Process for producing simvastatin
AssigneeBrantford Chemicals Inc.
InventorsK. S. Keshava Murthy, Stephen E. Horne, Gamini Weeratunga, Shawn Young
Life of this patent
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Abstract
A process for manufacturing Simvastatin is provided comprising reacting lovastatin with an organic boronic acid to produce a derivative of lovastatin (lovastatin phenylboronate) methylating the 2-methylbutyryloxy group on the lovastatin derivative to form a 2,2-dimethylbutyryloxy group on the lovastatin derivative and thereafter removing the boronate group to produce simvastatin.
Claims45
A process for the preparation of a compound of formula (II)
- by reacting a compound of formula (I)
- with an alkyl, cycloalkyl, or arylboronic acid in a non-polar solvent.
A process for the purification of lovastatin by a process wherein the compound of formula II
- is recovered from solution by filtration, the boronate group is removed from compound of formula (II) by reacting the compound of formula (II) with a hydroxylic reagent and recovering the resulting lovastatin by crystallization.
A compound of formula (II)
- where R is selected from alkyl of 1-6 carbons, cycloalkyl of 3-7 carbons, substituted or unsubstituted, or aryl optionally substituted by 1-4 substituents of halogen or lower alkyl in any combination.
A compound of formula (III)
- where R is selected from alkyl of 1-6 carbons, cycloalkyl of 3-7 carbons, substituted or unsubstituted, or aryl optionally substituted by 1-4 substituents of halogen or lower alkyl in any combination.
A process for manufacturing simvastatin comprising reacting lovastatin (I)
- with an organic boronic acid RB(OH)2 to produce a derivative of lovastatin (II)
- with a boronate group attached to the C-4 carbon of the pyranyl group, methylating the 2-methylbutyryloxy group of (II)
- to form the 2,2-dimethylbutyryloxy group of (III)
- and thereafter removing the boronate group to produce simvastatin (IV)
The process for the manufacture of simvastatin by the following steps:
The process of producing compound (III)
- from compound (II)
- by metallation of compound (II)
- using an alkalai metal salt of a secondary amine to generate an enolate and thereafter methylating the resultant intermediate by reacting with a methylating agent.
A process of boronating a compound containing a β-hydroxylactone group with available lactone α-hydrogens and also an aliphatic ester side-chain with available α-hydrogens, the process comprising reacting such compound with an organic boronic acid of the formula RB(OH)2.
The compound of the following structural formula:
- in which the bonds a-b and c-d are optionally single or double bonds;
- n=1 to 4;
- R is an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, or an aryl group optionally substituted by 1-4 substituents of halogen or lower alkyl in any combination;
- RI is selected from hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-7 carbon atoms, OH, ORIV wherein (RIV is alkyl, cycloalkyl, aryl);
- RII is selected from hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-7 carbon atoms;
- RIII is selected from hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-7 carbon atoms.
The process of producing simvastatin as follows:
The process of producing:
- by insertion of a boronate group into
- with an alkyl, cycloalkyl or aryl boronic acid in a non-polar solvent.
The process of methylating the 2-methylbutyryloxy group of compound II
- to produce
- wherein compound (II)
- is reacted with an alkalai metal salt of a secondary amine and thereafter methylating the intermediate compound so produced by reacting it with a methylating agent to produce the compound of formula (III)
The process of deboronating
- to produce
- by reacting the compound of formula (III)
- with a hydroxylic compound to produce the compound of formula (IV)
The process of clain 27 wherein the boronate is removed by using a diol or polyol.
A process for manufacturing simvastatin comprising reacting lovastatin (I) with an organic boronic acid RB(OH)2to produce a derivative of lovastatin (II) with a boronate group, methylating the 2-methylbutyryloxy group of (II) to form the 2,2-dimethylbutyryloxy group of (III) and thereafter removing the boronate group to produce simvastatin (IV) wherein R may be selected from an alkyl group of 1-6 carbons, cycloalkyl of 3-7 carbons, substituted or unsubstituted, or aryl optionally substituted by 1-4 substituients of halogen or lower alkyl or combinations thereof.
A process of boronating a compound containing a β-hydroxylactone group and also an aliphatic ester side-chain (with available α-hydrogens), the process comprising reacting such compound with an organic boronic acid of the formula RB(OH)2, wherein R may be selected from an alkyl group of 1-6 carbons, cycloalkyl of 3-7 carbons, substituted or unsubstituted, or aryl optionally substituted by 1-4 substituents of halogen or lower alkyl or combinations thereof.
Dependencies are inferred from the claim text.