Synthesis method of acetoxyacetyl chloride

Abstract

The invention provides a synthesis method of acetoxyacetyl chloride, and belongs to the field of medical intermediates and fine chemical engineering. The preparation method comprises the following steps: mixing glycolic acid and acetyl chloride for first reaction; then adding trichlorotoluene and a catalyst to carry out a second reaction; and rectifying and separating to obtain the product acetoxyacetyl chloride. According to the method, two raw materials react to generate two products, no sulfur dioxide or acidic mixed waste gas is generated, the utilization rate of the raw materials reaches 100% theoretically, and the method completely conforms to an environment-friendly and pollution-free green process. The safety of the used trichlorotoluene is far higher than that of thionyl chloride and phosgene, the reaction is mild, the reaction speed can be controlled by controlling the temperature and the input amount of the catalyst, the production operation is relatively safe, and the purity of the prepared acetoxyacetyl chloride product is greater than 99% and the yield is greater than 92%.

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceutical intermediates and fine chemicals, and particularly to a method for synthesizing acetoxyacetyl chloride. Background Art

[0002] Acetoxyacetyl chloride is an important intermediate for organic synthesis, pharmaceuticals, and pesticides. In the pharmaceutical industry, acetoxyacetyl chloride is used to produce ioversol drugs, paclitaxel, and roxatidine. Currently, there are three methods for preparing acetoxyacetyl chloride in the industry: thionyl chloride system; phosgene system; triphosgene system.

[0003] 1) Thionyl chloride system: Catalyzed by zinc chloride, using acetoxyacetic acid as the raw material and thionyl chloride as the chlorinating agent for chlorination. The reaction process is as follows:

[0004] CH 3 COOCH 2 COOH + SOCl 2 -----CH 3 COOCH 2 COCl + SO 2 + HCl

[0005] This process has simple process operation and easily available raw materials, and is a synthetic route suitable for industrial production; the disadvantage is that it generates acidic mixed waste gases such as sulfur dioxide and hydrogen chloride, and the treatment cost is relatively high, which does not meet the requirements of the current green environmental protection process.

[0006] 2) Phosgene system: Using phosgene to replace thionyl chloride, and chlorinating with acetoxyacetic acid as the raw material. The reaction process is as follows:

[0007] CH 3 COOCH 2 COOH + COCl 2 ---CH 3 COOCH 2 COCl + CO 2 + HCl

[0008] This process does not produce sulfur dioxide, and phosgene is cheaper than thionyl chloride, but phosgene itself is a highly toxic chemical with high toxicity, and it is inconvenient for transportation and storage.

[0009] 3) Triphosgene system: Using triphosgene as the chlorinating reagent and catalyzing the chlorination of acetoxyacetic acid. The reaction process is as follows:

[0010] CH 3 COOCH 2 COOH + CO(OCCl 3 ) 2 ----CH 3 COOCH2 COCl + CO 2 + HCl

[0011] Triphosgene is stable at room temperature and has low toxicity. However, during the reaction, at a relatively high temperature, triphosgene decomposes rapidly and is difficult to control. The reaction is prone to getting out of control, posing a great danger. Moreover, the catalyst recovery is difficult, which is not conducive to industrial production.

[0012] Due to the increasing market demand for acetoxyacetyl chloride, it is necessary to develop a synthesis method with high yield, which can meet the requirements of industrial production, has relatively low cost, and at the same time meets the requirements of green environmental protection processes. Summary of the Invention

[0013] The purpose of the present invention is to provide a synthesis method of acetoxyacetyl chloride. The reaction of the present invention involves two raw materials reacting to form two products, without generating sulfur dioxide or acidic mixed waste gas. Theoretically, the utilization rate of the raw materials reaches 100%, fully meeting the requirements of an environmentally friendly and pollution-free green process.

[0014] To achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0015] The present invention provides a synthesis method of acetoxyacetyl chloride, comprising the following steps:

[0016] Mix glycolic acid and acetyl chloride for a first reaction; then add benzotrichloride and a catalyst for a second reaction; then obtain the product acetoxyacetyl chloride through rectification and separation.

[0017] Preferably, the mass ratio of glycolic acid, acetyl chloride, benzotrichloride, and the catalyst is 1:2:5:(0.01 - 0.02).

[0018] Preferably, the mass concentration of glycolic acid is 70%.

[0019] Preferably, the catalyst is one or more of ferric chloride, zinc chloride, aluminum chloride, and antimony chloride.

[0020] Preferably, the temperature of the first reaction is 0 - 45°C, and the reaction time is 0.5 - 3 h.

[0021] Preferably, the temperature of the second reaction is 90 - 160°C, and the reaction time is 7 - 12 h.

[0022] Preferably, the unreacted acetyl chloride is recovered before the second reaction.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The reaction of the present invention involves two raw materials reacting to form two products, without the generation of sulfur dioxide or acidic mixed waste gas. Theoretically, the utilization rate of the raw materials reaches 100%, fully meeting the requirements of an environmentally friendly and pollution-free green process. The safety of benzotrichloride used is much higher than that of thionyl chloride and phosgene, and the reaction is mild. The reaction rate can be controlled by adjusting the temperature and the amount of catalyst added, making the production operation relatively safe. Since the utilization rate of the raw materials is 100%, in addition to acetyloxyacetyl chloride, the other product also has great market value, and the cost of treating the tail gas hydrogen chloride is low. Therefore, compared with other processes, the process of the present invention has low production costs and high efficiency. Detailed Embodiment

[0025] The present invention provides a method for synthesizing acetyloxyacetyl chloride, comprising the following steps:

[0026] Mix glycolic acid and acetyl chloride for the first reaction; then add benzotrichloride and a catalyst for the second reaction; and then obtain the product acetyloxyacetyl chloride through rectification separation.

[0027] In the present invention, glycolic acid and acetyl chloride are mixed for the first reaction.

[0028] In the present invention, the mass concentration of the glycolic acid is 70%.

[0029] In the present invention, the temperature of the first reaction is 0 - 45 °C, preferably 20 - 35 °C; the reaction time is 0.5 - 3 h, preferably 1 - 2 h. By adopting the above technical solution, in the first reaction, no solvent is required, and the reaction can be directly carried out without solvent stripping, and the second reaction can be directly carried out.

[0030] In the present invention, the reaction process of the first reaction is as follows:

[0031] HOCH 2 COOH + CH 3 COCl → CH 3 COOCH 2 COOH + HCl

[0032] The HCl generated in the first reaction of the present invention is easy to treat.

[0033] After the first reaction of the present invention is completed, benzotrichloride and a catalyst are added for the second reaction.

[0034] By adopting the above technical solution, the safety of benzotrichloride in the present invention is much higher than that of thionyl chloride and phosgene, and the reaction is mild. The reaction rate can be controlled by adjusting the temperature and the amount of catalyst added, making the production operation relatively safe.

[0035] In the present invention, the temperature of the second reaction is 90 - 160 °C, preferably 110 - 130 °C, the reaction time is 7 - 12 h, preferably 9 - 11 h.

[0036] In the present invention, unreacted acetyl chloride is recovered before the second reaction.

[0037] In the present invention, the reaction process of the second reaction is as follows:

[0038] CH 3 COOCH 2 COOH + C 6 H 5 Cl 3 →CH 3 COOCH 2 COCl + C 6 H 5 COCl + HCl

[0039] The second reaction of the present invention produces HCl, which is the same as the first reaction and does not generate mixed waste gas, and the overall treatment process is simple.

[0040] By adopting the above technical solution, the reaction of the present invention is that two raw materials react to generate two products, without the generation of sulfur dioxide and acidic mixed waste gas. The utilization rate of raw materials theoretically reaches 100%, which fully meets the green process of environmental protection and pollution-free.

[0041] The product finally obtained by rectification in the present invention, in addition to acetyl oxyacetyl chloride, the other product also has great market value. Moreover, the treatment cost of the tail gas hydrogen chloride generated in the first and second reactions is low. Therefore, compared with other processes, the process of the present invention has low production cost and high efficiency.

[0042] Now, various exemplary embodiments of the present invention will be described in detail. This detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and implementation schemes of the present invention.

[0043] It should be understood that the terms described in the present invention are only for describing specific embodiments and are not used to limit the present invention. In addition, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.

[0044] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although this invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to those documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0045] Without departing from the scope or spirit of this invention, various improvements and changes can be made to the specific embodiments of the description of this invention, which will be obvious to those skilled in the art. Other embodiments obtained from the description of this invention will be obvious to those skilled in the art. The description and examples of this application are merely exemplary.

[0046] Regarding the use of "comprising", "including", "having", "containing", etc. herein, they are all open-ended terms, meaning including but not limited to.

[0047] As used in this invention, "room temperature" and "normal temperature" are both calculated as 25 ± 2 °C unless otherwise specified.

[0048] All raw materials used in the following examples of this invention are obtained commercially.

[0049] Example 1

[0050] This example provides a method for synthesizing acetoxyacetyl chloride:

[0051] Add 100 g (0.92 mol) of glycolic acid (content 70%) to a 500 mL four-necked flask, then add 200 g (2.53 mol) of acetyl chloride, control the reaction temperature at 5 °C. After the reaction is complete, add 500 g (2.55 mol) of benzotrichloride (content 99%) and recover the unreacted acetyl chloride. Then, using 1 g of anhydrous ferric chloride as a catalyst, stir and heat up to 125 °C, keep the temperature for reaction for 11 hours, and perform rectification to obtain the fore-fraction (114 g of acetoxyacetyl chloride product, purity 99.1%, molar yield 90.28%); obtain the after-fraction (420 g, which is benzoyl chloride product, purity 99.2%, molar yield 93.43%).

[0052] Example 2

[0053] This example provides a method for synthesizing acetoxyacetyl chloride:

[0054] Add 100 g (0.92 mol) of glycolic acid (content 70%) to a 500 mL four-necked flask, then add 200 g (2.53 mol) of acetyl chloride. Control the reaction temperature at 15°C. After the reaction is complete, add 500 g (2.55 mol) of benzotrichloride (content 99%) and recover the unreacted acetyl chloride. Then, using 1 g of anhydrous zinc chloride as a catalyst, stir and heat up to 115°C, keep the temperature for reaction for 12 hours, and perform rectification to obtain the fore-fraction (116 g of chloroacetoxyacetyl chloride product, purity 99.1%, molar yield 92%); obtain the after-fraction (425 g, which is benzoyl chloride product, purity 99.2%, molar yield 94%).

[0055] Example 3

[0056] This example provides a method for synthesizing chloroacetoxyacetyl chloride:

[0057] Add 100 g (0.92 mol) of glycolic acid (content 70%) to a 500 mL four-necked flask, then add 200 g (2.53 mol) of acetyl chloride. Control the reaction temperature at 40°C. After the reaction is complete, add 500 g (2.55 mol) of benzotrichloride (content 99%) and recover the unreacted acetyl chloride. Then, using 1 g of anhydrous aluminum chloride as a catalyst, stir and heat up to 110°C, keep the temperature for reaction for 12 hours, and perform rectification to obtain the fore-fraction (115 g of chloroacetoxyacetyl chloride product, purity 99.1%, molar yield 91%); obtain the after-fraction (423 g, which is benzoyl chloride product, purity 99.2%, molar yield 93%).

[0058] Example 4

[0059] Add 100 g (0.92 mol) of glycolic acid (content 70%) to a 500 mL four-necked flask, then add 200 g (2.53 mol) of acetyl chloride. Control the reaction temperature at 30°C. After the reaction is complete, add 500 g (2.55 mol) of benzotrichloride (content 99%) and recover the unreacted acetyl chloride. Then, using 1 g of anhydrous antimony chloride as a catalyst, stir and heat up to 125°C, keep the temperature for reaction for 12 hours, and perform rectification to obtain the fore-fraction (117 g of chloroacetoxyacetyl chloride product, purity 99.4%, molar yield 93%); obtain the after-fraction (428 g, which is benzoyl chloride product, purity 99.2%, molar yield 95%).

[0060] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing acetoxyacetyl chloride, characterized in that: The following steps are involved: The first reaction is carried out by mixing hydroxyacetic acid and acetyl chloride; then benzotrichloride and a catalyst are added to carry out a second reaction; and then the product acetoxyacetyl chloride is obtained through distillation separation.

2. The synthesis method according to claim 1, characterized in that The mass ratio of the glycolic acid, acetyl chloride, trichlorotoluene and the catalyst is 1:2:5:(0.01-0.02).

3. The synthesis method according to claim 1 or 2, characterized in that The mass concentration of the glycolic acid is 70%.

4. The synthesis method according to claim 1 or 2, characterized in that The catalyst is one or more of ferric chloride, zinc chloride, aluminum chloride and antimony chloride.

5. The synthesis method according to claim 1, characterized in that The temperature of the first reaction is 0-45°C, and the reaction time is 0.5-3h.

6. The synthesis method according to claim 1, characterized in that The temperature of the second reaction is 90-160° C., and the reaction time is 7-12 hours.

7. The synthesis method according to claim 1, characterized in that The unreacted acetyl chloride is recovered before the second reaction.