Preparation method of cyclopropanecarbonyl chloride by using phosphorus trichloride as chlorination reagent

Abstract

The invention discloses a method for preparing cyclopropanecarboxylic acid by using phosphorus trichloride as a chlorination reagent, and belongs to the technical field of medicines and pesticides, the method comprises the following steps: adding cyclopropanecarboxylic acid into a reactor, starting stirring, heating to the reaction temperature of 40-60 DEG C, introducing nitrogen to carry out nitrogen replacement, carrying out nitrogen sealing in the whole process, starting dropwise adding phosphorus trichloride, controlling the dropwise adding speed, and reacting for 1-2 hours; the temperature of the reaction system is maintained at the reaction temperature, and the fluctuation temperature does not exceed + / -2 DEG C; after the dropwise adding of the phosphorus trichloride is finished, continuously carrying out heat preservation reaction for 0.5-2 hours, and then standing and separating the reaction liquid to obtain an upper layer which is a cyclopropanecarbonyl chloride crude product; and distilling the crude product of cyclopropanecarbonyl chloride to obtain a refined product of cyclopropanecarbonyl chloride. The method provided by the invention solves the problems of low chlorine atom utilization rate, incomplete catalysis of the adopted catalyst, easy generation of impurities, generation of toxic by-products sulfur dioxide and carbon monoxide, great threat to the environment, and three-waste emission in the existing acyl chloride preparation method.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical pesticides, and relates to the synthesis of quinolone antibacterial drugs such as ciprofloxacin, ciprofloxacin, sparfloxacin, and the like, as well as an important intermediate of a pesticide plant growth regulator trinexapac-ethyl, and specifically is a method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorination agent. Background Art

[0002] Acid chloride is a basic reagent for acylation reaction in organic synthesis and is widely used in medicine, pesticide, fuel industry, etc. Usually, acid chloride is prepared by reacting the corresponding carboxylic acid with a chlorination reagent, including "sulfoxide chloride method, oxalyl chloride method, phosphorus trichloride method, phosphorus pentachloride method, phosgene method, carbon tetrachloride method". However, for some chlorination reagents, one equivalent of HCl will be produced during the reaction, and the utilization rate of chlorine atoms is low (no more than 50%); the catalysts used in some processes are not completely catalytic, which is easy to cause impurities; some processes even produce toxic byproducts of sulfur dioxide and carbon monoxide, which pose a great threat to the environment and have the problem of three waste discharge. For example, the boiling point of the acid chloride generated by the sulfoxide chloride method is close to that of sulfoxide chloride and is not easy to separate. In addition, the amount of sulfoxide chloride used is large, the production cost is high, and the equipment is severely corroded. Phosgene is a highly toxic substance and is prohibited from transportation, requiring specific production qualifications. Summary of the invention

[0003] In view of the above technical problems existing in the prior art, the purpose of the present application is to provide a method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorination agent, which solves the problems of low chlorine atom utilization rate, incomplete catalysis of the catalyst used, easy impurities, toxic byproducts of sulfur dioxide and carbon monoxide, and three wastes emission in other processes. The production method has the characteristics of high atom utilization rate, simple post-processing procedures, and non-toxic and easy-to-separate byproduct phosphorous acid.

[0004] The technical solution adopted by the present invention is as follows:

[0005] A method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorinating agent comprises the following steps:

[0006] S1: Add cyclopropanecarboxylic acid to the reactor, start stirring, heat to the reaction temperature of 40-60°C, introduce nitrogen for nitrogen replacement, seal with nitrogen throughout the process, start to drop phosphorus trichloride, control the drop rate, keep the temperature of the reaction system at the reaction temperature, and the temperature fluctuation does not exceed ±2°C;

[0007] S2: After the phosphorus trichloride is added dropwise, the reaction is continued at a temperature of 0.5-2 hours, and then the reaction solution is transferred to a separatory funnel for standing. After the solution is separated and the upper layer is clarified, the upper layer is the crude cyclopropanecarbonyl chloride;

[0008] S3: The crude cyclopropanecarbonyl chloride is distilled to obtain a refined cyclopropanecarbonyl chloride.

[0009] Furthermore, in step S1, the molar ratio of cyclopropanecarboxylic acid to phosphorus trichloride is 1:0.4-0.6, preferably 1:0.45-0.5.

[0010] Furthermore, in step S1, the reaction temperature is 50°C±2°C.

[0011] Furthermore, in step S2, the insulation time is 1-1.5 hours, and the static stratification time is more than 5 hours.

[0012] Further, the distillation step in step S3 includes the following two steps:

[0013] 1) Removal of low boiling point substances: Under the operating pressure of 20kPa±2kPa, start from room temperature and heat up step by step. Distill for 0.5-1.5h every time the temperature rises by 8-12℃ until the temperature reaches 55℃±2℃. Distill until no fraction is produced.

[0014] 2) Collecting the target fraction: Keep the operating pressure of step 1) unchanged, switch the fraction, continue to increase the temperature, and collect the fraction at 60-90° C., which is cyclopropanecarbonyl chloride.

[0015] The beneficial effects of the present invention are:

[0016] 1) The problem of low chlorine atom utilization rate, incomplete catalysis of the catalyst used, easy to cause impurities, toxic byproducts of sulfur dioxide and carbon monoxide, and three wastes discharged in other processes is solved. The production method has the characteristics of high atom utilization rate, simple post-processing procedures, and the byproduct phosphorous acid is non-toxic and easy to separate.

[0017] 2) According to literature research, acyl chloride is prepared by thionyl chloride, oxalyl chloride and phosgene. Since one equivalent of HCl is produced during the reaction, the maximum utilization rate of chlorine atoms does not exceed 50%. In the present invention, the utilization rate of chlorine atoms can reach 61% based on the yield of 92%.

[0018] 3) The present invention adopts phosphorus trichloride as the chlorination reagent and develops the best process parameter conditions through process exploration. The final product obtained has high purity and high yield. Compared with the prior art, the present invention has high atom utilization rate, no harmful by-products are generated during the reaction process, among which the phosphorous acid by-product is non-toxic and easy to separate, and no specific production qualification is required. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is the gas chromatogram of cyclopropanecarbonyl chloride of experimental data in the embodiment of the present invention. DETAILED DESCRIPTION

[0020] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0021] Embodiment 1:

[0022] A method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride, the specific steps are as follows:

[0023] Step 1: Build an experimental device, including an oil bath with a magnetic stirring function, fix a dry 500 ml round-bottom flask in the oil bath, and connect the flask ports to a nitrogen protection device, a thermometer, a 200 ml constant pressure dropping funnel, and a spherical condenser (the top port is connected to a tail gas absorption device);

[0024] Step 2: Add 2.32 mol of cyclopropanecarboxylic acid into the flask at one time, start stirring, heat to 50°C, introduce nitrogen for nitrogen replacement, seal with nitrogen throughout the process, start to drop phosphorus trichloride, control the drop rate, keep the system temperature in the range of 50±2°C, and the total amount of phosphorus trichloride added is 0.928-1.16 mol;

[0025] Step 3: After the phosphorus trichloride is added dropwise, continue to heat and react for 1-3 hours;

[0026] Step 4, transfer the reaction solution to a separatory funnel, let it stand for more than 5 hours, and separate the solution after the upper layer is clear. The upper layer is the crude cyclopropanecarbonyl chloride;

[0027] Step 5, distilling the crude cyclopropanecarbonyl chloride, first removing low-boiling substances, and stepwise heating from room temperature at an operating pressure of 20 kPa, distilling for 1 hour at each 10°C increase in temperature, until the temperature is raised to about 55°C and distilling until no fraction is produced;

[0028] Step 6, switch the fraction, continue to raise the temperature, and collect the fraction at 60-90°C, which is cyclopropanecarbonyl chloride.

[0029] The following are the experimental data obtained in the product process of this application through the examples:

[0030] 1. Selection of experimental conditions

[0031] (1) Molar ratio

[0032] Theoretically, the reaction molar ratio of cyclopropanecarboxylic acid and phosphorus trichloride is 3:1. Since excess phosphorus trichloride helps to improve the conversion rate, we tried three different molar ratios of cyclopropanecarboxylic acid and phosphorus trichloride, 1:0.4, 1:0.45, and 1:0.5, and compared the experiments. We obtained different yields, and conducted kilogram-scale pilot tests to verify the consistent repeatability. We determined that the optimal ratio was 1:0.5.

[0033] (2) Reaction temperature and reaction time

[0034] We conducted comparative experiments in four reaction temperature ranges of 40±2, 45±2℃, 50±2, and 55±2℃. Starting from the end of the addition of phosphorus trichloride, samples were taken every 1h, and liquid chromatography was used for central control to detect the conversion rate. The conversion rate at different reaction times under different reaction temperatures was obtained, and the optimal reaction temperature was determined to be 50±2℃ and the reaction time was 1h.

[0035] 2. Test data under various experimental conditions

[0036] According to the experimental conditions of Example 1, the only difference is that:

[0037] In step 2, the total amount of phosphorus trichloride added is 0.928 mol, 1.044 mol or 1.16 mol, so that the molar ratio of cyclopropanecarboxylic acid to phosphorus trichloride is 1:0.4, 1:0.45 or 1:0.5;

[0038] In step 2 and step 3, the reaction temperature is 40±2, 45±2°C, 50±2 or 55±2°C;

[0039] In step 3, the heat preservation reaction time is 1h, 2h or 3h.

[0040] The test results under various experimental conditions are shown in Table 1.

[0041] Table 1. Process optimization test data

[0042]

[0043] In Table 1, numbers A1-A6 represent a group of experiments respectively, and the conversion rate is the result of the change of the conversion rate with the extension of the insulation time during the monitoring reaction process. The insulation reaction time 0h refers to the conversion rate result of cyclopropanecarboxylic acid after the addition of phosphorus trichloride in each experimental step is completed. The reaction yield of cyclopropanecarboxyl chloride in Table 1 refers to the cyclopropanecarboxyl chloride yield result finally obtained after the insulation reaction for 3h, and the reaction yield is calculated based on cyclopropanecarboxylic acid. The purity data in Table 1 are also the purity results of cyclopropanecarboxyl chloride finally obtained.

[0044] As can be seen from Table 1, after the addition of phosphorus trichloride in each experimental step is completed, the reaction can reach a very high degree by continuing the heat preservation reaction for about 1 hour.

[0045] 1. Product quality evaluation

[0046] At present, there is no national standard or industry standard for cyclopropanecarbonyl chloride. We have summarized the market enterprise standards and formulated the technical indicators of cyclopropanecarbonyl chloride in combination with customer requirements. The cyclopropanecarbonyl chloride product obtained by the experiment numbered A1 in Table 1 is compared with the market product indicators, as shown in Table 2:

[0047] Table 2. Cyclopropanecarbonyl chloride test data

[0048] project index Test Data Appearance Colorless transparent liquid Colorless transparent liquid purity ≥99.0 99.86 Chroma ≤50 0.5 Free fatty acids ≤0.5 ≤0.05

[0049] 2. Gas chromatography of cyclopropanecarbonyl chloride

[0050] The cyclopropanecarbonyl chloride product finally obtained from the experiment No. A1 in Table 1 was dissolved in methanol, and the gas chromatogram of the mixed solution was shown in the attached Figure 1 . Figure 1 The substance corresponding to the peak time of about 1.05min is methanol, and the substance corresponding to the peak time of 1.132min is cyclopropanecarbonyl chloride. Figure 1 Almost no impurities can be seen in the product, indicating that the product is of high purity.

[0051] 3. Conclusion

[0052] The invention adopts phosphorus trichloride method to prepare cyclopropanecarbonyl chloride as chlorination reagent, and under the optimal feed ratio, reaction temperature, reaction time and reduced pressure distillation conditions of the invention, obtains a product that meets market standards and has a yield of more than 92.0%, has high product yield, is simple to operate, and has no three wastes pollution.

[0053] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorinating agent, characterized in that The following steps are involved: S1: Add cyclopropanecarboxylic acid to the reactor, start stirring, heat to the reaction temperature of 40-60°C, introduce nitrogen for nitrogen replacement, seal with nitrogen throughout the process, start to drop phosphorus trichloride, control the drop rate, keep the temperature of the reaction system at the reaction temperature, and the temperature fluctuation does not exceed ±2°C; S2: After the phosphorus trichloride is added dropwise, the reaction is continued at a temperature of 0.5-2 hours, and then the reaction solution is transferred to a separatory funnel for standing. After the solution is separated and the upper layer is clarified, the upper layer is the crude cyclopropanecarbonyl chloride; S3: The crude cyclopropanecarbonyl chloride is distilled to obtain a refined cyclopropanecarbonyl chloride.

2. A method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorinating agent as claimed in claim 1, characterized in that In step S1, the molar ratio of cyclopropanecarboxylic acid to phosphorus trichloride is 1:0.4-0.6, preferably 1:0.45-0.

5.

3. A method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorinating agent as claimed in claim 1, characterized in that In step S1, the reaction temperature is 50°C±2°C.

4. A method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorinating agent as claimed in claim 1, characterized in that In step S2, the time in the heat preservation range is 1-1.5 hours, and the time for standing and stratifying is more than 5 hours.

5. A method for preparing cyclopropanecarbonyl chloride using phosphorus trichloride as a chlorinating agent as claimed in claim 1, characterized in that The distillation step in step S3 includes the following two steps: 1) Removal of low boiling point substances: Under the operating pressure of 20kPa±2kPa, start from room temperature and heat up step by step. Distill for 0.5-1.5h every time the temperature rises by 8-12℃ until the temperature reaches 55℃±2℃. Distill until no fraction is produced. 2) Collect the target fraction: Keep the operating pressure of step 1) unchanged, switch the fraction, continue to increase the temperature, and collect the fraction at 60-90°C, which is cyclopropanecarbonyl chloride.

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