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Simple and convenient preparation method of fluorine-containing alkyl-1,5-benzodiazepin-2-one

A benzodiazepine and fluorine-containing alkyl technology, which is applied in the field of preparation of fluorine-containing alkyl-1,5-benzodiazepin-2-one, can solve the problem of expensive argon gas, relatively high environmental requirements, and production problems. Low yield and other problems, to achieve the effect of mild reaction conditions, high product yield, convenient post-treatment

Inactive Publication Date: 2016-06-22
SHANGHAI UNIV
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Third, the method provided has limited exploration of the universality of substituted o-phenylenediamines
[0023] First of all, the method provided is reflux in an argon atmosphere, the reaction has relatively high environmental requirements, and argon is expensive
[0024] Secondly, the fluorine-containing alkyl-1,5-benzodiazepin-2-one compound prepared by the method provided has a low yield, generally around 20%, and has no practical production application value
[0025] Third, the fluorine-containing alkyl-1,5-benzodiazepin-2-one compound prepared by the method provided has low universality
The substrates of substituted o-phenylenediamines are not very practical

Method used

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  • Simple and convenient preparation method of fluorine-containing alkyl-1,5-benzodiazepin-2-one
  • Simple and convenient preparation method of fluorine-containing alkyl-1,5-benzodiazepin-2-one
  • Simple and convenient preparation method of fluorine-containing alkyl-1,5-benzodiazepin-2-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Add ethyl trifluoroacetoacetate (184.0mg, 1.0mmol), o-phenylenediamine (108.1mg, 1.0mmol) and 10mL EtOH as solvent in a 25ml round bottom flask, add L-proline (17.3mg, 0.15mmol) , 78 ° C reflux stirring for 4 hours. TLC spot plate tracking, after the completion of the reaction, the solvent was rotatably evaporated, and the residue was separated by column chromatography, using petroleum ether: ethyl acetate = 4:1 (v / v) as eluent, and purified by column chromatography. Product compound (193.8 mg, 85%).

[0045] The structure of this compound is:

[0046] ,

[0047] Molecular formula: C 10 h 7 f 3 N 2 o

[0048] Chinese name: 4-trifluoromethyl-1H-benzo[b][1,4]diazepin-2(3H)one

[0049] English name: 4-(Trifluoromethyl)-1H-benzo[b][1,4]diazepin-2(3H)-one

[0050] Molecular weight: 228.05

[0051] Melting point: 183.9-185.8 oC

[0052] Appearance: white powder

[0053] Proton NMR spectrum: 1 HNMR (500MHz, CDCl 3 ):δ3.35(s,2H,CH 2 ),7.17(dd,J 1 =1.0Hz,J 2 ...

Embodiment 2

[0057] Add ethyl trifluoroacetoacetate (184.0mg, 1.0mmol), o-dimethylphenylenediamine (136.1mg, 1.0mmol) and 10mL EtOH as solvent in a 25ml round bottom flask, add L-proline (17.3mg, 0.15mmol), stirred at reflux at 78°C for 6 hours. TLC spot plate tracking, after the completion of the reaction, the solvent was rotatably evaporated, and the residue was separated by column chromatography, using petroleum ether: ethyl acetate = 6:1 (v / v) as eluent, and purified by column chromatography. Product compound (225.3 mg, 88%).

[0058] The structure of this compound is:

[0059]

[0060] Molecular formula: C 12 h 11 f 3 N 2 o

[0061] Chinese name: 7,8-dimethyl-4-trifluoromethyl-1H-benzo[b][1,4]diazepin-2(3H)one

[0062] English name: 7,8-Dimethyl-4-(trifluoromethyl)-1H-benzo[b][1,4]diazepin-2(3H)-one

[0063] Molecular weight: 256.08

[0064] Melting point: 200.1-201.5 o C

[0065] Appearance: white powder

[0066] Proton NMR spectrum: 1 HNMR (500MHz, acetone-d 6 ):δ2....

Embodiment 3

[0070] Add ethyl trifluoroacetoacetate (184.0mg, 1.0mmol), o-dichlorophenylenediamine (176.0mg, 1.0mmol) and 10mL EtOH as solvent in a 25ml round bottom flask, add L-proline (23.0mg, 0.20 mmol), stirred under reflux at 78°C for 8 hours. TLC spot plate tracking, after the completion of the reaction, the solvent was rotatably evaporated, and the residue was separated by column chromatography, using petroleum ether: ethyl acetate = 4:1 (v / v) as eluent, and purified by column chromatography. Product compound (236.8mg, 80%).

[0071] The structure of this compound is:

[0072]

[0073] Molecular formula: C 10 h 5 Cl 2 f 3 N 2 o

[0074] Chinese name: 7,8-dichloro-4-trifluoromethyl-1H-benzo[b][1,4]azepin-2(3H)one

[0075] English name: 7,8-Dichloro-4-(trifluoromethyl)-1H-benzo[b][1,4]diazepin-2(3H)-one

[0076] Melting point: 203.3-204.7 o C

[0077] Molecular weight: 295.97

[0078] Appearance: white powder

[0079] Proton NMR spectrum: 1 HNMR (500MHz, CDCl 3 ):δ3...

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Abstract

The invention relates to a preparation method of fluorine-containing alkyl-1,5-benzodiazepin-2-one. The method comprises the following steps of dissolving acyl fluoroacetate and substituted o-phenylenediamine in an organic solvent according to a molar ratio of (1.0 to 1.5): (1.0 to 1.2), adding a catalytic amount of L-proline as a catalyst into an obtained first mixture, refluxing, agitating and reacting until the reaction is completed, and then removing the solvent, afterwards, separating an obtained substance through column chromatography, so as to obtain a fluorine-containing alkyl-1,5- benzodiazepin-2-one compound. The preparation method provided by the invention has the advantages that the method is environmentally-friendly. Moreover, raw materials are obtained easily; an organic small molecule is used for catalysis; a reaction condition is mild; the universality is strong; the post treatment is convenient; further, the yield of a product is higher.

Description

technical field [0001] The invention relates to a preparation method of fluorine-containing alkyl-1,5-benzodiazepin-2-one. Background technique [0002] 1,5-Benzodiazepine compounds have strong pharmaceutical and biological activities. 1,5-Benzodiazepines are used as anti-anxiety, anti-convulsant, anti-depressant, anti-spasmodic and sedative-hypnotics, etc., and they can also be produced on an industrial scale as anti-inflammatory drugs. [0003] L-proline (L-Proline abbreviated L-Pro), also known as L-pyrrolidine-2-carboxylic acid, hydrogenated pyrrole carboxylic acid, is a pyrrolidine-containing imidic acid. L-proline is one of the important amino acids for the synthesis of human protein, an important raw material for amino acid infusion, and an important intermediate for the synthesis of first-line antihypertensive drugs such as captopril and enalapril, and has been widely used in food and medicine. pharmaceutical industry. L-proline is a kind of organic chiral small m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/12
CPCC07D243/12
Inventor 宋力平石玮刘晓庆王阳张敏
Owner SHANGHAI UNIV
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