Preparation method of Pralatrexate

A preparation step and propargyl technology are applied in the field of organic synthesis route design and the preparation of raw materials and intermediates, which can solve the problems of difficult separation, rare raw materials, and high cost, and achieve the advantages of simple process, easy availability of raw materials, and promotion of development. Effect

Inactive Publication Date: 2015-05-20
江苏兰亭市政园林有限公司
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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, the industrialized production of this product is hindered due to rare raw materials, many steps, difficult separation and high cost.

Method used

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  • Preparation method of Pralatrexate
  • Preparation method of Pralatrexate
  • Preparation method of Pralatrexate

Examples

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Effect test

Embodiment 1

[0021] Add N-[4-(1-(2-propynyl)-3,4-dioxo-n-butyl)benzoyl]-L-glutamic acid dimethyl ester (II) (4.01 g, 10 mmol), 30 mL of 1M sodium hydroxide solution and 30 mL 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 extraction with dichloromethane, the extract was dried and evaporated to dryness to obtain a light yellow oily substance N-[4-(1-(2-propynyl)-3,4-dioxo-n-butyl)benzoyl] - 3.3 g of L-glutamic acid (IV), the yield is 88.5%.

Embodiment 2

[0023] Add N-[4-(1-(2-propynyl)-3,4-dioxo-n-butyl)benzoyl]-L-glutamic acid (IV) (2.24g, 6mmol ), acetone oxime (5.01g, 7mmol) and 50mL of distilled water, 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) (0.70 g, 5 mmol), react at room temperature for 4 hours, then raise the temperature to reflux for 6 hours, and a precipitate appears. Cooling, crystallization, and filtration gave 1.92 g of off-white solid pralatrexate (I), with a yield of 80.5%.

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Abstract

The invention discloses a preparation method of Pralatrexate (I). The preparation method comprises the following steps of: hydrolyzing N-[4-(1-(2-propinyl)-3,4-dioxo n-butyl)benzoyl]-L-glutamic acid dialkyl ester (II) to generate an intermediate N-[4-(1-(2-propinyl)-3,4-dioxo n-butyl)benzoyl]-L-glutamic acid (IV); and performign cyclization reaction on the intermediate (IV) and 2,4,5,6-tetra-aminopyrimidine (III) under the condition of oxime formation to prepare the Pralatrexate (I). The raw materials are easily available, the process is simple, and the preparation method is economical, environmentally-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 江苏兰亭市政园林有限公司
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