Method for industrial preparation of raltitrexed and novel raltitrexed crystal form for pharmacy

A technology of raltitrexed and process scheme, which is applied in the field of synthesis and preparation of the antineoplastic drug raltitrexed, and can solve the problems of consuming large elution solvents and difficulty in preparing a large amount of raltitrexed
CN103570702AInactive Publication Date: 2014-02-12NANJING YOKO PHARMA GRP CO LTD +1
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
NANJING YOKO PHARMA GRP CO LTD
Publication Date
2014-02-12
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention discloses a synthesis preparation technology of raltitrexed as an antitumor drug and a specific raltitrexed crystal form. The synthesis preparation technology comprises that N-(5-methylamino-2-thenoyl)-L-glutamate diethyl ester and 6-bromomethyl-3,4-dihydro-2-methyl-quinazoline-4-one undergo base catalysis and acid-binding synthesis reactions in the presence of an organic solvent to produce a C-N coupling product N-[5-[N-(3,4-dihydro-2-methyl-4-oxo-6-quinazoline)-methyl]-N-methyl]-2-thenoyl-L-glutamate diethyl ester; the C-N coupling product undergoes a hydrolysis reaction under the alkaline condition and the hydrolysis product is subjected to acid precipitation so that a raltitrexed crude product is obtained; and the raltitrexed crude product is subjected to recrystallization and the crystals are dried so that a high-purity raltitrexed raw drug in the specific crystal form is obtained. The specific crystal form is characterized definitely by an X-ray diffraction technology. The synthesis preparation technology utilizes extraction and crystallization processes to purify an intermediate and a product, is simple, economic and efficient, and is suitable for large-scale industrial preparation of raltitrexed.
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Description

technical field

[0001] The technical invention belongs to a preparation process of chemically synthesized drugs, in particular to a synthesis preparation method of an antineoplastic drug Raltitrexed and a new process technology including crystal form research. Background technique

[0002] Raltitrexed is a quinazoline antifolate agent that produces antitumor effects by specifically inhibiting thymidylate synthase (TS), which is one of the key enzymes in the process of DNA biosynthesis First, raltitrexed is quickly metabolized into various forms of polyglutamic acid in cells to exert a powerful inhibitory effect on this enzyme, thereby inhibiting the growth and reproduction of tumor cells. In the treatment of colorectal cancer, its The curative effect is better than or similar to the combination of 5-fluorouracil and folinic acid, but it avoids the toxic and side effects of 5-fluorouracil, and is convenient to use and has high patient compliance. It has become the first-line ...

Claims

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