Synthesis method of L-acetoxypropionyl chloride

Abstract

The invention provides a synthesis method of L-acetoxypropionyl chloride, and belongs to the field of medical intermediates and fine chemical engineering. The preparation method comprises the following steps: mixing L-lactic acid and acetyl chloride for first reaction; then adding trichlorotoluene and a catalyst to carry out a second reaction; and then rectifying and separating to obtain the product L-acetoxypropionyl 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 L-acetoxypropionyl chloride product is greater than 99%, and the yield is greater than 90%.

Description

Technical Field

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

[0002] L-acetoxypropionyl chloride is an important organic synthesis intermediate, as well as an intermediate for pharmaceuticals and pesticides. In the pharmaceutical industry, L-acetoxypropionyl chloride is an important raw material for the production of the contrast agent iopamidol. Currently, there are three methods for preparing L-acetoxypropionyl chloride in the industry: the thionyl chloride system; the phosgene system; and the triphosgene system.

[0003] Thionyl chloride system: L-lactic acid and acetyl chloride are reacted to form acetoxypropionic acid as the raw material, and thionyl chloride is used as the chlorinating reagent for chlorination. The reaction process is as follows:

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

[0005] This process has simple raw material process operations and easily available raw materials, and is a synthetic route suitable for industrial production; the disadvantages are that it generates acidic mixed waste gases such as sulfur dioxide and hydrogen chloride, with relatively high treatment costs, and the price of 90% lactic acid is high, resulting in high production costs, which does not meet the requirements of the current green environmental protection process.

[0006] Phosgene system: Phosgene is used to replace thionyl chloride, and acetoxypropionic acid is used as the raw material for chlorination. The reaction process is as follows:

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

[0008] This process does not generate 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] Triphosgene system: Triphosgene is used as the chlorinating reagent, and the catalyst catalyzes the chlorination of acetoxyacetic acid to obtain it. The reaction process is as follows:

[0010] CH 3COOCH 2 CH 2 COOH + CO(OCCL 3 ) 2 ----CH 3 COOCH 2 CH 2 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, with great danger, and the catalyst recovery is difficult, which is not conducive to industrial production.

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

[0013] The purpose of the present invention is to provide a synthesis method of L-acetoxypropionyl chloride. The reaction of the present invention is that two raw materials react to form two products, without the generation of sulfur dioxide or acidic mixed waste gas. The utilization rate of raw materials theoretically reaches 100%, which fully conforms to the green process of environmental protection and no pollution.

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

[0015] The present invention provides a synthesis method of L-acetoxypropionyl chloride, including the following steps:

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

[0017] Preferably, the mass ratio of L-lactic acid, acetyl chloride, benzotrichloride, and the catalyst is 1:1.6:3.9:(0.001 - 0.02).

[0018] Preferably, the mass concentration of L-lactic acid is 80%.

[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 is that two raw materials react to form two products, without the generation of sulfur dioxide or acidic mixed waste gas. In theory, the utilization rate of raw materials reaches 100%, which fully meets the green process of environmental protection and pollution-free. The safety of the used benzotrichloride is much higher than that of thionyl chloride and phosgene, and the reaction is mild. The reaction rate can be controlled by controlling the temperature and the amount of catalyst input, and the production operation is relatively safe. Since the utilization rate of raw materials is 100%, in addition to L-acetoxypropionyl chloride, the other product also has great market value, and the treatment cost of tail gas hydrogen chloride is low. Therefore, compared with other processes, the process of the present invention has low production cost and high efficiency. Detailed implementation manners

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

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

[0027] The present invention mixes L-lactic acid and acetyl chloride for the first reaction.

[0028] In the present invention, the mass concentration of the L-lactic 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 needed and the reaction can be directly carried out without solvent removal 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] CH 3 CHOHCOOH + CH 3 COCl → CH 3 COOCH 2 CH 2 COOH + HCl

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

[0033] After the first reaction of the present invention, 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 controlling the temperature and the amount of catalyst input, and the production operation is relatively safe.

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

[0036] In the present invention, the 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 CH 2 COOH + C 6 H 5 Cl 3 →CH 3 COOCH 2 CH 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 produce 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 form 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 L-acetoxypropionyl chloride, the other product also has great market value, and 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 regarded 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 used in the present invention are only for describing specific embodiments and are not intended to limit the present invention. Additionally, 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 may 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 the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the 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 the present invention, various improvements and changes can be made to the specific embodiments of the present invention specification, which are obvious to those skilled in the art. Other embodiments obtained from the specification of the present invention are obvious to those skilled in the art. The specification 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 the present 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 the present invention are obtained commercially.

[0049] Example 1

[0050] This example provides a method for synthesizing L-acetoxypropionyl chloride:

[0051] Charge 1000 kg of L-lactic acid with a mass concentration of 80% into a 5000 L synthesis kettle. At 10 °C, dropwise add 1600 kg of acetyl chloride. After addition, keep the temperature for reaction for 3 hours. Add 5 kg of catalyst ferric chloride, raise the temperature to 80 °C, dropwise add 3900 kg of benzotrichloride, and recover acetyl chloride. After the dropwise addition is completed, raise the temperature to 130 °C and react for 7 h to complete the reaction. Transfer the material to a 5000 L rectification kettle, control the reflux, collect the product acetoxypropionyl chloride with a content of 99.3% and a yield of over 94%. Finally, collect benzoyl chloride with a content of over 99.3% and a yield of greater than 93%.

[0052] Example 2

[0053] This example provides a method for synthesizing L-acetoxypropionyl chloride:

[0054] Put 1000 kg of L-lactic acid with a mass concentration of 80% into a 5000 L synthesis kettle. At 20 °C, dropwise add 1600 kg of acetyl chloride. After adding, keep the temperature for reaction for 2 hours. Add 5 kg of catalyst zinc chloride, raise the temperature to 70 °C, dropwise add 3900 kg of benzotrichloride, and recover acetyl chloride. After the dropwise addition is completed, raise the temperature to 120 °C and react for 9 h to make the reaction complete. Transfer the material to a 5000 L rectification kettle, control the reflux, collect the product acetyl-oxypropionyl chloride with a content of 99.4% and a yield of over 95%. Finally, collect benzoyl chloride with a content of over 99.1% and a yield of greater than 92%.

[0055] Example 3

[0056] This example provides a method for synthesizing L-acetoxypropionyl chloride:

[0057] Put 1000 kg of L-lactic acid with a mass concentration of 80% into a 5000 L synthesis kettle. At 30 °C, dropwise add 1600 kg of acetyl chloride. After adding, keep the temperature for reaction for 3 hours. Add 10 kg of catalyst aluminum chloride, raise the temperature to 90 °C, dropwise add 3900 kg of benzotrichloride, and recover acetyl chloride. After the dropwise addition is completed, raise the temperature to 100 °C and react for 12 h to make the reaction complete. Transfer the material to a 5000 L rectification kettle, control the reflux, collect the product acetyl-oxypropionyl chloride with a content of 99.6% and a yield of over 96%. Finally, collect benzoyl chloride with a content of over 99% and a yield of greater than 90%.

[0058] Example 4

[0059] This example provides a method for synthesizing L-acetoxypropionyl chloride:

[0060] Put 1000 kg of L-lactic acid with a mass concentration of 80% into a 5000 L synthesis kettle. At 45 °C, dropwise add 1600 kg of acetyl chloride. After adding, keep the temperature for reaction for 3 hours. Add 3 kg of catalyst antimony chloride, raise the temperature to 70 °C, dropwise add 3900 kg of benzotrichloride, and recover acetyl chloride. After the dropwise addition is completed, raise the temperature to 120 °C and react for 10 h to make the reaction complete. Transfer the material to a 5000 L rectification kettle, control the reflux, collect the product acetyl-oxypropionyl chloride with a content of 99.2% and a yield of over 95%. Finally, collect benzoyl chloride with a content of over 99.3% and a yield of greater than 94%.

[0061] The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing L-acetoxypropionyl chloride, characterized in that: The following steps are involved: L-lactic acid and acetyl chloride are mixed to carry out a first reaction; then trichlorotoluene and a catalyst are added to carry out a second reaction; and then the product L-acetoxypropionyl chloride is obtained through distillation separation.

2. The synthesis method according to claim 1, characterized in that The mass ratio of the L-lactic acid, acetyl chloride, trichlorotoluene and catalyst is 1:1.6:3.9:(0.001-0.02).

3. The synthesis method according to claim 1 or 2, characterized in that The mass concentration of the L-lactic acid is 80%.

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.