Method for producing pitavastatin calcium
Production of pitavastatin calcium safely on an industrial scale with a high yield and high selectivity at low cost. A method of producing pitavastatin calcium including step (i) for acetalizing a compound represented by the formula (1) to give a compound represented by the formula (3), step (ii) for reacting a compound represented by the formula (3) with an acid to give a compound represented by the formula (4), and step (iii) for hydrolyzing a compound represented by the formula (4) and reacting same with a calcium compound.
1. A method for producing pitavastatin calcium comprising
(i) acetalizing a compound represented by the following formula (1):
wherein R is a straight chain alkyl group having a carbon number of 1-8 or a branched alkyl group having a carbon number of 3-8 and X is an acid, to give a compound represented by the following formula (3):
wherein R 3 and R 4 are each independently an alkyl group having a carbon number of 1-4 and R is as defined above;
(ii) reacting said compound represented by the formula (3) with an acid to give a compound represented by the following formula (4):
wherein R is as defined above; and
(iii) hydrolyzing said compound represented by the formula (4) and reacting the compound with a calcium compound to give pitavastatin calcium.
2. The production method according to claim 1 , wherein the compound represented by the formula (1) used in (i) is obtained by
(iv) reacting a compound represented by the following formula (6):
wherein R is a straight chain alkyl group having a carbon number of 1-8 or a branched alkyl group having a carbon number of 3-8, with an acid.
3. The production method according to claim 2 , wherein the compound represented by the formula (6) used in (iv) is obtained by
(v) condensing a compound represented by the following formula (7):
and a compound represented by the following formula (8):
wherein R 5 is a straight chain alkyl group having a carbon number of 1-8 or a branched alkyl group having a carbon number of 3-8 provided R 5 is different from R in said formula (1), in the presence of a base to give a compound represented by the following formula (9):
wherein R 5 is as defined above;
(vi) reacting said compound represented by the formula (9) obtained in (v) with alcohol represented by R—OH wherein R is a straight chain alkyl group having a carbon number of 1-8 or a branched alkyl group having a carbon number of 3-8 to give a compound represented by the following formula (10):
wherein R is as defined above; and
(vii) reacting said compound represented by the formula (10) obtained in (vi) 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.
4. The production method according to claim 2 , wherein the compound represented by the formula (6) used in (iv) is obtained by
(viii) reacting a compound represented by the following formula (12):
in the presence of a titanium catalyst with a compound represented by the following formula (13):
wherein R is a straight chain alkyl group having a carbon number of 1-8 or a branched alkyl group having a carbon number of 3-8, to give a compound represented by the following formula (14):
wherein R is as defined above; and
(ix) reacting said compound represented by the formula (14) obtained in (viii) 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.