Preparation method for Regorafenib hydrate

A technology of regorafenib and compound, applied in the field of preparation of regorafenib, can solve the problems of unstable chemical properties of excipients, increased production cost, difficult post-processing, etc., and achieves a short cycle, convenient operation and few reaction steps. Effect

Active Publication Date: 2016-02-17
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of 4-chloro-3-trifluoromethylbenzene isocyanate is difficult to purchase, and it is generally synthesized

Method used

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  • Preparation method for Regorafenib hydrate
  • Preparation method for Regorafenib hydrate
  • Preparation method for Regorafenib hydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Example 1: Synthesis of (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 4)

[0035] Sodium hydroxide aqueous solution (400mL, 2.5M) was added dropwise to 4-chloro-3-trifluoromethylaniline (compound 2) (78.2g, 400mmol) in 400ml ethyl acetate solution, the temperature was controlled below 5°C, and Stir at 0°C to 5°C for 30min; add propylene chloroformate (compound 3) (59.5ml, 560mmol) dropwise, and control the temperature of the dropwise addition process below 5°C; stir the reaction mixture at room temperature for 1-3 hours, separate the liquids, The aqueous phase was extracted with ethyl acetate (3×800mL), the combined organic phases were washed with water (3×1000mL), anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate to the crude product, add ethyl acetate:n-heptane (1:2) for recrystallization, filter with suction, and dry to obtain (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 4 ) 101.0g, yield 90.3%, purity 99.3% (HPLC meth...

Embodiment 2

[0036] Embodiment 2: Synthesis of (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 4)

[0037] Sodium hydroxide aqueous solution (100mL, 3.5M) was added dropwise into 100ml ethyl acetate solution of 4-chloro-3-trifluoromethylaniline (compound 2) (19.6g, 100mmol), the temperature was controlled below 5°C, and Stir at 0°C to 5°C for 30min; add propylene chloroformate (compound 3) (32ml, 300mmol) dropwise, and control the temperature of the dropping process below 5°C; stir the reaction mixture at room temperature for 1-3 hours, separate liquid, and phase was extracted with ethyl acetate (3×200mL), the organic phases were combined, washed with water (3×500mL), anhydrous Na 2 SO 4Dry, filter, and concentrate the filtrate to the crude product, add ethyl acetate:n-heptane (1:2) for recrystallization, filter with suction, and dry to obtain (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 4 ) 25.5g, yield 91.3%, purity 99.2% (HPLC method).

Embodiment 3

[0038] Example 3: Synthesis of (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 4)

[0039] Add sodium ethoxide (6.85g, 100mmol) and 4-chloro-3-trifluoromethylaniline (compound 2) (19.6g, 100mmol) into 100ml ethanol solution, control the temperature below 5°C, and Stir at ℃ for 30min; add propylene chloroformate (compound 3) (11ml, 100mmol) dropwise, and control the dropwise addition process temperature below 5℃; the reaction mixture is stirred at room temperature for 1-3 hours, concentrated, and extracted with ethyl acetate (3 ×200mL), combined the organic phases, washed with water (3×500mL), anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate to the crude product, add ethyl acetate:n-heptane (1:2) for recrystallization, filter with suction, and dry to obtain (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 4 ) 25.7g, yield 92.0%, purity 99.4% (HPLC method).

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Abstract

The invention relates to a preparation method for Regorafenib hydrate. The method includes the steps that creatively, 4-chloro-1-trifluoromethyl phenylamine (compound 2) and allyl chloroformate (compound 3) react to generate (4-chloro-3-trifluoromethyl phenylamine)-formic acid allyl ester (compound 4); (4-chloro-3-trifluoromethyl phenylamine)-formic acid allyl ester (compound 4) and 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-formamide (compound 9) are subjected to a substitution reaction under the catalysis of N-methyl pyrrolidine or trialkylaluminium to obtain Regorafenib hydrate. According to the method, cost is low, operation is easy, few reaction steps are needed, the period is short, energy consumption is low, the yield is high, purity is high, the process is safe, no high-toxicity reagent is used, and the obtained product has no potential safety problem and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of regorafenib. Background technique [0002] Regorafenib (regorafenib), the chemical name is 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N -picoline-2-carboxamide, having the chemical structure shown in formula 1. It is a new multi-kinase inhibitor anticancer drug developed by Bayer Healthcare in Germany, which can inhibit the IT, FGFR1 and other enzymes that promote the growth of cancer cells, and then play a role in inhibiting tumor angiogenesis and tumor cell proliferation. It is the first drug for the treatment of An oral small molecule multikinase inhibitor for metastatic colorectal cancer, mainly used for the treatment of metastatic advanced rectal cancer. Its structure is similar to that of sorafenib, another kinase targeting inhibitor already on the market, but its inhibitory activity and in...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 孙松李强侯孝龙
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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