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Preparation method and product of 4-halo-3-oxo-pentanoic acid (4-nitrophenyl) methyl ester

A technology of nitrobenzene and oxo, which is applied in the preparation of organic compounds, organic chemical methods, chemical instruments and methods, etc., can solve the problem of high preparation cost of intermediates, and achieve high molecular utilization, simple overall steps, and molecular economy. good effect

Active Publication Date: 2018-10-30
JIANGXI FUSHINE PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Aiming at the technical problem of high intermediate preparation cost in the prior art, the present invention provides a synthetic intermediate compound of antibiotic drugs with low preparation cost

Method used

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  • Preparation method and product of 4-halo-3-oxo-pentanoic acid (4-nitrophenyl) methyl ester
  • Preparation method and product of 4-halo-3-oxo-pentanoic acid (4-nitrophenyl) methyl ester
  • Preparation method and product of 4-halo-3-oxo-pentanoic acid (4-nitrophenyl) methyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Dissolve 108.5kg of 2-chloropropionic acid in 550L of dichloromethane, add 165kg of N,N'-carbonyldiimidazole, and react at a temperature of 18-20°C for 1 hour. After the reaction is complete, cool down to 0°C, add 100kg of magnesium chloride and 239kg of mono-p-nitrobenzyl malonate in sequence, react at 0°C for 15 minutes, then raise the temperature to reflux for 2 hours. After the reaction is over, add hydrochloric acid with a mass fraction of 10%, adjust the pH value to 3-4, let stand and separate layers, add 500L of mass fraction of potassium carbonate aqueous solution to the organic layer to wash, and then use a mass fraction of 10% to the organic layer. sodium chloride aqueous solution to neutrality. After dehydration with anhydrous magnesium sulfate, decolorization with activated carbon, and desolvation under reduced pressure, the feed solution was crystallized at 20-25°C for 1 hour by adding 500L of n-hexane, then centrifuged and dried at 40°C to obtain 250kg of ...

Embodiment 2

[0061] Dissolve 108.5kg of S-2-chloropropionic acid in 500L of chloroform, add 169kg of N,N'-carbonyldiimidazole, and react at a temperature of 0-5°C for 2 hours. After the reaction was complete, 100kg of magnesium fluoride and 240kg of mono-p-nitrobenzyl malonate were added successively, reacted at 0°C for 15min, and then heated to reflux for 5h. After the reaction is finished, add hydrochloric acid with a mass fraction of 5%, adjust the pH value to 3-4, let stand for stratification, add 600L mass fraction of 10% sodium bicarbonate aqueous solution to the organic layer for washing, and then use a mass fraction of 8 to the organic layer. % calcium chloride aqueous solution to neutrality. After the feed liquid is dehydrated with anhydrous sodium sulfate, decolorized with silica gel, and desolvated under normal pressure, add 700L n-heptane to crystallize at 20-25°C for 1 hour, then centrifuge and dry at 35°C to obtain 230kg(s)-4-chloro -3-oxo-valeric acid (4-nitrophenyl) methyl...

Embodiment 3

[0063] Dissolve 110kg of L-2-chloropropionic acid in 500L of dichloromethane, add 170kg of N,N'-carbonyldiimidazole, and react at a temperature of 15°C for 2 hours. After the reaction was complete, 100kg of magnesium fluoride and 240kg of mono-p-nitrobenzyl malonate were added successively, reacted at 20°C for 30min, and then heated to reflux for 3h. After the reaction was finished, add 10% hydrochloric acid by mass fraction, adjust the pH value to 3-4, let stand to separate layers, add 400L mass fraction of 1% sodium hydroxide aqueous solution to the organic layer, and wash the organic layer with a mass fraction of 15% % sodium chloride aqueous solution to neutrality. After dehydration with anhydrous magnesium sulfate, decolorization with silica gel, precipitation at normal pressure, add 550L of petroleum ether to crystallize at 20-25°C for 2 hours, then centrifuge and dry at 30°C to obtain 220kg(L)-4-chloro-3 -Oxo-valeric acid (4-nitrophenyl) methyl ester, the yield is 77%,...

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Abstract

The invention discloses a preparation method for 4-halo-3-oxo-pentanoic acid-(4-nitrobenzene)methyl ester and a product thereof. The method comprises the following steps: reacting a compound A with N,N'-carbonyldiimidazole in an organic solvent B, wherein the compound A is 2-halopropionic acid; carrying out cooling to -20 to 30 DEG C, adding magnesium halide and mono-p-nitrobenzyl malonate and carrying out a reaction; adding an aqueous hydrochloric acid solution, adjusting the pH value of the solution to 2 to 5, carrying out layering, and washing an organic phase until the organic phase is neutral; and carrying out dehydration, decoloring and desolventization, adding an organic solvent C and carrying out crystallization so as to obtain 4-halo-3-oxo-pentanoic acid-(4-nitrobenzene)methyl ester. According to the invention, 2-fluoropropionic acid and 2-chloropropionic acid with weak chemical activity are used as raw materials; when the raw materials are subjected to a reaction in N,N'-carbonyldiimidazole, a certain impurity is not produced, a conversion rate is as high as 97% or above, and quantitative conversion is basically realized. The preparation method provided by the invention is simple in steps and aftertreatment process, does not need column chromatography and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of intermediate preparation of antibiotic drugs, and in particular relates to a preparation method of 4-halo-3-oxo-pentanoic acid (4-nitrophenyl) methyl ester and a product thereof. Background technique [0002] Antibiotics used to be called antibiotics. In fact, they can not only kill bacteria but also have a good inhibitory and killing effect on mold, mycoplasma, chlamydia, spirochetes, rickettsia and other pathogenic microorganisms. Antibiotics are usually renamed as antibiotics . Antibiotics can be a substance produced during the growth and reproduction of certain microorganisms. The antibiotics used to treat diseases are not only directly extracted from this, but also completely or partially artificially synthesized. In layman's terms, antibiotics are drugs used to treat various non-viral infections. However, many side effects have been shown in clinical use. [0003] Antibiotics are a class of subst...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C201/12C07C205/39C07B53/00
CPCC07B53/00C07B2200/07C07C201/12C07C205/39
Inventor 杨栽根柴建华鄢俊万军
Owner JIANGXI FUSHINE PHARMA CO LTD
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