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A preparation method suitable for industrial scale-up production of pralatrexate

An industrial and intermediate technology, which is applied in the field of preparation and purification of the antineoplastic drug pralatrexate raw material and its important intermediates, can solve the problems of low yield and purity, difficult reaction and post-processing, etc., and achieve purity High, simple and feasible post-reaction treatment, reducing the effect of side reactions

Active Publication Date: 2016-01-13
SINOPHARM A THINK PHARMA
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Problems solved by technology

[0005] There are many problems in the existing synthetic technology: as the mixture of monopropargyl and bispropargyl (impurity) is produced during the synthesis of intermediate C, that is, intermediate C containing one-third to one-half of the impurity (" J.Med.Chem.1993,36,2228-2231 "JosephI.DeGraw; JWilliamT.Colwell), the yield and purity of C are all low, and 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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  • A preparation method suitable for industrial scale-up production of pralatrexate
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  • A preparation method suitable for industrial scale-up production of pralatrexate

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Embodiment Construction

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

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

[0037] Add 80.0g of p-carboxyphenylacetic acid to a 2L reactor, stir to dissolve with 800mL of anhydrous methanol, add 8.0g of p-toluenesulfonic acid, stir and heat to reflux for 24h, spin out the methanol under reduced pressure, add 240mL of water to the residue, use acetic acid Extract with ethyl ester (240 mL×3), combine the organic phases, wash the organic phase with 3% NaOH solution (80 mL×2), and then dry with 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 proton nuclear magnetic spectrum data is as follows:

[0039] 1 HNMR (300MHz, CDCl 3 )Δ7.91(d, J =6.3Hz,2H),7.42(d, J =6.3Hz, 2H), 3.84 (s, 3H), 3.79 (s, 2H), 3.62 (s, 3H).

[0040] Step 2 Synthesis of intermediate ...

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Abstract

The invention relates to the technical field of medicinal chemistry, in particular to the synthesis of anticancer drug 10-Propargyl-10-deazaaminopterin Pralatrexate and its intermediates. The present invention provides a method with simpler operation, lower product-related impurity content, easier purification of intermediates, avoiding the purification method of column chromatography, and can be applied to the preparation of large-scale production of pralatrexate raw materials and its important intermediates and purification methods.

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.MedicalChem.36:2228-2231 (1993) by JosephI.DeGraw; JWilliamT.Colwell et al. Then Sirotanaketal. and O'Connoretal. 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, methyl phenylace...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/08
CPCC07D475/08
Inventor 不公告发明人
Owner SINOPHARM A THINK PHARMA
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