Salts of HMG-CoA reductase inhibitors

A process for preparation of the salt of an HMG-CoA reductase inhibitor with an amine, characterized in that the amine is added to a crude medium of the HMG-CoA reductase inhibitor and that said amine is selected from the group consisting of amines of the following formulae I and II:

• wherein:
• a1) R1, R2, R3 and R4 independently denote:
• a hydrogen atom;
• a straight or a branched alkyl group having 1 to 8 carbon atoms;
• a cycloalkyl group having 3 to 8 carbon atoms;
• an arylalkyl group wherein the alkyl group is methyl or ethyl or the aryl group is phenyl, which is optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is an alkyl having 1 to 4 carbon atoms;
• an arylalkyl group which is optionally substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
• a hydroxyalkyl group having 2 to 4 carbon atoms;
• or
• an aminoalkyl group having 3 to 4 carbon atoms, which are optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is an alkyl having 1 to 4 carbon atoms;
• X denotes a hydrogen atom, a hydroxyl group, a halogen or a methyl group;
• m and n independently denote an integer from 0 to 5;
• or
• a2) NR1R2 or NR3R4 denote a heterocyclic ring having 3 to 7 methylene groups, one of these groups being optionally substituted by an oxygen or a sulfur atom or an amine group;
• and X, m and n are the same as defined above;
• wherein:
• b1) R′1, R′2, and R′3 are the same or different and denote hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl or alkenyl, or substituted amino-alkyl or alkenyl, wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, provided that R′1, R′2, and R′3 are not hydrogen at the same time;
• or
• b2) R′1 and R′2, and optionally R′3, together with the nitrogen atom form a heterocyclic ring system including the nitrogen atom as a ring member, and optionally including an additional hetero atom, and if R′3 is not part of the ring system it is independently selected from hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
• or
• b3) R′1 is a group of general formula III,
• R′—(CHR′4)m— III
• wherein m is zero or an integer from 1 to 5, R′ is an aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring optionally substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, R′4 is hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, substituted amino-alkyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, or a group of the same general formula as R′1 as defined herein above;
• R′2 and R′3 are the same as R′1 or hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl or alkenyl, wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
• or
• b4) R′1 is an optionally substituted aryl group of general formula IV:
• wherein R′5 is hydrogen or one or more substituents, selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, and m is zero or an integer from 1 to 5;
• and R′2 and R′3 may be independently hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, or groups of the same general formula R′1.

A process for preparing a desired HMG-CoA reductase inhibitor comprising the steps:

• 1) providing an amine salt of an HMG-CoA reductase inhibitor as a processing aid, starting substance, or an intermediate substance wherein the starting substance or intermediate substance is:
• i) in a purified form;
• ii) in a modified form;
• iii) in a pharmaceutically active salt form;
• or
• iv) in a lactone form,
• characterized in that said amine salt is formed from an amine selected from the group consisting of amines of the following formulae I and II:
• wherein:
• a1) R1, R2, R3, and R4 independently denote:
• a hydrogen atom;
• a straight or branched alkyl group having 1 to 8 carbon atoms;
• a cycloalkyl group having 3 to 8 carbon atoms;
• an arylalkyl group wherein the alkyl group is methyl or ethyl or the aryl group is phenyl, which is optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is an alkyl having 1 to 4 carbon atoms;
• an arylalkyl group which is optionally substituted by one or more
• substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
• a hydroxyalkyl group having 2 to 4 carbon atoms;
• or
• an aminoalkyl group having 3 to 4 carbon atoms, which are optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is an alkyl having 1 to 4 carbon atoms;
• X denotes a hydrogen atom, a hydroxyl group, a halogen or a methyl group;
• m and n independently denote an integer from 0 to 5;
• or
• a2) NR1R2 or NR3R4 denote a heterocyclic ring having 3 to 7 methylene groups, one of these groups being optionally substituted by an oxygen or a sulfur atom or an amine group;
• and X, m and n are the same as defined above;
• wherein:
• b1) R′1, R′2, and R′3 are the same or different and denote hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl or alkenyl, or alkenyl, or substituted amino-alkyl or alkenyl, wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, provided that R′1, R′2, and R′3 are not hydrogen at the same time;
• or
• b2) R′1 and R′2, and optionally R′3, together with the nitrogen atom form a heterocyclic ring system including the nitrogen atom as a ring member, and optionally including an additional hetero atom, and if R′3 is not part of the ring system it is independently selected from hydrogen, alkyl, alkenyl, amino or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
• or
• b3) R′1 is a group of general formula III,
• R′1—(CHR′4)m— III
• wherein m is zero or an integer from 1 to 5, R′ is an aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring, optionally substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, R′4 is hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alky, substituted amino-alkyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, or a group of the same general formula as R′1 as defined herein above;
• R′2 and R′3 are the same as R′1 or hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl or alkenyl, wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
• or
• b4) R′1 is an optionally substituted aryl group of general formula IV:
• wherein R′5 is hydrogen or one or more substituents, selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, and m is zero or an integer from 1 to 5;
• and R′2 and R′3 may be independently hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, or groups of the same general formula R′1.