Process for the preparation of an aforana key intermediate

Abstract

The present application belongs to the technical field of veterinary drugs, and particularly relates to a preparation method of a key intermediate of Afugan. The present application uses an economic and easily available raw material trifluorotoluene, and through bromination, Grignard reagent method preparation of trifluoroacetone, chlorination, 3-chloro-5-trifluoromethyl trifluorophenyl ethanone can be obtained, the shortcoming of long route in the prior art method is overcome, and the dangerous diazotization process is avoided. The method is simple in operation, mild in condition, and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug technology, and specifically relates to a method for preparing a key intermediate of afolanar. Background Technology

[0002] Afoxolaner, marketed as NexGard, is Boehringer Ingelheim's first oral deworming medication for dogs, targeting both ticks and fleas, launched in China in August 2017. It belongs to the isoxazoline class of compounds and works by inhibiting the GABA chloride ion channels in arthropods, leading to hyperexcitability and death. Currently, there are over 62 million pet dogs in China. Dogs are naturally active and susceptible to various parasites, which can harm both their own health and that of their owners, necessitating a series of measures to eliminate them. Afoxolaner begins killing fleas two hours after administration, preventing them from laying eggs and avoiding environmental pollution. It effectively prevents flea egg-laying for up to five weeks and also kills eight common cicada species, with effects lasting over a month. 3-Chloro-5-trifluoromethyltrifluoroacetophenone is an important intermediate in the synthesis of afoxolaner; it contains a relatively reactive trifluoroacetyl group and is also used in the synthesis of many pesticides.

[0003] CN113636919A discloses a method for synthesizing 3-chloro-5-trifluoromethyltrifluoroacetophenone: using o-aminotrifluorotoluene as a starting material, the method involves bromination, chlorination, diazotization, reduction with hypophosphorous acid, preparation of a Grignard reagent, and finally reaction with a trifluoroacetylation reagent to prepare 3-chloro-5-trifluoromethyltrifluoroacetophenone. The reaction formula is as follows: .

[0004] The aforementioned route involves lengthy steps and hazardous processes such as diazotization. Therefore, finding a mild, simple, and low-cost method for the industrial production of 3-chloro-5-trifluoromethyltrifluoroacetophenone, a key intermediate of afolanar, is a pressing technical problem that needs to be solved in this field. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, this invention provides a method for preparing a key intermediate of afolanar.

[0006] This invention is achieved through the following technical solution: A method for preparing a key intermediate of afolanar, the synthetic route of which is shown in the following reaction formula. .

[0007] Further steps include the following: (1) Trifluorotoluene reacts with bromine to give 3-bromotrifluorotoluene; (2) 3-Bromotrifluorotoluene and magnesium shavings are prepared into a Grignard reagent in tetrahydrofuran solvent, and then reacted with a trifluoroacetylation reagent to generate 3-trifluoromethyltrifluoroacetophenone; (3) 3-Trifluoromethyltrifluoroacetophenone reacts with a chlorinating agent to give 3-chloro-5-trifluoromethyltrifluoroacetophenone; Further, step (1) involves adding 1 part of trifluorotoluene and 0.01-0.1 parts of catalyst iron powder to the reaction vessel by mass, adding 1-1.5 parts of bromine at a controlled temperature of 20-50℃, and then maintaining the temperature at 40-50℃ for 12 hours; then cooling to 20-30℃, filtering to remove the catalyst iron powder, washing the filtrate with 2-5 parts of 15% sodium bisulfite aqueous solution, allowing it to stand to separate the aqueous phase, and distilling the organic phase under reduced pressure to obtain 3-bromotrifluorotoluene.

[0008] Furthermore, the vacuum distillation step in step (1) is as follows: the organic phase is distilled under reduced pressure at 20-30 mmHg, and the fraction at 80-90℃ is collected.

[0009] Further, in step (2), under nitrogen protection, 0.10 to 0.15 parts by mass of magnesium shavings, 3 to 5 parts by mass of tetrahydrofuran, and 0.01 to 0.05 parts by mass of iodine are added as initiators. The mixture is heated to 50°C, and 0.1 parts by mass of 3-bromotrifluorotoluene are added first. After the reaction is initiated, the remaining 0.9 parts by mass of 3-bromotrifluorotoluene are slowly added dropwise at 50 to 60°C. After the addition is completed in 1 to 3 hours, the mixture is kept at the temperature for another 1 hour. Then, the reaction solution is cooled to 0 to 10°C, and 0.6 to 1.2 parts by mass of ethyl trifluoroacetate are added dropwise at 0 to 10°C. After the addition is completed in 1 to 3 hours, the mixture is kept at the temperature for another 1 hour. Then, 2 to 5 parts by mass of 10% hydrochloric acid solution are added dropwise at 0 to 10°C. After the addition is completed in 1 to 3 hours, the mixture is kept at the temperature for another 1 hour. The mixture is allowed to stand and separated. After the organic phase is evaporated to dryness, an oily substance is obtained. The mixture is then distilled under reduced pressure to obtain 3-trifluoromethyltrifluoroacetophenone.

[0010] Furthermore, in step (2), the organic phase is concentrated under reduced pressure at 40-50 mmHg / 50℃ until no obvious liquid flows out to obtain an oily substance. The oily substance is then distilled under reduced pressure at 20-30 mmHg, and the fraction collected at 60-70℃ is used to obtain 3-trifluoromethyltrifluoroacetophenone.

[0011] Further, step (3) involves adding 1 part of 3-trifluoromethyltrifluoroacetophenone, 0.2-1 part of acetic acid, and 2-5 parts of sulfuric acid to the reaction vessel. The temperature is controlled at 25-50°C, and 0.5-1 part of NCS (N-chlorosuccinimide) is added in batches over 1-3 hours. The reaction is then maintained at this temperature for 12 hours. The reaction solution is poured into 10-20 parts of ice water at 0-20°C, then extracted with 5-10 parts of dichloromethane. After standing and separating the liquids, the organic phase is washed once with 2-5 parts of saturated saline solution. The organic phase is then evaporated to dryness to obtain an oily substance. Finally, the product is distilled under reduced pressure to obtain 3-chloro-5-trifluoromethyltrifluoroacetophenone.

[0012] Furthermore, in step (3), the organic phase is concentrated under reduced pressure at 40-50 mmHg / 50℃ until no obvious liquid flows out, resulting in an oily substance; the oily substance is distilled under reduced pressure at 20-30 mmHg, and the fraction at 80-100℃ is collected to obtain 3-chloro-5-trifluoromethyltrifluoroacetophenone.

[0013] The beneficial effects of this invention are as follows: This invention utilizes readily available and economical trifluorotoluene as a raw material to prepare trifluoroacetone via bromination and Grignard reagent method, followed by chlorination to obtain 3-chloro-5-trifluoromethyltrifluoroacetoluene. This overcomes the drawbacks of long routes in existing methods and avoids the dangerous diazotization process. The method is simple to operate, operates under mild conditions, and is suitable for industrial production. Attached Figure Description

[0014] The invention will now be further described with reference to the accompanying drawings.

[0015] Appendix Figure 1 The product made for this invention has the same peak elution time as the standard sample and a purity greater than 99%. Detailed Implementation

[0016] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention. Example

[0017] (1) Trifluorotoluene reacts with bromine to give 3-bromotrifluorotoluene; Specifically, step (1) involves adding 1 part of trifluorotoluene and 0.01 to 0.1 parts of catalyst iron powder to the reaction vessel, controlling the temperature at 20-50℃, adding 1 to 1.5 parts of bromine (elemental bromine, CAS Registry No. 7726-95-6), and then controlling the temperature at 40-50℃ for 12 hours; then cooling to 20-30℃, filtering to remove the catalyst, washing the filtrate with 2 to 5 parts of 15% (mass parts) sodium bisulfite aqueous solution, allowing it to stand to separate the aqueous phase, and distilling the organic phase under reduced pressure (distilling the organic phase under reduced pressure at 20-30 mmHg, collecting the fraction at 80-90℃) to obtain 3-bromotrifluorotoluene.

[0018] (2) 3-Bromotrifluorotoluene and magnesium shavings are prepared into a Grignard reagent in tetrahydrofuran solvent, and then reacted with a trifluoroacetylation reagent to generate 3-trifluoromethyltrifluoroacetophenone; Specifically, in step (2), under nitrogen protection, add 0.10 to 0.15 parts of magnesium shavings, 3 to 5 parts of tetrahydrofuran, and 0.01 to 0.05 parts of iodine as an initiator. Heat to 50°C, then add 0.1 parts of 3-bromotrifluorotoluene (1 part in total). After the reaction is initiated (by observing the color change of the reaction solution; from brown to colorless), slowly add the remaining 0.9 parts of 3-bromotrifluorotoluene (1 part in total) dropwise at 50-60°C. After the addition is completed in 1-3 hours, keep the temperature high for another hour. Then cool the reaction solution to 0-10°C, and add 0.6 to 1.2 parts of ethyl trifluoroacetate dropwise at 0-10°C. After the addition is completed in 1-3 hours, keep the temperature high for another hour. Then add 2 to 5 parts of 10% (mass fraction) hydrochloric acid solution dropwise at 0-10°C. After the addition is completed in 1-3 hours, keep the temperature high for another hour. After standing and separating the liquids, the organic phase was evaporated to dryness (the organic phase was concentrated under reduced pressure at 40-50 mmHg / 50℃ until no obvious liquid flowed out) to obtain an oily substance. The oily substance was then further distilled under reduced pressure (the oily substance was distilled under reduced pressure at 20-30 mmHg, and the fraction at 60-70℃ was collected) to obtain 3-trifluoromethyltrifluoroacetophenone.

[0019] (3) 3-Trifluoromethyltrifluoroacetophenone reacts with a chlorinating agent to give 3-chloro-5-trifluoromethyltrifluoroacetophenone; Specifically, step (3) involves adding 1 part of 3-trifluoromethyltrifluoroacetophenone, 0.2 to 1 part of acetic acid, and 2 to 5 parts of sulfuric acid to the reaction vessel. The temperature is controlled at 25-50℃, and 0.5 to 1 part of NCS (N-chlorosuccinimide) is added in batches over 1-3 hours. The reaction is then maintained at this temperature for 12 hours. The reaction solution is poured into 10-20 parts of ice water at 0-20℃, then extracted with 5 to 10 parts of dichloromethane. After standing and separating the liquids, the organic phase is washed once with 2 to 5 parts of saturated brine. The organic phase is then evaporated to dryness to obtain an oily substance. Finally, it is distilled under reduced pressure (specifically, the organic phase is concentrated under reduced pressure at 40-50 mmHg / 50℃ until no obvious liquid flows out, yielding an oily substance; the oily substance is then distilled under reduced pressure at 20-30 mmHg, and the fraction at 80-100℃ is collected) to obtain 3-chloro-5-trifluoromethyltrifluoroacetophenone. Example

[0020] Preparation of 3-bromotrifluorotoluene 146 g of trifluorotoluene and 1.5 g of iron catalyst powder were added to the reaction vessel. 150 g of bromine was added while maintaining the temperature at 20-50°C. The temperature was then maintained at 40-50°C for 12 hours. The temperature was then lowered to 20-30°C, and the catalyst was removed by filtration. The filtrate was washed with 350 g of 15% sodium bisulfite aqueous solution, allowed to stand to separate the aqueous phase, and the organic phase was subjected to vacuum distillation to obtain 171 g of 3-bromotrifluorotoluene, with a yield of 70%. Preparation of 3-trifluoromethyltrifluoroacetophenone Under nitrogen protection, 26 g of magnesium shavings, 800 g of tetrahydrofuran, and 2 g of iodine as an initiator were added. The mixture was heated to 50°C. First, 24.4 g of 3-bromotrifluorotoluene (total 244 g) was added. After the reaction was initiated, the remaining 219.6 g of 3-bromotrifluorotoluene (total 244 g) was slowly added dropwise over 1-3 hours. The reaction was then maintained at this temperature for another hour. The reaction solution was then cooled to 0-10°C, and 240 g of ethyl trifluoroacetate was added dropwise over 1-3 hours. The reaction was then maintained at this temperature for another hour. Next, 500 g of 10% hydrochloric acid solution was added dropwise over 1-3 hours. The reaction was then maintained at this temperature for another hour. After standing and separation, the organic phase was evaporated to dryness to obtain an oily substance. Further distillation under reduced pressure yielded 194 g of 3-trifluoromethyltrifluoroacetophenone, with a yield of 80%. Preparation of 3-chloro-5-trifluoromethyltrifluoroacetophenone 242 g of 3-trifluoromethyltrifluoroacetophenone, 50 g of acetic acid, and 500 g of sulfuric acid were added to a reaction vessel. 130 g of NCS (N-chlorosuccinimide) was added in portions over 1-3 hours while maintaining the temperature at 25-50°C. The reaction mixture was then kept at this temperature for 12 hours. The reaction solution was poured into 2500 g of ice water at 0-20°C, and then extracted with 1500 g of dichloromethane. After standing and separation, the organic phase was washed once with 500 g of saturated brine. The organic phase was then evaporated to dryness to obtain an oily substance, which was finally distilled under reduced pressure to obtain 210 g of 3-chloro-5-trifluoromethyltrifluoroacetophenone, with a yield of 76%.

[0021] The products prepared in this application have a purity greater than 99%. Unless otherwise specified, all reagents and raw materials used in this invention are commercially available. In cases where the Chinese nomenclature of a compound conflicts with its structural formula, the structural formula shall prevail, except where the structural formula is obviously incorrect. Unless otherwise specified, the quantities of each raw material in this application are by mass.

Claims

1. A method for preparing a key intermediate of afolanar, the synthetic route of which is shown in the following reaction formula. 。 2. The preparation method according to claim 1, characterized in that, Includes the following steps: (1) Trifluorotoluene reacts with bromine to give 3-bromotrifluorotoluene; (2) 3-Bromotrifluorotoluene and magnesium shavings are prepared into a Grignard reagent in tetrahydrofuran solvent, and then reacted with a trifluoroacetylation reagent to generate 3-trifluoromethyltrifluoroacetophenone; (3) 3-Trifluoromethyltrifluoroacetophenone reacts with a chlorinating agent to obtain 3-chloro-5-trifluoromethyltrifluoroacetophenone.

3. The preparation method according to claim 2, characterized in that, Step (1) involves adding 1 part by mass of trifluorotoluene and 0.01-0.1 parts by mass of catalyst iron powder to the reaction vessel, adding 1-1.5 parts by mass of bromine at a controlled temperature of 20-50℃, and then maintaining the temperature at 40-50℃ for 12 hours. The temperature is then lowered to 20-30℃, the catalyst iron powder is removed by filtration, the filtrate is washed with 2-5 parts by 15% sodium bisulfite aqueous solution, the aqueous phase is separated by standing, and the organic phase is distilled under reduced pressure to obtain 3-bromotrifluorotoluene.

4. The preparation method according to claim 3, characterized in that, The vacuum distillation step in step (1) is as follows: the organic phase is distilled under reduced pressure at 20-30 mmHg, and the fraction at 80-90℃ is collected.

5. The preparation method according to claim 2, characterized in that, Step (2) involves adding 0.10 to 0.15 parts by mass of magnesium shavings, 3 to 5 parts by mass of tetrahydrofuran, and 0.01 to 0.05 parts by mass of iodine under nitrogen protection as an initiator. The mixture is heated to 50°C, and 0.1 parts by mass of 3-bromotrifluorotoluene are added first. After the reaction is initiated, the remaining 0.9 parts by mass of 3-bromotrifluorotoluene are slowly added dropwise at 50-60°C. The addition is completed in 1-3 hours, and the reaction is maintained at this temperature for another hour. The reaction solution is then cooled to 0-10°C, and 0.6 to 1.2 parts by mass of ethyl trifluoroacetate are added dropwise at 0-10°C. The addition is completed in 1-3 hours, and the reaction is maintained at this temperature for another hour. Then, 2-5 parts by mass of 10% hydrochloric acid solution are added dropwise at 0-10°C. The addition is completed in 1-3 hours, and the reaction is maintained at this temperature for another hour. The mixture is allowed to stand and separated. The organic phase is evaporated to dryness to obtain an oily substance. The product is then further distilled under reduced pressure to obtain 3-trifluoromethyltrifluoroacetophenone.

6. The preparation method according to claim 5, characterized in that, In step (2), the organic phase is concentrated under reduced pressure at 40-50 mmHg / 50℃ until no obvious liquid flows out to obtain an oily substance. The oily substance is then distilled under reduced pressure at 20-30 mmHg, and the fraction collected at 60-70℃ is used to obtain 3-trifluoromethyltrifluoroacetophenone.

7. The preparation method according to claim 2, characterized in that, Step (3) involves adding 1 part of 3-trifluoromethyltrifluoroacetophenone, 0.2-1 part of acetic acid, and 2-5 parts of sulfuric acid to a reaction vessel. The temperature is controlled at 25-50℃, and 0.5-1 part of NCS (N-chlorosuccinimide) is added in batches over 1-3 hours. The reaction is then maintained at this temperature for 12 hours. The reaction solution is poured into 10-20 parts of ice water at 0-20℃, then extracted with 5-10 parts of dichloromethane. After standing and separating the liquids, the organic phase is washed once with 2-5 parts of saturated brine. The organic phase is then evaporated to dryness to obtain an oily substance. Finally, the substance is distilled under reduced pressure to obtain 3-chloro-5-trifluoromethyltrifluoroacetophenone.

8. The preparation method according to claim 2, characterized in that, In step (3), the organic phase is concentrated under reduced pressure at 40-50 mmHg / 50℃ until no obvious liquid flows out, and an oily substance is obtained; the oily substance is distilled under reduced pressure at 20-30 mmHg, and the fraction at 80-100℃ is collected to obtain 3-chloro-5-trifluoromethyltrifluoroacetophenone.

Images