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US 9,315,470 B2Granted
Convenient process for the preparation of statins
AssigneeF.I.S. Fabbrica Italiana Sintetiei S.p.A.
InventorsOttorino De Lucchi, Stefano Tartaggia, Clark Ferrari, Marco Galvagni, Marta Pontini, Stefano Fogal, Riccardo Motterle, Rosa Maria Moreno, Alex Comely
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Abstract
Object of the present invention is an improved process for the preparation of key intermediates for the synthesis of statins.
Claims13
A process for preparing a compound of formula (I):
- wherein Z is chosen from OH, O−, OR, SR, O(CO)OR, NH2, NHR, and NR2,
- wherein R is chosen from linear or branched C1-7 alkyl, linear or branched C2-7 alkenyl or alkynyl, C3-7 cycloalkyl, and aryl-C0-4 alkyl, and
- wherein in NR2 the two R groups are optionally joined, forming a C2-10 alkyl or alkenyl ring;
- PG is a hydroxyl protecting group chosen from tetrahydropyranyl (THP), camphanoyl, bornyl, menthyl, R, (CO)R, CH2OR, CH2SR, and SiR3,
- wherein R in SiR3 is the same or different, and is chosen from linear or branched C1-7 alkyl, linear or branched C2-7 alkenyl or alkynyl, C3-7 cycloalkyl, and aryl-C0-4 alkyl;
- and
- Q is chosen from the following radicals;
- wherein the symbol * specifies the bonding position;
- R1 is hydrogen or methyl;
- and
- R2 is chosen from hydrogen, methyl, hydroxyl, hydroxymethyl, and O-PG wherein, PG is as defined above;
- the process comprising reacting a compound of formula (II):
- wherein PG and Z are as defined for the compound of formula (I), with a compound of formula (III):
- wherein Q is as defined for the compound of formula (I).
11 more elements
A process of making a statin or a salt thereof, comprising
- (a) preparing a compound of formula (I):
- wherein Z is chosen from OH, O−, OR, SR, O(CO)OR, NH2, NHR, and NR2,
- wherein R is chosen from linear or branched C1-7 alkyl, linear or branched C2-7 alkenyl or alkynyl, C3-7 cycloalkyl, and aryl-C0-4 alkyl, and
- wherein in NR2 the two R groups are optionally joined, forming a C2-10 alkyl or alkenyl ring;
- PG is a hydroxyl protecting group chosen from tetrahydropyranyl (THP), camphanoyl, bornyl, menthyl, R, (CO)R, CH2OR, CH2SR, and SiR3,
- wherein R in SiR3 is the same or different, and is chosen from linear or branched C1-7 alkyl, linear or branched C2-7 alkenyl or alkynyl, C3-7 cycloalkyl, and aryl-C0-4 alkyl;
- and
- Q is chosen from the following radicals:
- wherein the symbol * specifies the bonding position;
- R1 is hydrogen or methyl;
- and
- R2 is chosen from hydrogen, methyl, hydroxyl, hydroxymethyl, and O-PG wherein, PG is as defined above;
- by a process comprising reacting a compound of formula (II):
- wherein PG and Z are as defined for the compound of formula (I), with a compound of formula (III):
- wherein Q is as defined for the compound of formula (I),
- (b) cleaving the hydroxyl protecting group of a compound of formula (I);
- (c) enantioselectively reducing the alpha-beta unsaturated carbonyl of the product from step (b);
- and
- (d) converting the Z group to a carboxyl group or to a corresponding lactone form;
- wherein the statin is chosen from Rosuvastatin, Cerivastatin, Pitavastatin, Fluvastatin, Simvastatin, Lovastatin, Mevastatin, and Pravastatin.
17 more elements
Dependencies are inferred from the claim text.