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Synthetic method of monoamino inhibitor intermediate monoethyl 2-acetylamino-2-benzylmalonate

A technology of benzyl monoethyl malonate and monoethyl malonate, which is applied in the field of synthesis of compound 2-acetylamino-2-benzyl monoethyl malonate, can solve the problems of poor economy, 2-acetyl Amino-2-benzylmalonate monoethyl ester has the problems of high production cost and expensive starting materials, and achieves the effects of low cost, strong operability and simple reaction

Active Publication Date: 2017-07-14
苏州汉德创宏生化科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The above-mentioned routes all use 2-acetylamino-2-benzyl ethyl malonate as a raw material to obtain the target product through selective deesterification. However, the above-mentioned route starting materials are expensive, resulting in 2-acetylamino-2-benzyl The production cost of monoethyl malonate is higher, and the economy is poor

Method used

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  • Synthetic method of monoamino inhibitor intermediate monoethyl 2-acetylamino-2-benzylmalonate
  • Synthetic method of monoamino inhibitor intermediate monoethyl 2-acetylamino-2-benzylmalonate
  • Synthetic method of monoamino inhibitor intermediate monoethyl 2-acetylamino-2-benzylmalonate

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Experimental program
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Effect test

Embodiment 1

[0028] Under ice-cooling, diethyl aminomalonate (17.5g, 0.1mol) and triethylamine (20g, 0.2mol), 250ml of dichloromethane, di-tert-butyl dicarbonate (26g, 0.12mol) were added to the three-neck In the bottle, it was gradually raised to room temperature and the reaction was stirred at this temperature, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, dichloromethane was added to the residue for extraction (200ml×2), and the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain diethyl 2-Boc-aminopropanediol as a colorless oil Acid 27g (yield 98%).

[0029] Under ice-cooling, diethyl 2-Boc-aminomalonic acid (27.5g, 0.1mol) and DMF (200ml) were added into a three-necked flask, and then sodium hydride (4.8g, 0.12mol) was added in batches under stirring, Then the mixed solution was raised to room temperature, benzyl bromide (19g, 0.11mol) was added, the react...

Embodiment 2

[0034] Under ice-cooling, add diethyl aminomalonate (17.5g, 0.1mol) and triethylamine (20g, 0.2mol), 250ml methanol, di-tert-butyl dicarbonate (26g, 0.12mol) into a three-necked flask , was gradually raised to room temperature and the reaction was stirred at this temperature, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, dichloromethane was added to the residue for extraction (200ml×2), and the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain diethyl 2-Boc-aminopropanediol as a colorless oil Acid 26.7g.

[0035] Under ice-cooling, diethyl 2-Boc-aminomalonic acid (27.5g, 0.1mol) and NMP (200ml) were added into a three-necked flask, and then sodium hydride (4.8g, 0.12mol) was added in batches under stirring, Then the mixed solution was raised to room temperature, benzyl bromide (19g, 0.11mol) was added, the reaction solution was stirred at room te...

Embodiment 3

[0040] Under ice bath, diethyl aminomalonate (17.5g, 0.1mol) and N-ethyldiisopropylamine (25.8g, 0.2mol), 200ml ethanol, di-tert-butyl dicarbonate (26g, 0.12mol) Add it into a three-necked flask, gradually rise to room temperature and stir the reaction at this temperature, and monitor the end of the reaction by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, dichloromethane was added to the residue for extraction (200ml×2), and the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain diethyl 2-Boc-aminopropanediol as a colorless oil Acid 26.5g.

[0041] Under ice-cooling, diethyl 2-Boc-aminomalonic acid (27.5g, 0.1mol) and methanol (200ml) were added into a three-necked flask, and then sodium methoxide (6.48g, 0.12mol) was added in batches under stirring, Then the mixed solution was raised to room temperature, added benzyl bromide (19g, 0.11mol), the reaction solution was stirred at r...

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Abstract

The invention discloses a synthetic method of a monoamino inhibitor intermediate monoethyl 2-acetylamino-2-benzylmalonate. The method comprises the following steps: 1, carrying out amino protection on a compound I diethyl aminomalonate and di-tert-butyl dicarbonate to obtain a compound II diethyl-2-Boc-aminomalonic acid; 2, reacting the compound II with benzyl bromide to obtain a compound III diethyl 2-(N-(tertbutyloxycarbonyl)amino)-2-benzylmalonate; 3, removing monoester from the compound III to obtain a compound IV monoethyl 2-(N-(tertbutyloxycarbonylamino)-2-benzyl-malonate; 4, carrying out amino deprotection on the compound IV to obtain a compound V monoethyl 2-amino-2-benzyl-malonate; and 5, carrying out an acetylation reaction on the compound V to prepare a compound VI monoethyl 2-(N-acetylamino)-2-benzyl-malonate. The method has the advantages of simple reactions, easily available raw materials, simple post-treatment, high yield, low cost, high operationality, and suitableness for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and relates to a preparation process of a pharmaceutical intermediate, in particular to a synthesis method of the compound 2-acetylamino-2-benzylmalonate monoethyl ester. Background technique [0002] 2-Acetylamino-2-benzylmalonate monoethyl ester is an important structural unit in the field of drug synthesis, widely exists in many drug structures, and can be further reacted with alcohol to prepare 2-acetyl-2-amino acid compounds , or synthesis of 2-aminoalcohol compounds, etc. At present, there are few synthetic methods for the compound 2-acetylamino-2-benzylmalonate monoethyl ester, such as the following method: Tetrahedron Letters, No. 3, pp. 191-194, 1976: CANADIAN JOURNAL OF CHEMISTRY, Volume 32, Pages 31-39: [0003] [0004] The above-mentioned routes all use 2-acetylamino-2-benzyl ethyl malonate as a raw material to obtain the target product through selective deesterifica...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/47
CPCY02P20/55C07C231/02C07C227/18C07C269/04C07C271/22C07C229/36C07C233/47
Inventor 茅仲平马东旭张磊
Owner 苏州汉德创宏生化科技有限公司
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