CN103360256A - Preparation method of 4-chloroacetoacetic acid ethyl ester - Google Patents
Preparation method of 4-chloroacetoacetic acid ethyl ester Download PDFInfo
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- CN103360256A CN103360256A CN2013103215706A CN201310321570A CN103360256A CN 103360256 A CN103360256 A CN 103360256A CN 2013103215706 A CN2013103215706 A CN 2013103215706A CN 201310321570 A CN201310321570 A CN 201310321570A CN 103360256 A CN103360256 A CN 103360256A
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Abstract
The invention discloses a preparation method of 4-chloroacetoacetic acid ethyl ester. The preparation method takes acety ketene as the original raw material, after chlorination reactions and esterification reactions, and 4-chloroacetoacetic acid ethyl ester is produced. The compound is a key intermediate of a new generation intelligence development drug (Oxiracetam). The preparation method of 4-chloroacetoacetic acid ethyl ester has the advantages of simple synthesis technology, low production cost, high general yield, little pollution and suitability for industry production.
Description
Technical field
The present invention relates to compounds process for production thereof, be specifically related to a kind of preparation method of 4-chloroacetyl acetacetic ester.
Technical background
4-chloroacetyl acetacetic ester outward appearance is colourless liquid, density is 1.218, English name 4-Chloroacetoacetic acid ethyl ester, CAS is 638-07-3, key intermediate for nootropics oxiracetam of new generation, oxiracetam is at first synthetic by Italian ISF company in 1974, goes on the market in Italy with Neuromet first in 1987, goes on the market in Portugal with Neupan in 1991.It is a kind of cholinergic nootropics of reticular formation of brain stem that acts on, by stimulating adenosine diphosphate (ADP) to improve the level of ATP in the brain to being converted of Triphosaden (ATP), accelerate the metabolism of large kephalin, stimulate the synthetic of cerebral nucleus saccharic acid and protein, strengthen pallium to the tolerance of anoxic, reduce cerebral vascular resistance, recover cerebral blood flow (CBF), stop secondary affection to occur, to enforcing one's memory, recover function of brain cell certain effect is arranged, syndromes patient's disordered brain function after energy improvement dementia and the cerebral concussion, therefore be with a wide range of applications, have huge market outlook.
Summary of the invention
The objective of the invention is: a kind of preparation method of 4-chloroacetyl acetacetic ester is provided, satisfies the requirement of suitability for industrialized production.
Technical solution of the present invention is: take ketene dimer as starting raw material, through chlorination, esterification, get product 4-chloroacetyl acetacetic ester; Comprise the steps:
(a) chlorination reaction: with ketene dimer, solvent, the chilled brine cooling is lower, passes into the chlorine of some amount, the insulation reaction certain hour; React complete after, be directly used in the next step;
(b) esterification: step (a) product is heated to certain temperature, splashes into the ethanol of some amount, the insulation reaction certain hour; React complete after, transfer in another reactor, wash the dried solvent of rear distillation twice, the high vacuum underpressure distillation gets the 4-chloroacetyl acetacetic ester.
Wherein, the mass ratio of the described ketene dimer of step (a), solvent, chlorine is 1:6-8:0.8-1.2.
Wherein, the solvent in the step (a) is ethylene dichloride, methylene dichloride, tetracol phenixin.
Wherein, the chilled brine of step (a) is cooled to-10-0 ℃, the reaction times is 6-8 hour.
Wherein, the temperature of reaction in the step (a) is 0-5 ℃, and the reaction times is 2-4 hour.
Wherein, the mass ratio of step (b) described step (a) product and ethanol is 1:0.5～0.8.
Wherein, the temperature of reaction of step (b) is 20-40 ℃, and the reaction times is 1-3 hour.
The present invention has the following advantages: 1, through two-step reaction, total recovery reaches 81.2%, and raw materials cost is low, pollutes littlely, is fit to industrialized production; 2, the first step chlorination reaction does not need purification process, is directly used in esterification of lower step, and simplified control is saved energy consumption, shortens the production cycle, and production cost is low; 3, the recyclable again usefulness of solvent in the reaction not only reduces raw materials cost but also reduce pollution.
Embodiment
Further specify technical solution of the present invention below in conjunction with embodiment, these embodiment can not be interpreted as it is restriction to technical scheme.
Embodiment 1:
The preparation of 4-chloracetyl acetic acid:The 1800G ethylene dichloride is added in the 3L reaction flask, adds ketene dimer 300G, chilled brine is cooled to-10 ℃, passes into 240G chlorine within 6 hours, finishes post-heating to 0 ℃ insulation 4 hours;
The preparation of 4-chloroacetyl acetacetic ester:Reactant of upper step is heated to 20 ℃, splash into 150G ethanol, drip and finish rear insulation 3 hours, insulation is transferred in another reaction flask after finishing, wash twice rear normal pressure and boil off ethylene dichloride (solvent recuperation is used again), again high vacuum underpressure distillation gets colourless liquid product 477G, and the two-step reaction total recovery is 81.2%.
Embodiment 2:
The preparation of 4-chloracetyl acetic acid:The 2100G tetracol phenixin is added in the 3L reaction flask, adds ketene dimer 300G, chilled brine is cooled to-5 ℃, passes into 300G chlorine within 7 hours, finishes post-heating to 2.5 ℃ insulation 3 hours;
The preparation of 4-chloroacetyl acetacetic ester:Reactant of upper step is heated to 30 ℃, splash into 195G ethanol, it is rear in insulation 2 hours to drip end, insulation is transferred in another reaction flask after finishing, wash twice rear normal pressure and boil off tetracol phenixin (solvent recuperation is used again), again high vacuum underpressure distillation gets colourless liquid product 471G, and the two-step reaction total recovery is 80.2%.
Embodiment 3;
The preparation of 4-chloracetyl acetic acid:The 2400G methylene dichloride is added in the 3L reaction flask, adds ketene dimer 300G, chilled brine is cooled to 0 ℃, passes into 360G chlorine within 8 hours, finishes post-heating to 5 ℃ insulation 2 hours;
The preparation of 4-chloroacetyl acetacetic ester:Reactant of upper step is heated to 40 ℃, splash into 240G ethanol, drip and finish rear insulation 1 hour, insulation is transferred in another reaction flask after finishing, wash twice rear normal pressure steaming vibrating dichloromethane (solvent recuperation is used again), again high vacuum underpressure distillation gets colourless liquid product 474G, and the two-step reaction total recovery is 80.7%.
Claims (7)
1.4-the preparation method of chloroacetyl acetacetic ester is characterized in that this preparation method comprises the steps:
(a) chlorination reaction: with ketene dimer, solvent, chilled brine cooling is lower, passes into the chlorine of some amount, and the insulation reaction certain hour reacts and is directly used in the next step after complete;
(b) esterification: step (a) product is heated to certain temperature, splashes into the ethanol of some amount, the insulation reaction certain hour; React complete after, transfer in another enamel reaction still, distill dried solvent, the high vacuum underpressure distillation gets 4-chloracetyl Acetyl Chloride 98Min..
2. the preparation method of described 4-chloroacetyl acetacetic ester according to claim 1, it is characterized in that: the mass ratio of the described ketene dimer of step (a), solvent, chlorine is 1:6-8:0.8-1.2.
3. the preparation method of described 4-chloroacetyl acetacetic ester according to claim 1, it is characterized in that: the solvent in the step (a) refers to ethylene dichloride, methylene dichloride, tetracol phenixin.
4. the preparation method of described 4-chloroacetyl acetacetic ester according to claim 1 is characterized in that: the chilled brine in the step (a) is cooled to-and 10-0 ℃, the reaction times is 6-8 hour.
5. the preparation method of described 4-chloroacetyl acetacetic ester according to claim 1, it is characterized in that: the temperature of reaction in the step (a) is 0-5 ℃, the reaction times is 2-4 hour.
6. the preparation method of described 4-chloroacetyl acetacetic ester according to claim 1, it is characterized in that: the mass ratio of step (b) product and ethanol is 1:0.5～0.8.
7. the preparation method of described 4-chloroacetyl acetacetic ester according to claim 1, it is characterized in that: the temperature of reaction in the step (b) is 20-40 ℃, the reaction times is 1-3 hour.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787883A (en) * | 2014-02-18 | 2014-05-14 | 山东汇海医药化工有限公司 | Preparation method of 4-chloracetyl ethyl acetate |
| CN107915622A (en) * | 2017-10-31 | 2018-04-17 | 南通醋酸化工股份有限公司 | A kind of solvent-free 4 chlorine, 3 oxobutyric continuous stream synthetic method and system |
| CN107915623A (en) * | 2017-10-31 | 2018-04-17 | 南通醋酸化工股份有限公司 | A kind of solvent-free 4 chloro methyl acetoacetate continuous stream synthetic method and system |
| CN109456192A (en) * | 2018-12-18 | 2019-03-12 | 深圳市第二人民医院 | The synthetic method of oxiracetam intermediate 4- chloroacetyl acetacetic ester |
| CN109704971A (en) * | 2018-12-20 | 2019-05-03 | 江苏恒安化工有限公司 | A kind of preparation method of 4- chloroacetyl acetacetic ester |
| CN111960946A (en) * | 2020-08-28 | 2020-11-20 | 江苏恒安化工有限公司 | Preparation method of ethyl 4-chloroacetoacetate |
| CN111978182A (en) * | 2020-08-31 | 2020-11-24 | 江苏恒安化工有限公司 | Post-treatment method for continuously synthesizing 4-chloroacetoacetic acid methyl ester |
| CN112028769A (en) * | 2020-08-28 | 2020-12-04 | 江苏恒安化工有限公司 | Preparation method of high-purity 4-chloroacetoacetic acid methyl ester |
| CN112500290A (en) * | 2020-12-02 | 2021-03-16 | 江苏恒安化工有限公司 | Method for synthesizing 4-chloroacetoacetic acid methyl ester or 4-chloroacetoacetic acid ethyl ester |
| CN113200852A (en) * | 2021-05-17 | 2021-08-03 | 宁夏恒钛科技有限公司 | Preparation method of ethyl 4-chloroacetoacetate |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787883A (en) * | 2014-02-18 | 2014-05-14 | 山东汇海医药化工有限公司 | Preparation method of 4-chloracetyl ethyl acetate |
| CN103787883B (en) * | 2014-02-18 | 2016-03-02 | 山东汇海医药化工有限公司 | A kind of preparation method of 4-chloroacetyl acetacetic ester |
| CN107915622A (en) * | 2017-10-31 | 2018-04-17 | 南通醋酸化工股份有限公司 | A kind of solvent-free 4 chlorine, 3 oxobutyric continuous stream synthetic method and system |
| CN107915623A (en) * | 2017-10-31 | 2018-04-17 | 南通醋酸化工股份有限公司 | A kind of solvent-free 4 chloro methyl acetoacetate continuous stream synthetic method and system |
| CN109456192B (en) * | 2018-12-18 | 2022-04-01 | 深圳市第二人民医院 | Synthetic method of oxiracetam intermediate 4-ethyl chloroacetoacetate |
| CN109456192A (en) * | 2018-12-18 | 2019-03-12 | 深圳市第二人民医院 | The synthetic method of oxiracetam intermediate 4- chloroacetyl acetacetic ester |
| CN109704971A (en) * | 2018-12-20 | 2019-05-03 | 江苏恒安化工有限公司 | A kind of preparation method of 4- chloroacetyl acetacetic ester |
| CN109704971B (en) * | 2018-12-20 | 2022-04-01 | 江苏恒安化工有限公司 | Preparation method of ethyl 4-chloroacetoacetate |
| CN111960946A (en) * | 2020-08-28 | 2020-11-20 | 江苏恒安化工有限公司 | Preparation method of ethyl 4-chloroacetoacetate |
| CN112028769A (en) * | 2020-08-28 | 2020-12-04 | 江苏恒安化工有限公司 | Preparation method of high-purity 4-chloroacetoacetic acid methyl ester |
| CN112028769B (en) * | 2020-08-28 | 2022-04-19 | 江苏恒安化工有限公司 | Preparation method of high-purity 4-chloroacetoacetic acid methyl ester |
| CN111960946B (en) * | 2020-08-28 | 2022-04-19 | 江苏恒安化工有限公司 | Preparation method of ethyl 4-chloroacetoacetate |
| CN111978182A (en) * | 2020-08-31 | 2020-11-24 | 江苏恒安化工有限公司 | Post-treatment method for continuously synthesizing 4-chloroacetoacetic acid methyl ester |
| CN111978182B (en) * | 2020-08-31 | 2022-04-19 | 江苏恒安化工有限公司 | Post-treatment method for continuously synthesizing 4-chloroacetoacetic acid methyl ester |
| CN112500290A (en) * | 2020-12-02 | 2021-03-16 | 江苏恒安化工有限公司 | Method for synthesizing 4-chloroacetoacetic acid methyl ester or 4-chloroacetoacetic acid ethyl ester |
| CN113200852A (en) * | 2021-05-17 | 2021-08-03 | 宁夏恒钛科技有限公司 | Preparation method of ethyl 4-chloroacetoacetate |
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Application publication date: 20131023 |