Production of N-(pyrrolo[2,3-d] pyrimidine-5-) acyl glusate derivative and intermediate

A carboxyl protecting group and product technology, applied in the field of preparing pharmaceutically valuable N-acyl glutamic acid derivatives, can solve the problems of low condensation and cyclization yields, and difficult product separation

Active Publication Date: 2006-05-31
重庆凯林制药有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The present invention aims at the low yield of condensation and cyclization with L-glutamic acid diester existing in this process, and the problems such as difficult product separation are improved, and a kind of method that can increase condensation and cyclization for preparing the compound of formula (I) is provided. Cyclization Yield, Improved Method to Simplify Separation Operations and an Important Intermediate

Method used

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  • Production of N-(pyrrolo[2,3-d] pyrimidine-5-) acyl glusate derivative and intermediate
  • Production of N-(pyrrolo[2,3-d] pyrimidine-5-) acyl glusate derivative and intermediate
  • Production of N-(pyrrolo[2,3-d] pyrimidine-5-) acyl glusate derivative and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] 4-[3-(2,6-Diamino-1,4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl]benzoic acid (compound XI)

[0108] In a 1L reaction flask, use 32.0g (800mmol) of sodium hydroxide and 400ml of water to form a solution. After cooling to room temperature, add 4-[3-(2,6-diamino-1,4-dihydro-4- Oxypyrimidin-5-yl)-4-nitrobutyl]ethyl benzoate (compound IV, prepared according to WO0011004 method) 50.0g (133mmol), stirred at room temperature for 1 hour, and cooled the reaction system to 0~5℃, add 2mol / L dilute hydrochloric acid solution dropwise, with the addition of hydrochloric acid, the system gradually precipitates a yellow solid, control the dropping speed to keep the internal temperature of the system at 0~5℃, when the pH of the system is 3~4 Stop dripping; filter, wash the filter cake with water, and dry to obtain 4-[3-(2,6-diamino-1,4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl Base] benzoic acid 44.6g, light yellow solid, yield 96.5%.

[0109] IR (KBr): 3505, 3469, 3402, 3363, 3222, 31...

Embodiment 2

[0113] N-[4-[3-(2,6-Diamino-1,4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl]benzoyl]-L-glutamine Acid diethyl ester (compound XII)

[0114] In a 1L dry reaction flask, add 40.0 g of 4-[3-(2,6-diamino-1,4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl]benzoic acid g (115mmol) and 600ml of tetrahydrofuran, cooled to 0-5°C with an ice bath, and added 26.2g (149mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methyl Morpholine 32.7g (323mmol), stirred at 0-5°C for 40 minutes; then added 35.7g (149mmol) of L-diethyl glutamate hydrochloride at one time, removed from the ice bath, and reacted at room temperature for 2 hours ; filter, wash the filter cake with tetrahydrofuran, combine the filtrate and washings, evaporate tetrahydrofuran under reduced pressure to obtain a yellow solid, and dry under reduced pressure at 50°C to obtain N-[4-[3-(2,6-diamino-1 , 4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl]benzoyl]-L-glutamic acid diethyl ester 50.5g, yellow solid, yield 82.5%.

[0115] IR ...

Embodiment 3

[0119] N-[4-[3-(2,6-Diamino-1,4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl]benzoyl]-L-glutamine diethyl ester p-toluenesulfonate

[0120] In a 250ml three-necked flask, add N-[4-[3-(2,6-diamino-1,4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl]benzyl Acyl]-L-glutamic acid diethyl ester 10.0g (18.7mmol), p-toluenesulfonic acid monohydrate 5.4g (28.2mmol) and absolute ethanol 100ml, heated to reflux for 20 minutes, stirred and cooled, a large amount of white solid precipitated , and continue to stir for 1 hour after cooling to room temperature; the precipitated solid is collected by filtration, the filter cake is washed with absolute ethanol, and dried under reduced pressure at 50°C to obtain N-[4-[3-(2,6-diamino-1 , 4-dihydro-4-oxopyrimidin-5-yl)-4-nitrobutyl]benzoyl]-L-glutamic acid diethyl ester p-toluenesulfonate 11.6g, white solid, yield 88.0%.

[0121] IR (KBr): 3339, 3242, 2981, 1725, 1637, 1587, 1541, 1439, 1380, 1353, 1207, 1102, 1022, 856, 790cm -1 .

[0122] 1 H NMR ...

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Abstract

Production of N-(pyrrolo(2,3-d)pyramine-5-radical)acyl glutamic acid derivative and its intermediate are disclosed. The typical derivative is antineoplastic agent, Z is thienyl bi-radical and furan bi-radical or substituted or non-substituted 1,4-phenylene, R1 and R2 are hydrogen or carboxy protecting group, they can be same or different. Carbon atom with *mark is S type, R type or mixed type of S and R.

Description

technical field [0001] The invention relates to the fields of synthetic organic chemistry and pharmacy. The invention provides a method and an intermediate for preparing pharmaceutically valuable N-(pyrrolo[2,3-d]pyrimidin-5-yl)acyl glutamic acid derivatives. Background technique [0002] Recently, a series of N-(pyrrolo[2,3-d]pyrimidin-5-yl)acylglutamic acids of general formula (I) and their pharmaceutically acceptable salts have been disclosed as folic acid antagonists, such as EP334636, EP432677 and so on. Known compounds with antifolate activity are all recognized as having anticancer activity. [0003] [0004] In the formula: [0005] Z is thiophenediyl, furanediyl, or substituted or unsubstituted 1,4-phenylene; [0006] The carbon atom configuration marked with * is S type, R type or a mixed type of S and R. [0007] Wherein when Z is unsubstituted 1,4-phenylene, the carbon atom configuration marked with * is S type, and the compound of general formula (I) is th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D405/06C07D409/06C07D487/04
CPCY02P20/55
Inventor 罗杰叶文润邓杰周永春
Owner 重庆凯林制药有限公司
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