Method for preparing raltitrexed intermediate, i.e., N-(5-methylamino-2-thiophene formyl)-L-glutamate diethyl ester

Abstract

The invention belongs to the technical field of medicine, and particularly disclose a method for preparing a raltitrexed intermediate, i.e., N-(5-methylamino-2-thiophene formyl)-L-glutamate diethyl ester. In the preparation method, N-(5-methylamino-2-thiophene formyl)-L-glutamate diethyl ester is taken as a raw material. The method is characterized by comprising the following steps of: dissolving the raw material into ethyl acetate, adding a condensing agent, reacting while stirring at the temperature of 30-60 DEG C, filtering, and concentrating under reduced pressure to obtain an oily matter; and dissolving the oily matter into absolute ethyl alcohol, adding sodium borohydride in batches, reacting at the temperature of 20-40 DEG C, adding water for stopping the reaction, concentrating under reduced pressure to dryness, adding water and methylene dichloride for laminating, drying an organic phase by using anhydrous magnesium sulfate to obtain a product. The method has milder reaction conditions, is easier to operate under the condition of not lowering the yield, and is more suitable for industrial production; and the problems of toxicity and safety are solved.

Description

(1) Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of N-(5-methylamino-2-thienyl)-L-glutamic acid diethyl ester, an intermediate of raltitrexed. (2) Background technology [0002] Raltitrexed is an antineoplastic drug used to treat advanced colon cancer, head and neck tumors, and hormone-resistant prostate cancer. It is the first new first-line cytotoxic agent for the treatment of colon cancer registered in the UK in 30 years. There has been no new drug in the field of colon cancer treatment for 40 years, and its effect in treating rectal and colon cancer has been hailed as a major advancement in the past 35 years. Raltitrexed is a quinoline folate analog whose anticancer effect is produced through the specific inhibition of thymidine synthase. Its characteristic is that its curative effect is similar to that of fluorouracil, and its toxicity is small, so it can replace fluorouracil. ...

AI Technical Summary

Problems solved by technology

[0005] , the disadvantage is that n-BuLi is used, the cost is high, and it is not suitable for industrialization;

[0006] (2) , the disadvantage is that methyl iodide is used in the last step of nitrogen methylation, which is highly toxic, and there will be two methyl by-products, the reaction is difficult to control, and it is not suitable for industrial production;

[0007] (3) , the disadvantage is that methyl iodide is used in the last step of nitrogen methylation, which is highly toxic and not suitable for industrial production, and the final de-Boc reaction causes many side reactions, the yield is low, and the purification of substances is difficult;

[0008] (4) , the disadvantage is that the methylation reaction of nitrogen uses methyl iodide or dimethyl sulfate, which is highly toxic and not suitable for industrial production

[0009] In addition, the patent CN200610044811.7 for the preparation of N-(5-methylamino-2-thiophenoyl)-L-glutamic acid diethyl ester, related documents Journal of Medicinal Chemistry, 1991, Vol.34, No.5, 1594 and Journal of East China University of Science and Technology, 2005, 2, 184, using N-(5-amino-2-thiophenoyl)-L-glutamic acid diethyl ester reacted with methyl iodide to directly obtain N-(5-methylamino-2- Thienoyl)-L-glutamic acid diethyl ester, but the amount of methyl iodide cannot be strictly controlled, and the target species obtained will always have N-(5,5-dimethylamino-2-thiopheneformyl)-L - Diethyl glutamate impurity is generated, and it cannot be effectively controlled to reduce the generation of dimethylamino, and it is also difficult to purify the target product, and the toxicity of methyl iodide is relatively high

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