Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Patent
1996-03-27
1999-06-08
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C07C25507, C07C25533, C07C25542
Patent
active
059106018
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to chiral compounds. In particular, it relates to a process for the manufacture of verapamil and analogues thereof, more particularly the manufacture of the single enantiomers thereof, and intermediates in that process.
BACKGROUND OF THE INVENTION
Verapamil is presently in clinical use as the racemate and is used extensively for treatment of hypertension. The (S)-isomer has the majority of the calcium channel antagonist activity, see DE-A-2059923, whilst the (R)-isomer differs in having sodium channel and other cell-pump actions in addition to a higher bioavailability, with slower clearance rate. For the treatment of hypertension, the (S)-isomer may provide a safer treatment than the racemate, with an extended therapeutic window. The (R)-isomer may be of benefit for the treatment of multidrug resistance in cancer chemotherapy, see J.F. Eliason, H. Ramuz and F. Kaufmann, Int. J. Cancer (1990) 46: 113-117; in this case hypotensive action by admixture with (S)-isomer would be undesirable. The preferential use of one of the isomers for migraine treatment is also possible, see S.J. Peroutka, Ann. Neurol. (1988) 23: 500-504.
The preparation of the single enantiomers of verapamil is a difficult chemical problem. DE-A-3723654 discloses that the isomers have been separated by resolution with, for example, binaphthol bis (dihydrogen phosphate), but this would appear to be an expensive process. Similarly, the resolution of a racemic carboxylic acid precursor with brucine, as disclosed in DE-A-2059923, and the multi-step process thereafter, does not look attractive for bulk manufacture, nor does a lengthy synthesis from the enantiomers of propane-1,2-diol, see L.J. Theodore and W.L. Nelson, J. Org. Chem. (1987) 52: 1309-1315, or separation of the final product by chromatography, see JP-A-03027326.
SUMMARY OF THE INVENTION
According to a first aspect of the present invention, a process for preparing a substantially single enantiomer (R or S) of
reacting command II with R'NH.sub.2 to give wherein Ar is aryl, R and R' are each independently C.sub.1-20 alkyl, X is a halo atom and A is a leaving group which, upon reaction of R--CH(Ar)--CN and X--(CH.sub.2).sub.3 --A leaves X--(CH.sub.2).sub.3 --A as A.sup.- and the resolution is carried out using a chiral acid.
According to a second aspect of the present invention, a process for preparing a substantially single enantiomer (R or S) of a compound of the formula invention and reacting the product thereof with Ar'--(CH.sub.2).sub.2 --A', wherein Ar' is aryl and A' is a leaving group which, upon reaction of Ar'--(CH.sub.2).sub.2 --A' with the product of the first aspect of the invetnion, leaves Ar'(CH.sub.2).sub.2 --A' as A'.sup.-.
According to a third aspect of the present invention, a process for preparing a substantially single enantiomer (R or S) of verapamil comprises carrying out the process according to the second aspect of the invention, wherein Ar and Ar' are both 3,4-dimethoxyphenyl, R is isopropyl and R' is methyl.
Resolution of CH.sub.3 --NH--(CH.sub.2).sub.3 --C(Ar)(CN)--CH(CH.sub.3).sub.2, Ar being 3,4-dimethoxyphenyl, is relatively easy compared with resolution of verapamil. For example, the novel resolution can directly achieve around 90%, or greater, enantiomeric excess, and after recrystallisation this may be increased to 99%, or greater, enantiomeric excess.
Apart from ease, a further benefit of resolution of CH.sub.3 --NH--(CH.sub.2).sub.3 --C(Ar)(CN)--CH(CH.sub.3).sub.2, and its subsequent conversion to verapamil, over resolution of verapamil itself is that, given the inability to utilise both enantiomers of verapamil (which are not readily interconvertible), the amount of waste enantiomer will be reduced.
DESCRIPTION OF THE INVENTION
The process of the invention is suitable for the manufacture of a wide range of chiral compounds having Ar, Ar' and R as defined above. Preferably, the process is for preparing verapamil and analogues thereof, such as emopamil (Ar=Ar'=phenyl, R=isopropyl, R'=methyl), gall
REFERENCES:
Hackh's Chemical Dictionary, J. Grant, Ed. (1969), McGraw-Hill Publisher, Inc.; pp. 432-433).
McCague Raymond
Wang Shouming
Darwin Discovery Limited
Oswecki Jane C.
Richter Johann
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