Key intermediate of lotinib and preparation method of key intermediate

Abstract

The invention belongs to the field of medical intermediate compounds and organic synthesis, and particularly relates to a key intermediate of lotinib and a preparation method of the key intermediate of lotinib, the preparation method comprises the following steps: (1) in an organic solvent, organic alkali, 5-acetyl-3-methyl-2-thiophene carboxylic acid and 2, 2, 2-trifluoro-1-(3, 4, 5-trichlorobenzene) ethanone react to obtain an intermediate 1; (2) dehydrating the intermediate 1 into double bonds to obtain an intermediate 2; and (3) reacting the intermediate 2 with a ligand to obtain the key intermediate of lotinib. According to the preparation method, the steps of a synthetic route can be shortened, the period is shortened, the yield is improved, the cost is reduced, the reaction conditions are milder, and a new technology suitable for industrial production is provided for the key intermediate of lotinia.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate compounds and organic synthesis, specifically a key intermediate of loteranal, its preparation method, and its application. Background Technology

[0002] Loteranar's chemical name is (S)-5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid-[2,2,2-trifluoro-ethyl-carbamoyl)-methyl]-amide, and its chemical structure is shown in Formula 1. Loteranar is a non-competitive antagonist of γ-aminobutyric acid (GABA) receptors. GABA is an important neurotransmitter in animals, mainly found in the central nervous system, and is converted from glutamate through enzymatic metabolism. As an inhibitory neurotransmitter, GABA is released from the presynaptic membrane of nerve cells, reaches the postsynaptic membrane through the synaptic cleft, and specifically binds to GABA receptors on the postsynaptic membrane. This causes the chloride ion channels on the cell membrane to open, allowing chloride ions from outside the membrane to enter the cell, producing hyperpolarization, thereby inhibiting nerve cell excitation and exerting its physiological effects. Studies show that GABA receptor antagonists are selective between mammals and insects, making γ-aminobutyric acid-gated chloride channels an important insecticide target.

[0003] (Equation 1)

[0005] The inventors discovered the following problems with the disclosed methods for preparing loteranar during their practical research:

[0006] CN117447443A discloses a method for preparing loteranar racemates from 3-aldehyde-3-methyl-thiophene-2-carboxylic acid and 2-amino-trifluoroethyl-acetamide via a 5-step reaction. The single configuration loteranar is then obtained by chiral column separation, followed by a final step of chiral cyclization to purify the isomers. However, this method has low yields, significant losses, and high costs.

[0007]

[0008] CN116194450A discloses a method for obtaining loteranar racemate by reacting ethyl magnesium chloride with CO2 gas. However, this method requires harsh conditions, is difficult to control, and has high costs, making it unsuitable for industrial production.

[0009]

[0010] WO2022 / 20585 discloses that 3-aldehyde-3-methyl-thiophene-2-carboxylic acid first forms a methyl ester, then undergoes cyclization, and finally hydrolyzes it. This process involves a long reaction time and high cost.

[0011]

[0012] Loterana intermediate Loteranal can be obtained by reacting with 2-amino-trifluoroethyl-acetamide, which can directly simplify the synthesis steps of loteranal and has good application prospects. Therefore, it is particularly important to develop a route suitable for industrial-scale production of loteranal intermediates to realize the industrialization of loteranal. Summary of the Invention

[0013] This invention provides a key intermediate for loteranal, its preparation method, and its applications, solving the problems of low yield, high cost, and harsh reaction conditions in existing loteranal preparation methods. The preparation method of this invention shortens the synthetic route steps and cycle time, while improving yield and reducing cost. The reaction conditions of this invention are more moderate, resulting in a loteranal key intermediate with fewer impurities and higher purity, providing a new technology suitable for the industrial production of loteranal key intermediates.

[0014] This invention provides a method for preparing a key intermediate of loteranar, characterized by comprising the following steps: (1) In an organic solvent, an organic base, 5-acetyl-3-methyl-2-thiophenic acid and 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone are reacted to give intermediate 1; (2) Intermediate 1 is dehydrated to form double bonds to obtain intermediate 2; (3) Intermediate 2 reacts with the ligand to obtain the key intermediate of loteranal.

[0015]

[0016] The organic solvent in step (1) is one of methyl tert-butyl ether, toluene, and tetrahydrofuran.

[0017] In step (1), the molar ratio of 5-acetyl-3-methyl-2-thiophenic acid and 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone is 1:1-2.

[0018] The organic base in step (1) is either diethylamine or triethylamine.

[0019] In steps (1) and (2), intermediate 1 is one of free base, triethylamine salt, or diethylamine salt.

[0020] The dehydrating agent in step (2) is thionyl chloride or acetic anhydride.

[0021] The ligand in step (3) is one of (1S,2S,4S,5R)-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-1-(3,4,5-tris(benzyloxy)benzyl)-5-vinylquinine-1-ammonium chloride and N-(acridin-9-ylmethyl)quinine bromide.

[0022] In step (3), the feeding ratio of intermediate 2 to ligand is 1:0.1-0.2.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0024] The present invention shortens the synthetic route steps and cycle of the intermediate, improves the yield and reduces the cost. The reaction conditions of the present invention are milder, resulting in loteranal key intermediates with fewer impurities and higher purity, providing a new technology suitable for the industrial production of loteranal key intermediates.

[0025] The raw materials used in this invention are safe, readily available, and inexpensive, effectively reducing production costs. Furthermore, the method of this invention shortens the reaction steps, reduces the difficulty of intermediate purification, and also improves product quality and yield, ultimately enhancing the product's competitiveness. Detailed Implementation

[0026] The specific embodiments of this application are described in detail below. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.

[0027]

[0028] Step 1: Preparation of Intermediate 1 Example 1

[0029] At room temperature, 1000 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 109.9 g (1.08 mol, 2 eq) of triethylamine. The temperature was controlled, and then 225.9 g (0.82 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask. The temperature was controlled to ≤30℃. 100.15 g (0.54 mol, 1 eq) of 5-acetyl-3-methyl-2-thiophene carboxylic acid was weighed and added to the reaction flask. The solid did not completely dissolve, forming a suspension. After the addition was complete, the mixture was heated in an oil bath and stirred for 16-24 hours. During the reaction, the system initially dissolved and then a large amount of solid precipitated. The mixture was allowed to cool naturally to room temperature, then cooled to 0-10°C in an ice-water bath. It was then subjected to concentrated hydrochloric acid at pH 2-3, stirred, and separated. The organic phase was dried and concentrated to obtain intermediate 1, a yellow solid, weighing approximately 226g, with a yield of 90% and a liquid phase purity of 96.3%.

[0030] Mass spectrometry: [MH] - 459 MRI: 1 H NMR (400 MHz, DMSO) δ 13.50(br,1H), 7.96(S,1H), 7.90(S,2H),7.26(S,1H), 4.35-4.39(d,1H), 3.85-3.90(d,1H), 2.50(S,3H).

[0031] Example 2 At room temperature, 10 L of methyl tert-butyl ether was added to a 20 L reaction flask, followed by 1099 g (10.8 mol, 2 eq) of triethylamine. The temperature was controlled, and then 2259 g (8.2 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask. The temperature was controlled to ≤30℃. 1001.5 g (5.4 mol, 1 eq) of 5-acetyl-3-methyl-2-thiophene carboxylic acid was weighed and added to the flask. The solid did not completely dissolve, forming a suspension. After the addition was complete, the mixture was heated in an oil bath and stirred for 16-24 h. During the reaction, the system first dissolved completely and then a large amount of solid precipitated. The mixture was allowed to cool naturally to room temperature, then cooled to 0-10℃ in an ice-water bath and stirred for 2 h. The filter cake was filtered and washed five times with 1.5 L of pre-cooled methyl tert-butyl ether (0~10℃) to obtain intermediate 1 triethylamine salt, which was a pale yellow solid of about 3060 g, with a yield of 100% and a liquid phase purity of 97.5%.

[0032] Mass spectrometry: [M-C6H] 15 NH] - 460.9 MRI: 1 H NMR (400 MHz, DMSO) δ 7.88(S,2H), 7.75(S,1H), 7.28(br,1H),4.24-4.28(d,1H), 3.79-3.83(d,1H), 2.98(m,4H), 2.44(S,3H), 1.15(t,9H).

[0033] Example 3 At room temperature, 1000 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 79.5 g (1.08 mol, 2 eq) of diethylamine. While maintaining the temperature, 225.9 g (0.82 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, maintaining the temperature at ≤30℃. Then, 100.15 g (0.54 mol, 1 eq) of 5-acetyl-3-methyl-2-thiophene carboxylic acid was weighed and added to the flask. The solid did not completely dissolve, forming a suspension. After the addition was complete, the mixture was heated in an oil bath and stirred for 16-24 hours. During the reaction, the system initially dissolved completely before precipitating a large amount of solid. The mixture was then allowed to cool naturally to room temperature, followed by cooling in an ice-water bath to 0-10℃ and stirring for 2 hours. The filter cake was filtered and washed five times with 150 ml of pre-cooled methyl tert-butyl ether (0~10℃) to obtain approximately 266 g of diethylamine salt of pale yellow solid intermediate 1, with a yield of 92% and a liquid phase purity of 96.8%.

[0034] Example 4 At room temperature, 1000 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 109.9 g (1.08 mol, 2 eq) of triethylamine. While maintaining the temperature, 150.8 g (0.54 mol, 1 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, maintaining the temperature ≤30℃. Then, 100.15 g (0.54 mol, 1 eq) of 5-acetyl-3-methyl-2-thiophene carboxylic acid was added to the flask. The solid did not completely dissolve, forming a suspension. After the addition was complete, the mixture was heated in an oil bath and stirred for 16-24 hours. During the reaction, the system initially dissolved completely before precipitating a large amount of solid. The mixture was then allowed to cool naturally to room temperature, followed by cooling in an ice-water bath to 0-10℃ and stirring for 2 hours. The filter cake was filtered and washed five times with 150 ml of pre-cooled methyl tert-butyl ether (0~10℃) to obtain about 184 g of triethylamine salt of pale yellow solid intermediate 1, with a yield of 60% and a liquid phase purity of 93.5%.

[0035] Example 5 At room temperature, 1000 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 109.9 g (1.08 mol, 2 eq) of triethylamine. While maintaining the temperature, 301.6 g (1.08 mol, 2 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, maintaining the temperature at ≤30℃. Then, 100.15 g (0.54 mol, 1 eq) of 5-acetyl-3-methyl-2-thiophene carboxylic acid was added to the flask. The solid did not completely dissolve, forming a suspension. After the addition was complete, the mixture was heated in an oil bath and stirred for 16-24 hours. During the reaction, the system initially dissolved completely before precipitating a large amount of solid. The mixture was then allowed to cool naturally to room temperature, followed by cooling in an ice-water bath to 0-10℃ and stirring for 2 hours. The filter cake was filtered and washed five times with 150 ml of pre-cooled methyl tert-butyl ether (0~10℃) to obtain approximately 300 g of triethylamine salt of intermediate 1, with a yield of 98% and a liquid phase purity of 97.7%.

[0036] Example 6

[0037] At room temperature, 1000 ml of toluene was added to a 2000 ml reaction flask, followed by 109.9 g (1.08 mol, 2 eq) of triethylamine. While maintaining the temperature, 225.9 g (0.82 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, maintaining the temperature at ≤30℃. Then, 100.15 g (0.54 mol, 1 eq) of 5-acetyl-3-methyl-2-thiophene carboxylic acid was added to the flask. The solid did not completely dissolve, forming a suspension. After the addition was complete, the mixture was heated in an oil bath and stirred for 16-24 hours. During the reaction, the system initially dissolved completely before precipitating a large amount of solid. The mixture was then allowed to cool naturally to room temperature, followed by cooling in an ice-water bath to 0-10℃ and stirring for 2 hours. The filter cake was filtered and washed five times with 150 ml of pre-cooled toluene (0-10℃) to obtain approximately 303 g of pale yellow solid intermediate 1 triethylamine salt, with a yield of 99% and a liquid phase purity of 98.1%.

[0038] Example 7 At room temperature, 1000 ml of tetrahydrofuran was added to a 2000 ml reaction flask, followed by 109.9 g (1.08 mol, 2 eq) of triethylamine. While maintaining the temperature, 225.9 g (0.82 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, maintaining the temperature at ≤30℃. Then, 100.15 g (0.54 mol, 1 eq) of 5-acetyl-3-methyl-2-thiophene carboxylic acid was added to the flask. The solid did not completely dissolve, forming a suspension. After the addition was complete, the mixture was heated in an oil bath and stirred for 16-24 hours. During the reaction, the system initially dissolved completely before a large amount of solid precipitated. The mixture was then allowed to cool naturally to room temperature, followed by cooling in an ice-water bath to 0-10℃ and stirring for 2 hours. The filter cake was filtered and washed five times with 150 ml of pre-cooled tetrahydrofuran (0~10℃) to obtain approximately 294 g of pale yellow solid intermediate 1 triethylamine salt, with a yield of 96% and a liquid phase purity of 98.2%.

[0039] Example 8

[0040] At 0-10℃, add 102g (0.18mol, 1eq) of triethylamine salt of intermediate 1, 500ml of methyl tert-butyl ether, and 65.7g (0.65mol, 3.6eq) of triethylamine to a 1000ml three-necked flask and start stirring. Maintain the temperature below 30℃, weigh 33.5g (0.28mol, 1.56eq) of thionyl chloride, and add it dropwise to the reaction flask over approximately 0.5-1h. After the addition is complete, raise the temperature to 60-65℃ and react for 4h. Cool to 30-40℃, remove the remaining thionyl chloride by vacuum distillation, followed by one distillation in 300ml of dichloromethane. After concentration, obtain a brown oily substance. Dissolve the substance in 800ml of DCM, then add 800ml of purified water dropwise while stirring. Initially, the addition process may be exothermic due to residual thionyl chloride; carefully control the adding rate. Once the exothermic phenomenon ceases, the water addition rate can be increased. Stir for 30 min, let stand and separate the liquids. Wash the organic phase twice with 500 ml of purified water (2). After drying and concentrating the organic phase, perform column chromatography to obtain 75 g of pale yellow solid intermediate 2, with a yield of 93.3% and an HPLC purity of 98%.

[0041] Mass spectrometry: [MH] - 440.9 MRI: 1 H NMR (400 MHz, DMSO) δ 13.64(s,1H), 8.11(s,1H), 7.85(s,1H), 7.68(s,2H), 2.50(s,3H).

[0042] Example 9 At 0-10℃, add 102g (0.18mol, 1eq) of triethylamine salt of intermediate 1, 500ml of methyl tert-butyl ether, and 65.7g (0.65mol, 3.6eq) of triethylamine to a 1000ml three-necked flask and start stirring. Maintain the temperature below 30℃, and add 28.6g (0.28mol, 1.56eq) of acetic anhydride dropwise to the reaction flask over approximately 0.5-1h. After the addition is complete, add 2.2g (0.018mol, 0.1eq) of 4-dimethylaminopyridine and react at 60-65℃ for 4h. Cool to 30-40℃, remove residual acetic anhydride by vacuum distillation, distill once with 300ml of dichloromethane, concentrate to obtain a brown oily substance, add 800ml of DCM to dissolve, and then add 800ml of purified water dropwise while stirring. Initially, the addition process may cause exothermic reactions due to residual acetic anhydride; carefully control the adding rate. Once the exothermic reaction stops, the water addition rate can be increased. Stir for 30 minutes, allow to stand, and separate the liquid. Wash the organic phase twice with 500ml of purified water (2 times), dry and concentrate the organic phase, and then perform column chromatography to obtain 72.4g of pale yellow solid intermediate 2, yield 90.1%, HPLC purity 96.4%.

[0043] Example 10 At 0-10℃, add 102g (0.18mol, 1eq) of triethylamine salt of intermediate 1 and 500ml of methyl tert-butyl ether to a 1000ml three-necked flask and start stirring. Maintain the temperature below 30℃, weigh 33.5g (0.28mol, 1.56eq) of thionyl chloride and add it dropwise to the reaction flask over approximately 0.5-1h. After the addition is complete, raise the temperature to 60-65℃ and react for 4h. Cool to 30-40℃, remove the remaining thionyl chloride by vacuum distillation, followed by one distillation in 300ml of dichloromethane. After concentration, obtain a brown oily substance. Dissolve the substance in 800ml of DCM, then add 800ml of purified water dropwise while stirring. Initially, the addition process may be exothermic due to residual thionyl chloride; carefully control the adding rate. Once the exothermic phenomenon ceases, the water addition rate can be increased. Stir for 30 min, let stand and separate the liquids. Wash the organic phase twice with 500 ml of purified water (2). After drying and concentrating the organic phase, perform column chromatography to obtain 69.4 g of intermediate 2, a pale yellow solid, with a yield of 86.3% and an HPLC purity of 97.1%.

[0044] Example 11 At 0-10℃, add 183.1g (0.18mol, 1eq) of free intermediate, 500ml of methyl tert-butyl ether, and 18.2g (0.18mol, 1eq) of triethylamine to a 1000ml three-necked flask and start stirring. Maintain the temperature below 30℃, weigh 33.5g (0.28mol, 1.56eq) of thionyl chloride, and add it dropwise to the reaction flask over approximately 0.5-1h. After the addition is complete, raise the temperature to 60-65℃ and react for 4h. Cool to 30-40℃, remove the remaining thionyl chloride by vacuum distillation, followed by one distillation in 300ml of dichloromethane. After concentration, obtain a brown oily substance. Dissolve the substance in 800ml of DCM, then add 800ml of purified water dropwise while stirring. Initially, the addition process may be exothermic due to residual thionyl chloride; carefully control the adding rate. Once the exothermic phenomenon ceases, the water addition rate can be increased. Stir for 30 min, let stand and separate the liquids. Wash the organic phase twice with 500 ml of purified water (2). After drying and concentrating the organic phase, perform column chromatography. The intermediate 2 is a pale yellow solid, 71.4 g, yield 89.4%, HPLC purity 94.2%.

[0045] Step 3: Preparation of key intermediates for loteranar

[0046] Example 12 At room temperature, with magnetic stirring, 128 ml of dichloromethane, 16 g (36 mmol, 1 eq) of intermediate 2 (94.9% purity), and 3.22 g (5.4 mmol, 0.15 eq) of ligand (N-(acridin-9-ylmethyl)quinine bromide) were added to a 250 ml reaction flask A. After stirring for 30 min, the mixture was cooled to -15 to -10 °C. A 20% sodium hydroxide aqueous solution was prepared in a 100 ml reaction flask B, stirred until dissolved, and then cooled to -15 to -10 °C. A 50% hydroxylamine aqueous solution was weighed and added dropwise to reaction flask B at a controlled temperature of -15 to -10 °C. The addition process was exothermic and took approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10 °C (external temperature) with stirring for 20 min. The reaction solution in reaction flask B was added dropwise to reaction flask A at a controlled temperature of -15 to -10°C. During the dropwise addition, the reaction system became viscous, and the exothermic reaction was not significant. The dropwise addition time was approximately 15 to 30 minutes. After the dropwise addition was complete, the mixture was kept at this temperature and stirred for 16 to 20 hours. The temperature was then raised to 15 to 20°C, and 100 ml of purified water was added to reaction flask A. After stirring for 30 minutes, the mixture was allowed to stand and separated. The organic phase was washed with 200 ml of 10% citric acid, dried, concentrated, and crystallized to obtain 14.9 g of intermediate solid, with a yield of 90.1% and a purity of 99.6%.

[0047] Mass spectrometry: [MH] - 457.92 MRI: 1H NMR (400 MHz, CDCl3) δ 7.62(s,2H), 7.13(s,1H), 4.05-4.09(d,1H), 3.66-3.70(d,1H), 2.56(s,3H).

[0048] Example 13 At room temperature, with magnetic stirring, 128 ml of dichloromethane, 16 g (36 mmol, 1 eq) of intermediate 2 (94.9% purity), and 2.14 g (3.6 mmol, 0.1 eq) of ligand (N-(acridin-9-ylmethyl)quinine bromide) were added to a 250 ml reaction flask A. After stirring for 30 min, the mixture was cooled to -15 to -10 °C. A 20% sodium hydroxide aqueous solution was prepared in a 100 ml reaction flask B, stirred until dissolved, and then cooled to -15 to -10 °C. A 50% hydroxylamine aqueous solution was weighed and added dropwise to reaction flask B at a controlled temperature of -15 to -10 °C. The addition process was exothermic and took approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10 °C (outer temperature) with stirring for 20 min. The reaction solution in reaction flask B was added dropwise to reaction flask A at a controlled temperature of -15 to -10°C. During the dropwise addition, the reaction system became viscous, and the exothermic reaction was not significant. The dropwise addition time was approximately 15 to 30 minutes. After the dropwise addition was complete, the mixture was kept at this temperature and stirred for 16 to 20 hours. The temperature was then raised to 15 to 20°C, and 100 ml of purified water was added to reaction flask A. After stirring for 30 minutes, the mixture was allowed to stand and separated. The organic phase was washed with 200 ml of 10% citric acid, dried, concentrated, and crystallized to obtain 12.7 g of solid, with a yield of 76.8% and a purity of 95.4%.

[0049] Example 14 At room temperature, with magnetic stirring, 128 ml of dichloromethane, 16 g (36 mmol, 1 eq) of intermediate 2 (94.9% purity), and 4.28 g (7.2 mmol, 0.2 eq) of ligand (N-(acridin-9-ylmethyl)quinine bromide) were added to a 250 ml reaction flask A. After stirring for 30 min, the mixture was cooled to -15 to -10 °C. A 20% sodium hydroxide aqueous solution was prepared in a 100 ml reaction flask B, stirred until dissolved, and then cooled to -15 to -10 °C. A 50% hydroxylamine aqueous solution was weighed and added dropwise to reaction flask B at a controlled temperature of -15 to -10 °C. The addition process was exothermic and took approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10 °C (outer temperature) with stirring for 20 min. The reaction solution in reaction flask B was added dropwise to reaction flask A at a controlled temperature of -15 to -10°C. During the dropwise addition, the reaction system became viscous, and the exothermic reaction was not significant. The dropwise addition time was approximately 15 to 30 minutes. After the dropwise addition was complete, the mixture was kept at this temperature and stirred for 16 to 20 hours. The temperature was then raised to 15 to 20°C, and 100 ml of purified water was added to reaction flask A. After stirring for 30 minutes, the mixture was allowed to stand and separated. The organic phase was washed with 200 ml of 10% citric acid, dried, concentrated, and crystallized to obtain 14.5 g of solid, with a yield of 87.7% and a purity of 97.4%.

[0050] Example 15 At room temperature, with magnetic stirring, 128 ml of dichloromethane, 16 g (36 mmol, 1 eq) of intermediate 2 (94.9% purity), and 2.77 g (3.6 mmol, 0.1 eq) of ligand ((1S,2S,4S,5R)-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-1-(3,4,5-tris(benzyloxy)benzyl)-5-vinylquinine-1-ammonium chloride) were added to a 250 ml reaction flask A. After stirring for 30 min, the mixture was cooled to -15 to -10 °C. A 20% sodium hydroxide aqueous solution was prepared in a 100 ml reaction flask B, stirred until dissolved, and then cooled to -15 to -10 °C. A 50% hydroxylamine aqueous solution was weighed and added dropwise to reaction flask B at a controlled temperature of -15 to -10 °C. The addition process was exothermic and took approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10°C (external temperature) and stirred for 20 minutes. The reaction solution in reaction flask B was then added dropwise to reaction flask A at a controlled temperature of -15 to -10°C. During the addition process, the reaction system became viscous, and the exothermic reaction was not significant. The addition time was approximately 15 to 30 minutes. After the addition was complete, the mixture was kept at this temperature and stirred for 16 to 20 hours. The temperature was then raised to 15 to 20°C, and 100 ml of purified water was added to reaction flask A. After stirring for 30 minutes, the mixture was allowed to stand and separated. The organic phase was washed with 200 ml of 10% citric acid, dried, concentrated, and crystallized to obtain 11.6 g of solid, with a yield of 70.1% and a purity of 95.8%.

[0051] Example 16 At room temperature, with magnetic stirring, 128 ml of dichloromethane, 16 g (36 mmol, 1 eq) of intermediate 2 (94.9% purity), and 4.15 g (5.4 mmol, 0.15 eq) of ligand ((1S,2S,4S,5R)-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-1-(3,4,5-tris(benzyloxy)benzyl)-5-vinylquinine-1-ammonium chloride) were added to a 250 ml reaction flask A. After stirring for 30 min, the mixture was cooled to -15 to -10 °C. A 20% sodium hydroxide aqueous solution was prepared in a 100 ml reaction flask B, stirred until dissolved, and then cooled to -15 to -10 °C. A 50% hydroxylamine aqueous solution was weighed and added dropwise to reaction flask B at a controlled temperature of -15 to -10 °C. The addition process was exothermic and took approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10°C (external temperature) and stirred for 20 minutes. The reaction solution in reaction flask B was then added dropwise to reaction flask A at a controlled temperature of -15 to -10°C. During the addition process, the reaction system became viscous, and the exothermic reaction was not significant. The addition time was approximately 15 to 30 minutes. After the addition was complete, the mixture was kept at this temperature and stirred for 16 to 20 hours. The temperature was then raised to 15 to 20°C, and 100 ml of purified water was added to reaction flask A. After stirring for 30 minutes, the mixture was allowed to stand and separated. The organic phase was washed with 200 ml of 10% citric acid, dried, concentrated, and crystallized to obtain 12.7 g of solid, with a yield of 76.8% and a purity of 96.9%.

[0052] Example 17 At room temperature, with magnetic stirring, 128 ml of dichloromethane, 16 g (36 mmol, 1 eq) of intermediate 2 (94.9% purity), and 5.54 g (7.2 mmol, 0.2 eq) of ligand ((1S,2S,4S,5R)-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-1-(3,4,5-tris(benzyloxy)benzyl)-5-vinylquinine-1-ammonium chloride) were added to a 250 ml reaction flask A. After stirring for 30 min, the mixture was cooled to -15 to -10 °C. A 20% sodium hydroxide aqueous solution was prepared in a 100 ml reaction flask B, stirred until dissolved, and then cooled to -15 to -10 °C. A 50% hydroxylamine aqueous solution was weighed and added dropwise to reaction flask B at a controlled temperature of -15 to -10 °C. The addition process was exothermic and took approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10°C (external temperature) and stirred for 20 minutes. The reaction solution in reaction flask B was then added dropwise to reaction flask A at a controlled temperature of -15 to -10°C. During the addition process, the reaction system became viscous, and the exothermic reaction was not significant. The addition time was approximately 15 to 30 minutes. After the addition was complete, the mixture was kept at this temperature and stirred for 16 to 20 hours. The temperature was then raised to 15 to 20°C, and 100 ml of purified water was added to reaction flask A. After stirring for 30 minutes, the mixture was allowed to stand and separated. The organic phase was washed with 200 ml of 10% citric acid, dried, concentrated, and crystallized to obtain 14.2 g of solid, with a yield of 85.85% and a purity of 97.6%.

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application and are not intended to limit it. Although this application has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of this application without departing from the spirit and scope of the technical solutions of this application, and all such modifications or substitutions should be covered within the scope of the claims of this application.

Claims

1. A process for the preparation of a key intermediate of Rotigaptin characterized in that The preparation method of the lotiliran key intermediate comprises the following steps: (1) reacting 5-acetyl-3-methyl-2-thiophene carboxylic acid and 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethanone in an organic solvent, an organic base, to obtain intermediate 1; (2) dehydrating intermediate 1 to obtain intermediate 2; (3) reacting intermediate 2 with a ligand to obtain the lotiliran key intermediate.

2. A process for the preparation of a key intermediate of Lotilaner as claimed in claim 1, wherein, The organic solvent in step (1) is one of methyl tert-butyl ether, toluene, and tetrahydrofuran.

3. A process for the preparation of a key intermediate of Lotilaner as claimed in claim 1, wherein, The molar ratio of 5-acetyl-3-methyl-2-thiophene carboxylic acid to 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethanone in step (1) is 1:1-2.

4. A process for the preparation of a key intermediate of Lotilaner as claimed in claim 1, wherein, The organic base in step (1) is one of diethylamine and triethylamine.

5. A process for the preparation of a key intermediate of Lotilaner as claimed in claim 1, wherein, Intermediate 1 in steps (1) and (2) is one of free base, triethylamine salt, and diethylamine salt.

6. A process for the preparation of a key intermediate of Lotilaner as claimed in claim 1, wherein, The dehydrating agent in step (2) is one of thionyl chloride and acetic anhydride.

7. A process for the preparation of a key intermediate of Lotilaner as claimed in claim 1, wherein, The ligand in step (3) is one of (1S,2S,4S,5R)-2-((R)-hydroxy(6-methoxyquinoline-4-yl) methyl)-1-(3,4,5-tris(benzyloxy) benzyl)-5-vinyl quinine-1-ammonium chloride and N-(acridine-9-ylmethyl) quinine bromide.

8. A process for the preparation of a key intermediate of Lotilaner as claimed in claim 1, wherein, The molar ratio of intermediate 2 to the ligand in step (3) is 1:0.1-0.

2.

9. Use of the lotiliran key intermediate of claim 1 in the preparation of lotiliran.

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