Patent EA-003668-B1 (EA)
Title: Method for making 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline
Inventor: DAMON DAVID B
IPC: C07D215/42
Filed: 2000-11-29
Abstract: 1. 4-(3,5-Bis-trifluoromethylbenzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl acid ethyl ester, 4-toluene-sulfonate. 2. The stereoisomer (-)-(2R,4S)-4-(3,5-bis-trifluoromethylbenzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl acid ethyl ester or salts thereof. 3. The stereoisomer as recited in claim 2 wherein the salt is the 4-toluene-sulfonate. 4. The (-)di-p-toluoyl-L-tartaric acid salt of cis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. 5. The (-)di-benzoyl-L-tartrate salt ofcis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. 6. (-)(2R,4S)-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or salts thereof. 7. The stereoisomer as recited in claim 6 wherein the salt is the (-)di-benzoyl-L-tartrate salt. 8. The stereoisomer as recited in claim 6 wherein the salt is the (-)di-p-toluoyl-L-tartaric acid salt. 9. A process for preparing (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carb oxylic acid ethyl ester comprising combining (-)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, tosylate salt, sodium carbonate and methyl chloroformate in tetrahydrofuran at a temperature of about 20 degree C to about 25 degree C. 10. A process for preparing (-)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 4-toluene-sulfonate comprising a). combining 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) dibenzoyl-L-tartaric acid or((-)di-p-toluoyl-L-tartaric acid to form the (-) dibenzoyl-L-tartaric acid salt or di-p-toluoyl-L-tartaric acid salt thereof; b). combining the resulting salt, 1,2-dichloroethane and an aqueous base with 3,5-bis(trifluoromethyl)benzaldehyde, followed by the addition of sodium triacetoxyborohydride; and c). adding 4-toluene sulfonic acid monohydrate. 11. The process as recited in claim 10 wherein 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-) dibenzoyl-L-tartaric acid (anhydrous) are combined. 12. A process for preparing cis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising combining cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium/carbon to form a slurry and heating the resulting slurry at a temperature of about 35 degree C to about 60 degree C for about 30 minutes to about 3 hours. 13. A process for preparing cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R<1>-ester wherein R<1> is benzyl, tert-butyl or (C1-C4)alkyl comprising: combining vinyl-carbamic acid-R, (1-benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine and 4-toluene-sulfonic acid monohydrate in toluene at a temperature of about 50 degree C to about 90 degree C. 14. The process as recited in claim 13 with the additional step of combining the resulting cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R<1>-ester with pyridine and ethyl chloroformate in dichloromethane in to prepare cis-4-R<1>-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. 15. A process for preparing (-)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carb oxylic acid ethyl ester comprising a). combining vinyl-carbamic acid-R<1>, wherein R<1> is benzyl, (1-benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine and 4-toluene-sulfonic acid monohydrate in toluene at a temperature of about 50 degree C to about 90 degree C to prepare cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R-ester wherein R<1> is benzyl; b). combining the resulting cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid-R<1>-ester with pyridine and ethyl chloroformate in dichloromethane to prepare cis-4-R<1>-oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; c). combining cis-4-R<1> oxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and ammonium formate in methanol with palladium/carbon to form a slurry and heating the resulting slurry at a temperature of about 35 degree C to about 60 degree C for about 30 minutes to about 3 hours to prepare 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; d). combining 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and (-)dibenzoyl-L-tartaric acid or (-)di-p-toluoyl-L-tartaric acid to form the (-)dibenzoyl-L-tartaric acid salt or (-)di-p-toluoyl-L-tartaric acid salt thereof; e). combining the resulting salt, 1,2-dichloroethane and an aqueous base with 3,5-bis(trifluoromethyl)benzaldehyde, followed by the addition of sodium triacetoxyborohydride to form a product; f). combining said product and 4-toluene sulfonic acid monohydrate to prepare (-)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 4-toluene-sulfonate; and g). combining (-)-(2R,4S)-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, tosylate salt, sodium carbonate and methyl chloroformate in tetrahydrofuran at a temperature of about 20 degree C to about 25 degree C.