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Preparation method of pemetrexed disodium key intermediate

A technology for pemetrexed disodium and intermediates, which is applied in the field of high-yield preparation of pemetrexed disodium intermediates, can solve the problems of low yield, poor product purity, difficult reaction control 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

[0003] Pemetrexed as a folic acid antagonist for the treatment of cancer has been disclosed in U.S. Patents US4996206, US5028608, and US 534493, and its preparation methods have also been reported in multiple patents, such as CN1055182, CN 1271338, CN 1087910, US 5254687, and US 6013828 , US5416211, but the above-mentioned preparation methods all have the problems of low yield and poor product purity
[0004] At present, there are many preparation methods for the pemetrexed disodium formula (I) intermediate, and there are also literatures that record the method of preparing the formula (I) intermediate by carrying out the ring-closing reaction of the compound of formula (V), but there are The defect that the rate is not high, because the ring-closing reaction is the key to prepare the intermediate of formula (I) by this method, but due to the influence of the reactivity and solubility of the reactant, the effect of the ring-closing reaction of the pyrrole ring is not ideal, and the reaction is difficult to control
Therefore, although the method for preparing the intermediate of formula (I) has a simple route, it has not been widely used in the industrial field because of the low yield.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: Preparation of 4-ethoxyformylphenylpropanal (compound of formula III)

[0023] The raw material 27.6g (0.1mol) ethyl p-iodobenzoate (compound of formula II), 8.4g (0.1mol) NaHCO 3 , 32.6g (0.1mol) tetrabutylamine bromide was added to the reaction flask, stirred, added N2 protection, added 8.7g (0.15mol) propenyl alcohol, N,N-dimethylformamide 150ml, 35 ~ 40 ℃ reaction After 20 hours, concentrate under reduced pressure, pour the residue into 100ml of water, extract the water layer 3 times with 50ml of petroleum ether, combine the organic layers, dry, filter, concentrate, and distill the residue under reduced pressure to collect fractions at 142-144°C at 670Pa to obtain 9.8 g of 4-ethoxyformylphenylpropionaldehyde (compound of formula III) is a transparent liquid, and the yield is 94.2%.

Embodiment 2

[0024] Example 2: Preparation of 1-nitro-4-(4-ethoxymethanesulfonylphenyl)-2-butene (compound of formula IV)

[0025] Add 5.2g (0.025mol) of 4-ethoxyformylphenylpropanal, 2.3g (0.025mol) of nitromethane, and 1.0g (0.0125mol) of triethylamine into the reaction flask, stir at room temperature for 12h, then add dichloromethane 30ml, cooled in an ice bath, dropwise added 2.6g (0.025mol) of methanesulfonyl chloride, 1.3g (0.0125mol) of aluminum oxide, 3.0g (0.0375mol) of triethylamine to the reaction solution, stirred for half an hour, and used 1N Wash with hydrochloric acid, then wash with water until neutral, dry, filter, and concentrate to obtain a light yellow oily substance 1-nitro-4-(4-ethoxymethanesulfonylphenyl)-2-butene (compound of formula IV) 6.1 g, yield 97.5%.

Embodiment 3

[0026] Example three: 1-nitro-2-(2,6-diamino-4-(3H) oxopyrimidin-5-yl)-4-(4-carboxyphenyl)-1-butane (formula V compound) preparation

[0027] 4.98g (0.02mol) 1-nitro-4-(4-ethoxymethanesulfonylphenyl)-2-butene, 2.28g (0.02mol) 2,6-diamino-4-(3H)oxy Pyrimidine was added to the reaction vessel, and then sodium methoxide / methanol solution (0.54g sodium methoxide, 10ml methanol) was added, and the reaction was carried out at a constant temperature of 50°C for 2h. Cool to room temperature, adjust the reaction solution to pH = 6 with acetic acid, filter and dry, the product is 1-nitro-2-(2,6-diamino-4-(3H)oxopyrimidin-5-yl) -4-(4-carboxyphenyl)-1-butane (compound of formula V), yield 92%.

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Abstract

The invention relates to a preparation method of a pemetrexed disodium key intermediate, more specifically to a high-yield preparation method of the pemetrexed disodium key intermediate. The preparation method comprises the following steps: (a) with a compound of a formula (I) as a raw material, carrying out a Heck reaction with allyl alcohol to obtain a compound of a formula (III); (b) removing one molecule of water by utilizing a dehydrating agent after condensing the compound of the formula (III) with nitromethane to obtain a compound of a formula (IV); (c) carrying out a Michael addition reaction on the compound of the formula (IV) to generate a compound of a formula (V); and (d) carrying out a Nef reaction on the compound of the formula (V) to obtain a compound of a formula (I). The preparation method of the pemetrexed disodium key intermediate has the advantages of having a short reaction process, not existing harsh reaction conditions, shortening the reaction time and being capable of remarkably improving the yield of products.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for preparing a pemetrexed disodium intermediate 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 syn...

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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