Rosuvastatin calcium and process for producing intermediate thereof
AssigneeApi Corporation
InventorsNaoyuki WATANABE, Tomoko MAEDA, Yasumasa DEKISHIMA, Hiroshi KAWABATA, Masaki NAGAHAMA
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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.
Claims14
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.
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.
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.
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°).
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.
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.
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.
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°).
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°).
Rosuvastatin calcium comprising not less than 1 ppm and not more than 1500 ppm of a compound represented by the following formula (11):
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).
Dependencies are inferred from the claim text.