Patent Watch

September 9, 2013

Here are more efficient routes to important drug intermediates. R. P. Frutos and co-inventors synthesized compounds (e.g., 3) that are used as pharmaceutical intermediates. They state that alternative syntheses give only low-to-moderate yields and that some require the use of expensive reagents such as S-alkylisothioureas.

The inventors’ method for synthesizing 3 is shown in the first reaction sequence in the figure. The first step is a condensation reaction of tetrahydrothiophene derivative 1 with urea in the presence of a mineral acid to form intermediate urea derivative 2. Product 2 is isolated in 95% yield by adding concd HCl and then cooling the acidified reaction mixture.

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Intermediate 2 is treated with NaOMe to cyclize it to desired intermediate 3, isolated in 95% yield. Compound 3 can also be obtained without isolating 2 by treating the acidic mixture with NaOMe; 3 is isolated in 80–85% yield. The preferred process is the one in which 2 is isolated before it is converted to 3. 1H and 13C NMR data for 2 and 3 are reported.

The inventors do not describe the preparation of compound 1 in detail, but they mention that it can be obtained by using the second sequence in the figure. The first step is a condensation reaction in the presence of a base, and the cyclization reaction is effected by a titanium alkoxide.

The inventors describe methods for preparing analogues of 2 and 3 in which the tetrahydrothiophene ring contains a methyl, ethyl, or phenyl substituent. The process is also applied to preparing indene derivative 5 (third sequence in figure). The final product is isolated in 93% yield. 1H and 13C NMR data for 4 and 5 are reported.

The examples in the patent do not specify the quantities of reagents or the scales of the experiments. The details contain only the amounts of each reagent in terms of equivalents. But the process appears to provide an improved, high-yield method for preparing the desired compounds. (Boehringer Ingelheim International GmbH [Ingelheim am Rhein, Germany]. US Patent 8,471,010, June25, 2013; Keith Turner)

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