Method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride

Abstract

The present invention discloses a method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride and (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

Description

[Technical field]

[0001] The present invention relates to the technical field of compound synthesis, in particular to a method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride and (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. [Background technology]

[0002] 3-(2,2,2-trifluoroethyl)pyrrolidine is an important intermediate compound. In the literature, Journal of Organic Chemistry, 2019, p.16105-16115 (10.1021 / acs.joc.9b02596), the synthesis route shown in Figure 2 is disclosed, and the disadvantages of the preparation method using expensive 3,3,3-trifluoropropionaldehyde as a raw material in patent WO2013 / 53725 by Ussebe Pharma, Belgium, are pointed out, and a preparation method using pyrrolidine-3-formic acid as a raw material and sulfur tetrafluoride as a fluorination reagent is proposed. However, sulfur tetrafluoride, which is a fluorination reagent used in this method, is a toxic gas with a melting point of -121.5 to -120.5 ° C (lit.), a boiling point of -40.4 ° C (lit.), and a pressure of 140 psi (21 ° C). Thus, processes using such reagents require tetrafluoroethylene vessels at ultra-low temperatures, which limits the scale-up of this method. Summary of the Invention

[0003] The present invention relates to a method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, which comprises the steps of: reacting N-benzylpyrrolidone with trifluoroacetic anhydride to obtain 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole; dissolving 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole in methanol and carrying out a substitution reaction in the presence of a catalyst and hydrogen to obtain 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone. The present invention discloses a preparation method including the steps of reacting 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone with borane, then adding methanol into the reaction mixture for further reaction to obtain 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, and dissolving 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine in methanol and reacting in the presence of a catalyst and hydrogen to obtain the above 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. By defining the specific process and parameters in the preparation method, the above 3-(2,2,2-trifluoroethyl)pyrrolidine can be obtained in high yield and purity.

[0004] [ka]

[0005] The present invention discloses a method for preparing (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, which includes the steps of reacting R-naphthylethylamine with 4-chlorobutyryl chloride to obtain product 1, reacting the above product 1 with trifluoroacetic anhydride to obtain product 2, dissolving the above product 2 in methanol and carrying out a substitution reaction in the presence of a catalyst and hydrogen to obtain product 3, reacting the above product 3 with borane, adding methanol to the reaction mixture for further reaction to obtain product 4, and dissolving the above product 4 in methanol and carrying out a reaction in the presence of a catalyst and hydrogen to obtain the above (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. By defining the specific process and parameters in the above preparation method, the above (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride can be obtained in high yield and purity.

[0006] [ka]

[0007] It is an object of the present invention to provide a process for the preparation of 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, which uses readily available raw materials and produces the product in high purity and yield.

[0008] In order to achieve the above objectives of the present invention, the following technical solutions are adopted.

[0009] A first aspect of the present invention is a process for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride comprising the steps of: (a) reacting N-benzylpyrrolidone with trifluoroacetic anhydride to obtain 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole; (b) dissolving 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole in methanol and carrying out a substitution reaction in the presence of a catalyst and hydrogen to obtain 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone; (c) reacting 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone with borane, and adding methanol to the reaction mixture for further reaction to obtain 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine; and (d) dissolving 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine in methanol, reacting in the presence of a catalyst and hydrogen, filtering the reaction mixture after the reaction, recovering the filtrate, adding a dioxane solution of hydrogen chloride to the filtrate, and concentrating the solvent to obtain a crude product; dissolving the crude product in water, extracting with ethyl acetate, and freeze-drying the aqueous phase to obtain the 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0010] Preferably, in the above step (a), N-benzylpyrrolidone is reacted with trifluoroacetic anhydride, specifically The method involves dissolving N-benzylpyrrolidone in N,N-dimethylformamide, cooling the mixture to 3-8°C, and then sequentially adding and reacting trifluoroacetic anhydride and aluminum trichloride.

[0011] Preferably, in the step (a), the mass ratio of N-benzylpyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride is 1:(1-20):(1-4):(1-3); The reaction temperature is 55 to 65°C, and the reaction time is 12 to 40 hours.

[0012] Preferably, the step (a) further comprises subjecting the mixture obtained after the reaction to extraction and column chromatography, the solvent used in the extraction being ethyl acetate, and the developer used in the column chromatography being PE and EA in a volume ratio of 10:1.

[0013] Preferably, in the step (b), the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole, methanol, and the catalyst is 1:(1 to 20):(0.01 to 0.50); The catalyst is 10% Pd / C.

[0014] Preferably, in step (b), the conditions for the substitution reaction are The reaction temperature is room temperature, and the reaction time is 10-15 hours. Preferably, the step (b) further includes filtering the mixture obtained after the reaction, recovering the filtrate, concentrating the filtrate, extracting with ethyl acetate 2 to 4 times, washing the organic phase with a saturated aqueous sodium bicarbonate solution until it becomes neutral, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain the 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone.

[0015] Preferably, in the above step (c), 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone is reacted with borane, specifically The method includes dissolving 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone in anhydrous tetrahydrofuran, cooling the mixture to 0-4°C, and then adding a solution of borane in tetrahydrofuran to react, wherein the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone to anhydrous tetrahydrofuran to the solution of borane in tetrahydrofuran is 1:(1-20):(2-10), the concentration of the solution of borane in tetrahydrofuran is 0.8-1.2 mol / L, the reaction temperature is 30-65°C, and the reaction time is 3.5-4.5 hours.

[0016] Preferably, in the above step (c), methanol is added to the reaction mixture to further react, specifically, cooling the reaction mixture, quenching the reaction by adding methanol having a volume 0.1 to 10 times the volume of the reaction mixture, concentrating the solvent, and then reacting by adding methanol having a volume 1 to 10 times the volume of the reaction mixture, the reaction temperature being 65 to 75° C. and the reaction time being 1 to 8 hours; Preferably, the step (c) further comprises concentrating the mixture obtained after the reaction, dissolving it in an aqueous hydrochloric acid solution, extracting it with ethyl acetate, discarding the organic phase, adjusting the aqueous phase to alkaline, and extracting it further with ethyl acetate 2 to 4 times, and then combining the organic phases, drying it over anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain the 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, and the concentration of the aqueous hydrochloric acid solution is 3 to 5 mol / L.

[0017] Preferably, in the step (d), the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, methanol, and the catalyst is 1:(1 to 20):(0.01 to 0.50); The catalyst is 10% Pd / C.

[0018] Preferably, in the above step (d), the reaction conditions are a reaction temperature of room temperature and a reaction time of 10 to 30 hours; Preferably, the mass ratio of the hydrogen chloride dioxane solution to the filtrate is 1:0.10-2, and the concentration of the hydrogen chloride dioxane solution is 3.5-4.5 mol / L.

[0019] Compared with the prior art, the present invention includes at least the following beneficial effects: That is, the preparation method of the present invention uses N-benzylpyrrolidone as raw material to prepare 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. By defining the specific process and parameters in the preparation method, the 3-(2,2,2-trifluoroethyl)pyrrolidine can be obtained with high yield and purity. Moreover, the preparation method is simple in operation and can be realized for mass production.

[0020] It is an object of the present invention to provide a process for the preparation of (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, which uses readily available raw materials and produces the product in high purity and yield.

[0021] In order to achieve the above objectives of the present invention, the following technical solutions are adopted.

[0022] A first aspect of the present invention is a process for preparing (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, comprising the steps of: (a) reacting R-naphthylethylamine with 4-chlorobutyryl chloride to obtain N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone; (b) reacting N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone with trifluoroacetic anhydride to obtain 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone; (c) dissolving 3-(2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone in methanol and carrying out a substitution reaction in the presence of a catalyst and hydrogen to obtain (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone; (d) reacting (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone with borane, and adding methanol to the reaction mixture for further reaction to obtain (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-((naphthalen-1-yl)ethyl)pyrrolidine; and (e) providing a preparation method including the steps of dissolving (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine in methanol, reacting in the presence of a catalyst and hydrogen, filtering the reaction mixture after the reaction, recovering the filtrate, adding a dioxane solution of hydrogen chloride to the filtrate, and concentrating the solvent to obtain a crude product, and then dissolving the crude product in water, extracting with ethyl acetate, and freeze-drying the aqueous phase to obtain the (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0023] Preferably, in the above step (a), reacting R-naphthylethylamine with 4-chlorobutyryl chloride specifically comprises the steps of: The method includes dissolving R-naphthylethylamine in dichloromethane, adding aqueous sodium hydroxide solution, vigorously stirring, adding dropwise a dichloromethane solution of 4-chlorobutyryl chloride, reacting at room temperature for 1 hour, and then increasing the temperature of the reaction solution to 55-65°C and further reacting for 2-4 hours, or reacting at room temperature for 20-30 hours.

[0024] Preferably, in the above step (a), the mass ratio of R-naphthylethylamine, dichloromethane, aqueous sodium hydroxide solution, and dichloromethane solution of 4-chlorobutyryl chloride is 1:(5-10):(0.6-2.8):(0.4-4), the concentration of the aqueous sodium hydroxide solution is 50%, and the concentration of the dichloromethane solution of 4-chlorobutyryl chloride is 50%.

[0025] Preferably, in the above step (b), N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone is reacted with trifluoroacetic anhydride, specifically The method involves dissolving N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone in N,N-dimethylformamide, cooling the mixture to 3-8°C, and then reacting by sequentially adding trifluoroacetic anhydride and aluminum trichloride.

[0026] Preferably, in the step (b), the mass ratio of N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride is 1:(1-20):(1-4):(0.3-3); The reaction temperature is 55 to 65°C, and the reaction time is 12 to 40 hours.

[0027] Preferably, the step (b) further comprises subjecting the mixture obtained after the reaction to extraction and column chromatography, the solvent used in the extraction being ethyl acetate, and the developer used in the column chromatography being PE and EA in a volume ratio of 10:1.

[0028] Preferably, in the step (c), the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone, methanol, and the catalyst is 1:(1 to 50):(0.1 to 1); The catalyst is Raney nickel.

[0029] Preferably, in step (c), the conditions for the substitution reaction are The reaction temperature is room temperature, and the reaction time is 20-24 hours.

[0030] Preferably, the step (c) further includes filtering the mixture obtained after the reaction, recovering the filtrate, concentrating the filtrate, and then extracting with ethyl acetate for 2 to 4 times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain the (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone.

[0031] Preferably, in the above step (d), (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone is reacted with borane, specifically, The method includes dissolving (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone in anhydrous tetrahydrofuran, cooling the mixture to 0-4°C, and then adding a tetrahydrofuran solution of borane to react, wherein the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone to anhydrous tetrahydrofuran to the tetrahydrofuran solution of borane is 1:(1-20):(2-10), the concentration of the tetrahydrofuran solution of borane is 0.8-1.2 mol / L, the reaction temperature is 30-65°C, and the reaction time is 3.5-4.5 hours.

[0032] Preferably, in the above step (d), methanol is added to the reaction mixture to further react, specifically, cooling the reaction mixture, quenching the reaction by adding methanol having a volume 0.1 to 10 times the volume of the reaction mixture, concentrating the solvent, and then reacting by adding methanol having a volume 1 to 10 times the volume of the reaction mixture, the reaction temperature being 65 to 75° C. and the reaction time being 1 to 8 hours; Preferably, the step (d) further includes concentrating the mixture obtained after the reaction, dissolving it in an aqueous hydrochloric acid solution, extracting it with ethyl acetate, discarding the organic phase, adjusting the aqueous phase to alkaline, and extracting it further with ethyl acetate 2 to 4 times, and then combining the organic phases, drying it over anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain the (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine, and the concentration of the aqueous hydrochloric acid solution is 3 to 5 mol / L.

[0033] Preferably, in the step (e), the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine, methanol, and the catalyst is 1:(1 to 20):(0.01 to 0.50); The catalyst is 10% Pd / C.

[0034] Preferably, in the above step (e), the reaction conditions are a reaction temperature of room temperature and a reaction time of 10 to 30 hours.

[0035] Preferably, in the step (e), the mass ratio of the hydrogen chloride dioxane solution to the filtrate is 1:(0.10 to 2), and the concentration of the hydrogen chloride dioxane solution is 3.5 to 4.5 mol / L.

[0036] Compared with the prior art, the present invention includes at least the following beneficial effects: That is, the preparation method of the present invention uses R-naphthylethylamine as raw material to prepare (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. By defining the specific process and parameters in the preparation method, the (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride can be obtained with high yield and purity. Furthermore, the preparation method is simple in operation and can be realized for mass production. [Brief description of the drawings]

[0037] In order to illustrate the technical solutions in certain embodiments of the present invention or more specifically in the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art are briefly introduced below. In all the drawings, similar components or parts are generally designated by similar reference numerals. In the drawings, each component or part is not necessarily drawn to scale. [Figure 1] FIG. 1 is a diagram of a synthetic procedure for 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride according to one embodiment of the present invention. [Diagram 2]FIG. 2 is a diagram of a prior art synthesis procedure provided in the Background of the Invention. [Diagram 3] FIG. 3 is a diagram of a synthesis procedure for (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride according to an embodiment of the present invention. [Figure 4] FIG. 4 is a diagram of a prior art synthesis procedure provided in the Background of the Invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] The embodiments of the technical solution of the present invention are described in detail below in combination with examples. The following examples are only used to more clearly illustrate the technical solution of the present invention, and are therefore illustrative and non-limiting to the protection scope of the present invention.

[0039] However, unless otherwise specified, technical and scientific terms used herein have the common meaning as understood by one of ordinary skill in the art to which this invention belongs. EXAMPLES

[0040] This embodiment is a method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. As shown in Figure 1, the preparation method includes the following steps:

[0041] (a) N-benzylpyrrolidone was dissolved in N,N-dimethylformamide, and the mixture was cooled to 4°C. Then, trifluoroacetic anhydride was added, and aluminum trichloride was gradually added and stirred until completely dissolved to obtain a mixed solution. The temperature of the mixed solution was raised to 60°C and reacted for 20 hours. The reaction solution was cooled to room temperature, and water was added to quench the reaction. Extraction was performed with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated, and column chromatography (petroleum ether / ethyl acetate=10:1) was performed to obtain the product 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole as a dark oil.

[0042] Here, the mass ratio of N-benzylpyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride was 1:4.49:3.60:1.14.

[0043] (b) 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole was dissolved in methanol, 10% Pd / C was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 12 hours. The reaction solution was filtered, the filtrate was collected, the filtrate was concentrated, and the mixture was extracted with ethyl acetate three times. The product was washed with saturated sodium bicarbonate until it became neutral. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone as a pale yellow oil.

[0044] Here, the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole, methanol, and 10% Pd / C catalyst was 1:5.17:0.10.

[0045] (c) 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone was dissolved in anhydrous tetrahydrofuran, the mixture was cooled to 2°C, then a solution of borane in tetrahydrofuran was added, and the mixture was reacted at 60°C for 4 hours. The reaction solution was cooled to room temperature, and methanol was added in a volume 5 times that of the reaction solution to quench the reaction, the solvent was concentrated, and methanol was added again in a volume 5 times that of the reaction solution, and the mixture was reacted at 70°C for 7 hours. The reaction solution was then evaporated to dryness by rotary evaporation, dissolved in a 4 mol / L aqueous hydrochloric acid solution, back-extracted with ethyl acetate, the organic phase was discarded, the aqueous phase was adjusted to alkaline with a 6 mol / L aqueous sodium hydroxide solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine as a pale yellow oil.

[0046] Here, the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone, anhydrous tetrahydrofuran, and the tetrahydrofuran solution of borane was 1:1.40:6.99, and the concentration of the tetrahydrofuran solution of borane was 1 mol / L.

[0047] (d) 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine was dissolved in methanol, and 10% Pd / C was added as a catalyst. The mixture was then reacted under hydrogen at room temperature for 12 hours. The reaction solution was filtered, the filtrate was collected, and a 4 mol / L solution of hydrogen chloride in dioxane was added to the filtrate. The solvent was concentrated to obtain a crude product. The crude product was then dissolved in water and extracted with ethyl acetate. The organic phase was discarded, and the aqueous phase was freeze-dried to obtain 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0048] Here, the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, methanol, and 10% Pd / C catalyst was 1:10.8:0.11. EXAMPLES

[0049] This example is a method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, which includes the following steps:

[0050] (a) N-benzylpyrrolidone was dissolved in N,N-dimethylformamide, the mixture was cooled to 4°C, trifluoroacetic anhydride was added, aluminum trichloride was gradually added, and the mixture was stirred until completely dissolved to obtain a mixed solution. The temperature of the mixed solution was raised to 60°C and reacted for 12 hours. The reaction solution was cooled to room temperature, water was added to quench the reaction, and extraction was performed with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated, and column chromatography (petroleum ether / ethyl acetate=10:1) was performed to obtain the product 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole as a dark oil.

[0051] Here, the mass ratio of N-benzylpyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride was 1:1.43:1.06:2.7.

[0052] (b) 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole was dissolved in methanol, 10% Pd / C was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 8 hours. The reaction solution was filtered, the filtrate was collected, the filtrate was concentrated, and the mixture was dissolved in ethyl acetate, and the product was washed with saturated sodium bicarbonate until it became neutral. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone as a pale yellow oil.

[0053] Here, the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole, methanol, and 10% Pd / C catalyst was 1:16.38:0.50.

[0054] (c) 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone was dissolved in anhydrous tetrahydrofuran, the mixture was cooled to 2° C., then a solution of borane in tetrahydrofuran was added, and the mixture was reacted at 30° C. for 4 hours. The reaction solution was cooled to room temperature, and methanol was added in a volume 5 times that of the reaction solution to quench the reaction, the solvent was concentrated, and methanol was added again in a volume 5 times that of the reaction solution, and the mixture was reacted at 70° C. for 2 hours. The reaction solution was then evaporated to dryness by rotary evaporation, dissolved in a 4 mol / L aqueous hydrochloric acid solution, and back-extracted with ethyl acetate, the organic phase was discarded, and the aqueous phase was adjusted to alkaline with a 6 mol / L aqueous sodium hydroxide solution, and extracted three more times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine as a pale yellow oil.

[0055] Here, the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone, anhydrous tetrahydrofuran, and the tetrahydrofuran solution of borane was 1:10.20:2.85, and the concentration of the tetrahydrofuran solution of borane was 1 mol / L.

[0056] (d) 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine was dissolved in methanol, 10% Pd / C was added as a catalyst, and the mixture was reacted under hydrogen at room temperature for 30 hours. The reaction solution was filtered, the filtrate was collected, and a 4 mol / L solution of hydrogen chloride in dioxane was added to the filtrate. The solvent was concentrated, the crude product was dissolved in water, and extraction was performed with ethyl acetate. The organic phase was discarded, and the aqueous phase was freeze-dried to obtain 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0057] Here, the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, methanol, and 10% Pd / C catalyst was 1:5.4:0.32. EXAMPLES

[0058] This example is a method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine, which includes the following steps:

[0059] (a) N-benzylpyrrolidone was dissolved in N,N-dimethylformamide, the mixture was cooled to 4°C, trifluoroacetic anhydride was added, aluminum trichloride was gradually added, and the mixture was stirred until completely dissolved to obtain a mixed solution. The temperature of the mixed solution was raised to 60°C and reacted for 20 hours. The reaction solution was cooled to room temperature, water was added to quench the reaction, and extraction was performed with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated, and column chromatography (petroleum ether / ethyl acetate=10:1) was performed to obtain the product 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole as a dark oil.

[0060] Here, the mass ratio of N-benzylpyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride was 1:9.48:2.4:1.14.

[0061] (b) 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole was dissolved in methanol, 10% Pd / C was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 12 hours, the reaction solution was filtered, the filtrate was collected, the filtrate was concentrated, dissolved in ethyl acetate, the product was washed with saturated sodium bicarbonate until it became neutral, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone as a pale yellow oil.

[0062] Here, the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole, methanol, and 10% Pd / C catalyst was 1:7.91:0.05.

[0063] (c) 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone was dissolved in anhydrous tetrahydrofuran, the mixture was cooled to 2°C, then a solution of borane in tetrahydrofuran was added, and the mixture was reacted at 60°C for 4 hours. The reaction solution was cooled to room temperature, and methanol was added in a volume 5 times that of the reaction solution to quench the reaction, the solvent was concentrated, and methanol was added again in a volume 5 times that of the reaction solution, and the mixture was reacted at 70°C for 7 hours. The reaction solution was then evaporated to dryness by rotary evaporation, dissolved in 4 mol / L aqueous hydrochloric acid, back-extracted with ethyl acetate, the organic phase was discarded, the aqueous phase was adjusted to alkaline with 6 mol / L aqueous sodium hydroxide, and extracted three more times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine as a pale yellow oil.

[0064] Here, the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone, anhydrous tetrahydrofuran, and the tetrahydrofuran solution of borane was 1:4.45:4.00, and the concentration of the tetrahydrofuran solution of borane was 1 mol / L.

[0065] (d) 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine was dissolved in methanol, and 10% Pd / C was added as a catalyst. The mixture was then reacted under hydrogen at room temperature for 12 hours. The reaction solution was filtered, the filtrate was collected, and a 4 mol / L solution of hydrogen chloride in dioxane was added to the filtrate. The solvent was concentrated to obtain a crude product. The crude product was then dissolved in water and extracted with ethyl acetate. The organic phase was discarded, and the aqueous phase was freeze-dried to obtain 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0066] Here, the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, methanol, and 10% Pd / C catalyst was 1:15.8:0.05.

[0067] Experimental Example

[0068] According to Examples 1 to 3, 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride was prepared, and the yield of the product prepared in each step of each Example was calculated according to the following calculation method.

[0069] The formula for calculating the reaction yield in each step is m p ×M s / (m s ×M p ) × 100%, where m p is the actual amount of product produced, and M s is the molar mass of the raw material, m s is the theoretical amount of raw material added, and M p is the molar mass of the product.

[0070] The calculation results are shown in Table 1.

[0071] [Table 1]

[0072] The following can be seen from Table 1:

[0073] The preparation method of the present invention realizes the preparation of 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride by using N-benzylpyrrolidone as raw material. By defining the specific process and parameters in the preparation method, 3-(2,2,2-trifluoroethyl)pyrrolidine can be obtained with high yield and purity. Moreover, the preparation method is simple in operation and feasible for mass production. EXAMPLES

[0074] This embodiment is a method for preparing (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. As shown in Figure 3, the preparation method includes the following steps:

[0075] (a) R-naphthylethylamine was dissolved in dichloromethane, and aqueous sodium hydroxide solution was added. The mixture was stirred vigorously, and a solution of 4-chlorobutyryl chloride in dichloromethane was added dropwise. The mixture was reacted at room temperature for 1 hour. Then, the temperature of the reaction solution was raised to 60°C, and the mixture was further reacted for 3 hours. After the reaction was completed, the liquid was separated, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone as a yellow oil.

[0076] Here, the mass ratio of R-naphthylethylamine, dichloromethane, aqueous sodium hydroxide solution, and dichloromethane solution of 4-chlorobutyryl chloride was 1:6:1.6:0.82, the concentration of the aqueous sodium hydroxide solution was 50%, and the concentration of the dichloromethane solution of 4-chlorobutyryl chloride was 50%.

[0077] (b) N-(R)-(1-(naphthalene-1-yl)ethyl)pyrrolidone was dissolved in N,N-dimethylformamide, and the mixture was cooled to 4°C. Then, trifluoroacetic anhydride was added, and aluminum trichloride was gradually added and stirred until completely dissolved to obtain a mixed solution. The temperature of the mixed solution was raised to 60°C and reacted for 22 hours. The reaction solution was cooled to room temperature, and water was added to quench the reaction. Extraction was performed with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated, and column chromatography (petroleum ether / ethyl acetate=10:1) was performed to obtain the product 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone as a dark oil.

[0078] Here, the mass ratio of (R)-N-(1-(naphthalen-1-yl)ethyl)pyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride was 1:5.11:2.64:0.84.

[0079] (c) 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone was dissolved in methanol, Raney nickel was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 22 hours. The reaction solution was filtered, the filtrate was collected, the filtrate was concentrated, and the mixture was extracted with ethyl acetate three times. The product was washed with saturated sodium bicarbonate until it became neutral. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone as a colorless oil.

[0080] Here, the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone, methanol, and the catalyst Raney nickel was 1:10.0:0.40.

[0081] (d) Dissolve (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone in anhydrous tetrahydrofuran, cool the mixture to 2° C., then add a tetrahydrofuran solution of borane, react at 60° C. for 4 hours, cool the reaction solution to room temperature, add methanol in an amount 5 times the volume of the reaction solution to quench the reaction, concentrate the solvent, add methanol in an amount 5 times the volume of the reaction solution again, and react at 70° C. for 6 hours, then The reaction solution was then rotary evaporated to dryness, dissolved in 4 mol / L aqueous hydrochloric acid, back-extracted with ethyl acetate, the organic phase discarded, the aqueous phase adjusted to alkaline with 6 mol / L aqueous sodium hydroxide, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and the solvent concentrated to obtain the product (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine as a pale yellow oil.

[0082] Here, the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone to anhydrous tetrahydrofuran to the tetrahydrofuran solution of borane was 1:4.35:6.23, and the concentration of the tetrahydrofuran solution of borane was 1 mol / L.

[0083] (e) (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine was dissolved in methanol, 10% Pd / C was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 20 hours. The reaction solution was filtered, the filtrate was collected, and a 4 mol / L dioxane solution of hydrogen chloride was added to the filtrate. The solvent was concentrated to obtain a crude product. The crude product was then dissolved in water, extracted with ethyl acetate, the organic phase was discarded, and the aqueous phase was freeze-dried to obtain (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0084] Here, the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine, methanol, and 10% Pd / C catalyst was 1:10.8:0.11. EXAMPLES

[0085] This embodiment is a method for preparing (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. As shown in Figure 3, the preparation method includes the following steps:

[0086] (a) R-naphthylethylamine is dissolved in dichloromethane, sodium hydroxide solution is added, and the mixture is stirred vigorously. A solution of 4-chlorobutyryl chloride in dichloromethane is added dropwise, and the mixture is reacted at room temperature for 24 hours. After the reaction is completed, the liquid is separated, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is concentrated to obtain the product N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone as a yellow oil.

[0087] Here, the mass ratio of R-naphthylethylamine, dichloromethane, aqueous sodium hydroxide solution, and dichloromethane solution of 4-chlorobutyryl chloride was 1:10:0.8:0.8, the concentration of the aqueous sodium hydroxide solution was 50%, and the concentration of the dichloromethane solution of 4-chlorobutyryl chloride was 50%.

[0088] (b) N-(R)-(1-(naphthalene-1-yl)ethyl)pyrrolidone was dissolved in N,N-dimethylformamide, the mixture was cooled to 4°C, trifluoroacetic anhydride was added, and then aluminum trichloride was gradually added and stirred until completely dissolved to obtain a mixed solution. The temperature of the mixed solution was raised to 65°C and reacted for 15 hours, the reaction solution was cooled to room temperature, water was added to quench the reaction, and extraction was performed with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated, and column chromatography (petroleum ether / ethyl acetate=10:1) was performed to obtain the product 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone as a dark oil.

[0089] Here, the mass ratio of (R)-N-(1-(naphthalen-1-yl)ethyl)pyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride was 1:10:1:2.

[0090] (c) 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone was dissolved in methanol, Raney nickel was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 24 hours. The reaction solution was filtered, the filtrate was collected, the filtrate was concentrated, and the mixture was extracted with ethyl acetate three times. The product was washed with saturated sodium bicarbonate until it became neutral. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone as a colorless oil.

[0091] Here, the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone, methanol, and the catalyst Raney nickel was 1:20:0.1.

[0092] (d) dissolving (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone in anhydrous tetrahydrofuran, cooling the mixture to 2° C., then adding a tetrahydrofuran solution of borane, reacting at 30° C. for 4.5 hours, cooling the reaction solution to room temperature, adding methanol in an amount 5 times the volume of the reaction solution to quench the reaction, concentrating the solvent, adding methanol in an amount 5 times the volume of the reaction solution again, and reacting at 75° C. for 2 hours; The reaction solution was then rotary evaporated to dryness, dissolved in 4 mol / L aqueous hydrochloric acid, back-extracted with ethyl acetate, the organic phase discarded, the aqueous phase adjusted to alkaline with 6 mol / L aqueous sodium hydroxide, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and the solvent concentrated to give the product (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine as a pale yellow oil.

[0093] Here, the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone to anhydrous tetrahydrofuran to the tetrahydrofuran solution of borane was 1:1:10, and the concentration of the tetrahydrofuran solution of borane was 0.8 mol / L.

[0094] (e) (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine was dissolved in methanol, 10% Pd / C was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 25 hours. The reaction solution was filtered, the filtrate was collected, and a 4.5 mol / L dioxane solution of hydrogen chloride was added to the filtrate. The solvent was concentrated to obtain a crude product. The crude product was then dissolved in water, extracted with ethyl acetate, the organic phase was discarded, and the aqueous phase was freeze-dried to obtain (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0095] Here, the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine, methanol, and 10% Pd / C catalyst was 1:5:0.5. EXAMPLES

[0096] This embodiment is a method for preparing (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. As shown in Figure 3, the preparation method includes the following steps:

[0097] (a) R-naphthylethylamine was dissolved in dichloromethane, and aqueous sodium hydroxide solution was added. The mixture was stirred vigorously, and a solution of 4-chlorobutyryl chloride in dichloromethane was added dropwise. The mixture was reacted at room temperature for 1 hour. The temperature of the mixture was then raised to 55°C and the mixture was further reacted for 4 hours. After the reaction was completed, the liquid was separated, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone as a yellow oil.

[0098] Here, the mass ratio of R-naphthylethylamine, dichloromethane, aqueous sodium hydroxide solution, and dichloromethane solution of 4-chlorobutyryl chloride was 1:6:1.6:0.82, the concentration of the aqueous sodium hydroxide solution was 50%, and the concentration of the dichloromethane solution of 4-chlorobutyryl chloride was 50%.

[0099] (b) N-(R)-(1-(naphthalene-1-yl)ethyl)pyrrolidone was dissolved in N,N-dimethylformamide, the mixture was cooled to 4°C, trifluoroacetic anhydride was added, and then aluminum trichloride was gradually added and stirred until completely dissolved to obtain a mixed solution. The temperature of the mixed solution was raised to 55°C and reacted for 30 hours, the reaction solution was cooled to room temperature, water was added to quench the reaction, and extraction was performed with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated, and column chromatography (petroleum ether / ethyl acetate=10:1) was performed to obtain the product 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone as a dark oil.

[0100] Here, the mass ratio of (R)-N-(1-(naphthalen-1-yl)ethyl)pyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride was 1:20:3:3.

[0101] (c) 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone was dissolved in methanol, Raney nickel was added as a catalyst, and then the mixture was reacted under hydrogen at room temperature for 20 hours. The reaction solution was filtered, the filtrate was collected, the filtrate was concentrated, and the mixture was extracted with ethyl acetate three times. The product was washed with saturated sodium bicarbonate until it became neutral. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated to obtain the product (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalene-1-yl)ethyl)pyrrolidone as a colorless oil.

[0102] Here, the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone, methanol, and the catalyst Raney nickel was 1:40:1.

[0103] (d) dissolving (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone in anhydrous tetrahydrofuran, cooling the mixture to 2° C., then adding a tetrahydrofuran solution of borane, reacting at 65° C. for 3.5 hours, cooling the reaction solution to room temperature, adding methanol in an amount 5 times the volume of the reaction solution to quench the reaction, concentrating the solvent, adding methanol in an amount 5 times the volume of the reaction solution again, and reacting at 65° C. for 8 hours; The reaction solution was then rotary evaporated to dryness, dissolved in 4 mol / L aqueous hydrochloric acid, back-extracted with ethyl acetate, the organic phase discarded, the aqueous phase adjusted to alkaline with 6 mol / L aqueous sodium hydroxide, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered, and the solvent concentrated to give the product (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine as a pale yellow oil.

[0104] Here, the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone to anhydrous tetrahydrofuran to the tetrahydrofuran solution of borane was 1:10:4, and the concentration of the tetrahydrofuran solution of borane was 1.2 mol / L.

[0105] (e) (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine was dissolved in methanol, 10% Pd / C was added as a catalyst, and then the mixture was reacted at room temperature under hydrogen for 15 hours. The reaction solution was filtered, the filtrate was collected, and a 3.5 mol / L dioxane solution of hydrogen chloride was added to the filtrate. The solvent was concentrated to obtain a crude product. The crude product was then dissolved in water, extracted with ethyl acetate, the organic phase was discarded, and the aqueous phase was freeze-dried to obtain (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride.

[0106] Here, the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine, methanol, and 10% Pd / C catalyst was 1:20:0.3.

[0107] Experimental Example

[0108] According to Examples 4 to 6, each of (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride salts was prepared, and the yield of the product prepared in each step of each Example was calculated according to the following calculation method.

[0109] The formula for calculating the reaction yield in each step is m p ×M s / (m s ×M p ) × 100%, where m p is the actual amount of product produced, and M s is the molar mass of the raw material, m s is the theoretical amount of raw material added, and M p is the molar mass of the product.

[0110] The calculation results are shown in Table 2.

[0111] [Table 2]

[0112] The following can be seen from Table 2:

[0113] The preparation method of the present invention realizes the preparation of (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride by using R-naphthylethylamine as raw material. By defining the specific process and parameters in the preparation method, (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride can be obtained with high yield and purity. Moreover, the preparation method is simple in operation and feasible for mass production.

[0114] Finally, the above embodiments are only used to illustrate the technical solutions of the present invention, not to limit them. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments can be further modified, or part or all of the technical features therein can be equivalently replaced, and these modifications and replacements do not essentially depart the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention, and are to be covered by the claims and descriptions of the present invention.

Claims

A method for preparing (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, comprising: (a) reacting R-naphthylethylamine with 4-chlorobutyryl chloride to obtain N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone; (b) reacting N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone with trifluoroacetic anhydride to obtain 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone; (c) dissolving 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone in methanol and performing a substitution reaction in the presence of a catalyst and hydrogen to obtain (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone; (d) reacting (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone with borane, adding methanol to the reaction mixture and further reacting to obtain (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-((naphthalen-1-yl)ethyl)pyrrolidine; and (e) dissolving (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine in methanol, reacting in the presence of a catalyst and hydrogen, and filtering the reaction mixture after the reaction to obtain the (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. The preparation method comprising the above steps. Claim 2 In the step (b), the reaction of N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone with trifluoroacetic anhydride is specifically Dissolve N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone in N,N-dimethylformamide, cool the mixture to 3-8 °C, and then continuously add trifluoroacetic anhydride and aluminum trichloride to react. Preferably, the mass ratio of N-(R)-(1-(naphthalen-1-yl)ethyl)pyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride is 1:(1-20):(1-4):(0.3-3), the reaction temperature is 55-65 °C, and the reaction time is 12-40 hours. The preparation method according to claim 1.

3. In the step (c), the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone, methanol, and the catalyst is 1:(1-50):(0.1-1), The preparation method according to claim 1, wherein the catalyst is Raney nickel.

4. In the step (c), the conditions for the substitution reaction are a reaction temperature of room temperature and a reaction time of 20-24 hours, Preferably, the step (c) further includes filtering the mixture obtained after the reaction, recovering the filtrate, concentrating the filtrate, then extracting with ethyl acetate 2-4 times, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone. The preparation method according to claim 1.

5. In the step (d), reacting (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone with borane specifically involves Dissolve (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone in anhydrous tetrahydrofuran, cool the mixture to 0 - 4 °C, and then add a tetrahydrofuran solution of borane to react. The mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidone, anhydrous tetrahydrofuran, and the tetrahydrofuran solution of borane is 1:(1 - 20):(2 - 10), the concentration of the tetrahydrofuran solution of borane is 0.8 - 1.2 mol / L, the reaction temperature is 30 - 65 °C, the reaction time is 3.5 - 4.5 hours, or · Adding methanol to the reaction mixture to further react, specifically, After cooling the reaction mixture, adding methanol in a volume 0.1 - 10 times that of the reaction mixture to quench, concentrating the solvent, and then adding methanol in a volume 1 - 10 times that of the reaction mixture to react. The reaction temperature is 65 - 75 °C, and the reaction time is 1 - 8 hours. Preferably, in step (d), the mixture obtained after the reaction is concentrated, then dissolved in an aqueous hydrochloric acid solution, extracted with ethyl acetate, the organic phase is discarded, the aqueous phase is adjusted to be alkaline, and extraction is further carried out 2 - 4 times with ethyl acetate. Then, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is concentrated to obtain the (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine. The concentration of the aqueous hydrochloric acid solution is 3 - 5 mol / L. The preparation method according to claim 1.

6. In step (e), the mass ratio of (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine, methanol, and the catalyst is 1:(1 - 20):(0.01 - 0.50). The preparation method according to claim 1, wherein the catalyst is 10% Pd / C. **Claim 7**: The method according to claim 1, wherein step (e) comprises dissolving (S)-3-(2,2,2-trifluoroethyl)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidine in methanol, reacting in the presence of a catalyst and hydrogen, filtering the reaction mixture after the reaction, collecting the filtrate, adding a dioxane solution of hydrogen chloride to the filtrate, concentrating the solvent to obtain a crude product, then dissolving the crude product in water, extracting with ethyl acetate, and lyophilizing the aqueous phase to obtain the (S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. **Claim 8**: In step (e), the reaction conditions are a reaction temperature of room temperature and a reaction time of 10 to 30 hours, and the mass ratio of the dioxane solution of hydrogen chloride to the filtrate is 1:(0.10 to 2), and the concentration of the dioxane solution of hydrogen chloride is 3.5 to 4.5 mol / L. The method according to claim 1. **Claim 9** A method for preparing 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride, comprising: (a) reacting N-benzylpyrrolidone with trifluoroacetic anhydride to obtain 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole; (b) dissolving 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole in methanol and performing a substitution reaction in the presence of a catalyst and hydrogen to obtain 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone; (c) reacting 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone with borane, adding methanol to the reaction mixture and further reacting to obtain 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine; and (d) dissolving 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine in methanol and reacting in the presence of a catalyst and hydrogen to obtain the 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. The preparation method comprising the above steps. **Claim 10** In step (a), reacting N-benzylpyrrolidone with trifluoroacetic anhydride specifically comprises Dissolve N-benzylpyrrolidone in N,N-dimethylformamide, cool the mixture to 3-8 °C, and then continuously add trifluoroacetic anhydride and aluminum trichloride to react. Preferably, the mass ratio of N-benzylpyrrolidone, N,N-dimethylformamide, trifluoroacetic anhydride, and aluminum trichloride is 1:(1-20):(1-4):(1-3). The preparation method according to claim 9, wherein the reaction temperature is 55-65 °C and the reaction time is 12-40 hours.

11. In the step (b), the mass ratio of 3-(1-chloro-2,2,2-trifluoroethylidene)-N-benzylpyrrole, methanol, and the catalyst is 1:(1-20):(0.01-0.50). The preparation method according to claim 9, wherein the catalyst is 10% Pd / C.

12. In the step (b), the conditions for the substitution reaction are a reaction temperature of room temperature and a reaction time of 10-15 hours. Preferably, the step (b) further includes filtering the mixture obtained after the reaction, collecting the filtrate, concentrating the filtrate, then performing extraction with ethyl acetate 2-4 times, then washing the organic phase with a saturated aqueous sodium bicarbonate solution until it becomes neutral, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain the 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone. The preparation method according to claim 9.

13. In the step (c), · Reacting 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone with borane specifically includes dissolving 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone in anhydrous tetrahydrofuran, cooling the mixture to 0-4 °C, and then adding a tetrahydrofuran solution of borane to react. The mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidone, anhydrous tetrahydrofuran, and the tetrahydrofuran solution of borane is 1:(1-20):(2-10), the concentration of the tetrahydrofuran solution of borane is 0.8-1.2 mol / L, the reaction temperature is 30-65 °C, and the reaction time is 3.5-4.5 hours, or · Adding methanol to the reaction mixture to further react specifically includes After cooling the reaction mixture, methanol in a volume 0.1 to 10 times that of the reaction mixture is added for quenching, the solvent is concentrated, and then methanol in a volume 1 to 10 times that of the reaction mixture is added for reaction, where the reaction temperature is 65 to 75 °C and the reaction time is 1 to 8 hours, Preferably, in step (c), the mixture obtained after the reaction is concentrated, then dissolved in an aqueous hydrochloric acid solution, extracted with ethyl acetate, the organic phase is discarded, the aqueous phase is adjusted to be alkaline, and extraction is further performed 2 to 4 times with ethyl acetate. Then, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is concentrated to further obtain the 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, where the concentration of the aqueous hydrochloric acid solution is 3 to 5 mol / L. The preparation method according to claim 9.

14. In step (d), the mass ratio of 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine, methanol, and the catalyst is 1:(1 to 20):(0.01 to 0.50), The preparation method according to claim 9, where the catalyst is 10% Pd / C.

15. Step (d) involves dissolving 3-(2,2,2-trifluoroethyl)-N-benzylpyrrolidine in methanol, performing the reaction in the presence of the catalyst and hydrogen, filtering the reaction mixture after the reaction, recovering the filtrate, adding a dioxane solution of hydrogen chloride to the filtrate, concentrating the solvent to obtain a crude product, then dissolving the crude product in water, performing extraction, and lyophilizing the aqueous phase to obtain the 3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. Preferably, the reaction conditions are a reaction temperature of room temperature and a reaction time of 10 to 30 hours, The mass ratio of the dioxane solution of hydrogen chloride to the filtrate is 1:0.10 to 2, and the concentration of the dioxane solution of hydrogen chloride is 3.5 to 4.5 mol / L. The preparation method according to any one of claims 9 to 14.

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