CN114685274A - Esterification method for preparing 4-methyl chloroacetoacetate - Google Patents
Esterification method for preparing 4-methyl chloroacetoacetate Download PDFInfo
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- CN114685274A CN114685274A CN202011628271.3A CN202011628271A CN114685274A CN 114685274 A CN114685274 A CN 114685274A CN 202011628271 A CN202011628271 A CN 202011628271A CN 114685274 A CN114685274 A CN 114685274A
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000005886 esterification reaction Methods 0.000 title claims abstract description 30
- 230000032050 esterification Effects 0.000 title abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 78
- HFLMYYLFSNEOOT-UHFFFAOYSA-N methyl 4-chloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)CCl HFLMYYLFSNEOOT-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000000047 product Substances 0.000 claims abstract description 34
- 239000012535 impurity Substances 0.000 claims abstract description 28
- 239000003112 inhibitor Substances 0.000 claims abstract description 26
- 239000006227 byproduct Substances 0.000 claims abstract description 23
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 14
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 7
- 239000012442 inert solvent Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- GEYBMYRBIABFTA-UHFFFAOYSA-N O-methyltyrosine Chemical compound COC1=CC=C(CC(N)C(O)=O)C=C1 GEYBMYRBIABFTA-UHFFFAOYSA-N 0.000 claims description 6
- VUFOSBDICLTFMS-UHFFFAOYSA-M ethyl-hexadecyl-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)CC VUFOSBDICLTFMS-UHFFFAOYSA-M 0.000 claims description 6
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 3
- HXWGXXDEYMNGCT-UHFFFAOYSA-M decyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCC[N+](C)(C)C HXWGXXDEYMNGCT-UHFFFAOYSA-M 0.000 claims description 3
- JGHLBORZQVXAIL-UHFFFAOYSA-M didodecyl(diethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](CC)(CC)CCCCCCCCCCCC JGHLBORZQVXAIL-UHFFFAOYSA-M 0.000 claims description 3
- ZCPCLAPUXMZUCD-UHFFFAOYSA-M dihexadecyl(dimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCC ZCPCLAPUXMZUCD-UHFFFAOYSA-M 0.000 claims description 3
- QLPMKRZYJPNIRP-UHFFFAOYSA-M methyl(trioctyl)azanium;bromide Chemical compound [Br-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC QLPMKRZYJPNIRP-UHFFFAOYSA-M 0.000 claims description 3
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 3
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 3
- SYZCZDCAEVUSPM-UHFFFAOYSA-M tetrahexylazanium;bromide Chemical compound [Br-].CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC SYZCZDCAEVUSPM-UHFFFAOYSA-M 0.000 claims description 3
- ODTSDWCGLRVBHJ-UHFFFAOYSA-M tetrahexylazanium;chloride Chemical compound [Cl-].CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC ODTSDWCGLRVBHJ-UHFFFAOYSA-M 0.000 claims description 3
- VJFXTJZJJIZRKP-UHFFFAOYSA-M tetraphenylazanium;bromide Chemical compound [Br-].C1=CC=CC=C1[N+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VJFXTJZJJIZRKP-UHFFFAOYSA-M 0.000 claims description 3
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical compound [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 claims description 3
- FBEVECUEMUUFKM-UHFFFAOYSA-M tetrapropylazanium;chloride Chemical compound [Cl-].CCC[N+](CCC)(CCC)CCC FBEVECUEMUUFKM-UHFFFAOYSA-M 0.000 claims description 3
- QEXITCCVENILJI-UHFFFAOYSA-M tributyl(phenyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)C1=CC=CC=C1 QEXITCCVENILJI-UHFFFAOYSA-M 0.000 claims description 3
- PIVZYJMLIVYZJA-UHFFFAOYSA-M trioctyl(propyl)azanium;bromide Chemical compound [Br-].CCCCCCCC[N+](CCC)(CCCCCCCC)CCCCCCCC PIVZYJMLIVYZJA-UHFFFAOYSA-M 0.000 claims description 3
- 239000012043 crude product Substances 0.000 description 16
- JNYMRXDQVPIONI-HYXAFXHYSA-N methyl (z)-4-chloro-3-methoxybut-2-enoate Chemical compound COC(=O)\C=C(\CCl)OC JNYMRXDQVPIONI-HYXAFXHYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 230000003472 neutralizing effect Effects 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 4
- 239000003507 refrigerant Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 2
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 2
- 229960002542 dolutegravir Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- 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 provides an esterification method for preparing 4-methyl chloroacetoacetate. Specifically, the method of the invention comprises the following steps: firstly, carrying out chlorination reaction in a diketene solution, and then carrying out esterification reaction on a chlorination reaction solution and methanol in an inert solvent in the presence of a byproduct inhibitor to form 4-chloroacetoacetic acid methyl ester; wherein the byproduct inhibitor comprises a quaternary ammonium salt. The method provided by the invention can be used for remarkably reducing the content of 4-chloro-3-methoxy-2-methyl crotonate impurities, improving the purity of a finished product and meeting the requirements of higher specification and quality.
Description
Technical Field
The invention relates to the field of chemical industry, in particular to an esterification method for preparing 4-methyl chloroacetoacetate.
Background
The 4-chloroacetoacetic acid methyl ester is mainly used in the fields of medicines and pesticides, especially as an intermediate of anti-AIDS medicine Dolutegravir (Dolutegravir), and has wide market prospect.
The conventional production method of methyl 4-chloroacetoacetate, which is mainly used in industrial production, is batch production. Dissolving diketene in a solvent, cooling to-30 to-10 ℃, starting stirring, introducing a certain amount of chlorine into a reaction kettle at a certain flow rate, preserving heat for 1-2 hours at-30 to-10 ℃, dripping a certain amount of methanol into the reaction kettle after chlorination reaction is finished, controlling the reaction temperature to be 0-5 ℃, heating to 20-25 ℃ after dripping is finished, preserving heat for 1 hour, neutralizing the solution with alkali after esterification reaction is finished, evaporating the solvent, and then distilling under reduced pressure to obtain a colorless liquid finished product, namely 4-methyl chloroacetoacetate. The reaction of introducing chlorine is a chlorination reaction, and the reaction of adding methanol is an esterification reaction.
At present, the 4-chloro-3-methoxy-2-methyl crotonate impurity in the methyl 4-chloroacetoacetate industrial product produced by a plurality of suppliers on the market according to a conventional production method is large, the content of the impurity is between 0.7 and 2.0 percent, and further the purity of the methyl 4-chloroacetoacetate is between 97.0 and 98.8 percent and is low, so that the methyl 4-chloroacetoacetate serving as a medical intermediate is difficult to meet the higher specification and quality requirements required by customers.
In addition, the difference of the boiling points of the 4-chloroacetoacetic acid methyl ester and the 4-chloro-3-methoxy-2-butenoic acid methyl ester (shown as a formula II) impurities is very small (about 2-3 ℃ under a reduced pressure condition), the content of the impurities in the rectified 4-chloroacetoacetic acid methyl ester finished product is more than 0.5 percent, and the impurities are difficult to be reduced to be within 0.1 percent at one time.
Therefore, there is an urgent need in the art for a method for preparing high-purity methyl 4-chloroacetoacetate, thereby reducing the content of impurities such as methyl 4-chloro-3-methoxy-2-butenoate.
Disclosure of Invention
The invention aims to provide a method for preparing 4-chloroacetoacetic acid methyl ester, so that the content of impurities such as 4-chloro-3-methoxy-2-butenoic acid methyl ester is reduced, and the quality of a finished product of the 4-chloroacetoacetic acid methyl ester is improved.
The invention provides an esterification method for preparing 4-methyl chloroacetoacetate, which comprises the following steps:
(a) esterifying a feed comprising a compound of formula Ia with methanol in an inert solvent in the presence of a byproduct inhibitor to form methyl 4-chloroacetoacetate;
wherein the byproduct inhibitor comprises a quaternary ammonium salt.
In another preferred embodiment, the byproduct inhibitor is selected from the group consisting of: tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate, phenyltriethylammonium chloride, phenyltributylammonium chloride, tributylpropylammonium chloride, tetrahexylammonium bromide, tetrahexylammonium chloride, tetraphenylammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide, trioctylpropylammonium bromide, trinonylmethylammonium chloride, trinonylmethylammonium bromide, decyltrimethylammonium chloride, didodecyldiethylammonium bromide, hexadecyltrimethylammonium chloride, hexadecyldimethylethylammonium bromide, dihexadecyldimethylammonium chloride, or a combination thereof.
In another preferred embodiment, the byproduct inhibitor is selected from the group consisting of: tetrabutylammonium bromide, phenyltriethylammonium chloride, hexadecyldimethylethylammonium bromide, or a combination thereof.
In another preferred embodiment, in step (a), the inert solvent is selected from the group consisting of: chloroform, petroleum ether, dichloromethane, n-hexane, or combinations thereof.
In another preferred embodiment, in step (a), the inert solvent is dichloromethane.
In another preferred embodiment, in step (a), the reaction conditions include: controlling the reaction temperature to be 0-5 ℃, adding methanol, heating to 20-25 ℃ after dripping, and carrying out heat preservation reaction for 1-2 h.
In another preferred example, the step (a) includes the steps of: the byproduct inhibitor and methanol are added into the reaction system simultaneously or sequentially.
In another preferred embodiment, the step (a) includes the steps of: the esterification reaction is carried out by adding the byproduct inhibitor to the raw material containing the compound of formula Ia, and then adding methanol.
In another preferred example, the step (a) includes the steps of: a mixture of a by-product inhibitor and anhydrous methanol was added to the starting material containing the compound of formula Ia to carry out the esterification reaction.
In another preferred example, before step (a), the method further comprises:
(a0) introducing chlorine into the diketene solution to carry out chlorination reaction, thereby obtaining the raw material containing the compound of the formula Ia
In another preferred embodiment, the molar ratio of the byproduct inhibitor to diketene is 1: 5 to 2000.
In another preferred embodiment, the molar ratio of the byproduct inhibitor to diketene is 1:10 to 1000.
In another preferred embodiment, in the step (a0), the flow rate of the chlorine gas is 10-50g/h, preferably 15-40 g/h.
In another preferred example, the method further comprises:
(b) working up the reaction mixture formed in step (a) to obtain the finished methyl 4-chloroacetoacetate.
In another preferred embodiment, the post-treatment is selected from the group consisting of: water washing, alkali neutralization, solvent evaporation under reduced pressure, extraction, rectification under reduced pressure, or a combination thereof.
In another preferred embodiment, the step (b) includes:
(b1) carrying out post-treatment on the reaction mixture to obtain a crude product of the methyl 4-chloroacetoacetate; and
(b2) and (3) carrying out vacuum rectification on the crude product of the methyl 4-chloroacetoacetate so as to obtain a finished product of the methyl 4-chloroacetoacetate.
In another preferred embodiment, the purity of the methyl 4-chloroacetoacetate finished product is P1 ≥ 99.2%, more preferably P1 ≥ 99.3%.
In another preferred embodiment, the content of the impurity methyl 4-chloro-3-methoxy-2-butenoate in the finished product of methyl 4-chloroacetoacetate is less than or equal to 0.3 percent of C1, and more preferably less than or equal to 0.1 percent of C1.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies and, as a result, have surprisingly found for the first time that, in the presence of a specific by-product inhibitor, the content of impurities difficult to separate, such as methyl 4-chloro-3-methoxy-2-butenoate, can be significantly reduced without substantially modifying the process, and thus methyl 4-chloroacetoacetate having a high purity can be produced. Experiments show that compared with the conventional process, the method disclosed by the invention can improve the purity of the finished product, reduce the content of 4-chloro-3-methoxy-2-methyl crotonate impurities and improve the quality of the finished product. Based on the above findings, the inventors have completed the present invention.
4-Chloroacetoacetic acid methyl ester
Methyl 4-chloroacetoacetate is a colorless to pale yellow transparent liquid, molecular weight: 150.56, melting point: 14-16 ℃, boiling point: 212 ℃, relative density: 1.287, water solubility: 71g/L (20 ℃ C.).
Impurities
Previous studies have shown that one of the major impurities is methyl 4-chloro-3-methoxy-2-butenoate, which is an impurity that is difficult to separate from the product methyl 4-chloro-3-methoxy-2-butenoate, and is difficult to separate from each other efficiently by conventional methods.
Preparation method of 4-chloroacetoacetic acid methyl ester
The invention provides a preparation method for preparing 4-chloroacetoacetic acid methyl ester, which comprises the following steps:
(a0) introducing chlorine into the diketene solution to carry out chlorination reaction, thereby forming a raw material containing the compound of the formula Ia;
(a) adding a by-product inhibitor and anhydrous methanol to the raw material (reaction liquid) containing the compound of formula Ia obtained in step (a0) to perform an esterification reaction, thereby obtaining a reaction mixture containing methyl 4-chloroacetoacetate;
(b1) carrying out post-treatment on the reaction mixture to obtain a crude product of the methyl 4-chloroacetoacetate;
(b2) and (3) carrying out vacuum rectification on the crude product of the methyl 4-chloroacetoacetate so as to obtain a finished product of the methyl 4-chloroacetoacetate.
The esterification reaction uses a quaternary ammonium salt inhibitor selected from the group consisting of: tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate, phenyltriethylammonium chloride, phenyltributylammonium chloride, tributylpropylammonium chloride, tetrahexylammonium bromide, tetrahexylammonium chloride, tetraphenylammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide, trioctylpropylammonium bromide, trinonylmethylammonium chloride, trinonylmethylammonium bromide, decyltrimethylammonium chloride, didodecyldiethylammonium bromide, hexadecyltrimethylammonium chloride, hexadecyldimethylethylammonium bromide, dihexadecyldimethylammonium chloride, or a combination thereof. Tetrabutylammonium bromide, phenyltriethylammonium chloride, hexadecyldimethylethylammonium bromide, or a combination thereof is preferred.
In the esterification reaction, the molar ratio of the quaternary ammonium salt inhibitor to the diketene is 1: 5 to 2000, preferably 1:10 to 1000.
The esterification reaction comprises the following reaction conditions: adding a byproduct inhibitor and methanol, heating and carrying out heat preservation reaction for 1-2.5 h, preferably 1.5-2 h.
In the esterification reaction, the reaction temperature is-5-15 ℃ and preferably 0-5 ℃ when the byproduct inhibitor and methanol are added.
In the esterification reaction, the reaction temperature after the byproduct inhibitor and methanol are added is 10-35 ℃, and preferably 20-25 ℃.
The esterification reaction and post-treatment method comprises the following steps: adding water for washing, adding alkali for neutralization, washing with water, then removing the solvent by evaporation under reduced pressure to obtain a crude product of the methyl 4-chloroacetoacetate, and then rectifying the crude product under reduced pressure to obtain a finished product of the methyl 4-chloroacetoacetate.
The esterification reaction, comprising the steps of: the esterification reaction is carried out by adding the byproduct inhibitor to the raw material containing the compound of formula Ia and then adding methanol.
The esterification reaction, comprising the steps of: a mixture of a by-product inhibitor and anhydrous methanol was added to the starting material containing the compound of formula Ia to carry out the esterification reaction.
In the chlorination reaction, the flow rate of the introduced chlorine is 10-50g/h, preferably 15-40 g/h.
The chlorination reaction is carried out at the reaction temperature of-40-0 ℃ and preferably-25-15 ℃.
The solvent is selected from the group consisting of: chloroform, petroleum ether, dichloromethane, n-hexane, or combinations thereof; dichloromethane is preferred.
Compared with the prior art, the invention has the main advantages that:
1. compared with the prior art for synthesizing 4-chloroacetoacetic acid methyl ester, the preparation method disclosed by the invention has the advantages that the generation of various impurities is reduced by adding the inhibitor quaternary ammonium salt, and particularly, the generation amount of the 4-chloro-3-methoxy-2-butenoic acid methyl ester impurity can be remarkably reduced, so that the impurity content of the 4-chloro-3-methoxy-2-butenoic acid methyl ester in a 4-chloroacetoacetic acid methyl ester finished product can be controlled to be very low (such as less than or equal to 0.1%);
2. the purity of the finished product of the methyl 4-chloroacetoacetate is improved to at least 99 percent (such as more than or equal to 99.2 percent or higher), and the higher specification and quality requirements required by customers can be met.
The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
And (2) sequentially adding 100.0g of diketene and 400ml of dichloromethane into a 1000ml reaction bottle with a mechanical stirrer, starting stirring, cooling the reaction liquid to the internal temperature of-20 ℃ by using a refrigerant, stably introducing 88.5g of chlorine (17.7g/h) within 5h, keeping the internal temperature of-20 +/-5 ℃ in the chlorine introducing process, keeping the temperature of-20 +/-5 ℃ after the chlorine is introduced, continuing to react for 2h, and finishing the chlorination reaction. Adding 3.8g of tetrabutylammonium bromide into the reaction solution, controlling the reaction temperature to be 0-5 ℃, dropwise adding 57.2g of anhydrous methanol at a constant speed, heating to 20-25 ℃ after the methanol is dropwise added, keeping the temperature for reaction for 2 hours, and finishing the esterification reaction. Washing with water, neutralizing with sodium bicarbonate, washing with water again, evaporating the solvent under reduced pressure to obtain a crude product of methyl 4-chloroacetoacetate, and rectifying the crude product under reduced pressure to obtain a finished product of methyl 4-chloroacetoacetate, wherein the finished product is 150.4 g.
The purity and impurity content of the finished product of the methyl 4-chloroacetoacetate are measured by a conventional method.
Example 2
And (2) sequentially adding 100.0g of diketene and 450ml of dichloromethane into a 1000ml reaction bottle with a mechanical stirrer, starting stirring, cooling the reaction liquid to the internal temperature of-20 ℃ by using a refrigerant, stably introducing 92.3g of chlorine gas for 3h, keeping the internal temperature of-20 +/-5 ℃ in the chlorine gas introduction process, keeping the temperature of-20 +/-5 ℃ after the chlorine gas is introduced, continuing to react for 1h, and finishing the chlorination reaction. Adding 12.7g of phenyltriethylammonium chloride into the reaction solution, controlling the reaction temperature to be 0-5 ℃, dropwise adding 76.5g of anhydrous methanol at a constant speed, heating to 20-25 ℃ after the methanol is dropwise added, keeping the temperature for reaction for 2 hours, and finishing the esterification reaction. Adding water for washing, neutralizing by sodium bicarbonate, washing by water again, evaporating the solvent under reduced pressure to obtain a crude product of the methyl 4-chloroacetoacetate, and rectifying the crude product under reduced pressure to obtain a finished product of the methyl 4-chloroacetoacetate, namely 152.8 g.
The purity and impurity content of the finished product of the methyl 4-chloroacetoacetate are measured by a conventional method.
Example 3
And sequentially adding 100.0g of diketene and 500ml of dichloromethane into a 1000ml reaction bottle with a mechanical stirrer, starting stirring, cooling the reaction liquid to the internal temperature of-20 ℃ by using a refrigerant, stably introducing 87.0g of chlorine gas within 2.5h, keeping the internal temperature of-20 +/-5 ℃ during the chlorine gas introduction process, keeping the temperature of-20 +/-5 ℃ after the chlorine gas is introduced, continuing the reaction for 2h, and finishing the chlorination reaction. Adding 6.5g of hexadecyl dimethyl ethyl ammonium bromide into the reaction solution, controlling the reaction temperature to be 0-5 ℃, dropwise adding 45.8g of anhydrous methanol at a constant speed, heating to 20-25 ℃ after the methanol is dropwise added, keeping the temperature for reaction for 1.5h, and finishing the esterification reaction. Adding water for washing, neutralizing by sodium bicarbonate, washing by water again, evaporating the solvent under reduced pressure to obtain a crude product of the 4-methyl chloroacetoacetate, and rectifying the crude product under reduced pressure to obtain a finished product of the 4-methyl chloroacetoacetate of 148.7 g.
The purity and impurity content of the finished product of the methyl 4-chloroacetoacetate are measured by a conventional method.
Example 4
Example 1 was repeated, with the difference that: and after the chlorination reaction is finished, dropwise adding a mixture of 3.8g of tetrabutylammonium bromide and 57.2g of anhydrous methanol into the reaction liquid, heating to 20-25 ℃, keeping the temperature for reaction for 2 hours, and finishing the esterification reaction. Washing with water, neutralizing with sodium bicarbonate, washing with water again, evaporating the solvent under reduced pressure to obtain a crude product of methyl 4-chloroacetoacetate, and rectifying the crude product under reduced pressure to obtain a finished product of methyl 4-chloroacetoacetate, wherein the finished product is 150.2 g.
The purity and impurity content of the finished product of the methyl 4-chloroacetoacetate are measured by a conventional method.
Comparative example 1
And sequentially adding 100.0g of diketene and 400ml of dichloromethane into a 1000ml reaction bottle with a mechanical stirrer, starting stirring, cooling the reaction liquid to the internal temperature of-20 ℃ by using a refrigerant, stably introducing 87.7g of chlorine gas for 4 hours in use, keeping the internal temperature of-20 +/-5 ℃ in the chlorine gas introduction process, keeping the temperature of-20 +/-5 ℃ after the chlorine gas is introduced, continuously reacting for 2 hours, and ending the chlorination reaction. And (3) dropwise adding 53.4g of anhydrous methanol at a constant speed at the reaction temperature of 0-5 ℃, heating to 20-25 ℃ after the methanol is dropwise added, keeping the temperature for reaction for 2 hours, and finishing the esterification reaction. Adding water for washing, neutralizing by sodium bicarbonate, washing by water again, evaporating the solvent under reduced pressure to obtain a crude product of the methyl 4-chloroacetoacetate, and rectifying the crude product under reduced pressure to obtain a finished product of the methyl 4-chloroacetoacetate, wherein the finished product of the methyl 4-chloroacetoacetate is 143.3 g.
The purity and impurity content of the finished product of the methyl 4-chloroacetoacetate are measured by a conventional method.
Results
The results of the purity and the impurity content of methyl 4-chloro-3-methoxy-2-butenoate obtained after refining in each of examples 1 to 4 and comparative example 1 are shown in Table 1.
TABLE 1 purity and impurity content of methyl 4-chloroacetoacetate in the finished product
Comparing examples 1-4 with comparative example 1, it can be found that when quaternary ammonium salt is added in the esterification reaction process, the method has a remarkable effect of reducing 4-chloro-3-methoxy-2-methyl crotonate impurities in a 4-chloroacetoacetic acid methyl ester finished product, and the purity of the finished product is improved to more than 99.2%.
Example 5
In this example, it was further investigated whether the separation and purification process (including purification) had an influence on the reduction of the content of methyl 4-chloro-3-methoxy-2-butenoate as an impurity.
In this example, example 1 was repeated and samples were taken directly after the end of the esterification reaction to determine the relative amounts of both methyl 4-chloroacetoacetate and methyl 4-chloro-3-methoxy-2-butenoate in the samples.
The results show that the relative content ratio of methyl 4-chloroacetoacetate to methyl 4-chloro-3-methoxy-2-butenoate in the product after the esterification reaction is 99.33: 0.05.
combining the data from example 1 and example 5, the analysis showed that subsequent separation and purification processes (including purification) had substantially no effect on the reduction of the content of the impurity methyl 4-chloro-3-methoxy-2-butenoate.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for the preparation of methyl 4-chloroacetoacetate, comprising the steps of:
(a) esterifying a feed comprising a compound of formula Ia with methanol in an inert solvent in the presence of a byproduct inhibitor to form methyl 4-chloroacetoacetate;
wherein the byproduct inhibitor comprises a quaternary ammonium salt.
2. The method of claim 1, wherein the byproduct inhibitor is selected from the group consisting of: tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium bisulfate, phenyltriethylammonium chloride, phenyltributylammonium chloride, tributylpropylammonium chloride, tetrahexylammonium bromide, tetrahexylammonium chloride, tetraphenylammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide, trioctylpropylammonium bromide, trinonylmethylammonium chloride, trinonylmethylammonium bromide, decyltrimethylammonium chloride, didodecyldiethylammonium bromide, hexadecyltrimethylammonium chloride, hexadecyldimethylethylammonium bromide, dihexadecyldimethylammonium chloride, or a combination thereof.
3. The method according to claim 1, wherein in step (a), the inert solvent is selected from the group consisting of: chloroform, petroleum ether, dichloromethane, n-hexane, or combinations thereof.
4. The method of claim 1, wherein in step (a), the reaction conditions comprise: and (3) controlling the reaction temperature to be 0-5 ℃, dropwise adding methanol at a constant speed, heating to 20-25 ℃ after dropwise adding, and carrying out heat preservation reaction for 1-2 hours.
5. The method of claim 1, wherein said step (a) comprises the steps of: the esterification reaction is carried out by adding the byproduct inhibitor to the raw material containing the compound of formula Ia and then adding methanol.
6. The method of claim 1, wherein prior to step (a), the method further comprises:
(a0) introducing chlorine into the diketene solution to carry out chlorination reaction, thereby obtaining the raw material containing the compound of the formula Ia
7. The method of claim 6, wherein the molar ratio of byproduct inhibitor to diketene is from 1: 5 to 2000.
8. The method of claim 6, wherein in step (a0), the chlorine gas is introduced at a flow rate of 10-50 g/h.
9. The method of claim 1 or 6, further comprising:
(b) working up the reaction mixture formed in step (a) to obtain the finished methyl 4-chloroacetoacetate.
10. The method according to claim 9, wherein the purity P1 of the methyl 4-chloroacetoacetate finished product is more than or equal to 99.2%; and/or
The content of 4-chloro-3-methoxy-2-methyl crotonate as an impurity in the finished product of the methyl 4-chloroacetoacetate, C1, is less than or equal to 0.3 percent.
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