Refining method of pralatrexate intermediate

A refining method and pralatrexate technology, applied in the field of medicine, can solve the problem of no refining method for pralatrexate finished products, and achieve the effects of cost saving, simplified process operation and simple operation method.

Active Publication Date: 2018-05-25
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And the finished product of pralatrexate does not have a better refining method

Method used

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  • Refining method of pralatrexate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 15g of crude pralatrexate intermediate PLQS-6 and 225ml of methanol into a 500ml three-necked flask, heat until completely dissolved, add 4.5g of activated carbon to decolorize for 0.5h while it is hot, filter while it is hot, cool the filtrate to 0-5°C and stir Crystallize, filter, rinse the filter cake with methanol, and dry to obtain 13.9 g of the refined product of pralatrexate intermediate PLQS-6. The purity is 99.89%, and the yield is 92.7%.

Embodiment 2

[0022] Add 15g of the crude product of pralatrexate intermediate PLQS-6 and 75ml of methanol into a 500ml three-neck flask, heat until completely dissolved, add 1.5g of activated carbon to decolorize for 0.5h while it is hot, filter while it is hot, cool the filtrate to 0-5°C and stir Crystallize, filter, rinse the filter cake with methanol, and dry to obtain 14.0 g of the refined product of pralatrexate intermediate PLQS-6. The purity is 99.83%, and the yield is 93.3%.

Embodiment 3

[0024] Add 15g of crude pralatrexate intermediate PLQS-6 and 300ml of methanol into a 500ml three-neck flask, heat until completely dissolved, add 6.0g of activated carbon to decolorize for 0.5h while it is hot, filter while it is hot, cool the filtrate to 0-5°C and stir Crystallize, filter, rinse the filter cake with methanol, and dry to obtain 13.4 g of the refined product of pralatrexate intermediate PLQS-6. The purity is 99.85%, and the yield is 89.3%.

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Abstract

The invention belongs to the technical field of medicine and particularly relates to a refining method of a pralatrexate intermediate. The method comprises the following steps: adding a crude productof an intermediate 10-propargyl-10-deazaaminopterin dimethyl ester (PLQS-6) to a refining solvent to be heated and dissolved; performing activated carbon decoloration and hot filtration; cooling, stirring and crystallizing the filtrate; and washing the filter cake with the refining solvent so as to obtain a high-purity pralatrexate intermediate PLQS-6. The used refining solvent is a low-boiling-point solvent, so that the problem of excessive solvent residues such as DMF (dimethyl formamide) and DMSO (dimethyl sulfoxide) is avoided, the refining solvent can also be recycled, and the cost is saved. The method provided by the invention has the advantages that application of column chromatography separation is avoided, the yield is improved, the whole technological operation is simplified, theoperation method is simple, the yield and the purity of the obtained pralatrexate intermediate are higher, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for refining a pralatrexate intermediate. 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. It was then studied by Sirotanak et al and O'Connor et al. 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, methyl phenylacetate (PLQS-1), the intermediate ɑ-propargyl-(4-methyl formate)-methyl phenylacetate (PLQ...

Claims

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Application Information

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IPC IPC(8): C07D475/08
CPCC07D475/08
Inventor 张贵民李燕陈成富
Owner LUNAN PHARMA GROUP CORPORATION
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