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US 7,803,586 B2Granted
Chemical Process
AssigneeAstraZeneca AB
InventorsDavid Brown, John Peter Gilday, Philip Anthony Hopes, Jonathan David Moseley, Evan William Snape, Andrew Wells
Life of this patent
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Abstract
Enzymatic and chemical processes for the preparation of certain of 3-phenyl-2-arylalkylthiopropionic acid derivatives which have utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance and other manifestations of the metabolic syndrome are described and also certain novel intermediates used in these processes.
Claims8
A process for the preparation of an enantiomerically enriched compound of formula I and pharmaceutically acceptable salts thereof
- in which R1 represents chloro, fluoro, or hydroxy;
- which comprises hydrolysing a compound of formula II
- in which R1 is as initially defined;
- X is O or S;
- and,
- R2 is a C1-10alkyl group, a C1-6haloalkyl, a C2-6alkenyl group, an aryl, or an arylC1-6alkylene group, with or without additional hetero substitution;
- with a lipase selected from the group consisting of
- (a) Mucor miehei lipase, Candida rugosa lipase, Candida cylindracia lipase, Thermomyces lanuginosa lipase, Mucor javanicus lipase, and Rhizopus delemar lipase, when X is O;
- and,
- (b) Pseudomonas cepacia lipase, when X is S;
- in the presence of a reaction medium at a temperature in the range of 10-60° C.
8 more elements
A process for the preparation of an enantiomerically enriched compound of formula I and pharmaceutically acceptable salts thereof
- in which R1 represents chloro, fluoro, or hydroxy;
- which comprises hydrolysing a compound of formula II
- in which R1 is as initially defined;
- X is O;
- and,
- R2 is a C1-10alkyl group;
- with a lipase selected from the group consisting of Mucor miehei lipase, Candida rugosa lipase, Candida cylindracia lipase, Thermomyces lanuginosa lipase, Mucor javanicus lipase, and Rhizopus delemar lipase, in the presence of a reaction medium.
4 more elements
A process for the preparation of an enantiomerically enriched compound of formula I or a pharmaceutically acceptable salt thereof
- in which R1 represents chloro, fluoro, or hydroxy;
- which comprises hydrolysing a compound of formula II
- in which R1 is as initially defined;
- X is S;
- and,
- R2 is a C1-10alkyl group;
- with Pseudomonas cepacia lipase in the presence of a reaction medium.
4 more elements
A process for the preparation of a compound of formula III or a pharmaceutically acceptable salt thereof
- comprising hydrolysing a compound of formula IV
- in which R2 is a C1-10alkyl group, a C1-6haloalkyl, a C2-6alkenyl group, an aryl, or an arylC1-6alkylene group, with or without additional hetero substitution;
- with a lipase selected from the group consisting of Mucor miehei lipase, Candida rugosa lipase, Candida cylindracia lipase, Thermomyces lanuginosa lipase, Mucor javanicus lipase, and Rhizopus delemar lipase, in a reaction medium.
A process for the preparation of a compound of formula III or a pharmaceutically acceptable salt thereof
- comprising hydrolysing a compound of formula V
- in which R2 is a C1-10alkyl group, a C1-6haloalkyl, a C2-6alkenyl group, aryl or an arylC1-6alkylene group, with or without additional hetero substitution;
- with Pseudomonas cepacia lipase in a reaction medium.
A process for the preparation of a compound of formula I which comprises,
- (a) reacting a compound of formula VI
- with a compound of formula VII
- in which R5 represents a C1-6alkyl group;
- and,
- R6 represents p-tolyl in an inert solvent;
- in the presence of a base at a temperature in the range of 0° to 150° C. to give a compound of formula VIII
- in which R5 is as initially defined;
- (b) reacting a compound of formula VIII with an acid HA,
- wherein HA represents HCl, HBr, or trifluoroacetic acid to give a salt of formula IX
- in which HA is as initially defined;
- (c) diazotising a compound of formula IX in the presence of hydrochloric acid to give a diazonium salt solution at a temperature in the range of −5° C. to 10° C.;
- and,
- reacting the diazonium salt solution with acrylic acid in an aqueous reaction medium, optionally in the presence of a catalyst;
- and,
- reacting the product obtained with ammonia to give a compound of formula X
- (d) reacting a compound of formula X with an acid and then with an alcohol of formula R2OH, optionally in the presence of a water scavenging system to give a compound of formula XI,
- in which R2 is a C1-10alkyl group, a C1-6haloalkyl, a C2-6alkenyl group, an aryl, or an arylC1-6alkylene group, with or without additional hetero substitution;
- (e) reacting the ester of formula XI with a compound of formula XII
- in which R1 is chloro, fluoro, or hydroxy;
- and,
- R4 is methyl or phenyl;
- in the presence of a base to give a compound of formula XIII
- in which R1 and R2 are as initially defined, and X is O;
- and,
- (f) hydrolysing a compound of formula XIII with a lipase selected from the group consisting of
- (a) Mucor miehei lipase, Candida rugosa lipase, Candida cylindracia lipase, Thermomyces lanuginosa lipase, Mucor javanicus lipase, and Rhizopus delemar lipase;
- in a suitable reaction medium at a temperature in the range of 10-50° C. to give a compound of formula I
- which is enantiomerically enriched;
- and,
- (g) optionally reacting the compound of formula I with tert-butylamine in a suitable reaction medium to give the tert-butylammonium salt of the compound of formula I.
27 more elements
A telescoped process comprising,
- (a) reacting a compound of formula X
- with an acid and then with an alcohol of formula R2OH optionally in the presence of a water scavenging system to give a compound of formula XI
- in which R2 is a C1-10alkyl group, a C1-6haloalkyl, a C2-6alkenyl group, an aryl, or an arylC1-6alkylene group, with or without additional hetero substitution;
- (b) reacting the ester of formula XI with a compound of formula XII
- in which R1 is chloro, fluoro, or hydroxy;
- and,
- R4 is methyl or phenyl;
- in the presence of a base to give a compound of formula XIII
- in which R1 and R2 are as initially defined, and X is O;
- and,
- (c) hydrolysing a compound of formula XIII with a lipase selected from the group consisting of
- (a) Mucor miehei lipase, Candida rugosa lipase, Candida cylindracia lipase, Thermomyces lanuginosa lipase, Mucor javanicus lipase, and Rhizopus delemar lipase,
- in a suitable reaction medium at a temperature in the range of 10-50° C. to give a compound of formula I
- which is enantiomerically enriched;
- and,
- (d) optionally reacting the compound of formula I with tert-butylamine in a suitable reaction medium to give the tert-butylammonium salt of the compound of formula I.
13 more elements
Dependencies are inferred from the claim text.