Preparation method for 4-substituted acylamino cyclohexanone

A technology of amido and cyclohexanone, which is applied in the field of preparation of 4-substituted amido cyclohexanone, can solve the problems of cumbersome process operation, environmental pollution, high cost, etc., and achieve high yield, reasonable route and mild reaction conditions Effect

Inactive Publication Date: 2012-07-18
ZHEJIANG UNIV OF TECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention also overcomes the prior art CrO 3 The defects of high cost, low yield, cumbersome process operation and environmental pollution are more conducive to industrial production

Method used

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  • Preparation method for 4-substituted acylamino cyclohexanone
  • Preparation method for 4-substituted acylamino cyclohexanone
  • Preparation method for 4-substituted acylamino cyclohexanone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Preparation of 4-acetamidocyclohexanone

[0031] Under mechanical stirring in a cooling bath at -3°C, TEMPO (0.79 g, 5 mmol), sodium bromide (0.52 g, 5 mmol) were added to 60 ml of acetone, and 4-acetamidocyclohexanol (or the hydrogenated product of acetaminophen) was obtained. ) (15.7g, 100mmol), stir for half an hour, dropwise at a concentration of 10% sodium hypochlorite (170g, 230mmol) below 10 ° C, after the reaction, reclaim acetone, steam off 1 / 2 of the water, and extract 3 times with dichloromethane, 60ml each time, the organic layers were combined, washed with water, washed with saturated brine, dried with 4g of anhydrous sodium sulfate, and the solvent was recovered by distillation under reduced pressure to obtain 15.4g of crude product, which was recrystallized from ethyl acetate to obtain a white crystalline solid 11.8 g (melting point 135-136°C).

[0032] 1 H NMR (400MHz, CDCl 3 , δ, ppm): 5.51(s, 1H), 4.25(m, 1H), 2.55-2.34(m, 4H), 2.31-2.20...

Embodiment 2

[0033] Example 2: Preparation of 4-acetamidocyclohexanone

[0034]Under mechanical stirring in a cooling bath at -3°C, TEMPO (0.16 g, 1 mmol), sodium bromide (0.52 g, 5 mmol) were added to 60 ml of acetone, and 4-acetamidocyclohexanol (or the hydrogenation product of acetaminophen) was taken. ) (15.7g, 100mmol), stir for half an hour, dropwise at a concentration of 10% sodium hypochlorite (170g, 230mmol) below 10 ° C, after the reaction, reclaim acetone, steam off 1 / 2 of the water, and extract 3 times with dichloromethane, 60ml each time, the organic layers were combined, washed with water, washed with saturated brine, dried with 4g of anhydrous sodium sulfate, and the solvent was recovered by distillation under reduced pressure to obtain 9.6g of crude product, which was recrystallized from ethyl acetate to obtain a white crystalline solid 7.7g.

Embodiment 3

[0035] Example 3: Preparation of 4-acetamidocyclohexanone

[0036] Under mechanical stirring in a cooling bath at -3°C, TEMPO (0.79 g, 5 mmol), sodium bromide (0.52 g, 5 mmol) were added to 60 ml of acetone, and 4-acetamidocyclohexanol (or the hydrogenated product of acetaminophen) was obtained. ) (15.7g, 100mmol), stir for half an hour, dropwise at a concentration of 5% sodium hypochlorite (340g, 230mmol) below 10 ° C, after the reaction, reclaim acetone, steam off 1 / 2 of the water, extract 3 times with dichloromethane, 60ml each time, the organic layers were combined, washed with water, washed with saturated brine, dried with 4g of anhydrous sodium sulfate, and the solvent was recovered by distillation under reduced pressure to obtain 2.1g of an oily product, which could not be recrystallized.

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Abstract

The invention relates to a method for preparing 4- substituted acylamino cyclohexanone through oxidizeing 4- substituted acylamino cyclohexanol. The 4- substituted acylamino cyclohexanone prepared by the method can be used for preparing Pramipexole. The method comprises the following steps: adding 4- substituted acylamino cyclohexanol as is shown in formula I, catalyst 2, 2, 6, 6- tetramethyl piperidine - nitrogen - oxide, NaBr, into organic solvent, then dropwise adding sodium hypochlorite water solution for reaction until oxidation reaction is complete, and obtaining the 4- substituted acylamino cyclohexanone shown in formula II after separation and purification to reaction solution; and the method provided by the invention mainly has the following benefits: a novel chemical synthesis method for producing key intermediate of medicine Pramipexole is found, the route is enabled to be more reasonable, the reaction conditions are milder, the yield is higher, and the method is environment-friendly and suitable for large scale industrial production.

Description

(1) Technical field [0001] This invention relates to a method for preparing 4-substituted amidocyclohexanone by oxidation of 4-substituted amidocyclohexanol. The 4-substituted amidocyclohexanone obtained by the method can be used to prepare pramipexole. The synthesis process of 4-substituted amidocyclohexanone, an intermediate of pramipexole, a drug for treating Parkinson's disease, is improved. (2) Technical background [0002] With the aging of society, the drug pramipexole for the treatment of Parkinson's disease has great market prospects. 4-Substituted amidocyclohexanone is a key intermediate of the drug pramipexole. [0003] In the synthesis reaction of 4-substituted amidocyclohexanone, the amino reactivity of aminocyclohexanol is very high, and it must be protected before oxidation and bromocyclization. There are many protective groups for 4-aminocyclohexanol. For example, EP186087 uses phthaloyl protection, but the protective group is too large, which affects the r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C233/32C07C233/76C07C235/62
Inventor 李振华苏为科汪文婷林介邦张锦红王建
Owner ZHEJIANG UNIV OF TECH
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