Pralatrexate preparation method

A technology of propargyl and diaminopteridine, applied in the direction of organic chemistry, etc., can solve the problems of environment, operator threat, unfavorable industrial production, high vacuum equipment, etc., to improve productivity and appearance, good industrial application prospect, Process green effect

Inactive Publication Date: 2015-05-20
SHENZHEN NEPTUNUS PHARM CO LTD
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reported yield of this pathway is very low, especially in the high-temperature decarboxylation step of dicarboxylic acid, the yield is only 29% (purity is only 82%), and the step intermediate product L-diethyl glutamate is reacted to obtain 10-propargyl The purification of base-10-deazaaminopterin diethyl ester also needs to be separated by column, and the resulting final product, pralatrexate, is at the milligram level, which is only suitable for the synthesis of trace products
[0004] Patents PCT Int.Appl.2012061469, PCT Int.Appl.2012021392, U.S.Pat.Appl.Publ.20110190305, U.S.Pat.Appl.Publ.20110111436, U.S.Pat.Appl.Publ.20100248249, etc. are used in conjunction with Joseph I.D...

Method used

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Embodiment 1

[0027] Embodiment 1, the synthesis of 4-(2-carboxy-1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl)benzoic acid

[0028]Embodiment 1. Take 1.02g of Compound I in a 100mL single-necked bottle, add 10mL of absolute ethanol, and after magnetically stirring for 5 minutes, add 10mL of purified water. After stirring for 5 minutes, add 10mL of 10% NaOH solution drop by drop. Stir, TLC monitors the reaction process, and the reaction ends after about 20 hours; add glacial acetic acid dropwise to adjust the pH to 6, remove ethanol by rotary evaporation, add 30 mL of purified water, adjust the pH to 6 with glacial acetic acid, and vacuum-dry the obtained solid at room temperature to obtain 0.59 g of the product. Yield 63%.

[0029] Embodiment 2. Take 10.30g of Compound I in a 1L single-necked bottle, add 100mL of methanol, stir magnetically for 5min, add 100mL of purified water, stir for 5min, add 100mL of 10% NaOH solution dropwise, and stir at room temperature after the addition is complete...

Embodiment 2

[0031] Example 2, Synthesis of 4-(1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl)benzoic acid;

Embodiment approach 1

[0032] Embodiment 1. Heat the oil bath to 120oC in advance, take 6.2g of compound II in a 250mL single-mouth bottle, add 100mL DMSO, stir magnetically, put nitrogen in the oil bath after 5min, react under nitrogen atmosphere, and monitor the reaction process by TLC. The reaction ended after about 20 min. After the reaction solution was cooled to room temperature, it was poured into 500mL of purified water, and a large amount of yellow precipitates were precipitated immediately. After standing for 10 minutes, filtered, the filter cake was dissolved with dilute ammonia water, and the pH was adjusted to 6 with glacial acetic acid. The obtained precipitate was filtered, and the filter cake was dissolved with dilute ammonia water. Adjust the pH to 6 with glacial acetic acid, filter the resulting precipitate, and dry the filter cake under vacuum at room temperature to obtain 2.8 g of the product with a yield of 50%.

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Abstract

The present invention discloses a practical synthesis process of a new anticancer drug pralatrexate. According to the present invention, 10-propargyl-10-methoxycarbonyl-4-deoxy-4-amino-10-deaza pteroic acid methyl ester is adopted as a starting raw material, a saponification reaction is performed to obtain 4-(2-carboxy-1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid, the 4-(2-carboxy-1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid is subjected to decarboxylation to obtain 4-(1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid, the 4-(1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid reacts with L-diethyl glutamate to obtain 10-propargyl-10-deaza aminopterin diethyl ester, and finally a saponification reaction is performed to obtain the target product pralatrexate, wherein the green, high yield and convenient synthesis of the pralatrexate is completed, the final product can achieve the level from several grams to tens of grams, the purity is more than or equal to 90%, and the good industrial application prospects are provided.

Description

technical field [0001] The invention relates to a preparation method of an anticancer drug pralatrexate, which belongs to the technical field of medicine. Background technique [0002] Pralatrexate (pralatrexate) is a new type of dihydrofolate reductase inhibitor, which was approved by the FDA in 2009 and became the first drug for the treatment of peripheral T-cell lymphoma. The trade name of pralatrexate is Folotyn, which is an orphan drug. Its price is very expensive, more than three times the price of common anticancer drugs, and the total cost within the course of treatment (3 to 5 months) reaches 126,000 US dollars. Therefore, there is an urgent need to develop new practical synthetic processes to effectively reduce the research and development costs of this drug, thereby reducing the economic burden on patients. [0003] In terms of foreign patents or literature, Joseph I.DeGraw et al took the lead in reporting the synthetic route of pralatrexate in 1993. They used me...

Claims

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Application Information

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IPC IPC(8): C07D475/08
CPCC07D475/08
Inventor 金锋唐田李隆军吴婧高媛马春铭王彦青彭江华
Owner SHENZHEN NEPTUNUS PHARM CO LTD
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