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Preparation method of Pralatrexate suitable for industrial large scale production

A synthetic method and industrial technology, applied in the field of preparation and purification of the antineoplastic drug pralatrexate raw material and its important intermediates, can solve the problems of difficult reaction and post-processing, low yield and purity, etc., and achieve the goal of reaction Post-processing is simple and feasible, with high purity and the effect of reducing side reactions

Active Publication Date: 2014-04-23
SINOPHARM A THINK PHARMA
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Problems solved by technology

[0005] There are many problems in the existing synthesis technology: For example, when synthesizing intermediate C, a mixture of monopropargyl and dipropargyl (impurity) is produced, that is, it contains three Intermediate C ("J. Med. Chem. 1993,36, 2228-2231" Joseph I. De Graw; J William T. Colwell) with one-half to one-half of the impurities, the yield and purity of C are higher than Low, the generation situation of impurity is as shown in following reaction equation:
[0007]This brings difficulties to the next reaction and post-processing.

Method used

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  • Preparation method of Pralatrexate suitable for industrial large scale production
  • Preparation method of Pralatrexate suitable for industrial large scale production
  • Preparation method of Pralatrexate suitable for industrial large scale production

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Embodiment Construction

[0035] The present invention will be further described below by specific embodiment.

[0036] Synthesis of step 1 intermediate 4-methyl formate phenylacetate (B)

[0037]Add 80.0g of p-carboxyphenylacetic acid into a 2 L reaction kettle, stir and dissolve with 800 mL of anhydrous methanol, add 8.0g of p-toluenesulfonic acid, stir and heat under reflux for 24 h, spin out the methanol under reduced pressure, and add 240 mL of water to the residue , extracted with ethyl acetate (240mL×3), combined the organic phases, washed with 3% NaOH solution (80mL×2), and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure and cooled to obtain Compound B as a white solid. Weight: 84.1g, yield: 91.1%, HPLC content: 97.8%.

[0038] The H NMR spectrum data are as follows:

[0039] 1 H NMR (300 MHz, CDCl 3 )δ 7.91(d, J = 6.3 Hz, 2H), 7.42(d, J = 6.3 Hz, 2H), 3.84(s, 3H), 3.79(s, 2H), 3.62(s, 3H).

[0040] Step 2 Synthesis of intermediate ɑ-propargyl...

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Abstract

The invention relates to the field of pharmaceutical chemistry technology, and more specifically relates to an anticarcinogen 10-Propargyl-10-deazaaminopterin (Pralatrexate) and synthesis of an intermediate thereof. The invention has the advantages of simple operation, low contents of related impurities, easiness in purification of intermediate, thereby avoiding purification mode of column chromatography, and the invention can be applied to large scale production of Pralatrexate bulk drug as well as preparation and purification method of important intermediates.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation process and a purification method of an antineoplastic drug pralatrexate raw material and an important intermediate thereof. Background technique [0002] Pralatrexate, trade name Folotyn, is the first new targeted folic acid preparation approved by the FDA for the treatment of peripheral T-cell lymphoma. The chemical name of pralatrexate is 10-propargyl-10-desazaaminopterin. First disclosed in "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin" J. Medical Chem.36:2228-2231 (1993) by Joseph I. DeGraw; J William T. Colwell et al. Then Sirotanak et al. and O’Connor et al. also studied it. Its molecular structure is as follows: [0003] [0004] Pralatrexate is synthesized from p-carboxyphenylacetic acid as a starting material through a series of chemical transformations. Firstly, the intermediate 4-methyl formate, meth...

Claims

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Application Information

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IPC IPC(8): C07D475/08
CPCC07D475/08
Inventor 不公告发明人
Owner SINOPHARM A THINK PHARMA
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