Synthetic method of MAP kinase inhibitor for treating malignant tumors

A technology of kinase inhibitors and synthetic methods, applied in antineoplastic drugs, drug combinations, organic chemistry, etc., to achieve the effects of cheap raw materials, easy purchase of raw materials, and short production cycle

Inactive Publication Date: 2018-09-11
刘凤娟
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are no MKK1 / 2 or ERK1 / 2 inhibitors developed for clinical use, Raf kinase inhibitors (such as sorafenib) targeting various types of cancer have successfully marketed anti-tumor drugs

Method used

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  • Synthetic method of MAP kinase inhibitor for treating malignant tumors
  • Synthetic method of MAP kinase inhibitor for treating malignant tumors
  • Synthetic method of MAP kinase inhibitor for treating malignant tumors

Examples

Experimental program
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Embodiment 1

[0029] 6-methyl-4-((2-methyl-4-(propylcarbamoyl)phenyl)amino)-pyrrolo[2,1-f][1,2,4]triazine-5- The synthetic conditions of ethyl carboxylate 3 are:

[0030] 4-Chloro-6-methylpyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid ethyl ester 1 (130g), 4-amino-3-methyl-N- Propyl benzamide 2 (160g) and dimethylformamide (1300mL) were mixed, stirred at 0-50°C for 12 hours; water (1000mL) was added to the system; stirred for 2 hours, filtered to obtain 6-methyl- 4-((2-Methyl-4-(propylcarbamoyl)phenyl)amino)-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid ethyl ester 3 (170g).

[0031] 1 H NMR (400MHz, DMSO-d6)δ=8.46(s,1H),8.02(s,1H),7.84(s,1H),7.78(s,1H),7.67(d,1H),7.38(d, 1H), 4.38(q, 2H), 2.83(m, 1H), 2.81(s, 3H), 2.22(s, 3H), 1.54(m, 2H), 1.32(t, 3H), 0.69(m, 2H ),0.55(m,2H)ppm; m / z(MS-ESI):394.31[M+1] + .

[0032] 6-methyl-4-((2-methyl-4-(propylcarbamoyl)phenyl)amino)-pyrrolo[2,1-f][1,2,4]triazine-5- The synthesis conditions of carboxylic acid 4 are:

[0033] 6-methyl-4-((2-met...

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Abstract

The invention discloses a synthetic method of a MAP kinase inhibitor for treating malignant tumors. The method comprises the steps that 4-chlorine-6-methylpyrrolo[2,1-f][1,2,4]triazine-5-nonaoic acid-ethyl ester 1 and 4-amino-3-methyl-N-propylbenzamide 2 are subjected to a substitution reaction, and 6-methyl-4-((2-methyl-4-(propylcarbamoyl)phenyl)amino)-pyrrolo[2,1-f][1,2,4]triazine-5-nonaoic acid-ethyl ester 3 is obtained. Then, 6-methyl-4-((2-methyl-4-(propylcarbamoyl)phenyl)amino)-pyrrolo[2,1-f][1,2,4]triazine-5-nonaoic acid-ethyl ester 3 is hydrolyzed under the action of sodium hydroxide,and obtained 6-methyl-4-((2-methyl-4-(propylcarbamoyl)phenyl)amino)-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid 4 and aminocyclopropane are subjected to condensation to obtain N-cyclopropyl-6-methyl-4-((2-methyl-4-(propylcarbamoyl)phenyl)amino)-pyrrolo[2,1-f][1,2,4]triazine-5-amide. According to the synthetic condition and method, operation is easy, raw materials are low in price and easy to purchase, and the production cycle is short.

Description

technical field [0001] The field of the invention belongs to the field of drug synthesis, in particular to a MAP kinase inhibitor N-cyclopropyl-6-methyl-4-((2-methyl-4-(propylcarbamoyl) for the treatment of malignant tumors ) phenyl) amino)-pyrrolo [2,1-f] [1,2,4] the synthetic method of triazine-5-amide. Background technique [0002] Mitogen-activated protein kinase (MAPK or MAP kinase) is a protein kinase specific for the amino acids serine and threonine (ie, serine / threonine-specific protein kinase). MAPKs are involved in directing cellular responses to various stimuli such as mitogens, osmotic stress, heat shock and pro-inflammatory cytokines. They regulate a variety of cellular functions, including proliferation, gene expression, differentiation, mitosis, cell survival and apoptosis. MAPKs belong to the CMGC (CDK / MAPK / GSK3 / CLK) kinase group. The closest relatives of MAPKs are the cyclin-dependent kinases (CDKs). [0003] Most MAPKs share many common features, such a...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04A61P35/00
Inventor刘凤娟
Owner刘凤娟