Process for the preparation of 2-alkoxy-N-(1-azabicyclo[2.2.2])octan-3-yl)aminobenzamides

Claim 2

A process which comprises reacting a 3-aminoquinuclidine acid addition salt having the formula: ##STR11## wherein R is hydrogen or loweralkyl, and X is the anion of a strong mineral acid and the equivalent ratio of HX to quinuclidine nitrogen is about 1:1 with an aminobenzoic acid derivative having the formula ##STR12## wherein R 1 is loweralkyl; R 2 is selected from the group consisting of hydrogen, halo or loweralkoxy; and Am is selected from amino, methylamino or dimethylamino, in the presence of the condensation agent an N,N'-dialkylcarbodiimide in a pyridine water solution wherein the volume of pyridine to volume % water ratio ranges from 50:50 to 90:10 at a temperature of about 0°-50° C. to give a mixture comprised of pyridine, water, an N-(1-azabicyclo[2.2.2]octan-3-yl aminobenzamide acid addition salt having the formula ##STR13## wherein R, R 1 , R 2 , Am and X are as defined above and by-product N,N'-dialkylurea.

Claim 3

A process of claim 1 wherein the 3-aminoquinuclidine acid addition salt is 3-aminoquinuclidine monohydrochloride.

Claim 4

A process of claim 1 wherein the aminobenzoic acid derivative is 4-amino-5-chloro-2-methoxy benzoic acid.

Claim 5

A process of claim 1 wherein the 3-aminoquinuclidine acid addition salt is 3-aminoquinuclidine monohydrochloride and the aminobenzoic acid derivative is 4-amino-5-chloro-2-methoxybenzoic acid and the benzamide produced is 4-amino-N-(1-azabicyclo[2.2.2]octan-3-yl)-5-chloro-2-methoxybenzamide monohydrochloride.

Claim 6

The process of claim 1 wherein the 3-aminoquinuclidine acid addition salt is 3-aminoquinuclidine monohydrochloride and the aminobenzoic acid derivative is 4-(N-methylamino)-5-chloro-2-methoxybenzoic acid and the banzamide produced is N-(1-azabicyclo[2.2.2]octan-3-yl)-5-chloro-2-methoxy-4-(methylamino)-benzamide monohydrochloride.

Claim 7

The process of claim 1 wherein the N,N'-dialkylcarbodiimide is N,N'-dicyclohexylcarbodiimide and the N,N'-dialkylurea is N,N'-dicyclohexylurea.

Claim 8

The process of claim 1 wherein the volume % ratio of pyridine to water ranges from 75:25 to 85:15.

Claim 9

A process which comprises the steps of: Step 1, reacting a 3-aminoquinuclidine acid addition salt having the formula: ##STR14## wherein R is hydrogen or loweralkyl and X is the anion of a strong mineral acid, and the equivalent ratio of HX to quinuclidine nitrogen is about 1:1 with an aminobenzoic acid derivative having the formula: ##STR15## wherein R 1 is loweralkyl; R 2 is selected from the group consisting of hydrogen, halo or loweralkoxy; and Am is selected from amino, methylamino or dimethylamino in the presence of the condensation agent an N,N'-dialkylcarbodiimide in a pyridine water solution wherein the volume % pyridine to volume % water ratio may range from 50:50 to 90:10 at a temperature of about 0°-50° C. to give a mixture comprised of pyridine, water, an N-(1-azabicyclo[2.2.2]octan-3-yl-aminobenzamide acid addition salt having the formula: ##STR16## wherein R, R 1 , R 2 , Am and X are defined above and by-product N,N'-dialkylurea;

Claim 10

A process which comprises the steps of: Step 1, reacting a 3-aminoquinuclidine acid addition salt having the formula: ##STR14## wherein R is hydrogen or loweralkyl and X is the anion of a strong mineral acid, and the equivalent ratio of HX to quinuclidine nitrogen is about 1:1 with an aminobenzoic acid derivative having the formula: ##STR15## wherein R 1 is loweralkyl; R 2 is selected from the group consisting of hydrogen, halo or loweralkoxy; and Am is selected from amino, methylamino or dimethylamino in the presence of the condensation agent an N,N'-dialkylcarbodiimide in a pyridine water solution wherein the volume % pyridine to volume % water ratio may range from 50:50 to 90:10 at a temperature of about 0°-50° C. to give a mixture comprised of pyridine, water, an N-(1-azabicyclo[2.2.2]octan-3-yl-aminobenzamide acid addition salt having the formula: ##STR16## wherein R, R 1 , R 2 , Am and X are defined above and by-product N,N'-dialkylurea;

Claim 11

Step 2, diluting the mixture prepared in Step 1, if necessary, with water to dissolve any precipitated said benzamide acid addition salt, separating by-product N,N'-dialkylurea to give a pyridine-water solution of said benzamide acid addition salt and removing pyridine at reduced pressure as a water pyridine azatrope adding water, if necessary, and separating a small amount of N,N'-dialkylurea to give a water solution of said benzamide acid addition salt; Step 3, adding a strong base to the water solution prepared in Step 2 to neutralize the acid component of the acid addition salt, cooling and crystallizing, filtering, washing, and drying the crystals to obtain the free base of said 2-alkoxy-N-(1-azabicyclo[2.2.2]octan-3-yl)-aminobenzamide having the formula: ##STR17## wherein R, R 1 , R 2 and Am are as defined above.

Claim 12

Step 2, diluting the mixture prepared in Step 1, if necessary, with water to dissolve any precipitated said benzamide acid addition salt, separating by-product N,N'-dialkylurea to give a pyridine-water solution of said benzamide acid addition salt and removing pyridine at reduced pressure as a water pyridine azatrope adding water, if necessary, and separating a small amount of N,N'-dialkylurea to give a water solution of said benzamide acid addition salt; Step 3, adding a strong base to the water solution prepared in Step 2 to neutralize the acid component of the acid addition salt, cooling and crystallizing, filtering, washing, and drying the crystals to obtain the free base of said 2-alkoxy-N-(1-azabicyclo[2.2.2]octan-3-yl)-aminobenzamide having the formula: ##STR17## wherein R, R 1 , R 2 and Am are as defined above.

Claim 13

A process for the preparation of an N-(1-azabicyclo[2.2.2]octan-3-yl)aminobenzamide and addition salt having the formula: ##STR18## wherein R is hydrogen or loweralkyl; R 1 is loweralkyl; R 2 is selected from the group consisting of hydrogen, halo or loweralkoxy; Am is selected from amino, methylamino or dimethylamino, and X is the anion of a strong mineral acid in a pyridine-water solution which comprises mixing a first solution which is an aqueous solution comprised of a 3-aminoquinuclidine acid addition salt having the formula: ##STR19## wherein R and X are as defined above, and the equivalent ratio of H + to quinuclidine nitrogen is about 1:1 with a second solution, a pyridine solution having dissolved therein an amino benzoic acid derivative having the formula: ##STR20## wherein R 1 , R 2 , and Am are as defined above to give a third solution having a volume % pyridine to water ratio ranging from 50:50 to 90:10 and adding thereto the condensation agent: N,N'-dialkylcarbodiimide in an amount sufficient to bring about conversion of substantially all the said quinuclidine salt to the said benzamide acid addition salt at about 0°-50° C. over a period of time, and thereafter filtering to remove by-product N,N'-dialkylurea to give a pyridine-water solution of said N-(1-azabicyclo[2.2.2]octan-3-yl)aminobenzamide acid addition salt.

Claim 14

A process for the preparation of an N-(1-azabicyclo[2.2.2]octan-3-yl)aminobenzamide and addition salt having the formula: ##STR18## wherein R is hydrogen or loweralkyl; R 1 is loweralkyl; R 2 is selected from the group consisting of hydrogen, halo or loweralkoxy; Am is selected from amino, methylamino or dimethylamino, and X is the anion of a strong mineral acid in a pyridine-water solution which comprises mixing a first solution which is an aqueous solution comprised of a 3-aminoquinuclidine acid addition salt having the formula: ##STR19## wherein R and X are as defined above, and the equivalent ratio of H + to quinuclidine nitrogen is about 1:1 with a second solution, a pyridine solution having dissolved therein an amino benzoic acid derivative having the formula: ##STR20## wherein R 1 , R 2 , and Am are as defined above to give a third solution having a volume % pyridine to water ratio ranging from 50:50 to 90:10 and adding thereto the condensation agent: N,N'-dialkylcarbodiimide in an amount sufficient to bring about conversion of substantially all the said quinuclidine salt to the said benzamide acid addition salt at about 0°-50° C. over a period of time, and thereafter filtering to remove by-product N,N'-dialkylurea to give a pyridine-water solution of said N-(1-azabicyclo[2.2.2]octan-3-yl)aminobenzamide acid addition salt.

Claim 15

A solution comprised of pyridine, water, a 3-aminoquinuclidine mono-strong acid salt of the formula: ##STR21## wherein R is hydrogen or loweralkyl, and the ratio of strong acid to quinuclidine nitrogen is about 1:1, an aminobenzoid acid compound of the formula: ##STR22## wherein R 1 is loweralkyl, R 2 is selected from the group consisting of hydrogen, halo or loweralkoxy, and Am is selected from amino, methylamino or dimethylamino and wherein the amount of said 3-aminoquinuclidine mono-strong acid salt ranges from about 5-15 wt. %, the amount of said aminobenzoic acid ranges from about 5-15 wt. % and the volume % ratio of pyridine to volume % water ranges from 50:50 to 90:10.

Claim 16

A solution comprised of pyridine, water, a 3-aminoquinuclidine mono-strong acid salt of the formula: ##STR21## wherein R is hydrogen or loweralkyl, and the ratio of strong acid to quinuclidine nitrogen is about 1:1, an aminobenzoid acid compound of the formula: ##STR22## wherein R 1 is loweralkyl, R 2 is selected from the group consisting of hydrogen, halo or loweralkoxy, and Am is selected from amino, methylamino or dimethylamino and wherein the amount of said 3-aminoquinuclidine mono-strong acid salt ranges from about 5-15 wt. %, the amount of said aminobenzoic acid ranges from about 5-15 wt. % and the volume % ratio of pyridine to volume % water ranges from 50:50 to 90:10.