Patent GB-682160-A (GB)
Title: Improvements in and relating to the preparation of substituted aminoalcohols, alkenylamines, aminoalkanes and quaternary salts thereof
Inventor: BARRETT PAUL ANTHONY
IPC: C07D333/20
Filed: 1948-10-18
Abstract: 682,160. Substituted #-(tertiary amino)- alcohols, alkanes and alkenes and their quaternary salts. WELLCOME FOUNDATION, Ltd. Oct. 18, 1949 [Oct. 18, 1948], No. 27119/48. Class 2 (iii). A process for the production of substituted #(tertiary aminoalkyl)-carbinols of the formula wherein R 1  and R 2  are alike or different and are alkyl, aralkyl, thienyl or pyridyl groups, or aryl groups optionally substituted by alkyl or alkoxy groups containing up to 4 carbon atoms or by halogen atoms, R 3  and R 4  are alkyl, alkenyl, cycloalkyl, or aralkyl groups or R 3  and R. together with the adjacent nitrogen atom constitute a morpholino, pyrrolidino, piperidino N<SP>1</SP>-alkyl-N-piperazino group and -(CH 2 ) n - is a straight chain which may carry alkyl substituents, n being an integer from 4 to 10, comprises reacting an ester of the formula or a salt thereof with an organo lithium compound of the formula R 1 Li or R 2 Li or a ketone of the formula or a salt thereof with an organo lithium compound of the formula R 2 Li where R is an alkyl group, and R 1 , R 2'  R 3 , R 4  and n have the above meanings (except that R 1  may not be pyridyl) and hydrolysing the organo-metallic compound so formed. Ketones of formula III used in preforming the carbinols where R 1  and R 2  are unlike, are described in Specification 682,161. The carbinols I obtained are converted to the corresponding alkenes or where R 1  is alkyl or aralkyl, to an isomer with the double bond in a different position, by treatment with a dehydrating agent, e.g. mineral acids, carboxylic acid chlorides or anhydrides, or (where R 1  or R 2  are pyridyl or benzyl), thionyl chloride. The aminoalkanes (IV) are converted to the corresponding aminoalkanes R 1 R 2 CH(CH 2 ) n NR 3 R 3  in which R 1 , R 2 , R 3 , R 4  and n have the above meanings (except that R 1  or R 2  may not be thienyl and R 3  or R 4  may not be alkenyl) by reduction of the alkanes (IV) (in which R 1  and R 2  may not be thienyl). Corresponding quaternary ammonium salts of the amino-alcohols, alkanes or alkenes, are formed by reaction with an alkyl or aralkyl ester or salt R,X in which X is an acid radical, e.g. chloride, bromide, iodide or methosulphate radical. Examples describe the preparation of (1) 1 : 1-diphenyl-6-(1<SP>1</SP>-piperidino) hexan-1-ol, its hydrochloride and methiodide, from 5-N-piperidino amyl phenyl ketone and lithium phenyl; (2) 1 : 1-diphenyl-5- diethylaminopentan-1-ol, its hydrochloride and its methiodide, from 4-diethylaminovaleric acid ethyl ester and lithium phenyl. Similarly to (1) are prepared (10) 11-N-piperidino-1 : 1-diphenylundecan-1-ol and its oxalate; (12) 1-N- piperidino-6-phenyloctan-6-ol and its oxalate; (13) 1 - N - piperidino - 6 - ethyldecan - 6 - ol; (16) 7 - N - pyrrolidino - 1 : 2 - diphenylheptan - 2 - ol; (17) 1 - N - pyrrolidino - 6- phenyl - 6 - p - - tolylhexan - 6 - ol ; (18) 1 - N- pyrrolidyl - 6 - phenyl - 6 - p - methoxyphenylhexan - 6 - ol ; (19) 6 - N - methyl - N - benzyl 1 : 1 - diphenyl hexan - 1 - ol ; (20) 6 - N- morpholino - 1 : 1 - diphenylhexan - 1 - ol ; (21) 6 - N - piperidino - 1 - (21 - thienyl) - 1- phenylhexan - 1 - ol ; (22) 6 - N - piperidino- 1 (21 - pyridyl) - 1 - phenylhexan - 1 - ol; (23) 6 - diallylamino - 1 : 1 - diphenylhexan - 1 - ol; (25) 6 - N - morpholino - 1 - phenyl - 1 - (2<SP>1</SP>- thienyl) hexan - 1 - ol (26) 6 - N - pyrrolidino - 1 - phenyl - 1 - (2<SP>1</SP> - thienyl) - hexan - 1- ol; (27) 5 - N - piperidino - 1 - phenyl - 1 - (2<SP>1</SP>- thienyl) - pentan - 1 - ol and its oxalate; (28) 9 - N - piperidino - 1 - phenyl - 1 - (21 - thienyl)- nonan - 1 - ol; (29) 9 - N - - pyrrolidino - 1- phenyl 1 - (2<SP>1</SP> - thienyl) - nonan - 1 - ol; (30) 11 - N - piperidino - 1 - phenyl - 1 - (21 - thienyl)- undecan - 1 - ol; (32) 9 - N - pyrrolidino - 1- phenyl - 1 (21 - pyridyl) - nonan - 1 - ol; (33) 6 - dicyclohexylamino - 1 : 1 - diphenylhexan- 1 - ol; (34) 5 - dimethylamino - 1 - (21 - pyridyl)- 1 - phenyl - pentan - 1 - ol; (35) 5 - N - pyrrolidino - 1 - (21 - pyridyl) - 1 - phenylpentan - 1- ol; (39) 6 - N - piperidino - 1 - phenyl - 1 - pchlorophenylhexan - 1 - ol; (40) 6 - Nl - methyl- N - piperazino - 1 - phenyl - 1 - (2<SP>1</SP> - thienyl) hexan - 1 - ol; (40) 6 - butylamino - 1 - phenyl- 1 - (2<SP>1</SP> - thienyl) hexan - 1 - ol. Similarly to (2) are prepared (3) 1 : 1-diphenyl-6-diethylaminohexan-1-ol; (4) 1 : 1-diphenyl-7-N-piperidinoheptan - 1 - ol; (5) 1 : 1 - diphenyl - 7 - diethylaminoheptan - 1 - ol; (9) 9 - piperidino- 1 : 1 - diphenylnonan - 1 - ol; (11) 11 - (1<SP>1</SP>- pyrrolidino) 1 : 1 - diphenylundecan - 1 - ol; (14) 6 - N - pyrrolidino - 1 : 1 - diphenylhexan - 1 - ol; (15) 6 - butylamino - 1 : 1 - diphenylhexan - 1 - ol; (24) 9 - N - pyrrolidino- 1 : 1 - diphenylnonan - 1 - ol; (31) 5 - N - pyrrolidino - 1 : 1 - di - (2<SP>1</SP> - thienyl) - pentan - 1- ol; (36) 9 - N - piperidino - 1 : 1 - di - (21- thienyl) - nonan - 1 - ol; (37) 5 - dimethylamino- 1 : 1 - diphenylpentan - 1 - ol; (38) 6 - Nlmethyl - N - piperazino - 1 : 1 - diphenylhexan- 1 - ol; (42) 6 - dimethylamino - 1 : 1 - di -(2<SP>1</SP>- pyridyl) - hexan - 1 - ol; (43) 5 - N - pyrrolidino- 1 : 1 - di - (2<SP>1</SP> - pyridyl) - hexan - 1 - ol; (44) 5 - dimethylamino - 1 : 1 - di - (2<SP>1</SP> - thienyl)- hexan-1-ol. In example (6) 5-N-piperidino- 1 : 1 - diphenylpent - 1 - ene is prepared by dehydrating 1 : 1 - diphenyl - 5 - (1<SP>1</SP> - piperidino) - pentan - 1 - ol and converted to salts and quaternary ammonium compounds. Similarly prepared are (7) 6-diethylamino-1 :1- diphenylhex-1-ene; (8) 7-N-piperidino-1 :.1- diphenyl-hept-1-ene, its salts and its quaternary ammonium compounds. A list of further alkenes is given of formula IV, where R 1  is phenyl or ethyl, R 2  is phenyl, butyl, benzyl, ptolyl, p-anisyl or 2-thienyl, n is 4 to 10 and -NR 3 R 4  is a piperidino, pyrrolidino, dibutylamino, morpholino, N-methyl-N-benzylamino- or a dicyclohexylamino radical, and their oxalates, hydrochlorides and hydrobromides. Such alkenes are hydrogenated (examples 64 to 66) giving aminoalkanes of the above formula where R 1  and R 2  are phenyl, n is 8 or 10, -NR 3 R 4  is a piperidino or pyrrolidion radical, and their oxalates. Reference is made to Specification 646,198 as open to inspection under Sect. 91.