Preparation method of triphenylchloromethane and application thereof

Abstract

The application provides a preparation method of triphenyl chloromethane, comprising the following steps: adding water-soluble salt into triphenyl chloromethane hydrolysate, stirring uniformly, and then carrying out ultrasonic treatment. In the application, soluble salt is added in the preparation process of triphenyl chloromethane, so that the density difference in the triphenyl chloromethane hydrolysate is increased, and the separation effect of the organic phase and the aqueous phase is improved. Meanwhile, the triphenyl chloromethane hydrolysate is treated by ultrasonic, so that the combination of aluminum chloride and water is promoted, and the purposes of promoting the decomposition of the complex and shortening the hydrolysis time are achieved, and the generation of the emulsion layer is effectively avoided. In the preparation method of the triphenyl chloromethane, the potassium chloride and the ultrasonic treatment work synergistically, no side reaction is generated, the method is simple, efficient, safe and clean, the hydrolysis effect is effectively improved, the production cost is reduced, the emulsion layer hazardous waste treatment cost is saved, and the method is suitable for popularization and application.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical intermediates synthesis, in particular to a preparation method of triphenylmethyl chloride. BACKGROUND

[0002] Triphenylmethyl chloride, also known as triphenylmethyl chloride, is a very important pharmaceutical intermediate and chemical raw material, mainly used for the synthesis of candesartan and other sartan drugs for treating cardiovascular diseases. Triphenylmethyl chloride is a white crystalline substance, easily soluble in benzene, carbon disulfide and petroleum ether, slightly soluble in alcohol and ether, and becomes triphenylmethanol after water absorption. The melting point is 110-112℃, and the boiling point is 230-235℃ (20mmHg). Triphenylmethyl chloride is a highly active halogenated hydrocarbon, which is prone to nucleophilic substitution reaction and has high reactivity. It is often used for hydroxyl protection in organic and drug synthesis, and has excellent market prospects.

[0003] In current industrial production, the main synthesis method of triphenylmethyl chloride is the Friedel-Crafts alkylation reaction of benzene and carbon tetrachloride in the presence of Lewis acid, producing a complex of triphenylmethyl chloride and aluminum chloride. After hydrolysis, filtration, decolorization, and post-treatment such as recrystallization with petroleum ether and toluene, triphenylmethyl chloride is obtained.

[0004] In the hydrolysis process, the anchor type stirring is currently used in the hydrolysis kettle to stir the mixed hydrolysis liquid and the synthesis liquid. On the one hand, the separation effect of aluminum chloride complex in this method is poor, and on the other hand, due to the similar density of the water phase and the organic phase, long-time stirring can easily produce an emulsion layer, which affects the separation of the water phase and the organic phase and reduces the hydrolysis effect. In order to avoid the influence of the emulsion layer on the purity of the product, the current treatment method is to separate the emulsion layer and dispose it as hazardous waste, which increases the treatment cost and reduces the overall yield of triphenylmethyl chloride.

[0005] However, there is no technical method to solve this problem and improve the hydrolysis effect of triphenylmethyl chloride. SUMMARY

[0006] The purpose of the present application is to provide a simple and efficient, safe and clean preparation method of triphenylmethyl chloride, which improves the hydrolysis effect of triphenylmethyl chloride and increases the yield and purity of triphenylmethyl chloride, effectively avoids the generation of emulsion layer in the hydrolysis process of triphenylmethyl chloride, and promotes the decomposition of triphenylmethyl chloride complex.

[0007] On the one hand, the present application provides a preparation method of triphenylmethyl chloride, which comprises adding a water-soluble salt into the triphenylmethyl chloride hydrolysis liquid and stirring uniformly, and then performing ultrasonic treatment.

[0008] Further, the water-soluble salt is selected from one or more of potassium chloride, sodium chloride, ammonium chloride, calcium chloride, ammonium nitrate, sodium nitrate, potassium nitrate; preferably, the water-soluble salt is potassium chloride.

[0009] Further, the mass ratio of the triphenylchloromethane hydrolysate to the water-soluble salt is 1:(0.01-0.1); preferably, the mass ratio of the triphenylchloromethane hydrolysate to the water-soluble salt is 1:0.02.

[0010] Further, the ultrasonic treatment has an ultrasonic frequency of 20-100 KHz.

[0011] Further, the ultrasonic treatment has a treatment time of 1-3 h; preferably, the treatment time is 1 h.

[0012] In the present application, on one hand, the water-soluble salt is added to increase the density of the water phase, thereby increasing the density difference between the organic phase and the water phase and improving the separation degree of the organic phase and the water phase; on the other hand, the ultrasonic wave is used to promote the combination of aluminum chloride and water by virtue of the difference in hydrophilicity between aluminum chloride and triphenylchloromethane, so as to promote the decomposition of the aluminum chloride complex and shorten the hydrolysis time. Thus, the triphenylchloromethane hydrolysate is treated by the water-soluble salt and the ultrasonic wave in the method provided by the present application, which effectively avoids the generation of the emulsion layer, improves the hydrolysis effect of the triphenylchloromethane, improves the purity and yield of the triphenylchloromethane, and saves the industrial cost.

[0013] In a preferred embodiment, a method for preparing triphenylchloromethane, the method comprising: adding potassium chloride to the triphenylchloromethane hydrolysate, stirring uniformly, and then performing ultrasonic treatment at 20-100 KHz for 1-3 h.

[0014] No emulsion layer is found in the triphenylchloromethane hydrolysate after the above treatment, and the content of triphenylchloromethane in the organic phase of the triphenylchloromethane hydrolysate is increased to 31.65% or more, and can be as high as 33.78%.

[0015] Further, the preparation process of the triphenylchloromethane hydrolysate comprises the following steps:

[0016] Step one, mixing benzene and carbon tetrachloride to perform a Friedel-Crafts alkylation reaction to obtain a mixed solution;

[0017] Step two, mixing benzene, hydrochloric acid and the mixed solution to obtain the triphenylchloromethane hydrolysate.

[0018] Further, the Friedel-Crafts alkylation reaction is performed in the presence of a catalyst; preferably, the catalyst is aluminum chloride.

[0019] Further, the mass ratio of benzene and carbon tetrachloride in the Friedel-Crafts alkylation reaction is 1:(0.1-0.5); preferably, the mass ratio of benzene and carbon tetrachloride in the Friedel-Crafts alkylation reaction is 1:0.332; or,

[0020] The mass ratio of benzene and aluminum chloride in the Friedel-Crafts alkylation reaction is 1:(0.1-0.3); preferably, the mass ratio of benzene and aluminum chloride in the Friedel-Crafts alkylation reaction is 1:0.29; or,

[0021] The Friedel-Crafts alkylation reaction temperature is 18-30℃, and the reaction time is 4.5-8h.

[0022] Further, in the second step, the hydrochloric acid is a 10%-30% hydrochloric acid aqueous solution; preferably, the hydrochloric acid is a 20% hydrochloric acid aqueous solution; preferably, the mass ratio of benzene, hydrochloric acid, and mixed solution is 1:(1-3):(2-4); more preferably, the mass ratio of benzene, hydrochloric acid, and mixed solution in the second step is 1:1.95:3.86.

[0023] The amount of hydrochloric acid added is proportional to the amount of wastewater treated and the treatment cost, so through repeated experiments, it is confirmed that when the mass ratio of benzene, hydrochloric acid, and mixed solution is 1:1.95:3.86, the treatment method of the present application can ensure the minimum amount of wastewater treated and the minimum treatment cost.

[0024] In a preferred embodiment, a method for preparing triphenylmethyl chloride comprises the following steps:

[0025] Step 1, mixing benzene and carbon tetrachloride, and performing Friedel-Crafts alkylation reaction under the catalysis of aluminum chloride at 18-30℃ for 4.5-8h to obtain a mixed solution;

[0026] Step 2, mixing benzene, hydrochloric acid solution, and the mixed solution to obtain a triphenylmethyl chloride hydrolysate;

[0027] Step 3, adding potassium chloride to the triphenylmethyl chloride hydrolysate, stirring uniformly, and then performing 20-100KHz ultrasonic treatment for 1-3h.

[0028] On the other hand, the present application also provides the application of the above-mentioned method in the industrial production of triphenylmethyl chloride.

[0029] The present application has the following beneficial effects:

[0030] 1. The present application provides a new method for preparing triphenylmethyl chloride, which specifically adds potassium chloride to the triphenylmethyl chloride hydrolysate, increases the density difference in the triphenylmethyl chloride hydrolysate, and improves the separation effect of the organic phase and the aqueous phase;

[0031] 2. This application also uses ultrasonic treatment of triphenylchloromethane hydrolysate for the first time. By taking advantage of the difference in hydrophilicity between aluminum chloride and triphenylchloromethane, ultrasonic treatment is used to promote the combination of aluminum chloride and water, thereby promoting the decomposition of complex and shortening the hydrolysis time.

[0032] 3. In the preparation method of triphenylchloromethane provided in this application, potassium chloride and ultrasonic treatment work synergistically to effectively avoid the formation of an emulsion layer. This method does not produce side reactions, is simple, efficient, safe and clean, effectively improves the hydrolysis effect, reduces production costs, and also saves on the cost of hazardous waste treatment of the emulsion layer. Detailed Implementation

[0033] To more clearly illustrate the overall concept of this application, a detailed description is provided below by way of embodiments. Numerous specific details are set forth in the following description to provide a more thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention can be practiced without one or more of these details. In other instances, certain technical features well-known in the art have not been described to avoid confusion with the invention.

[0034] Unless otherwise specified in the examples, the conditions shall be performed according to the standard conditions or the conditions recommended by the manufacturer.

[0035] Unless otherwise specified, in the following embodiments, reagents or instruments whose manufacturers are not indicated are all conventional products that can be purchased commercially.

[0036] Example 1: Preparation of Triphenylchloromethane

[0037] Weigh 250g of benzene and 72.5g of aluminum chloride into a 1000mL four-necked flask, start stirring and mix evenly. Control the temperature at 18℃-30℃ and add 83g of carbon tetrachloride dropwise. The addition is completed in 4.5-8h, and 405.5g of a mixture of triphenylchloromethane and triphenylchloromethane complex is obtained.

[0038] Example 2: Treatment of Triphenylchloromethane Hydrolysate

[0039] Prepare 105g benzene and 205g 20% ​​hydrochloric acid as hydrolysate. Add 405.5g of the triphenylchloromethane and triphenylchloromethane complex mixture from Example 1 to the hydrolysate to obtain triphenylchloromethane hydrolysate. Add 15.5g potassium chloride and treat the hydrolysate mixture with an ultrasonic device for 1 hour. After standing for 30 minutes, the mixture separates into layers, and no emulsion layer is found.

[0040] The 20% hydrochloric acid is a 20% hydrochloric acid aqueous solution with an ultrasonic frequency of 20-100KHz; the mass ratio of benzene, hydrochloric acid and the mixture is 1:1.95:3.86.

[0041] Example 3

[0042] Prepare 105 g of benzene, 205 g of 20% hydrochloric acid as a hydrolysis solution, and drop 405.5 g of the mixture of triphenylmethyl chloride and triphenylmethyl chloride complex in Example 1 into the hydrolysis solution to obtain a triphenylmethyl chloride hydrolysis solution. Add 15.5 g of sodium chloride, treat the hydrolysis mixture with an ultrasonic device for 1 h, and stand for 30 min to separate the layers. No emulsion layer is found.

[0043] The 20% hydrochloric acid is a 20% hydrochloric acid aqueous solution, and the ultrasonic frequency is 20-100 KHz.

[0044] Example 4

[0045] Prepare 105 g of benzene, 205 g of 20% hydrochloric acid as a hydrolysis solution, and drop 405.5 g of the mixture of triphenylmethyl chloride and triphenylmethyl chloride complex in Example 1 into the hydrolysis solution to obtain a triphenylmethyl chloride hydrolysis solution. Add 15.5 g of ammonium chloride, treat the hydrolysis mixture with an ultrasonic device for 1 h, and stand for 30 min to separate the layers. No emulsion layer is found.

[0046] The 20% hydrochloric acid is a 20% hydrochloric acid aqueous solution, and the ultrasonic frequency is 20-100 KHz.

[0047] Example 5

[0048] Prepare 105 g of benzene, 205 g of 20% hydrochloric acid as a hydrolysis solution, and drop 405.5 g of the mixture of triphenylmethyl chloride and triphenylmethyl chloride complex in Example 1 into the hydrolysis solution to obtain a triphenylmethyl chloride hydrolysis solution. Add 15.5 g of potassium chloride, treat the hydrolysis mixture with an ultrasonic device for 4 h, and stand for 30 min to separate the layers. No emulsion layer is found.

[0049] The 20% hydrochloric acid is a 20% hydrochloric acid aqueous solution, and the ultrasonic frequency is 20-100 KHz.

[0050] Example 6

[0051] Prepare 105 g of benzene, 205 g of 20% hydrochloric acid as a hydrolysis solution, and drop 405.5 g of the mixture of triphenylmethyl chloride and triphenylmethyl chloride complex in Example 1 into the hydrolysis solution to obtain a triphenylmethyl chloride hydrolysis solution. Add 15.5 g of potassium chloride, stand for 30 min to separate the layers, and find an emulsion layer.

[0052] The 20% hydrochloric acid is a 20% hydrochloric acid aqueous solution.

[0053] Example 7

[0054] Prepare 105 g of benzene, 205 g of 20% hydrochloric acid as hydrolysis solution, add 405.5 g of triphenylmethyl chloride and triphenylmethyl chloride complex mixture in Example 1 into the hydrolysis solution, obtain the triphenylmethyl chloride hydrolysis solution, treat the hydrolysis mixture with ultrasonic equipment for 1 h, stand for 30 min, and separate the layers, and find that the emulsion layer is obvious.

[0055] The 20% hydrochloric acid is a 20% hydrochloric acid aqueous solution, and the ultrasonic frequency is 20-100 KHz.

[0056] Blank control group

[0057] Prepare 105 g of benzene, 205 g of 20% hydrochloric acid as hydrolysis solution, add 405.5 g of triphenylmethyl chloride and triphenylmethyl chloride complex mixture in Example 1 into the hydrolysis solution, obtain the triphenylmethyl chloride hydrolysis solution, stand for 30 min, separate the layers, and find that the emulsion layer is obvious.

[0058] The 20% hydrochloric acid is a 20% hydrochloric acid aqueous solution.

[0059] Example 8

[0060] The organic phase of the triphenylmethyl chloride hydrolysis solution treated in the above Examples 2-7 and the organic phase of the triphenylmethyl chloride hydrolysis solution of the blank control group are detected and analyzed, the content of triphenylmethyl chloride in the organic phase is detected, three measurements are taken, and the detection results are shown in Table 1.

[0061] The standard sample solution is prepared as follows:

[0062] Accurately weigh 0.10 g (accurate to 0.0002 g) of triphenylmethyl chloride standard sample, and place it in a 100 mL volumetric flask. Add 60 mL of methanol, and ultrasonically oscillate for 5 min to dissolve it. Cool to room temperature, dilute to the mark with methanol, and shake well. Take 5 mL of the above solution with a pipette into a 25 mL volumetric flask, dilute to the mark with methanol, shake well, and filter through a 0.45 μm filter membrane for use.

[0063] The sample solution is prepared as follows:

[0064] Accurately weigh 0.10 g (accurate to 0.0002 g) of the sample containing the sample, and place it in a 100 mL volumetric flask. Add 60 mL of methanol, and ultrasonically oscillate for 5 min to dissolve it. Cool to room temperature, dilute to the mark with methanol, and shake well. Take 5 mL of the above solution with a pipette into a 25 mL volumetric flask, dilute to the mark with methanol, shake well, and filter through a 0.45 μm filter membrane for use.

[0065] The chromatographic conditions are as follows:

[0066] Instrument: high performance liquid chromatograph; column: C18 column, 25 cm x 4.6 mm x 5 μm; reagent: mobile phase: methanol, filtered by 0.45 μm filter membrane, and used after ultrasonic treatment for 10 min; flow rate: 1.0 mL / min; column temperature: room temperature (the temperature difference change should be not more than 2℃); detection wavelength: 245 nm; injection volume: 10 μL; running time: 30 min.

[0067] The determination method is as follows:

[0068] Under the above operation conditions, after the instrument baseline is stable, several standard sample solutions are continuously injected, and the relative variation of the peak area of triphenylmethyl chloride of the adjacent two injections is not more than 1.0%. The determination is carried out in the order of standard sample solution, sample solution, sample solution, and standard sample solution.

[0069] The calculation method is as follows:

[0070] The peak areas of triphenylmethyl chloride in the two sample solutions and the two standard sample solutions before and after the sample are averaged, respectively. The mass fraction X1 (%) of triphenylmethyl chloride in the sample is calculated according to formula (1);

[0071]

[0072] In the formula:

[0073] A1 is the average value of the peak area of triphenylmethyl chloride in the standard sample solution;

[0074] A2 is the average value of the peak area of triphenylmethyl chloride in the sample solution;

[0075] m1 is the mass of the standard sample, g;

[0076] m2 is the mass of the sample, g;

[0077] P is the mass fraction of triphenylmethyl chloride in the standard sample, %.

[0078] The difference between the results of two parallel determinations should be not more than 1.0%.

[0079] Table 1

[0080] Examples Triphenylchloromethane content Example 2 33.78％ Example 3 32.24％ Example 4 32.1％ Example 5 31.65％ Example 6 28.39％ Example 7 28.84％ Blank control group 28.63％

[0081] As can be seen from the results in Table 1, the hydrolysis liquid mixture treated by the method effectively avoids the generation of emulsion layer, and the emulsion layer does not need to be treated subsequently. The content of triphenylmethyl chloride in the organic phase of the triphenylmethyl chloride hydrolysis liquid is improved, indicating that the hydrolysis effect is improved.

[0082] The above merely provides an example of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. within the spirit and principle of the present application should be included in the scope of claims of the present application.

Claims

1. A process for the preparation of triphenylchloromethane, characterized in that, The method comprises: adding a water-soluble salt into a triphenylmethyl chloride hydrolysate, stirring uniformly, and then performing ultrasonic treatment; the water-soluble salt is potassium chloride; the mass ratio of the triphenylmethyl chloride hydrolysate to the water-soluble salt is 1:0.02; the ultrasonic treatment has an ultrasonic frequency of 20-100 KHz and a treatment time of 1 h; The preparation process of the triphenylmethyl chloride hydrolysate comprises the following steps: Step one, mixing benzene and carbon tetrachloride, performing a Friedel-Crafts alkylation reaction, and obtaining a mixed liquid; Step two, mixing benzene, hydrochloric acid and the mixed liquid to obtain the triphenylmethyl chloride hydrolysate.

2. The method of claim 1, wherein, The Friedel-Crafts alkylation reaction is performed in the presence of a catalyst.

3. The method of claim 2, wherein, The catalyst is aluminum chloride.

4. The method of claim 1, wherein, The mass ratio of benzene to carbon tetrachloride in the Friedel-Crafts alkylation reaction is 1:(0.1-0.5).

5. The method of claim 4, wherein, The mass ratio of benzene to carbon tetrachloride in the Friedel-Crafts alkylation reaction is 1:0.

332.

6. The method of claim 3, wherein, The mass ratio of benzene to aluminum chloride in the Friedel-Crafts alkylation reaction is 1:(0.1-0.3).

7. The method of claim 6, wherein, The mass ratio of benzene to aluminum chloride in the Friedel-Crafts alkylation reaction is 1:0.

29.

8. The method of claim 1, wherein, The Friedel-Crafts alkylation reaction temperature is 18-30℃, and the reaction time is 4.5-8 h.

9. The method of claim 1, wherein, In step two, the hydrochloric acid is a hydrochloric acid aqueous solution with a concentration of 10%-30%.

10. The method of claim 9, wherein, The hydrochloric acid is a hydrochloric acid aqueous solution with a concentration of 20%.

11. The method of claim 1, wherein, In step two, the mass ratio of benzene, hydrochloric acid and the mixed liquid is 1:(1-3):(2-4).

12. The method of claim 11, wherein, In step two, the mass ratio of benzene, hydrochloric acid and the mixed liquid is 1:1.95:3.86.

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