Resolution of the enantiomers of amlodipine

Details Resolution of the enantiomers of amlodipine Resolution of the enantiomers of amlodipine

2002-08-16

2003-11-11

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06646131

ABSTRACT:

TECHNICAL FIELD
The invention provides a feasible method for the separation of both (S)-(−)-enantiomer and (R)-(+)-enantiomer of racemic amlodipine. The chiral reagent for separation is tartaric acid and the chiral auxiliary reagent is hexadeuterium dimethyl sulphoxide (DMSO-d
6
).
BACKGROUND
(S)-(−)-amlodipine and its salts are long-acting calcium channel blockers, and are thus useful for the treatment of hypertension and angina and (R)-(+)-amlodipine also exhibits activity in the treatment or prevention of atherosclerosis.
Pfizer invented a feasible method for the separation of the enantiomers of amlodipine (W095/25722), in very good optical purity and yield. The use of both dimethyl sulphoxide (DMSO) and chiral reagent tartaric acid are essential to this method.
The invention indicates that hexadeuterium dimethyl sulphoxide (DMSO-d
6
), in optical purity of up to 100% e.e. and very good yield, is a chiral auxiliary reagent better than DMSO.
CONTENTS OF THE INVENTION
The invention provides a feasible method for the separation of racemic amlodipine. The chiral reagent for separation is L-tartaric acid or D-tartaric acid and the chiral auxiliary reagent is hexadeuterium dimethyl sulphoxide (DMSO-d
6
), in the amlodipine and tartaric acid mole ratio of about 1:0.25. The resulting precipitate is (S)-(−)-amlodipine-hemi-D-tartrate-mono-DMSO-d
6
solvate or (R)-(+)-amlodipine-hemi-L-tartrate-mono-DMSO-d
6
solvate.
The separation methods used for precipitate are filtration, centrifugation or decantation.
The above precipitate can further be treated to give (R)-(+)-amlodipine or (S)-(−)-amlodipine.
The mother solution after removal of the above precipitate can be treated with 0.25-mole equivalent of the antipode of tartaric acid (such as originally used L-tartaric acid and now used D-tartaric acid), which results in precipitation of the antipodal amlodipine and tartrate and DMSO-d
6
solvate.
The hexadeuterium dimethyl sulphoxide solvents for carrying out the resolution are sulphoxides, ketones, alcohols, ethers, amides, esters, chlorohydro-carbons, water, nitrites and hydrocarbons. The common solvents are DMSO-d
6
, DMSO, acetone, methylethyl ketone, isopropyl alcohol, diethyl ether, tetrahydrofuran, N,N′-dimethylformamide, N,N-dimethylpropylene-urea, ethyl acetate, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, acetonitrile and toluene.
The maximum amount of some solvent employed is variable. A man skilled in the art will readily be able to establish the appropriate proportion, but DMSO-d
6
/amlodipine 1 (mole ratio).
Recrystallisation solvents for the tartrate salt are alcohols, such as methanol.
The bases for the preparation of amlodipine from its salts are metal hydroxides, oxides, carbonates and amides. The most convenient is sodium hydroxide.
The crystalline precipitate constituent is (S)-(−)-amlodipine-hemi-tartrate-mono-DMSO-d
6
solvate or R-(+)-amlodipine-hemi-tartrate-mono-DMSO-d
6
solvate respectively.
IMPLEMENTATION OF THE INVENTION
In the following examples, optical purities were measured by chiral HPLC. The HPLC conditions used for this separation were as follows: chiral column-ultron ES-OVM, Ovomucoid, 15 cm; flow rate, 0.3 ml/min; detection wavelength, 360 nm; mobile phase, disodium hydrogenphosphate (20 mM, PH 7)/acetonitrile=80/20. Samples were dissolved in acetonitrile/water=50/50, 0.3 mg/ml solution.


REFERENCES:
patent: 5750707 (1998-05-01), Spargo
patent: 6046338 (2000-04-01), Spargo
patent: 1144523 (1995-03-01), None
patent: 0331315 (1989-09-01), None
patent: WO95/25722 (1995-09-01), None
Goldman et al, Angew. Chemie, Int. Ed. Engl, vol. 301, 1991. pp. 1559-1578, 1,4-Dihydropyridines: Effects of Chirality . . . .

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