Patent EA-004399-B1 (EA)
Title: Process for the preparation of (+/-)3-(3,4-dipchlorophenyl)-2-dimethylamino-2-methylpropan-1-ol or cericlamine (inn)
Inventor: NICOLAS MARC
IPC: C07C229/36
Filed: 1998-04-06
Abstract: 1. Process for the preparation of (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol (I) or cericlamine which consists: i)-in arylating methacrylic acid with the diazonium chloride of 3,4-dichloroaniline, prepared in situ, to obtain (+/-)2-chloro-3-(3,4-dichlorophenyl)-2-methylpropionic acid (IV), ii)-in aminating the acid (IV) with an amine HNR1R2 in which R1 and R2 are independently hydrogen or methyl, to obtain an amino acid (III) in which M is an alkali or alkaline earth metal or else hydrogen, R1 and R2 being as defined above, then iii)-in esterifying an acid (III), then, when R1 and/or R2 are hydrogen, in methylating the amine with formaldehyde and formic acid to obtain a (+/-)3-(3,4-dichlorophenyl)-2-dimethyl-amino-2-methylpropionic acid ester (II) in which M is methyl, and R is alkyl having 1-4 carbon atoms, then iv)-in reducing the ester (II) by a metal or organometal hydride to obtain (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol or cericlamine (INN) of formula (I) and in making the addition salt with hydrochloric acid. 2. Process according to claim 1, in which the diazonium chloride of 3,4-dichloroaniline is employed at a rate of 1 mol for the arylation with 1.5 mol of methacrylic acid in the presence of 0.02 mol of cuprous chloride to obtain the acid (IV). 3. Process according to claim 1 or 2 in which 1 mol of acid (IV) is aminated in acetonitrile by heating under pressure at 40 degree C for 15 to 20 hours with 1 mol of soda and from 3 to 10 mol of dimethylamine to obtain the amino acid (III) in which M is sodium, R1 and R2 are both methyl. 4. Process according to claim 1 or 3 in which 1 mol of amino acid (III) is esterified in toluene with 1.4 to 2.8 mol of dimethyl sulphate and then N-methylated with formaldehyde and formic acid when in (III) R1 and R2 are hydrogen, and with 1.2 to 2.0 mol of dimethyl sulphate when in (III) R1 and R2 are methyl, to obtain the amino ester (II) in which R, R1 and R2 are methyl. 5. Process according to claim 1 or 4 in which amino ester (II) is reduced in toluene with a lithium aluminium hydride-tetrahydrofuran addition complex with lithium aluminium hydride to amino ester mol ratio, equal about (0.57-0.60):1 to obtain (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol (I) which is optionally salified with hydrochloric acid. 6. Process according to claim 1 in which: the diazonium chloride of 3,4-dichloroaniline is employed at a rate of 1 mol for the arylation with 1.5 mol of methacrylic acid in the presence of 0.02 mol of cuprous chloride to obtain the acid (IV), 1 mol of acid (IV) is aminated in acetonitrile by heating under pressure at 40 degree C. for 15 to 20 hours with 1 mol of soda and from 3 to 10 mol of dimethylamine to obtain the amino acid (III) in which M is sodium, R1 and R2 are both methyl, 1 mol of amino acid (III) is esterified in toluene with 1.4 to 2.8 mol of dimethyl sulphate and then N-methylated with formaldehyde and formic acid when in (III) R1 and R2 are hydrogen, and with 1.2 to 2.0 mol of dimethyl sulphate when in (III) R1 and R2 are methyl, to obtain the amino ester (II) in which R1 and R2 are methyl, amino ester (II) is reduced in toluene with a lithium aluminium hydride-tetrahydrofuran addition complex with lithium aluminium hydride to amino ester mol ratio, equal about (0.57-0.60):1 to obtain (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol (I) or cericlamine which is optionally salified with hydrochloric acid. 7. Intermediate compounds selected from the group comprising (+/-)2-chloro-3-(3,4-dichlorophenyl)-2-methylpropionic acid, (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropionic acid and its sodium salt, methyl (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropionic acid.