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Synthesizing method for binimetinib

A technology of binitinib and synthesis method, applied in the direction of organic chemistry, etc., can solve problems such as unfavorable scale-up production and industrialization promotion, harsh reaction conditions and process, complicated operation, etc., and achieves favorable purification and purity, high yield , the effect of simple operation

Active Publication Date: 2016-08-03
湖南欧亚药业有限公司
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Problems solved by technology

[0011] The steps of the above two synthetic routes are relatively long, and the reaction conditions and processes are relatively harsh and complicated, so the operation is cumbersome and the cost is high, which is not conducive to the scale-up production and industrialization promotion. Therefore, it is necessary to explore short process flow, simple operation and low cost Synthetic method of binitinib which is cheap and suitable for industrialized production

Method used

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  • Synthesizing method for binimetinib
  • Synthesizing method for binimetinib
  • Synthesizing method for binimetinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] A) Preparation of N-(2-tert-butoxyethoxy)-2,3,4-trifluoro-5-nitrobenzamide:

[0034]2,3,4-Trifluoro-5-nitrobenzoic acid (25.0g, 0.11mol) and N,N'-carbonyldiimidazole (22.9g, 0.14mol) were dissolved in tetrahydrofuran (110mL), stirred, and O- (2-tert-butoxyethyl)hydroxylamine (18.1g, 0.14mol), N,N-diisopropylethylamine (58.5g, 0.45mol) was added dropwise, and the reaction mixture was stirred at 50°C for 8h, followed by TLC spotting After confirming that the reaction is complete, the reaction solution is concentrated to dryness by rotary evaporation, adjusted to neutrality by adding dilute hydrochloric acid, extracted by adding ethyl acetate, dried over magnesium sulfate, concentrated by rotary evaporation to dryness, and recrystallized from methanol to obtain N-(2-tert-butoxy Ethoxy)-2,3,4-trifluoro-5-nitrobenzamide, off-white solid (33.5g), yield 88.0%, the reaction formula of this step is as follows:

[0035]

[0036] B) Preparation of N-(2-tert-butoxyethoxy)-2,4-d...

Embodiment 2

[0049] A) Preparation of N-(2-tert-butoxyethoxy)-2,3,4-trifluoro-5-nitrobenzamide:

[0050] 2,3,4-trifluoro-5-nitrobenzoic acid (30.0g, 0.14mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (27.4g, 0.18mol ) was dissolved in chloroform (240mL), stirred, O-(2-tert-butoxyethyl) hydroxylamine (23.5g, 0.18mol) was added, triethylamine (61.8g, 0.61mol) was added dropwise, and the reaction mixture was stirred at 55°C After reacting for 9 hours, TLC spotting confirmed that the reaction was complete, the reaction solution was concentrated to dryness by rotary evaporation, adjusted to neutrality by adding dilute hydrochloric acid, extracted by adding ethyl acetate, dried by magnesium sulfate, concentrated by rotary evaporation to dryness, and recrystallized from methanol to obtain N-( 2-tert-butoxyethoxy)-2,3,4-trifluoro-5-nitrobenzamide, off-white solid (39.9g), yield 87.4%, the reaction formula of this step is the same as that of Example 1 ;

[0051] B) Preparation of N-(2-ter...

Embodiment 3

[0060] A) Preparation of N-(2-tert-butoxyethoxy)-2,3,4-trifluoro-5-nitrobenzamide:

[0061] 2,3,4-trifluoro-5-nitrobenzoic acid (32.0g, 0.14mol) and 1-hydroxybenzotriazole (27.4g, 0.20mol) were dissolved in acetonitrile (150mL), stirred, and O- (2-tert-butoxyethyl)hydroxylamine (24.1g, 0.18mol), 4-dimethylaminopyridine (67.2g, 0.55mol) was added dropwise, and the reaction mixture was stirred at 60°C for 10h, and TLC was spotted to confirm that the reaction was complete. The reaction solution was concentrated to dryness by rotary evaporation, adjusted to neutrality by adding dilute hydrochloric acid, extracted by adding ethyl acetate, dried over magnesium sulfate, concentrated by rotary evaporation to dryness, and recrystallized from methanol to obtain N-(2-tert-butoxyethoxy) -2,3,4-trifluoro-5-nitrobenzamide, off-white solid (41.8g), yield 85.8%, the reaction formula of this step is the same as that of Example 1;

[0062] B) Preparation of N-(2-tert-butoxyethoxy)-2,4-diamino-...

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Abstract

The invention discloses a synthesizing method for binimetinib. The method comprises the steps that 2,3,4-trifluoro-5-nitrobenzoic acid and O-(2-tert-butoxy ethyl)hydroxylamine are subjected to a condensation reaction, and obtained N-(2-tert-butoxy ethyoxyl)-2,3,4-trifluoro-5-nitrobenzamide and ammonium hydroxide are subjected to an ammonolysis reaction; obtained N-(2-tert-butoxy ethyoxyl)-2,4-diamino-3-fluoro-5-nitrobenzamide and formic acid are subjected to a ring-closure reaction in a Pearlman's catalyst; obtained N-(2-tert-butoxy ethyoxyl)-6-amino-7-fluoro-3H-benzimidazole-5-formamide and 4-bromo-2-fluoro-1-iodobenzene are subjected to a substitution reaction; obtained N-(2-tert-butoxy ethyoxyl)-6-[(4-bromo-2-fluoro-phenyl)amino]-7-fluoro-3H-benzimidazole-5-formamide is firstly subjected to a methylation reaction with methyl iodide and then subjected to a deprotection reaction with phosphoric acid, and binimetinib is obtained. The synthesizing method is short in route, operation is simplified, cost is low, and the synthesizing method is environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of a new antitumor drug, binitinib. Background technique [0002] The chemical name of the mitogen-activated protein kinase (MEK) inhibitor binitinib (Binimetinib, MEK162) is N-(2-hydroxyethoxy)-6-[(4-bromo-2-fluorophenyl)amino ]-7-fluoro-3-methyl-3H-benzimidazole-5-carboxamide, its chemical structural formula is: [0003] [0004] Binitinib is a new anti-tumor drug developed by Array Biopharma in the United States. It is used for the treatment of patients with NRAS gene mutant melanoma, BRAF gene mutant melanoma and recurrent low-grade plasma ovarian cancer. It is currently in Phase III clinical trials The success of the trial has given patients an effective targeted therapy drug and may provide a new treatment option for cancer patients with few effective treatments. [0005] A synthetic route for preparing binitinib...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/06
CPCC07D235/06
Inventor 陈健
Owner 湖南欧亚药业有限公司
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