Cabozantinib preparation method

A technology of cabozantinib and organic solvents, applied in the field of preparation of cabozantinib, can solve problems such as poor economic benefits and environmental impact, low synthesis process yield, complicated operation, etc., and achieve simplified reaction process and post-treatment Process, optimized preparation process, simple operation effect

Active Publication Date: 2017-05-10
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] As described in the subsequent comparative examples, in the existing synthesis process, the total yield of the four-step reaction is only 20%, and the second step uses expensive 1,1-cyclopropyl dicarboxylic acid as the starting material; the second step The four steps use an autoclave and stir at 165°C, the reaction is dangerous and the operation is complicated
On the whole, the yield of the existing synthesis process is low, and the economic benefit and environmental impact are not good.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The first step: the synthesis of ethyl 3-(4-fluorophenylamino)-3-oxopropionate.

[0033] A solution of diethyl malonate (0.3mol, 48mL) in xylene (500ml) was added to a solution of 4-fluoroaniline (0.25mol, 23ml) in xylene (200ml), and the reaction mixture was refluxed for 1.5 hours. Spot the plate to monitor the completion of the reaction, the reaction solution was cooled to room temperature, n-hexane (200ml) was added to the reaction solution, filtered, the filter residue was washed with 1000ml of water, and the residue was recrystallized with ethanol to obtain a white solid (51.23g, yield 91%).

[0034] After testing, the nuclear magnetic spectrum is as follows, and it can be determined that the solid is ethyl 3-(4-fluorophenylamino)-3-oxopropionate.

[0035] 1 H NMR(CDCl3)1.30(t,3H),3.48(s,2H),4.20(q,2H),7.03(t,2H),7.61(dd,2H),9.40(s,1H)

[0036] The second step: the synthesis of 3-(4-fluorophenylamino)-3-oxopropionic acid.

[0037] Sodium hydroxide solution (1N, ...

Embodiment 2

[0054] The first step: the synthesis of ethyl 3-(4-fluorophenylamino)-3-oxopropionate.

[0055] A solution of diethyl malonate (0.3mol, 48mL) in toluene (500ml) was added into a solution of 4-fluoroaniline (0.25mol, 23ml) in toluene (200ml), and the reaction mixture was refluxed for 1.5 hours. Spot the plate to monitor the completion of the reaction, the reaction solution was cooled to room temperature, n-hexane (200ml) was added to the reaction solution, filtered, the filter residue was washed with 1000ml water, and the residue was recrystallized with ethanol to obtain a white solid 3-(4-fluorophenylamino)- Ethyl 3-oxopropanoate (52.1 g, yield 92.5%).

[0056] The second step: the synthesis of 3-(4-fluorophenylamino)-3-oxopropionic acid.

[0057] Lithium hydroxide solution (1N, 600ml) was added at 0°C in methanol (700ml) of ethyl 3-(4-fluorophenylamino)-3-oxopropionate (100g, 0.444mol), and the reaction solution was Stir at 20°C for 1 hour. The reaction solution was spin-d...

Embodiment 3

[0066] The first step: the synthesis of ethyl 3-(4-fluorophenylamino)-3-oxopropionate.

[0067] A solution of diethyl malonate (0.275mol, 44mL) in xylene (500ml) was added to a solution of 4-fluoroaniline (0.25mol, 23ml) in xylene (200ml), and the reaction mixture was refluxed for 1.5 hours. Spot the plate to monitor the completion of the reaction, the reaction solution was cooled to room temperature, n-hexane (200ml) was added to the reaction solution, filtered, the filter residue was washed with 1000ml water, and the residue was recrystallized with ethanol to obtain a white solid 3-(4-fluorophenylamino)- Ethyl 3-oxopropanoate (52.9 g, yield 93.96%).

[0068] The second step: the synthesis of 3-(4-fluorophenylamino)-3-oxopropionic acid.

[0069] Potassium hydroxide solution (1N, 600ml) was added at 0°C to ethyl 3-(4-fluorophenylamino)-3-oxopropionate (100g, 0.444mol) in tetrahydrofuran (700ml), and the reaction solution was Stir at 10°C for 1 hour. The reaction solution wa...

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Abstract

The invention discloses a cabozantinib preparation method. The target product cabozantinib is prepared by performing five-step reaction on diethyl malonate, 4-fluoroaniline, 4-chloro-6,7-dimethoxyquinoline, 4-aminophenol, 1,2-dibromoethane and the like used as raw materials. The preparation method is simple to operate and friendly to environment; the comprehensive yield is more than 50% and is obviously increased in comparison with the yield of 20% in the prior art; and the preparation method greatly lowers the existing medicine production cost, and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of cabozantinib. Background technique [0002] Cabozantinib, developed by Exelixis, was approved by the US Food and Drug Administration (FDA) on November 29, 2012 for the treatment of unresectable malignant locally advanced or metastatic medullary thyroid carcinoma (MTC). Medullary thyroid carcinoma (MTC) is a rare, refractory, slowly progressive disease. Cabozantinib is an oral drug that exerts anti-tumor effects by targeting and inhibiting MET, VEGFR2 and RET signaling pathways. It can kill tumor cells, reduce metastasis and inhibit angiogenesis. [0003] Cabozantinib, the molecular formula is C 28 h 24 FN 3 o 5 , molecular weight 501.51, Chinese name: N-[4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N'-(4-fluorophenyl)-1, 1-cyclopropane dicarboxamide, the English name is N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 王治国宋艳红马秀娟田贝贝李世江李超李涛张欣
Owner SHANGHAI ZAIQI BIO TECH
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