CN102746151A - Method for preparing 4-chloroacetoacetic acid ethyl ester - Google Patents
Method for preparing 4-chloroacetoacetic acid ethyl ester Download PDFInfo
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- CN102746151A CN102746151A CN201210257429XA CN201210257429A CN102746151A CN 102746151 A CN102746151 A CN 102746151A CN 201210257429X A CN201210257429X A CN 201210257429XA CN 201210257429 A CN201210257429 A CN 201210257429A CN 102746151 A CN102746151 A CN 102746151A
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Abstract
The invention relates to a method for preparing 4-chloroacetoacetic acid ethyl ester. The method comprises the following steps of: (1), putting an organic solvent into a container, cooling to 30 DEG C below zero-0 DEG C; (2) adding diketene, uniformly stirring, and controlling the reaction temperature at 30 DEG C below zero-0 DEG C; (3) controlling the temperature of a reaction liquid at 30 DEG C below zero-10 DEG C while stirring, and introducing chlorine gas; (4) keeping the temperature of the reaction liquid at 30 DEG C below zero-10 DEG C while stirring, and dropwise adding ethanol; (5) heating the reaction liquid to 0-30 DEG C while stirring; (6) distilling the reaction liquid, and recovering the organic solvent till no fraction flows out; and (7) refining oily matters, and collecting a colorless or slightly-yellow transparent liquid to obtain a target product, i.e., 4-chloroacetoacetic acid ethyl ester. The yield of the 4-chloroacetoacetic acid ethyl ester prepared with a process method is 75-88 percent.
Description
Technical field
The invention belongs to chemical technology field, particularly the preparation method of 4-chloroacetyl acetacetic ester.
Background technology
The 4-chloroacetyl acetacetic ester (have another name called: 4-chloro-ethyl 3-hydroxybutanoate), molecular formula is:
Be the main intermediate of producing bulk drugs such as nitrogen Flordipine, oxiracetam, atorvastatincalcuim, therefore with at a low price, easy, safe production technique synthesizes 4-chloro-ethyl 3-hydroxybutanoate with regard to important.And existing suitability for industrialized production (R, S)-technology of 4-chloro-ethyl 3-hydroxybutanoate is to obtain 4-chloro-3-hydroxybutyronitrile with sodium cyanide and epichlorohydrin reaction, then obtains target product with the ethanol solution hydrochloride reaction; Hypertoxic sodium cyanide, ethanol solution hydrochloride and expensive palladium-carbon catalyst have been used in this technology; Complex process, cost is high, and yield is low; Cost is high, is not easy to realize industriallization.
Summary of the invention
Goal of the invention: in order to solve above-mentioned technical barrier, the present invention provides that a kind of technology is simple, safety, lower-cost 4-chloroacetyl acetacetic ester preparation method.
The technical scheme that the present invention adopts: a kind of preparation method of 4-chloroacetyl acetacetic ester may further comprise the steps:
1, is that the organic solvent of CnHm or CnHm-C1 places container with general formula, is cooled to-30～0 ℃;
2, add ketene dimer, stir, the control reacting liquid temperature is at-30～0 ℃;
3, stir down, the control reacting liquid temperature is-30～10 ℃, feeds chlorine;
4, stir down, the temperature that keeps reaction solution drips ethanol at-30～10 ℃;
5, stir down, reaction solution is warming up to 0-30 ℃;
6, above-mentioned reaction solution is distilled, reclaim organic solvent, flow out until no cut;
7, will remain oily matter and carry out rectifying, collect colourless or little yellow transparent liquid, be title product 4-chloroacetyl acetacetic ester.
As preferably, described organic solvent can be chloroparaffin (like methylene dichloride, trichloromethane, 1, a 2-ethylene dichloride etc.); Also can be alkane (like normal hexane, hexanaphthene, normal heptane, the sherwood oil under the different boiling etc.).
As preferably, the mass ratio of said organic solvent, ketene dimer is 10: 1.5～2.5.
As preferably, the rectifying described in the step 7 is carried out under low-pressure state.
As preferably, before step 4 drips ethanol, reaction solution is carried out fractionation earlier, reclaim 1/3～1/2 organic solvent.
As preferably, ketene dimer described in step 2 and the step 3, chlorine are joined the organic solvent described in the step 1 react, ketene dimer adds the reduction reactivity hazard step by step.
Preferred as especially, the temperature of reaction when leading to chlorine is at-10～0 ℃.
Useful effect: synthesis route of the present invention is simple, feed way safety, and supplementary material cheaply is easy to get, and equipment requirements is simple, and the solvent recuperation utilization ratio is high, and cost is low, is easy to realize suitability for industrialized production, can create higher economic value.
Embodiment
Below in conjunction with embodiment the present invention is described further, but protection scope of the present invention is not limited to following embodiment.
Embodiment one
The 100g methylene dichloride is added in the there-necked flask of 250ml, disposable adding 15g ketene dimer stirs down, and reacting liquid temperature drops to-5 ℃, feeds 13g chlorine, accomplishes in 1 hour, and control reaction temperature is at-5～0 ℃, and logical finishing continues to stir half a hour down synthermal.In reaction solution, drip 8.6g ethanol, and the temperature that keeps reaction solution drips and finish at 0 ℃, reaction solution is warming up to 25 ℃, stir 1 lab scale; Reaction solution is carried out fractionation, reclaim methylene dichloride, till not having cut to flow out, then residual reaction liquid is carried out rectifying, collect colourless transparent liquid 22g, be title product 4-chloroacetyl acetacetic ester.The yield of 4-chloroacetyl acetacetic ester is 75% in the present embodiment.
Embodiment two
The 200g methylene dichloride is added in the there-necked flask of 500ml, disposable adding 50g ketene dimer stirs down, and reacting liquid temperature drops to-5 ℃, feeds 44g chlorine, accomplishes in 1 hour, and control reaction temperature is at-5～0 ℃, and logical finishing continues to stir half a hour down synthermal.In reaction solution, drip 28.7g ethanol, and the temperature that keeps reaction solution drips and finish at 0 ℃, reaction solution is warming up to 25 ℃, stir 1 lab scale; Reaction solution is carried out fractionation, reclaim methylene dichloride, till not having cut to flow out, then residual reaction liquid is carried out rectifying, collect colourless transparent liquid 78.4g, be title product 4-chloroacetyl acetacetic ester.The yield of 4-chloroacetyl acetacetic ester is 80% in the present embodiment.
Embodiment three
The 200g methylene dichloride is added in the there-necked flask of 500ml, disposable adding 50g ketene dimer stirs down; Reacting liquid temperature drops to-30 ℃, feeds 44g chlorine, accomplishes in 1.5 hours; Control reaction temperature is at-10～-5 ℃, and logical finishing continues to stir half a hour down synthermal.In reaction solution, drip 28.7g ethanol, and the temperature that keeps reaction solution drips and finish at 0 ℃, reaction solution is warming up to 25 ℃, stirred 1 hour; Reaction solution is carried out fractionation, reclaim methylene dichloride, till not having cut to flow out, then residual reaction liquid is carried out rectifying, collect colourless transparent liquid 83.3g, be title product 4-chloroacetyl acetacetic ester.The yield of 4-chloroacetyl acetacetic ester is 85% in the present embodiment.
Embodiment four
The 500g methylene dichloride is added in the there-necked flask of 1000ml, reacting liquid temperature drops to-20 ℃, stirs down; Drip the 100g ketene dimer, feed 88g chlorine simultaneously, notice that the rate of addition of control ketene dimer is faster slightly than the feeding speed of chlorine; Guarantee completion in 2 hours; Control reaction temperature is at-5～0 ℃, and logical finishing continues to stir half a hour down synthermal.Dropwise 5 7.4g ethanol in reaction solution, and the temperature that keeps reaction solution drips and finishes at 10 ℃, and reaction solution is warming up to 30 ℃, stirs 1 hour; Reaction solution is carried out fractionation, reclaim methylene dichloride, till not having cut to flow out, then residual reaction liquid is carried out rectifying, collect colourless transparent liquid 172g, be title product 4-chloroacetyl acetacetic ester.The yield of 4-chloroacetyl acetacetic ester is 88% in the present embodiment.
Embodiment five
Organic solvent is replaced by trichloromethane, repeats above-mentioned experimental procedure, can collect colourless transparent liquid, be title product 4-chloroacetyl acetacetic ester.
Embodiment six
Organic solvent is replaced by 1, and the 2-ethylene dichloride repeats above-mentioned experimental procedure, can collect colourless transparent liquid, is title product 4-chloroacetyl acetacetic ester.
Embodiment seven
Organic solvent is replaced by a kind of in the sherwood oil under hexane, hexanaphthene, normal heptane, the different boiling, repeats above-mentioned experimental procedure, can collect colourless transparent liquid, be title product 4-chloroacetyl acetacetic ester.
Claims (9)
1. the preparation method of a 4-chloroacetyl acetacetic ester is characterized in that: may further comprise the steps:
1), be that the organic solvent of CnHm or CnHm-Cl places container with general formula, be cooled to-30～0 ℃;
2), add ketene dimer, stir, the control reacting liquid temperature is at-30～0 ℃;
3), stir down, the control reacting liquid temperature be-30～10 ℃, feeding chlorine;
4), stir down, the temperature that keeps reaction solution drips ethanol at-30～10 ℃;
5), stir down, reaction solution is warming up to 0-30 ℃;
6), above-mentioned reaction solution is distilled, reclaim organic solvent, until no cut outflow;
7), will remain oily matter and carry out rectifying, collect colourless or little yellow transparent liquid, be title product 4-chloroacetyl acetacetic ester.
2. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1 is characterized in that: described organic solvent is a kind of in chloroparaffin, the alkane.
3. the preparation method of 4-chloroacetyl acetacetic ester according to claim 2 is characterized in that: described chloroparaffin is methylene dichloride, trichloromethane, 1, a kind of in the 2-ethylene dichloride.
4. the preparation method of 4-chloroacetyl acetacetic ester according to claim 2 is characterized in that: described alkane is a kind of in normal hexane, hexanaphthene, normal heptane, the sherwood oil.
5. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1 is characterized in that: the mass ratio of said organic solvent, ketene dimer is 10: 1.5～2.5.
6. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1 is characterized in that: the distillation described in the step 7) is carried out under low-pressure state.
7. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1 is characterized in that: before step 4) drips ethanol, reaction solution is carried out fractionation earlier, reclaim 1/3～1/2 said organic solvent.
8. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1 is characterized in that: with step 2) and step 3) described in ketene dimer, chlorine join simultaneously in the organic solvent described in the step 1).
9. the preparation method of 4-chloroacetyl acetacetic ester according to claim 1 is characterized in that: the temperature of reaction when leading to chlorine is at-10～0 ℃.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN110724059A (en) * | 2019-09-30 | 2020-01-24 | 安徽金禾实业股份有限公司 | Synthesis method of 4-chloroacetoacetic acid ethyl ester |
| CN111203170A (en) * | 2020-03-16 | 2020-05-29 | 山东昌邑灶户盐化有限公司 | Green synthesis device of 4-chloroacetoacetic acid esters |
| 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 |
| 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 |
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2012
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN110724059A (en) * | 2019-09-30 | 2020-01-24 | 安徽金禾实业股份有限公司 | Synthesis method of 4-chloroacetoacetic acid ethyl ester |
| CN111203170A (en) * | 2020-03-16 | 2020-05-29 | 山东昌邑灶户盐化有限公司 | Green synthesis device of 4-chloroacetoacetic acid esters |
| 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 |
| 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 |
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Application publication date: 20121024 |