Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-12-16
1999-12-28
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D45302
Patent
active
060083573
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for resolving 1-azabicyclo[2.2.2]octan-3-amine, 2-(diphenylmethyl)-N-[[2-methoxy-5-(1-methylethyl)phenyl]methyl].
The above compound (hereinafter also referred to as "the racemate") and the (2S, 3S) enantiomer of such compound (hereinafter also referred to as "the (2S, 3S) enantiomer") are substance P receptor antagonists that are useful in the treatment and prevention of a wide variety of central nervous system, gastrointestinal, inflammatory and other disorders. The racemate and the (2S, 3S) enantiomer, as well as methods by which they can be prepared, are referred to in U.S. patent application Ser. No. 08/211,120, which was filed on May 23, 1994 as the U.S. national phase of International Patent Application PCT/U.S. 92/03317, which was filed on Apr. 28, 1992. U.S. patent application Ser. No. 08/211,120 is incorporated herein by reference in its entirety. Both the above compounds and methods for preparing them are referred to, generically, in U.S. Pat. No. 5,162,339, which issued on Nov. 10, 1992. This patent is also incorporated herein by reference in its entirety.
SUMMARY OF THE INVENTION
This invention relates to a process for resolving 1-azabicyclo[2.2.2]octan-3-amine, 2-(diphenylmethyl)-N-[[2-methoxy-5-(1-methylethyl)phenyl]methyl] comprising reacting 1-azabicyclo[2.2.2]octan-3-amine, 2-(diphenylmethyl)-N-[[2-methoxy-5-(1-methylethyl)phenyl]methyl] with 1R-(-)-10-camphorsulfonic acid in an appropriate solvent to form the camphorsulfonic acid salt of (2S, 3S)-1-azabicyclo[2.2.2]octan-3-amine, 2-(diphenylmethyl)-N-[[2-methoxy-5-(1-methylethyl)phenyl]methyl], and then optionally hydrolyzing such salt to obtain the free base of the (2S, 3S) enantiomer.
The method of the present invention is a substantial improvement over the most practical of the methods described heretofore for preparing the (2S, 3S) stereoisomer of 1-azabicyclo-[2.2.2]octan-3-amine, 2-(diphenyl-methyl)-N-{[2-methoxy-5-(1-methylethyl)phenyl]methyl}, described in detail further below as the method beginning with a compound of formula XI, which has the same absolute stereochemistry as the desired product. This method is also described in detail in above-cited WO 92/21677. In this method a compound of formula XI is subjected to catalytic debenzylation whereby the benzyl or methoxy-benzyl group at the 3-position is hydrolytically removed to give the corresponding 3-amine, i.e., a compound of formula VI, with the same desired stereochemistry. Compound VI is then reacted with a compound of formula VII, which is an aldehyde comprising the desired group: 2-methoxy-5-(1-methylethyl)-phenylmethyl, to yield the desired final product having said desired group at the 3-position as well as the desired stereochemistry.
A compound of formula XI, the starting material for the above-described prior art method, is prepared by reductive amination of 3-keto-2-benzhydrylquinuclidine, in accordance with procedures such as the ones described in U.S. Pat. No. 5,162,339 under "Preparation F". These procedures comprise reductive amination of commercially available 3-keto-2-benzhydrylquinuclidine having the desired 2S configuration, using the primary amines benzylamine or methoxy-benzylamine, followed by reduction of the resulting imine intermediate to provide the amine of formula XI. Accordingly, the above-described preferred method of the prior art for preparing the (2S, 3S) or (2S, cis) enantiomer of 1-azabicyclo-[2.2.2]octan-3-amine, 2-(diphenyl-methyl)-N-{[2-methoxy-5-(1-methyl-ethyl)-phenyl]methyl}, may be described as initially comprising the following two steps: (1) subjecting 3-keto-2-benzhydrylquinuclidine having the desired 2S stereochemistry, to reductive amination with benzylamine or methoxybenzylamine to give the corresponding 3-(benzyl or methoxybenzyl)amine and separating out the desired 2S, 3S diastereomer of formula XI; followed by (2) catalytic debenzylation to give the corresponding 3-amine of formula VI having the desired stereochemistry, which is later reacted with an aldehyde of formula VII, as already
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Jacques et al., Enantiomers, Racemates, and Resolutions, pp. 380-383, 1981.
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Meltz Morgan
Tickner Derek L.
Coleman Brenda
Ginsburg Paul H.
Levine Jacob M.
Pfizer Inc
Richardson Peter C.
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