A kind of preparation method of indiplon

An indiplon and alkaline technology, applied in the field of preparing indiplon, can solve the problems of expensive reagents, pollution, unsafe environment and the like, and achieve the effects of no environmental pollution, good technical performance and simple process operation

Active Publication Date: 2016-04-13
LINHAI LIMIN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In a word, above-mentioned several reaction routes all can synthesize medicine indiplon, but, all there are some deficient places in synthetic route and synthetic technology, as reaction time is long, reaction condition is harsh, reagent is expensive, highly toxic, unsafe and Environmental pollution, etc.

Method used

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  • A kind of preparation method of indiplon
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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] In a 1000 ml three-necked flask, 6.3 g (0.05 mmol) of 2-acetylthiophene, three-( N,N -Dimethylethyl) benzyl ammonium chloride 55g (0.15mmol), dimethylformamide dimethyl acetal 22g (0.15mmol), after stirring and reacting at 100°C for 10 hours, add hydroxylamine 1.7g ( 0.05mmol), stirred and reacted at 100°C for 10 hours, added 6.8g (0.05mmol) of guanidine aminonitrate and appropriate amount of water, stirred and reacted at 80°C for 1 hour, added N -[3-[3-(Dimethylamino)-1-oxyl-2-propenyl]-phenyl]- N -Methylacetamide 12.3g (0.05mmol), stirred at 100°C for 5 hours, cooled to 20°C, added 100ml of dichloromethane for extraction, dried over anhydrous magnesium sulfate, filtered, distilled off the dichloromethane to obtain an oil , recrystallized with methanol to obtain 10.7 g of yellow needle-like solid product, yield, 57%. m.p.174-176°C. MS( m / e ):376.

[0032] 1 HNMR (CD 3 Cl) δ: 2.01 ( s ,3H),3.35( s ,3H),7.17( d , J =4.2z,1H),7.21( t ,

[0033] 1H), 7.27(...

Embodiment 2

[0035] In a 1000 ml three-necked flask, 6.3 g (0.05 mmol) of 2-acetylthiophene, three-( N,N -Dimethylbutyl) benzyl ammonium chloride 202g (0.5mmol), dimethylformamide dimethyl acetal 22g (0.15mmol), after stirring and reacting at 150°C for 1 hour, add hydroxylamine 1.7g ( 0.05mmol), stirred and reacted at 150°C for 5 hours, added 6.8g (0.05mmol) of guanidine aminonitrate and appropriate amount of water, stirred and reacted at 150°C for 1 hour, added N -[3-[3-(Dimethylamino)-1-oxyl-2-propenyl]-phenyl]- N -Methylacetamide 12.3g (0.05mmol), stirred at 100°C for 5 hours, cooled to 10°C, added 100ml of dichloromethane for extraction, dried over anhydrous magnesium sulfate, filtered, distilled off the dichloromethane to obtain an oil , recrystallized with methanol to obtain 11 g of yellow needle-like solid product, yield, 58%.

Embodiment 3

[0037] In a 1000 ml three-necked flask, 6.3 g (0.05 mmol) of 2-acetylthiophene, three-( N,N -Dimethylethyl) benzyl ammonium chloride 110g (0.03mmol), dimethylformamide dimethyl acetal 37g (0.25mmol), after stirring and reacting at 100°C for 10 hours, add hydroxylamine 1.7g ( 0.05mmol), stirred and reacted at 100°C for 10 hours, added 6.8g (0.05mmol) of guanidine aminonitrate and appropriate amount of water, stirred and reacted at 80°C for 5 hours, addedN -[3-[3-(Dimethylamino)-1-oxyl-2-propenyl]-phenyl]- N -Methylacetamide 12.3g (0.05mmol), stirred at 100°C for 5 hours, cooled to 30°C, added 100ml of dichloromethane for extraction, dried over anhydrous magnesium sulfate, filtered, distilled off the dichloromethane to obtain an oil , recrystallized with methanol to obtain 10.4 g of yellow needle-like solid product, yield, 56%.

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Abstract

The invention discloses a preparation method of indiplon, which is characterized in that the preparation method uses 2-acetylthiophene as a starting material, and undergoes a DMFDMA condensation reaction under the action of a basic quaternary ammonium salt catalyst represented by formula (II). , and then successively react with hydroxylamine and aminoguanidine nitrate for ring closure reaction, and finally add N-[3-[3-(dimethylamino)-1-oxyl-2-propenyl]-phenyl]-N-methyl Acetamide reaction to obtain the target compound shown in formula (I); (I),? (II); wherein, in formula (II), R is a C1-C10 N,N-dimethyl-substituted alkyl group. Compared with the prior art, the present invention uses an alkaline quaternary ammonium salt catalyst in the reaction process to conduct series reactions of multiple components, and has the advantages of simple process operation, good technical performance, and no pollution to the environment.

Description

technical field [0001] The invention relates to a method for preparing indiplon, in particular to a method for preparing indiplon by using 2-acetylthiophene as a starting material. Background technique [0002] Indiplon is a drug used to treat insomnia. The chemical name is N-methyl-N-[3-[3-(2-thiopheneacetyl)-pyrazole-[1,5-α-pyrimidin-7-yl]phenyl]acetamide. In 1998, NeurocrineBtiosciences and Pfizer obtained the license of the drug from DOV Pharmaceuticals in the United States. In May 2005, the two companies jointly submitted the marketing application of Indiplon to the FDA (US Food and Drug Administration). In July 2005, the FDA accepted Indiplon's new drug application. At present, there is no domestic manufacturer producing it. [0003] Indiplon is a third-generation non-BDz drug (BDz: benzodiazepines). The survey shows that the consumption of the third-generation hypnotics and non-BDz drugs is growing steadily, and domestic imports of such drugs are mainly Mainly, t...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor何建明刘乘风裴文何甫长
OwnerLINHAI LIMIN CHEM