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Preparation method of flumazenil

A technology of flumazenil and condensation reaction, which is applied in the field of drug synthesis, can solve problems such as water source, environmental pollution, cumbersome paths, and reaction failures, and achieve the effects of shortening the reaction path, reducing environmental risks, and reducing production costs

Active Publication Date: 2021-06-18
NANHU LAB +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Wherein path a, b, c all prepare this intermediate by anthranilic acid method, and the chloroformic ester compound or phosgene used in this step are all highly toxic, pollute water source and environment relatively, and reaction conditions require Strict, improper operation can easily reduce the yield or fail the reaction
The route d uses the isatin oxidation method to prepare the intermediate. This method is commonly used with chromium trioxide or peroxyacid, which will easily increase the related substances of flumazenil and affect the efficacy and safety.
[0010] In the above-mentioned synthetic pathway e of flumazenil, midazolam is constructed by the Wohl–Ziegler reaction. This step often uses highly toxic non-polar solvents such as benzene and carbon tetrachloride, which are harmful to experimenters, the environment, and the quality of the final product. It is easy to produce poison; and the path is cumbersome, the reaction conditions are harsh, and the economic benefit is low, which is not conducive to large-scale production of enterprises

Method used

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  • Preparation method of flumazenil
  • Preparation method of flumazenil
  • Preparation method of flumazenil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] The preparation of embodiment 1 flumazenil

[0088] (1) Preparation of N-(5-fluoro-2-nitrobenzoyl)-N-methylglycine methyl ester

[0089]

[0090] Weigh 5-fluoro-2-nitrobenzoic acid (1.0g, 5.4mmol, CAS No.320-98-9; Anaiji chemical), 1-ethyl-(3-dimethylaminopropyl) carbon Imide hydrochloride (1.2g, 6.5mmol; EDCI, CAS No.: 25952-53-8, Anaiji Chemical), 1-hydroxybenzotriazole (0.87g, 6.5mmol; CAS No: 2592 -95-2, Anaiji Chemicals) was placed in a reaction bottle (100mL), added dichloromethane (20mL) and stirred to dissolve, and activated at room temperature for 30min; separately weighed sarcosine methyl ester hydrochloride (0.75g, 5.4mmol , CAS No.13515-93-0, Anaiji Chemical), triethylamine (1.0g, 10.8mmol, Sinopharm Group) were dissolved in dichloromethane (10mL), added to the reaction flask in sequence, and reacted at room temperature for 12h. Sampling by TLC to detect the reaction, the raw material point completely disappeared, and the reaction was terminated. Quenc...

Embodiment 2

[0104] (1) Same as Example 1, except that the base used is replaced by 4-dimethylaminopyridine (DMAP), and the solvent is replaced by N,N-dimethylformamide (DMF); wherein, 5-fluoro-2 - Nitrobenzoic acid: sarcosine methyl ester hydrochloride: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI): 4-dimethylaminopyridine (4 -DMAP) molar ratio is 1:1:1:2, 5-fluoro-2-nitrobenzoic acid:N,N-dimethylformamide (DMF) is 1:20g / mL, reaction temperature is 35~ 40°C, the time is 24h; the yield of the obtained product is 80%.

[0105] (2) Same as Example 1, the difference is: the solvent is replaced by methanol; wherein, the quality of Raney nickel is the quality of N-(5-fluoro-2-nitrobenzoyl)-N-methylglycine methyl ester 5%, N-(5-fluoro-2-nitrobenzoyl)-N-methylglycine methyl ester: methanol is 1:20g / mL; the product yield is 75%;

[0106] (3) 7-fluoro-3,4-dihydro-4-methyl-1H-[1,4]benzodiazepine-2,5-dione (3.48g, 16.7mmol), N,N - Dimethylformamide (7.0mL), phosphorus oxychlori...

Embodiment 3

[0110] (1) Same as Example 1, except that the base used is replaced by 4-dimethylaminopyridine (4-DMAP); wherein, 5-fluoro-2-nitrobenzoic acid: methyl sarcosine hydrochloride: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI): 4-DMAP in a molar ratio of 1:1:1:2; 5-fluoro-2-nitro Benzoic acid: dichloromethane ratio is 1:20g / mL, reaction temperature is 37±2°C, time is 24h; the yield of the obtained product is 85%.

[0111] (2) with embodiment 1, difference is: the quality of Raney nickel is 15% of N-(5-fluoro-2-nitrobenzoyl)-N-methylglycine methyl ester quality; Embodiment 1 Methanol / purified water (v:v=1:3) in methanol / purified water (v:v=1:1) is replaced by methanol / purified water (v:v=1:1); Change " 120 ℃ of reaction 8h " in embodiment 1 to " 90 ℃ of reaction 8h "; The resulting product yield is 83%.

[0112] (3) With embodiment 2, product yield is 90%.

[0113] (4) With embodiment 2, the product yield obtained is 37%.

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Abstract

The invention discloses a preparation method of flumazenil, and belongs to the field of medicine synthesis. The method comprises the following steps: by taking 5-fluoro-2-nitrobenzoic acid as a raw material, carrying out condensation on 5-fluoro-2-nitrobenzoic acid and sarcosine ester, and then carrying out ring closing while reducing, so as to obtain 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone; and finally, carrying out halogenation and cycloaddition reaction to obtain flumazenil. According to the novel synthesis method of the flumazenil key intermediate 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone, provided by the invention, a green synthesis process is adopted, an intramolecular cyclization reaction is performed while a nitro group is reduced, and compared with a known flumazenil synthesis method, a strong oxidant, a highly toxic reagent (such as ethyl chloroformate) and the like are not needed, and the yield is higher.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of flumazenil. Background technique [0002] Flumazenil (Flumazenil, FMZ) is a specific blocker of benzodiazepines (BZDs), and it is often used clinically for detoxification, awakening and diagnosis of BZDs. In addition, studies have shown that FMZ has a certain therapeutic effect on alcoholism and Alzheimer's disease (Alzheimer's disease, AD). [0003] The synthetic method of flumazenil mainly has the following five ways of a, b, c, d, e: [0004] The synthetic route a of flumazenil (see figure 1 ): Starting from 2-amino-5-fluorobenzoic acid, phosgene or chloroformic acid esters, 6-fluoroisatoic anhydride is obtained through condensation and ring closure, and then 7-fluoro-3.4-di Hydrogen-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (hereinafter referred to as 7-fluorodiketone), chlorinated by phosphorus oxychloride, Ethyl acetate is condensed to give fluma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02A50/30
Inventor 何新华张学敏周涛李爱玲
Owner NANHU LAB
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