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Method for synthesizing 7-amino clonazepam compound

A technology of aminochlorine and compounds, applied in the direction of organic chemistry, etc., can solve the problems of high temperature, low yield, difficulty in synthesizing intermediates, etc.

Active Publication Date: 2021-07-06
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In addition, EP2687854A1 discloses a para-substituted aniline, which undergoes Friedel-Crafts acylation reaction to form an intermediate (I). If the para-substituent is replaced by a halogen atom in this method, the reaction can normally occur, but if When the para-position is substituted by nitro, the synthesis of intermediate (I) is difficult at first, and the temperature is as high as 200°C, and the subsequent ring closure into intermediate (IV) will be accompanied by the appearance of six-membered ring by-products, resulting in a high yield. lower

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  • Method for synthesizing 7-amino clonazepam compound
  • Method for synthesizing 7-amino clonazepam compound
  • Method for synthesizing 7-amino clonazepam compound

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Experimental program
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Embodiment 1

[0036] A method for synthesizing 7-aminoclonazepam compound, comprising the following steps:

[0037] (1) Synthetic Intermediate I:

[0038]

[0039] Weigh Pd(TFA) 2 , (276mg, 1.5mmol), L (276mg, 1.5mmol) in sealed tube, N 2 50 mL of 2-methyltetrahydrofuran was added under protection, and after stirring for 30 minutes, S1 (1.63 g, 10 mmol), S2 (3.12 g, 20 mmol), and water (25 mL) were added, and MsOH (9.6 g, 10 mL) was injected under an ice-water bath, Gabi, Blow N 2 Seal the tube and heat to 100°C for 36 hours. Cool to room temperature, add water 50mL, extract with ethyl acetate (50mL*3) and combine organic phase, saturated NaHCO 3 Wash the organic phase with solution, wash once with saturated NaCl solution, anhydrous NaSO 4 Drying, concentration under reduced pressure, eluting with petroleum ether / ethyl acetate=8:1~5:1 in column chromatography, the obtained synthetic intermediate I was 1.7 g of light yellow solid, and the yield was 95%;

[0040] (2) Synthesis of int...

Embodiment 2

[0057] (1) Synthetic Intermediate I:

[0058]

[0059] Weigh Pd(TFA) 2 , (276mg, 1.5mmol), L (276mg, 1.5mmol) in a sealed tube, THF 50mL, after stirring for 30 minutes, add S1 (1.63g, 10mmol), S2 (3.12g, 20mmol), water (25mL), MsOH (9.6 g, 10 mL) was added by injection under an ice-water bath. After the addition was complete, it was heated to 100° C. and reacted for 48 h. Cool to room temperature, add water 50mL, extract with ethyl acetate (50mL*3) and combine organic phase, saturated NaHCO 3 Wash the organic phase with solution, wash once with saturated NaCl solution, anhydrous NaSO 4 Drying, concentration under reduced pressure, column chromatography petroleum ether / ethyl acetate = 8:1 ~ 5:1 elution, the obtained synthetic intermediate I was 0.9 g of light yellow solid, yield 50.3%;

[0060] The method of synthesizing intermediate II, III, IV is identical with embodiment 1;

[0061]

[0062] Synthesis of target product V:

[0063] Add 20mL of ethanol and 20mL of H...

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Abstract

The invention discloses a method for synthesizing a 7-amino clonazepam compound, and belongs to the technical field of organic synthesis. The preparation method comprises the steps that 2-cyano-4-nitroaniline serves as an initial raw material, and a target compound is obtained through oxidative coupling, amidation, affinity substitution reaction, intramolecular Wittig reaction, reduction reaction and other processes. According to the invention, a brand new synthetic route is provided for 7-amino nitrazepam, the method has the advantages of short synthetic steps, safe operation and simple post-treatment, only conventional acid-base and solvent are used in the whole reaction process, the cost is low, and the yield is increased by more than 20%.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 7-aminoclonazepam compounds. Background technique [0002] Clonazepam belongs to benzodiazepines, which was approved by the US Food and Drug Administration (FDA) in 1975. Its effect is similar to that of diazepam (stable), but its anticonvulsant effect is 5 to 10 times stronger than that of diazepam. It has obvious and rapid effects on hypnosis, anti-anxiety, epilepsy and convulsions. As its metabolite, 7-aminoclonazepam is essential for its research. [0003] At present, there are few reports about the synthesis method of 7-aminoclonazepam. Documents Steiger.N., Sach.G., J.Med.Chem.1963, 6, 3, 261–265. reported that the product was directly nitrated and then reduced, but the problem of selectivity was involved, and the specific operation was more complicated. difficulty. [0004] [0005] In addition, EP2687854A1 discloses a para-substi...

Claims

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Application Information

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IPC IPC(8): C07D243/26
CPCC07D243/26
Inventor 袁伟成杨磊赵建强周鸣强王浩宇王振华游勇
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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