Preparation method of indiplon

An indiplon and alkaline technology, which is applied in the field of preparing indiplon, can solve problems such as unsafe environment, expensive reagents, pollution, etc., and achieve the effects of simple process operation, no pollution to the environment, and good technical performance

Active Publication Date: 2014-09-03
LINHAI LIMIN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] 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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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] In a 1000 ml three-necked flask, 6.3 g (0.05 mmol) of 2-acetylthiophene and 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.

[0033] 1 H NMR (CD 3 Cl) δ: 2.01 ( s , 3H), 3. 35 ( s , 3H), 7. 17( d , J = 4. 2z, 1H), 7.21( t ,

...

Embodiment 2

[0036] 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

[0038] In a 1000 ml three-necked flask, 6.3 g (0.05 mmol) of 2-acetylthiophene and 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, 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 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. The preparation method of indiplon is characterized in that 2-acetyl thiophene is taken as a starting material, a DMFDMA condensation reaction is carried out under the action of an alkaline quaternary ammonium salt catalyst shown in a formula (II), a cyclization reaction is sequentially respectively carried out on the alkaline quaternary ammonium salt catalyst as well as hydroxylamine and aminoguanidine nitrate, and finally N-[3-[3-(dimethylamino)-1-oxyl-2-propenyl]-pheyl]-N-methyl acetamide is added for carrying out reaction, so that the target compound shown in a formula (I) is obtained, and the formula (I) and the formula (II) are described in the specification, wherein R is CC1-C10 N,N-dimethyl substituted alkyl. Compared with the prior art, the alkaline quaternary ammonium salt catalyst is used in a reaction process, and series reaction is carried out on multiple components, so that the preparation method of indiplon has the advantages of simple technological operation, good technical performance and no environment pollution.

Description

[0001] technical field [0002] 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 [0003] 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, Neurocrine Btiosciences and Pfizer obtained the license rights 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. [0004] 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 ...

Claims

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Application Information

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