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A kind of pemetrexed disodium intermediate and preparation method thereof

A technology for pemetrexed disodium and intermediates, applied in the field of pemetrexed disodium intermediate 4-[2-ethyl]benzoic acid and its preparation, capable of solving the problem of pemetrexed disodium preparation yield Low cost, high production cost, low purity and other problems, to achieve the effect of high yield, reduced production cost and simple operation

Active Publication Date: 2022-02-22
LUNAN BETTER PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In order to overcome the problems of low preparation yield, high production cost, instability and low purity of pemetrexed disodium in the prior art, the invention provides a pemetrexed disodium intermediate II-1 and its preparation Method and the preparation method of pemetrexed disodium IV

Method used

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  • A kind of pemetrexed disodium intermediate and preparation method thereof
  • A kind of pemetrexed disodium intermediate and preparation method thereof
  • A kind of pemetrexed disodium intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of L-diethyl glutamate:

[0045] Weigh L-glutamic acid diethyl ester hydrochloride (48g 0.2mol) and add in the 500ml four-necked bottle, after adding 120ml pure water and stirring to dissolve, add 18g potassium carbonate to react for 0.5 hour, add 100ml dichloromethane and stir the liquid separation, The aqueous layer was extracted three times with 80ml×3 pure water, the organic phase was collected, dried and evaporated to obtain the product L-diethyl glutamate (97.5% molar yield, 94.3% purity).

Embodiment 2

[0047] Preparation of 4-[2-(2-acetylamino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid:

[0048]Weigh 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (60g 0.2mol) Add to a 500ml four-neck flask, add 200ml of acetic acid and heat up to 30°C, stir to dissolve, add dropwise acetic anhydride (0.2mol), raise the temperature to 40°C and keep it warm for 1 hour, evaporate the acetic acid to dryness under reduced pressure, add 300ml of pure water and stir, use 5 % sodium hydroxide solution to adjust the pH to 5, stir and crystallize for 2 hours, cool down to 0-5°C for suction filtration, and dry to obtain the product 4-[2-(2-acetylamino-4,7-dihydro-4-oxo -3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (molar yield 96.3%, purity 99.2%).

[0049] Mass Spectrum of 4-[2-(2-Acetamido-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid [M-H] + = 341.3.

[0050] 1 H-NMR: 1 H NMR (400MHz,D 2 O) δ:

[0051] ...

Embodiment 3

[0054] Preparation of 4-[2-(2-acetylamino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid:

[0055] Weigh 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (60g 0.2mol) Add to a 500ml four-neck bottle, add 200ml of acetic acid and heat up to 30°C, stir to dissolve, add dropwise acetic anhydride (0.4mol), heat up to 50°C and keep it for reaction for 1 hour, evaporate the acetic acid to dryness under reduced pressure, add 300ml of pure water and stir, use 5 % sodium hydroxide solution to adjust the pH to 6, stir and crystallize for 2 hours, cool down to 0-5°C for suction filtration, and dry to obtain the product 4-[2-(2-acetylamino-4,7-dihydro-4-oxo -3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (molar yield 96.9%, purity 99.0%).

[0056] Mass spectrum of 4-[2-(2-acetylamino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, 1 H-NMR, 13 C-NMR see embodiment 2

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Abstract

The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a pemetrexed disodium intermediate II-1 and a preparation method thereof. With 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid as starting material, in The acylation reaction occurs in acetic acid and acetic anhydride, and the intermediate Ⅱ-1 is obtained after the reaction is completed. The preparation of the intermediate II-1 of the present invention is relatively simple, the amino group is protected to avoid the reaction of itself to produce impurity V, and at the same time, the problem of oxidation and discoloration caused by the instability of the amino group during the reaction process is prevented. The conditions are mild, the yield is high, and the product is relatively stable. conducive to actual production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and specifically provides a pemetrexed disodium intermediate 4-[2-(2-acetylamino-4,7-dihydro-4-oxo-3H-pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoic acid and process for its preparation. Background technique [0002] Pemetrexed is an antifolate preparation with a pyrrolic pyrimidine group in its structure. It can inhibit the growth of tumors by destroying the normal metabolic process dependent on folic acid in cells and inhibiting cell replication. In vitro studies have shown that pemetrexed can inhibit the activities of thymidylate synthase, dihydrofolate reductase and glycinamide nucleotide formyltransferase, which are all enzymes necessary for the synthesis of folic acid and participate in the thymidine nucleogenesis. Bioresynthesis of nucleotides and purine nucleotides. Pemetrexed disodium is a multi-target antifolate agent, which interferes with the folic acid-dependent metab...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 臧超
Owner LUNAN BETTER PHARMA
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