Patent Watch

June 25, 2012

A catalytic reduction leads to a desirable intermediate. H. Oooka and S. Fukuhara report a preparation of compound 2 (R = Bn), an intermediate in the synthesis of agrochemicals and pharmaceuticals. Its trans isomer 3 is not as desirable. The synthesis of similar alkyl-substituted compounds usually involves the reduction of the corresponding ketone 1. The production of the cis alcohol with high selectivity is not always efficient or commercially viable.

The inventors discuss several methods for making 2 that they say are unsuitable for industrial production:

  • The methyl ketone 1 (R = Me) is reduced with metallic sodium and benzophenone to give the cis alcohol, but the process requires heating for 230 h.
  • The trans isomer is prepared from methyl ketone 1, converted to the trifluoromethanesulfonate, and inverted with acid.
  • A process that uses a transition-metal catalyst involves a racemization step. It gives only 50% yield, and the other isomer is lost.

The process disclosed by the inventors involves the formation of an asymmetric tert-hydroxyl group by a hydrogen-transfer reaction. The alcohol is isomerized with a transition-metal complex to form the thermodynamically more stable diastereomer. The figure shows the method to prepare 2 (R = Bn) from 1 by using i-PrOH as the source of hydrogen atoms and catalyst RuCl2(PPh3)3 in the presence of t-BuOK. In one example, a 98:2 mixture of 2 and 3 was produced in 49% yield.

The inventors carried out an isomerization reaction starting with a 49:51 mixture of 2 and 3. With RuCl2(PPh3)3 in the presence of t-BuOK, the product was recovered in 69% yield and contained 98% 2.

The procedure gives high selectivity to the desired cis isomer, and the isomerization step can be applied to cis–trans mixtures to increase the yield of cis isomer. (Nippon Soda [Tokyo]. US Patent 8,188,286, May 29, 2012; Keith Turner)

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