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Method for preparing osimertinib mesylate

A technology of meritinib and methanesulfonic acid, applied in the field of medicinal chemistry, can solve the problems of being unsuitable for industrial production, unfavorable to protect the environment, and large adsorption of iron powder, so as to reduce the risk of genotoxic impurities and reduce costs , the effect of small adsorption

Inactive Publication Date: 2017-09-22
LUOXIN PHARM SHANGHAI CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method for reducing the nitro group is ferric ammonium reduction method. In the post-treatment process, the ion-exchange resin is firstly used for pretreatment, which is costly and unsuitable for industrialized production; and the iron powder has a large adsorption, resulting in low yield and the generated waste residue There is also a lot of waste liquid, which is not conducive to protecting the environment

Method used

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  • Method for preparing osimertinib mesylate
  • Method for preparing osimertinib mesylate
  • Method for preparing osimertinib mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] (1) compound shown in preparation formula (II)

[0063] At room temperature, add 1000 ml of 2-pentanol to a 2L reaction flask, add 50 g of 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole, 42 g of 4-fluoro- 2-methoxyl-5-nitroaniline, 3.54 g of p-toluenesulfonic acid, the mixture was heated to 80°C, and reacted for 6 hours. The mixture was cooled to 25°C-28°C, filtered with suction, and the filter cake was washed with 50 ml of 2-pentanol. After the filter cake was drained, it was dried in a vacuum drying oven to obtain 80.1 g of a yellow solid, with a yield of 99.0%. 1 HNMR (400MHz, DMSO) δ3.92(3H, s), 4.00(3H, s), 7.14(1H, dd), 7.30-7.33(1H, m), 7.44-7.52(2H, m), 7.60(1H , d), 8.22 (1H, m), 8.35 (1H, d), 8.68 (1H, s), 8.79 (1H, d), 9.76 (1H, s). m / z(M+H) + = 394.20.

Embodiment 2

[0065] Compound shown in the preparation formula (III)

[0066] At room temperature, 801 milliliters of N,N-dimethylacetamide was added to a 2L reaction flask, 80.1 grams of the compound shown in formula (II), 20.6 grams of N,N,N'-trimethylethylenediamine were added, 28.1 grams of potassium carbonate. The mixture was heated at 110°C and reacted for 7 hours. Slowly lower the temperature to 25°C-28°C, slowly add 801 ml of water, stir and crystallize for 1 hour. Suction filtration, the filter cake was washed with 160 ml of water. The filter cake was dried in a vacuum drying oven to obtain 92.8 g of orange-red solid, yield: 95.9%. 1 HNMR (400MHz, DMSO) δ2.16 (6H, s), 2.48 (2H, t), 2.86 (3H, s), 3.27 (2H, t), 3.87 (3H, s), 3.95 (3H, s), 6.84(1H,s), 7.12(1H,t), 7.22(1H,d), 7.25(1H,t), 7.52(1H,d), 8.11(1H,s), 8.31(1H,d), 8.32 (1H,s), 8.36(1H,d), 8.64(1H,s). m / z(M+H) + = 476.20.

Embodiment 3

[0068] Compound shown in the preparation formula (IV)

[0069] Under nitrogen protection, 928 milliliters of methanol was added to a 2L four-necked flask, then 92.8 grams of the compound shown in formula (III) was added, and under stirring, 18.6 g of Raney nickel (water-containing wet product) was added, and the hydrogenation reduction was carried out at 8 atmospheric pressure. , the reaction temperature was 25°C, and the reaction was carried out for 6 hours. Filtration and spinning to obtain 82.6 g of gray solid, yield: 95.0%. 1 HNMR(400MHz,DMSO)δ2.18(6H,s),2.37(2H,t),2.63(3H,s),2.89(2H,t),3.74(3H,s),3.88(3H,s), 4.62(2H,s), 6.76(1H,brs), 7.14-7.19(2H,m), 7.23-7.26(1H,m), 7.48(1H,s), 7.52(1H,d), 7.81(1H, s), 8.27(1H,d), 8.31(1H,s), 8.43(1H,d). m / z(M+H) + = 446.30.

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Abstract

The invention discloses a method for preparing Osimertinib mesylate. The method comprises the steps that after 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with 4-fluorine-2-methoxy-5-nitroaniline, 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to substitution reaction with N,N,N'-trimethyl-ethylenediamine, nitro is restored after catalytic hydrogenation, then 3-(2-chlorine-4-pyrimidinly)-1-methyl-1H-indole is subjected to coupling reaction with 3-chloropropionyl-chloride, osimertinib is obtained after elimination with sodium hydroxide, and osimertinib reacts with salt mesylate in acetone and water to obtain osimertinib mesylate, wherein a catalyst for restoring nitro by the catalytic hydrogenation is raney nickel, palladium carbon or palladium-carbon hydroxide. The method for preparing osimertinib mesylate is low in cost, high in yield, little in environmental pollution, simple and easy in production process operation and suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of meritinib mesylate. Background technique [0002] Meritinib mesylate is the third-generation oral, irreversible and selective EGFR mutation inhibitor developed by AstraZeneca, which can be used for activating and resistant mutant EGFR. For patients with advanced non-small cell lung cancer, 50% of acquired resistance to anti-EGFR therapy is caused by T790M mutation, and meritinib mesylate has a better therapeutic effect on non-small cell lung cancer with T790M mutation. [0003] The existing methods for preparing meritinib mesylate are 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole and 4-fluoro-2-methoxy-5-nitroaniline A substitution reaction occurs, and then a substitution reaction occurs with N,N,N'-trimethylethylenediamine, the nitro group is reduced, the coupling is eliminated, and then a salt is formed. The method for reducing the nitro group is fer...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07C309/04C07C303/32
CPCC07D403/04
Inventor 潘龙冈蔡正元李国亮杨文谦王铁林
Owner LUOXIN PHARM SHANGHAI CO LTD
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