A kind of intermediate of monepantel and preparation method thereof

Abstract

The present invention relates to an intermediate of monepantel and a preparation method thereof, and belongs to the field of medicine and chemical technology. The present invention provides a preparation method of a monepantel intermediate 1B, which is reacted as follows: wherein R1 is selected from benzyl or substituted benzyl, and the substituted benzyl is a benzyl arbitrarily substituted by 1 4 groups selected from the following groups on a phenyl ring: C1 4 alkyl, C1 4 alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy; comprising the following steps: step A: a compound of formula 1A is subjected to an acylating agent and an aminating agent to obtain a compound of formula 1B; the method provided by the present invention avoids the use of ethyl chloroformate and trifluoroacetic anhydride and the generation of esterification impurities, avoids nitration and diazotization reactions, makes the preparation process of monepantel easier and simpler, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to an intermediate of monepantel and a preparation method thereof, and belongs to the technical field of medicine and chemistry. Background Art

[0002] ZOLVIX oral solution is a broad-spectrum anthelmintic indicated for the treatment and control of gastrointestinal nematode infections and related diseases in sheep.

[0003] The active ingredient of ZOLVIX is monepantel, an anthelmintic drug belonging to the aminoacetonitrile derivative (AAD) class of molecules; it acts on the nematode-specific nicotinic acetylcholine receptor subunit Hco-MPTL-1.

[0004] The key intermediate of monepantel, 3-hydroxy-4-(trifluoromethyl)benzonitrile (CAS: 731002-50-9), is represented by Formula 4 and has the following structural formula:

[0005]

[0006] The existing reports on the preparation of compound 4 are as follows:

[0007] 1) Tetrahedron (2004), 60(23), 5019-5024 The published route is as follows,

[0008]

[0009] The total yield reported in the literature is only 4%, the cost is high, and it is not suitable for large-scale production.

[0010] 2) The routes disclosed in US20070155738A1 and WO2006128184A2 are as follows:

[0011]

[0012] The patented process uses ethyl chloroformate and trifluoroacetic anhydride, which produces esterified impurities of similar polarity that are difficult to separate. The nitration yield is low, and the isomer:product ratio is 3:1, with only about 20% of the desired product, resulting in a low effective yield. Furthermore, the process suffers from poor selectivity, and the nitration and diazotization reactions are relatively dangerous, posing significant safety risks for scaled-up production.

[0013] The present invention provides a new monepantel intermediate for preparing a key intermediate 4 and then preparing monepantel, avoiding the use of ethyl chloroformate and trifluoroacetic anhydride and the generation of esterification impurities, avoiding nitration and diazotization reactions, and making the process for preparing monepantel easier and simpler. The new monepantel intermediate provided by the present invention and the preparation method thereof are suitable for industrial production, and therefore have good market value and far-reaching practical significance. Summary of the Invention

[0014] In view of the above technical background, the present invention discloses a monepantel intermediate and a preparation method thereof.

[0015] The first aspect of the present invention provides a method for preparing monepantel intermediate 1B, which comprises the following steps:

[0016]

[0017] wherein R1 is selected from benzyl or substituted benzyl,

[0018] The term "substituted benzyl" refers to a benzyl group substituted on the phenyl ring by 1-4 groups selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy, wherein these substituents are in any possible position on the phenyl ring of the benzyl group.

[0019] The following steps are included:

[0020] Step B: Compound 1A is reacted with an acylating agent and an aminating agent to obtain compound 1B;

[0021] Preferably, the molar feed ratio of the compound of formula 1A to the acylating agent and the aminating agent is selected from 1: (1.05-3): (1.5-10), preferably 1: (1.8-2.5): (3-8);

[0022] Preferably, the acylating agent is selected from any one of oxalyl chloride, thionyl chloride and phosphorus oxychloride;

[0023] Preferably, the amination agent is selected from aqueous ammonia, ammonia gas, an organic ammonia solution, or any combination thereof;

[0024] Preferably, the organic ammonia solution is preferably a methanol solution of ammonia, an ethanol solution of ammonia, an isopropanol solution of ammonia or a dioxane solution of ammonia;

[0025] Preferably, the compound of formula 1A is subjected to an aminolysis reaction in the presence of aqueous ammonia and / or an organic ammonia solution to obtain a compound of formula 1B; more preferably, the compound of formula 1A is subjected to an aminolysis reaction in the presence of aqueous ammonia and / or an ammonia methanol solution to obtain a compound of formula 1B;

[0026] Preferably, the reaction temperature of step B may be 0 to 40°C, preferably 0 to 30°C;

[0027] Preferably, the reaction time of step B is 0.5 to 12 hours, preferably 1 to 5 hours;

[0028] Preferably, the reaction solvent in step B is selected from one or more of dichloromethane (DCM), N,N-dimethylacetamide (DMF), toluene, THF, diethyl ether, and water.

[0029] The second aspect of the present invention provides a method for preparing the compound of formula 1A, comprising the following reaction:

[0030]

[0031] wherein R1 is selected from benzyl or substituted benzyl,

[0032] The term "substituted benzyl" refers to a benzyl group substituted on the phenyl ring by 1 to 4 groups selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy, wherein these substituents are located at any possible position on the phenyl ring of the benzyl group;

[0033] R3 is selected from any one of OH, F, Cl, Br, and I;

[0034] The following steps are included:

[0035] Step A: reacting the compound of formula 2 with R1OH or R1X in the presence of a base to obtain a compound of formula 1A;

[0036] Wherein, X is selected from any one of Br and Cl,

[0037] Preferably, the molar feed ratio of the compound of formula 2 to R1OH or R1X is selected from 1:(1-5), preferably 1:(1.2-2);

[0038] Preferably, the base is selected from one or more of potassium tert-butoxide, sodium hydrogen, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, and sodium carbonate, preferably potassium tert-butoxide, sodium hydrogen, and sodium hydroxide;

[0039] Preferably, the reaction solvent of step A is selected from one or more of DMSO, N,N-dimethylacetamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane (DCM), and THF;

[0040] Preferably, the post-treatment method of step A comprises adjusting the pH to 1-3 using an acid (such as concentrated hydrochloric acid), and filtering to obtain compound 1A.

[0041] The post-treatment method provided by the present invention does not require recrystallization. A large amount of white solid is precipitated by adding an acid (such as concentrated hydrochloric acid) to adjust the pH to 1-3, and the product is obtained by filtration. The molar yield is above 90%, and the product HPLC purity is as high as above 99%.

[0042] The third aspect of the present invention provides a method for preparing compound 4, which comprises the following reaction:

[0043]

[0044] wherein R1 is selected from benzyl or substituted benzyl,

[0045] The term "substituted benzyl" refers to a benzyl group substituted on the phenyl ring by 1 to 4 groups selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy, wherein these substituents are located at any possible position on the phenyl ring of the benzyl group;

[0046] R3 is selected from any one of OH, F, Cl, Br, and I;

[0047] The following steps are included:

[0048] Step A: reacting the compound of formula 2 with R1OH or R1X in the presence of a base to obtain a compound of formula 1A;

[0049] Step B: Compound 1A is reacted with an acylating agent and an aminating agent to obtain a compound 1B;

[0050] Step C: Formula 1B is reacted with a reducing agent and a hydrogen donor to obtain compound 3.

[0051] Step D: Compound 3 is treated with a dehydrating agent to obtain compound 4.

[0052] In the preferred technical solution of the present invention, step A fully refers to the entire technical solution of the preparation method of the compound of formula 1A of step B described in the second aspect of the present invention;

[0053] The preferred technical solution of the present invention, step B all refers to the entire technical solution of the preparation method of a monepantel intermediate 1B in the first aspect of the present invention specification;

[0054] Preferably, the reducing agent in step C is selected from one or any combination of Pd / C, palladium hydroxide, platinum carbon or Raney nickel;

[0055] Preferably, the hydrogen donor in step C is selected from any one of hydrogen and ammonium formate;

[0056] Preferably, the solvent in step C is selected from one or more of THF, methanol, ethanol, ethyl acetate, dioxane, and DMF;

[0057] Preferably, in step C, the reaction pressure is 1-10 MPa; preferably 2-4 MPa;

[0058] Preferably, the reaction temperature of step C is 10°C to 100°C, preferably 30°C to 80°C;

[0059] Preferably, the reaction time of step C is 1 to 16 hours, preferably 3 to 12 hours;

[0060] Preferably, after the reaction in step C is completed, the mixture is concentrated and slurried to obtain high-purity compound 3; the slurrying solvent is selected from one or more of ether solvents such as DME, MTBE, diethyl ether, and dibutyl ether, or hydrocarbon solvents such as petroleum ether, n-hexane, n-heptane, n-pentane, and toluene; the mass volume ratio of compound 1B to the slurrying solvent is 1: (2-10) g / ml, preferably 1: (3-5) g / ml.

[0061] Preferably, the molar feed ratio of compound 3 to the dehydrating agent in step D is selected from 1:(2-10), preferably 1:(4-6);

[0062] Preferably, the dehydrating agent in step D is thionyl chloride or oxalyl chloride;

[0063] Preferably, the solvent in step D is selected from one or more of THF, methanol, ethanol, toluene, and xylene;

[0064] Preferably, the reaction temperature of step D is 10 to 110°C, preferably 20 to 105°C;

[0065] Preferably, the reaction time of step D is 0.5 to 8 hours, preferably 1 to 4 hours.

[0066] Preferably, after the reaction in step D is completed, the high-purity compound 4 is obtained by concentration and beating; the beating solvent is selected from one or more hydrocarbon solvents such as toluene, n-hexane, n-heptane, n-pentane, petroleum ether, etc.; the mass volume ratio of compound 3 to the beating solvent is 1: (1-8) g / ml, preferably 1: (1-3) g / ml.

[0067] As described above, the monepantel intermediate and preparation method thereof of the present invention have the advantages of avoiding esterified impurities when directly using 3-hydroxy-4-(trifluoromethyl)benzoic acid as a raw material, avoiding dangerous reactions such as nitration and diazotization, and reducing costs.

[0068] A fourth aspect of the present invention further provides a monepantel intermediate, the structural formula of which is shown in Formula 1:

[0069]

[0070] wherein R1 is selected from benzyl or substituted benzyl,

[0071] The term "substituted benzyl" refers to a benzyl group substituted on the phenyl ring by 1 to 4 groups selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy, wherein these substituents are located at any possible position on the phenyl ring of the benzyl group;

[0072] R2 is amino or hydroxy.

[0073] The fifth aspect of the present invention provides a process for synthesizing monepantel, which comprises providing a method for preparing monepantel intermediate 1B as provided in the first aspect above, or providing a method for preparing the compound of formula 1A as provided in the second aspect above, or providing a method for preparing compound 4 as provided in the third aspect of the present invention above, or using the monepantel intermediate of formula 1 as described above.

[0074] Beneficial technical effects of the present invention:

[0075] 1. Under the reaction system of the present invention, the new intermediate compound 1B did not suffer from catalyst deactivation in the hydrogenation debenzylation reaction of the catalyst palladium on carbon, and the reaction was completed in one go.

[0076] 2. Under the reaction system of the present invention, the reaction of preparing cyano group by dehydration using thionyl chloride is a one-time complete reaction, and there is no need to add thionyl chloride.

[0077] 3. The existing literature Journal of Medicinal Chemistry (2007), 50(15), 3540-3560 reports that the reaction in t-BuOK / BnOH and DMSO solvents was carried out at room temperature for 4 hours with a yield of 62%. The present inventors have creatively explored a post-treatment method of directly adjusting the pH to 1-3 with an acid (e.g., concentrated hydrochloric acid) after the reaction. This method eliminates the need for recrystallization, allowing a large amount of white solid to precipitate. The product is then filtered to obtain a molar yield of over 90% and a HPLC purity of over 99%. The results are surprisingly good and the reproducibility is excellent.

[0078] 4. If the intermediate compound 1A is first debenzylated and then subjected to an amidation reaction, the prepared intermediate acid chloride will react with the exposed phenolic hydroxyl group on the benzene ring, resulting in a large number of by-product impurities. Unexpectedly, the present invention cleverly adopts the method of first subjecting the intermediate compound 1A to an amidation reaction to obtain a new intermediate compound 1B, and then removing the protecting group to obtain compound 3, effectively avoiding the occurrence of side reactions.

[0079] 5. During experimental research, the present invention discovered that when R1=Bnbenzyl in intermediate compound 1A, the palladium-on-carbon debenzylation reaction was difficult to proceed. The present inventors speculate that this was related to the poisoning effect of residual DMSO from the previous step on the catalyst. The present invention's reaction system, using the novel amide intermediate compound 1B for the debenzylation reaction, performed amidation significantly more easily and completely, without the need for adding or replacing fresh palladium-on-carbon catalyst.

[0080] 6. The inventors of this application, referring to the example of CN101238127A, a homologous group of WO2006128184A2, adopted the practice of pre-debenzylation of Bn, i.e., first removing the benzyl group. Comparative test results show that the reaction of the present invention reduces the problem of difficult separation of byproducts and products due to their similar polarity, effectively avoiding the esterification side reaction caused by unprotected phenolic hydroxyl groups (-OH). The present invention first converts the carboxyl group to an amide, and then deprotects and dehydrates the cyano group to produce it. This effectively avoids the use of expensive ethyl chloroformate and trifluoroacetic anhydride, while also shortening the reaction time. This effectively addresses the issues of high production costs and low product purity, making it suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 HPLC spectrogram of the product obtained in Example 1 of the present invention

[0082] Figure 2 HPLC spectrogram of the product obtained in Example 2 of the present invention

[0083] Figure 3 HPLC spectrogram of the product obtained in Example 3 of the present invention

[0084] Figure 4 HPLC spectrogram of the product obtained in Example 4 of the present invention DETAILED DESCRIPTION

[0085] The present invention will be further described below in conjunction with specific examples. It should be understood that the following detailed description of the technical solutions of the present invention using examples will help to further understand the advantages and effects of the technical solutions of the present invention. The examples do not limit the scope of protection of the present invention, which is determined by the claims.

[0086] The experimental methods in the following examples where specific conditions are not specified are generally carried out under conventional conditions or conditions recommended by the manufacturers.

[0087] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0088] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used without further treatment.

[0089] Example 1:

[0090]

[0091] Compound 2A (1000 g, 4.81 mol) and benzyl alcohol (691 g, 6.39 mol) were dissolved in 9.5 L of DMSO at room temperature. Tert-butyl alcohol (1240 g, 11.05 mol) was added portionwise and stirred at 30°C for 20 h. After completion of the reaction as monitored by TLC, the reaction was quenched by adding 20 L of water at 20-30°C. Concentrated hydrochloric acid was then added to adjust the pH to 1-2. A large amount of solid precipitated. Stirring was continued for 1 h, and the mixture was filtered. The filter cake was rinsed with acid water at pH 1 and dried to yield 1323 g of a white solid, with a yield of 93% and a purity of 100% by HPLC. The spectrum is shown in the attached figure. Figure 1 shown. 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),7.75(d,J=8.1Hz,1H),7.65(d,J=8.2Hz,1H),7.50-7.43(m,2H),7.40(m,2H),7.33(m,1H),5.33(s,2H); 19 F NMR (376Hz, DMSO-d6): δ-61.52 (s, CF3).

[0092] Example 2:

[0093]

[0094] Compound 2A (20 g, 96.2 mmol) and benzyl alcohol (13.8 g, 127.8 mmol) were dissolved in 190 mL of DMSO at room temperature. Potassium tert-butoxide (24.8 g, 221 mol) was added portionwise and stirred at 30°C for 20 h. After completion of the reaction, monitored by TLC, the reaction was quenched by the addition of 400 mL of water, controlled at 20-30°C, and concentrated hydrochloric acid was added to adjust the pH to 2-3. A large amount of solid precipitated. Stirring was continued for 1 h, and the mixture was filtered. The filter cake was rinsed with acid water at pH 2-3 and dried to yield 26.33 g of a white solid, a yield of 92.5%. 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),7.75(d,J=8.1Hz,1H),7.65(d,J=8.2Hz,1H),7.50-7.43(m,2H),7.40(m,2H),7.33(m,1H),5.33(s,2H); 19 F NMR (376Hz, DMSO-d6): δ-61.52 (s, CF3).

[0095] Example 3:

[0096]

[0097] Compound 1A1 (685 g, 2.22 mol) was dissolved in DCM (4100 ml) and DMF (10 ml), and the atmosphere was replaced with nitrogen. The mixture was cooled to 0-5°C in an ice-water bath, and oxalyl chloride (587 g, 4.62 mol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was allowed to react for 2 h. After TLC monitoring, the reaction was completed and the mixture was concentrated under reduced pressure to obtain 690 g of a pale yellow solid crude product. DCM (2100 ml) was added to the crude product, and the mixture was stirred evenly. The temperature was controlled at 10-20°C, and the mixture was poured into 25% aqueous ammonia (2520 g) and stirred for 10 min to homogenize the system. The product was filtered and dried to obtain 628.1 g of a white solid with a yield of 92% and a purity of 100% by HPLC. The spectrum is shown in the attached figure. Figure 2 As shown. MS(EI):296[M] + ; 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.79(s,1H),7.74(d,J=8.1Hz,1H),7.65(s,1H) ,7.59(d,J=8.1Hz,1H),7.50-7.40(m,4H),7.36(dd,J=5.1,3.5Hz,1H),5.34(s,2H); 19 F NMR (376Hz, DMSO-d6): δ-61.52 (s, CF3).

[0098] Example 4:

[0099]

[0100] Compound 1B1 (100 g, 338.69 mol) was added to an autoclave and dissolved with methanol (300 ml) and tetrahydrofuran (300 ml). The nitrogen atmosphere was replaced with 5% Pd / C (5 g) to replace the hydrogen atmosphere. The mixture was hydrogenated and pressurized to 3.0 MPa. The reaction was allowed to proceed at 75°C for 8 h. After TLC monitoring, the reaction was completed, filtered, concentrated, and 300 ml of petroleum ether was added to slurry, filtered, and the filter cake was dried to obtain compound 3 (65.3 g) with a yield of 94% and a purity of 100% by HPLC. The spectrum is shown in the attached figure. Figure 3 As shown. MS(EI):206.2[M] + ; 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),8.07(s,1H),7.58(d,J=8.2Hz,1H),7.52(s,1H),7.48(s,1H),7.39(d,J=8.1Hz,1H); 19 F NMR(296z,DMSO-d6)δ-56.51(s,CF3).

[0101] Example 5:

[0102]

[0103] Compound 3 (63.7 g, 310.5 mmol) was dissolved in tetrahydrofuran (640 mL), and the temperature was controlled at 20-30 ° C. Thionyl chloride (184.7 g, 1.55 mol) was added dropwise. After the addition was complete, the temperature was raised to 105 ° C and refluxed for 3 h. After the reaction was completed under TLC monitoring, the mixture was concentrated under reduced pressure until almost no distillate was produced. 128 ml of toluene was added and the mixture was beaten for 0.5 h. The mixture was filtered and the filter cake was dried to obtain compound 4 (50.0 g) with a yield of 86% and a purity of 100% by HPLC. The spectrum is shown in the attached figure. Figure 4 As shown. MS(EI):188.0[M] + ; 1 H NMR (400MHz, DMSO-d6) δ11.47 (s, 1H), 7.73 (d, J = 8.0Hz, 1H), 7.49-7.33 (m, 2H).

[0104] Comparative Example 1:

[0105]

[0106] 3-Hydroxy-4-trifluoromethylbenzoic acid (2 g, 9.7 mmol) was added to a 12 ml THF solution and cooled to -30 to -20°C. Triethylamine (2.6 g, 25.7 mmol) was then added dropwise at -30 to -20°C, followed by the slow dropwise addition of ethyl chloroformate (2.28 g, 21 mmol). The mixture reacted for 1 hour and filtered to obtain a filtrate. 25% aqueous ammonia (2.8 g, 20 mmol) was then added dropwise at -30 to -20°C. The temperature was raised to 10°C and the reaction continued. TLC (developing solvent: DCM:MeOH = 5:1) was used to monitor the reaction. After 2 days of reaction, a large amount of starting material remained and numerous miscellaneous spots were observed.

Claims

1. A method for preparing compound 4, comprising the following steps: in, R1 is selected from benzyl or substituted benzyl, Substituted benzyl is a benzyl group optionally substituted on the phenyl ring by 1-4 groups selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy; R3 is selected from any one of F, Cl, Br, and I; The following steps are included: Step A: reacting the compound of formula 2 with R1OH in the presence of a base to obtain the compound of formula 1A; Step B: Compound 1A is reacted with an acylating agent and an aminating agent to obtain compound 1B; Step C: Formula 1B is treated with a reducing agent and a hydrogen donor to obtain compound 3. Step D: Compound 3 is treated with a dehydrating agent to obtain compound 4; Wherein, the acylating agent is selected from any one of oxalyl chloride, thionyl chloride, and phosphorus oxychloride; Wherein, the amination reagent is selected from ammonia water, ammonia gas, an organic solution of ammonia or any combination thereof.

2. A preparation method for monepantel intermediate 1B, reacting as follows: in, R1 is selected from benzyl or substituted benzyl, Substituted benzyl is a benzyl group optionally substituted on the phenyl ring by 1-4 groups selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy; The following steps are included: Step B: Compound 1A is reacted with an acylating agent and an aminating agent to obtain compound 1B; Wherein, the acylating agent is selected from any one of oxalyl chloride, thionyl chloride, and phosphorus oxychloride; Wherein, the amination reagent is selected from ammonia water, ammonia gas, an organic solution of ammonia or any combination thereof.

3. The preparation method according to claim 1 or 2, characterized in that: The molar feed ratio of the compound of formula 1A to the acylating agent and the aminating agent is selected from 1: (1.05-3): (1.5-10); And / or, the organic ammonia solution is a methanol solution of ammonia, an ethanol solution of ammonia, an isopropanol solution of ammonia or a dioxane solution of ammonia.

4. The preparation method according to claim 1 or 2, characterized in that: The molar feed ratio of the compound of formula 1A to the acylating agent and the aminating agent is selected from 1: (1.8-2.5): (3-8).

5. The preparation method according to claim 1 or 2, characterized in that: The compound of formula 1A is subjected to an aminolysis reaction in the presence of aqueous ammonia and / or an organic ammonia solution to obtain a compound of formula 1B.

6. The preparation method according to claim 1 or 2, characterized in that: The compound of formula 1A is subjected to an aminolysis reaction in the presence of aqueous ammonia and / or a methanolic ammonia solution to obtain a compound of formula 1B.

7. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step B is 0-40°C; And / or, the reaction time of step B is 0.5 to 12 hours; And / or, the reaction solvent of step B is selected from one or more of dichloromethane (DCM), N,N-dimethylformamide (DMF), toluene, THF, and diethyl ether.

8. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step B is 0°C to 30°C; And / or, the reaction time of step B is 1 to 5 hours.

9. The preparation method according to claim 1, wherein: The molar feed ratio of the compound of formula 2 to R1OH is selected from 1: (1 to 5); and / or, the base is selected from one or more of potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, and sodium carbonate; And / or, the reaction solvent of step A is selected from one or more of DMSO, N,N-dimethylformamide DMF, N,N-dimethylacetamide DMA, dichloromethane DCM, and THF; And / or, the post-treatment method of step A comprises adjusting the pH to 1-3 with an acid, and filtering to obtain high-purity compound 1A; the acid is concentrated hydrochloric acid.

10. The preparation method according to claim 1, characterized in that: The molar feed ratio of the compound of formula 2 to R1OH is selected from 1: (1.2 to 2); And / or, the base is selected from potassium tert-butoxide, sodium hydride, and sodium hydroxide.

11. The preparation method according to claim 1, characterized in that: The reducing agent in step C is selected from one or any combination of Pd / C, palladium hydroxide, platinum carbon or Raney nickel; And / or, the hydrogen donor in step C is selected from any one of hydrogen and ammonium formate; And / or, step C is carried out in one or more solvents selected from THF, methanol, ethanol, ethyl acetate, dioxane, and DMF; And / or, in step C, the reaction pressure is 1-10 MPa; And / or, the reaction temperature of step C is 10°C to 100°C; and / or, the reaction time of step C is 1 to 16 hours; And / or, after the reaction in step C is completed, the mixture is concentrated and slurried to obtain high-purity compound 3; the slurrying solvent is selected from one or more of DME, MTBE, ether, dibutyl ether ether solvents or petroleum ether, n-hexane, n-heptane, n-pentane, and toluene hydrocarbon solvents; the mass volume ratio of compound 1B to the slurrying solvent is 1:(2-10) g / ml; And / or, the molar feed ratio of the compound 3 in step D to the dehydrating agent is selected from 1:(2-10); And / or, the dehydrating agent in step D is thionyl chloride or oxalyl chloride; And / or, step D is carried out in one or more solvents selected from THF, methanol, ethanol, toluene, and xylene; and / or, the reaction temperature of step D is 10° C. to 110° C.; and / or, the reaction time of step D is 0.5 to 8 hours; And / or, after the reaction in step D is completed, the high-purity compound 4 is obtained by concentration and beating; the beating solvent is selected from one or more of toluene, n-hexane, n-heptane, n-pentane, and petroleum ether hydrocarbon solvents; the mass volume ratio of compound 3 to the beating solvent is 1: (1-8)g / ml.

12. The preparation method according to claim 1 or 11, characterized in that: In the step C, the reaction pressure is 2-4 MPa; And / or, the reaction temperature of step C is 30°C to 80°C; and / or, the reaction time of step C is 3 to 12 hours; And / or, after the reaction in step C is completed, the mixture is concentrated and slurried to obtain high-purity compound 3; the slurrying solvent is selected from one or more of DME, MTBE, ether, dibutyl ether ether solvents or petroleum ether, n-hexane, n-heptane, n-pentane, and toluene hydrocarbon solvents; the mass volume ratio of compound 1B to the slurrying solvent is 1:(3-5) g / ml; And / or, the molar feed ratio of the compound 3 in step D to the dehydrating agent is selected from 1:(4-6); and / or, the reaction temperature of step D is 20° C. to 105° C.; and / or, the reaction time of step D is 1 to 4 hours; And / or, after the reaction in step D is completed, the high-purity compound 4 is obtained by concentration and beating; the beating solvent is selected from one or more of toluene, n-hexane, n-heptane, n-pentane, and petroleum ether hydrocarbon solvents; the mass volume ratio of compound 3 to the beating solvent is 1: (1-3)g / ml.

13. A monepantel intermediate, the structural formula of which is shown in Formula 1: in, R1 is selected from benzyl or substituted benzyl, Substituted benzyl is a benzyl group optionally substituted on the phenyl ring by 1-4 groups selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy; R2 is an amino group.

14. A process for synthesizing monepantel, comprising the preparation method of compound 4 as claimed in claim 1.

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