Process for making S(-) Amlodipine salts

Details Process for making S(-) Amlodipine salts Process for making S(-) Amlodipine salts

2002-10-30

2003-08-19

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

06608206

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for the preparation of S(−) Amlodipine salts. More particularly it relates to the process for the preparation of pharmaceutically acceptable salts of S(−)Amlodipine such as besylate, succinate, maleate, oxalate and tosylate. The S (−) Amlodipine salts of general formula (1)
Wherein R=Benzene sulfonic acid, succinic acid, maleic acid, oxalic acid and p-toluene sulfonic acid.
BACKGROUND AND SUMMARY OF THE INVENTION
Salts of S(−) Amlodipine are prepared as per the procedure of the present invention from S (−) Amlodipine, the procedure for the preparation of the S(−) Amlodipine has been fully described and claimed in co-pending Indian patent application No. NF 383/2001.
Of all the salts of S (−) Amlodipine mentioned above, the compound S (−) Amlodipine besylate; (4-S)-2-{[(2-aminoethyl)oxy]methyl}-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzene sulfonate has commercial importance and is a potent and long acting calcium channel blocker.
(R,S)-Amlodipine besylate is currently being used for the treatment of cardiovascular disorders, in particular in the treatment of hypertension and angina, Amlodipine is a racemic compound and has chiral center at 4 position of dihydropyridine ring. The S(−) isomer has calcium channel blocker activity while the R(+)-isomer has little or no calcium channel blocking activity.
The compound R,S-Amlodipine is a potent and long acting calcium channel blocker having utility as an anti-ischaenic and anti-hypertensive agent. Although amlodipine is effective as the free base in practice it is best administered in the form of a salt of pharmaceutically acceptable acid, such as hydrochloride, hydrobromide, maleate, fumarate, tartarate and besylate.
Of these salts, besylate is disclosed as being particularly preferred as it has good solubility, good stability, nonhygroscopicity and processability for tablet formation (Ger. Offen.—DE—3710457, (1988), Edward Davison, James Ingram Wells).
In the prior art the preparation of R and S enantiomers of Amlodipine have been reported by resolution of amlodipine azide ester with optically active 2-methoxy-2-phenylethanol (
J. Med. Chem
., No. 29, p. 1696, (1986). J. E. Arrowsmith, S. F. Campbell, P. E. Cross, J. K. Stabs, R. A. Burges and EP Application No. 0331315A) or resolution of Amlodipine base with optically active camphanic acid (
J Med. Chem
., No. 35, p. 3341, (1992), S. Goldman, J. Stoltefuss and L. Born) or resolution of RS-amlodipine base to R(+) and S(−) isomer with L or D-tartaric acid respectively in organic solvent DMSO, (Peter L. Spargo U.S. Pat. No. 6,046,338; (2000), PCT 95/25722 (1995) which indicate the use of both tartaric acids is essential.
Preparation of R and S amlodipine maleate salt has been reported starting from azido precursor. The procedure involves resolution of azido precursor using 2-methoxy-2-phenyl ethanol as a resolving agent, separation of diastereomer, ester exchange with sodium methoxide, hydrogenation, chromatographic purification and maleate salt formation. (
J. Med. Chem
., No. 29, p. 1896, (1986). J. E. Arrowsmith, S. F. Campbell, P. E. Cross, J. K. Stabs, R. A. Burges).
Preparation of preferred amlodipine besylate salt has been disclosed in the publication (
J. Chrom.B
693 (1997) pp. 367-375, J. Luksa, Dj. Josic, B. Podobnik, B. Furlan, M. Kremser) describing the treatment of ethanolic solution of base with benzene sulfonic acid and isolation. The detailed procedures to obtain these salts have not been provided by the prior art. These prior art references also lack in providing physical or structural data given except the optical rotation except maleate. The main object of the present invention therefore to provide a process for the preparation of S (−) Amlodipine salts.
Another object is to provide the process to obtain the salts in good yields. Yet another object is to obtain the salts with high enantiomeric purity.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention provides a process for the preparation of S(−) Amlodipine salts of general formula (1)
Wherein R=Benzene sulfonic acid, succinic acid, maleic acid, oxalic acid and p-toluene sulfonic acid, which comprises reacting S (−) amlodipine base with a solution of an acid in presence of an organic solvent at room temperature, adding water to obtain the product in solid form.
In one of the embodiments of the present invention, the organic solvents used for the reaction may be alcohols, hydrocarbons or polar solvents such as dimethyl sulfoxide, 2-propanol, ethanol, methanol and toluene.
In another embodiment the acids used may be benzene sulfonic acid, succinic acid, maleic acid, oxalic acid and p-toluene sulfonic acid.
In another embodiment the acid employed may be 1 mole per mole of amlodipine.
In still another embodiment the water to organic solvent ratio is may be 5:1 to 8:1.
The unique feature of the invention is production of S (−) amlodipine besylate with the quality required for preparation of pharmaceutical composition i.e. tablet formulation.


REFERENCES:
patent: 5438145 (1995-08-01), Furlan et al.
patent: 6046337 (2000-04-01), Bozsing et al.
patent: 6476058 (2002-11-01), Foster

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