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Pralatrexate preparation method

A preparation step, the technology of benzoyl, applied in the field of preparation of pralatrexate, can solve problems such as hindering industrial production, difficult separation, rare raw materials, etc., and achieve the effects of promoting economic and technological development, simple process, and easy-to-obtain raw materials

Inactive Publication Date: 2015-03-11
安徽金太阳生化药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Although the above method can produce pralatrexate (I), the industrialized production of this product has been hindered due to rare raw materials, many steps, difficult separation and high cost.

Method used

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Examples

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Embodiment 1

[0021] Add N-[4-(1-(2-propynyl)-3,4-dioxo-n-butyl)benzoyl]-L-glutamic acid diethyl ester (II) ( 5.15g, 12mmol), acetone oxime (1.02g, 14mmol) and distilled water 100mL, 1N dilute hydrochloric acid was added dropwise to adjust the pH value of the reaction system to 2-3. The temperature was raised to 50-60°C, and the reaction was stirred for 2 hours. Cool down to room temperature, add 2,4,5,6-tetraaminopyrimidine (III) (1.40 g, 10 mmol), react at room temperature for 4 hours, then raise the temperature to reflux for 6 hours, and a light yellow flocculent precipitate appears. Adjust the pH to neutral with saturated sodium bicarbonate solution, cool and crystallize, and filter to obtain off-white solid N-[4-(1-(2,4-diamino-6-pteridine)methyl-3-butyne Base) benzoyl]-L-glutamic acid diethyl ester (IV) 4.68g, the yield was 87.8%.

Embodiment 2

[0023] Add N-[4-(1-(2,4-diamino-6-pteridine) methyl-3-butynyl) benzoyl]-L-glutamic acid diethyl ester (IV ) (2.67g, 5mmol), 15mL of 1M sodium hydroxide solution and 15mL of distilled water, stirred at room temperature for 3 hours, added activated carbon for decolorization for 30 minutes, and filtered. The filtrate was adjusted with 2N hydrochloric acid to adjust the pH value of the reaction system to 2-3, and the reaction was stirred for 2 hours. After filtration, 2.0 g of off-white solid pratrexed (I) was obtained with a yield of 83.9%.

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Abstract

The invention discloses a pralatrexate (I) preparation method, which comprises the following preparation steps: performing cyclization reaction on dialkyl N-[4-(1-(2-propinyl)-3,4-dioxo-n-butyl)benzoyl]-L-glutamate (II) and 2,4,5,6-tetraminopyrimidine (III) under oximation conditions to generate an intermediate compound alkyl N-[4-[1-(2,4-diamino-6-pteridine)methyl-3-butynyl]benzoyl]-L-glutamate (IV); and performing hydrolysis reaction on the intermediate compound (IV) to prepare pralatrexate (I). The preparation method is accessible in raw materials, simple in process, economic, environment-friendly and suitable for industrial production.

Description

[0001] This patent application can be cross-referenced with the applicant's previous invention patent application, its application number is: 2013101969677, and its application date is: 2013-5-24. technical field [0002] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of pralatrexate. Background technique [0003] Pralatrexate is a drug developed by Allos Therapeutics Inc in the United States for the treatment of relapsed and refractory peripheral T-cell lymphoma. Pralatrexate injection was approved by the US FDA on September 24, 2009 in the United States, with a trade name of Folotvn. The chemical name of pralatrexate (I) is N-[4-(1-(2,4-diamino-6-pteridine)methyl-3-butynyl)benzoyl]-L-glutamine acid. [0004] [0005] U.S. Patent No. US6028071, No. US2010248249, No. US2011111436 and World Patent No. WO2012061469 originally developed by A...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/08
Inventor 许学农
Owner 安徽金太阳生化药业有限公司
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