Patent Watch

January 23, 2012

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Improve the synthesis of cell-proliferation inhibitors. Inventors J. Merten, S. Renner, and C. Reichel report compounds such as 1 that are intermediates in the synthesis of indolinone drugs that are used to inhibit cell proliferation. Their claims cover 1 and the process for making it (shown in Figure 1). The reaction is carried out by heating a solution of 2 and Ac2O to reflux in toluene, adding trimethyl orthobenzoate, and distilling volatile reaction products. After workup, 1 is isolated as yellow crystals in yields up to 91.7%. Complete elemental analysis indicates that the product is very pure. 1H and 13C NMR data are provided.

The inventors also claim the preparation of 2 (Figure 2), which begins with the esterification of 3 to form 4, isolated in 88.8% yield with 99.8% purity by HPLC. The ester is treated with dimethyl malonate in the presence of the strong base sodium tert-amylate to form 5 in 95.4% yield and 99.9% purity (HPLC). (NMP is N-methylpyrrolidone.) Compound 5 is reductively cyclized with hydrogen over a Pd/C catalyst; 6 is obtained in 87.2% yield and 99.8% purity (HPLC).

In the last step, 6 is treated with chloroacetic anhydride to produce 2, isolated in 93.5% yield. 1H and 13C NMR data and full elemental analysis of the product are reported. The first three steps shown in Figure 2 are carried out on a multikilogram scale, indicating that this part of the process is suitable for commercial operation. The inventors describe alternative methods for preparing 6 and claim that their method is superior.

The claims include the use of 1 to prepare intermediate 7, as shown in Figure 3. Treating 1 with base converts it to 8 in 94.6% yield; it then reacts with 9 to give 7 in isolated 88.1% yield. Although the purity of 7 and 8 is not reported, full elemental analysis and NMR data are given for each compound.

Finally, the inventors describe the preparation of 9 (Figure 4). The first step is the reaction of 10 with chloroacetic anhydride to give 11, which is recovered in 92.7% yield and then condensed with N-methylpyrazine to form 12. This is not isolated; instead, the reaction mixture is washed with water and diluted with i-PrOH. The mixture is hydrogenated over a Pd/C catalyst to give 9 in 88% isolated yield. Again, the purity of 9 and 11 is not reported, but full elemental analysis and NMR data are provided.

(Boehringer Ingelheim International GmbH [Ingelheim am Rhein, Germany]. US Patent 8,067,617, Nov. 29, 2011; Keith Turner)

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