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Preparation method of pemetrexed or pemetrexed salt

A technology for pemetrexed and salt formation, applied in the field of preparation of pemetrexed or its salt, can solve the problems of few reaction steps, poor product purity, low yield and the like, achieve high product yield and reduce production cost , the effect of short reaction routes

Active Publication Date: 2013-04-10
JIANGSU HANSOH PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Pemetrexed has been used as a folic acid antagonist for the treatment of cancer and has been disclosed in U.S. Patents US4996206, US5028608, and US 534493, and its preparation method has also been reported in multiple patents, such as CN 1055182, CN 1271338, CN 1087910, US 5254687, US 6013828, US5416211, but the above-mentioned preparation methods all have the problems of low yield and poor product purity. In addition, Chinese patent CN1840530 specifically discloses the production of N-[4-[2-(2-amino-4,7-dihydro -4-oxo-3H-pyrrole [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid synthetic route of pemetrexed, this patent can prepare the product through less reaction steps, but It has been verified by experiments that the yield is still not high, and the optimal state of the reaction has not been reached, and it is difficult to meet the requirements of industrial production on cost and yield

Method used

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  • Preparation method of pemetrexed or pemetrexed salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] In a constant temperature water bath at 35°C, stir 100ml of deionized water, 10.0g (68.0mmol) of L-glutamic acid, and 7.0g (69.0mmol) of NMM (N-methylmorpholine) until completely dissolved, then add 300ml of N-methyl pyrrolidone (NMP) to give a clear solution.

[0020] Under nitrogen protection, 7.0g (69.0mmol) NMM and 11.7g (66.6mmol) 4-chloro-2,6-dimethoxytriazine (CDMT) were added to 4-[2-(2-amino-4 , 7-dihydro-4-oxo-3H-pyrrolo (2,3-d) pyrimidin-5-yl) ethyl] benzoic acid (10g, 33.5mmol) in NMP (150ml) solution, constant temperature water bath 35 Stir for 1 hour at °C. Slowly drop this reaction solution into the above-prepared L-glutamate solution within about 0.5 hours to obtain a clear reaction solution, stir in a constant temperature water bath at 35°C for 1 hour, filter with suction, and adjust the pH of the filtrate to 3-4 with 2N hydrochloric acid , transfer the reaction solution into a 5L reaction bottle, slowly add 4L deionized water, stir in a constant temp...

Embodiment 2

[0023] The method is the same as in Example 1, the difference is that the volume of NMP added when preparing the L-glutamate solution is 200ml, and finally 12.5g of a light green solid is obtained, and 4-[2-(2-amino-4,7-dihydro -4-oxo-3H-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl]benzoic acid, the yield was 87.4%.

[0024] 1H NMR (DMSO-d6) σ12.30 (2H, s), 10.55 (1H, s), 10.11 (1H, s), 8.42 (1H, d, J=7.7Hz), 7.78 (2H, d, J=7.9 Hz), 7.25 (2H, d, J=7.9Hz), 6.30 (1H, s), 5.97 (2H, s), 4.40 (1H, m), 2.98 (2H, t, J=7.0Hz), 2.86 ( 2H, t, J=7.0Hz), 2.35 (2H, t, J=7.5Hz), 2.13-2.06 (1H, m), 2.00-1.95 (1H, m).

Embodiment 3

[0026] The method is the same as in Example 1, the difference is that the volume of NMP added when preparing the L-glutamate solution is 100ml, and finally 12.2g of a light green solid is obtained, and 4-[2-(2-amino-4,7-dihydro -4-oxo-3H-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl]benzoic acid, the yield was 85.3%.

[0027] 1H NMR (DMSO-d6) σ12.31 (2H, s), 10.54 (1H, s), 10.12 (1H, s), 8.40 (1H, d, J=7.5Hz), 7.78 (2H, d, J=8.0 Hz), 7.27 (2H, d, J=8.0Hz), 6.31 (1H, s), 5.97 (2H, s), 4.42 (1H, m), 2.98 (2H, t, J=7.1Hz), 2.86 ( 2H,t,J=7.1Hz), 2.35(2H,t,J=7.5Hz), 2.10-2.05(1H,m), 2.00-1.96(1H,m).

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Abstract

The invention relates to a preparation method of pemetrexed or a pemetrexed salt. The preparation method comprises the following steps of (a) salifying L-glutamic acid and dissolving in a mixed solvent of N-methyl pyrrolidone and water; (b) reacting a compound of a formula (I) with CDMT (2-chloro-4,6-dimethoxy-1,3,5-triazine) to prepare an active ester; (c) adding the obtained active ester to the L-glutamic acid salt solution obtained in the step (a); and (d) adding acid to adjust a pH value of a reaction mixture of the step (c), and adding water to dilute to obtain pemetrexed. The preparation method of the pemetrexed or the pemetrexed salt disclosed by the invention has the advantages of short process, high product yield and reduced production cost of pemetrexed.

Description

technical field [0001] The invention relates to the field of compound synthesis, more specifically, to a preparation method of pemetrexed or a salt thereof. 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. Pemetrexed enters the cell through the folic acid-carrying carrier and the folic acid-binding protein transport system on the cell membrane. Once pemetrexed is inside the cell, it is converted to the polyglutamate form by the enzyme folyl polyglutamate synthetase. Polyglutamic acid rem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 吕爱锋
Owner JIANGSU HANSOH PHARMA CO LTD
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