CN113200852A - Preparation method of ethyl 4-chloroacetoacetate - Google Patents
Preparation method of ethyl 4-chloroacetoacetate Download PDFInfo
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- CN113200852A CN113200852A CN202110534603.XA CN202110534603A CN113200852A CN 113200852 A CN113200852 A CN 113200852A CN 202110534603 A CN202110534603 A CN 202110534603A CN 113200852 A CN113200852 A CN 113200852A
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- dichloromethane
- ethyl ester
- acid ethyl
- chloroacetoacetic acid
- chloroacetoacetate
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- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 99
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 36
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 18
- 230000032050 esterification Effects 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 238000004321 preservation Methods 0.000 claims abstract description 8
- 238000010521 absorption reaction Methods 0.000 claims description 30
- 239000012043 crude product Substances 0.000 claims description 20
- 238000007259 addition reaction Methods 0.000 claims description 16
- 239000007789 gas Substances 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 10
- 239000006227 byproduct Substances 0.000 claims description 10
- -1 chloroacetyl acetyl chloride dichloromethane Chemical compound 0.000 claims description 10
- 239000011552 falling film Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 5
- 230000005494 condensation Effects 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 2
- 230000003247 decreasing effect Effects 0.000 claims 2
- 238000011534 incubation Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 7
- 239000000460 chlorine Substances 0.000 abstract description 7
- 229910052801 chlorine Inorganic materials 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000000354 decomposition reaction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 238000005292 vacuum distillation Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 12
- 230000009286 beneficial effect Effects 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- GPDFVBIDCBPHSW-UHFFFAOYSA-N ethyl 2,4-dichloro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(=O)CCl GPDFVBIDCBPHSW-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical class C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- WVPAABNYMHNFJG-QDVBXLKVSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(z)-2-(2-amino-1,3-thiazol-4-yl)pent-2-enoyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical group N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 WVPAABNYMHNFJG-QDVBXLKVSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960001227 oxiracetam Drugs 0.000 description 1
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 1
- 229960004626 umifenovir Drugs 0.000 description 1
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Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4-chloroacetoacetic acid ethyl ester, which specifically comprises the following steps: (1) chlorination: carrying out primary cooling on dichloromethane, adding diketene, carrying out secondary cooling, introducing chlorine, and carrying out heat preservation; (2) esterification: dropwise adding absolute ethyl alcohol, and keeping the temperature; (3) desolventizing and deacidifying: heating and distilling to remove dichloromethane and hydrogen chloride; (4) and (3) rectification: rectifying and purifying to obtain the product. The invention uses the diketene as the raw material, has low and easily obtained raw material cost, simple synthesis steps and reduced production cost; by optimizing the material proportion of the process, the selectivity of the product 4-chloroacetoacetic acid ethyl ester is improved, and the yield is improved; through high vacuum low temperature distillation, the decomposition of the heat sensitive product 4-chloroacetoacetic acid ethyl ester is effectively prevented, and the yield and the product quality are improved.
Description
Technical Field
The invention relates to the technical field of chemical production, in particular to a preparation method of 4-chloroacetoacetic acid ethyl ester.
Background
Ethyl 4-chloroacetoacetate of formula: c6H9ClO3English name: 4-Chloroacetic acid ethyl ester, CAS number: 638-07-3, molecular weight: 164.59, structural formula:
the liquid is transparent colorless to light yellow red liquid, has acetic acid smell, is commonly used for anti-inflammatory drugs, fourth-generation cefcapene pivoxil side chains, anti-cardiovascular and cerebrovascular drugs, oxiracetam, antilipemic drugs, atorvastatin drugs, febuxostat drugs, antihypertensive drugs, amlodipine, anti-influenza virus arbidol and other drugs, and health-care food levocarnitine series very key intermediates, and is also used for the key intermediate of the latest drug for treating AIDS, namely ruticovir.
The pharmaceutical intermediates are chemical raw materials or chemical products used in the process of pharmaceutical synthesis. With the progress of science and technology, a plurality of medicines are continuously developed to benefit mankind, and the synthesis of the medicines depends on the production of novel and high-quality medicine intermediates matched with the medicines, so that the development space and the application prospect of the novel medicine intermediates in the domestic and foreign markets are very good.
The method has the advantages of meeting market demands, regulating and controlling the rising of medicine price caused by the shortage of medicine raw materials, reducing the treatment cost of patients, relieving the pain of the patients, ensuring the physical and mental health of the nation, realizing the large-scale production of the ethyl 4-chloroacetoacetate product, benefiting the nation and the people and having positive significance.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing ethyl 4-chloroacetoacetate, so as to solve the defects in the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of ethyl 4-chloroacetoacetate specifically comprises the following steps:
(1) chlorination of
Carrying out primary cooling on dichloromethane, adding diketene, carrying out secondary cooling, introducing chlorine gas, carrying out chlorination addition reaction, and carrying out heat preservation to obtain chloroacetyl acetyl chloride dichloromethane;
the reaction equation is:
(2) esterification
Dropwise adding absolute ethyl alcohol into chloroacetyl acetyl chloride dichloromethane for esterification addition reaction, and keeping the temperature to obtain dichloromethane containing the crude product of 4-chloroacetoacetic acid ethyl ester;
the reaction equation is:
(3) desolventizing and deacidifying
Heating and distilling dichloromethane containing the crude product of the 4-chloroacetoacetic acid ethyl ester, and removing dichloromethane and hydrogen chloride to obtain the crude product of the 4-chloroacetoacetic acid ethyl ester;
(4) rectification
Rectifying and purifying the 4-chloroacetoacetic acid ethyl ester crude product to obtain the 4-chloroacetoacetic acid ethyl ester.
Further, in the step (1), the mass ratio of the dichloromethane to the diketene is (3-5): 1.
Further, in the step (1), the temperature is reduced to-20 ℃ for the first time, and is reduced to (-27) - (-25) ℃ for the second time.
The adoption of the further technical scheme has the beneficial effects that the diketene is added after the dichloromethane is added and the temperature is firstly reduced to-20 ℃, because the diketene is easy to polymerize due to high temperature, and the temperature reduction before the addition aims at preventing the diketene from polymerizing at high temperature; the purpose of secondary cooling after adding the diketene is to reach the required temperature of chlorine-introducing reaction, which is beneficial to the normal operation of addition reaction.
Further, in the step (1), the mass ratio of the chlorine to the diketene is 1:1, and the introducing time is 12 hours.
The further technical scheme has the beneficial effects that if the dosage of chlorine is insufficient, the raw materials are not reacted completely, and the yield is low; if the amount of the chlorine is excessive, the impurity of the 2, 4-dichloroacetoacetic acid ethyl ester is increased, and the selectivity and the yield are reduced. If the chlorine gas is introduced at a too high speed, the reaction is subjected to violent heat release and difficult temperature control, and simultaneously, the impurity ethyl 2, 4-dichloroacetoacetate is increased, and the selectivity and the yield are reduced.
Further, in the step (1), the heat preservation time is 30 min.
The further technical scheme has the beneficial effects that the reaction time can be prolonged and the raw materials are completely converted by heat preservation.
Further, in the step (2), the molar ratio of the absolute ethyl alcohol to the bisvinyl ketone phase is (1.05-1.2):1, and the dropping time is 2 hours.
The further technical scheme has the beneficial effects that if the dosage of the ethanol is insufficient, the raw materials are not reacted completely, and the yield is low; if the dosage of the ethanol is excessive, the ethanol raw material is wasted, and the difficulty of solvent recovery is increased. If the dropping time is short and the speed is too high, the reaction has violent heat release, the temperature control is difficult, the local temperature is too high, the product 4-chloroacetoacetic acid ethyl ester is decomposed, and the yield is reduced.
Further, in the step (2), the heat preservation time is 30 min.
The further technical scheme has the beneficial effects that the reaction time can be prolonged and the raw materials are completely converted by heat preservation.
Further, the step (2) further includes the steps of: hydrogen chloride gas generated in the esterification addition reaction is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid.
Further, the step (3) further includes the steps of: the mixed gas distilled in the heating distillation process is subjected to secondary deep cooling condensation under the guide of a fan to recover dichloromethane, and the purified hydrogen chloride gas is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid.
Further, in the step (4), the temperature of rectification and purification is 65-75 ℃, and the vacuum degree is 50-100 Pa.
The further technical scheme has the beneficial effects that the product 4-chloroacetoacetic acid ethyl ester is decomposed at high temperature, so that the vacuum degree is improved, the rectification division can be reduced, the product decomposition is effectively reduced, and the yield is improved.
According to the technical scheme, compared with the prior art, the invention has the following beneficial effects:
1. the diketene is used as the raw material, so that the raw material is low in cost and easy to obtain, the synthesis steps are simple, and the production cost is reduced;
2. by optimizing the material proportion of the process, the selectivity of the product 4-chloroacetoacetic acid ethyl ester is improved, and the yield is improved;
3. through high vacuum low temperature distillation, the decomposition of the heat sensitive product 4-chloroacetoacetic acid ethyl ester is effectively prevented, and the yield and the product quality are improved.
Drawings
FIG. 1 is a process flow diagram of the preparation method of ethyl 4-chloroacetoacetate.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A preparation method of ethyl 4-chloroacetoacetate specifically comprises the following steps:
(1) chlorination of
Cooling dichloromethane to-20 ℃ for the first time, adding diketene, cooling to-27 ℃ for the second time, introducing chlorine gas for chlorination addition reaction, and keeping the temperature for 30min to obtain chloroacetyl acetyl chloride dichloromethane; wherein the mass ratio of the dichloromethane to the diketene is 3:1, the mass ratio of the chlorine to the diketene is 1:1, and the introducing time is 12 hours;
(2) esterification
Dropwise adding absolute ethyl alcohol into chloroacetyl acetyl chloride dichloromethane for esterification addition reaction, and keeping the temperature for 30min to obtain dichloromethane containing the crude product of 4-chloroacetoacetic acid ethyl ester; wherein the molar ratio of the absolute ethyl alcohol to the bisvinyl ketone phase is 1.05:1, the dripping time is 2 hours, and hydrogen chloride gas generated in the esterification addition reaction is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid;
(3) desolventizing and deacidifying
Heating and distilling dichloromethane containing the crude product of the 4-chloroacetoacetic acid ethyl ester, and removing dichloromethane and hydrogen chloride to obtain the crude product of the 4-chloroacetoacetic acid ethyl ester; wherein, the mixed gas distilled in the heating distillation process is firstly subjected to secondary deep cooling condensation under the guide of a fan to recover dichloromethane, and the purified hydrogen chloride gas is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid;
(4) rectification
Rectifying and purifying the 4-chloroacetoacetic acid ethyl ester crude product at 65 ℃ and the vacuum degree of 50Pa to obtain the 4-chloroacetoacetic acid ethyl ester.
Example 2
A preparation method of ethyl 4-chloroacetoacetate specifically comprises the following steps:
(1) chlorination of
Cooling dichloromethane to-20 ℃ for the first time, adding diketene, cooling to-26 ℃ for the second time, introducing chlorine gas for chlorination addition reaction, and keeping the temperature for 30min to obtain chloroacetyl acetyl chloride dichloromethane; wherein the mass ratio of the dichloromethane to the diketene is 4:1, the mass ratio of the chlorine to the diketene is 1:1, and the introducing time is 12 hours;
(2) esterification
Dropwise adding absolute ethyl alcohol into chloroacetyl acetyl chloride dichloromethane for esterification addition reaction, and keeping the temperature for 30min to obtain dichloromethane containing the crude product of 4-chloroacetoacetic acid ethyl ester; wherein the molar ratio of the absolute ethyl alcohol to the bisvinyl ketone phase is 1.1:1, the dripping time is 2 hours, and hydrogen chloride gas generated in the esterification addition reaction is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid;
(3) desolventizing and deacidifying
Heating and distilling dichloromethane containing the crude product of the 4-chloroacetoacetic acid ethyl ester, and removing dichloromethane and hydrogen chloride to obtain the crude product of the 4-chloroacetoacetic acid ethyl ester; wherein, the mixed gas distilled in the heating distillation process is firstly subjected to secondary deep cooling condensation under the guide of a fan to recover dichloromethane, and the purified hydrogen chloride gas is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid;
(4) rectification
Rectifying and purifying the 4-chloroacetoacetic acid ethyl ester crude product at the temperature of 70 ℃ and the vacuum degree of 80Pa to obtain the 4-chloroacetoacetic acid ethyl ester.
Example 3
A preparation method of ethyl 4-chloroacetoacetate specifically comprises the following steps:
(1) chlorination of
Cooling dichloromethane to-20 ℃ for the first time, adding diketene, cooling to-25 ℃ for the second time, introducing chlorine gas for chlorination addition reaction, and keeping the temperature for 30min to obtain chloroacetyl acetyl chloride dichloromethane; wherein the mass ratio of the dichloromethane to the diketene is 5:1, the mass ratio of the chlorine to the diketene is 1:1, and the introducing time is 12 hours;
(2) esterification
Dropwise adding absolute ethyl alcohol into chloroacetyl acetyl chloride dichloromethane for esterification addition reaction, and keeping the temperature for 30min to obtain dichloromethane containing the crude product of 4-chloroacetoacetic acid ethyl ester; wherein the molar ratio of the absolute ethyl alcohol to the bisvinyl ketone phase is 1.2:1, the dripping time is 2 hours, and hydrogen chloride gas generated in the esterification addition reaction is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid;
(3) desolventizing and deacidifying
Heating and distilling dichloromethane containing the crude product of the 4-chloroacetoacetic acid ethyl ester, and removing dichloromethane and hydrogen chloride to obtain the crude product of the 4-chloroacetoacetic acid ethyl ester; wherein, the mixed gas distilled in the heating distillation process is firstly subjected to secondary deep cooling condensation under the guide of a fan to recover dichloromethane, and the purified hydrogen chloride gas is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid;
(4) rectification
Rectifying and purifying the 4-chloroacetoacetic acid ethyl ester crude product at the temperature of 75 ℃ and the vacuum degree of 100Pa to obtain the 4-chloroacetoacetic acid ethyl ester.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A preparation method of 4-chloroacetoacetic acid ethyl ester is characterized by comprising the following steps:
(1) chlorination of
Carrying out primary cooling on dichloromethane, adding diketene, carrying out secondary cooling, introducing chlorine gas, carrying out chlorination addition reaction, and carrying out heat preservation to obtain chloroacetyl acetyl chloride dichloromethane;
(2) esterification
Dropwise adding absolute ethyl alcohol into chloroacetyl acetyl chloride dichloromethane for esterification addition reaction, and keeping the temperature to obtain dichloromethane containing the crude product of 4-chloroacetoacetic acid ethyl ester;
(3) desolventizing and deacidifying
Heating and distilling dichloromethane containing the crude product of the 4-chloroacetoacetic acid ethyl ester, and removing dichloromethane and hydrogen chloride to obtain the crude product of the 4-chloroacetoacetic acid ethyl ester;
(4) rectification
And (3) rectifying and purifying the crude product of the 4-chloroacetoacetic acid ethyl ester to obtain the 4-chloroacetoacetic acid ethyl ester.
2. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein in the step (1), the mass ratio of the dichloromethane to the diketene is (3-5): 1.
3. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein in the step (1), the temperature is decreased to-20 ℃ for the first time, and the temperature is decreased to (-27) - (-25) ℃ for the second time.
4. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein in the step (1), the mass ratio of the chlorine gas to the diketene is 1:1, and the feeding time is 12 h.
5. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein the incubation time in the step (1) is 30 min.
6. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein in the step (2), the molar ratio of the absolute ethyl alcohol to the bisvinyl ketone phase is (1.05-1.2):1, and the dropwise addition time is 2 h.
7. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein the time for the heat preservation in the step (2) is 30 min.
8. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein the step (2) further comprises the following steps: hydrogen chloride gas generated in the esterification addition reaction is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid.
9. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein the step (3) further comprises the following steps: the mixed gas distilled in the heating distillation process is subjected to secondary deep cooling condensation under the guide of a fan to recover dichloromethane, and the purified hydrogen chloride gas is subjected to secondary falling film absorption, primary water absorption and primary alkali absorption to prepare a byproduct 31% hydrochloric acid.
10. The method for preparing ethyl 4-chloroacetoacetate according to claim 1, wherein in the step (4), the temperature for rectification and purification is 65-75 ℃, and the vacuum degree is 50-100 Pa.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113603581A (en) * | 2021-08-17 | 2021-11-05 | 广西金源生物化工实业有限公司 | Continuous device and method for industrial production of ethyl 4-chloroacetoacetate |
| CN114180525A (en) * | 2021-12-30 | 2022-03-15 | 南通醋酸化工股份有限公司 | Separation method of hydrogen chloride/dichloromethane in synthesis of 4-chloroacetoacetic acid ethyl ester |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| CN113603581A (en) * | 2021-08-17 | 2021-11-05 | 广西金源生物化工实业有限公司 | Continuous device and method for industrial production of ethyl 4-chloroacetoacetate |
| 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 |
| CN114180525A (en) * | 2021-12-30 | 2022-03-15 | 南通醋酸化工股份有限公司 | Separation method of hydrogen chloride/dichloromethane in synthesis of 4-chloroacetoacetic acid ethyl ester |
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