Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-08-20
1994-07-05
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D40100
Patent
active
053268741
DESCRIPTION:
BRIEF SUMMARY
This is a National filing under 35 U.S.C. 371 based on PCT/US92/00029 filed Jan. 8, 1992, which was filed claiming priority from application Ser. No. 07/661,726 filed Feb. 27, 1991 now abandoned.
BACKGROUND OF THE INVENTION
The present invention is directed to processes for the preparation of a dialkyl trans-piperidine-2,5-dicarboxylate via a trans substituted piperidine derivative of the formula ##STR2## wherein R is (C.sub.1 -C.sub.3)alkyl. Said trans-piperidine derivatives are particularly useful as intermediates in the synthesis of certain neuroleptic, racemic or optically active perhydro-1H-pyrido[1,2-a]pyrazines having the relative stereochemical formula: ##STR3## wherein Z is H or Cl; R.sup.a (CH.sub.2).sub.m CO where m is 0, 1, 2 or 3 and R.sup.a is (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, phenyl, naphthyl, furyl, benzofuranyl, thienyl, benzothienyl, pyrrolyl, indolyl, isoindolyl or one of said groups substituted on aromatic or heteroaromatic ring with fluoro, chloro, (C.sub.1 -C.sub.2)alkyl or (C.sub.1 -C.sub.2)alkoxy; or ##STR4## where Y.sup.1 is CH.sub.2, S, O or NH; Y.sup.2 and Y.sup.3 are taken separately and Y.sup.2 and Y.sup.3 are each independently hydrogen or methyl, or Y.sup.2 and Y.sup.3 are taken together and are (CH.sub.2).sub.q ; p is 1 or 2; q is 2, 3, 4 or 5; and r is 0 or 1; ##STR5## where s is 0 or 1; and - - - represents a bond or no bond; ##STR6## where X.sup.1 is CH or N; ##STR7## where R.sup.b, R.sup.c and R.sup.d are each independently H or CH.sub.3 and - - - represents a bond or no bond; ##STR8## where R.sup.e is phenyl or phenyl substituted with F, Cl, (C.sub.1 -C.sub.2)alkyl or (C.sub.1 -C.sub.2)alkoxy; ##STR9## or a pharmaceutically acceptable acid addition salt thereof.
The compounds of the formula (A), their preparation and their utility as antipsychotics are fully described herein and in concurrently filed U.S. patent application Ser. No. 07/661,791 by Bright et al., for "Perhydro-1H-pyrido[1,2-a] pyrazine Derivatives Having Neuroleptic Activity."
Dimethyl trans-piperidine-2,5-dicarboxylate has been previously prepared by Mastafanova et al., Chemistry of Heterocyclic Compounds--Translated from Russian, v. 21, pp. 305-309 (1985), via trans-piperidine-2,5-dicarboxylic acid which was in turn obtained as an equilibrium mixture with cis-piperidine-2,5-dicarboxylic acid by prolonged heating of the cis-isomer at 200.degree. C. in a high pressure bomb in the presence of excess aqueous sodium hydroxide.
Yamada et al., J. Org. Chem., v. 48, pp. 843-846 (1983), have described a method for the racemization of optically active alpha-amino acids in which the amino acid is heated in a carboxylic acid (e.g., formic, acetic, or propionic acid) in the presence of an aliphatic or aromatic aldehyde.
SUMMARY OF THE INVENTION
We have now found that dialkyl cis-piperidinedicarboxylates can be equilibrated with the corresponding trans-isomer under mild conditions in the presence of an aliphatic or aromatic aldehyde (such as those noted above) in a carboxylic acid as solvent. This equilibration is accompanied by concurrent hydrolysis of the ester group at the 2-position of the piperidine ring. This is most fortuitous, since this acid is amenable to optical resolution via a diastereomeric salt with an optically active amine. Such optically active acids permit the highly efficient synthesis of those above-noted neuroleptic compounds which are optically active.
The present invention is specifically directed to the trans-substituted piperidine of the above formula (I). For its ease of preparation, the preferred compound is that wherein R is methyl.
The present invention is further directed to a process of preparing said trans-substituted piperidine of the formula (I) which comprises contacting a corresponding cis-substituted piperidine derivative of the formula ##STR10## wherein R is defined as above, with an aldehyde in a carboxylic acid R.sup.1 COOH, wherein R.sup.1 is hydrogen or (C.sub.1 -C.sub.3)alkyl; and separating said trans derivative of the formula (I) from the result
REFERENCES:
patent: 4018767 (1977-04-01), Buyniski et al.
patent: 4505911 (1985-03-01), Dolak et al.
Chem. Abstr., v. 107, No. 7, 1987, Kuleshova et al., Abstr. No. 58343h.
Yamada et al., J. Org. Chem., v. 48, pp. 843-846 (1983).
Mastafanova et al., Chem. Heterocyclic Compounds, Translated from Russian, v. 21, pp. 305-309 (1985).
J. Am. Chem. Soc., v. 97, No. 1, 159-167 (1975).
Chem. Abstr., v. 103, No. 23, 1985, Mastafanova et al., Abst. No. 195965u.
Benson Gregg C.
Covington Raymond
Ivy C. Warren
Jones James T.
Pfizer Inc.
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