Osimertinib preparation method

A technology for ostinib and compounds, applied in the field of preparation of ostinib, can solve the problems of unrealistic industrial production, poor production practicability, and inability to be used for production, and achieves stable and controllable reaction process, excellent quality and economical efficiency energy effect

Inactive Publication Date: 2018-10-09
上海赛诺克医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this method, compound 1 was synthesized using 2-pentanol as a reaction solvent, and the cost was relatively high. In the reaction of compound 2, trifluoromethylethanol was used as a solvent with a higher price, and the reaction was carried out at 140 degrees under microwave conditions. React, not for production
The iron powder / ammonium chloride system was selected as the third reduction system. Although the cost is low, the post-treatment of the reaction is very troublesome and the production practicability is very poor.
In the fourth step, compound 3 and acryloyl chloride were directly condensed to prepare compound 4. Although the activity is high, it is easy to cause acryloylation of multi-site N and generate by-products, which makes purification difficult.
Moreover, the post-treatment purification of compounds 2, 3 and 4 all used column chromatography, and the yields were all low, so industrial production is obviously unrealistic

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0057] Synthesis of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine

[0058] The raw material 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole 2.5kg (10.26mol) and 4-fluoro-2-methoxy-5-nitroaniline 2kg (10.74mol ) was added successively under stirring in a 50L ethanol reactor, after stirring evenly, the oil bath was heated to 120 degrees Celsius, slowly added p-toluenesulfonic acid 2.34kg (12.31mol), and then refluxed overnight to detect that the reaction was complete, stop heating, and cool down to Suction filtration at room temperature, rinse the filter cake with 5L of isopropanol, and dry to obtain 3.7 kg of a yellow solid with a yield of 91.5% (HPLC purity>95%).

Embodiment 2

[0060] N-[(4-Dimethylamino-ethylamino-2-methoxy-5-nitrophenyl)]-4-(1-methyl-1H-indol-3-yl)-2-pyrimidine Amine Synthesis

[0061] N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine 3.7kg (9.41mol) Add 37L of DMF to the reactor, then add 1.43kg (14.03mol) of diisopropylethylamine, stir well, then add N,N,N-trimethylethylenediamine, and heat to 85 degrees Celsius , reacted overnight. After the detection reaction was completed, the heating was stopped, 37 L of water was added, stirred overnight, centrifuged, washed with water, and dried to obtain 3.8 kg of orange-red solid powder with a yield of 84.9% (HPLC purity>99%).

Embodiment 3

[0063] N-[(4-dimethylamino-ethylamino-2-methoxy-5-aminophenyl)]-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine synthesis

[0064] The N-[(4-dimethylaminoethylamino-2-methoxy-5-nitrophenyl)]-4-(1-methyl-1H-indol-3-yl)- Add 3.8kg (7.99mol) of 2-pyrimidinamine into an autoclave with 38L of ethanol, then add 380g of palladium carbon into the system, replace with nitrogen three times, then replace with hydrogen twice, set the hydrogen pressure to 2MPa, and heat to 80 degrees React overnight. After the detection reaction is over, cool the autoclave, extract the reaction solution, filter through a diatomite filter cake, rinse the filter cake with ethanol, concentrate to 15kg, cool, stir and crystallize, return to room temperature for 2 hours, filter, and filter the cake Rinse with ethanol and dry to obtain 3.05 kg of silver gray powder with a yield of 85.6% (HPLC purity>99%).

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Abstract

The present invention relates to an osimertinib preparation method, which comprises: (1) carrying out a nucleophilic substitution reaction on 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole and 4-fluoro-2-methoxy-5-nitroaniline to prepare a compound 1; (2) carrying out a substitution reaction on the compound 1 and N,N,N-trimethylethylenediamine in the presence of an organic alkali to prepare a compound 2; (3) reducing the compound 2 in the presence of a reducing agent to prepare a compound 3; (4) carrying out condensation on the compound 3 and 3-chloropropionyl chloride in the presence of an alkali to obtain a compound 4; (5) carrying out a heat elimination reaction on the compound 4 through heating in the presence of an alkali to prepare a compound 5; and (6) carrying out salification on the compound 5 and methanesulfonic acid under a heating condition to obtain osimertinib. According to the present invention, the osimertinib synthesis process has characteristics of stability, controllability, no high-toxicity solvent is used, energy saving and environmental protection.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to ostinib, in particular to a preparation method of ostinib. Background technique [0002] Osimertinib (English name Osimertinib, code AZD-9291, molecular formula C 29 h 37 N 7 o 5 S, molecular weight 595.71) has the structural formula shown in formula I, and chemical name is N-[2-[[2-(dimethylamino) ethyl] methylamino]-4-methoxy-5-[[4 -(1-Methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-acrylamide methanesulfonate. Osimertinib is the third-generation EGFR inhibitor for advanced non-small cell lung cancer developed by AstraZeneca after the first-generation targeted drug gefitinib and the second-generation targeted drug afatinib Based on its disease control rate of up to 95% for the T790M mutation in clinical studies, it was granted accelerated marketing in the US and EU in November 2015 and February 2016, respectively. [0003] [0004] Document J.Med.Chem.2014,57,8249...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 张水龙王玉斌张奇能
Owner 上海赛诺克医药科技有限公司
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