US 5,514,812 AGranted

Preparation of stereochemically pure oximes with muscarinic activity

AssigneeWarner-Lambert Company

InventorsRuth Bucsh, Juan C. Jaen, Edgardo Laborde, Anthony J. Thomas

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Abstract

The instant invention is a selective formation of the Z-oxime and O-alkylation of 1-azabicyclo 2.2.1!heptan-3-one and 1-azabicyclo 2.2.2!heptan-3-one oximes to produce compounds with muscarinic activity. The process is capable of scale-up for industrial purposes as it provides better yields and ease of preparation. Intermediates are also described.

Claims5

Dependent claims

A process for the preparation of a compound of formula ##STR21## or a pharmaceutically acceptable acid addition salt thereof and includes racemic as well as enantiomerically pure forms and mixtures thereof wherein

n is an integer from 1 to 2;
R.sub.1 is hydrogen, a straight or branched lower alkyl group of from 1 to 6 carbon atoms, hydroxy, a straight or branched lower alkoxy group of from 1 to 4 carbon atoms, acyloxy group wherein the acyl moiety has from 2 to 5 carbon atoms, or the group --(CH.sub.2).sub.m NR.sub.11 R.sub.12 wherein m is an integer of from 0 to 4 and R.sub.11 and R.sub.12 are the same or different and are hydrogen, a straight or branched lower alkyl of from 1 to 4 carbon atoms, or R.sub.11 and R.sub.12 can form a ring of from 3 to 6 atoms;
R is
(a) hydrogen;
(b) a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms which is saturated or which is unsaturated and contains from 1 to 4 double and/or triple bonds;
(c) a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms which is saturated or which is unsaturated and contains from 1 to 4 double and/or triple bonds, and the terminal carbon of the hydrocarbon chain is substituted with a group selected from:
(i) a cycloalkyl group having from 3 to 8 carbon atoms or a cycloalkenyl group having from 4 to 8 carbon at ores;
(ii) an aromatic group selected from phenoxy, phenyl, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 3- or 5-(1,2,4)-thiadiazolyl, 3-(1,2,5)-thiadiazolyl, 2-(1,3,4)-thiadiazolyl, 2-triazinyl, 3- or 5-(1,2,4)-oxadiazolyl, 2-(1,3,4)-oxadiazolyl, 3-(1,2,5)-oxadiazolyl, 3- or 5-thiadiazolyl, 2- or 5-pyrimidinyl, 3- or 4-pyridazinyl, 2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-oxazolyl, or 2-pyrazinyl wherein the aromatic group is unsubstituted or is substituted with 1 or 2 substituents selected from straight or branched alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 4 carbon atoms, chlorine, fluorine, bromine, trifluoromethyl, nitro, hydroxy, trifluoromethoxy, or NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 have the meanings defined above,
(iii) --NR.sub.6 R.sub.7
wherein each of R.sub.6 and R.sub.7 is hydrogen, alkyl having from 1 to 4 carbon atoms, phenyl or benzyl, or --NR.sub.6 R.sub.7 taken together form a pyrrolidino, piperidino, piperazino, or morpholino ring;
(iv) ##STR22## wherein R.sub.6 and R.sub.7 have the meanings defined above;
##STR23## (v) wherein R.sub.8 is a straight or branched alkyl group having from 1 to 6 carbon atoms;
(vi) CN;
(vii) --CO.sub.2 R.sub.9
wherein R.sub.9 is hydrogen, a straight or branched hydrocarbon group having from 1 to 6 carbon atoms which is saturated or which is unsaturated and contains 1 or 2 double and/or triple bonds, or benzyl;
(viii) XR.sub.10
wherein X is oxygen or sulfur, and R.sub.10 is a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms which is saturated or which is unsaturated and contains 1 or 2 double and/or triple bonds and is unsubstituted or is substituted with an alkoxy group having from 1 to 4 carbon atoms;
(ix) biphenyl;
(d) the group --CH.sub.2 CH.sub.2 CH.dbd.C(Ph).sub.2 ;
or
(e) the group ##STR24## comprising:
(a) stirring a mixture of 1-azabicyclo 2.2.1!heptan-3-one or 1-azabicyclo 2.2.2!octan-3-one or a salt thereof, and hydroxylamine, or a salt thereof, in an alcohol solvent of sufficient dilution to keep reactants and products in solution at a temperature of from 0.degree. C. to 24.degree. C. for from 2 to 48 hours;
(b) removing the solvent, dissolving the remaining product, neutralizing it with base, extracting it into an organic solvent, and drying it to produce the stereochemically pure Z-oxime;
(c) adding the Z-oxime in portions to a suspension of a base with a mono- or dibasic counterion in an aprotic solvent with stirring for from 5 minutes to 5 hours from 0.degree. C. to 50.degree. C. producing the corresponding oxime anion;
(d) adding the product of Step (c) above to a solution of an alkylating agent of Formula R--X, where R is as defined above, and X is a leaving group, in an inert solvent and stirring the mixture at a temperature of from -78.degree. C. to 78.degree. C. for from 10 minutes to 48 hours;
(e) quenching the reaction, removing the solvent and filtering through silica gel to provide the desired specific oxime Z-isomer of Formula I.

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A process for the preparation of a compound of formula ##STR25## or a pharmaceutically acceptable acid addition salt thereof wherein

n is 1;
R.sub.1 is hydrogen;
R is a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms which is saturated or which is unsaturated and has from 1 to 4 double and/or triple bonds and the terminal carbon of the hydrocarbon chain is substituted with a group selected from:
an aromatic group selected from phenoxy, phenyl, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 3- or 5-(1,2,4)-thiadiazolyl, 3-(1,2,5)-thiadiazolyl, 2-(1,3,4)-thiadiazolyl, 2-triazinyl, 3- or 5-(1,2,4)-oxadiazolyl, 2-(1,3,4)-oxadiazolyl, 3-(1,2,5)-oxadiazolyl, 3- or 5-thiadiazolyl, 2- or 5-pyrimidinyl, 3- or 4-pridazinyl, 2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-oxazolyl, or 2-pyrazinyl wherein the aromatic group is unsubstituted or is substituted with 1 or 2 substituents selected from straight or branched alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 4 carbon atoms, chlorine, fluorine, bromine, trifluoromethyl, nitro, hydroxy, trifluoromethoxy, or NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 have the meanings defined above, comprising:
(a) stirring a mixture of 1-azabicyclo 2.2.1!heptan-3-one or 1-azabicyclo 2.2.2!octan-3-one and hydroxylamine, in an alcohol solvent of sufficient dilution to keep reactants and products in solution at a temperature of from 0.degree. to 24.degree. C. for from 2 to 48 hours;
(b) removing the solvent and dissolving the remaining product, neutralizing it with base, and extracting and drying it to produce the stereochemically pure Z-oxime;
(c) adding the Z-oxime in portions to a suspension of potassium hydride or potassium tert-butoxide or potassium bis(trimethylsilyl) amide in DMF of THF with stirring for from 10 minutes to 2 hours from 0.degree. C. to 30.degree. C. producing the desired oxime anion;
(d) adding the product of Step (c) above to a solution of R--X where R is as defined above, and X is OSO.sub.2 Ar or Br, in an inert solvent and stirring the mixture at a temperature of from -10.degree. C. to 50.degree. C. for from 0.5 hours to 18 hours;
(e) quenching the reaction, removing the solvent and filtering through silica gel to provide the desired specific oxime Z-isomer of Formula I.

6 more elements

Dependencies are inferred from the claim text.

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Abstract

n is an integer from 1 to 2;
R.sub.1 is hydrogen, a straight or branched lower alkyl group of from 1 to 6 carbon atoms, hydroxy, a straight or branched lower alkoxy group of from 1 to 4 carbon atoms, acyloxy group wherein the acyl moiety has from 2 to 5 carbon atoms, or the group --(CH.sub.2).sub.m NR.sub.11 R.sub.12 wherein m is an integer of from 0 to 4 and R.sub.11 and R.sub.12 are the same or different and are hydrogen, a straight or branched lower alkyl of from 1 to 4 carbon atoms, or R.sub.11 and R.sub.12 can form a ring of from 3 to 6 atoms;
R is
(a) hydrogen;
(b) a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms which is saturated or which is unsaturated and contains from 1 to 4 double and/or triple bonds;
(c) a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms which is saturated or which is unsaturated and contains from 1 to 4 double and/or triple bonds, and the terminal carbon of the hydrocarbon chain is substituted with a group selected from:
(i) a cycloalkyl group having from 3 to 8 carbon atoms or a cycloalkenyl group having from 4 to 8 carbon at ores;
(ii) an aromatic group selected from phenoxy, phenyl, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 3- or 5-(1,2,4)-thiadiazolyl, 3-(1,2,5)-thiadiazolyl, 2-(1,3,4)-thiadiazolyl, 2-triazinyl, 3- or 5-(1,2,4)-oxadiazolyl, 2-(1,3,4)-oxadiazolyl, 3-(1,2,5)-oxadiazolyl, 3- or 5-thiadiazolyl, 2- or 5-pyrimidinyl, 3- or 4-pyridazinyl, 2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-oxazolyl, or 2-pyrazinyl wherein the aromatic group is unsubstituted or is substituted with 1 or 2 substituents selected from straight or branched alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 4 carbon atoms, chlorine, fluorine, bromine, trifluoromethyl, nitro, hydroxy, trifluoromethoxy, or NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 have the meanings defined above,
(iii) --NR.sub.6 R.sub.7
wherein each of R.sub.6 and R.sub.7 is hydrogen, alkyl having from 1 to 4 carbon atoms, phenyl or benzyl, or --NR.sub.6 R.sub.7 taken together form a pyrrolidino, piperidino, piperazino, or morpholino ring;
(iv) ##STR22## wherein R.sub.6 and R.sub.7 have the meanings defined above;
##STR23## (v) wherein R.sub.8 is a straight or branched alkyl group having from 1 to 6 carbon atoms;
(vi) CN;
(vii) --CO.sub.2 R.sub.9
wherein R.sub.9 is hydrogen, a straight or branched hydrocarbon group having from 1 to 6 carbon atoms which is saturated or which is unsaturated and contains 1 or 2 double and/or triple bonds, or benzyl;
(viii) XR.sub.10
wherein X is oxygen or sulfur, and R.sub.10 is a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms which is saturated or which is unsaturated and contains 1 or 2 double and/or triple bonds and is unsubstituted or is substituted with an alkoxy group having from 1 to 4 carbon atoms;
(ix) biphenyl;
(d) the group --CH.sub.2 CH.sub.2 CH.dbd.C(Ph).sub.2 ;
or
(e) the group ##STR24## comprising:
(a) stirring a mixture of 1-azabicyclo 2.2.1!heptan-3-one or 1-azabicyclo 2.2.2!octan-3-one or a salt thereof, and hydroxylamine, or a salt thereof, in an alcohol solvent of sufficient dilution to keep reactants and products in solution at a temperature of from 0.degree. C. to 24.degree. C. for from 2 to 48 hours;
(b) removing the solvent, dissolving the remaining product, neutralizing it with base, extracting it into an organic solvent, and drying it to produce the stereochemically pure Z-oxime;
(c) adding the Z-oxime in portions to a suspension of a base with a mono- or dibasic counterion in an aprotic solvent with stirring for from 5 minutes to 5 hours from 0.degree. C. to 50.degree. C. producing the corresponding oxime anion;
(d) adding the product of Step (c) above to a solution of an alkylating agent of Formula R--X, where R is as defined above, and X is a leaving group, in an inert solvent and stirring the mixture at a temperature of from -78.degree. C. to 78.degree. C. for from 10 minutes to 48 hours;
(e) quenching the reaction, removing the solvent and filtering through silica gel to provide the desired specific oxime Z-isomer of Formula I.

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