Patent GB-1304502-A (GB)
Inventor: BORCK J
IPC: C07D307/14
Filed: 1971-01-19
Abstract: 1304502 Phenylalkanoic acid derivatives MERCK PATENT GmbH 19 Jan 1971 [20 March 1970] 2546/71 Heading C2C Novel compounds I and their salts in which R 1  is H or CH 3 ; R<SP>2</SP> is Cl, Br or CH 3 ; R<SP>3</SP> is O or H, OH; Z is COOH or COOR<SP>4</SP>; R<SP>4</SP> is 1-4C alkyl and n is 2 or 3; are prepared by: (1) oxidizing a compound II in which L is CHO or CH 2 OH; (2) reacting a compound III in which M<SP>1</SP> is a metal or Mg Hal; Hal is Cl, Br or I; R<SP>5</SP> is (H, OM<SP>2</SP>) and M<SP>2</SP> is H or M<SP>1</SP>; with CO 2  (3) decarboxylating a compound IV in which R<SP>6</SP>, R<SP>7</SP> and R<SP>8</SP> are H or COOH and at least one is COOH; (4) cyclizing a compound V in which X is Y-(CH 2 ) n -CR<SP>3</SP>-CH 2 -, or Y-CH 2 -CR<SP>3</SP>-(CH 2 ) n -, or a radical of Formula IX or X Y is a reactively esterified OH group; (5) chlorinating or brominating a compound VI (6) replacing the N 2 Y<SP>1</SP> group of a compound VII in which Y<SP>1</SP> is Cl or Br, by Cl or Br; (7) treating a compound VIII in which Q is COOH or functionally modified COOH; R<SP>9</SP> is R<SP>3</SP> or functionally modified R<SP>3</SP>; at least one of Q and R<SP>9</SP> being so modified, with a solvolysing, thermolysing or esterification agent to convert Q and/or R<SP>9</SP> to Z and/or R<SP>3</SP> followed, if desired, in any of (1)-(7) by oxidation of a resulting compound in which R<SP>3</SP> is H, OH or reduction of a resulting compound in which R<SP>3</SP> is O. Intermediates isolated are 2-[3-chloro-4-(3- hydroxypiperidino)-phenyl]-propanal, prepared by reaction of 3-chloro-4-(3-hydroxypiperidino)- acetophenone tetrahydropyranyl ether with methoxy methyl triphenyl phosphonium chloride followed by acid hydrolysis; 2-[3-chloro-4- (3 - oxo - piperidino) - phenyl] - 1 - propanol, prepared by reacting 2-(3-nitro-4-bromophenyl)- 1-propanol with 3-piperidone ethylene ketal, reduction of the resulting 2-[3.nitro-4(3,3- ethylenedioxy piperidino) - phenyl] - 1 - propanol to form the amino compound, diazotization with simultaneous ketal hydrolysis and Sandmeyer reaction: 2-methyl-2-[3-bromo-4:-(3- hydroxypiperidino) -phenyl] malonic acid, prepared by reacting 3-amino-4-(3-acetoxypiperidino(-phenyl-acetic acid ethyl ester with diethyl carbonate, alkylation of the resulting substituted malonic ester with CH 3 I, diazotization, Sandmeyer's reaction and saponification of the resulting diester; 2-(4-amino-3-chlorophenyl)- propionic acid, prepared by saponification of the corresponding nitrile; 1,5-dibromo-pentan-2-ol, prepared by treatment of tetrahydrofurfuryl alcohol with HBr; 2 - (3 - chloro - 4 tetrahydrofurfurylaminophenyl) -propionic acid, prepared by reaction of tetrahydrofurfuryl chloride with 2 - (3 - chloro - 4 - aminophenyl) - propionic acid ethyl ester, and alkaline saponification or the product; 2 - [3 - amino - 4 - (3 - hydroxypiperidino)-phenyl]-propionic acid, prepared by reacting 2 - (4 - chloro - 3 - nitrophenyl) - propionic acid with 3-hydroxypiperidine, followed by hydrogenation; 2-[3-chloro-4- (3-hydroxypiperidino)-phenyl]-propionic acid methyl ester, prepared by esterification of 2-[3-amino-4-(3- hydroxy piperidino).phenyl]-propionic acid with diazomethane followed by diazotization and Sandmeyer's reaction; 3 - chloro - 4 - [3 - (2- tetrahydropyranyloxy)- piperidino] - phenylacetic acid methyl ester, prepared by esterification of 3 - chloro - 4 - (3 - hydroxypiperidino)- phenylacetic acid with diazomethane, followed by reaction with dihydropyran; 3-chloro-4- (3 - hydroxypiperidino) - phenyl acetonitrile, prepared by reacting 3-nitro-4-bromobenzoic acid with 3-hydroxypiperidine, hydrogenation, diazotization, Sandmeyer's reaction, reduction with LiAlH 4 , heating with 48% aqueous HBr and reaction with NaCN; 3-chloro--4(3-hydroxypiperidino) - phenylthioacetic acid morpholide, prepared by reaction of 3-chloro-4-(3-hydroxypiperidino)-acetophenone with S and morpholine; 2 - [3 - chloro - 4 - (3 - acetoxypiperidino)- phenyl]-propionic acid, prepared by acetylation of 2 - [4 - (3 - hydroxypiperidino) - phenyl]- propionic acid followed by chlorination; 2- [3 - chloro - 4 - (3,3 - ethylenedioxypiperidino)- phenyl] - propionic acid ethyl ester, prepared by oxidation of 3-chloro-4-(3-hydroxypiperidino)phenylacetic acid ethyl ester, followed by ketalization and alkylation in the a position with CH 3 I; 2-[3-chloro-4:-(3-hydroxypiperidino)- phenyl]-2-hydroxyacetic acid) prepared by reaction of 2-chloroaniline with 1,5-dibromopentan-2-ol, further reaction with ethoxalyl chloride and AlCl 3  in benzene, catalytic hydrogenation and alkaline saponification; and 2- [3 - chloro - 4 - (3 - hydroxypiperidino)phenyl]. acrylic acid ethyl ester, prepared by dehydration of 2 - hydroxy - 2 - [3 - chloro - 4 - (3 - hydroxypiperidino) - phenyl] - propionic acid ethyl ester. Pharmaceutical compositions comprise a compound I together with a suitable diluent or carrier and are analgenics, antipyretics, diuretics, bacteriostatic agents, bactericides, and antiprotozoal, hypoglycemic, choleritic, hypocholesterolemic and anti-radiation agents.