Patent GB-1322270-A (GB)
Title: Piperidine derivatives their preparation and compositojs containing them
IPC: C07D317/58
Filed: 1971-11-19
Abstract: 1322270 1,4-Substituted piperidines and 3,4- dehydro-piperidines MERCK PATENT GmbH 19 Nov 1971 [10 Dec 1970] 53852/71 Heading C2C Piperidine derivatives of the Formula I: wherein Z is 1,3-benzodioxoyl-5, pyrazolyl-3 pyrazolyl-4, pyrazolyl-5 or thiazolyl-5, said pyrazolyl or thiazolyl groups being optionally substituted with one or more C 1-4  alkyl and said pyrazolyl groups also optionally being N-substituted with an acyl, alkoxycarbonyl, carbamoyl, N-alkyl carbamoyl or N,N-dialkylcarbamoyl group; A is a straight or branched C 1-6  alkylene; B<SP>1</SP> and B<SP>2</SP> are each H or OH or together form a C-C bond, provided that B<SP>1</SP> and B<SP>2</SP> are not simultaneously OH; and Ar is a phenyl group optionally substituted with one or more halogen and/or C 1-4  alkyl and/or C 1-4  alkoxy, with the proviso that when A is CH 2 CH 2 , Z is not 1,3-benzodioxolyl-5, and the physiologically acceptable acid addition and quaternary ammonium salts may be prepared by (a) condensing a compound Z-A-NH 2  with a compound III in which X<SP>2</SP> and X<SP>3</SP> are chlorine, bromine, iodine, hydroxyl or an esterified hydroxyl; (b) condensing a compound Z-A-X<SP>1</SP> where X<SP>1</SP> is the same as X<SP>2</SP> and X<SP>3</SP> above with a compound III in which X<SP>2</SP> and X<SP>3</SP> together are >NH; (c) reacting a nitrile group on the A grouping in I with a C 1-5  alkyl organometallic compound to form the required grouping A; (d) forming a pyrazole or thiazole ring from a compound VI: in which Q is R<SP>2</SP>COCHR<SP>3</SP>CO-, R<SP>2</SP>COCH(COR<SP>3</SP>), R<SP>2</SP>COCHX- or a pyrimidyl-4, pyrimidyl-5 or pyrimidyl-6 which is optionally substituted with one or more C 1-4  alkyl, R<SP>2</SP> and R<SP>3</SP> are H or C 1-4  alkyl, or a mono or diketal, mono or dienolacylate, mono or dienol ether or mono or dienamine of VI and a compound R<SP>4</SP>-L-NH 2  in which R<SP>4</SP> is H or C 1-4  alkyl, L is NH or CS or an N-acyl or acid addition salt of R<SP>4</SP>-L-NH 2 ; (e) reacting a compound VIII: with an organic metallic compound of Ar; (f) eliminating HE from a compound X: wherein one E is chlorine, bromine, iodine hydroxyl or an esterified hydroxyl or NH 2  and the other E is hydrogen; (g) treating a compound XI: with an acid to form a compound I in which B<SP>1</SP> is H and B<SP>2</SP> is OH or B<SP>1</SP> and B<SP>2</SP> together form a C-C bond; (h) reducing groups reducable to hydrogen, C-C multiple bonds and/or C-N multiple bonds; (i) lyolytically splitting off a group to form a hydrogen or hydroxyl group; (j) diazotizing a compound I which additionally contains an amino group followed by decomposition of the diazo group to a halogen or hydroxyl group; (k) hydrating a 3,4-dehydropiperidine ring; (1) acylating a free NH group in the pyrazole ring; (m) formation of salts. 1,5 - Dichloro - 3 - phenyl - pentane was prepared by reduction of 3-phenylglutaric acid followed by reaction with HCl. 1 - Methyl - 4 - (2 - aminoethyl) - pyrazole was prepared by reaction of 1-methyl-4(2-bromoethyl)-pyrazole with potassium phthalimide followed by hydrolysis. A mixture of 1-(4-phenyl-3,4-dehydro-piperidino) - pentane - 2,4 - dione - 2 - and - 4- ethylene ketal was prepared by reaction of the dione with ethylene glycol. A mixture of 1-(4-phenyl-piperidino)-4-acetoxy - 3 - penten - 2 - one and 1 - (4 - phenylpiperidino) - 2 - acetoxy - 2 - penten - 4 - one was prepared by reaction of 1-(4-phenyl piperidino)- pentane-2,4-dione with diazo methane. By reaction of the same dione with ketene and ammonia mixtures of 1-(4-phenyl-piperidino)-4- acetoxy-3-penten-2-one and 1-(4-phenyl-piperidino) - 2 - acetoxy - 2 - penten - 4 - one and 1 - (4- phenyl - piperidino) - 4 - amino - 3 - penten - 2- one and 1 - (4 - phenyl - piperidino) - 2 - amino- 2-penten-4-one respectively were obtained. 1 - [2 - (4 - Methylpyrimidyl - 5) - ethyl] - 4- phenyl piperidine was prepared from 4-methyl- 5-(2-chloroethyl)-pyrimidine and 4-phenyl piperidine. 3 - Bromo - 5 - (4 - phenyl - piperidino) - pentan- 2-one was prepared by reaction of 5-bromo-2- pentanone with 4-phenyl-piperidine followed by bromination of the product. 1 - [2 - (5 - Methyl - pyrazolyl - 3) - ethyl] - 3- chloro - 4 - phenyl - piperidine and the corresponding 3-bromo compound were prepared by reaction of the 3-hydroxy compound with thionyl chloride or phosphorus tribromide, respectively. 3 - [2 - (5 - Methyl - pyrazolyl - 3) - ethyl] - 6- methyl - 6 - phenyl - tetrahydro - 1,3 - oxazine was prepared by heating 2-(5-methyl-pyrazolyl-3)- ethylamine hydrochloride, α-methyl styrene and aqueous formaldehyde or by a process (b) as above. (5 - Methyl - pyrazolyl - 3) - acetic acid (4- phenyl - 3,4 - dehydropiperidide was prepared by reaction of 5-methyl-pyrazolyl-3-acetyl chloride with 4-phenyl-3,4-dehydropiperidine. 1 - (5 - Methyl - pyrazolyl - 3) - 4 - (4 - phenyl- 3,4 - dehydropiperidino) - 1 - butanol containing a little 1 - (5 - methyl - pyrazolyl - 3) - 4 - (4- phenyl - 3,4 - dehydropiperidino) - but - 1 - ene was prepared by reacting 3-formyl-5-methylpyrazole with a Grignard reagent of 1-(3-chloropropyl) - 4 - phenyl - 3,4 - dehydro - piperidine. 1 - (1 - Methyl - pyrazolyl - 4) - 2 - (4 - phenylpiperidino)-ethanone was prepared by reaction of 1 - methyl - 4 - bromoacetyl - pyrazole and 4-phenyl piperidine.  1 - (2,4 - Dimethyl - thiazolyl - 5) - 4 - (4- phenyl - piperidino) - butan - 2 - one was prepared either by reaction of (2,4-dimethylthiazolyl-5) acetone with formaldehyde and 4- phenylpiperidine or cyanoethylation of 4- phenyl-piperidine to yield 1-cyano-2-(4-phenylpiperidino)-ethane which was further reacted with 2,4 - dimethyl - thiazolyl - 5 - magnesium chloride to give the required compound. 1 - [2 - (5 - Methyl - pyrazolyl - 3) - ethyl] - 4- phenyl pyridinium chloride was prepared from 4 - phenyl - pyridine and 3 - (2 - bromoethyl)- 5-methyl pyrazole. 1 - [2 - (5 - Methyl - pyrazolyl - 3) - ethyl] - 4- bromo - 4 - phenyl - piperidine dihydrochloride was prepared by adding HBr to the 3,4-dehydropiperidine, 1 - [2 - (5 - Methyl - pyrazolyl - 3) - ethyl] - 3,4- dehydro - 4 - (m - aminophenyl) - piperidine was prepared by reduction of the corresponding mnitrophenyl compound. Pharmaceutical compositions of the compounds I show tranquillizing, narcosis potentiating, sedative, hypnotic, narcotic, adrenolytic, antihistaminic, serotoninolytic and spasmolytic activity when administered orally, parenterally or topically with the usual excipients.