IL42016A - Dopamine derivatives and their preparation - Google Patents

Abstract

1392674 Dopamine derivatives ELI LILLY & CO 9 April 1973 [12 April 1972] 16835/73 Heading C2C The invention comprises dopamine derivatives of Formula (I) in which R and R 1 are H or CH 3 , at least one being H; R 2 and R 3 are H or OH at least one being OH; n is 1 or 2; and when n is 1 and R 2 and R 3 are both OH, then either R or R 1 is CH 3 ; and the pharmaceutically acceptable addition salts thereof with mineral acids. They may be prepared by reacting a compound of Formula (II) in which R 1 is hydrogen, R 2 <SP>1</SP> and R 3 <SP>1</SP> are H or CH 3 O- at least one being methoxy, n is 1 or 2; and when n is 1 and R2<SP>1</SP> and R 3 <SP>1</SP> are both CH 3 O, then R or R 1 is CH 3 ; with hydrobromic acid and optionally converting to pharmaceutically acceptable salts. The methyl ethers used as starting materials may be prepared as follows: (a) the compounds of Formula II in which R is methyl and R 1 is hydrogen are prepared by the reductive alkylation of a methoxylated phenylethylamine or a methoxylated phenyl propyl amine with 3,4-dimethoxyphenylacetone; (b) the compounds in which R is methyl and R 1 is hydrogen may also be prepared by reacting 3,4- dimethoxyphenylacetone with a methoxylated phenethylamine or a methoxylated phenylpropylamine in the presence of p-toluene sulphonic acid to form the imine which is then reduced to the secondary amine; (c) the compounds in which R is hydrogen and R 1 is methyl may be prepared by the reductive alkylation of 3,4-dimethoxyphenylethylamine with the desired mono- or dimethoxylated phenyl butane-3-one (n=2) or the mono- or di-methoxylated phenylacetone (n = 1); (d) the compounds in which R is hydrogen and R 1 is methyl may also be prepared by the condensation of 3,4-dimethoxyphenylacetic acid with a methoxylated 1 -phenyl-3-aminobutane (n=2) or with a methoxylated 1-phenyl-2- aminopropane (n =1) to form as an intermediate the methoxylated amide which is reduced under nitrogen with borane to provide the secondary amine; and (e) the compounds in which R and R 1 are both hydrogen may be prepared by the alkylation of 3,4-dimethoxyphenylethylamine with a methoxylated phenyl-n-propyl bromide (n=2) or with a methoxylated phenyethyl bromide (n= 1). The products of Formula (I) are used in pharmaceutical agents. [GB1392674A]

Claims (10)

1. The dopamine derivative compound of the formula I wherein R and R]_ are hydrogen or methyl, at least one of R or R-. being hydrogen; R„ and R~ are hydrogen or hydroxy, J. at least one of R2 or ^ being hydroxy; n is 1 or 2; and when n is 1 and 2 and are both hydroxy then either R and is methyl; and when R is methyl, then 2 and are both hydroxy; and the pharmaceutically acceptable acid addition salts thereof with mineral acids.

2. The dopamine compound of claim 1 wherein said compound is 3,^-cLihydroxy-N-/ 3-(^-hydroxyphenyl)- l-methyl-n-propyl7^rPhenethylamine hydrochloride; 1-3,4- dihydroxy-N- "3-( -hydroxyphenyl)-l-methyl-n-propyl7- β- henθthylamine hydrochloride; 3, -d ihydroxy-N- "3- (3-^ydroxyphenyl ) -n- or propyl7- -Phenethylamine hydrochloride ; /3, ½-d ihydroxy-N-Z"3- ( 3 , ^-dihydroxyphenyl ) -n-propyl-p-phenethylamine hydro-chlorida.

3. A process for preparing the dopamine derivative compounds of Claim 1 which comprises reacting a com- 42016/2 FORMULA II wherein R and are hydrogen or methyl, at least one of R or RL being hydrogen;- and R^ are hydrogen or methoxy, at least one of R or R^ being methoxy; n is 1 or 2; and when n is 1 and R and ^ are both methox , then either R or Rx is methyl; and when R is methyl, then R and ^ are both methoxy; with hydrobromic acid and optionally converting to the pharmaceutically acceptable salts.

4. The process according to claim 3 which comprises refluxing the methoxy secondary amine of formula II with concentrated hydrobromic acid in the presence of an inert solvent.

5. · The process according to claim 3 or for preparing 3 , -dihydroxy-N- ~3- ( -hydroxyphenyl )-l-methyl- n-propyl7- -Phenethylamine which comprises catalyt ically hydrogenating a reaction mixture containing 1- ( -methoxy- phenyl)-3-butanone and homoveratrylamine in an inert solvent, to form 3, -dimethoxy-N- **3-(i).»inethoxyphenyl)-l-- methyl-n-propyl7-phenethylamine and reacting the trimethoxy secondary amine thus obtained with hydrobromic acid,

6. The process according to claim 3 or which comprises reacting 3-(^-methoxyphenyl)-l-methyl-n-propyl-, amine and acid, reducing the 42016/2 2- (3,^-dimethoxyphenyl)-N^ (^-methoxyphenyl-l-methyl-n-propyDacetamide thus obtained with borane, and reacting the resulting 3 ,iv-dimethoxy-N- ~3- ( -methoxyphenyl ) -1-methyl-n,-propyl7-P-phenethylamine with hydrobromic acid,

7. A process according to claim 3 or for pre¬ y-phenyl propenyl ketone with homoveratrylamine in the presence of an inert solvent, catalytically hydrogenating the 3- ( 3 , dimethoxyphenylethylamino ) -1- ( -methoxyphenyl ) -butane-l-one thus obtained, precipitating as a product ·" Uie catalytic hydrogenation 3,^-dimethoxy-N-(~3-( -me hoxyphenyl)-l-methyl-n-propyl7-P-phenethylamine hydrochloride, and treating the product with hydrogen bromide.

8. A process according to claim 3 or ^ for preparing 3 , ( 3-hydroxyphenyl ) -n-propyl7-β-phenethylamine which comprises reacting 3 , -dimethoxy-phenethylamine and 3-(3-methoxyphenyl)-n-propyl bromide, and treating the 3,^-dimethoxy-N- ~3-(3-methoxyphenyl-n-propyl7- -phenethylamine thus obtained with hydrogen bro-mide. 42016/2

9. A process according to claim 3 or for preparing 3,4-dihydroxy-N- ~3-(3,^-dihydroxyphenyl-n- propyl7- -phenethylamine which comprises reacting 3 - dimethoxyphenethylamine and p-(3„4-dimethoxyphenyl)- propionic acid, reducing the N-(3,^-dimethoxyphenyl- ethyl-3 , -dimethoxyphenylpropionamide thus obtained with borane, and reacting the resulting 3,i4—dimethoxy-N- ~3- (3,^-dimethoxyphenyl ) -n-propyl7-P-phenethylamine with hy- drobromic acid.

10. A process according to any of the preced- ing claims which comprises resolving a racemic mixture of a compound of formula II, and then individually reacting the resolved d- and 1- amines with hydrobromic acid to obtain the corresponding d- and 1,-phenolic amines. ND/rb