Chiral amphetamines from phenyl grignards

[Rhodium]

Process for the enantiospecific preparation of (S)-2-ethylamino-1-(3-trifluoromethylphenyl)propane

Patent EP0301925

Abstract
New process for the enantiospecific preparation of (S)-2-ethylamino-1-(3-trifluoromethylphenyl)propane, characterised in that benzaldehyde is condensed with (S)-alaninol and that, after reduction, the product originating from the reaction is condensed with acetaldehyde to obtain (S)-N-benzyl-N-ethyl alaninol, which is subjected to the action of thionyl chloride to give, after neutralisation, (S)-2-(N-benzyl-N-ethylamino)-1-chloropropane, which is in its turn condensed with 3-trifluoromethylphenylmagnesium bromide to give (S)-2-(N-benzyl-N-ethylamino)-1-(3-trifluoromethylphenyl)-propane which, after debenzylation by hydrogenolysis, produces (S)-2-ethylamino-1-(3-trifluoromethylphenyl)propane.

Experimental
^{(crude translation by yours truly)}

The precursor preparation is very simple. (S)-Alaninol and benzaldehyde is dissolved in methanol and the formed imine reduced by the addition of sodium borohydride. To this reaction mixture is then added acetaldehyde and more sodium borohydride to give ~80% (S)-N-Benzyl-N-Ethyl-Alaninol after standard workup. This tertiary aminoalcohol is then chlorinated with thionyl chloride to give (S)-N-benzyl-N-ethyl-1-chloro-2-aminopropane in ~80% yield.



(S)-N-Benzyl-N-Ethyl-3-Trifluoromethyl-Amphetamine
^{(S)-N-Benzyl-Fenfluramine}

In a 500 ml 3-neck RB equipped with a stirrer, 15.86g (S)-N-benzyl-N-ethyl-1-chloro-2-aminopropane, 200 mL THF and 1.6g Copper(I)Iodide. After cooling to -15°C, 100mL 1M 3-Trifluoromethyl-phenylmagnesium bromide (in THF?) is added and the solution is refluxed for 3h. The solution is cooled to -10°C and then quenched by the addition of 100 mL saturated aqueous ammonium chloride followed by 100 mL 25% ammonia. Stir for 15 min, separate the organic phase and extract the aqueous phase with 2x100mL ether. The pooled organic phases are washed with 2x50 mL saturated aqueous ammonium chloride and then dried over anhydrous sodium carbonate. The solvent was evaporated in vacuo to give 27.8g crude (S)-N-Benzyl-N-Ethyl-3-Trifluoromethyl-Amphetamine  which was distilled at 138°C/0.3 mmHg. Yield 67.5% (purity >86%) calculated on the haloamine.

The product is then hydrogenolyzed with H₂/Pd-C to give (S)-Fenfluramine in ~60% yield.