Pemetrexed methyl ester p-toluenesulfanate crystal form and preparation method thereof

A technology of pemetrexed dimethyl ester and p-toluenesulfonate, which is applied in the field of medicinal chemistry, can solve the problems of cumbersome purification of pemetrexed dimethyl ester, etc., so as to solve the cumbersome purification, ensure product quality, and improve purity Effect

Active Publication Date: 2012-03-14
QILU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the deficiencies in the prior art, the present invention provides a key intermediate of the folic acid inhibitor drug pemetrexed disodium and a preparation method thereof, and the provided crystal of pemetrexed dimethyl p-toluenesulfonate It has stable type and high purity,

Method used

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  • Pemetrexed methyl ester p-toluenesulfanate crystal form and preparation method thereof
  • Pemetrexed methyl ester p-toluenesulfanate crystal form and preparation method thereof
  • Pemetrexed methyl ester p-toluenesulfanate crystal form and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Dissolve 100g of pemetrexed dimethyl crude product in 2L of ethanol, add 80g of p-toluenesulfonic acid, stir and crystallize at room temperature for 1h, filter with suction, wash the filter cake with 500ml of ethanol, pemetrexed dimethyl toluene After the sulfonate salt was formed, it precipitated, and a yellow to off-white solid was obtained. After drying at 65-75°C for 8-8.5 hours, 101 g of the crystalline form of pemetrexed dimethyl ester p-toluenesulfonate was obtained. TLC detected that there was no Product; HPLC assay purity: 98.41%, figure 2 It is the HPLC collection of illustrative plates of the product obtained in this embodiment, wherein the specific parameters of each peak are as follows:

[0028] keep time

Embodiment 2

[0030] Dissolve 100g of crude pemetrexed dimethyl ester in 2L of acetone, add 80g of p-toluenesulfonic acid, crystallize at room temperature for 1h under stirring, filter with suction, and wash the filter cake with 500ml of acetone to obtain a yellow to off-white solid. Dry at -75°C for 8-8.5 hours to obtain 98 g of pemetrexed dimethyl p-toluenesulfonate crystalline form, and there is no product in the mother liquor as detected by TLC; the purity determined by HPLC method: 98.60%, image 3 It is the HPLC collection of illustrative plates of the product obtained in this embodiment, wherein the specific parameters of each peak are as follows:

[0031] keep time

Embodiment 3

[0033] Add 500 ml of 2 mol / L sodium hydroxide solution to 98 g of pemetrexed dimethyl p-toluenesulfonate crystal form, dissolve immediately after stirring, and react with stirring at room temperature for 2 hours. Then use 2mol / L hydrochloric acid solution to adjust the pH=3-4, filter with suction, wash the filter cake twice with 1L of purified water, and dry it to obtain an off-white solid, which is vacuum-dried at 80°C for 10 hours to obtain 63.7g of pemetrexed acid. Yield: 95.4%.

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Abstract

The invention belongs to the pharmaceutical chemistry field and relates to a crystal form of a key intermediate of the folic acid inhibitor medicine pemetrexed disodium and a preparation method of the intermediate. The pemetrexed methyl ester p-toluenesulfanate provided by the invention has stable crystal form and high purity, thus the purity of pemetrexed methyl ester can be effectively increased, the problem of the complicated extraction of pemetrexed methyl ester can be solved, the pemetrexed methyl ester p-toluenesulfanate has positive influence on the increase of the quality of the subsequent product pemetrexed disodium and industrial production can be performed easily.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a key intermediate of pemetrexed disodium, a folic acid inhibitor, pemetrexed dimethyl p-toluenesulfonate crystal form and a preparation method thereof. Background technique [0002] Pemetrexed disodium is a new anti-cancer drug launched by Eli Lilly and Company. The US FDA approved its combination with cisplatin to treat a rare cancer—malignant pleural mesothelioma. Pemetrexed disodium was approved as a second-line treatment for locally advanced lung cancer or metastatic non-small cell lung cancer. Pemetrexed disodium is a multi-target antimetabolite antineoplastic drug. It is a folic acid antagonist that can inhibit folate-dependent enzymes such as thymidylate synthase, dihydrofolate reductase, and glycine ribonucleoside formyltransferase. These enzymes are involved in the biosynthesis of thymidine and purine nucleosides to achieve anti-tumor effects. [0003] 4...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07C309/30C07C303/32
Inventor 王晶翼林栋冷传新范传文
Owner QILU PHARMA
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