Key intermediate of lotilaner and preparation method therefor

Abstract

The present invention relates to the fields of pharmaceutical intermediate compounds and organic synthesis, and specifically relates to a key intermediate of lotilaner and a preparation method therefor. The preparation method comprises: (1) reacting an organic base, 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylate, and 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone in an organic solvent to obtain an intermediate 1; (2) dehydrating the intermediate 1 to form a double bond to obtain an intermediate 2; and (3) reacting the intermediate 2 with a ligand to obtain a key intermediate of lotilaner. The intermediate is used for synthesizing lotilaner. The preparation method of the present invention has extremely high chiral selectivity, mild conditions, and stable yield, can be suitable for scale-up production, and provides a new technique suitable for industrial production for the key intermediate of lotilaner.

Description

A key intermediate of loteranar and its preparation method 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] [Corrected according to Rule 91, 03.07.2025] 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 structural formula 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 outside the membrane to enter the cell, producing hyperpolarization, thereby inhibiting nerve cell excitation and exerting 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] [Corrected from Rule 91 on 03.07.2025] Formula 1: Chemical structural formula of lotelanar.

[0004] The inventors discovered the following problems with the disclosed methods for preparing loteranar during their practical research:

[0005] 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.

[0006]

[0007] CN116194450A discloses a method for obtaining a loteranar intermediate by reacting ethyl magnesium chloride with CO2 gas, and then synthesizing loteranar. The obtained intermediate contains 91.34% S isomer and 8.67% R isomer. The high proportion of R isomer and the harsh conditions make the reaction difficult to control, resulting in high route costs and making it unsuitable for industrial production.

[0008]

[0009] CN116194450A also discloses a method of first adding an acetyl group to 3-methyl-2-thiophenecarboxylic acid, then synthesizing a methyl ester, followed by cyclization and hydrolysis. This method involves a long reaction process, high cost, and poor selectivity in the intermediate chirality (S:R = 89:11).

[0010]

[0011] CN117486869 discloses a two-step reaction to prepare loteranar using compound of formula a, 2-amino-trifluoroethyl-acetamide hydrochloride, hydroxylamine solution, and a chiral phase transfer catalyst (R)-N-benzylquinine halide as raw materials. The reactants are difficult to obtain and the cost is high.

[0012]

[0013] Therefore, developing a route for the industrial-scale production of loteranar intermediates with high chiral purity and low cost is particularly important for realizing the industrialization of loteranar. Summary of the Invention

[0014] This invention provides a key intermediate for loteranal, its preparation method, and its applications, solving the problems of low yield, high cost, harsh reaction conditions, and poor chiral selectivity in existing loteranal preparation methods. Based on the literature data, it is inferred that introducing a sterically hindered ester group improves the chiral selectivity of the reaction. The preparation method of this invention reduces the isomer ratio from 8.67% as described in the literature to less than 0.5%, achieving an ee value of over 99%, thus improving yield and reducing cost. The reaction conditions of this invention are milder, 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.

[0015] This invention provides a method for preparing a key intermediate of loteranar, characterized by comprising the following steps:

[0016] (1) In an organic solvent, an organic base, 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester and 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone are reacted to give intermediate 1.

[0017] (2) Intermediate 1 is dehydrated to form a double bond to obtain intermediate 2.

[0018] (3) Intermediate 2 reacts with the ligand to obtain the key intermediate of loteranal.

[0019]

[0020] The organic solvent in step (1) is one of methyl tert-butyl ether, toluene, and tetrahydrofuran.

[0021] In step (1), the molar ratio of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester and 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone is 1:1-2.

[0022] The organic base in step (1) is either diethylamine or triethylamine.

[0023] The dehydrating agent in step (2) is one of thionyl chloride and acetic anhydride.

[0024] 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.

[0025] In step (3), the feeding ratio of intermediate 2 to ligand is 1:0.1-0.2. Beneficial effects

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] This invention solves the problems of low yield, high cost, harsh reaction conditions, and poor chiral selectivity in existing loteranal preparation methods. By introducing a sterically hindered ester group, chiral selectivity is increased, resulting in isomers of less than 0.5% and ee values ​​greater than 99%. This improves yield, reduces cost, and provides milder reaction conditions, yielding loteranal key intermediates with fewer impurities and higher purity. It offers a new technology suitable for the industrial production of loteranal key intermediates. Detailed Implementation

[0028] 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.

[0029] Step 1: Preparation of Intermediate 1 Example 1

[0030] At room temperature, 1200 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 170.6 g (1.68 mol, 2 eq) of triethylamine. While maintaining the temperature, 350.8 g (1.26 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, and the temperature was maintained at ≤30℃. Then, 200 g (0.84 mol, 1 eq) of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester was added to the flask. The solid dissolved completely, forming a clear liquid. After the addition was complete, the mixture was heated in an oil bath and stirred for 4-6 hours until the system became clear. After naturally cooling to room temperature, add 1000ml of water, cool in an ice-water bath to 0~10℃, adjust the pH to 2-3 with concentrated hydrochloric acid, stir and separate the liquid, dry and concentrate the organic phase to obtain intermediate 1 as a yellow solid, about 420g, with a yield of 96.8% and a liquid phase purity of 98.9%.

[0031] Mass spectrometry: [M+H] + 238.05

[0032] MRI: 1 H NMR (400 MHz, DMSO) δ 8.02 (s, 1H), 7.90 (s, 2H), 7.28 (s, 1H), 4.45 (t, 2H), 4.39 (d, 1H), 3.90 (d, 1H), 3.03 (dd, 2H), 2.54 (s, 3H). Example 2

[0033] At room temperature, 1000 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 123.3 g (1.68 mol, 2 eq) of diethylamine. While maintaining the temperature, 350.8 g (1.26 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, and the temperature was maintained at ≤30℃. Then, 200 g (0.84 mol, 1 eq) of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester was added to the flask. The solid dissolved completely, forming a clear liquid. After the addition was complete, the mixture was heated in an oil bath and stirred for 4-6 hours until the system became clear. After naturally cooling to room temperature, add 1000ml of water, cool in an ice-water bath to 0~10℃, adjust the pH to 2-3 with concentrated hydrochloric acid, stir and separate the liquid, dry and concentrate the organic phase to obtain intermediate 1 as a yellow solid, about 403g, with a yield of 92.8% and a liquid phase purity of 97.7%. Example 3

[0034] At room temperature, 1200 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 170.6 g (1.68 mol, 2 eq) of triethylamine. While maintaining the temperature, 233.87 g (0.84 mol, 1 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, and the temperature was maintained at ≤30℃. Then, 200 g (0.84 mol, 1 eq) of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester was added to the flask. The solid dissolved completely, resulting in a clear liquid. After the addition was complete, the mixture was heated in an oil bath and stirred for 4-6 hours until the system became clear. After naturally cooling to room temperature, add 1000ml of water, cool in an ice-water bath to 0~10℃, adjust the pH to 2-3 with concentrated hydrochloric acid, stir and separate the liquids, dry and concentrate the organic phase to obtain intermediate 1 as a yellow solid, about 386g, with a yield of 88.9% and a liquid phase purity of 97.5%. Example 4

[0035] At room temperature, 1200 ml of methyl tert-butyl ether was added to a 2000 ml reaction flask, followed by 170.6 g (1.68 mol, 2 eq) of triethylamine. While maintaining the temperature, 467.7 g (1.68 mol, 2 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, and the temperature was maintained at ≤30℃. Then, 200 g (0.84 mol, 1 eq) of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester was added to the flask. The solid dissolved completely, resulting in a clear liquid. After the addition was complete, the mixture was heated in an oil bath and stirred for 4-6 hours until the system became clear. After naturally cooling to room temperature, add 1000ml of water, cool in an ice-water bath to 0~10℃, adjust the pH to 2-3 with concentrated hydrochloric acid, stir and separate the liquid, dry and concentrate the organic phase to obtain intermediate 1 as a yellow solid, about 417g, with a yield of 96.1% and a liquid phase purity of 98.4%. Example 5

[0036] At room temperature, 1200 ml of toluene was added to a 2000 ml reaction flask, followed by 170.6 g (1.68 mol, 2 eq) of triethylamine. The temperature was controlled, and then 350.8 g (1.26 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℃. 200 g (0.84 mol, 1 eq) of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester was weighed and added to the flask. The solid dissolved completely, forming a clear liquid. After the addition was complete, the mixture was heated in an oil bath and stirred for 4-6 hours until the system became clear. The mixture was allowed to cool naturally to room temperature, and 1000 ml of water was added. The mixture was then cooled to 0-10℃ in an ice-water bath, and the pH was adjusted to 2-3 with concentrated hydrochloric acid. The mixture was stirred and separated. The organic phase was dried and concentrated to obtain intermediate 1, a yellow solid, approximately 408 g, with a yield of 94% and a liquid phase purity of 97.0%. Example 6

[0037] At room temperature, 1200 ml of tetrahydrofuran was added to a 2000 ml reaction flask, followed by 170.6 g (1.68 mol, 2 eq) of triethylamine. While maintaining the temperature, 350.8 g (1.26 mol, 1.5 eq) of 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone was added to the flask, and the temperature was maintained at ≤30℃. Then, 200 g (0.84 mol, 1 eq) of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester was added to the flask. The solid dissolved completely, resulting in a clear liquid. After the addition was complete, the mixture was heated in an oil bath and stirred for 4-6 hours until the system became clear. After naturally cooling to room temperature, add 1000ml of water, cool in an ice-water bath to 0~10℃, adjust the pH to 2-3 with concentrated hydrochloric acid, stir and separate the liquids, dry and concentrate the organic phase to obtain intermediate 1 as a yellow solid, about 397g, with a yield of 91.5% and a liquid phase purity of 98.5%. Step 2: Preparation of Intermediate 2 Example 7

[0038] At 0-10℃, add 1400g (0.78mol, 1eq) of intermediate, 2000ml of methyl tert-butyl ether, and 157.3g (1.55mol, 2eq) of triethylamine to a 1000ml three-necked flask and start stirring. Maintain the temperature below 30℃, weigh 138.7g (1.16mol, 1.5eq) 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 liquid. Wash the organic phase twice with 500 ml of purified water (2 times). Dry and concentrate the organic phase to obtain intermediate 2 380 g of pale yellow solid, with a yield of 98.4% and a liquid phase purity of 99.1%.

[0039] Mass spectrometry [MH] - 396.9

[0040] MRI: 1 H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.86 (s, 1H), 7.69 (s, 2H), 4.45 (t, 2H), 3.02 (t, 2H), 2.54 (s, 3H). Example 8

[0041] At 0-10℃, add 1400g (0.78mol, 1eq) of intermediate, 2000ml of methyl tert-butyl ether, and 157.3g (1.55mol, 2eq) of triethylamine to a 1000ml three-necked flask and start stirring. Maintain the temperature below 30℃, weigh 119g (1.16mol, 1.5eq) of acetic anhydride, 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 acetic anhydride by vacuum distillation, and concentrate to obtain a brown oily substance. Add 800ml of DCM to dissolve the substance, 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 minutes, let stand and separate the liquid. Wash the organic phase twice with 500 ml of purified water. Dry and concentrate the organic phase to obtain 2364 g of intermediate pale yellow solid, with a yield of 94.3% and a liquid phase purity of 98.4%. Step 3: Preparation of key intermediates for loteranar

[0042] Example 9

[0043] At room temperature, with magnetic stirring, 150 ml of dichloromethane, 15 g (30.2 mmol, 1 eq) of intermediate 2, and 2.7 g (4.5 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. After stirring until dissolved, the solution was 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 the addition time was approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10 °C (outer temperature) and stirred for 20 min. The reaction solution in reaction flask B was then added dropwise to reaction flask A at a controlled temperature of -15 to -10 °C. The exothermic process was not significant, and the addition time was approximately 15 to 30 min. After the addition was complete, the mixture was kept at -15 to -10°C 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, separated, dried, concentrated, and crystallized to obtain 15 g of the key intermediate, with a yield of 97.06%, a purity of 99.3%, and an ee value of 99.5%.

[0044] Mass spectrometry: [M+NH4] + 529.9

[0045] MRI: 1H NMR (400 MHz, DMSO) δ 7.82 (s, 2H), 7.46 (s, 1H), 4.45 (dd, 2H), 4.38 (d, 2H), 3.03 (t, 2H), 2.52 (s, 3H). Example 10

[0046] Under room temperature and magnetic stirring, 150 ml of dichloromethane, 15 g (30.2 mmol, 1 eq) of intermediate 2, and 1.8 g (3 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. After stirring until dissolved, the solution was 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 min. The reaction solution in reaction flask B was added dropwise to reaction flask A at a controlled temperature of -15 to -10°C. The heat release during the addition was minimal, and the addition time was approximately 15 to 30 minutes. After the addition was complete, the mixture was kept at -15 to -10°C 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, separated, dried, concentrated, and crystallized to obtain 13.7 g of the key intermediate, with a yield of 88.7%, purity of 97.4%, and ee value of 99.0%. Example 11

[0047] At room temperature, with magnetic stirring, 150 ml of dichloromethane, 15 g (30.2 mmol, 1 eq) of intermediate 2, and 3.6 g (6 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. After stirring until dissolved, the solution was 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 the addition time was approximately 30 to 60 min. After the addition was complete, the mixture was kept at -15 to -10 °C (outer temperature) and stirred for 20 min. The reaction solution in reaction flask B was then added dropwise to reaction flask A at a controlled temperature of -15 to -10 °C. The exothermic process was not significant, and the addition time was approximately 15 to 30 min. After the addition was complete, the mixture was kept at -15 to -10°C 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, separated, dried, concentrated, and crystallized to obtain 14.8 g of the key intermediate, with a yield of 95.7%, a purity of 98.9%, and an ee value of 99.3%. Example 12

[0048] At room temperature, with magnetic stirring, 150 ml of dichloromethane, 15 g (30.2 mmol, 1 eq) of intermediate 2, and 2.32 g (3 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. After stirring until dissolved, the solution was 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 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. The heat release during the addition was minimal, and the addition time was approximately 15 to 30 minutes. After the addition was complete, the mixture was kept at -15 to -10°C 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, separated, dried, concentrated, and crystallized to obtain 13.8 g of the key intermediate, with a yield of 89.3%, purity of 98.2%, and ee value of 99.0%. Example 13

[0049] At room temperature, with magnetic stirring, 150 ml of dichloromethane, 15 g (30.2 mmol, 1 eq) of intermediate 2, and 3.48 g (4.5 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℃ (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℃. The heat release during the addition was not significant, and the addition time was approximately 15 to 30 minutes. After the addition was complete, the mixture was kept at -15 to -10℃ and stirred for 16 to 20 hours. The temperature was then raised to 15 to 20℃, 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, separated, dried, concentrated, and crystallized to obtain 14.6 g of the key intermediate, with a yield of 94.5%, a purity of 98.8%, and an ee value of 99.2%. Example 14

[0050] At room temperature, with magnetic stirring, 150 ml of dichloromethane, 15 g (30.2 mmol, 1 eq) of intermediate 2, and 4.64 g (6 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. After stirring until dissolved, the solution was 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 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. The heat release during the addition was minimal, and the addition time was approximately 15 to 30 minutes. After the addition was complete, the mixture was kept at -15 to -10°C 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, separated, dried, concentrated, and crystallized to obtain 15.2 g of the key intermediate, with a yield of 98.3%, purity of 99.2%, and ee value of 99.4%.

[0051] Example 15

[0052] At room temperature, with magnetic stirring, 30 ml of methanol, 30 g (58.6 mmol, 1 eq) of the key intermediate, 60 g of water, and 3.5 g (87.9 mmol, 1.5 eq) of sodium hydroxide were added to a 250 ml reaction flask. The mixture was stirred for 3-5 h, concentrated under reduced pressure to remove methanol, cooled to 0-10 °C, and the pH was adjusted to 2-3 with concentrated hydrochloric acid. After filtration, drying, and crystallization, 26.4 g of loterana intermediate was obtained, with a yield of 98.2%, purity of 99.4%, and ee value of 99.4%.

[0053] Mass spectrometry: [MH] - 457.92

[0054] MRI: 1 H 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). Example 16

[0055] At room temperature, with magnetic stirring, add 26 g (56.7 mmol 1 eq) of loteranar intermediate, 250 g of toluene, and 13.5 g (113 mmol 2 eq) of thionyl chloride to a 500 ml reaction flask, and heat to 110 °C. Stir for 4-6 h, and after the reaction is complete, concentrate under reduced pressure and dilute with 160 g of dichloromethane for later use.

[0056] Take a 500 ml reaction flask, add 13 g (68 mmol 1.2 eq) 2-amino-trifluoroethyl-acetamide hydrochloride, 150 g dichloromethane, and 17.2 g (170 mmol 3 eq) triethylamine dropwise, maintaining the temperature at 15-25℃. After the addition is complete, cool to 0-10℃, add the above dichloromethane solution dropwise, stir for 4-6 h, add 100 g water, adjust the pH to 2-3 with concentrated hydrochloric acid, separate the layers, wash twice with 100 ml of water, dry and concentrate, crystallize, and dry to obtain 31.87 g loteranar, yield 94.2%, ee value 99.8%.

[0057] 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 method for preparing a key intermediate of loteranar, characterized in that... The method for preparing the key intermediate of loteranar includes the following steps: (1) In an organic solvent, an organic base, 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester 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 a ligand to give the key intermediate of loteranar; 。 2. The method for preparing a key intermediate of loteranar according to claim 1, characterized in that, The organic solvent in step (1) is one of methyl tert-butyl ether, toluene, and tetrahydrofuran.

3. The method for preparing a key intermediate of loteranar according to claim 1, characterized in that, In step (1), the molar ratio of 2-cyanoethyl 5-acetyl-3-methylthiophene-2-carboxylic acid ester and 2,2,2-trifluoro-1-(3,4,5-trichlorobenzene) ethyl ketone is 1:1-2.

4. The method for preparing a key intermediate of loteranar according to claim 1, characterized in that, The organic base in step (1) is either diethylamine or triethylamine.

5. The method for preparing a key intermediate of loteranar according to claim 1, characterized in that, The dehydrating agent in step (2) is one of thionyl chloride and acetic anhydride.

6. The method for preparing a key intermediate of loteranar according to claim 1, characterized in that, 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.

7. The method for preparing a key intermediate of loteranar according to claim 1, characterized in that, In step (3), the molar ratio of intermediate 2 to ligand is 1:0.1-0.

2.

8. The application of the loteranal key intermediate according to claim 1 in the preparation of loteranal.

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