Patent Watch

April 25, 2011

Make chiral intermediates for neurotransmitter uptake inhibitors. The compounds covered by this patent are intermediates for preparing serotonin or noradrenaline (norepinephrine) uptake inhibitors. M. Eckert and co-inventors point out that usually only one enantiomer of the intermediate is desirable and that new processes must be stereoselective.

The main claim of the patent covers amide intermediates such as 1, and the remaining claims cover the preparation of 3-aminopropanol 2 by reducing 1. The synthesis of 2 begins with the reaction of 2-acetylthiophene (3) with (MeO)2CO in the presence of a strong base to form keto ester 4. The MeOH byproduct is removed by azeotropic distillation with toluene. Compound 4 is isolated as a light yellow liquid in 74% yield and 98% purity after vacuum distillation.

The next step is the stereoselective conversion of 4 to give 5; it is apparently the key feature of the patent. This step is a hydrogen transfer reaction that uses a chiral ruthenium catalyst, obtained by dissolving reagents 6 and 7 and base Et3N in CH2Cl2; Ts is p-toluenesulfonyl. The catalyst mixture is ready to use after 15 min. The synthesis of 5 takes place in a two-phase mixture of HCO2H and Et3N. After acidification, crude product 5 is isolated and used in the next step without further purification. GC analysis shows that the conversion of 3 is 100% with 98.2% ee.

Treating 5 with MeNH2 gives 1, which is recovered in 88% yield and 86% purity. The crude product can be used directly in the next step, or the intermediate can be obtained as a white crystalline solid or purified by distillation. In the final step, 1 is reduced to 2 with LiAlH4. The crude product is isolated in 80% yield and 84% purity, but no details are given for purifying it. The claims also cover the use of a boron hydride for this reduction, but there are no examples. 1H and 13C NMR data for 2 are given.

The process is highly stereoselective with potential commercial importance. (Lanxess Deutschland [Leverkusen, Germany]. US Patent 7,893,281, Feb. 22, 2011; Keith Turner)

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