Method for preparing isoxazoline through continuous reaction

Abstract

The invention provides a method for preparing isoxazoline through continuous reaction, which comprises the following steps: A, oximation reaction: stirring hydroxylamine hydrochloride, alkali and an organic solvent, dissolving, adding substituted aryl formaldehyde (S1), heating and stirring until S1 is completely converted into P1, and cooling to room temperature after the reaction is finished; b, halogenation reaction: adding a halogenation reagent until the P1 is completely converted into P2; c, 1, 3-dipole addition reaction: adding substituted aryl ethylene (S2) and alkali into P2 until the reaction is complete; d, post-treatment; and E, recrystallizing. According to the reaction, the isoxazoline-containing intermediate is synthesized by adopting a one-pot method, an intermediate product does not need to be separated in the reaction process, the operation and post-treatment steps are greatly reduced, the molar yield of the obtained product is up to 60%, and the purity is detected to be more than 95.0%.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to the preparation of isoxazoline-based pet anti-parasitic drugs. Specifically, it relates to a method for continuously reacting to prepare isoxazoline. Background Art

[0002] Fluralaner, afoxolaner, sarolaner, and lotilaner, as the latest generation of pet anti-parasitic drugs, have the characteristics of rapid onset, long-lasting efficacy, and safety for pets. The main synthetic methods for their key isoxazoline include the chalcone method and the dipolar addition method. Among them, the dipolar addition method is difficult to apply to industrial production due to its complex operation, many side reactions, and low yield. Therefore, it is of great significance to study how to reduce the side reactions of the dipolar addition method, improve the yield and product purity, reduce labor costs, and improve the industrial application prospects. At the same time, it also helps to promote the domestic development and research of such drugs and improve the core competitiveness, which has great practical significance.

[0003] Currently, the prior art document patent CN12457267 reports a synthetic route 1, specifically as follows:

[0004] This route is applicable to the synthesis of lotilaner. Starting from 5-bromo-3-methylthiophene-2-carboxylic acid and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene, an isoxazoline intermediate is obtained through two steps of reaction. However, it is limited by the expensive raw materials, and palladium catalyst and the toxic reagent nitromethane are used in the reaction process, which is not suitable for industrialization.

[0005] The prior art document patent CN109879826 reports a synthetic route 2, specifically as follows:

[0006]

[0007] This route is also used for the synthesis of lotilaner. The isoxazoline synthesis is completed through three steps of reaction: oximation, chlorination, and dipolar addition of the intermediate formylthiophene amide. However, the starting material 5-formyl-3-methylthiophene-2-carboxylic acid is expensive, and different solvents are used in the oximation reaction and the chlorination reaction. After the reaction, extraction is required in both cases. Although no further treatment is necessary, the two-step extraction operation already occupies a large amount of time cost and is time-consuming and laborious.

[0008] The prior art document patent CN10176***5592 reports a synthetic route 3, specifically as follows:

[0009] This route also has the problems of different reaction solvents and cumbersome operations such as multiple post-treatments, and is not suitable for industrial production.

[0010] Based on the current methods for synthesizing isoxazoline via the dipolar addition route, the solvents used in both the chlorination reaction and the dipolar addition reaction are DMF, while the solvent for the oximation reaction is other solvents such as methanol or tetrahydrofuran. After the oximation reaction is completed, operations such as extraction are required, and then it needs to be changed to DMF for subsequent reactions. This results in cumbersome reaction operations, a large loss of intermediates, low yields, and may increase side reactions, bringing bottlenecks to the subsequent product purification and industrialization. Therefore, optimizing the dipolar addition reaction method is of great significance for the process development of existing products and the design and synthesis of new compounds. Summary of the Invention

[0011] The object of the present invention is to solve the drawbacks existing in the prior art, and provide a method for preparing isoxazoline through a continuous dipolar addition reaction. This method uses a substituted aryl aldehyde as the starting material and completes the oximation reaction, halogenation reaction, and dipolar addition reaction in one pot using one or several combined solvents to complete the synthesis of the isoxazoline-containing compound.

[0012] The technical solution adopted by the present invention is as follows: A method for continuously reacting to prepare isoxazoline, comprising the following steps: A. Oximation reaction: After stirring and dissolving hydroxylamine hydrochloride, a base, and an organic solvent until clear, add a substituted aryl aldehyde (S1), heat and stir until S1 is completely converted to P1, and after the reaction is completed, cool to room temperature; B. Halogenation reaction: Add a halogenating reagent until the above-mentioned P1 is completely converted to P2; C. 1,3-Dipolar addition reaction: Add a substituted aryl ethylene (S2) and a base to P2 until the reaction is complete; D. Post-treatment: After the reaction is completed, add water, then add an organic solvent, stir and separate the phases, discard the aqueous phase, wash the organic phase with an appropriate amount of water, dry with anhydrous sodium sulfate, filter by suction, and concentrate until there is no solvent to obtain a crude product; E. Recrystallization: Add an organic solvent to the above-mentioned crude product, heat to dissolve completely, then slowly cool to crystallize, filter by suction, and dry to obtain the product.

[0013] Furthermore, the base in the oximation reaction includes one of K2CO3, Na2CO3, NaOH, DIPEA, DIPA, DBU, DABCO, DMAP, pyridine, and triethylamine.

[0014] Furthermore, the organic solvent used in the oximation reaction includes one or a combination of methanol, ethanol, isopropanol, dioxane, DMSO, DMF, DMA, acetonitrile, toluene, and acetone.

[0015] Further, the feed for the oximation reaction is in a molar ratio of aryl aldehyde: hydroxylamine hydrochloride: base = 1: 1-3: 1-3; Further, the temperature of the oximation reaction is 25-80 °C, preferably 25-55 °C, more preferably 25-45 °C.

[0016] Further, the halogenating reagents used in the halogenation reaction include N -N-chlorosuccinimide (NCS), N -N-bromosuccinimide (NBS), N -N-iodosuccinimide (NIS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) and sodium hypochlorite (NaClO).

[0017] Further, the feed for the halogenation reaction is in a molar ratio of P1: halogenating reagent = 1: 1-3, preferably 1: 1-1.5.

[0018] Further, the bases used in the 1,3-dipolar cycloaddition reaction include one of K2CO3, Na2CO3, NaOH, DIPEA, DIPA, DBU, DABCO, DMAP, pyridine, and triethylamine; Further, the feed for the 1,3-dipolar cycloaddition reaction is in a molar ratio of P2: substituted aryl ethylene: base = 1: 1-2: 1-2.

[0019] Further, the organic solvents in the post-treatment include one of ethyl acetate (EA), dichloromethane (DCM), methyl tert-butyl ether (MTBE), ether, and toluene; The organic solvents used in the recrystallization include one or more of methanol, ethanol, isopropanol, acetonitrile, toluene, acetone, ethyl acetate, n-hexane, petroleum ether, n-heptane, and chloroform.

[0020] The beneficial effects obtained by the present invention are as follows: The raw materials of this reaction are more readily available, and each step involved in the reaction process uses the same solvent system and is carried out in the same reaction flask. The isoxazoline-containing intermediate is synthesized by a one-pot method. The intermediate products do not need to be separated during the reaction process, which greatly reduces the operation and post-treatment steps. At the same time, the overall reaction process takes a short time, saves solvents and time, and greatly improves the reaction efficiency; in addition, the molar yield of the obtained product is as high as 60%, and the purity is detected to be above 95.0%.

[0021] The product obtained by the synthesis method of the present invention has an increased yield, saves raw materials and time. This synthesis route is simple, the raw materials are readily available, the synthesis cost is low, and at the same time, the efficiency is improved because of reducing the post-treatment operation, which is suitable for large-scale production and can meet the large market demand. Description of the Drawings

[0022] Figure 1 This is the HPLC chromatogram of the product obtained in Example 1 of the present invention; Figure 2 This is the synthesis general formula of the present invention. Detailed implementation manners

[0023] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.

[0024] Example 1: First step: Oximation reaction

[0025] Add 7.79 g (112 mmol) of hydroxylamine hydrochloride and 200 mL of DMF to a 1000 mL three-necked flask, stir, then add 11.34 g (112 mmol) of triethylamine, control the temperature at 20 - 30 °C, stir for 30 min, then add 20 g (93 mmol) of 1-S1. After adding, keep the temperature at 35 - 45 °C for 0.5 h, and use the developing agent of EA:Hex = 1:5 (volume ratio) for TLC monitoring until the reaction of 1-S1 is complete.

[0026] Second step: Halogenation reaction

[0027] Cool the above reaction solution to 25 - 35 °C, and slowly add 16.21 g (121 mmol) of NCS in batches. After adding, keep the temperature at 25 - 35 °C for 0.5 h, and monitor the complete reaction of 1-P1 by TLC (EA:Hex = 1:5).

[0028] Third step: 1,3-dipolar cycloaddition reaction

[0029] Add 25.64 g (93 mmol) of 1-S2 and 9.45 g (93 mmol) of triethylamine to the reaction solution obtained in the second step, and keep the temperature for reaction for 2 h. Monitor the complete reaction of 1-P2 by TLC (EA:Hex = 1:10).

[0030] Slowly add the reaction solution to 1 L of purified water while stirring. Then add ethyl acetate (200 mL × 2) for extraction. Combine the organic phases, wash twice with water (200 mL × 2), dry with anhydrous sodium sulfate, filter by suction. The crude product after concentrating the filtrate is recrystallized with ethanol, filtered, and dried to obtain 32.65 g of the product, with a molar yield of 67.2%.

[0031] To analyze the purity of the obtained product, the obtained product was subjected to HPLC testing. The relevant information of the chromatograph and chromatographic column used is shown in Table 1.

[0032] Table 1 Relevant information of the chromatograph and chromatographic column

[0033] The detection conditions for HPLC testing were as follows: Octadecylsilane-bonded silica gel was used as the filler (Agilent Zorbax-SBC18 column, 4.6 * 250 mm, 5 μm or a chromatographic column with equivalent efficiency); the mobile phase was gradient eluted with methanol / acetonitrile (50:50): water; the flow rate was 1.0 ml per minute; the detection wavelength was 225 nm; the injection volume was 5 μl. The obtained liquid chromatogram was as shown in Figure 1 shown. From Figure 1 it can be concluded that the purity of the obtained product was 98.54%.

[0034] Example 2:

[0035] 10.16 g (146 mmol) of hydroxylamine hydrochloride and 200 mL of DMSO were added to a 1000 mL three-necked flask, stirred, and then 14.79 g (146 mmol) of triethylamine was added. The temperature was controlled at 20 - 30 °C, and the mixture was stirred for 30 min. Then 20 g (122 mmol) of 2-S1 was added. After addition, the mixture was kept at 35 - 45 °C for 0.5 h and monitored by TLC (EA: Hex = 1:5) until the reaction of 2-S1 was complete. The temperature was lowered, and then 21.15 g (158 mmol) of NCS was slowly added to the reaction flask in batches. After addition, the mixture was kept at 25 - 35 °C for 1 h and monitored by TLC (EA: Hex = 1:5) until the reaction of 2-P1 was complete. 29.41 g (122 mmol) of 2-S2 and 12.33 g (122 mmol) of triethylamine were added to the reaction solution, and the mixture was kept at a certain temperature for 3 h and monitored by TLC (EA: Hex = 1:10) until the reaction of 2-P2 was complete.

[0036] The reaction solution was slowly added to 1 L of purified water while stirring. Subsequently, ethyl acetate (200 mL × 2) was added for extraction. The organic phases were combined, washed twice with water (200 mL × 2), dried over anhydrous sodium sulfate, filtered by suction. The crude product after concentration of the filtrate was recrystallized with methanol, filtered, and dried to obtain 31.33 g of the product, with a molar yield of 61.5% and a purity of 98.7% detected by HPLC.

[0037] Example 3:

[0038] Add 8.13 g (117 mmol) of hydroxylamine hydrochloride and 200 mL of DMA to a 1000 mL three-necked flask, stir, then add 11.84 g (117 mmol) of triethylamine, control the temperature at 20 - 30 °C, stir for 30 min, then add 20 g (98 mmol) of 3-S1. After adding, keep the temperature at 35 - 45 °C for heat preservation reaction for 0.5 h, monitor by TLC (EA: Hex = 1: 5) until the reaction of 3-S1 is complete. Cool down, then slowly add 25.02 g (127 mmol) of DCDMH to the reaction flask in batches. After adding, keep the temperature at 25 - 35 °C for heat preservation reaction for 1 h, monitor the reaction of 3-P1 by TLC (EA: Hex = 1: 5) until it is complete. Add 26.87 g (98 mmol) of 3-S2 and 9.87 g (98 mmol) of triethylamine to the reaction solution, keep the temperature for reaction for 3 h, monitor the reaction of 3-P2 by TLC (EA: Hex = 1: 10) until it is complete.

[0039] Slowly add the reaction solution to 1 L of purified water while stirring. Then add dichloromethane (200 mL × 2) for extraction. Combine the organic phases, wash twice with water (200 mL × 2), dry with anhydrous sodium sulfate, filter by suction. The crude product after concentrating the filtrate is recrystallized with ethyl acetate / n-hexane, filtered, and dried to obtain 34.94 g of the product, with a molar yield of 72.6% and a purity of 99.2% detected by HPLC.

[0040] The above has described the embodiments of the present invention in detail, but the content described is only the preferred embodiments of the present invention and cannot be considered as used to limit the scope of implementation of the present invention. Any equal changes and improvements made according to the scope of the application of the present invention should still fall within the scope covered by the patent of the present invention.

[0041] As mentioned above, it is only the preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.

Claims

1. A method for continuously reacting to prepare isoxazoline, characterized in that: It includes the following steps: A. Oximation reaction: After stirring and dissolving hydroxylamine hydrochloride, a base, and an organic solvent until clear, add substituted aryl aldehyde S1, heat and stir until S1 is completely converted into P1, and after the reaction is completed, cool to room temperature; B. Halogenation reaction: Add a halogenating reagent until all of the above P1 is converted into P2; C. 1,3-dipolar addition reaction: Add substituted aryl ethylene S2 and a base to P2 until the reaction is complete; D. Post-treatment: After the reaction is completed, add water, then add an organic solvent, stir and separate the phases, discard the aqueous phase, wash the organic phase with an appropriate amount of water, dry with anhydrous sodium sulfate, filter by suction, and concentrate until there is no solvent to obtain a crude product; E. Recrystallization: Add an organic solvent to the above crude product, heat to dissolve completely, then slowly cool to crystallize, filter by suction, and dry to obtain the product.

2. The method for continuously preparing isoxazoline according to claim 1, wherein: The base in the oximation reaction includes one of K2CO3, Na2CO3, NaOH, DIPEA, DIPA, DBU, DABCO, DMAP, pyridine, and triethylamine.

3. The method for continuously reacting to prepare isoxazoline according to claim 1, characterized in that: The organic solvent used in the oximation reaction includes one or a combination of methanol, ethanol, isopropanol, dioxane, DMSO, DMF, DMA, acetonitrile, toluene, and acetone.

4. The method for continuously preparing isoxazoline according to claim 1, characterized in that: The feeding ratio of the oximation reaction is aryl aldehyde:hydroxylamine hydrochloride:base = 1:1-3:1-3 in terms of molar ratio.

5. The method for continuously preparing isoxazoline according to claim 1, characterized in that: The temperature of the oximation reaction is 25-80 °C.

6. The method for continuously reacting to prepare isoxazoline according to claim 1, characterized in that: The halogenating reagents used in the halogenation reaction include N -chlorosuccinimide, N -bromosuccinimide, N -iodosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, and sodium hypochlorite.

7. The method for continuously reacting to prepare isoxazoline according to claim 1, wherein:

8. The method for continuously preparing isoxazoline according to claim 1, characterized in that: The feeding ratio of the halogenation reaction is P1:halogenating reagent = 1:1-3 in terms of molar ratio.

9. The method for continuously preparing isoxazoline according to claim 1, characterized in that: The base used in the 1,3-dipolar addition reaction includes one of K2CO3, Na2CO3, NaOH, DIPEA, DIPA, DBU, DABCO, DMAP, pyridine, and triethylamine.

10. The method for continuously reacting to prepare isoxazoline according to claim 1, characterized in that: The feeding ratio of the 1,3-dipolar addition reaction is P2:substituted aryl ethylene:base = 1:1-2:1-2 in terms of molar ratio. The organic solvent in the post-treatment includes one of ethyl acetate, dichloromethane, methyl tert-butyl ether, ether, and toluene; The organic solvent used in the recrystallization includes one or several of methanol, ethanol, isopropanol, acetonitrile, toluene, acetone, ethyl acetate, n-hexane, petroleum ether, n-heptane, and chloroform.

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