Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby

A technology for pemetrexed disodium and intermediates, which is applied in the field of organic synthesis, can solve the problems of unsatisfactory yield of closed-loop reaction, low yield of pemetrexed disodium, etc., and achieves the solution of easy oxidation of aldehyde group and synthetic route. Reasonable and improve the effect of total yield

Active Publication Date: 2009-10-21
山东立新制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, the yield of this ring-closing reaction is still not ideal in practical application, and condensation occurs by the ring-closing product, hydrolysis, and the yield of pemetrexed disodium prepared by the salt-forming reaction is low

Method used

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  • Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby
  • Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby
  • Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby

Examples

Experimental program
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Embodiment 1

[0037] A preparation method of compound (1), the process is as follows:

[0038] Add 0.1mol of p-bromobenzoic acid and 0.1mol of L-diethyl glutamate into a 500ml reaction flask, then add 300ml of dichloromethane and 10g of CDI (carbonyldiimidazole) to obtain a reaction solution, and keep the reaction solution at -5-0°C After 3 hours of heat preservation reaction, the reaction solution was concentrated to dryness under reduced pressure, and recrystallized with ethyl acetate to obtain 31 g of off-white product 4-bromobenzoyl-L-glutamic acid diethyl ester, which is compound (1). The yield was 80%.

Embodiment 2

[0040] A kind of preparation method of compound (2), its process is as follows: get 1000ml there-necked flask, drop into compound (1) prepared in 0.5mol embodiment 1 successively, 20g lithium acetate, 20g lithium chloride, 12g tetrabutyl ammonium chloride and 600ml DMF, add 0.55mol 3-butenol and 18g palladium acetate under the protection of nitrogen, heat up to 80 ℃ ~ 85 ℃, keep warm for 2 hours, add water and dichloromethane to extract, recover palladium by filtering the organic phase, wash with water, distill under reduced pressure, add Sodium bisulfate aqueous solution, stirred, filtered, the resulting product was hydrolyzed into aldehyde by adding dilute hydrochloric acid, extracted with dichloromethane, concentrated to dryness, and 173.7g of oily 4-butyraldehyde-benzoyl-L-glutamic acid diethyl ester was obtained. It is compound (2), and the yield is 90%.

Embodiment 3

[0042] A kind of preparation method of compound (3), its process is as follows: get 1000ml there-necked flask, drop into compound (2) prepared in 0.5mol embodiment 2, 500ml THF and 0.55molDBBA successively, pass into appropriate hydrogen bromide gas as catalyst, in After reacting for 1 h under stirring at 0-5°C, tetrahydrofuran was distilled off under reduced pressure, washed with water, and extracted with dichloromethane. The organic phase was concentrated to dryness to obtain 203 g of light yellow oil 4-(2-bromobutyraldehyde)-benzoyl-L-glutamic acid diethyl ester as compound (3), with a yield of 89%.

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Abstract

The invention relates to an intermediate of pemetrexed disodium, a preparation method thereof and a method for preparing pemetrexed disodium thereby; and the intermediate is (2-(4-(3-(2,4-diamino-6-oxy-1,6-dihydro-pyridine-5-group)-3-(1,3)dioxolane-2-group-propyl) benzylamine)sodium glutaric acid. The synthesis of the intermediate comprises the following steps: firstly, condensation reaction is conducted on 4-bromobenzoic acid or 4-iodobenzoic acid and L-glutamate diethylester, then Hack reaction is conducted, 4-bromo is replaced and 4-butyraldehyde is formed, then selective bromo replacement is conducted and the 4-butyladehyde is converted into 2-bromobutyraldehyde, and then condensation reaction of aldehyde and ethylene glycol is utilized for protecting the aldehyde, and pyrimidine ring is further synthesized, and finally the intermediate is obtained. Acid hydrolysis ring-closing reaction and sodium hydroxide salification are respectively conducted for once on the intermediate so as to obtain the pemetrexed disodium. The method for preparing pemetrexed disodium in the invention has high yield, low cost and easy operation and is applicable to industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a pemetrexed disodium intermediate. The invention also relates to a preparation method of the intermediate and a method for synthesizing pemetrexed disodium from the intermediate. Background technique [0002] Pemetrexed disodium (Alimta, pemetrexates disodium) is a new type of folic acid antitumor compound, its chemical name is 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2 , 3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-sodium glutamate, the structural formula is as follows: [0003] [0004] In the prior art, the synthesis process route of pemetrexed disodium is long, the yield is low, and the cost is high, which is unfavorable for industrialized production, so it is unfavorable for the popularization and application of pemetrexed disodium medicine. [0005] In view of the fact that among the many synthetic routes of pemetrexed disodium, the key step that affects its...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06C07D487/04A61P35/00B01J31/02
Inventor 张爱青舒亮包志坚
Owner 山东立新制药有限公司
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