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Preparation method of diethyl aminomalonate hydrochloride

A technology of diethyl aminomalonate and diethyl oximomalonate, which is applied in the field of drug synthesis, can solve the problems of expensive catalysts and easy deactivation, and achieve low cost, easy operation and good quality

Pending Publication Date: 2021-12-03
SUZHOU JINGYE MEDICINE & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] This method also has disadvantages such as expensive catalyst and easy deactivation.

Method used

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  • Preparation method of diethyl aminomalonate hydrochloride
  • Preparation method of diethyl aminomalonate hydrochloride
  • Preparation method of diethyl aminomalonate hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Add 80 grams of diethyl malonate, 400 milliliters of ethyl acetate and 90 grams of glacial acetic acid into a 1000 milliliter four-necked bottle, stir for 30 minutes, cool to 5 ° C, dropwise add sodium nitrite solution (69 grams of sodium nitrite dissolved in 81 grams of water) 150 grams, the temperature is controlled at 0-10°C during the dropwise addition, the dropwise addition time is 2 hours, stirred after the dropwise addition is completed, kept at 15-25°C for 20 hours, standing for stratification, and using 200ml of water for the lower layer Extract once with ethyl acetate, discard the water layer, wash the ethyl acetate layer with 200 ml of water, let stand to separate the layers, discard the washing water, evaporate the ethyl acetate layer under reduced pressure to obtain the oximino malonate di Ethyl ester 93 grams. The yield is 98.4%. The synthetic reaction formula of diethyl oximino malonate in embodiment 1 is as figure 1 shown.

[0049] The synthesis of di...

Embodiment 2

[0051] Put 240g of absolute ethanol into the hydrogenation kettle, add 60g of diethyl oximomalonate, 3.0g of AlNiFe three-way catalyst, close the hydrogenation kettle, replace the system with nitrogen, keep the hydrogen pressure at 1.0-2.0MPa, and the system temperature at 40 At ~50°C, the reaction was stirred for 6 hours. Cool, depressurize, and filter to remove catalyst. The filtrate was added into a 500 ml four-neck flask, stirred, and cooled. Add 50 g of 35% hydrogen chloride ethanol dropwise at 0-5°C, drop it in 1 hour, and stir for 1 hour. Ethanol was distilled off under reduced pressure, and 200 ml of acetone was added to the residue, stirred for 1 hour, and cooled to 5-10°C. Filter, wash the filter cake with acetone, and dry at 60°C to obtain 61 grams of the target product, diethyl aminomalonate hydrochloride. The yield is 91%. The content is 99.7%. The synthetic reaction formula of diethyl aminomalonate hydrochloride in embodiment 2 is as figure 2 shown.

Embodiment 3

[0053] Put 240g of absolute ethanol into the hydrogenation kettle, add 60g of diethyl oximomalonate, 3.0g of aluminum-nickel-molybdenum three-way catalyst, close the hydrogenation kettle, replace the system with nitrogen, keep the hydrogen pressure at 1.0-2.0MPa, and the system temperature at 40 At ~50°C, the reaction was stirred for 6 hours. Cool, depressurize, and filter to remove catalyst. The filtrate was added into a 500 ml four-neck flask, stirred, and cooled. Add 50 g of 35% hydrogen chloride ethanol dropwise at 0-5°C, drop it in 1 hour, and stir for 1 hour. Ethanol was distilled off under reduced pressure, and 200 ml of acetone was added to the residue, stirred for 1 hour, and cooled to 5-10°C. Filter, wash the filter cake with acetone, and dry at 60°C to obtain 59 grams of the target product, diethyl aminomalonate hydrochloride. Yield 88%. The content is 99.5%.

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Abstract

The invention discloses a preparation method of aminomalonic acid diethyl ester hydrochloride, which comprises the following steps: 1, carrying out nitrosation on malonic acid diethyl ester in acetic acid by using a nitrous acid aqueous solution to obtain oximido malonic acid diethyl ester; 2, carrying out catalytic hydrogenation reaction on the oximido diethyl malonate in an alcohol solvent by using a nickel-containing three-way catalyst to obtain aminodiethyl malonate; 3, filtering out the catalyst from the hydrogenated liquid, salifying the compound by using hydrogen chloride ethanol under cooling, desolventizing the solution, and crystallizing the liquid by using acetone to obtain the diethyl aminomalonate hydrochloride. The method has the characteristics of milder and safer reaction conditions, simplicity and convenience in operation, high yield, low cost, good quality and the like, and has a wide application prospect. In addition, according to the hydrogenation technology used in the method, waste residues, waste acid and the like generated by reduction of zinc powder are avoided, and the defects that a palladium-carbon catalyst is high in price and prone to poisoning and inactivation are overcome.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a preparation method of diethyl aminomalonate hydrochloride. Background technique [0002] Diethyl aminomalonate hydrochloride can be used as a pharmaceutical intermediate for the synthesis of pyrimidine heterocyclic compounds, as well as an intermediate for the synthesis of the influenza drug Favipiravir. [0003] Chinese name: diethyl aminomalonate hydrochloride [0004] English name: Diethyl aminomalonate hydrochloride [0005] Chinese alias: 2-aminomalonic acid diethyl ester hydrochloride; diethyl amino maleate; amino maleic acid diethyl ester. hydrochloride; [0006] Structural formula: [0007] [0008] Molecular formula: C7H14NO4.HCl [0009] Molecular weight: 211.64 [0010] Appearance: White or off-white crystalline powder, easily soluble in water. [0011] Melting point: 165°C-166°C [0012] Density: 1.129 g / cm3 [0013] Flash point: 52.3ºC [001...

Claims

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Application Information

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IPC IPC(8): C07C229/24C07C227/18
CPCC07C249/04C07C227/06C07C227/18C07C251/38C07C229/24
Inventor 沈建伟
Owner SUZHOU JINGYE MEDICINE & CHEM
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