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Preparation method of N,N-diethyl-2-hydroxyl-2-phenylacetamide

A technology of ethyl acetate and purification method, used in the field of medicinal chemistry, can solve the problems of large purification loss, high cost, and unsuitable for industrial production.

Inactive Publication Date: 2019-04-26
SHANGHAI TIANCI INT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] As the compound of formula (I) as its key intermediate, the existing literature reports are all small-scale synthesis methods in the laboratory, and the purification methods are limited to column chromatography and distillation purification, because N,N-diethyl-2-hydroxyl-2 - Phenylacetamide has poor thermal stability, the above method has a large purification loss and high cost, and is not suitable for industrial production, but there are still few reports on suitable industrial scale synthesis methods

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  • Preparation method of N,N-diethyl-2-hydroxyl-2-phenylacetamide
  • Preparation method of N,N-diethyl-2-hydroxyl-2-phenylacetamide

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preparation example Construction

[0065] The preparation method of formula (I) compound

[0066] The invention provides a preparation method of a compound of formula (I),

[0067]

[0068] The method comprises the steps of:

[0069] (1) In the first solvent, in the presence of a condensing agent, a condensation reaction occurs between the compound of formula (II) and the compound of formula (III) to obtain the compound of formula (IV),

[0070] and

[0071] (2) In the second solvent, a substitution reaction occurs between the compound of formula (IV) and the compound of formula (V) to obtain the compound of formula (I),

[0072]

[0073] In another preferred embodiment, the first solvent is selected from the group consisting of ethyl acetate, dichloromethane, tetrahydrofuran, and combinations thereof.

[0074] In another preferred embodiment, the condensing agent is selected from: dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and combinations thereof.

[0075]...

Embodiment 1

[0106] Add 50g (0.33mol) mandelic acid to 2L reactor, 1L ethyl acetate, 40g (0.35mol) N-hydroxysuccinimide, drop the ethyl acetate solution of dicyclohexylcarbodiimide (DCC) ( DCC130g (0.66mol), ethyl acetate 500ml), temperature control 20-25°C, dripping is completed, stirred for 8h (insulated at 20-25°C), filtered, the filtrate was added diethylamine 34ml (0.33mol), and the reaction was stirred for 16h (keep warm at 20-25°C), add 1L of water, stir for 5 minutes, let stand to separate the liquid, the organic phase is N,N-diethyl-2-hydroxy-2-phenylacetamide crude ethyl acetate solution.

[0107] Add the crude N,N-diethyl-2-hydroxy-2-phenylacetamide ethyl acetate solution from the previous step to a 2L reactor, add 73g (0.65mol) of anhydrous calcium chloride, 72g of water, keep warm at 40°C, and stir 6h, filter, add 500ml of toluene and 500ml of water to the obtained solid, stir for 30min, let stand to separate the liquid (keep warm at 20-25°C), evaporate the organic phase under...

Embodiment 2

[0109] Add 50g (0.33mol) of mandelic acid, 500ml of ethyl acetate, 57.5g (0.5mol) of N-hydroxysuccinimide to a 2L reactor, and dropwise add a solution of DCC in tetrahydrofuran (DCC65g (0.33mol), THF250ml). Warm at 20-25°C, after dropping, stir for 10 hours (keep warm at 20-25°C), filter, add 34ml (0.33mol) of diethylamine to the filtrate, stir and react for 16h after adding (keep warm at 20-25°C), add 500ml of water, stir After standing still for 5 minutes, the organic phase was N,N-diethyl-2-hydroxy-2-phenylacetamide crude ethyl acetate solution.

[0110] Add the N,N-diethyl-2-hydroxy-2-phenylacetamide crude ethyl acetate solution in the previous step to the 2L reactor, add 42g (0.38mol) of calcium chloride dihydrate, 24g of water, keep warm at 40°C, and stir 6h, filter, add 500ml of dichloromethane and 500ml of water to the obtained solid, stir for 30min, stand still and separate the liquid, evaporate the organic phase under reduced pressure to remove the solvent, and the l...

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Abstract

The invention provides a synthesis method of N,N-diethyl-2-hydroxyl-2-phenylacetamide. The N,N-diethyl-2-hydroxyl-2-phenylacetamide is obtained by condensing mandelic acid, serving as a raw material,with N-hydroxysuccinimide, and then performing substitution reaction with diethylamine. The method has the advantages of simple operation, mild conditions, convenient post-treatment and high yield, and is suitable for industrialized mass production.

Description

technical field [0001] The invention is in the field of medicinal chemistry, and specifically relates to a preparation method of N,N-diethyl-2-hydroxyl-2-phenylacetamide. Background technique [0002] N,N-diethyl-2-hydroxy-2-phenylacetamide has the structure of formula (I): [0003] [0004] The compound of formula (I) is a key intermediate for synthesizing a compound of formula (A) which is an NPY Y2 receptor inhibitor (WO2009006185A1). [0005] [0006] Formula (A), Y2 receptor antagonist can be used for the treatment of depression and anxiety disorder, and it can improve memory and performance score (Flood, people Brain Res.1987,421,280) in the animal learning model, can be used as treatment Alzheimer Cognitive enhancers in neurodegenerative diseases such as Alzheimer's disease (AD). [0007] As the compound of formula (I) as its key intermediate, the existing literature reports are all small-scale synthesis methods in the laboratory, and the purification methods ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/34C07C231/02C07C231/24C07D207/46
CPCC07C231/02C07C231/24C07D207/46C07C235/34
Inventor 李勇刚王卓黄晓笠殷保胜沙飞
Owner SHANGHAI TIANCI INT PHARMA