Method for enzymatic synthesis of mono-4-nitrobenzyl malonate

A technology of nitrobenzyl alcohol malonate and p-nitrobenzyl alcohol, which is applied in the field of enzyme-catalyzed synthesis of p-nitrobenzyl alcohol malonate, can solve the problems of low yield, large reaction energy consumption, High raw material costs and other issues, to achieve the effect of high product purity and yield, simple post-processing, and easy operation

Inactive Publication Date: 2014-01-29
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] p-nitrobenzyl alcohol malonate can be prepared from malonic acid and p-nitrobenzyl alcohol through esterification, alkali-acid adjustment and refining (see US5087734); it can also be prepared from malonate bis(4-nitrobenzyl alcohol phenylmethyl) esters and malonic acid are prepared by reacting in the presence of a catalyst (referring to US5516934); however, the methods disclosed in these documents have high raw material costs, large reaction energy consumption, and low yields (prone to generate by-product propane Dibenzyl diacid), and product purity and post-processing methods still need to be improved

Method used

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  • Method for enzymatic synthesis of mono-4-nitrobenzyl malonate

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Synthesis of p-nitrobenzyl alcohol malonate:

[0024] Add 1.53g (0.01mol) of p-nitrobenzyl alcohol, 2.08g (0.02mol) of malonic acid, 40.5ml (0.5mol) of tetrahydrofuran into a 150ml Erlenmeyer flask. Novozymes) 0.1g (0.001mol), add anhydrous CaCl210g (0.09mol), react at 45°C for 48 hours, filter to remove lipase; the reaction liquid is distilled under reduced pressure to remove the solvent, and the obtained residue is added to toluene 40ml and 20% Sodium carbonate solution 100ml, stirred, allowed to stand for stratification, and the separated aqueous phase was acidified with 20% hydrochloric acid until solids were precipitated, filtered under reduced pressure, and washed. The solid product was obtained by drying, and the white product p-nitrobenzyl malonate was obtained, weighing 1.68 g, and the yield was 70.2%.

Embodiment 2

[0026] Synthesis of p-nitrobenzyl alcohol malonate:

[0027] Add 1.53g (0.01mol) of p-nitrobenzyl alcohol, 5.20g (0.05mol) of malonic acid, 10ml (0.1mol) of xylene and acetone (6.3ml of xylene, 3.7ml of acetone) into a 150ml Erlenmeyer flask, and heat in a water bath to 40°C, equilibrate for 20 minutes, add Novozym435 (Novozym, Denmark) 0.8g (0.008mol), add anhydrous MgSO430g, react at 40°C for 24 hours, filter to remove lipase; the reaction solution is distilled off under reduced pressure to obtain Add 40ml of benzene and 80ml of 20% sodium bicarbonate solution to the residue, stir, let stand to separate layers, and acidify the separated aqueous phase with 20% hydrochloric acid until solids are precipitated, filter under reduced pressure, and wash. The solid product was obtained by drying, and the white product p-nitrobenzyl malonate was obtained, weighing 1.73 g, and the yield was 72.5%.

Embodiment 3

[0029] Synthesis of p-nitrobenzyl alcohol malonate:

[0030] Add 1.53g (0.01mol) of p-nitrobenzyl alcohol, 1.25g (0.01mol) of sodium malonate, 27ml (0.24mol) of xylene and tetrahydrofuran (22.2ml of xylene, 4.8ml of tetrahydrofuran) into a 150ml Erlenmeyer flask , heated in a water bath to 30°C, equilibrated for 20 minutes, added Candida sp.Lipase (Beijing New Century Kaitai Biotechnology Co., Ltd.) 0.1g (0.01mol), reacted at 30°C for 10 hours, filtered to remove the lipase; the reaction solution was distilled off under reduced pressure Solvent, add 40ml of toluene and 100ml of 20% sodium carbonate solution to the obtained residue, stir, let stand to separate layers, and acidify the separated aqueous phase with 20% hydrochloric acid until solid precipitates, filter under reduced pressure, and wash. The solid product was obtained by drying, and the white product, p-nitrobenzyl malonate, weighed 2.04 g, and the yield was 85.5%.

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Abstract

The invention relates to a method for synthesizing mono-4-nitrobenzyl malonate. The method comprises the steps of adding para-nitrobenzyl alcohol, malonic acid or malonate and a reaction solvent to a reaction flask at a mol ratio of 1: (1-10): (10-50); heating in a water bath until being balanced; adding lipase and a water absorbent to the reaction flask at a mol ratio of (0.1-1): (0-100) with the para-nitrobenzyl alcohol; controlling temperature at 30-50 DEG C, reacting for 10-48 hours, filtering to remove the lipase to obtain a reaction solution, and carrying out reduced pressure distilling on the reaction solution to remove the solvent, to obtain reaction residue; adding a mixing solution of an organic solvent and a salt solution to the reaction residue, stirring and layering, acidifying an obtained water phase, carrying out suction filtering and drying to obtain the mono-4-nitrobenzyl malonate. The method is easily available in raw materials, few in reaction step, moderate in reaction condition, few in side product, and simple and convenient to operate; the method, because the adopted organic solvent can be recycled, is low in environmental impact, simple in post-treatment, relatively high in production purity and yield, and suitable for industrial production.

Description

Technical field: [0001] The invention relates to a method for preparing a p-nitrobenzyl alcohol malonate pharmaceutical intermediate, in particular to a method for enzymatically synthesizing p-nitrobenzyl malonate. Background technique: [0002] p-Nitrobenzyl alcohol malonate is a class of important biomedical intermediates and an important industrial raw material for the preparation of antibiotic drugs. [0003] The chemical name of p-nitrobenzyl malonate is: Mono-4-nitrobenzyl Malonate, the CAS number is: 77359-11-6, and the chemical structure is: [0004] [0005] p-nitrobenzyl alcohol malonate can be prepared from malonic acid and p-nitrobenzyl alcohol through esterification, alkali-acid adjustment and refining (see US5087734); it can also be prepared from malonate bis(4-nitrobenzyl alcohol phenylmethyl) esters and malonic acid are prepared by reacting in the presence of a catalyst (referring to US5516934); however, the methods disclosed in these documents have high ...

Claims

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Application Information

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IPC IPC(8): C12P7/62
Inventor 韩萍芳赵四方李亚郭杰
Owner NANJING UNIV OF TECH
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