Patent GB-1286861-A (GB)
Title: New benzofuran derivatives, their preparation and use
IPC: C07D307/80
Filed: 1969-09-05
Abstract: 1286861 2 - (p - Alkoxybenzyl) - 3 - (2 - aminoethyl)-benzofurans CIBA GEIGY AG 5 Sept 1969 [6 Sept 1968] 44057/69 Heading C2C Novel 2 - (p - alkoxybenzyl) - 3 - (2 - aminoethyl)-benzofurans of the general formula wherein R 1  is a hydrogen, fluorine, chlorine or bromine atom or a C 1-2  alkyl, C 1-2  alkoxy or nitro group, R 2  is a hydrogen, fluorine, chlorine or bromine atom or a C 1-2  alkyl or C 1-2  alkoxy group, R3 is a C 1-4  alkyl group and R 4  and R 5  are each a C 1-4  alkyl group or NR 4 R 5  is a pyrrolidino, piperidino or morpholino group, and acid addition salts thereof are prepared (a) by reaction of a reactive ester of a 2-(p-alkoxybenzyl) - 3 - (2 - hydroxyethyl) - benzofuran of the general formula with an amine of the general formula R 4 R 5 NH; (b) by reduction of an amide of the general formula wherein one of Z 1  and Z 2  is a methylene group and the other is a carbonyl group, and R 4 <SP>1</SP> is a C 1-3  alkyl group or R 5 NZ 2 R 4 <SP>1</SP> is an optionally carbonyl-substituted pyrrolidino, piperidino or morpholino group, depending on the meaning of Z 2 , with a complex hydride directly or after reaction with triethyloxonium fluoroborate; (c) by reaction of a 2-(p-alkoxybenzyl)-3-(2- aminoethyl)-benzofuran of the general formulµ wherein R 5 <SP>1</SP> is a hydrogen atom or a C 1-4  alkyl group, with a C 1-4  oxoalkane under reducing conditions, or with a reactive ester of a C 1-4  alkanol in the presence of an acid-binding agent, using in each case at least the molar equivalent amount of the oxoalkane or ester corresponding to the number of hydrogen atoms bound to the nitrogen atom to be replaced, or, if R 5 <SP>1</SP> is a hydrogen atom, alternatively with a reactive ester of 1,4-butanediol, 1,5-pentanediol or diethylene glycol in the presence of an acidbinding agent; (d) by reduction of a 2-(p-alkoxybenzyl)-3-benzofuranyl aminomethyl ketone of the general formula  with a complex hydride in the presence of a Lewis acid and in an ethereal solvent; (e) by subjection of a 2-(p-alkoxybenzyl)-3-hydroxy- 3-(2-aminoethyl)-2,3-dihydrobenzofuran of the general formula to conditions under which water is eliminated; (f) by reduction of a 3-(2-aminoethyl)-2-benzofuranyl p-alkoxyphenyl ketone of the general formula with a complex hydride or hydrazine hydrate in the presence of an alkali metal hydroxide; (g) by reduction of a 2-(p-alkozybenzoyl)-3-carbamoylmethylbenzofuran of the general formula with a complex metal hydride; and (h) when NR 4 R 5  is a piperidino group and R 1  is not a nitro group, by reduction of a pyridinium salt of the general formula wherein R 1  is not a nitro group and X# is a monovalent anion or the normal equivalent of a polyvalent anion, with catalytically activated hydrogen; followed optionally by salification of the product. 2 - (p - Alkozybenzyl) - 3 - (2 - hydroxy ethyl)- benzofurans of the second general formula above (which may be esterified to form reactive esters) are prepared by condensation of a 3(2H)-benzofuranone with a p-alkoxybenzaldehyde, hydrogenation of the resulting 2-p-alkoxybenzylidene) derivative, reaction of the resulting 2-(p-alkoxybenzyl) - 3(2H) - benzofuranone of the general formula with a 2-bromoacetic acid alkyl ester and zinc in benzene, dehydration of the hydroxy-ester of the general formula wherein R 6  is a C 1-4  alkyl group, so produced and reduction of the resulting ester of the general formula with a complex hydride. Esters of the general formula immediately above may also be hydrolysed to form the corresponding acid of the general formula 5 - (p - Ethoxybenzyl) - 5 - methoxy - 3(2H)- benzofuranone is prepared by treatment of [4- methoxy - 2 - (methoxy- or ethoxy - carbonyl)- phenoxy]-acetic acid methyl or ethyl ester with sodium in toluene, p-ethoxybenzyl bromide and then methanolic potassium hydroxide solution. 2 - [2 - p - Ethoxybenzyl) - 3 - benzofuran] - ethylamine is prepared by reaction of 2(3H)-benzofuranone with bromoacetic acid methyl ester and zinc in benzene, followed by treatment with dilute sulphuric acid, reduction of the resulting 3 - benzofuranacetic acid methyl ester (the 5-methyl derivative is produced analogously) with LiAlH 4 , esterification of the resulting 2-(3.benzofuran). ethanol with p-toluenesulphonyl chloride, treatment of the sulphonate thus obtained with ammonia, reaction of the resulting 2-(3-benzofuran)-ethylamine with p-ethoxybenzoyl chloride, treatment of the N.[2- ( 3-benzofuranyl) - ethyl] - p - ethoxybenzamide so produced with phosphorus pentoxide and phosphorus oxychloride under reflux and treatment of the resulting 1 - (p - ethoxyphenyl) - 3,4 - dihydrobenzofuro[2,3-c]pyridine hydrochloride with diethylene glycol and hydrazine hydrate under heating. 1 - (p - Ethoxyphenyl) - 6 - methyl - 3,4- dihydro - benzofuro[2,3-c] - pyridine hydrochloride is prepared as indicated above for the 6-unsubstituted compound, starting from 2-(5- methyl - 3 - benzofuran) - ethanol, which is prepared by LiAlH 4  reduction of the corresponding acetic acid derivative. N,N,5.Trimethyl-2-(p. ethoxybenzyl) - 3 - benzofuranacetamide is prepared by reaction of the corresponding acetic acid methyl ester with dimethylamine; similar compounds are prepared analogously. 2-(p- Ethoxybenzyl) - 3 - pyrrolidinoacetyl - benzofuran hydrochloride is prepared by treatment of 2.(pethoxybenzyl)-benzofuran with acetyl chloride, tin tetrachloride and carbon disulphide, reaction of the resulting 2-(p-ethoxybenzyl)-3-acetyl-benzofuran [some 2 - (p - hydroxybenzyl) - 3 - acetylbenzofuran is also produced] with bromide in the presence of dibenzoyl peroxide and reaction of the resulting 2- (p.ethoxybenzyl)- 3-bromoacetylbenzofuran with pyrrolidine and hydrogen chloride; other aminoacetyl derivatives are produced analogously. 2 - (p - Ethoxybenzyl)- benzofuran is prepared by reaction of salicylaldehyde with p-ethoxyphenacyl bromide and reduction of the resulting 2-(p-ethoxybeezoyl)- benzofuran with hydrazine hydrate (other substituted 2 - (p - ethoxybenzyl) - beezofurans being produced in the same way). 2-(p-Alkoxybenzyl)- 3 - hydroxy - 3 - (2 - aminoethyl) - 2,3 - dihydrobenzofurans of the seventh general formula above are prepared by LaAlH 4  reduction of a 2-(palkoxybenzyl) - 3 - hydroxy - 2,3 - dihydro - 3- benzofuranacetic acid ethyl ester, esterification of the resulting benzofuranethanol with ptoluenesulphonyl chloride and treatment of the resulting sulphonate with an amine. 5,6-Dimethyl - 3(2H) - benzofuranone is prepared by treatment of 2 - chloro - 2<SP>1</SP> - hydroxy - 4<SP>1</SP>,5<SP>1</SP>- dimethyl-acetophenone with sodium acetate and ethanol. 2 - (p . Ethoxybenzyl) - 5 - nitro - 3(2H)- benzofuranone is prepared by treatment of [4- nitro - 2 - (ethoxycarbonyl) - phenoxy] acetic acid ethyl ester with sodium hydride and pethoxybenzyl bromide and treatment of the resulting 2 - (p - ethoxybenzyl) - 5 - nitro - 3(2H)- oxo - 2 - benzofuran - carboxylic acid ethyl ester with boiling sodium hydroxide solution. 2-(p- Alkoxybenzyl) - 3 - benzofuran - acetamide derivatives of the third general formula above are prepared by reaction of the corresponding 3- benzofuran-acetic acid with thionyl chloride and an amine. N - Propyl - N - [2 - [2 - (pethoxybenzyl) - 5 - methyl - 3 - benzofuran] ethyl]- propionic acid amide is prepared by reaction of p-toluenesulphonio acid 2-[2-(p-ethoxybenzyl)- 5 - methyl - 3 - benzofuranyl] - ethyl ester with propylamine and reaction of the resulting N - propyl - 2 - [2 - (p - ethoxybenzyl) - 5 - methyl- 3-benzofuran] ethylamine with propionic acid chloride. 3 - (2 - Aminoethyl) - 2 - benzofuranyl p-alkoxyphenyl ketones of the eighth general formula above are prepared by LaAlH 4  reduction of a 3-benzofuranacetic acid, reaction of the resulting 3-benzofuranethanol with acetic anhydride, reaction of the resulting 3-benzofuranethyl acetic acid ester with a p-alkoxybenzoyl chloride in the presence of tin tetrachloride and carbon disulphide, hydrolysis of the 2-(palkoxybenzoyl) - 3 - benzofuranethyl acetic acid ester thus obtained, esterification of the resulting 3-benzofuronethanol with p.toluenesulphonyl chloride and reaction of the resulting sulphonate with an amine. 6-Ethyl-3-benzofuranacetic acid is prepared by reaction of 3-ethylphenol with acetone dicarboxylic acid and concentrated sulphuric acid, treatment of the resulting 7- ethyl-4-coumarin-acetic acid with bromine in acetic acid, heat treatment of the 7-ethyl-4- coumarin-1<SP>1</SP>-bromoacetic acid thus obtained and alkaline hydrolysis of the resulting 7-ethyl-4- bromomethyl-coumarin. 5 - Chloro - 3 - benzofuranacetic acid is prepared by reaction of 5- chloro - 3 ( 2H) -benzofuranone with cyanoacetic acid ethyl ester. p-Toluenesulphonic acid 2-[2- (p - ethoxybenzi/l) - 2,3 - dihydro - 3 - hydroxy - 5- methyl-3-benzofuranyl]-ethyl ester is prepared by LiAlH 4  reduction of 2-(p-ethoxybenzyl)-2,3- dihydro - 3 - hydroxy - 5 - methyl - 3 - benzofuranacetic acid methyl ester and esterification of the resulting 3-benzofuranethanol with ptoluenesulphonyl chloride. 1 -[2- (2-p-Ethoxybenzyl - 5 - methyl - 3 - benzofuranyl) - ethyl]- pyridinium hydrogen sulphate is prepared by treatment of 5-methyl-2-p-ethoxybenzyl-3-benzofuranethanol with thionyl bromide, followed by pyridine and sulphuric acid. N-Ethyl-2-[2- (p - ethoxybenzyl) - 5 - methyl - 3 - benzofuran]- ethylamine is prepared by reaction of 2-[2-(pethoxybenzyl) - 5 - methyl - 3 - benzofuranethyl]amine with acetic anhydride and LiAlH 4  reduction of the resulting N-[2-(3-benzofvran)- ethyl] acetamide. 2 - (p - Alkoxybenzoyl) - 3- carbamoylmethylbenzofurans of the ninth general formula above are prepared by treatment of a 3-benzofuranacetic acid with methanol in the presence of concentrated sulphuric acid, reaction of the resulting methyl ester with a p-alkoxybenzoyl chloride and treatment of the resulting 2 -