Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Patent
1994-06-07
1995-10-10
Brust, Joseph Paul
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
558390, C07C25330, C07C25334
Patent
active
054572240
DESCRIPTION:
BRIEF SUMMARY
Verapamil [1,7-bis(3,4-dimethoxyphenyl)-3-methyl-aza-7-cyano-8-methylnonane] has been disclosed in DE-C 1 154 810. It was for a long time not possible to resolve this racemic compound into the optical antipodes (Helv. Chim. Acta 58 (1975) 2050). It was therefore necessary to synthesize it from optically active precursors (DE-C 20 59 985, DE-C 20 59 923).
EP-C 29 175 describes the resolution of racemic gallopamil with the aid of the O,O'-dibenzoyl derivative of unnatural (+)-D-tartaric acid. However, the resolution of racemic verapamil is not described in this patent.
By contrast, DE-A 3 723 684 describes a process for the resolution of racemic verapamil with the aid of R- or S-2,2'-(1,1'-binaphthyl)phosphoric acid. However, this substance is extremely costly to prepare so that economic preparation of the antipodes of verapamil continues to be impossible.
It was necessary to assume from this prior art that resolution of racemic verapamil is very difficult and costly.
We have now found a very favorable process which can be used to resolve verapamil into its antipodes.
The present invention relates to a process for the resolution of racemic verapamil, which comprises reacting the free base of the compound with optically active dibenzoyltartaric acid or ditoluoyltartaric acid in the molar ratio from 1:1 to 1:2 in a methanol/water mixture in the ratio from 1:1 to 3:1 or acetone/water mixture in the ratio from 0.5:1 to 2:1, separating the mixture of diastereomers obtained in this way by crystallization, and converting the diastereomers obtained in this way into the free bases and subsequently into their salts if required.
Verapamil and the optically active acid are reacted together in the molar ratio from 1:1 to 1:2, preferably 1:1.5. On cooling the solution in methanol/ water or acetone/water, the salt of one antipode crystallizes out while the other antipode remains in the mother liquor. When the acid used is (-)-O,O'-dibenzoyl-L-tartaric acid, the dibenzoyl-L-tartrate of (S)-verapamil crystallizes out first, and if it is (+)-O,O'-dibenzoyl-D-tartaric acid, the dibenzoyl-D-tartrate of (R)-verapamil crystallizes out first.
After removal of the precipitated diastereomeric salt, the solvent is removed by distillation, and the base is liberated from the residue and converted with the other enantiomeric form of O,O'-dibenzoyltartaric acid into the hydrogen tartrate. The procedure for the ditoluyltartaric acid salts corresponds. The dibenzoyl and ditoluoyl derivatives of natural L-tartaric acid are advantageously employed for the racemate resolution.
The resolution of racemic verapamil is particularly advantageous and low-cost on addition of an inorganic mineral acid. This makes it possible to save up to 1.5 mol of the tartaric acid per mol of verapamil. It is most favorable to carry out the resolution with optically active dibenzoyl-or ditoluoyltartaric acid in the presence of mineral acid in the molar ratio 1: 0.75:0.5 (verapamil : tartaric acid : mineral acid). The crystallizing diastereomeric salt of one enantiomer has the same optical purity. The other enantiomer remains in solution and can be isolated therefrom in a conventional manner, for example by concentration of the solution. Particularly suitable mineral acids are phosphoric acid and sulfuric acid, and hydrochloric acid is preferably used.
(R)- or (S)-verapamil is liberated from the diastereomeric salts in a conventional way using a base in aqueous medium and is isolated by extraction. The bases obtained in this way can be converted into their salts with physiologically tolerated acids by conventional processes.
EXAMPLE 1
a) 250 g (0.55 mol) of racemic verapamil and 310 g (0.82 mol) of (-)-O,O'-dibenzoyl-L-tartaric acid hydrate were dissolved by heating in 1.3 1 of methanol/water=2:1. The crystals which separated out overnight were filtered off with suction and dried. The crystals have a melting point of 103.degree.-107.degree. C. and a rotation [.alpha]sup.20.sub.D =-53.3.degree. (ethanol, c=15 mg/ml). The crystals obtained after three recrystalliza
REFERENCES:
patent: 4305887 (1981-12-01), Herrling
"The American Heritage Dictionary", 2nd College Edition, p. 873, (1982).
"Academic Press Dictionary of Science and Technology," Edited by Christopher Morris, p. 1523, (1985), Academic Press, N.Y.
Helvetica Chimica Acta. vol. 58, Fasc 7 (1975); Ramuy, pp. 2050-2060.
Ehrmann Oskar
Nagel Herbert
Brust Joseph Paul
Knoll Aktiengesellschaft
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