code	B2
Filing date	May 19, 2017
Priority date	Feb 6, 2014
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

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

What is claimed is:

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, the method comprising:
(i) 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 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).

2. The production method according to claim 1 , wherein the gene encoding said enzyme is a DNA comprising the 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 the compound represented by formula (2), and
(F) the base sequence shown in SEQ ID NO: 1 wherein 60 or less bases are substituted, deleted or added, and encodes a polypeptide having an activity to convert the compound represented by formula (1a) to the compound represented by formula (2).

3. The production method according to claim 1 , wherein (i) is performed in the presence of a polyhydric alcohol.

Assignees

• Api Corp

Inventors

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

Classifications

• 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

• A61P3/06

  Antihyperlipidemics · 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