Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-09-18
1998-05-12
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546319, 546356, C07D21380, C07D213803
Patent
active
057507074
DESCRIPTION:
BRIEF SUMMARY
The invention described herein provides an efficient method for the separation of the optical isomers of amlodipine via salt formation with tartaric acid in the presence of dimethyl sulphoxide.
BACKGROUND
Amlodipine 1a, and its salts are long-acting calcium channel blockers, and are thus useful for the treatment of cardiovascular disorders, such as angina, hypertension and congestive heart failure. The two enantiomers of amlodipine, and their salts, have different pharmacological profiles. The S-(-)-isomer is the more potent calcium channel blocker, and the R-(+)-isomer also exhibits activity in the treatment or prevention of atherosclerosis.
J. E. Arrowsmith et al in J.Med.Chem (1986) 29 1696, described the preparation of the two enantiomers of amlodipine via separation of the diastereotopic azide esters 1b, and J. E. Arrowsmith, in EPA 331315, disclosed the use of cinchonidine salts of acid 1c for the resolution of intermediates to eventually give enantiomerically pure amlodipine isomers. S. Goldman et al, in J.Med.Chem. (1992) 25 3341, described the chromatographic separation of diastereomeric amide isomers 1d. ##STR2##
None of the disclosed methods for resolution of amlodipine intermediates or derivatives offer an efficient and economic method susceptible of industrial application. Other methods of providing enantiomerically enriched amlodipine isomers are thus needed.
A recent review by S. Goldman et al, in Angew.Chem.lnt.Edn.(Engl.) (1991) 30 1559, describes various methods of providing chiral 1,4-dihydropyridines in high enantiomeric excess (e.e.). This review paper, in section 2.2 (Resolution of Racemic Mixtures of Basic Dihydropyridine Derivatives), states that "Chiral acids such as camphorsulphonic acid and substituted tartaric acids have been used to separate the enantiomers of basic dihydropyridine derivatives in yields of up to 30%" (emphasis added). The use of these methods for the resolution of amlodipine into its enantiomers gave unsatisfactory results, in terms of both yield and enantiomeric purity. The "substituted tartaric acid" used most commonly in the reported methods was O,O'-dibenzoyltartaric acid, and various solvents, most commonly alcohols, were used with this reagent.
THE INVENTION
We herein describe a new, simple, economic and efficient process for preparing both enantiomers of amlodipine 1a and their salts, in unexpectedly good yield and enantiomeric purity. The invention provides a method for the separation of the R-(+)-and S-(-)-isomers of amlodipine from mixtures thereof, which comprises the reaction of the mixture of isomers with either L- or D-tartaric acid in an organic solvent containing sufficient dimethyl sulphoxide (DMSO) for the precipitation of, respectively, a DMSO solvate of an L-tartrate salt of R-(+)-amlodipine, or a DMSO solvate of a D-tartrate salt of S-(-)-amlodipine. The use of both tartaric acid and DMSO are essential to this unique separation process.
Preferably, either about 0.5 mole or about 0.25 mole of either L- or D-tartaric acid per mole of amlodipine is used.
Preferably, the precipitate is a hemitartrate monosolvate of amlodipine. These solvates also form part of the invention.
Following separation of the precipitate, which may be carried out by methods well-known in the art, for example by filtation, centrifugation or decantation, either the precipitate or the filtrate or supernatant, now suitably enriched in the desired isomer, can be processed further. As is well-known in the art, the further processing method applicable to one diastereomer may be equally applied to its antipode.
The precipitated DMSO-solvate may be treated further in a number of ways. Recrystallisation from an organic solvent can give the amlodipine tartrate free from DMSO. This can further be treated with a base to give the free enantiomerically-pure amlodipine isomer. The precipitated DMSO-solvate may also be treated with a base to give the optically-pure amlodipine free base directly, without the need for isolation of the amlodipine tartrate.
The filtrate or supernatan
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Benson Gregg C.
Jones James T.
Pfizer Inc.
Richardson Peter C.
Rotman Alan L.
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