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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

Inactive Publication Date: 2014-02-12
NANJING YOKO PHARMA GRP CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In previous patents and other literature reports, LT12 was obtained by cyclic preparative chromatography or column chromatography, which not only consumes a large amount of elution solvent but also requires special equipment, and is not easy to prepare a large amount of raltitrexed. These methods are not It is not suitable for industrialized large-scale production of raltitrexed, but in recent years, the global incidence of tumors has generally been increasing year by year. According to statistics, there are more than 1 million colorectal cancer patients in my country alone , coupled with the drug needs of patients with other tumor diseases, raltitrexed is the first-line treatment drug for advanced colorectal cancer and is effective for a variety of cancers, so it is necessary to be able to mass-produce its raw materials in an industrialized manner

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0023] (1), N-[5-[N-(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)-methyl]-N-methyl]-2- Synthesis of Diethyl Thiophenoyl-L-Glutamate (LT12)

[0024] I. Reaction formula:

[0025]

[0026] II. Feeding table: (Table 2)

[0027]

[0028] III. Operation:

[0029]Suspend 5.1g (20.2mmol) LTS2 in 40ml of DMF dried with 4A molecular sieves, add 12g (142.9mmol) of sodium bicarbonate into a stirred 500ml three-necked flask equipped with a thermometer, stir for 15 minutes, and then Add 7.6g (22.2mmol) of LTS1 dissolved in 40ml DMF in advance into the reaction flask, heat up to 40°C under nitrogen protection, react for 24 hours, add 6g of sodium bicarbonate, and continue the reaction for about 12 hours under nitrogen protection, (with The basic complete reaction of the bromide on the spot plate is the basis for judging. TLC detects the developing agent condition: ethyl acetate / methanol=10 / l), stops the reaction, cools to room temperature, adds 240 ml of dichloromethane, stirs for ha...

Embodiment 2

[0046] The catalyst used in the first step reaction was changed to 2,6-lutidine, and the equivalent used was 5 times that of LTS2. The rest of the operations were basically the same as in Example 1, and then LT12 with a purity of 95.7% and a yield of 61% was obtained. Using LT12 of this purity, raltitrexed was obtained through alkali hydrolysis and acid analysis, the operation was the same as in Example 1, and finally the finished product of raltitrexed was obtained, the total yield of the second step reaction and the third step refining was 76%, the product The purity reaches 99.81%, without impurities greater than 0.1%.

[0047] (4) Determination of the crystal form of raltitrexed

[0048] Through X-ray diffraction analysis, it can be seen from the spectrum that the obtained raltitrexed is a crystalline compound, and the characteristic diffraction 2θ angle values ​​are: 8.066, 10.059, 10.389, 12.751, 13.129, 14.810, 15.390, 17.032, 17.486, 19.141, 20.930, 24.047 , 25.647, 2...

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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.

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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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 常江张峰高建兴曹燕锋刁岩忠孙兴华
Owner NANJING YOKO PHARMA GRP CO LTD
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