Nitro compounds and their application in preparation of pemetrexed

A technology of pemetrexed and compounds, applied in the field of nitro compounds and its application in the preparation of pemetrexed, capable of solving problems such as complex process and long operation cycle

Active Publication Date: 2006-09-06
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In these methods, the preparation of the compound of formula VIII needs to be carried out under anhydrous conditions, and the product needs to be purified by

Method used

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  • Nitro compounds and their application in preparation of pemetrexed
  • Nitro compounds and their application in preparation of pemetrexed
  • Nitro compounds and their application in preparation of pemetrexed

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Preparation of 4-(3-hydroxy-4-nitrobutyl)benzoic acid (IX)

[0057] Add 25.3g (0.10mol) 4-(3-hydroxy-4-nitro-butyl) benzoic acid methyl ester and 200ml of anhydrous methanol to a three-necked flask, stir at room temperature for 15min, and add 480ml of 1N (0.48mol) Hydroxide Sodium aqueous solution, the solution appears red. Stir for 1.5h, after the reaction is completed, the methanol is evaporated under reduced pressure, the aqueous phase is adjusted to pH=3 with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, and the organic phase is dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure to obtain 21.8 g of a yellow solid with a yield of 91.2%.

[0058] 1 HNMR(DMSO-d 6 , 400MHz) δ 12.79 (s, 1H), 7.87 (d, 2H), 7.34 (d, 2H), 5.47 (s, 1H), 4.73 to 4.69 (m, 1H), 4.39 to 4.37 (m, 1H) , 4.10 (s, 1H), 2.80 ~ 2.70 (m, 2H), 1.75 ~ 1.70 (m, 2H).

Embodiment 2

[0060] Preparation of N-[4-(3-hydroxy-4-nitrobutyl)benzoyl]-L-glutamic acid diethyl ester (X)

[0061] Add 23.9g (0.10mol) of 4-(3-hydroxy-4-nitrobutyl)benzoic acid to 400ml DMF, stir and dissolve all at room temperature, add 35.7g (0.15mol) L-glutamate diethyl hydrochloride , N-methylmorpholine 18.2g (0.18mol), stir at room temperature for 20min, add 4-(4,6-dimethoxy-1,3,5-s-triazin-2-yl)-4-methyl 41.5g (0.15mol) of morpholinium chloride, stirred at room temperature for 10h. The reaction solution was added with 1000 ml of water, extracted with dichloromethane 700 ml×2, and the organic phase was dried with anhydrous sodium sulfate. The dichloromethane was removed by evaporation, silica gel chromatography (ethyl acetate: petroleum ether = 1:2), and the solvent was evaporated to dryness to obtain 33.8 g of a yellow waxy solid with a yield of 79.7%.

[0062] 1 HNMR(DMSO-d 6 , 400MHz) δ8.64(d,1H), 7.82(d,2H), 7.32(d,2H), 5.46(d,1H), 4.73~4.69(m,1H), 4.42~4.37(m,1H) , 4.47~4.43(m,1H), ...

Embodiment 3

[0064] Preparation of N-[4-(4-nitro-3-butenyl)benzoyl]-L-glutamic acid diethyl ester (XI)

[0065] Add 42.4g (0.10mol) of N-[4-(3-hydroxy-4-nitrobutyl)benzoyl]-L-glutamic acid diethyl ester and 1000ml of dichloromethane into a three-necked flask, and cool to 5 ℃, add 10ml (0.12mol) of methanesulfonyl chloride, stir for 15min, add 33.3ml (0.24mol) of triethylamine dropwise, react for 5h, add 1000ml of water to the reaction solution, separate the layers, and extract the water layer with 200ml×2 dichloromethane. The organic phases were combined, dried over sodium sulfate, and the solvent was evaporated to obtain 34.6 g of white crystalline solid with a yield of 85.2%.

[0066] 1 HNMR(DMSO-d 6 , 400MHz) δ8.65(d, 1H), 7.82(d, 2H), 7.37~7.27(m, 4H), 4.45~4.44(m, 1H), 4.11(q, 2H), 4.05(q, 2H) , 2.88 (t, 2H), 2.63 (q, 2H), 2.44 (t, 2H), 2.15 to 1.98 (m, 2H), 1.19 (t, 3H), 1.17 (t, 3H).

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Abstract

The invention relates to a nitro compound and process of its preparation, as well as the use in the preparation of pemetrexed, a kind of anti-tumor medicament, which has the advantages of simplified post-reaction treatment, high product purity, and facilitation of industrialized production.

Description

Technical field [0001] The present invention relates to nitro compounds and their use in pemetrexed, namely N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d] Application in the preparation of pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid. Background technique [0002] Pemetrexed, the structure is as 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] 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), by inhibiting these key enzymes, affect the synthesis of purines and pyrimidines, thereby inhibiting DNA synthesis. Clinical studies have proved that its single agent is effective against a variety of tumors, including non-small cell lung cancer, malignant pleural me...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07C233/83C07C235/42C07D487/04A61K31/519A61P35/00
Inventor 林栋范传文朱屹东王晶翼张明会代连花
Owner QILU PHARMA HAINAN
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