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Preparation method of multi-receptor tyrosine kinase inhibitor and intermediate thereof

A tyrosine kinase and receptor technology, applied in the field of drug synthesis, can solve the problems of unsuitability for industrial production, high reaction temperature, and low yield

Pending Publication Date: 2019-06-04
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Compared with the method of WO2005030140, the method of CN103664776A also has the characteristics of high reaction temperature, low yield and complicated operation, so it is also not suitable for industrial production

Method used

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  • Preparation method of multi-receptor tyrosine kinase inhibitor and intermediate thereof
  • Preparation method of multi-receptor tyrosine kinase inhibitor and intermediate thereof
  • Preparation method of multi-receptor tyrosine kinase inhibitor and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Preparation of 4-(6,7-dimethoxy-quinolin-4-yloxy)aniline (II)

[0042]

[0043] Add compound (I) (1000g, 4.47mol) and 4-aminophenol (690g, 6.32mol) into the reaction flask, add N,N-dimethylacetamide (6L), cool down to 0-5°C, add dropwise Sodium tert-butoxide (860g) in N,N-dimethylacetamide (4L) suspension, after dropping, raise the temperature to 100-110°C and keep it warm for 4-5 hours. Cool down to -5-0°C, add ice water (20 L), stir and crystallize for 15-16 hours. After filtering, the filter cake was washed with a small amount of water, and air-dried at 50° C. for 15-16 hours to obtain 1180 g of a light yellow solid with a yield of 89.0% and a purity of 99.7% by HPLC.

Embodiment 2

[0044] Example 2N-(4-{[6,7-bis(methoxy)quinolin-4-yl]oxy}phenyl)-N 1 Preparation of -(4-fluorophenyl)cyclopropane-1,1-diacid amide (III)

[0045]

[0046] 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (500g, 2.24mol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (850g, 2.24mol), triethylamine (380g) and N,N-dimethylacetamide (2L) were added to the reaction flask, and compound (II) (550g, 1.86mol) was added under stirring, and After completion, the reaction was stirred at 60°C for 5-6 hours. Add water (16L) to the reaction solution, stir and crystallize at 10-20°C for 1-2 hours, filter, and vacuum-dry the filter cake at 40-50°C for 23-24 hours to obtain 867g of off-white solid, yield 93.1%, HPLC purity 99.5 %.

[0047]1 H NMR (400MHz, d 6 -DMSO): δ10.2 (s, 1H), 10.08 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.4 ( s, 1H), 7.24 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H).

[0048] MS(ESI): m / z 502[...

Embodiment 3

[0050] 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (200g, 0.90mol), O-benzotriazole-tetramethyluronium hexafluorophosphate (307g, 0.81mol), DIEA (50ml) Add N,N-dimethylacetamide (3 L) into the reaction flask, add compound (II) (220 g, 0.74 mol) under stirring, after the addition is complete, stir and react at 70°C for 3-4 hours. Add water (6L) to the reaction solution, stir and crystallize at 10-20°C for 1-2 hours, filter, and vacuum-dry the filter cake at 40-50°C for 23-24 hours to obtain 334g of off-white solid, yield 90.1%, HPLC purity 98.5 %, nuclear magnetic data is basically the same as embodiment 2.

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Abstract

The invention relates to a preparation method of cabozantinib. The method includes: taking 4-chloro-6, 7-dimethoxyquinoline (I) as the starting raw material, and conducting substitution and condensation to obtain cabozantinib. Compared with other preparation methods, the preparation method provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions, high total yield and high product purity, at the same time avoids high temperature production, reduces risk, simplifies operation, and is more beneficial to industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of a multi-receptor tyrosine kinase inhibitor cabozantinib and an intermediate thereof. Background technique [0002] Cabozantinib, chemical name: N-(4-{[6,7-bis(methoxy)quinolin-4-yl]oxy}phenyl)-N 1 -(4-Fluorophenyl)cyclopropane-1,1-dioic acid amide, a multi-receptor tyrosine kinase inhibitor (tyrosinekinases inhibitor), targeting RET, MET, VEGFR-1,-2,- 3. KIT, TRKB, FLT-3, AXL, TIE-2, etc. Tyrosine kinases play a very important role in the occurrence and development of tumors. The research and development of drugs targeting tyrosine kinases has become a hot spot in the research of anti-tumor drugs in the world. Tyrosinase inhibitors achieve anti-tumor effects by inhibiting the damage repair of tumor cells, arresting cell division in the G1 phase, inducing and maintaining cell apoptosis, and anti-angiogenesis. First-line drugs for the treatment of ...

Claims

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Application Information

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IPC IPC(8): C07D215/22
Inventor 张亮范兴宝陈安丰周炳城
Owner 连云港恒运药业有限公司
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