Preparation method of amide compounds

An amide compound, organic amine technology, applied in the field of organic chemistry or pharmaceutical intermediates, can solve the problems of difficult separation of by-products, narrow substrate adaptability, incomplete reaction, etc. mild effects

Active Publication Date: 2018-09-21
SHANGHAI UNIV OF ENG SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The first method starts from the carboxylic acid, uses the activation group to convert the carboxylic acid into a corresponding higher activity ester, and then reacts with the amine to form an amide. The commonly used reagents are Ph 3 P / I 2 , HATU, etc., but this method generally takes a long time to react, the reaction is not complete or the by-products formed are not easy to separate, etc.
The second method is to start from aldehydes, catalyzed by transition metals, or carbene-catalyzed oxidative amination to form amides, but this method also has some limitations, such as substrate adaptability, long reaction time, etc.
[0006] It can be seen that because the direct oxidative amination method of aldehydes (method two) has the problem of narrow substrate adaptability, method one is still the most important method, but there are also certain defects in method one, and the reaction time is longer. The reaction is not complete or the formed by-products are not easy to separate, etc. Therefore, it is necessary to develop a route with short reaction time, simple operation, good substrate adaptability and high yield

Method used

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  • Preparation method of amide compounds

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Experimental program
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Effect test

Embodiment 1

[0029] A kind of preparation method of amides compound, reaction equation is as follows:

[0030]

[0031] Under nitrogen atmosphere, nitrogen heterocyclic carbene III (33.6mg, 0.15mmol) was dissolved in tetrahydrofuran (2.0mL), DBU (22.8mg, 0.15mmol) and benzoate I-a (121.61mg, 0.5mmol) were added under stirring , the reaction system dropped to zero, slowly added benzylamine II-a (64.3mg, 0.6mmol) dropwise, stirred at room temperature for 15min, after the reaction solution was concentrated, extracted with dichloromethane 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, The crude product was purified by column chromatography to obtain 98.2 mg of pure product (IV-a), with a yield of 93%. The NMR characterization data are as follows: 1 H-NMR (400M, CDCl 3 ):7.79-7.77(m,2H),7.5-7.46(m,1H),7.42-7.38(m,2H),7.34-7.25(m,5H),6.65(s,1H),4.61(d,J =8.0Hz, 1H).

Embodiment 2

[0033] A kind of preparation method of amides compound, reaction equation is as follows:

[0034]

[0035] Under nitrogen atmosphere, nitrogen heterocyclic carbene III (33.6mg, 0.15mmol) was dissolved in tetrahydrofuran (2.0mL), DBU (22.8mg, 0.15mmol), benzoate I-b (136.62mg, 0.5mmol) were added under stirring , the reaction system dropped to zero, slowly dropwise added benzylamine II-a (64.3mg, 0.6mmol), stirred at room temperature for 15min, after the reaction solution was concentrated, extracted with dichloromethane 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, The crude product was purified by column chromatography to obtain 112.2 mg of pure product (IV-b), with a yield of 93%. The NMR characterization data are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.75(d, J=9.6Hz, 2H), 7.35-7.26(m, 5H), 6.90(d, J=9.2Hz, 2H), 6.39(s, 1H), 4.62(d, J=5.6 Hz, 2H), 3.84(s, 3H).

Embodiment 3

[0037] A kind of preparation method of amides compound, reaction equation is as follows:

[0038]

[0039] Under nitrogen atmosphere, nitrogen heterocyclic carbene III (33.6mg, 0.15mmol) was dissolved in tetrahydrofuran (2.0mL), DBU (22.8mg, 0.15mmol), benzoate I-c (43.2mg, 0.5mmol) were added under stirring , the reaction system dropped to zero, slowly dropwise added benzylamine II-a (64.3mg, 0.6mmol), stirred at room temperature for 15min, after the reaction solution was concentrated, extracted with dichloromethane 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, The crude product was purified by column chromatography to obtain 120.4 mg of pure product (IV-c), with a yield of 94%. The NMR characterization data are as follows: 1 H NMR (400MHz, CDCl 3 ) 8.02 (d, J = 8.8Hz, 1H), 7.66-7.26 (m, 9H), 6.28 (bs, 1H), 4.60 (d, J = 6.4Hz, 2H).

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Abstract

The invention relates to a preparation method of amide compounds. The method comprises the followings steps: feeding n-heterocyclic carbine and alkali into a reactor filled with an organic solvent inan inert gas atmosphere, stirring, sequentially feeding organic acid ester and organic amine, performing extraction through an extraction agent after reaction is accomplished, and performing chromatographic purification on residual crude products through a silicagel column, so as to obtain the amide compounds. Compared with the prior art, the method has the advantages that the n-heterocyclic carbine is taken as a catalyst, ester and amine compound rapidly form the corresponding amide compounds in the presence of the organic solvent, the reaction condition is mild, amide preparation flow is simpler and more efficient, environmentally friendly, and non-irritant, and does not generate an anaphylactic substance, the total yield is high, and volume production is easy to realize.

Description

technical field [0001] The invention relates to the field of organic chemistry or pharmaceutical intermediates, in particular to a preparation method of amide compounds. Background technique [0002] Data show that about 25% of drug molecules contain amide bonds. Therefore, amide compounds are of great significance in many chemical fields such as organic synthesis, chemical biology and biochemistry. At present, the method for preparing amide compounds mainly contains the following two methods: [0003] (1) [0004] (2) [0005] The first method starts from the carboxylic acid, uses the activation group to convert the carboxylic acid into a corresponding higher activity ester, and then reacts with the amine to form an amide. The commonly used reagents are Ph 3 P / I 2 , HATU, etc., but this method generally takes a long time to react, the reaction is not complete or the by-products formed are not easy to separate. The second method is to start from aldehydes, catalyzed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/65C07C235/46C07C233/11C07C233/75B01J31/02
CPCB01J31/0284C07C231/02C07C233/65C07C235/46C07C233/11C07C233/75
Inventor 陈玲艳吴梅芳王威
Owner SHANGHAI UNIV OF ENG SCI
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