Preparation method of lotinib

Abstract

The invention provides a preparation method of lotinib, which comprises the following steps: A, oxidation reaction: dissolving 3-hexyne-2, 5-diol in a solvent, and adding an oxidizing agent for oxidation reaction to obtain 3-hexyne-2, 5-diketone (intermediate 1); b, thiophene synthesis reaction; c, hydrolysis reaction; d, amide condensation reaction; e, aldol condensation and dehydration reaction; and F, cyclization reaction: dissolving the intermediate 5, hydroxylamine hydrochloride and alkali in a solvent, and carrying out cyclization reaction to obtain lotirasodium. The method has the following advantages: 1, starting materials 3-hexyne-2, 5-diol and mercaptoacetate are cheap and easily available, so that the material cost is greatly reduced; 2, the technological operation is simple, and a complicated post-treatment process is not needed; and 3, no dangerous reagent is used in the reaction, the reaction is safe and controllable, and the method is friendly to operators and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical production, and particularly relates to a preparation method of lotilaner. Background Art

[0002] After consulting relevant materials, there have been multiple patents and literatures reporting the synthesis methods of lotilaner, such as Routes 1-3.

[0003] Route 1

[0004]

[0005] Patent CN109879826 describes the synthesis of lotilaner. This patent uses 5-formyl-3-methylthiophene-2-carboxylic acid as the starting material, undergoes an oximation reaction with hydroxylamine and then an amide condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide, and finally undergoes a chlorination reaction with NCS and a 1,3-dipolar cycloaddition reaction with 3′,4′,5′-trichloro-2,2,2-trifluoroacetophenone to prepare lotilaner. The disadvantages are that the raw materials are expensive and not easily available, there are a large number of uncontrollable side reactions in the 1,3-dipolar addition reaction, there are many impurities, purification is difficult, and the cost is relatively high.

[0006] Route 2

[0007]

[0008] Patent CN115504971 describes another synthesis route of lotilaner. Although the synthesis method of this patent is simple, the raw materials are expensive, and a toxic reagent POCl3 is used when introducing the aldehyde group, which has a certain risk.

[0009] Route 3

[0010]

[0011] Patent WO2014090918 describes another synthesis route of lotilaner. This patent uses the same aldol condensation reaction and ring-closing reaction to construct the key isoxazoline ring, and prepares lotilaner with a single configuration through chiral resolution. The synthesis method is simple, but the raw material price is relatively expensive, and the loss in chiral resolution is large, resulting in a relatively high production cost.

[0012] Based on the current preparation methods of lotilaner, the starting materials used in the process are currently expensive, directly resulting in a relatively high material cost for lotilaner. Moreover, existing methods all involve the step of ring closure to prepare the isoxazoline intermediate, and there are side reactions or incomplete reactions during the ring closure process, resulting in complex impurities in the entire preparation process, bringing bottlenecks to subsequent product purification and industrial production. Summary of the Invention

[0013] In order to overcome the deficiencies of the above-mentioned prior art, the present invention provides a preparation method of lotilaner. The preparation method provided by the present invention has the advantages of wide raw material sources, low cost, high yield, simple operation, and no dangerous operations.

[0014] The technical solution adopted by the present invention is as follows: A preparation method of lotilaner, comprising the following steps: A. Oxidation reaction: After dissolving 3-hexyne-2,5-diol in a solvent, an oxidizing agent is added for an oxidation reaction to obtain 3-hexyne-2,5-dione, that is, intermediate 1; B. Thiophene synthesis reaction: After dissolving intermediate 1 and thiol acetate in a solvent, a base is added for a thiophene synthesis reaction to obtain 5-acetyl-3-methylthiophene-2-carboxylate, that is, intermediate 2; C. Hydrolysis reaction: After dissolving intermediate 2 in a solvent, an acid or a base is added for a hydrolysis reaction to obtain 5-acetyl-3-methylthiophene-2-carboxylic acid, that is, intermediate 3; D. Amide condensation reaction: Intermediate 3 and a carboxyl activating reagent are dissolved in DMF for carboxyl activation. The obtained product is successively mixed with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine for a condensation reaction to obtain intermediate 4; E. Aldol condensation and dehydration reaction: Intermediate 4, 3′,4′,5′-trichloro-2,2,2-trifluoroacetophenone and a base are dissolved in a solvent for an aldol condensation reaction, and then a dehydrating agent is added for a dehydration reaction to obtain intermediate 5; F. Cyclization reaction: Intermediate 5, hydroxylamine hydrochloride and a base are dissolved in a solvent for a cyclization reaction to obtain lotilaner; Preferably, in step A, the molar ratio of 3-hexyne-2,5-diol to the oxidizing agent is 1:1 to 10; the oxidizing agent includes one of 2-iodoxybenzoic acid, Dess-Martin, hydrogen peroxide, tert-butyl hydroperoxide, manganese dioxide, PDC, p-benzoquinone, Jones reagent, dimethyl peroxide ketone; the solvent used for the oxidation reaction is one or more of dichloromethane, dimethyl sulfoxide, acetone, DMF, water, methanol, ethanol, isopropanol, tert-butanol, toluene, benzene.

[0015] Preferably, the thioglycolate in step B includes, but is not limited to, methyl thioglycolate, ethyl thioglycolate, propyl thioglycolate, butyl thioglycolate, or cyclohexyl thioglycolate; The molar ratio of intermediate 1 to thioglycolate is 1:1 to 2; The base in step B is an organic base or an inorganic base, specifically sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or triethylamine; The solvent in step B is one of methanol, ethanol, isopropanol, and tert-butanol.

[0016] Preferably, when the hydrolysis reaction in step C is carried out under acidic conditions, the acidic conditions are provided by sulfuric acid, hydrochloric acid, glacial acetic acid, or phosphoric acid; When the hydrolysis reaction in step C is carried out under acidic conditions, the temperature of the hydrolysis reaction is 30 to 80 °C, and the time of the hydrolysis reaction is 1 to 12 h; The solvent in step C is one of tetrahydrofuran, acetone, dichloromethane, dichloroethane, carbon tetrachloride, and DMF.

[0017] Preferably, when the hydrolysis reaction is carried out under basic conditions, the basic conditions are provided by sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium carbonate, or sodium carbonate; The temperature of the hydrolysis reaction is 30 to 50 °C, and the time of the hydrolysis reaction is 1 to 12 h; The solvent in step C is one of tetrahydrofuran, acetone, dichloromethane, dichloroethane, carbon tetrachloride, and DMF.

[0018] Preferably, the carboxyl activating reagent in step D includes one of thionyl chloride, oxalyl chloride, acetyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, CDI, EDCI, HATU, and PyBoP.

[0019] Preferably, the molar ratio of intermediate 3 to 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is 1:1 to 1.5.

[0020] Preferably, the molar ratio of intermediate 4 to 3′,4′,5′-trichloro-2,2,2-trifluoroacetophenone in step E is 1:1 to 2; the molar ratio of intermediate 4 to the base is 1:1 to 2; the molar ratio of intermediate 4 to the dehydrating agent is 1:1 to 3.

[0021] Preferably, the base in step E includes one or more of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium oxide, magnesium oxide, calcium hydroxide, magnesium hydroxide, triethylamine, diisopropylethylamine, DBU, TBD, and DABCO; The dehydrating agent includes acetic anhydride, thionyl chloride, and acetyl chloride.

[0022] The solvent is one or more of toluene, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, and acetone.

[0023] Preferably, the molar ratio of intermediate 5 to hydroxylamine hydrochloride in step F is 1:1 to 2; the temperature of the cyclization reaction is -20 to 30 °C; the time of the cyclization reaction is 1 to 3 h; The solvent in step F is one of toluene, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, acetone, methanol, ethanol, isopropanol, DMF, N-methylpyrrolidone, and ethyl acetate.

[0024] The beneficial effects obtained by the present invention are as follows: The present invention provides a preparation method of the veterinary anthelmintic lotilaner, which includes the following steps: Using 3-hexyne-2,5-diol and thioglycolate as starting materials, lotilaner is synthesized through six steps of reaction, namely oxidation reaction, thiophene synthesis reaction, hydrolysis reaction, amide condensation reaction, aldol condensation reaction, and cyclization reaction. Compared with the prior art, the present invention has the following advantages: 1. The starting materials 3-hexyne-2,5-diol and thioglycolate are cheap and easily available, greatly reducing the material cost; 2. The process operation is simple and does not require complex post-treatment processes; 3. In the prior art, Grignard reagent and CO2 are needed to introduce a carboxyl group at the 2-position of thiophene, which has certain safety risks; in this synthetic route, by changing the raw materials, a methyl carboxylate is directly introduced at the 2-position of thiophene, and the reaction is safer; 4. By introducing the side chain first and finally forming the isoxazoline ring, it is beneficial to reduce the generation of by-products and ensure the yield, and it is suitable for large-scale preparation of lotilaner. Description of the Drawings

[0025] Figure 1 It is the general formula of the synthetic route of the present invention; Figure 2 It is the liquid chromatogram of lotilaner prepared in Example 1 of the present invention. Detailed Embodiments

[0026] In order to make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0027] Example 1 Step 1: Synthesis of 3-hexyne-2,5-dione Into a 1000 mL reaction flask equipped with a stirrer and a thermometer, add 171.2 g (1.5 mol) of 3 - hexyn - 2,5 - diol, 171 mL of dimethyl sulfoxide, and 924 g (3.3 mol) of 2 - iodoxybenzoic acid. Then slowly heat up to 80 °C and react for 4 h. After the reaction is completed, add 400 mL of water to the reaction solution, extract with dichloromethane (400 mL × 2), combine the organic phases, wash once with 400 mL of water, dry over anhydrous sodium sulfate, and concentrate to obtain 130.48 g of a pale yellow liquid with a yield of 79%.

[0028] Step 2: Synthesis of methyl 5 - acetyl - 3 - methylthiophene - 2 - carboxylate Into a 1000 mL reaction flask equipped with a stirrer and a thermometer, add 165.1 g (1.5 mol) of 3 - hexyn - 2,5 - dione, 191 g (1.8 mol) of methyl mercaptoacetate, 330 mL of methanol, and 124.2 g (2.3 mol) of sodium methoxide. React at room temperature for 24 h. Add saturated sodium bicarbonate to neutralize the reaction solution, extract with dichloromethane (300 mL × 2), combine the organic phases, wash once with 300 mL of water, and recrystallize the concentrated crude product with ethyl acetate / n - hexane to obtain 282.5 g of a pale yellow powder (i.e., methyl 5 - acetyl - 3 - methylthiophene - 2 - carboxylate).

[0029] Step 3: Synthesis of 5 - acetyl - 3 - methylthiophene - 2 - carboxylic acid Alkaline hydrolysis: Into a 1000 mL four - necked flask equipped with a stirrer and a thermometer, sequentially add 300 mL of water, 300 mL of tetrahydrofuran, 35.9 g (1.5 mol) of lithium hydroxide, and 148.7 g (0.75 mol) of methyl 5 - acetyl - 3 - methylthiophene - 2 - carboxylate. Heat up to 40 °C and react for 5 h. Distill off tetrahydrofuran under reduced pressure. While stirring in an ice bath, add dilute hydrochloric acid (1 mol / L) to adjust the pH to 1 - 2. A pale yellow solid precipitates, filter and dry to obtain 117.98 g of 5 - acetyl - 3 - methylthiophene - 2 - carboxylic acid with a yield of 85.4%.

[0030] Step 4: Synthesis of Intermediate 4 Into a 1000 mL three - necked reaction flask equipped with a stirrer and a thermometer, add 92.1 g (0.5 mol) of 5 - acetyl - 3 - methylthiophene - 2 - carboxylic acid and 460 mL of dichloromethane. Drop in two drops of N,N - dimethylformamide, heat up to 40 °C and stir, then dropwise add 237.9 g (1.0 mol) of thionyl chloride. Stir for 1.5 h and then set aside.

[0031] Take another 1000 mL three-necked flask, add 105.6 g (0.55 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, 100 mL of dichloromethane, and 55.7 g (0.55 mol) of triethylamine. Cool the mixture to about 5 °C, and dropwise add the prepared acyl chloride dichloromethane solution. After the addition is complete, keep the temperature for 1 h. Then add 500 mL of water, adjust the pH to 1 - 2 with hydrochloric acid, separate the layers, extract the aqueous phase with dichloromethane (200 mL) once, combine the organic phases, concentrate, and recrystallize the crude product to obtain 141.2 g of a pale yellow solid (i.e., intermediate 4), with a yield of 87.6%.

[0032] Step 5: Synthesis of intermediate 5 Into a 500 mL three-necked flask equipped with a stirrer and a thermometer, add 64.5 g (0.2 mol) of intermediate 4, 130 mL of toluene, 40.5 g (0.4 mol) of triethylamine, and 83.2 g (0.3 mol) of 3′,4′,5′-trichloro-2,2,2-trifluoroacetophenone. Heat the mixture to 90 °C and stir for 7 h. Cool to 35 °C, add 47.6 g (0.4 mol) of thionyl chloride, and stir for 1 h.

[0033] After the reaction is completed, quench with saturated sodium bicarbonate aqueous solution, separate the layers, wash the organic layer with water (100 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 89.1 g of a yellow oil (i.e., intermediate 5), with a yield of 76.5%. The crude product is directly used for the next cyclization reaction.

[0034] Step 6: Synthesis of lotilaner Into a 500 mL three-necked flask equipped with a stirrer and a thermometer, add 11.6 g (0.02 mol) of intermediate 5 and 100 mL of ethanol. Keep the temperature at 10 - 25 °C, and dropwise add a 10 mL aqueous solution of 1.53 g (0.022 mol) of hydroxylamine hydrochloride and 0.88 g (0.022 mol) of sodium hydroxide. After the addition is complete, stir at room temperature for 1 h. A white solid gradually precipitates from the reaction solution. Filter the white solid, dry it, and recrystallize it with ethyl acetate / n-heptane to obtain 8.62 g of a white solid (i.e., lotilaner), with a yield of 72.3%.

[0035] Example 2 Step 1: Synthesis of 3-hexyne-2,5-dione Into a 100 mL reaction flask equipped with a stirrer and a thermometer, 4.0 g (0.035 mol) of 3-hexyne-2,5-diol and 20 mL of dichloromethane were added. The temperature was lowered to 0 - 5 °C in an ice bath, and 22.48 g (0.053 mol) of Dess-Martin periodinane was slowly added in portions. The mixture was stirred at a constant temperature for 2 h. After the reaction was completed, saturated sodium thiosulfate was added to the reaction solution to quench it. The phases were separated, and the aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 3.67 g of a pale yellow liquid with a yield of 96%.

[0036] Step 2: Synthesis of methyl 5-acetyl-3-methylthiophene-2-carboxylate Into a 100 mL reaction flask equipped with a stirrer and a thermometer, 4.4 g (0.04 mol) of 3-hexyne-2,5-dione, 5.51 g (0.052 mol) of methyl mercaptoacetate, 13 mL of methanol, and 7.45 g (0.06 mol) of triethylamine were added. The reaction was carried out at room temperature for 24 h. Saturated sodium bicarbonate was added to neutralize the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed once with 30 mL of water, and the concentrated crude product was recrystallized from ethyl acetate / n-hexane to obtain 7.34 g of a pale yellow powder (i.e., methyl 5-acetyl-3-methylthiophene-2-carboxylate) with a yield of 92.6%.

[0037] Step 3: Synthesis of 5-acetyl-3-methylthiophene-2-carboxylic acid Acid hydrolysis: Into a 100 mL four-necked flask equipped with a stirrer and a thermometer, 30 mL of tetrahydrofuran and 6.94 g (0.035 mol) of methyl 5-acetyl-3-methylthiophene-2-carboxylate were added in sequence. Subsequently, 2 mol / L dilute hydrochloric acid (52.5 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 40 °C and the reaction was carried out for 3 h. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (30 mL × 2). The organic phase was dried and concentrated to obtain 5.9 g of 5-acetyl-3-methylthiophene-2-carboxylic acid with a yield of 91.6%.

[0038] Step 4: Synthesis of Intermediate 4 Into a 100 mL three-necked reaction flask equipped with a stirrer and a thermometer, 6.08 g (0.033 mol) of 5-acetyl-3-methylthiophene-2-carboxylic acid and 30 mL of dichloromethane were added. Two drops of N,N-dimethylformamide were added dropwise, and the temperature was raised to 40 °C and stirred. 8.38 g (0.066 mol) of oxalyl chloride was added dropwise, and the mixture was stirred for 1.5 h and then set aside.

[0039] Take another 150 mL three-necked flask, add 7.68 g (0.04 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, 30 mL of dichloromethane, and 4.05 g (0.04 mol) of triethylamine. Cool the temperature to about 5 °C, and dropwise add the prepared acyl chloride dichloromethane solution. After the addition is complete, keep the temperature for 1 h. Then add 20 mL of water, adjust the pH to 1 - 2 with hydrochloric acid, separate the layers, extract the aqueous phase with dichloromethane (20 mL) once, combine the organic phases, concentrate, and recrystallize the crude product to obtain 8.28 g of a pale yellow solid (i.e., intermediate 4), with a yield of 77.9%.

[0040] Step 5: Synthesis of Intermediate 5 Into a 100 mL three-necked flask equipped with a stirrer and a thermometer, add 6.45 g (0.02 mol) of intermediate 4, 30 mL of toluene, 4.05 g (0.04 mol) of triethylamine, and 8.32 g (0.03 mol) of 3′,4′,5′-trichloro-2,2,2-trifluoroacetophenone. Heat the temperature to 90 °C and stir for 7 h. Cool to 35 °C, add 4.76 g (0.04 mol) of thionyl chloride, and stir for 1 h.

[0041] After the reaction is completed, quench with saturated aqueous sodium bicarbonate, separate the layers, wash the organic layer with water (20 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 9.56 g of a yellow oil (i.e., intermediate 5), with a yield of 82.3%. The crude product is directly used for the next ring-closing reaction.

[0042] Step 6: Synthesis of Lotilaner Into a 500 mL three-necked flask equipped with a stirrer and a thermometer, add 11.6 g (0.02 mol) of intermediate 5 and 100 mL of ethanol. Keep the temperature at 10 - 25 °C, and dropwise add a 13 mL aqueous solution of 1.53 g (0.022 mol) of hydroxylamine hydrochloride and 0.88 g (0.022 mol) of sodium hydroxide. After the addition is complete, stir at room temperature for 1 h. A white solid gradually precipitates from the reaction solution. Filter the white solid, dry it, and recrystallize it with ethyl acetate / n-heptane to obtain 8.66 g of a white solid (i.e., Lotilaner), with a yield of 72.6%.

[0043] Example 3 Step 1: Synthesis of 3-hexyne-2,5-dione Into a 100 mL reaction flask equipped with a stirrer and a thermometer, add 2.3 g (0.02 mol) of 3-hexyne-2,5-diol and 20 mL of dichloromethane. Add 17.4 g (0.2 mol) of activated manganese dioxide in batches, and keep the temperature for stirring for 5 h. After the reaction is completed, filter directly, wash the filter cake with 20 mL of dichloromethane, and concentrate the filtrate to obtain 2.08 g of a pale yellow liquid, with a yield of 94.6%.

[0044] Step 2: Synthesis of Ethyl 5-acetyl-3-methylthiophene-2-carboxylate In a 100 mL reaction flask equipped with a stirrer and a thermometer, 2.2 g (0.02 mol) of 3-hexyne-2,5-dione, 2.88 g (0.024 mol) of ethyl mercaptoacetate, 13 mL of ethanol, and 2.05 g (0.03 mol) of sodium ethoxide were added. The reaction was carried out at room temperature for 20 h. Saturated sodium bicarbonate was added to neutralize the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed once with 30 mL of water, and the concentrated crude product was recrystallized from ethyl acetate / n-hexane to obtain 3.64 g of a pale yellow powder (i.e., ethyl 5-acetyl-3-methylthiophene-2-carboxylate), with a yield of 85.6%.

[0045] Step 3: Synthesis of 5-acetyl-3-methylthiophene-2-carboxylic acid Into a 100 mL single-necked flask equipped with a stirrer and a thermometer, 10 mL of water, 40 mL of acetone, 1.2 g (0.03 mol) of sodium hydroxide, and 4.24 g (0.02 mol) of ethyl 5-acetyl-3-methylthiophene-2-carboxylate were added in sequence. The temperature was raised to 40 °C and the reaction was carried out for 2 h. Acetone was distilled off under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added under ice bath stirring to adjust the pH to 1 - 2, and a pale yellow solid was precipitated. After filtration and drying, 3.3 g of 5-acetyl-3-methylthiophene-2-carboxylic acid was obtained, with a yield of 90%.

[0046] Step 4: Synthesis of Intermediate 4 Reaction solution A: In a 100 mL single-necked reaction flask equipped with a stirrer and a thermometer, 3.68 g (0.02 mol) of 5-acetyl-3-methylthiophene-2-carboxylic acid and 15 mL of N,N-dimethylformamide were added. 3.6 g (0.022 mol) of CDI was added in batches at room temperature. After stirring for 15 min, it was set aside for use.

[0047] Reaction solution B: Take another 100 mL single-necked flask, add 3.84 g (0.02 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, 15 mL of DMF, and 2.03 g (0.02 mol) of triethylamine. After stirring at room temperature for 15 min, it was filtered, and the filtrate was added to the above reaction solution A. After stirring at room temperature for 30 min, 60 mL of water was added dropwise to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 5.5 g of a pale yellow solid (i.e., Intermediate 4), with a yield of 85.5%.

[0048] Step 5: Synthesis of Intermediate 5 Into a 100 mL three-necked flask equipped with a stirrer and a thermometer, 6.45 g (0.02 mol) of intermediate 4, 30 mL of methyl tert-butyl ether, 4.05 g (0.04 mol) of triethylamine and 8.32 g (0.03 mol) of 3′,4′,5′-trichloro-2,2,2-trifluoroacetophenone were added. The temperature was raised to 60 °C and stirred for 2 h. It was cooled to 0 - 5 °C in an ice bath, and 6.12 g (0.06 mol) of acetic anhydride was added and stirred for 1 h.

[0049] After the reaction was completed, it was quenched by adding saturated aqueous sodium bicarbonate, and the layers were separated. The organic layer was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10.23 g of a yellow oil (i.e., intermediate 5), with a yield of 88.2%. The crude product was directly used for the next cyclization reaction.

[0050] Step 6: Synthesis of lotilaner Into a 500 mL three-necked flask equipped with a stirrer and a thermometer, 11.6 g (0.02 mol) of intermediate 5 and 100 mL of ethanol were added. While maintaining the temperature at 10 - 25 °C, a 13 mL aqueous solution of 1.53 g (0.022 mol) of hydroxylamine hydrochloride and 0.88 g (0.022 mol) of sodium hydroxide was added dropwise. After the addition was completed, it was stirred at room temperature for 1 h, and white solid gradually precipitated from the reaction solution. The white solid was filtered, dried, and recrystallized with ethyl acetate / n-heptane to obtain 9.55 g of a white solid (i.e., lotilaner), with a yield of 80%.

[0051] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, not all of them. Any slight modification or equivalent change and improvement made with reference to the present invention or in accordance with the scope of the present invention application shall fall within the scope covered by the patent of the present invention.

Claims

1. A preparation method of lotilaner, characterized in that, It includes the following steps: A. Oxidation reaction: After dissolving 3 - hexyn - 2,5 - diol in a solvent, an oxidant is added to carry out an oxidation reaction to obtain 3 - hexyn - 2,5 - dione, namely intermediate 1; B. Thiophene synthesis reaction: After dissolving intermediate 1 and thiol acetate in a solvent, a base is added to carry out a thiophene synthesis reaction to obtain 5 - acetyl - 3 - methylthiophene - 2 - carboxylate, namely intermediate 2; C. Hydrolysis reaction: After dissolving intermediate 2 in a solvent, an acid or a base is added to carry out a hydrolysis reaction to obtain 5 - acetyl - 3 - methylthiophene - 2 - carboxylic acid, namely intermediate 3; D. Amide condensation reaction: Intermediate 3 and a carboxyl activating reagent are dissolved in DMF for carboxyl activation. The obtained product is successively mixed with 2 - amino - N - (2,2,2 - trifluoroethyl)acetamide hydrochloride and triethylamine, and then a condensation reaction is carried out to obtain intermediate 4; E. Aldol condensation and dehydration reaction: Intermediate 4, 3′,4′,5′ - trichloro - 2,2,2 - trifluoroacetophenone and a base are dissolved in a solvent to carry out an aldol condensation reaction, and then a dehydrating agent is added for a dehydration reaction to obtain intermediate 5; F. Cyclization reaction: Intermediate 5, hydroxylamine hydrochloride and a base are dissolved in a solvent to carry out a cyclization reaction to obtain lotilaner.

2. The preparation method of lotilaner according to claim 1, characterized in that, In step A, the molar ratio of 3 - hexyn - 2,5 - diol to the oxidant is 1:1 - 10; the oxidant includes one of 2 - iodoxybenzoic acid, Dess - Martin, hydrogen peroxide, tert - butyl hydroperoxide, manganese dioxide, PDC, p - benzoquinone, Jones reagent, dimethyldioxirane; the solvent used in the oxidation reaction is one or several of dichloromethane, dimethyl sulfoxide, acetone, DMF, water, methanol, ethanol, isopropanol, tert - butanol, toluene, benzene.

3. The preparation method of lotilaner according to claim 1, characterized in that, In step B, the thiol acetate includes but is not limited to methyl thiolacetate, ethyl thiolacetate, propyl thiolacetate, butyl thiolacetate or cyclohexyl thiolacetate; The molar ratio of intermediate 1 to the thiol acetate is 1:1 - 2; In step B, the base is an organic base or an inorganic base, specifically sodium methoxide, sodium ethoxide, sodium tert - butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or triethylamine; In step B, the solvent is one of methanol, ethanol, isopropanol, tert - butanol.

4. The preparation method of lotilaner according to claim 1, wherein, When the hydrolysis reaction in step C is carried out under acidic conditions, the acidic conditions are provided by sulfuric acid, hydrochloric acid, glacial acetic acid or phosphoric acid; When the hydrolysis reaction in step C is carried out under acidic conditions, the temperature of the hydrolysis reaction is 30 - 80 °C, and the time of the hydrolysis reaction is 1 - 12 h; In step C, the solvent is one of tetrahydrofuran, acetone, dichloromethane, dichloroethane, carbon tetrachloride, DMF.

5. The preparation method of lotilaner according to claim 1, wherein, When the hydrolysis reaction in step C is carried out under basic conditions, the basic conditions are provided by sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium carbonate or sodium carbonate; The temperature of the hydrolysis reaction is 30 - 50 °C, and the time of the hydrolysis reaction is 1 - 12 h; In step C, the solvent is one of tetrahydrofuran, acetone, dichloromethane, dichloroethane, carbon tetrachloride, DMF.

6. The preparation method of lotilaner according to claim 1, wherein In the step D, the carboxyl activating reagent includes one of thionyl chloride, oxalyl chloride, acetyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, CDI, EDCI, HATU, and PyBoP.

7. The preparation method of lotilaner according to claim 1, characterized in that, The molar ratio of the intermediate 3 to 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is 1:1 to 1.

5.

8. The preparation method of lotilaner according to claim 1, characterized in that, In the step E, the molar ratio of the intermediate 4 to 3′,4′,5′-trichloro-2,2,2-trifluoroacetophenone is 1:1 to 2; the molar ratio of the intermediate 4 to the base is 1:1 to 2; the molar ratio of the intermediate 4 to the dehydrating agent is 1:1 to 3.

9. The preparation method of lotilaner according to claim 1, wherein, In the step E, the base includes one or more of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium oxide, magnesium oxide, calcium hydroxide, magnesium hydroxide, triethylamine, diisopropylethylamine, DBU, TBD, and DABCO; The dehydrating agent includes acetic anhydride, thionyl chloride, and acetyl chloride; The solvent is one or more of toluene, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, and acetone.

10. The preparation method of lotilaner according to claim 1, wherein, In the step F, the molar ratio of the intermediate 5 to hydroxylamine hydrochloride is 1:1 to 2; the temperature of the cyclization reaction is -20 to 30 °C; the time of the cyclization reaction is 1 to 3 h; The solvent in step F is one of toluene, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, acetone, methanol, ethanol, isopropanol, DMF, N N-methylpyrrolidone, and ethyl acetate.

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