Chiral synthetic method of temsirolimus

Abstract

The invention relates to the field of organic compound synthesis, and particularly relates to a chiral synthetic method of temsirolimus. A chiral synthetic method of temsirolimus comprises the following steps: reacting rapamycin with a chiral compound to generate a synthetic temsirolimus precursor, and then hydrolyzing the temsirolimus precursor into temsirolimus. In the invention, a chiral ester compound is used for direct reaction with rapamycin, the space effect of the chiral compound is used, so that the reaction is carried out in a single point of reaction, and the whole reaction has selectivity. Therefore, the invention provides a temsirolimus synthetic method with simple procedure, high yield and low cost and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic compound synthesis, in particular to a chiral synthesis method of temsirolimus. Background technique [0002] Tesirolimus (temsirolimus), also known as temsirolimus ester compound; rapamycin 42-[-3-hydroxyl 2-(hydroxymethyl)-2-methacrylate, which is a kind of The medicine (now merged into Pfizer) develops a targeted antineoplastic drug for the treatment of advanced renal cancer, and is also the first targeted therapy drug for the treatment of renal cancer, and is the only marketed drug that specifically inhibits mTOR kinase . The mTOR kinase is an important protein for regulating cell proliferation, growth and cell survival. In vitro studies have found that the inhibition of mTOR kinase by temsirolimus leads to a decrease in the level of certain angiogenic growth factors such as vascular endothelial growth factor, thereby preventing the development of new blood vessels, resulting in the death of cancer ce...

AI Technical Summary

Problems solved by technology

[0003] In 1994, Jerauld, S.Skotnicki, etc. reported the preparation methods and biological activities of temsirolimus for the first time (US5362718). Propionic acid reacts with 2,4,6-trichlorobenzoyl chloride to obtain acid anhydride, and then condenses with rapamycin to obtain intermediate A-1 through isolation, and finally deprotects to obtain temsirolimus, but The disadvantage of this method is that the separation of the by-product and the product of the simultaneous esterification of the 31 and 42 hydroxyl groups is difficult, and the total yield is 20%.

Although this method can increase the total yield to 47%, the disadvantage is that there are many reaction steps and the operation process is cumbersome

Based on the synthetic route of Shaw, Chia-Cheng, etc., Warren, Chew, etc. used phenylboronic acid to protect 2,2-dimethylolpropionic acid, and finally deprotected it with 2-methyl-2,4-pentanediol to obtain Tesirolimus (US2005033046), although the yield of the method is high, the production cost is also high

In summary, the preparation method of temsirolimus provided by existing literature has the disadvantages of low yield, many reaction steps, cumbersome operation process and high production cost.

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