Patent Watch

August 29, 2011

Here is a large-scale synthesis of some “male drugs”. D. D. Miller, K. A. Veverka, and K. Chung report the large-scale synthesis of androgen-receptor modulators exemplified by 3a and 3b. These compounds have a variety of pharmaceutical applications related to male sex hormones, such as male contraceptives and drugs for treating prostate-related conditions. The inventors describe the kilogram-scale production of 3a and 3b by condensing 1 with 2a or 2b, as shown in Figure 1.

The reaction is carried out in the presence of a substantial excess of Cs2CO3 in THF. For the preparation of 3a, 6.17 mol Cs2CO3 is used with 3.37 mol 1; for 3b, 5.4 mol Cs2CO3 and 2.7 mol 1 are used. (Disconcertingly, the patent shows the formula of the base as CsCO3, although the calculation of the molar amount is correct.) The preparation of 3a takes 3 h at 50 °C and is monitored by HPLC. TLC is used to monitor the synthesis of 3b, which takes 8 h in refluxing THF.

To purify 3a, deionized water is added to an EtOH solution at room temperature to precipitate it; this process is repeated three times. The final yield of 3a is 83%. Purifying the product by using an alcohol and water is a key aspect of the patent and is covered in the claims. However, no analytical data are given to support the claimed purity. The workup of 3b also involves EtOH and water, but solvents EtOAc and MeO-t-Bu are also used; the product is isolated in 52% yield.

The inventors also describe the synthesis of compound 1 at kilogram scale (Figure 2). Acid chloride 5 is prepared by the reaction of carboxylic acid 4 with SOCl2. The acid chloride is not isolated, but it is treated with a solution of aniline derivative 6 and Et3N in THF over 3 h. After it is warmed to room temperature, the mixture is heated to 50 °C for 15 h. The reaction is monitored by TLC; 3.7 kg 1 is isolated by crystallization from warm toluene in 70.3% yield.

The multikilogram-scale synthesis of 4 is also described. The route, shown in Figure 3, starts with the preparation of compound 9 by simultaneously adding 4 M NaOH and a solution of acid chloride 8 in acetone to a mixture of carboxylic acid 7 and 4 M NaOH in acetone. The pH of the reaction mixture is kept at >10 by adding more 4 M NaOH as needed. Intermediate 9 is isolated by crystallization from MeO-t-Bu in 55.6% yield; it is then treated with N-bromosuccinimide (NBS) in DMF to cyclize it to 10. This is isolated in 87.7% yield by adding water to the reaction mixture. The final step is heating 10 to reflux in 24% aq HBr to produce 4, isolated as a crystalline solid from hot toluene in 81.3% yield.

The patent claims cover compounds related to 3a and 3b in which the nitro group is replaced by nitrile. Unfortunately, no examples are given describing the synthesis of these compounds. This is an efficient process for synthesizing 3a and 3b, and the inventors show that it is suitable for large-scale production. (University of Tennessee Research Foundation [Knoxville]. US Patent 7,968,721, June 28, 2011; Keith Turner)

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