November 7, 2011
Here are three routes to an experimental cancer drug. Onrigin (3; referred to in this patent as VNP40101M) is an alkylating agent under investigation for treating high-grade brain tumors. An existing process for preparing 3 gives a poor overall yield of 10%, and it uses methyl isocyanate (MeNCO), a toxic compound not favored by the pharmaceutical industry.
Inventors X. Lin and I. King report three syntheses of 3; the first is shown in Figure 1. This route proceeds through intermediate 2, which is obtained by treating compound 1 with COCl2 in the presence of i-Pr2NEt. The intermediate is not isolated but treated with MeNH2 and additional i-Pr2NEt. The reaction is monitored by TLC and HPLC–UV. After workup and crystallization, 3 is isolated in 94% yield and 97% purity.
A second route to onrigin (Figure 2) starts from methanesulfonate 4, which is converted directly to 3 by the reaction with acyl chloride 5 in the presence of Et3N. After workup and crystallization, 3 is isolated in 67% yield and 97% purity. Another synthesis from 4 proceeds through ester intermediate 7, formed by treating 4 with ester 6. Compound 7 is isolated in 63% yield and then treated with MeNH2 in the presence of AlCl3 to give 3, isolated in 68% yield and 97% purity after crystallization.
The preparation of 4 and its conversion to 1 are outlined in Figure 3. The reaction of hydroxy hydrazine 8 with MsCl gives 4 in 58% isolated yield. The purity is not reported, but the inventors state that the 1H NMR spectrum is “clean”. Chloro compound 1 is prepared from 4 in a reaction with LiCl that requires 24 h. The product is isolated in 88% yield; again, the NMR spectrum is "clean” and identical to reported spectra.
Some of the experiments are carried out on the 500-g scale, suggesting the process’s advanced stage of development. Although the process avoids the dangers of using MeNCO, it does use extremely hazardous COCl2, which is only safe to use when it is generated onsite. (Nanotherapeutics Inc. [Alachua, FL]. US Patent 8,026,395, Sept. 27, 2011; Keith Turner)
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