CN103787883B - A kind of preparation method of 4-chloroacetyl acetacetic ester - Google Patents
A kind of preparation method of 4-chloroacetyl acetacetic ester Download PDFInfo
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- CN103787883B CN103787883B CN201410054429.9A CN201410054429A CN103787883B CN 103787883 B CN103787883 B CN 103787883B CN 201410054429 A CN201410054429 A CN 201410054429A CN 103787883 B CN103787883 B CN 103787883B
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- chloroacetyl acetacetic
- acetacetic ester
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- chloroacetyl
- ketene dimer
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
Abstract
A kind of preparation method of 4-chloroacetyl acetacetic ester, take ketene dimer as starting raw material, through superchlorination and esterification two step synthesis 4-chloroacetyl acetacetic ester crude product, then finished product is obtained through rectifying, in described chlorinating step, add stablizer anhydrous cupric sulfate, its add-on is the 0.02-1% of ketene dimer quality.Relative to existing technology, the present invention has the following advantages: adding 1, by stablizer anhydrous cupric sulfate, decrease the growing amount of by product 2-chloroacetyl acetacetic ester, in 4-chloroacetyl acetacetic ester crude product, the growing amount of by product 2-chloroacetyl acetacetic ester can control below 0.5%, and distillation yield is improved greatly; 2, the yield of 4-chloroacetyl acetacetic ester is more than 94.5%, and cost significantly reduces.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, relate to a kind of preparation method of 4-chloroacetyl acetacetic ester in particular.
Background technology
4-chloroacetyl acetacetic ester is a kind of colourless to light yellow transparent liquid, is mainly used in field of medicaments, especially the key intermediate of oxiracetam, has wide market outlook.
Through searching related data and comparative analysis, the operational path of synthesis 4-chloroacetyl acetacetic ester mainly contains two both at home and abroad at present, as follows respectively:
1: ethyl chloroacetate method is using benzene as solvent, under mercury chloride exists, two mol-chloric ethyl acetate are carried out condensation one step and are obtained 4-chloroacetyl acetacetic ester, but there is report in patent documentation (Fr1438387) only abroad, although the transformation efficiency of this route higher (70%-85%) simultaneously, but use deadly poisonous compound mercury chloride and benzene in this route, higher on safety and environmental protection and production cost, be only applicable to laboratory synthesis on a small scale, be not suitable for suitability for industrialized production.
Ethyl chloroacetate method reaction equation
2: diethenone process take ketene dimer as starting raw material, through superchlorination and esterification two step synthesis 4-chloroacetyl acetacetic ester, its raw material is all cheap and easy to get and become the production method of main flow, realize industrialization (as CN201210257429.X and CN201310321570.6) at present, but it also has shortcoming to be inherently exactly that product yield is on the low side, only has 75%-88%, cause high expensive, and the reason causing yield low is exactly to generate a certain amount of 2-chloroacetyl acetacetic ester (about 5%) in reaction process, and the boiling point of 2-chloroacetyl acetacetic ester and reactor product 4-chloroacetyl acetacetic ester difference seldom (are about 2-3 at reduced pressure conditions
oc), therefore usually want distill repeatedly when rectifying purifying, cause a large amount of decomposition of product, finally cause yield on the low side.
Diethenone process reaction equation.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of preparation method of 4-chloroacetyl acetacetic ester, overcomes the problems such as the yield that the ubiquitous because by product 2-chloroacetyl acetacetic ester of prior art causes is low, production cost is higher
Technical scheme is: take ketene dimer as starting raw material, through superchlorination and esterification two step synthesis 4-chloroacetyl acetacetic ester crude product, then obtain finished product through rectifying, it is characterized in that, in described chlorinating step, add stablizer anhydrous cupric sulfate, its add-on is the 0.02-1% of ketene dimer quality.
Such scheme comprises further:
In described 4-chloroacetyl acetacetic ester crude product, the growing amount of by product 2-chloroacetyl acetacetic ester controls at 0.3-0.5%.
Described chlorinating step is: in reactor, add ketene dimer 84g, methylene dichloride 220g and anhydrous cupric sulfate 0.08-0.84g, opens and stirs, be cooled to-10 DEG C, pass into chlorine 44g;
Described esterif iotacation step is: drip ethanol 55g after ventilation, steams methylene dichloride and obtain 4-chloroacetyl acetacetic ester crude product after having reacted.
Just start us and thought that copper sulfate just plays the effect of dewatering agent in system, therefore we have attempted the dewatering agent of other kinds successively as molecular sieve, silica gel, other neutral salt etc., but all do not obtain satisfied result, therefore we infer, copper sulfate has stronger interaction in chlorination process and between ketene dimer and chlorine, and ketene dimer is tended towards stability, for generation intermediate 4-chloracetyl Acetyl Chloride 98Min. advantageously.
Relative to existing technology, the present invention has the following advantages:
Adding 1, by stablizer anhydrous cupric sulfate, decrease the growing amount of by product 2-chloroacetyl acetacetic ester, in 4-chloroacetyl acetacetic ester crude product, the growing amount of by product 2-chloroacetyl acetacetic ester can control below 0.5%, and distillation yield is improved greatly;
2, the yield of 4-chloroacetyl acetacetic ester is more than 94.5%, and cost significantly reduces.
Embodiment
By the following examples the present invention is described, but is not limited to this.
Embodiment 1:
Ketene dimer 84g is added in reactor, methylene dichloride 220g, anhydrous cupric sulfate 0.4g(0.48%), open and stir, be cooled to-10 DEG C, pass into chlorine 44g, after ventilation, drip ethanol 55g, steam methylene dichloride after having reacted and obtain 4-chloroacetyl acetacetic ester crude product (2-chloroacetyl acetacetic ester content 0.42%).Product 156.3g is obtained, yield 95.04% after rectifying.
Embodiment 2:
Ketene dimer 84g is added in reactor, methylene dichloride 220g, anhydrous cupric sulfate 0.84g(1%), open and stir, be cooled to-10 DEG C, pass into chlorine 44g, after ventilation, drip ethanol 55g, steam methylene dichloride after having reacted and obtain 4-chloroacetyl acetacetic ester crude product (2-chloroacetyl acetacetic ester content 0.49%).Product 155.5g is obtained, yield 94.55% after rectifying.
Embodiment 3:
Ketene dimer 84g is added in reactor, methylene dichloride 220g, anhydrous cupric sulfate 0.08g(0.1%), open and stir, be cooled to-10 DEG C, pass into chlorine 44g, after ventilation, drip ethanol 55g, steam methylene dichloride after having reacted and obtain 4-chloroacetyl acetacetic ester crude product (2-chloroacetyl acetacetic ester content 0.31%).Product 158g is obtained, yield 96.08% after rectifying.
Below be only the part exemplary embodiments of this programme; those skilled in the art can adopt other embodiment to realize completely within the protection domain of the technical program; and all can make the appropriate adjustments parameters such as proportioning raw materials, temperature of reaction, times, just do not repeat one by one at this.
Claims (1)
1. the preparation method of a 4-chloroacetyl acetacetic ester, take ketene dimer as starting raw material, through superchlorination and esterification two step synthesis 4-chloroacetyl acetacetic ester crude product, then finished product is obtained through rectifying, it is characterized in that, described chlorinating step is: in reactor, add ketene dimer 84g, methylene dichloride 220g and anhydrous cupric sulfate 0.08g, opens and stirs, be cooled to-10 DEG C, pass into chlorine 44g; Described esterif iotacation step is: drip ethanol 55g after ventilation, steams methylene dichloride and obtain 4-chloroacetyl acetacetic ester crude product after having reacted.
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113045417B (en) * | 2019-12-29 | 2023-04-07 | 南通醋酸化工股份有限公司 | Process for producing acetoacetic ester by catalytic method |
| CN112500290B (en) * | 2020-12-02 | 2021-07-30 | 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 |
| CN113248375A (en) * | 2021-05-17 | 2021-08-13 | 宁夏恒钛科技有限公司 | Preparation method of 4-chloroacetoacetic acid methyl ester |
| CN113603581B (en) * | 2021-08-17 | 2023-09-15 | 广西金源生物化工实业有限公司 | Continuous device and method for industrial production of 4-chloroacetoacetic acid ethyl ester |
| CN113877504A (en) * | 2021-11-03 | 2022-01-04 | 江苏恒安化工有限公司 | Preparation device and method of ethyl 4-chloroacetoacetate |
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| CN101747298A (en) * | 2010-02-01 | 2010-06-23 | 宁波王龙科技股份有限公司 | Process for preparing high-purity diketene |
| CN102276464A (en) * | 2011-09-09 | 2011-12-14 | 南通醋酸化工股份有限公司 | Method for producing methyl acetoacetate |
| CN102746151A (en) * | 2012-07-23 | 2012-10-24 | 江苏诚信制药有限公司 | Method for preparing 4-chloroacetoacetic acid ethyl ester |
| CN103360256A (en) * | 2013-07-29 | 2013-10-23 | 江苏恒安化工有限公司 | Preparation method of 4-chloroacetoacetic acid ethyl ester |
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2014
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE890341C (en) * | 1951-07-31 | 1953-09-17 | Bayer Ag | Method of stabilizing diketene |
| CN101747298A (en) * | 2010-02-01 | 2010-06-23 | 宁波王龙科技股份有限公司 | Process for preparing high-purity diketene |
| CN102276464A (en) * | 2011-09-09 | 2011-12-14 | 南通醋酸化工股份有限公司 | Method for producing methyl acetoacetate |
| CN102746151A (en) * | 2012-07-23 | 2012-10-24 | 江苏诚信制药有限公司 | Method for preparing 4-chloroacetoacetic acid ethyl ester |
| CN103360256A (en) * | 2013-07-29 | 2013-10-23 | 江苏恒安化工有限公司 | Preparation method of 4-chloroacetoacetic acid ethyl ester |
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Denomination of invention: A preparation method of ethyl 4-chloroacetoacetate Effective date of registration: 20211130 Granted publication date: 20160302 Pledgee: Dongying Hekou District sub branch of China Post Savings Bank Co.,Ltd. Pledgor: SHANDONG HUIHAI PHARMACEUTICAL& CHEMICAL Co.,Ltd. Registration number: Y2021980013568 |
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