Process for preparing optically active amide derivatives

Details Process for preparing optically active amide derivatives Process for preparing optically active amide derivatives

1995-04-11

1997-06-10

Datlow, Philip I.

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

540598, 540607, 544335, 544336, 544359, 544393, 546195, 546207, 546226, 546233, 546336, 560 41, 560 44, 564169, C07D22304, C07D40306

Patent

active

056377010

DESCRIPTION:

BRIEF SUMMARY
This is a 35 USC 371 National Stage application of International application PCT/GB93/0290 filed Oct. 8, 1993.
This invention relates to a novel asymmetric synthesis for preparing amide derivatives and to intermediates useful in the synthesis.
The invention particularly relates to a process for preparing optically active amides of the general formula ##STR3## and the pharmaceutically acceptable salts thereof.
In formula A, ##STR4## R represents a mono or bicyclic aryl or heteroaryl group, R.sup.1 is an aryl or heteroaryl radical, 3 to 12 carbon atoms, cycloalkyl-(lower)alkyl, aryl or aryl(lower)alkyl or attached represent a saturated heterocyclic ring which may contain a further hetero atom [eg an azetidino, pyrrolidino, piperidino, hexahydroazepino, heptamethyleneimino, morpholino or piperazino ring which may be optionally substituted by, for example, lower alkyl, aryl, aryl(lower)alkyl, lower alkoxy, halogen or halo(lower)alkyl].
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, pentyl and isopentyl. When R.sup.3 is an alkyl group a particularly preferred radical is a tertiary alkyl radical such as tert.butyl.
A cycloalkyl group can contain 3 to 12 carbon atoms. Preferably a cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl, most preferably cyclohexyl. Cycloalkyl groups also include bicyclic, tricyclic and tetracyclic groups, eg adamantyl.
When used herein "aryl" means an aromatic radical having 6 to 12 carbon atoms (eg phenyl or naphthyl) which optionally may be substituted by one or more substituents commonly used in medical chemistry, eg substituents such as lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy), loweralkylthio, halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, cyano, carboxamido, (lower)alkoxycarbonyl, amino, (lower)alkylamino or di(lower)alkylamino substituents. Two substituents on the aromatic ring may be connected together to form another ring system.
For example R may be a bicyclic oxygen-containing radical such as a optionally substituted radical of the formula ##STR5##
The term "heteroaryl" refers to an aromatic radical containing one or more hetero atoms (eg oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. Some examples of suitable substituents are given above in connection with "aryl" radicals. The heteroaryl radical may, for example, contain up to 10 ring atoms; for example the heteroaryl radical may be a monocyclic radical containing 5 to 7 ring atoms. Preferably the hetero ring contains a nitrogen hetero atom with or without one or more further hetero atoms.
When R is a heteroaryl radical it is preferably an optionally substituted pyrimidyl (particularly 2-pyrimidyl), quinolinyl or indolyl [particularly indol-4-yl which may be optionally substituted eg by (lower)alkoxycarbonyl] radical.
When R.sup.1 is a heteroaryl or heteroaryl-lower alkyl the "heteroaryl" group is preferably a nitrogen containing heteroaryl radical (eg an optionally substituted pyridinyl, pyrimidinyl or pyrazinyl radical) or a heteroaryl radical containing an oxygen or sulphur atom as a hetero atom eg an optionally substituted thienyl or furyl group.
Preferred compounds of formula A have the following characteristics either singly or in any possible combination: ##STR6## (b) R is optionally substituted phenyl, eg o-alkoxy-phenyl (particularly o-methoxyphenyl) both attached represent a saturated heterocyclic ring, particularly hexahydroazepino.
Compounds of formula (A) are useful because of their pharmacological activity, eg as 5-HT.sub.1A -antagonists. The compounds and their uses are disclosed, for example, in GB 2230780 A, GB 2290781 A, GB 2248836 A, GB 2254324 A, GB 2262093 A and WO-GB 93/01542. The prior specifications refer to the preparation of enantiomers by, for example, resolution of the racemates. The process of the present invention a

REFERENCES:
patent: 2776282 (1957-01-01), Cusic
patent: 4921958 (1990-05-01), Abou-Gharbia
patent: 4988814 (1991-01-01), Abou-Gharbia
Rokach et al J. Organic Chemistry, 31 (12), (1966), pp. 4210-4215.
Jonczyk et al, Chemical Abstract 119:249841 for Polish Patent PL 158,537 (Sep. 30, 1992).

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