A process for the production of a clotrimazole intermediate (2-chlorophenyl)diphenylmethanol

Abstract

The application belongs to the technical field of medical intermediates, and relates to a production method of a clotrimazole intermediate (2-chlorophenyl)diphenylmethanol. In the method, 2-methyltetrahydrofuran or cyclopentyl methyl ether is used as a reaction solvent, an ethyl o-chlorobenzoate solution is added dropwise into a phenyl magnesium bromide solution with a concentration of 2.5-3.5 M under the conditions of 60-80 DEG C and inert atmosphere, the reaction is continuously carried out after the dropwise addition is completed, a water solution of a quenching agent is added after the reaction to quench, then, liquid separation is carried out, and the organic phase after the liquid separation is concentrated to obtain a crude product; the crude product is refined by using a reaction solvent and petroleum ether, and (2-chlorophenyl)diphenylmethanol is obtained. The production method can efficiently and stably produce high-quality (2-chlorophenyl)diphenylmethanol, reduces production cost and safety hazards, and can be used for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate preparation technology, and relates to a method for producing (2-chlorophenyl)diphenylmethanol, an intermediate of crizolidinium. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] The traditional synthesis of clotrimazole involves the Grignard reaction, hydrolysis, chlorination, and condensation of an ester with Grignard reagent. In the Grignard reaction step, the traditional solvents are tetrahydrofuran, diethyl ether, and benzene. However, tetrahydrofuran and diethyl ether have low boiling points and form peroxides, which are not only dangerous but also detrimental to the reaction, making them unsuitable for industrial production. Benzene is a highly toxic substance and a Group 1 carcinogen, further unsuitable as a solvent for synthesizing human drugs. Therefore, selecting a suitable solvent is urgently needed.

[0004] Furthermore, the inventors discovered during the experimental research phase that the reaction conversion rate and impurity levels are closely related to the type and concentration of the Grignard reagent. Weaker Grignard reagents cause the reaction to stop at the transition state, resulting in very little product. Low-concentration Grignard reagents, in order to increase the conversion rate, prolong the reaction time, leading to an increase in chlorine-depleted impurities. These impurities can be transferred to the API, becoming EP impurity F (limit 0.1%). Because its polarity is very similar to clotrimazole, it is extremely difficult to remove, resulting in API non-compliance.

[0005]

[0006] According to the inventor's research, the vast majority of commercially available (2-chlorophenyl)diphenylmethanol products are small-scale samples prepared in laboratories by reagent companies or companies that customize impurities. Occasionally, factories can supply kilogram-scale products, but the purity is only 98%, with single impurities >0.5%, and the supply is unstable. The market for clotrimazole is huge, and as a key intermediate for clotrimazole, (2-chlorophenyl)diphenylmethanol has almost no domestic industrial-scale production enterprises. Its development, research, and industrial production are of great significance. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a method for producing (2-chlorophenyl)diphenylmethanol, an intermediate of crizotinib. This method can efficiently and stably produce high-quality (2-chlorophenyl)diphenylmethanol, reducing production costs and safety hazards, thereby enabling large-scale industrial production.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

[0009] On one hand, a method for producing the crizocarbamide intermediate (2-chlorophenyl)diphenylmethanol involves using 2-methyltetrahydrofuran or cyclopentylmethyl ether as a reaction solvent. Under conditions of 60–80°C and an inert atmosphere, an ethyl o-chlorobenzoate solution is added dropwise to a 2.5–3.5 M magnesium phenyl bromide solution. After the addition is complete, the reaction is continued at this temperature. Following the reaction, an aqueous solution of a quencher is added to quench the reaction. The mixture is then separated, and the organic phase after separation is concentrated to obtain a crude product. The crude product is then purified using the reaction solvent and petroleum ether to obtain the final product.

[0010] This invention uses 2-methyltetrahydrofuran as the reaction solvent, which avoids the generation of peroxides during the reaction process and eliminates potential production safety hazards. Furthermore, oral toxicity studies of solutions of 2-methyltetrahydrofuran and cyclopentylmethyl ether showed negative results for both genotoxicity and mutagenicity. Therefore, using 2-methyltetrahydrofuran or cyclopentylmethyl ether as the reaction solvent can significantly reduce both production safety hazards and medication safety hazards.

[0011] Secondly, the present invention uses a high-concentration magnesium phenyl bromide solution and adds materials by adding ethyl o-chlorobenzoate solution dropwise to the magnesium phenyl bromide solution, which can improve the reaction efficiency and thus avoid increasing the amount of chlorine impurities.

[0012] Furthermore, further research on the reaction system based on 2-methyltetrahydrofuran or cyclopentylmethyl ether as the reaction solvent revealed that using 2-methyltetrahydrofuran and petroleum ether can not only significantly reduce dechlorination impurities in the product, but also ensure the stability of the purity of each batch of (2-chlorophenyl)diphenylmethanol.

[0013] On the other hand, a (2-chlorophenyl)diphenylmethanol raw material has a purity of 99.0-99.6%, a chlorine depletion impurity of 0.04-0.05%, and other elemental substances of <0.1%.

[0014] The beneficial effects of this invention are as follows:

[0015] (1) The present invention uses 2-methyltetrahydrofuran or cyclopentylmethyl ether as the reaction solvent, which is more stable to acids and bases and less likely to form peroxides, making the reaction controllable, eliminating the danger of scale-up production, and suitable for industrial production.

[0016] (2) The present invention uses a highly active Grignard reagent—magnesium phenyl bromide for the reaction, which is conducive to the further reaction of the transition state to generate (2-chlorophenyl)diphenylmethanol, which is conducive to the smooth progress of the reaction, improves the reaction yield, and the yield can reach more than 80%, thereby reducing the product cost.

[0017] (3) The present invention uses a high concentration of Grignard reagent—2.5 to 3.5 M phenyl magnesium bromide (2-methyltetrahydrofuran) solution, which increases the reaction rate, shortens the reaction time, reduces the generation of chlorine impurities, and improves the quality of (2-chlorophenyl)diphenylmethanol product.

[0018] (4) The present invention uses 2-methyltetrahydrofuran as the reaction solvent, which increases the temperature of the system, exceeding the reflux temperature of conventional solvents tetrahydrofuran (66°C) and diethyl ether (34.5°C), reduces the activation energy of the reaction, increases the reaction rate, and shortens the reaction time. Together with high-concentration Grignard reagents and highly active Grignard reagents, it achieves the effect of high yield, high quality and low cost.

[0019] (5) The post-processing of this invention uses a mixture of reaction solvent (2-methyltetrahydrofuran or cyclopentylmethyl ether) and petroleum ether for purification, which has a significant effect on removing chlorine impurities, further reducing the impurity content, and ensuring that high-quality (2-chlorophenyl)diphenylmethanol with a purity >99.0% and a single impurity <0.1% can be stably produced. Attached Figure Description

[0020] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0021] Figure 1 The liquid phase spectrum of (2-chlorophenyl)diphenylmethanol prepared in Example 1 of this invention;

[0022] Figure 2 The liquid phase spectrum of (2-chlorophenyl)diphenylmethanol prepared in Example 2 of this invention;

[0023] Figure 3 The liquid phase spectrum of (2-chlorophenyl)diphenylmethanol prepared in Example 3 of this invention;

[0024] Figure 4 The liquid phase spectrum of (2-chlorophenyl)diphenylmethanol prepared in Comparative Example 1 of this invention is shown.

[0025] Figure 5 The liquid phase spectrum of (2-chlorophenyl)diphenylmethanol prepared in Comparative Example 2 of this invention is shown.

[0026] Figure 6 The liquid phase spectrum of (2-chlorophenyl)diphenylmethanol prepared in Comparative Example 3 of this invention is shown. Detailed Implementation

[0027] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. 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.

[0028] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0029] In view of the problems of high risk, low yield, difficult purification and low purity in the existing preparation of (2-chlorophenyl)diphenylmethanol, the present invention proposes a method for producing (2-chlorophenyl)diphenylmethanol, an intermediate of crizolidinium.

[0030] A typical embodiment of the present invention provides a method for producing the crizocarbamide intermediate (2-chlorophenyl)diphenylmethanol. Using 2-methyltetrahydrofuran or cyclopentylmethyl ether as the reaction solvent, under conditions of 60–80°C and an inert atmosphere, an ethyl o-chlorobenzoate solution is added dropwise to a 2.5–3.5 M magnesium phenyl bromide solution. After the addition is complete, the reaction is continued at this temperature. After the reaction, an aqueous solution of a quencher is added to quench the reaction, followed by separation. The organic phase after separation is concentrated to obtain a crude product. The crude product is then purified using the reaction solvent and petroleum ether to obtain the final product.

[0031] The ethyl o-chlorobenzoate solution of this invention is formed by dissolving ethyl o-chlorobenzoate in a portion of the reaction solvent. The phenyl magnesium bromide solution of this invention is formed by dissolving phenyl magnesium bromide in another portion of the reaction solvent.

[0032] In some embodiments, the reaction solvent is 2-methyltetrahydrofuran. Studies have shown that using 2-methyltetrahydrofuran as the reaction solvent results in better dispersion of the materials, which is beneficial for improving reaction efficiency.

[0033] In some embodiments, the mass ratio of ethyl o-chlorobenzoate to solvent in the ethyl o-chlorobenzoate solution is 1:0.1 to 1.0, preferably 1:0.4 to 0.6. Excessive addition of solvent should be avoided, as it may affect the reaction efficiency.

[0034] In some embodiments, the molar ratio of ethyl o-chlorobenzoate to magnesium phenyl bromide is 1:2 to 3, preferably 1:2.4 to 2.6.

[0035] In some embodiments, the temperature of the added ethyl o-chlorobenzoate solution is 68–72°C.

[0036] In some embodiments, the reaction temperature is 73–77°C.

[0037] In some embodiments, the reaction time is 0.5 to 1.5 hours, preferably 0.9 to 1.1 hours.

[0038] In some embodiments, the aqueous solution of the quenching agent is an ammonium chloride solution or a dilute hydrochloric acid solution with a mass fraction of less than 20%, preferably an ammonium chloride solution.

[0039] In some embodiments, during the purification process, the weight of the added reaction solvent is 1 to 3 times the weight of ethyl o-chlorobenzoate, preferably 1.5 to 2.5 times.

[0040] In some embodiments, during the refining process, the weight of petroleum ether added is 5 to 10 times that of ethyl o-chlorobenzoate, preferably 5.5 to 6.5 times.

[0041] In some embodiments, the refining process is as follows: the crude product is added to a reaction solvent and heated to dissolve, then petroleum ether is added to cool and crystallize, followed by filtration and drying.

[0042] In one or more embodiments, the solution is dissolved by heating to 70–80°C.

[0043] In one or more embodiments, the crystallization temperature is -10 to 20°C, preferably 3 to 7°C.

[0044] In one or more embodiments, the crystallization time is 1 to 3 hours, preferably 1.5 to 2.5 hours.

[0045] In another embodiment of the present invention, a (2-chlorophenyl)diphenylmethanol raw material is provided, wherein the purity of (2-chlorophenyl)diphenylmethanol is 99.0-99.6%, the dechlorination impurity is 0.04-0.05%, and the remaining elemental substances are <0.1%.

[0046] Specifically, the (2-chlorophenyl)diphenylmethanol raw material is obtained by the above-described production method.

[0047] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0048] Example 1:

[0049] (1) Under nitrogen protection, add 4.5 kg of 3M phenyl magnesium bromide in 2-methyltetrahydrofuran solution to a 20L glass reactor and stir to raise the temperature to 70℃.

[0050] (2) Slowly add 1.0 kg / 0.5 kg of ethyl o-chlorobenzoate in a 2-methyltetrahydrofuran solution.

[0051] (3) Control the temperature at 75℃ and react for 1 hour.

[0052] (4) Add 7 kg of water and 1.5 kg of ammonium chloride to another 20 L glass reactor, stir and cool down to 5 °C.

[0053] (5) Add the reaction system dropwise into the ammonium chloride solution and keep the temperature below 20°C.

[0054] (6) Stir and separate the liquids. Store the organic phase temporarily and extract the aqueous phase once with 1 kg of 2-methyltetrahydrofuran.

[0055] (7) Combine the organic phases and concentrate under reduced pressure (45℃, -0.09MPa) to obtain crude product.

[0056] (8) Add 2 kg of 2-methyltetrahydrofuran, stir and heat to 75°C to dissolve, and add 8 kg of petroleum ether dropwise.

[0057] (9) Cooling and crystallization: Maintain temperature at 5℃ and stir for 2 hours. Filter, rinse, and dry to obtain 1.3 kg M1, yield 80.8%, purity 99.5%, chlorine impurities removed 0.04%, other single impurities <0.1%. Figure 1 As shown.

[0058] Example 2

[0059] (1) Under nitrogen protection, add 20 kg of 3M phenyl magnesium bromide in 2-methyltetrahydrofuran solution to a 50L glass reactor and stir to raise the temperature to 70℃.

[0060] (2) Slowly add 5 kg / 2 kg of ethyl o-chlorobenzoate in a 2-methyltetrahydrofuran solution.

[0061] (3) Control the temperature at 75℃ and react for 1 hour.

[0062] (4) Add 35kg of purified water and 8kg of ammonium chloride to a 100L enamel reactor, stir and cool to 5℃.

[0063] (5) Slowly add the reaction system dropwise into the ammonium chloride solution in a 100L enamel reactor, and control the temperature to <20℃.

[0064] (6) Separate the liquid phase, and extract the aqueous phase with 5 kg of 2-methyltetrahydrofuran, leaving the organic phase in the reactor.

[0065] (7) Separate the organic phase into a 100L reactor, add 1kg of anhydrous sodium sulfate to dry, filter, concentrate under reduced pressure (45℃, -0.09MPa) to obtain crude product.

[0066] (8) Add 10 kg of 2-methyltetrahydrofuran and heat to 75°C to dissolve, then add 30 kg of petroleum ether dropwise.

[0067] (9) Cooling and crystallization: Maintain temperature at 5℃ and stir for 2 hours. Filter, rinse, and dry to obtain 6.5 kg M1, yield 80.8%, purity 99.4%, chlorine impurities removed 0.05%, other single impurities <0.1%. Figure 2 As shown.

[0068] Example 3

[0069] (1) Under nitrogen protection, add 45 kg of 3M phenyl magnesium bromide in 2-methyltetrahydrofuran solution to a 100L enamel reactor and stir to raise the temperature to 70℃.

[0070] (2) Use a dropper to slowly add 10 kg / 5 kg of ethyl o-chlorobenzoate in a 2-methyltetrahydrofuran solution.

[0071] (3) Control the temperature at 75℃ and react for 1 hour.

[0072] (4) Add 70.0 kg of purified water and 15 kg of ammonium chloride to a 200 L enamel reactor, stir and cool to 5 °C.

[0073] (5) Slowly add the reaction system from the 100L glass reactor to the 200L enamel reactor, and control the temperature to <20℃.

[0074] (6) Separate the aqueous phase into a 100L reactor and extract with 10kg of 2-methyltetrahydrofuran. Leave the organic phase in the 200L reactor.

[0075] (7) Separate the organic phase into a 200L reactor, add 2kg of anhydrous sodium sulfate and dry for 2 hours, filter, transfer the filtrate to a 100L reactor and concentrate under reduced pressure (45℃, -0.09MPa) to obtain the crude product.

[0076] (8) Add 20 kg of 2-methyltetrahydrofuran and heat to 75 °C to dissolve, then add 60 kg of petroleum ether dropwise.

[0077] (9) Cooling and crystallization: Maintain temperature at 5℃ and stir for 2 hours. Filter, wash, and dry to obtain 13.1 kg of white powder (2-chlorophenyl)diphenylmethanol, yield 81.5%, purity 99.6%, chlorine impurities removed 0.04%, and other single impurities <0.1%. Figure 3 As shown.

[0078] Comparative Example 1:

[0079] Under nitrogen protection, 1.4 L of 1M phenyl magnesium chloride tetrahydrofuran solution was added to a 2 L glass reaction flask. The temperature was raised to 60 °C, and 100 g of ethyl o-chlorobenzoate was added dropwise. The mixture was refluxed for 4 hours, cooled, and then added dropwise to an ammonium chloride solution (150 g dissolved in 700 ml water) that had been pre-cooled to 5 °C. The mixture was extracted, separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Crystallization was then performed using tetrahydrofuran / petroleum ether at 0 °C, but no solid precipitated. The mixture was then concentrated back to an oily substance, and the purity was determined to be 18.2%. Figure 4 As shown.

[0080] Comparative Example 2:

[0081] Under nitrogen protection, 1.4 L of 1M phenyl magnesium bromide tetrahydrofuran solution was added to a 2 L glass reaction flask. The temperature was raised to 60 °C, and 100 g of ethyl o-chlorobenzoate was added dropwise. The mixture was refluxed for 4 hours, cooled, and then added dropwise to an ammonium chloride solution (150 g dissolved in 700 ml water) that had been pre-cooled to 5 °C. The mixture was extracted, separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. Crystallization was then performed using tetrahydrofuran / petroleum ether at 0 °C, but no solid precipitated. The mixture was then concentrated back to an oily substance, and the purity was determined to be 55.1%. Figure 5 As shown.

[0082] Comparative Example 3:

[0083] Under nitrogen protection, 1.4 L of 1M phenyl magnesium chloride 2-methyltetrahydrofuran solution was added to a 2L glass reaction flask. The mixture was heated to 70°C, and 100 g of ethyl o-chlorobenzoate was added dropwise. The mixture was refluxed for 4 hours, cooled, and then added dropwise to an ammonium chloride solution (150 g dissolved in 700 ml water) that had been pre-cooled to 5°C. The mixture was extracted, separated, and the organic phase was concentrated under reduced pressure to obtain an oily substance. This substance was then cooled to 0°C with tetrahydrofuran / petroleum ether to induce crystallization. The system agglomerated, and the purity was determined to be 64.3%. Figure 6 As shown.

[0084] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for producing the crizocarbamide intermediate (2-chlorophenyl)diphenylmethanol, characterized in that, The ethyl o-chlorobenzoate solution is added dropwise to a phenyl magnesium bromide solution with a concentration of 2.5-3.5 M under the conditions of 2-methyltetrahydrofuran or cyclopentyl methyl ether as the reaction solvent, 60-80 ℃ and inert atmosphere, and the reaction is continued after the dropwise addition is completed at a temperature of 73-77 ℃ for 0.5-1.5 h; after the reaction, a water solution of a quenching agent is added for quenching, then the organic phase after the separation is concentrated to obtain a crude product; the crude product is refined by using the reaction solvent and petroleum ether, and the ethyl 2-chlorostyrene is obtained.

2. The production method of the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to claim 1, characterized by, The reaction solvent is 2-methyltetrahydrofuran.

3. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 1, characterized by, In the ethyl o-chlorobenzoate solution, the mass ratio of ethyl o-chlorobenzoate to solvent is 1:0.1-1.

0.

4. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 3, characterized by, In the ethyl o-chlorobenzoate solution, the mass ratio of ethyl o-chlorobenzoate to solvent is 1:0.4-0.

6.

5. The method for producing the crizocarbamide intermediate (2-chlorophenyl)diphenylmethanol as described in claim 1, characterized in that, The molar ratio of ethyl o-chlorobenzoate to phenyl magnesium bromide is 1:2-3.

6. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 5, characterized by, The molar ratio of ethyl o-chlorobenzoate to phenyl magnesium bromide is 1:2.4-2.

6.

7. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 1, characterized by, The temperature of the dropwise added ethyl o-chlorobenzoate solution is 68-72 ℃.

8. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 1, characterized by, The reaction time is 0.9-1.1 h.

9. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 1, characterized by, The water solution of the quenching agent is an ammonium chloride solution or dilute hydrochloric acid with a mass fraction of less than 20%.

10. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 9, characterized by, The water solution of the quenching agent is an ammonium chloride solution.

11. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 1, characterized by, In the refining process, the added weight of the reaction solvent is 1-3 times the weight of ethyl o-chlorobenzoate.

12. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 11, characterized by, In the refining process, the added weight of the reaction solvent is 1.5-2.5 times the weight of ethyl o-chlorobenzoate.

13. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 1, characterized by, In the refining process, the added weight of petroleum ether is 5-10 times the weight of ethyl o-chlorobenzoate.

14. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 13, characterized by, In the refining process, the added weight of petroleum ether is 5.5-6.5 times the weight of ethyl o-chlorobenzoate.

15. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 1, characterized by, The refining process is: the crude product is added to the reaction solvent for heating and dissolving, petroleum ether is added for cooling and crystallization, and then filtration and drying are performed.

16. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 15, characterized by, Heating to 70-80 ℃ for dissolving.

17. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 15, characterized by, The crystallization temperature is -10-20 ℃.

18. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 17, wherein The crystallization temperature is 3-7 ℃.

19. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 15, characterized by, The crystallization time is 1-3 h.

20. The method for producing the intermediate of caspofungin (2-chlorophenyl)diphenylmethanol according to Claim 19, wherein The crystallization time is 1.5-2.5 h.

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