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Preparation method of R-2-acylamino-3-methyl methoxypropionate

A technology of methyl methoxypropionate and acylamino, which is applied in the field of preparation of lacosamide intermediates, achieving the effects of mild reaction conditions, high yield and simple post-treatment

Inactive Publication Date: 2018-06-08
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the process is simple and the yield is high, the amount of dimethyl sulfate is 4 times the equivalent of D-N-acetylserine, and an expensive TBAB phase transfer catalyst is used

Method used

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  • Preparation method of R-2-acylamino-3-methyl methoxypropionate
  • Preparation method of R-2-acylamino-3-methyl methoxypropionate
  • Preparation method of R-2-acylamino-3-methyl methoxypropionate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1) According to the amount ratio of N-acetylglycine: bis(trichloromethyl)carbonate: N,N-dimethylformamide is 1.0:0.32:1.0; in a 1L dry reaction bottle, add N - Acetylglycine 35.1g, N,N-dimethylformamide 21.9g, control the reaction temperature at 0-5°C; dissolve 28.5g of bis(trichloromethyl)carbonate in 285mL of n-hexane, add dropwise to the reaction bottle; after the dropwise addition, raise the temperature and react at 60°C for 12 hours. After the reaction, add the reaction solution into the ice-water mixture, adjust the pH to 8 with ammonia water, separate layers, take the organic phase, and evaporate to dryness under reduced pressure 27.9 g of white solid (E)-4-((dimethylamino)methylene)-2-methyloxazol-5(4H)-one was obtained, with a yield of 60%;

[0045] Step (2): In a 1L dry reaction flask, add the intermediate (E)-4-((dimethylamino)methylene)-2-methyloxazole-5( 4H)-ketone 23.1g and methanol 70mL, add 2N NaOH aqueous solution 75mL at room temperature; stir overni...

Embodiment 2

[0049] (1) According to the amount ratio of N-acetylglycine: bis(trichloromethyl)carbonate: N,N-dimethylformamide is 1.0:0.5:1.5 feeding; in a 1L dry reaction bottle, add N - Acetylglycine 35.1g, N,N-dimethylformamide 32.9g, control the reaction temperature at 0-5°C; dissolve 44.5g of bis(trichloromethyl)carbonate in 350mL of cyclohexane, add dropwise Reaction bottle; after the dropwise addition, raise the temperature and react at 20°C for 24 hours. After the reaction, add the reaction liquid to the ice-water mixture, adjust the pH to 8 with ammonia water, separate layers, take the organic phase, and evaporate under reduced pressure. Dry to obtain 24.6 g of (E)-4-((dimethylamino)methylene)-2-methyloxazol-5(4H)-one as a white solid, with a yield of 53%;

[0050] Step (2): In a 1L dry reaction flask, add the intermediate (E)-4-((dimethylamino)methylene)-2-methyloxazole-5( 4H)-ketone 23.1g and ethanol 140mL, add 2N NaOH aqueous solution 225mL at room temperature; stir overnight,...

Embodiment 3

[0054] (1) According to the amount ratio of N-acetylglycine: bis(trichloromethyl)carbonate N,N-diethylformamide is 1.0:0.7:3.0; in a 1L dry reaction bottle, add N- Acetylglycine 35.1g, N,N-diethylformamide 91.0g, control the reaction temperature at 0-5°C; dissolve 62.3g of bis(trichloromethyl)carbonate in 300mL of dichloromethane, add dropwise to the reaction bottle; after the dropwise addition, raise the temperature and react at 40°C for 16 hours. After the reaction, add the reaction solution into the ice-water mixture, adjust the pH to 8 with ammonia water, separate layers, take the organic phase, and evaporate to dryness under reduced pressure Obtained 44.6 g of white solid (E)-4-((diethylamino)methylene)-2-methyloxazol-5(4H)-one, yield 82%;

[0055] Step (2): In a 1L dry reaction flask, add the intermediate (E)-4-((diethylamino)methylene)-2-methyloxazole-5( 27.3g of 4H)-ketone and 270mL of acetonitrile, 225mL of 2N KOH aqueous solution was added at room temperature; stirr...

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Abstract

The invention discloses a preparation method of R-2-acylamino-3-methyl methoxypropionate shown in a formula (I). The preparation method is characterized by comprising the following steps: firstly, enabling N-acyl protected glycine, which is used as a raw material and shown in a formula (II), bis(trichloromethyl) carbonate (III) and N, N-disubstituted formamide shown (IV) to be subjected to a cyclization reaction so as to obtain an intermediate (V); then, carrying out alkali treatment, acid ring-opening and methyl etherification to obtain an intermediate (VII); finally, carrying out asymmetrichydrogenation reduction to generate a target product (I). The preparation method provided by the invention has the advantages that the raw materials are simple and easy to obtain, the cost is low, reaction conditions are mild, the yield is high, the aftertreatment is simple, three wastes are less, and the economic benefit is good, thus being an environment-friendly process suitable for industrialproduction. (The formulas (I), (II), (III), (IV), (V), (VI) and (VII) are shown in the description.).

Description

(1) Technical field [0001] The invention discloses a method for preparing a lacosamide intermediate, in particular to a method for methyl R-2-acylamino-3-methoxypropionate. (2) Background technology [0002] Lacosamide, chemical name R-(-)-2-acetamido-3-methoxy-N-benzylpropionamide, is the third-generation treatment of epilepsy and neuropathic pain developed by Belgium UCB Pharmaceutical Co., Ltd. The drug was approved by the European Commission and the US Food and Drug Administration (FDA) in September 2008 and October 2008, respectively. The drug has a unique dual mode of action, thereby stabilizing the hyperexcitatory nerve cell membrane and inhibiting the repeated discharge of neurons. It is different from other antiepileptic drugs currently used clinically. , has received extensive attention. [0003] [0004] R-2-acetylamino-3-methoxypropionic acid is a key intermediate in the synthesis of lacosamide, and its structure is shown below: [0005] [0006] Based o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C233/83C07C231/10C07C271/22C07C269/06C07C251/28C07C249/02C07D263/42
CPCC07B2200/07C07C231/10C07C249/02C07C269/06C07D263/42C07C251/28C07C233/47C07C233/83C07C271/22
Inventor 贾建洪叶孙斌冯东胡成坤李唐张久明
Owner ZHEJIANG UNIV OF TECH
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