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Preparation method of pemetrexed or pemetrexed salt

A technology for pemetrexed and a compound is applied in the field of high-yield preparation of pemetrexed and its salts, and can solve the problems of unsatisfactory effect of pyrrole ring closing reaction, difficult reaction control, low yield and the like

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

AI Technical Summary

Problems solved by technology

[0004] At present, there are many preparation methods for pemetrexed, but due to the influence of the reactivity and solubility of the reactants, the effect of the ring closure reaction of the pyrrole ring is not ideal, and the reaction is difficult to control
Therefore, there is the defect that the yield is not high in the prior art

Method used

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  • Preparation method of pemetrexed or pemetrexed salt

Examples

Experimental program
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Effect test

Embodiment 1

[0022] The preparation of embodiment one, ethyl 4-iodobenzoate

[0023] Mix 24.7g (0.1mol) of 4-iodobenzoic acid, 29ml (0.5mol) of anhydrous ethanol, 250ml of toluene, and 4.8ml (0.03mol) of concentrated sulfuric acid, then stir, and react with water at 110°C for 24 hours, then cool. Wash with 5% Na2CO3 solution (50ml×3), wash with water (50ml×3), dry, filter, concentrate to obtain a yellow liquid, distill under reduced pressure, collect fractions at 60-62°C / 670Pa, and obtain a colorless liquid which is Ethyl 4-iodobenzoate, weighing 25.1g, yield 91.3%.

Embodiment 2

[0024] The preparation of embodiment two, 4-ethoxyformyl phenylpropanal

[0025] 13.8 g (0.05 mol) of ethyl 4-iodobenzoate, Pd (CH 3 COO) 2 0.2g (0.01mol), K 2 CO 3 13.6g (0.1mol), 16.3g (0.05mol) of tetrabutylammonium bromide, mix and stir, add nitrogen protection, add 4.35g (0.075mol) of propenyl alcohol, 150ml of N,N-dimethylformamide, 40℃ After reacting for about 30 hours, concentrate under reduced pressure, pour the residual liquid into 100ml of water, extract the aqueous layer with 50ml×3 petroleum ether, combine the organic layers, dry, filter, concentrate, distill the residual liquid under reduced pressure, and collect 142-144℃ / 670Pa Fractions were obtained as a colorless transparent liquid, namely 4-ethoxyformylbenzaldehyde, with a weighing quality of 9.0 g and a yield of 90.5%.

Embodiment 3

[0026] Example 3, Preparation of 1-nitro-4-(4-ethoxyformylphenyl)-2-butene

[0027] 5.2g (0.025mol) of 4-carboethoxybenzaldehyde prepared in the previous step, 2.3g (0.025mol) of nitromethane, Na 2 CO 3 (0.125mol), stirred at room temperature for 12h, added CH 2 Cl 2 25ml, washed with 1mol / l HCl, then washed with water until neutral, dried, filtered, and concentrated to obtain 6.5g of light yellow solid.

[0028] Take 5.3g (0.02mol) of the reaction product from the previous step, 6.4g (0.063mol) of acetic anhydride, and 8g of pyridine, react at room temperature for 2 hours, pour the reaction solution into 20ml of 2mol / l hydrochloric acid, extract with ether (10ml×3), and combine The organic layer was washed with water until neutral, dried, filtered, concentrated, dissolved the product in 40ml of toluene, added 5.3g of potassium carbonate, stirred and refluxed for 5h, cooled and filtered, the filtrate was washed with water (30ml×3), dried and concentrated to obtain 4.3 g of...

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Abstract

The invention relates to a preparation method of pemetrexed or a pemetrexed salt, more specifically to a high-yield preparation method of pemetrexed or the pemetrexed salt. The preparation method comprises the following steps of (a) with ethyl 4-iodobenzoate of a formula (I) as a raw material, carrying out a Heck reaction with allyl alcohol to obtain a compound of a formula (II); (b) removing one molecule of water after condensing the compound of the formula (II) with nitromethane to obtain a compound of a formula (III); (c) carrying out a Michael addition reaction on the compound of the formula (III) to generate a compound of a formula (IV); (d) carrying out a Nef reaction on the compound of the formula (IV) to obtain a compound of a formula (V); and (e) esterifying the compound of the formula (V) into an active ester to react with L-glutamic acid salt to finally obtain pemetrexed, wherein optionally, pemetrexed can be salified with alkali metal or alkaline-earth metal to obtain corresponding pemetrexed salt, and the step (c) is carried out in a water and tetrahydrofuran solvent system. The preparation method of pemetrexed or the pemetrexed salt disclosed by the invention has the advantages of being capable of remarkably improving the yield of pemetrexed or the pemetrexed salt and shortening the reaction time.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for preparing pemetrexed and its salts with high yield. 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. ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 吕爱锋
Owner JIANGSU HANSOH PHARMA CO LTD
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