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Pralatrexate preparation method

A technology of benzoyl and cyclization reaction, which is applied in the field of organic synthesis route design and the preparation of raw materials and intermediates, can solve problems such as hindering industrial production, separation difficulties, and rare raw materials, so as to promote the development of economic technology and process The effect of simplicity and easy access to raw materials

Inactive Publication Date: 2013-09-04
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] N-[4-(1-(2-propynyl)-3,4-dioxo-n-butyl)benzoyl]-L-glutamic acid diethyl ester (II) ( 5.15 g, 12 mmol), acetone oxime (1.02 g, 14 mmol) and 100 mL of distilled water, 1N dilute hydrochloric acid was added dropwise, and the pH value of the reaction system was adjusted to 2-3. The temperature was raised to 50-60°C, and the reaction was stirred for 2 hours. Cooled to room temperature, added 2,4,5,6-tetraaminopyrimidine (III) (1.40 g, 10 mmol), reacted at room temperature for 4 hours, then heated to reflux for 6 hours, and a pale yellow flocculent precipitate appeared. Adjust pH to neutrality with saturated sodium bicarbonate solution, crystallize by cooling, and filter to obtain off-white solid N-[4-(1-(2,4-diamino-6-pteridine)methyl-3-butyne] yl)benzoyl]-L-glutamic acid diethyl ester (IV) 4.68 g, 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 ) (2.67 g, 5 mmol), 15 mL of 1M sodium hydroxide solution and 15 mL of distilled water, stirred at room temperature for 3 hours, added activated carbon to decolorize for 30 minutes, and filtered. The pH of the filtrate was adjusted to 2-3 with 2N hydrochloric acid, and the reaction was stirred for 2 hours. After filtration, 2.0 g of off-white solid pralatrexed (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, the application number is: 2013101969677, and the application date is: 2013-5-24. technical field [0002] The invention belongs to the technical field of organic synthesis route design and preparation of bulk drugs and intermediates, in particular to a preparation method of pralatrexate. Background technique [0003] Pralatrexate is a drug developed by Allos Therapeutics Inc for the treatment of relapsed and refractory peripheral T-cell lymphoma. Pralatrexate injection was approved by the US FDA on September 24, 2009 to be marketed in the United States under the 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] US Patent Nos. US6028071, US2010248249, US2011111436 and World Patent No. WO2012061469, originally developed by Aros Therapeutics, report th...

Claims

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Application Information

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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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