Process for the preparation of an optically pure aminoalcohol
AssigneeSanofi
InventorsMarcel Descamps, Joel Radisson, Gilles Anne-Archard
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Abstract
A process is described for the preparation of (+)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine (I) by reaction of 3,4-dichlorophenylacetonitrile (II) with an alkali metal halogenoacetate, treatment of the 3-cyano-3-(3,4-dichlorophenyl)propionic acid (III) with D-(-)-N-methylglucamine, with second-order asymmetric conversion, hydrolysis of the D-(-)-N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid and enantioconservative reduction of the resulting levorotatory cyanoacid with a borane.
Claims13
A process for the preparation of (+)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine of formula (I):
- ##STR23## which comprises (a) treating 3,4-dichlorophenylacetonitrile of formula (II):
- ##STR24## with an alkali metal chloroacetate or bromoacetate in liquid ammonia or in a polar aprotic solvent, in the presence of a strong base, at a temperature of -40.degree. C. to +25.degree. C.;
- (b) treating the resulting racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid of formula (III):
- ##STR25## with D-(-)-N-methylglucamine in order to crystallize all the acid (III) in the form of the D-(-)-N-methylglucamine salt of the levorotatory acid;
- (c) treating said salt with a strong acid;
- and
- (d) subjecting the freed (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid of formula (IV):
- ##STR26## to enantioconservative reduction with a borane.
A process for the preparation of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid, which comprises treating racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid with D-(-)-N-methylglucamine and treating the resulting D-(-)-N-methylglucamine salt of (-)-3-cyano- 3-(3,4-dichlorophenyl)propionic acid with a strong acid.
A salt which is the D-(-)-N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid.
A process for the preparation of (-)-N-methyl-N- 4-(4-phenyl-4-acetylaminopiperidyl)-2-(3,4-dichloro-phenyl )butyl!benzamide and its pharmaceutically acceptable salts with organic or inorganic acids which comprises:
- (a) reacting a compound of formula (I) ##STR27## with an acid chloride of benzoic acid, (b) reacting the (-)-N- 2-(3,4-dichlorophenyl-4-hydroxy)butyl!benzamide thus obtained of formula (VIII) ##STR28## with dihydropyrane, (c) reacting the O-protected compound thus obtained of formula (IX) ##STR29## with dimethylsulfate, (d) O-deprotecting the compound thus obtained of formula (X) ##STR30## in an acidic medium, (e) treating the compound thus obtained of formula (XI) ##STR31## with an acid chloride of benzenesulfonic acid, (f) reacting the benzenesulfonate thus obtained of formula (XII) ##STR32## with 4-acetylamino-4-phenylpiperidine, and (g) isolating the (-)-N-methyl-N- 4-(4-phenyl-4-acetylamino-piperidyl)-2-(3,4-dichloro-pheny l)butyl!benzamide, or optionally converting it to one of its pharmaceutically acceptable salts with organic or inorganic acids.
Dependencies are inferred from the claim text.