Patent Watch

September 10, 2012

Here are two ways to make a kinase inhibitor intermediate. J. Graeser and co-inventors describe indole derivatives such as 4 and 12 as intermediates for preparing IκB kinase inhibitors. Although indoles can be prepared by the classical Fisher synthesis, the inventors state that this method is not satisfactory when it is used for making the desired compounds. Severe reaction conditions are needed, and oligomeric compounds are formed that are difficult to remove.

The inventors describe two routes for preparing the desired compounds. The first route (Figure 1, top) begins with the reaction of indoleboronic acid 1 and chloropyrimidine 2 in the presence of (Ph3P)4Pd to form 3, which is isolated in 93% yield and 96% purity. Compound 3 is converted to amine derivative 4 by treating it with MeNH2. The product was isolated in quantitative yield and with 97.6% purity. If desired, the ester group in 4 can be hydrolyzed with NaOH to produce sodium salt 5.

Indoleboronic acid 1 is obtained by treating tert-butoxycarbonyl (Boc)–protected indole 6 with B(O-i-Pr)3 in the presence of LiN-i-Pr2 (Figure 1, bottom) The reaction initially forms Boc-protected compound 7. After acid hydrolysis, 1 is isolated in 61% yield with 92.7% purity.

The inventors mention the advantage of using unprotected indole 1 in the reaction with 2 rather than the N-protected compound. Their explanation is that although some 6 is formed by the loss of the boronate group from 1 during the coupling reaction with 2, 6 does not subsequently react with 2. Hence the yield of 3 in the coupling step is not reduced.

The second route to the desired compound is quite different from the first. Figure 2 (top) outlines the process for preparing 12, the methyl ester analogue of 4. This route starts with the preparation of silylated acetylene compound 8, isolated in 90% yield with 99% purity after what is described as an aqueous workup. In the next step, the silyl group is removed, and primary alkyne 9 is isolated in quantitative yield. Alkyne 9 is treated with chloropyrimidine 10 in the presence of CuI and a palladium catalyst in DMF to give 11, which is isolated after aqueous workup in 85% yield and 99.7% purity. The cyclization of 11 to form 12 is carried out with a strong base such as KO-t-Bu. The product is isolated after an aqueous workup in 58% yield and 92.3% purity.

Although the inventors do not provide details for preparing 10, they state that it can be synthesized by the route shown at the bottom of Figure 2. The reaction produces isomers 10 and 13, which can be separated by chromatographic methods or steam distillation.

The inventors describe an alternative route to 4 in which 1 reacts with 10 in place of 2. They point out that 1 reacts with a mixture of 10 and 13 to give 4. Although it may be expected that 13 would react to give an isomer of 4, they claim that this reaction does not take place. No examples of the reaction of 1 and 10 with or without 13 are given Also, the inventors mention “aqueous workup” several times but do not explain what this means.

These processes provide alternative routes to a drug intermediate that overcome product isolation problems. (Sanofi [Paris]. US Patent 8,232,395, July 31, 2012; Keith Turner)

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