CS272434B1 - Process for preparing 1-phenyl-2-methylaminopropane hydrochloride - Google Patents

Abstract

The racemic form of both enantiomers of l-phenyl-2-methylaminopropane hydrochloride finds application as an important chiral synthon in the production of biologically active substances. This salt is newly prepared by first converting l-phenyl-1-chloro-2-methylaminopropane hydrochloride with potassium acetate to acetate, which is hydrogenolyzed over a catalyst generated in situ from palladium chloride and activated carbon. Both steps are carried out in ethanol or methanol, the catalyst can be reused in hydrogenolysis.

Description

The invention relates to a process for the preparation of 1-phenyl-2-methylaminopropane hydrochloride.

This salt is known in both racemic and optically active forms; finds use in pharmacy in itself and as an important intermediate product for the production of biologically active substances.

Several methods for making this salt are known in the literature. It can be obtained in low yield by reduction of ephedrine or paatraephedrine with phosphorus and hydroiodic acid (Emde H.i Helv. Chim. Acta 12, 365 (1929)) or by reduction of bromephedrine hydrobromide with zinc in an acidic medium. on palladium in the presence of a mineral acid (Rosenmund KW, Karg. E .: Ber. Dtsch. Chem. Ges. 75, 1850 (1942), US 2243295 and Ger. 968545), or by hydrogenation of pseudoephedrine-O-sulfuric acid (Emde H The disadvantages of the processes are the high corrosivity of the medium (presence of a strong mineral acid), the use of high pressures and temperatures, and the need to produce a hydrogeneration catalyst beforehand. ephedrine or pseudoephedrine on platinum (Ger. 749809 and 767186) Chlorine or bromopseudoephedrine can also be hydrogenated to Pd / BaSO 4 (Emde H .: Helv. Chim. Acta 12, 365 (1929)) in the presence of sodium acetate. the procedure has a disadvantage du in the catalyst used, which must first be laboriously prepared and from which palladium is difficult to recover after hydrogenation.

The process according to the invention overcomes these disadvantages by treating a solution of 1-phenyl-1-chloro-2-methylaminopropane hydrochloride in ethanol or methanol first with potassium acetate in the same alcohol and then with hydrogen in the presence of a palladium catalyst source. in the pressure range 0.1 to 5 MPa.

In the hydrogenation, a mixture of palladium chloride and activated carbon in ethanol or methanol is preferably used as the palladium catalyst source. In this case, it is advantageous to filter off the palladium catalyst formed after the hydrogenation and to reuse it in the hydrogenation of further batches of the chlorine derivative without affecting the yield.

In carrying out the process according to the invention, it is possible to use the racemate hydrochloride and both enantiomers of the starting amine with equally good results.

When potassium acetate is treated with the hydrochloride of the substrate, sparingly soluble potassium chloride is precipitated from solution and 1-phenyl-1-chloro-2-methylaminopropane acetate is therefore used for hydrogenation. Upon its hydrogenolysis, the hydrogen chloride formed forms a salt with the amine present and acetic acid is liberated. The whole process is therefore carried out under neutral to weakly acidic conditions. After completion of the hydrogenation, the reaction mixture is worked up simply by filtering off the catalyst and concentrating the filtrate for crystallization.

We have found that 1-phenyl-2-methylaminopropane hydrochloride can be produced under economically advantageous and technologically easy-to-implement conditions.

The following examples merely illustrate, but in no way limit, the generality of the production method according to the invention.

Example 1

To a stirred suspension of 22.0 g (0.1 mol) of (-) - chloropseudoephedrine hydrochloride in ethanol (44 ml) was added a solution of 10 g of sodium acetate (90%) in 50 ml of denatured ethanol over 5 minutes. The mixture is filtered and the solid is washed with 10 ml of ethanol, the filtrate is placed in an autoclave, a mixture of 1.2 ml of 40% palladium chloride solution, 6 g of Kolorex K and 25 ml of ethanol is added (20 ml of ethanol are used for rinsing) The reaction mixture is stirred for a further 1 hour, then the catalyst is filtered off and washed with 20 ml of ethanol, the combined filtrates are boiled briefly, 0.2 g of carborafin are added, boiled again briefly and The mixture is concentrated while hot, the filtrate is concentrated to a volume of about 30 to 40 ml, allowed to cool to 20 DEG C. and then to stand for 10 hours at 5 DEG C. The precipitated crystals are filtered off with suction, washed with 10 ml of pre-cooled ethanol and 13.52 g (72.9%) of (R) - (-) - 1-phenyl-2-methylamino] hydrochloride are obtained.

CS 272 434 B1 2 propane with a melting point of 170-174 ° C and / λ / ρθ-16.25 ^ο (c 5.0; water).

Example 2

Following the procedure of Example 1, except that methanol was used instead of ethanol and the hydrogenation was carried out at 0.1 MPa, (±) -1-phenyl-1-chloro-2-methylaminopropane hydrochloride was prepared from (±) hydrochloride. -1-phenyl-2-methylaminopropane in 67.9% yield. The melting point of the salt is in the range from 130.5 to 134 ° C.

Example 3 '

Following the procedure of Example 1, except that the hydrogenation uses a palladium catalyst filtered off after completion of the hydrogenolysis in Example 1, and the hydrogenation is carried out at an initial pressure of 5 mPa, (S) - (+) hydrochloride is prepared from (+) - chlorpsudoephedrine hydrochloride. -1-phenyl-2-methylaminopropane in a yield of 74.1%. The salt has a melting point of 169.5 to 173 ° C and a specific rotation / Λ / ρθ + 15.3 ° (c 5.0; water).

Claims (3)

A process for the preparation of 1-phenyl-2-methylaminopropane hydrochloride, characterized in that a solution of 1-phenyl-1-chloro-2-methylaminopropane hydrochloride in ethanol or methanol is first treated with potassium acetate in the same alcohol and then with hydrogen in the presence of palladium catalyst sources in the pressure range of 0.1 to 5 MPa. 2. The process of claim 1, wherein the palladium catalyst source is a mixture of palladium chloride and activated carbon in the same alcohol. 3. The process of claim 1, wherein the palladium catalyst source is a catalyst filtered off after the hydrogenation of the reaction mixture.