Prior Art

Mixed stereoisomers of 2-amino-1-phenylpropanol can be readily prepared by reacting benzaldehyde with nitroethane in the presence of an alkaline catalyst to produce 2- nitro-1-phenylpropanol which is then reduced to the amine. E.g., Hoover and Hass, Journal of Organic Chemistry, 12, 506, (1947). This reaction gives excellent yields at low cost. However, separating the stereoisomers produced by this reaction has not been satisfactory. As a result, heretofore, the only practical stereospecific synthesis of 2-amino-1-phenylpropanols involves the reduction of propiophenone derivatives to the racemic erythro diastereoisomers and fractional crystallization of the amine salt of an optically active acid.

The DL-erythro forms can be readily obtained from the appropriate propiophenone derivatives or by inversion of DL-threo derivatives. Since the pharmacological properties of the D and L isomers differ, it is desirable to separate the two, resulting in maximum therapeutic utility. While such potentially useful products can also be prepared, the difficulty of separating, i.e. "resolution", the isomers has prevented their development.

Specifically, the base is converted to a salt of an optically active acid. For example, the DL-base is reacted with a D-acid. This results in the formation of a mixture of D-base-D-acid and L-base-D-acid. These two salts differ in solubility. When the mixture is cooled and allowed to stand, the D-base-D-acid, typically being the less soluble, precipitates out of the solution first. By removing the precipitate at the appropriate time, the collected precipitate is largely the D-base-D-acid, while the L- base-D-acid remains in solution.

While this results in purification of the optical isomers to some extent, substantial impurities often remain. These impurities are removed to some degree by fractional crystallization. The "pure" D and L bases are then liberated by adding a sufficient amount of an alkali to a solution of the "pure" salt to produce a pH above 7.

The above process is very tedious, time consuming, and inefficient. In addition, a base with the same configuration as the resolving acid is more easily separated and purified than the opposite enantiomer. Consequently, in practice, the desired isomeric base must be matched with an optically active acid of the same configuration to achieve maximum yields.

Description Of Invention

It has been discovered that if a benzaldehyde derivative is reacted with a nitroalkane in the presence of a tertiary amine, the nitroalcohol formed is of a threo configuration rather than a mixture of threo and erythro isomers which results when sodium hydroxide is used as the catalyst. The reaction is best conducted in an aqueous aliphatic alcohol.

The tertiary amine employed must be free of primary and secondary amines which interfere with the reaction. These can be removed from the commercial products by refluxing with acetic or phthalic anhydride followed by distillation.

In a preferred embodiment of the synthetic method of the present invention, a benzaldehyde derivative is reacted with nitroethane in the presence of triethylamine in aqueous ethanol. The mixture is allowed to react at room temperature for twenty-four hours. The mixture is then acidified with an organic acid since mineral acids tend to promote decomposition, as does heat. Excess solvents and reactants are evaporated and the nitroalcohol extracted.

The nitroalcohol can easily be reduced by catalytic hydrogenation or conventional reducing agents such as zinc and acid. Lithium aluminum hydride has been found to work exceptionally well. The racemic threo isomers can readily be inverted to the racemic erythro isomers by reaction with acetic anhydride and thionyl chloride and hydrolysis. N-methyl derivatives can be prepared by adding an equimolecular amount of aqueous formaldehyde to the primary amine and reducing the Schiff base The use of a primary aliphatic alkylamine results in the formation of the dehydration product of the nitroalcohol - the beta-nitrostyrene. By employing a secondary or tertiary amine in the presence of water, nitrostyrene formation is completely eliminated. The use of a secondary or tertiary amine prevents the formation of a Schiff base amine, the necessary intermediary for nitrostyrene formation.

Instead of the usual fractional crystallization of the amine-acid salt, the method of resolving stereo isomers of the present invention uses a novel phase transfer resolution. It has been discovered that if the amine base is rapidly stirred with a mono alkali metal salt of a tartaric acid ester in a two-phase system of a hydrocarbon and water, a rapid and efficient resolution can be achieved.

In a practical embodiment of the resolution method of the present invention, a DL-2-amino-1-phenylpropanol derivative in dichloromethane is combined and stirred with dibenzoyltartaric acid in water, and aqueous sodium hydroxide for from about one to three hours. The reaction mixture is then allowed to stand for the about same length of time. The dichloromethane phase is separated and dried over anhydrous magnesium sulfate. Evaporation gives the L-threo isomer in nearly quantitative yield. The aqueous phase is made alkaline with ammonia and extracted with dichloromethane. The dichloromethane extract is dried over anhydrous magnesium sulfate and evaporated to give the D-threo isomer in nearly quantitative yield.