Rosuvastatin calcium and process for producing intermediate thereof
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.
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.