An esterification method for preparing 4-chloroacetic acid methyl ester

Abstract

The present application provides an esterification method for preparing 4-chloroacetyl methyl acetate. Specifically, the method comprises the following steps: first, chlorination reaction in a divinyl ketone solution, and then esterification reaction of the chlorination reaction solution with methanol in the presence of a by-product inhibitor in an inert solvent, so as to form 4-chloroacetyl methyl acetate; wherein the by-product inhibitor comprises a quaternary ammonium salt. The method of the present application significantly reduces the content of 4-chloro-3-methoxy-2-butenoic acid methyl ester impurities, improves the purity of the finished product, and meets higher specification quality requirements.

Description

TECHNICAL FIELD

[0001] The present application relates to the chemical industry, in particular to an esterification method for preparing 4-chloroacetyl methyl acetate. BACKGROUND

[0002] 4-chloroacetyl methyl acetate is mainly used in the fields of medicine and pesticide, especially as an intermediate of anti-AIDS drug Dolutegravir, and has a broad market prospect.

[0003] At present, the main conventional production method of 4-chloroacetyl methyl acetate in industrial production is batch production. First, divinyl ketone is dissolved in a solvent and cooled to -30℃ to -10℃, and then stirring is started. A certain amount of chlorine is introduced into the reaction kettle at a certain flow rate, and the chlorination reaction is carried out at -30℃ to -10℃ for 1 to 2 hours. After the chlorination reaction is completed, a certain amount of methanol is added dropwise, and the reaction temperature is controlled at 0 to 5℃. After the dropwise addition is completed, the temperature is raised to 20 to 25℃, and the esterification reaction is carried out for 1 hour. After the esterification reaction is completed, the reaction is neutralized with a base, the solvent is removed by evaporation, and then vacuum distillation is carried out to obtain colorless liquid product, which is 4-chloroacetyl methyl acetate. The reaction of introducing chlorine is a chlorination reaction, and the reaction of adding methanol is an esterification reaction.

[0004] At present, the main conventional production method of 4-chloroacetyl methyl acetate in industrial production is batch production. First, divinyl ketone is dissolved in a solvent and cooled to -30℃ to -10℃, and then stirring is started. A certain amount of chlorine is introduced into the reaction kettle at a certain flow rate, and the chlorination reaction is carried out at -30℃ to -10℃ for 1 to 2 hours. After the chlorination reaction is completed, a certain amount of methanol is added dropwise, and the reaction temperature is controlled at 0 to 5℃. After the dropwise addition is completed, the temperature is raised to 20 to 25℃, and the esterification reaction is carried out for 1 hour. After the esterification reaction is completed, the reaction is neutralized with a base, the solvent is removed by evaporation, and then vacuum distillation is carried out to obtain colorless liquid product, which is 4-chloroacetyl methyl acetate. The reaction of introducing chlorine is a chlorination reaction, and the reaction of adding methanol is an esterification reaction.

[0005] In addition, the boiling point difference between 4-chloroacetyl methyl acetate and 4-chloro-3-methoxy-2-butenoic acid methyl ester (as shown in formula II) is very small (about 2 to 3℃ under reduced pressure), and the content of this impurity in the 4-chloroacetyl methyl acetate product after rectification is >0.5%, which is difficult to reduce to ≤0.1% at one time.

[0006]

[0007] Therefore, there is an urgent need in the art for a method for preparing high-purity 4-chloroacetyl methyl acetate to reduce the content of impurities such as 4-chloro-3-methoxy-2-butenoic acid methyl ester. SUMMARY

[0008] The purpose of the present application is to provide a method for preparing 4-chloroacetyl methyl acetate to reduce the content of impurities such as 4-chloro-3-methoxy-2-butenoic acid methyl ester, and to improve the quality of the finished product of 4-chloroacetyl methyl acetate.

[0009] The present application provides a method for preparing 4-chloroacetic acid methyl ester, comprising the following steps:

[0010] (a) esterifying a starting material containing a compound of Formula Ia with methanol in the presence of a by-product inhibitor in an inert solvent to form 4-chloroacetic acid methyl ester;

[0011]

[0012] wherein the by-product inhibitor comprises a quaternary ammonium salt.

[0013] In another preferred embodiment, the by-product inhibitor is selected from the group consisting of tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 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, cetyltrimethylammonium chloride, cetyl dimethyl ethyl ammonium bromide, dicetyl dimethyl ammonium chloride, or a combination thereof.

[0014] In another preferred embodiment, the by-product inhibitor is selected from the group consisting of tetrabutylammonium bromide, phenyltriethylammonium chloride, cetyl dimethyl ethyl ammonium bromide, or a combination thereof.

[0015] In another preferred embodiment, in step (a), the inert solvent is selected from the group consisting of chloroform, petroleum ether, dichloromethane, n-hexane, or a combination thereof.

[0016] In another preferred embodiment, in step (a), the inert solvent is dichloromethane.

[0017] In another preferred embodiment, in step (a), the reaction conditions include controlling the reaction temperature to be 0-5°C, adding methanol, after the dropwise addition is completed, increasing the temperature to 20-25°C, and maintaining the reaction for 1-2 hours.

[0018] In another preferred embodiment, step (a) includes the step of simultaneously or sequentially adding the by-product inhibitor and methanol to the reaction system.

[0019] In another preferred embodiment, step (a) includes the step of adding the by-product inhibitor to the starting material containing the compound of Formula Ia, and then adding methanol to perform the esterification reaction.

[0020] In another preferred embodiment, step (a) includes the step of adding a mixture of the by-product inhibitor and anhydrous methanol to the starting material containing the compound of Formula Ia to perform the esterification reaction.

[0021] In another preferred embodiment, before step (a), the method further comprises:

[0022] (a0) introducing chlorine into the diketene solution to perform a chlorination reaction, thereby obtaining a raw material containing the compound of Formula Ia

[0023]

[0024] In another preferred embodiment, the molar ratio of the byproduct inhibitor to diketene is 1:5-2000.

[0025] In another preferred embodiment, the molar ratio of the byproduct inhibitor to diketene is 1:10-1000.

[0026] In another preferred embodiment, in step (a0), the flow rate of the introduced chlorine is 10-50 g / h, preferably 15-40 g / h.

[0027] In another preferred embodiment, the method further comprises:

[0028] (b) post-treating the reaction mixture formed in step (a), thereby obtaining the finished product of methyl 4-chloroacetoacetate.

[0029] In another preferred embodiment, the post-treatment is selected from the group consisting of water washing, base neutralization, solvent evaporation under reduced pressure, extraction, vacuum distillation, or a combination thereof.

[0030] In another preferred embodiment, step (b) comprises:

[0031] (b1) post-treating the reaction mixture, thereby obtaining the crude product of methyl 4-chloroacetoacetate; and

[0032] (b2) vacuum distilling the crude product of methyl 4-chloroacetoacetate, thereby obtaining the finished product of methyl 4-chloroacetoacetate.

[0033] In another preferred embodiment, the finished product of methyl 4-chloroacetoacetate has a purity P1 of methyl 4-chloroacetoacetate of ≥99.2%, more preferably P1 of ≥99.3%.

[0034] In another preferred embodiment, the finished product of methyl 4-chloroacetoacetate has a content C1 of the impurity methyl 4-chloro-3-methoxy-2-butenoate of ≤0.3%, more preferably C1 of ≤0.1%.

[0035] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0036] The present inventors have made a long-term and in-depth study, and through a large number of experiments and screening, for the first time, it is accidentally found that in the presence of a specific by-product inhibitor, the content of 4-chloro-3-methoxy-2-butenoic acid methyl ester and other difficult-to-separate impurities can be significantly reduced without substantially changing the process, so that high-purity 4-chloroacetoacetic acid methyl ester can be prepared. Experiments show that compared with the conventional process, the method described in the present application can increase the purity of the finished product, reduce the content of 4-chloro-3-methoxy-2-butenoic acid methyl ester impurities, and improve the quality of the finished product. Based on the above findings, the inventors have completed the present application.

[0037] 4-chloroacetoacetic acid methyl ester

[0038] 4-chloroacetoacetic acid methyl ester is a colorless to pale yellow transparent liquid, with a molecular weight of 150.56, a melting point of 14-16°C, a boiling point of 212°C, a relative density of 1.287, and a water solubility of 71g / L (20°C).

[0039] Impurities

[0040] Existing research shows that one of the main impurities is 4-chloro-3-methoxy-2-butenoic acid methyl ester, which is a difficult-to-separate impurity, and the product 4-chloro-3-methoxy-2-butenoic acid methyl ester is difficult to separate from each other by conventional methods.

[0041] Method for preparing 4-chloroacetoacetic acid methyl ester

[0042] The present application provides a method for preparing 4-chloroacetoacetic acid methyl ester, which comprises the following steps:

[0043] (a0) passing chlorine into a solution of diketene to perform a chlorination reaction, thereby forming a raw material containing a compound of Formula Ia;

[0044]

[0045] (a) adding a by-product inhibitor and anhydrous methanol to the raw material containing the compound of Formula Ia obtained in step (a0) (reaction solution) to perform an esterification reaction, thereby obtaining a reaction mixture containing 4-chloroacetoacetic acid methyl ester;

[0046]

[0047] (b1) performing post-treatment on the reaction mixture, thereby obtaining a crude product of 4-chloroacetoacetic acid methyl ester;

[0048] (b2) performing vacuum rectification on the crude product of 4-chloroacetoacetic acid methyl ester, thereby obtaining a finished product of 4-chloroacetoacetic acid methyl ester.

[0049] 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 hydrogen sulfate, 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, hexadecyldiethylammonium bromide, bis-hexadecyl dimethylammonium chloride, or a combination thereof. Preferably, tetrabutylammonium bromide, phenyltriethylammonium chloride, hexadecyldiethylammonium bromide, or a combination thereof.

[0050] The esterification reaction uses a quaternary ammonium salt inhibitor in a molar ratio of 1:5-2000, preferably 1:10-1000, to divinyl ketone.

[0051] The esterification reaction includes a reaction condition of heating and incubating for 1-2.5 h, preferably 1.5-2 h, after adding the byproduct inhibitor and methanol.

[0052] The esterification reaction has a reaction temperature of -5-15°C, preferably 0-5°C, when the byproduct inhibitor and methanol are added.

[0053] The esterification reaction has a reaction temperature of 10-35°C, preferably 20-25°C, after the byproduct inhibitor and methanol are added.

[0054] The esterification reaction includes a post-treatment method comprising the steps of washing with water, neutralizing with a base, washing with water again, and then removing the solvent under reduced pressure to obtain a crude methyl 4-chloroacetoacetate, and then performing reduced pressure distillation on the crude product to obtain a finished product of methyl 4-chloroacetoacetate.

[0055] The esterification reaction includes the steps of adding the byproduct inhibitor to the raw material containing the compound of Formula Ia first, and then adding methanol to perform the esterification reaction.

[0056] The esterification reaction includes the steps of adding a mixture of the byproduct inhibitor and anhydrous methanol to the raw material containing the compound of Formula Ia to perform the esterification reaction.

[0057] The chlorination reaction uses a flow rate of 10-50 g / h, preferably 15-40 g / h, of chlorine gas.

[0058] The chlorination reaction has a reaction temperature of -40-0°C, preferably -25--15°C.

[0059] The solvent is selected from the group consisting of chloroform, petroleum ether, dichloromethane, n-hexane, or a combination thereof; preferably dichloromethane.

[0060] The main advantages of the present application compared with the prior art are:

[0061] 1. Compared with the prior art for synthesizing methyl 4-chloroacetoacetate, the preparation method of the present application reduces the generation of various impurities by adding a suppressor quaternary ammonium salt, especially significantly reduces the generation amount of methyl 4-chloro-3-methoxy-2-butenoate impurities, so that the content of methyl 4-chloro-3-methoxy-2-butenoate impurities in the finished product of methyl 4-chloroacetoacetate can be controlled very low (such as ≤0.1%).

[0062] 2. The purity of the finished product of methyl 4-chloroacetoacetate is increased to at least 99% (such as ≥99.2% or higher), which can meet the higher specification quality requirements required by customers.

[0063] The present application will be further described in conjunction with specific implementations. It should be understood that these examples are only used to illustrate the present application and are not used to limit the scope of the present application. The experimental methods in the following examples are not specified, which are usually carried out according to the conventional conditions or the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one skilled in the art. In addition, any method and material similar or equivalent to those described can be applied to the method of the present application. The preferred implementation methods and materials described herein are only for demonstration.

[0065] Example 1

[0066] 1000ml reaction bottle with mechanical stirring was sequentially added with 100.0g divinyl ketone, 400ml dichloromethane, and the stirring was started. The reaction liquid was cooled to an internal temperature of -20°C using a refrigerant for 5h. 88.5g chlorine gas (17.7g / h) was introduced, and the internal temperature was maintained at -20±5°C during the chlorine gas introduction. After the chlorine gas was introduced, the reaction was continued at -20±5°C for 2h, and the chlorination reaction was completed. 3.8g tetrabutylammonium bromide was added to the reaction liquid, and 57.2g anhydrous methanol was added at a constant speed while controlling the reaction temperature at 0-5°C. After the methanol was added, the temperature was increased to 20-25°C and the reaction was continued for 2h, and the esterification reaction was completed. Water was added for washing, sodium bicarbonate was added for neutralization, and then water was added for washing. The solvent was removed under reduced pressure to obtain the crude product of methyl 4-chloroacetoacetate. The crude product was subjected to reduced pressure distillation to obtain the finished product of methyl 4-chloroacetoacetate 150.4g.

[0067] The purity and impurity content of the finished product of methyl 4-chloroacetoacetate were determined according to the conventional method.

[0068] Example 2

[0069] Into a 1000ml reaction flask with mechanical stirring, 100.0g of divinyl ketone and 450ml of dichloromethane were sequentially added. The stirring was started and the reaction liquid was cooled to an internal temperature of -20°C using a coolant. The chlorination reaction was carried out by stabilizing the temperature at -20±5°C and feeding 92.3g of chlorine gas in 3h. After the feeding of chlorine gas was completed, the reaction was continued at -20±5°C for 1h. Then, 12.7g of phenyltriethylammonium chloride was added to the reaction liquid, and 76.5g of anhydrous methanol was added dropwise at a constant rate while controlling the reaction temperature at 0-5°C. After the dropwise addition of methanol was completed, the temperature was raised to 20-25°C and the reaction was continued for 2h. The esterification reaction was completed. The reaction liquid was washed with water, neutralized with sodium bicarbonate, and washed with water again. The solvent was distilled off under reduced pressure to obtain 152.8g of crude methyl 4-chloroacetoacetate. The crude product was subjected to vacuum distillation to obtain 152.8g of methyl 4-chloroacetoacetate.

[0070] The purity and impurity content of the methyl 4-chloroacetoacetate product were determined by a conventional method.

[0071] Example 3

[0072] Into a 1000ml reaction flask with mechanical stirring, 100.0g of divinyl ketone and 500ml of dichloromethane were sequentially added. The stirring was started and the reaction liquid was cooled to an internal temperature of -20°C using a coolant. The chlorination reaction was carried out by stabilizing the temperature at -20±5°C and feeding 87.0g of chlorine gas in 2.5h. After the feeding of chlorine gas was completed, the reaction was continued at -20±5°C for 2h. Then, 6.5g of hexadecyldimethylethylammonium bromide was added to the reaction liquid, and 45.8g of anhydrous methanol was added dropwise at a constant rate while controlling the reaction temperature at 0-5°C. After the dropwise addition of methanol was completed, the temperature was raised to 20-25°C and the reaction was continued for 1.5h. The esterification reaction was completed. The reaction liquid was washed with water, neutralized with sodium bicarbonate, and washed with water again. The solvent was distilled off under reduced pressure to obtain 148.7g of crude methyl 4-chloroacetoacetate. The crude product was subjected to vacuum distillation to obtain 148.7g of methyl 4-chloroacetoacetate.

[0073] The purity and impurity content of the methyl 4-chloroacetoacetate product were determined by a conventional method.

[0074] Example 4

[0075] Example 1 was repeated, except that after the chlorination reaction was completed, a mixture of 3.8g of tetrabutylammonium bromide and 57.2g of anhydrous methanol was added dropwise to the reaction liquid. After the dropwise addition was completed, the temperature was raised to 20-25°C and the reaction was continued for 2h. The esterification reaction was completed. The reaction liquid was washed with water, neutralized with sodium bicarbonate, and washed with water again. The solvent was distilled off under reduced pressure to obtain 150.2g of crude methyl 4-chloroacetoacetate. The crude product was subjected to vacuum distillation to obtain 150.2g of methyl 4-chloroacetoacetate.

[0076] The purity and impurity content of the methyl 4-chloroacetoacetate product were determined by a conventional method.

[0077] Comparative Example 1

[0078] 1000ml reaction flask with mechanical stirring, 100.0g of divinyl ketone, 400ml of dichloromethane were sequentially added, the stirring was started, the reaction liquid was cooled to an internal temperature of -20°C using a refrigerant, and the process took 4h. 87.7g of chlorine was introduced, the internal temperature was maintained at -20±5°C during the chlorine introduction, and the chlorine introduction was completed. After the chlorine introduction, the temperature was maintained at -20±5°C for 2h, and the chlorination reaction was completed. The reaction temperature was controlled at 0-5°C, and 53.4g of anhydrous methanol was added at a constant speed. After the methanol was added, the temperature was increased to 20-25°C and maintained for 2h, and the esterification reaction was completed. Water was added for washing, sodium bicarbonate was added for neutralization, and then water was added for washing. The solvent was removed under reduced pressure to obtain crude methyl 4-chloroacetoacetate, and the crude product was subjected to reduced pressure distillation to obtain 143.3g of methyl 4-chloroacetoacetate product.

[0079] The purity and impurity content of the methyl 4-chloroacetoacetate product were determined according to the conventional method.

[0080] Results

[0081] The results of the purity and the content of methyl 4-chloro-3-methoxy-2-butenoate impurity in the methyl 4-chloroacetoacetate product obtained after refining for each of Examples 1-4 and Comparative Example 1 are shown in Table 1.

[0082] Table 1 Purity and impurity content of methyl 4-chloroacetoacetate product

[0083]

[0084] Comparative Examples 1-4 and Comparative Example 1 can be found that when a quaternary ammonium salt is added during the esterification reaction, it has a significant effect on reducing the content of methyl 4-chloro-3-methoxy-2-butenoate impurity in the methyl 4-chloroacetoacetate product, and the purity of the product is increased to more than 99.2%.

[0085] Example 5

[0086] In this example, it was further studied whether the separation and purification process (including refining) had an effect on the reduction of the content of the impurity methyl 4-chloro-3-methoxy-2-butenoate.

[0087] In this example, Example 1 was repeated, and after the esterification reaction was completed, the relative contents of both methyl 4-chloroacetoacetate and methyl 4-chloro-3-methoxy-2-butenoate in the sample were directly determined.

[0088] The results showed that the relative content ratio of methyl 4-chloroacetoacetate to methyl 4-chloro-3-methoxy-2-butenoate in the product after the esterification reaction was 99.33:0.05.

[0089] In combination with the data of Example 1 and Example 5, the analysis indicates that the subsequent separation and purification processes, including polishing, have essentially no effect on the reduction of the impurity 4-chloro-3-methoxy-2-butenoic acid methyl ester content.

[0090] All documents referred to in the present application are incorporated herein by reference as if each individual document were incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding use of the other embodiments. Other embodiments will occur to those skilled in the art upon consideration of the specification and may be had and practiced without departing from the spirit of the application. Therefore, the present application should be understood to include all such variations as fall within the scope of the appended claims. Moreover, unless otherwise indicated herein, the materials referring to the name of a single element include generic references to the same element whether the element is referred to by a single name or by multiple names.

Claims

1. A process for the preparation of methyl 4-chloroacetoacetate, characterized in that, The method comprises the following steps: (a) esterifying a raw material containing a compound of Formula Ia with methanol in an inert solvent in the presence of a by-product inhibitor to form methyl 4-chloroacetoacetate; In step (a), the by-product inhibitor and methanol are added to the reaction system simultaneously or sequentially. The by-product inhibitor comprises a quaternary ammonium salt, and the by-product inhibitor is selected from the group consisting of tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, 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, hexadecyldiethylammonium bromide, bis-hexadecyldimethylammonium chloride, or a combination thereof. In step (a), the inert solvent is selected from the group consisting of chloroform, petroleum ether, dichloromethane, n-hexane, or a combination thereof.

2. The method of claim 1, wherein, The by-product inhibitor is selected from the group consisting of tetrabutylammonium bromide, phenyltriethylammonium chloride, hexadecyldiethylammonium bromide, or a combination thereof.

3. The method of claim 1, wherein, In step (a), the inert solvent is dichloromethane.

4. The method of claim 1, wherein, In step (a), the reaction conditions include: controlling the reaction temperature to be 0-5 ℃ when adding methanol, and then increasing the temperature to 20-25 ℃ after the addition is completed, and maintaining the reaction for 1-2 h.

5. The method of claim 1, wherein, The esterification reaction has a reaction temperature of -5-15 ℃ when the by-product inhibitor and methanol are added. The esterification reaction has a reaction temperature of 10-35 ℃ after the by-product inhibitor and methanol are added.

6. The method of claim 5, wherein, The esterification reaction has a reaction temperature of 0-5 ℃ when the by-product inhibitor and methanol are added. The esterification reaction has a reaction temperature of 20-25 ℃ after the by-product inhibitor and methanol are added.

7. The method of claim 1, wherein, In step (a), the by-product inhibitor is first added to the raw material containing the compound of Formula Ia, and then methanol is added for esterification.

8. The method of claim 1, wherein, In step (a), a mixture of the by-product inhibitor and anhydrous methanol is added to the raw material containing the compound of Formula Ia for esterification.

9. The method of claim 1, wherein, Before step (a), the method further comprises: (a0) introducing chlorine into a solution of divinyl ketone to perform a chlorination reaction, thereby obtaining a raw material containing a compound of Formula Ia 10. The method of claim 9, wherein, The molar ratio of the by-product inhibitor to divinyl ketone is 1:5-2000.

11. The method of claim 9, wherein, The molar ratio of the by-product inhibitor to divinyl ketone is 1:10-1000.

12. The method of claim 9, wherein, In step (a0), the flow rate of the introduced chlorine is 10-50 g / h.

13. The method of claim 1 or 9, wherein, The method further comprises: (b) post-treating the reaction mixture formed in step (a) to obtain a finished product of methyl 4-chloroacetoacetate.

14. The method of claim 13, wherein, Step (b) comprises: (b1) post-treating the reaction mixture to obtain a crude product of methyl 4-chloroacetoacetate; and (b2) performing vacuum rectification on the crude product of methyl 4-chloroacetoacetate to obtain a finished product of methyl 4-chloroacetoacetate.

15. The method of claim 13, wherein, The purity P1 of the 4-chloroacetoacetic acid methyl ester product is greater than or equal to 99.2%; and / or The content C1 of the impurity 4-chloro-3-methoxy-2-butenoic acid methyl ester of the 4-chloroacetoacetic acid methyl ester product is less than or equal to 0.3%. The purity P1 of the 4-chloroacetoacetic acid methyl ester product is greater than or equal to 99.2%; and / or The content C1 of the impurity 4-chloro-3-methoxy-2-butenoic acid methyl ester of the 4-chloroacetoacetic acid methyl ester product is less than or equal to 0.3%. The purity P1 of the 4-chloroacetoac

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