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Improved method for synthetizing novel P38 mitogen-activated protein kinase inhibitor

A protein kinase inhibitor, mitogen activation technology, applied in the field of improved synthesis, can solve the problems of unsuitable environmental pollution, high toxicity, expensive reducing agent, etc., achieve simplified reaction steps, simple purification method, and overcome environmental pollution. Effect

Inactive Publication Date: 2012-07-04
上海本索医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to provide an improved synthetic method of novel P38 mitogen-activated protein kinase inhibitors, to overcome the above-mentioned existing method for synthesizing compound M, which uses highly toxic and explosive reagents, and uses highly toxic and expensive reduction methods. agents, cause great environmental pollution and are not suitable for industrial production and other defects

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  • Improved method for synthetizing novel P38 mitogen-activated protein kinase inhibitor
  • Improved method for synthetizing novel P38 mitogen-activated protein kinase inhibitor
  • Improved method for synthetizing novel P38 mitogen-activated protein kinase inhibitor

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Embodiment 1

[0044] Preparation of Compound C

[0045] Compound B (3Kg, 23.786mol), 16Kg of THF and N-benzyloxycarbonylglycine (5Kg, 23.9mol) were sequentially added into a 100L reactor. Control the temperature of the reaction solution at 35-40°C and add HOBT (0.63Kg, 4.662mol) in batches; 3Kg of DMF is added at one time. At the same temperature, EDCI (5Kg, 26.08mol) was added in batches; keep warm and stir the reaction for 10h. Add 18Kg of deionized water in batches. At a temperature below 65 °C, the reaction solvent was distilled to about 20 L. At a temperature of 35-40°C, add 35Kg of deionized water in batches. Centrifuge and dry to obtain the crude product, which is washed twice with deionized water, 30Kg each time. Vacuum drying at 50°C gave 6.83Kg of compound C (90.5%, molar yield).

[0046] 1 H-NMR(DMSO-d6)δ: 13.465(s, 1H), 8.273(s, 1H), 8.259(s, 1H), 7.257~7497(m, 5H), 6.861~6.867(d, 1H), 5.079 (s, 2H), 4.595 ~ 4.611 (d, 2H).

[0047] Preparation of Compound D

[0048] Com...

Embodiment 2

[0057] The preparation method of compound C, D, E is with embodiment 1, and the preparation method of compound M is roughly the same as the method of embodiment 1, and difference is that the condensing agent that adopts is TBTU:

[0058] Compound E (562g, 2.145mol), 10Kg of THF, Compound A (570g, 2.118mol) and TBTU (815g, 2.535mol) were sequentially added into a 50L reactor. Control the temperature at 35° C., and add 527 g of triethylamine in batches. The reaction solution was kept at 60-65°C and stirred for 20h. The reaction liquid was cooled to 25°C, and 6.5Kg of water was added dropwise while controlling the temperature of the reaction liquid at 20-25°C. Under heat preservation, stir for 30 minutes, centrifuge to dry, and wash the solid twice with 10Kg deionized water successively. 1.2Kg of wet compound M was obtained.

[0059] Add 1.2Kg of wet compound M, 3.5Kg of DMF and 5Kg of THF into a 10-degree kettle in sequence, and stir to dissolve the solid. Suction filter the...

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Abstract

The invention discloses an improved method for synthetizing novel P38 mitogen-activated protein kinase inhibitor with a structural formula M, comprising the steps of taking 5- pyrazol formhydrazide compound B as an initial raw material, performing condensation reaction with N-carboxybenzyl glycine, reacting with Lawesson reagent, disaffiliating from Cbz (Carbamazepine) protection under an acidic condition, finally carrying out the condensation reaction. Compared with a conventional method, the method disclosed by the invention has the advantages that highly toxic and dangerous sodium azide and expensive trimethylphosphine are replaced by the N-carboxybenzyl glycine to ensure that the defects of environmental pollution and high cost of the conventional method are overcome; the reaction step is simplified; the purification method of an intermediate is simple, and the intermediate is obtained through beating, filtration or direct filtration; and the industrial operation is simple, so that the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to an improved synthesis of novel p38 mitogen-activated protein kinase inhibitors. Background technique [0002] The p38 mitogen-activated protein kinase inhibitor (mitogen-activated protein kinase, MAPK) pathway is an important branch of the MAPK-mediated signaling pathway, involved in various physiological processes such as inflammation, proliferation, and apoptosis. At present, p38MAPK is considered to include four subtypes, including p38α, p38β, p38δ, and p38γ. Among them, p38α is most widely expressed in tissues and has rich biological functions, while other subtypes are relatively concentrated in expression and their biological functions are not very clear. [0003] In inflammation, apoptosis, cell cycle, cardiac hypertrophy, development, cell differentiation, aging and tumor suppression, p38MAPK plays an important role, among which the role in inflammation is the most prominent, pro-inflammatory factors, degrading e...

Claims

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Application Information

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IPC IPC(8): C07D417/14
Inventor 吴广傅浩
Owner 上海本索医药科技有限公司
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