Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1994-12-12
1998-02-17
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
544295, 544229, C07D47104, C07D48704
Patent
active
057192863
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application, filed pursuant to 35 U.S.C. .sctn.371, of PCT international application number PCT/US93/01208, filed Nov. 16, 1993.
BACKGROUND OF THE INVENTION
The present invention is directed to an improved process for intermediates useful for the synthesis of the anxiolytic agents represented by structures I and II below as well as new anxiolytic agents and intermediate compounds. Commonly owned European patent application A 038,217 filed Jan. 12, 1990 and U.S. patent applications Ser. Nos. 661,791, filed Feb. 27, 1991 (PCT/US91/08378, filed Nov. 18, 1991); 661,726, filed Feb. 27, 1991; and 661,730, filed Feb. 27, 1991 (PCT/US91/08400, filed Nov. 19, 1991) described the synthesis of Compound I and related intermediates in Scheme A shown below. ##STR2##
Commonly owned U.S. patent application Ser. No. 765,332, filed Sep. 25, 1991 claims an alpha-hydroxy derivative of Compound I with the structure shown below as Compound II. ##STR3##
U.S. Pat. No. 4,956,368 teaches that compounds hydroxylated at C-6 of the azaspirodecanedione portion of a molecule may rearrange to produce an oxaspirononanone of the type; ##STR4##
The text of commonly owned U.S. patent application Ser. Nos. 661,791; 661,726; 661,730; and 765,332 is herein incorporated by reference.
SUMMARY OF THE INVENTION
The present invention is directed toward an improved process for the synthesis of anxiolytic agents of Compounds I and II above and intermediate compounds used in this synthesis. The new synthesis also provides a facile synthesis of new anxiolytic compounds of formula III below. ##STR5##
The new synthesis provides Compound I in an overall yield of approximately 8% based on pyridine diester, representing an approximate 5 fold improvement over previous syntheses.
In one aspect this invention is directed toward substantially optically pure intermediates and anxiolytic compounds of the formula: ##STR6## wherein the substituent B is either cis or trans to the C.sub.9a -C.sub.1 bond and is selected from the group consisting of ##STR7## C is selected from the group consisting of --H, ##STR8## and a nitrogen protecting group which is removable by hydrogenation or acid treatment; and wherein R is (C.sub.1 -C.sub.8) alkyl, phenyl or alkyl substituted phenyl; X is N or CH; Y is O or S; and Z is H or Cl; and with the proviso that when B is cis to the C.sub.9a -C.sub.1 bond, B must be --CH.sub.2 OH or --CHO, and C must be a group other than --H; and acid salts thereof.
The preferred value of C is ##STR9## wherein Y is O and Z is H. The preferred value of R is methyl; and the preferred amine protecting group is tert-butoxycarbonyl.
In another aspect, this invention is directed toward a process for preparing a substantially optically pure compound of the formula ##STR10## having (7R,9aS-Trans) configuration wherein C is selected from the group consisting of ##STR11## and a nitrogen protecting group which is removable by hydrogenation or acid treatment; wherein X is N or CH; Y is O or S and Z is H or Cl; comprising: ##STR12## in a reaction inert solvent with an acid acceptor to form a racemic product which has formula ##STR13## (b) reacting the racemic product of step (a) with a slight molar excess of D-(-)-tartaric acid in a reaction inert solvent forming two diasteromeric salts; (c) separating the diasteromeric salts of step (b) and treating the salt having (7S,9aS-Cis) configuration with base to obtain a compound which has the formula ##STR14## having (7S, 9aS-Cis) configuration; (d) reacting the product of step (c) with sulfur trioxide-pyridine complex and dimethylsulfoxide in a reaction inert solvent to form a product of the formula ##STR15## having (7S,9aS-Cis) configuration. Isomerizing the product of step id) with a sodium carbonate in a reaction (e) inert solvent to produce a compound of the formula ##STR16## having (7R,9aS-Trans) configuration.
In a third aspect, this invention is directed toward a process for preparing a substantially optically pure compound of the formula ##STR17## having (7S, 9aS-Trans) configurat
REFERENCES:
patent: 4956368 (1990-09-01), Cipollina et al.
patent: 5122525 (1992-06-01), Bright et al.
patent: 5157034 (1992-10-01), Bright et al.
Ford John M.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Zielinski Bryan C.
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