N-[4-(butanal-4-group)-benzoyl]-L-glutamic acid dimethyl ester compound and method for preparing pemetrexed by using the compounds

A technology of dimethyl glutamate and benzoyl, which is applied in the preparation of organic compounds, carboxylic acid amide preparation, chemical instruments and methods, etc., and can solve the problems of difficult coupling reactions, limited industrial production, and anhydrous reactions Highly demanding problems, to achieve the effects of easy purification, mild conditions, and increased yield of acylation

Active Publication Date: 2008-12-31
QILU PHARMA +1
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The reaction conditions of this route are milder and the yield is higher, but there is still a coupling reaction by N-(p-bromobenzoyl)-L-glutamic acid diethyl ester and 3-buten-1-alcohol in the operational route It is not easy to carry out, there are many reaction by-products, and the defects of brominated reagents, especially bromine, are highly volatile and highly toxic, which affect the use in industrial production
[0024] Therefore, there are problems such as high anhydrous reaction requirements, long reaction steps or limited industrial production in the above-mentioned route, and it is necessary to research and develop a preparation method of pemetrexed that is more suitable for industrial production

Method used

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  • N-[4-(butanal-4-group)-benzoyl]-L-glutamic acid dimethyl ester compound and method for preparing pemetrexed by using the compounds
  • N-[4-(butanal-4-group)-benzoyl]-L-glutamic acid dimethyl ester compound and method for preparing pemetrexed by using the compounds
  • N-[4-(butanal-4-group)-benzoyl]-L-glutamic acid dimethyl ester compound and method for preparing pemetrexed by using the compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Preparation of N-(p-iodobenzoyl)-L-glutamic acid dimethyl ester (VII):

[0057]

[0058] Add 100g (0.403mol) of p-iodobenzoic acid to the three-necked flask, add 500ml of thionyl chloride, and reflux. When the insoluble solid disappears, the thionyl chloride is recovered by distillation under reduced pressure to obtain an off-white solid. The solid was dissolved in 1000 ml of dichloromethane, 91 g (0.43 mol) of L-glutamate dimethyl hydrochloride was added, the temperature was lowered to 5° C., 120 g (1.2 mol) of triethylamine was added dropwise, and the reaction was carried out at room temperature for 2 hours. Add 500ml of dichloromethane, wash with water, and dry with anhydrous sodium sulfate. The solvent was distilled off to obtain 140.8 g of white solid with a yield of 86.3%.

[0059] 1 HNMR(DMSO-d 6 , 600MHz) δ 8.81 (d, 1H), 7.87 (d, 2H), 7.66 (d, 2H), 4.42 (q, 1H), 3.69 (s, 2H), 3.65 (s, 2H), 2.44 (t , 2H), 2.07 to 2.11 (m, 1H), 1.96 to 2.02 (m, 1H), 1.15 to 1.19 (m,...

Embodiment 2

[0061] Preparation of N-[4-(butyraldehyde-4-yl)-benzoyl]-L-glutamic acid dimethyl ester (VIII):

[0062]

[0063] Add 70.0g (0.173mol) N-(p-iodobenzoyl)-L-glutamic acid dimethyl (VII), 800ml DMF into a three-necked flask, stir to dissolve at room temperature, add 114g tetrabutylammonium bromide, 78g Sodium bicarbonate, nitrogen gas was introduced for 10 minutes, and then 18.0 g (0.25 mol) of 3-buten-1-ol and 2 g of palladium chloride were added. The reaction was heated at 60°C for 8h. TLC analysis of the raw materials disappeared (developing solvent: ethyl acetate: petroleum ether = 2:3), 800ml×2 ethyl acetate and 1200ml water were extracted and separated, and the organic phase was combined and washed with 800ml×2 water. Dry the organic phase with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure. Column chromatography separation yielded 46.3 g of product as a pale yellow oil, with a yield of 78.0%.

[0064] 1 HNMR(DMSO-d 6 , 400MHz) δ 9.67(s, ...

Embodiment 3

[0066] Preparation of N-[4-(2-chloro-butyraldehyde-4-yl)-benzoyl]-L-glutamic acid dimethyl ester (IX):

[0067]

[0068] 46.0 g (0.132 mol) of N-[4-(butyraldehyde-4-yl)-benzoyl]-L-glutamic acid dimethyl ester (VIII) was dissolved in 400 ml of dichloromethane, and stirred to dissolve at room temperature. Add sulfonyl chloride 20g (0.148mol), stir at room temperature for 5h, wash with saturated sodium bicarbonate aqueous solution, wash with saturated sodium chloride aqueous solution until neutral, and dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance, which was directly used for the next reaction.

[0069] 1 HNMR(DMSO-d 6 , 400MHz) δ9.49 (s, 1H), 8.65 (t, 1H), 7.82 (d, 2H), 7.34 (dd, 2H), 4.83 (q, 0.5H), 4.63 (q, 0.5H), 4.40 ~4.46(q, 1H), 3.69(s, 2H), 3.64(s, 2H), 2.73~2.89(m, 2H), 2.43(t, 2H), 1.99~2.11(m, 2H), 1.88~1.98 (m, 2H), 1.10~1.23 (m, 6H).

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Abstract

The invention relates to a compound N-(4-(butyraldehyde-4-yl)-benzoyl)-L-glutamic acid dimethyl and a method which uses the compound to prepare anti-cancer drug pemetrexed. The preparation method for pemetrexed has simple post-reaction processing and high product purity, which is conducive to industrial production.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new intermediate compound N-[4-(butyraldehyde-4-yl)-benzoyl]-L-glutamic acid dimethyl ester and its application in the synthesis of pemetrexed . Background technique [0002] Pemetrexed, the structure is the formula I, the chemical name is N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidine -5-yl)ethyl]benzoyl]-L-glutamic acid, [0003] [0004] The configuration of the carbon indicated by * is the L configuration. [0005] Pemetrexed is an antitumor drug with multiple targets acting on the folate-dependent pathway. It is a cell cycle-specific antimetabolites. Its main targets are thymidylate synthase (TS) and dihydrofolate reductase ( DHFR), glycinamide nucleotide transformylase (GARFT), through the inhibition of these key enzymes affect the synthesis of purines and pyrimidines, thereby inhibiting DNA synthesis. Clinical studies have proved that its single a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/84C07C231/12C07D487/04
Inventor 范传文林栋朱屹东冷传新王丽娟张明会王晶翼
Owner QILU PHARMA
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