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Method for preparing sorafenib

An inert solvent, stage technology, applied in the field of medicinal chemistry, can solve the problems of difficult storage, long reaction time, poor stability, etc., and achieve the effects of easy transportation and storage, short reaction time, and easy metering.

Inactive Publication Date: 2011-10-19
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this operation is that the reaction time is too long, the operation is cumbersome, the equipment requirements are high, and the yield is low
Regardless of the method used, the prepared product (II') itself is a dangerous chemical with high reactivity and poor stability, which is difficult to store

Method used

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  • Method for preparing sorafenib
  • Method for preparing sorafenib
  • Method for preparing sorafenib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: 4-(4-{3-[3-(trifluoromethyl)-4-chlorophenyl]ureido}phenoxy)-N-methylpyridine-2-carboxamide (sorafil Ni, the preparation of IV)

[0055] Under nitrogen, dissolve triphosgene (0.55g, 1.85mmol) in anhydrous dichloromethane (10ml), and add 3-trifluoromethyl-4-chloroaniline (II) (0.98g , 5 mmol) and diisopropylethylamine (0.78 g, 6 mmol) in anhydrous dichloromethane (10 ml). After dropping, the mixture was stirred at the same temperature for another 30 minutes. Add 4-(4-aminophenoxy)-N-methyl-2- A solution of picolinamide (III) (1.1 g, 4.5 mmol) and diisopropylethylamine (0.7 g, 5.4 mmol) in anhydrous dichloromethane (10 ml). After dropping, stir at room temperature for 1 hour. After washing the obtained reaction solution with water, water (15 ml) was added, and sorafenib (IV) seed crystals were inoculated into the obtained two-phase system. Stir and crystallize at room temperature for 4 hours, filter and wash, and dry in vacuo to obtain Sorafenib (IV) (1.76 ...

Embodiment 2

[0058] Embodiment 2: the preparation of sorafenib p-toluenesulfonate (I)

[0059] Get the obtained Sorafenib of Example 1 (1.16g, 2.5mmol) and ethyl acetate (10ml) and water (0.25ml) mix, after heating to 70 ℃, dropwise add p-toluenesulfonic acid monohydrate (0.57g, 3mmol ) in ethyl acetate (0.5ml) and water (0.15ml), then concentrated under reduced pressure. Add absolute ethanol (22ml) to the resulting residue, reflux for 30 minutes, then cool to room temperature within 2 hours, filter with suction, wash the filter cake with absolute ethanol, and vacuum-dry at 50°C to obtain Sorafenib p-toluenesulfonate (I), as a slightly brown crystalline powder (1.45 g, 91%):

[0060] 1 H-NMR (DMSO-d 6 )δ: 9.33(s, 1H, exchangeable), 9.13(s, 1H, exchangeable), 8.86(d, J=4.4Hz, 1H, exchangeable), 8.55(d, J=5.6Hz, 1H), 8.11(d , J=2.4Hz, 1H), 7.68(dd, J=2.4, 8.8Hz, 1H), 7.57-7.63(m, 4H), 7.54(d, J=8.0Hz, 2H), 7.22(dd, J= 2.4, 5.6Hz, 1H), 7.18(d, J=9.2Hz, 2H), 7.14(d, J=8.0Hz, 2H), 2.82(d, ...

Embodiment 3

[0061] Example 3: 4-(4-{3-[3-(trifluoromethyl)-4-chlorophenyl]ureido}phenoxy)-N-methylpyridine-2-carboxamide (sorafil Ni, the preparation of IV)

[0062] Under nitrogen, triphosgene (0.55g, 1.85mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (9ml), and 3-trifluoromethyl-4-chloroaniline (II) was added dropwise at 24~30°C ( 0.98g, 5mmol) and diisopropylethylamine (0.78g, 6mmol) in dry 2-methyltetrahydrofuran (10ml). After dropping, the mixture was stirred at the same temperature for another 30 minutes. Add 4-(4-aminophenoxy)-N-methyl-2- A solution of picolinamide (III) (1.1 g, 4.5 mmol) and diisopropylethylamine (0.7 g, 5.4 mmol) in anhydrous 2-methyltetrahydrofuran (10 ml). After dropping, the mixture was stirred at about 40°C for 1 hour. The resulting reaction solution was washed successively with a mixture of saturated aqueous sodium bicarbonate (2ml) and water (4ml), and water (6ml), then concentrated under reduced pressure to about half the volume, and inoculat...

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Abstract

The invention discloses a method for preparing sorafenib, which comprises the steps of: 1) reacting triphosgene with 3-trimethyl fluoride-4-chloroaniline (II) in an inert solvent 1 under the existence of tertiary amine 1, thus obtaining a solution containing 3-trimethyl fluoride-4-chlorphenyl isocyanate (II'), wherein isolation and purification are not needed; and 2) reacting the 3-trimethyl fluoride-4-chlorphenyl isocyanate (II') with 4-(4-aminophenoxy)-N-methyl-2-pyridine carbonxamide (III) in an inert solvent 2 under the existence of tertiary amine 2, thus obtaining sorafenib (IV). The tertiary amine 1 and the tertiary amine 2 are the same or different, the inert solvent 1 and the inert solvent 2 are the same or different, and the feeding sequence of the 3-trimethyl fluoride-4-chloroaniline (II) and the 4-(4-aminophenoxy)-N-methyl-2-pyridine carbonxamide (III) can be interchangeable. The method is simple and convenient to operate, short for reaction time free from separation of intermediates with high reactivity, as well as is free from special equipment and conditions, and high in yield.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of sorafenib. Background technique [0002] Sorafenib tosylate (I) is an oral multikinase inhibitor jointly developed by Bayer and Onyx, which not only targets the RAF / MEK / ERK signal transduction pathway to block tumor cell proliferation, It also targets the VEGFR-2 / PDGFR-β signal transduction cascade to inhibit tumor angiogenesis; the trade name is Nexavar ), indications: advanced renal cell carcinoma and inoperable hepatocellular carcinoma. Sorafenib p-toluenesulfonate (I) chemical name: 4-(4-{3-[3-(trifluoromethyl)-4-chlorophenyl]ureido}phenoxy)-N-methyl Pyridine-2-carboxamide p-toluenesulfonate, the structural formula is as follows: [0003] [0004] Formula 1 Sorafenib tosylate (I) structural formula [0005] There are many synthetic reports about Sorafenib, such as PCT patent application WO00 / 42012, Bankston D etc. Industrial Journa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81
Inventor 张庆文
Owner SHANGHAI INST OF PHARMA IND CO LTD
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