In 2007, Shanghai Institute of Material Medica, Chinese Academy of Sciences, has carried out a series of modifications at the 9th site of camptothecin nucleus based on the 10-hydroxy camptothecin, (WO2005044821, WO2007104214), and finally found that 9-allyl-10-hydroxy-camptothecin (Jimmytecan, compound 6), among others, has shown an excellent anti-tumor activity in evaluation in vivo and in vitro. The water-soluble prodrug of the above, Ximingtecan hydrochloride (Compound 1H) has been subject to a thorough evaluation, and clinical trials has been applied from CFDA in October 2010, and clinical trial approval document has been obtained in May 2012, which is a promising candidate as anticancer drugs.

At present, the main synthetic method of Ximingtecan hydrochloride is condensation of 9-allyl-10-hydroxycamptothecin (compound 6) and piperidinyl piperidine chloride chloroformate (Compound 7).

In which there are mainly two synthetics methods for compound 6.
In one method, 10-hydroxy camptothecin is used as raw material, and the product is obtained through two steps of reaction, alkylation and Claisen Rearrangement (WO2005044821), and the route of the method is shown as follows:

This synthetic route is adopted in the pilot scale production at present. However, there are obvious demerits for this route: firstly, an isomer impurity which was rearranged at 11th site would be produced during rearrangement process (compound 9). This compound is difficult to be completely removed even if column chromatography is used; secondly, the duration of rearrangement reaction is up to 72 hours, and the compound 8 can not be completely converted to compound 6, and there are still large amount of compound 8 present in the reaction system when the reaction is stopped. Since the product is similar to the impurity in structure, overall yield is significantly lower and separation and purification of the product are difficult. In actual operation, we found that it is difficult to obtain compound 6 of purity over 95%; therefore, repeated recrystallization is necessary for the purification of the final product 1H, thereby further reducing the yield. The overall yield of this route is about 16-20% at present.

Another method to synthesize compound 6 reported in the literature is using metal palladium-catalyzed coupling reactions (Suzuki or Stille coupling) to give Compound 6 (CN101880285); the reaction route is as follows:

wherein X is Cl, Br or I, R is commonly used protecting group, particularly methoxymethyl, acetyl, ethoxycarbonyl, etc.
Although compound 6 of higher purity can be obtained and rearrangement isomer 9 can be avoided through the route, there are still significant problems: firstly, if Stille coupling was employed, highly toxic tin reagents are needed, use of which should be avoided in the production of drug; secondly, regarding to Suzuki coupling, compared with the previous synthetic route, there are two more steps during the reaction, while the overall yield was not significantly increased, which resulting the increase of labor and operating costs; thirdly, the palladium catalyst used in the reaction was of low activity, which make it impossible to achieve good yield; finally, there are two steps in the reaction involving chromatography purification, which will increase the complexity of operation and production costs. This route has not been used in the actual production.
Therefore, it will be of great significancy for the industrial production of medicaments in the future to develop a synthesis process for compound 1, which is of high efficiency, low cost, easy-amplification, and good repeatability.
USPTO Backgrounds
USPTO Backgrounds