A process for the preparation of a plomirapide intermediate

Abstract

The application relates to a preparation method of a plomiridine intermediate, and belongs to the technical field of organic chemistry. A reaction route is as follows: including the following steps: (S)-4-hydroxy-2-pyrrolidone is reacted with DAST to obtain (S)-4-fluoropyrrolidin-2-ketone; then sodium hydride catalysis is carried out to obtain (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-ketone; then the reaction is carried out with p-methylbenzenesulfonylmethyl isocyanide to obtain (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide; then dehydration is carried out to obtain (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-nitrile; finally, after a side chain is removed, the reaction is carried out with hydrochloric acid to obtain (4S,2S)-4-fluoro-pyrrolidin-2-nitrile hydrochloride. The raw material is easy to obtain, the intermediate can be separated through simple crystallization, the preparation process is simplified, and the material cost of the product is reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemistry, in particular to a preparation method of a plugeritine intermediate. BACKGROUND

[0002] Plugeritine tablet is a new drug of the first class of the Zhongqi Pharmaceutical affiliated to the Shenzhen Pharmaceutical Group, which is a new type of oral DPP-4 inhibitor with high selectivity and strong inhibition to DPP-4. By inhibiting DPP-4, the level of endogenous active glucagon-like peptide-1 (GLP-1) is increased to enhance the sensitivity of beta cells and alpha cells to glucose, increase glucose-stimulated insulin secretion and enhance the inhibition of glucagon secretion by glucose, thereby reducing blood glucose level without inducing hypoglycemia and increasing body weight. The effective component plugeritine has the following structure:

[0003]

[0004] The existing method for synthesizing plugeritine is mostly prepared by the method of patent CN101970402B, and the preparation route is as follows:

[0005] ;

[0006] Among them, 1-(2-bromoacetyl)-4-fluoro-pyrrolidine-2-carbonitrile is prepared from (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile and bromoacetyl bromide. The preparation method of (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile is mostly to use N-Boc-cis-4-fluoro-L-proline, respectively, to form a carboxylic acid by removing Boc, then to prepare an amide by reacting the carboxylic acid with an amine, and finally to obtain (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile by dehydration. The preparation route is as follows:

[0007] ;

[0008] The molecular weight of the starting material N-Boc-cis-4-fluoro-L-proline in the above route is 233.24, and the molecular weight of the product (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile is 133.12, so the atomic efficiency of converting N-Boc-cis-4-fluoro-L-proline into the target product (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile is relatively low. In addition, the price of N-Boc-cis-4-fluoro-L-proline is relatively high, which leads to a relatively high cost of the final preparation product. SUMMARY

[0009] In view of the problem of high price of the existing preparation of plugeritine intermediate, the present application provides a preparation method of plugeritine intermediate to solve the above problems.

[0010] The technical scheme of the present application is as follows:

[0011] A preparation method of a plomiridine intermediate, and a reaction route is as follows:

[0012] ;

[0013] Comprising the following steps:

[0014] (1) (S)-4-hydroxy-2-pyrrolidinone is reacted with DAST (diethylamine trifluoride) to obtain (S)-4-fluoropyrrolidin-2-one;

[0015] (2) (S)-4-fluoropyrrolidin-2-one is reacted with (S)-1-bromoethylbenzene under the catalysis of sodium hydride to obtain (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one;

[0016] (3) (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one is reacted with p-methylbenzenesulfonylmethyl isocyanide to obtain (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide in t-butanol;

[0017] (4) (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide is dehydrated to obtain (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carbonitrile;

[0018] (5) (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carbonitrile is reacted with hydrochloric acid after the side chain is removed to obtain (4S,2S)-4-fluoro-pyrrolidin-2-carbonitrile hydrochloride.

[0019] Further, the step (1) is: (S)-4-hydroxy-2-pyrrolidinone is added into dichloromethane, and after being dissolved, the system is lowered to-10~0 ℃, DAST is slowly added, and the temperature of the reaction system is controlled to be ≤0 ℃; after the addition is completed, the reaction is preserved for 2~3 hours; after the reaction is completed, the reaction liquid is washed with water, and the organic phase is washed with 10% sodium carbonate aqueous solution; after being concentrated, (S)-4-fluoropyrrolidin-2-one is obtained.

[0020] Further, in the step (1), the molar ratio of (S)-4-hydroxy-2-pyrrolidinone to DAST is 1:1.2~1.5.

[0021] Further, the step (2) is: (S)-4-fluoropyrrolidin-2-one is added into tetrahydrofuran, after stirring and dissolving, the temperature is lowered to -10~ -5℃, sodium hydride is added in batches, after the addition is completed, the temperature is kept and stirred for 0.5 hours, then (S)-1-bromoethylbenzene is added, the temperature is raised to 20~30℃ for reaction; TLC detection is performed to determine whether 4-fluoropyrrolidin-2-one is completely reacted; after the reaction is quenched by adding water, ethyl acetate is added for extraction, the organic phase is washed with saturated brine; after concentration, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one is obtained.

[0022] Further, in the step (2), the molar ratio of 4-fluoropyrrolidin-2-one to (S)-1-bromoethylbenzene is 1:1.1~1.2; the molar ratio of 4-fluoropyrrolidin-2-one to sodium hydride is 1:1.2~1.5.

[0023] Further, the step (3) is: under nitrogen protection, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one is added into tert-butyl alcohol, potassium tert-butoxide is added, after stirring uniformly, the system is cooled to -10~0℃; then p-tolylsulfonylmethyl isocyanide is added dropwise; after the dropwise addition is completed, the reaction is carried out under heat preservation, the whole process is under nitrogen protection; TLC detection is carried out to determine whether (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one and the cyano intermediate state react completely, the reaction liquid is warmed to 20~30℃, water is slowly added dropwise for crystallization, the amount of water is 0.5~0.8 ml / ml based on the amount of tert-butyl alcohol; after the solid is precipitated, heat preservation stirring is carried out for 1 hour; (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide is obtained by filtration. The reaction of step (3) involves two steps, first (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one reacts with p-tolylsulfonylmethyl isocyanide under the catalysis of potassium tert-butoxide to obtain a cyano intermediate state, and then the reaction continues to obtain a mixture of (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide and (4S,2R)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide; it is found through crystallization experiments that by controlling the amount of water during crystallization, the two can be separated. When the amount of water is less than 0.5 ml / ml (based on the amount of tert-butyl alcohol added), (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide is not completely precipitated, and the yield is too low; when the amount of water is greater than 0.8 ml / ml (based on the amount of tert-butyl alcohol added), the isomer (4S,2R)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide begins to precipitate in large quantities, and the isomer cannot be completely removed in subsequent reactions and purification. The optimal amount of water is 0.6~0.7 ml / ml (based on the amount of tert-butyl alcohol added), at which point there is almost no isomer in the precipitated intermediate, and the yield is ideal, and when the amount of water continues to increase, although a small amount of isomer is precipitated, the isomer can be removed in subsequent reactions. Therefore, the selected range of the amount of water is 0.5~0.8 ml / ml based on the amount of tert-butyl alcohol.

[0024] Further, in step (3), the molar ratio of (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one to p-tolylsulfonylmethyl isocyanide is 1:1.1~1.3; the molar ratio of (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one to potassium tert-butoxide is 1:3~3.5.

[0025] Further, the step (4) is: (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile is added into N,N-dimethylformamide, and is cooled to -5~5℃, and tricyanogen is added in batches, and is incubated; TLC detection (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile reaction is complete; 5% sodium carbonate aqueous solution is added into the reaction liquid, and the pH of the reaction liquid is controlled to be 9~10; then ethyl acetate is added for extraction; the organic phase is washed with saturated brine; and (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile is obtained by concentrating the organic phase.

[0026] Further, in the step (4), the molar ratio of (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile to tricyanogen is 1:0.45~0.55.

[0027] Further, the step (5) is: (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile is added into methanol, and after stirring and dissolving, ammonium formate and palladium hydroxide are added, and the reaction system is heated to reflux; TLC detection (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile reaction is complete; filtration is carried out, 4mol / L hydrochloric acid is added into the filtrate, the pH of the reaction liquid is controlled to be 3~4, the reaction liquid is concentrated, methyl tert-butyl ether is added into the concentrate, and (4S,2S)-4-fluoro-pyrrolidine-2-carbonitrile hydrochloride is obtained by filtration.

[0028] Further, in the step (5), the molar ratio of (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile to ammonium formate is 1:2~2.5.

[0029] The present application has the following beneficial effects:

[0030] The preparation method of the plomagliatin intermediate provided by the present application has the advantages that raw materials are easy to obtain, and the prepared intermediate can be separated by simple crystallization through the introduction of a chiral group, without the need for chiral column separation, so that the preparation process is simplified, and the material cost of the product is reduced.

[0031] The molecular weight of (S)-4-hydroxy-2-pyrrolidone used in the present application is 101.10, compared with the starting material N-Boc-cis-4-fluoro-L-proline used in the prior art, more atoms are converted into the target product in the reaction process, the byproduct is relatively less, and the atom utilization rate is higher, which reduces the waste of raw materials to a certain extent and improves the economic benefits. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the accompanying drawings needed to be used in the embodiments or prior art description will be briefly introduced. Obviously, for those skilled in the art, based on these drawings, other drawings can be obtained without any creative work.

[0033] Figure 1 is the HPLC spectrum of (S)-4-fluoropyrrolidin-2-one prepared in Example 3 of the present application.

[0034] Figure 2 is the HPLC spectrum of (S)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidin-2-one prepared in Example 3 of the present application.

[0035] Figure 3 is the HPLC spectrum of (4S,2S)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide prepared in Example 3 of the present application.

[0036] Figure 4 is the HPLC spectrum of (4S,2S)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidin-2-carbonitrile prepared in Example 3 of the present application.

[0037] Figure 5 is the HPLC spectrum of (4S,2S)-4-fluoro-pyrrolidin-2-carbonitrile hydrochloride prepared in Example 3 of the present application.

[0038] Figure 6 is the HNMR spectrum of (4S,2S)-4-fluoro-pyrrolidin-2-carbonitrile hydrochloride prepared in Example 3 of the present application.

[0039] Figure 7 is the MS spectrum of (4S,2S)-4-fluoro-pyrrolidin-2-carbonitrile hydrochloride prepared in Example 3 of the present application. DETAILED DESCRIPTION

[0040] In order to make the technical personnel in the art better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without any creative work should belong to the scope of protection of the present application.

[0041] Example 1

[0042] A preparation method of a linagliptin intermediate, the reaction route is as follows:

[0043] ;

[0044] comprising the steps of:

[0045] (1) (S)-4-hydroxy-2-pyrrolidinone 101.0 g (1.0 mol) was added into 500 ml dichloromethane, after dissolution, the system was lowered to -10 °C, DAST (diethylamine sulfur trifluoride) 209.5 g (1.3 mol) was slowly added dropwise, the temperature of the reaction system was controlled not to exceed 0 °C; the dropwise addition time was 20 minutes. After the dropwise addition was completed, the reaction was incubated for 2 hours; after the reaction was completed, the reaction liquid was washed with 500 ml water, the organic phase was washed with 500 ml 10% sodium carbonate aqueous solution, the organic phase was dried with anhydrous sodium sulfate for 0.5 hours, and was suction filtered; after vacuum concentration, (S)-4-fluoropyrrolidin-2-one 94.2 g was obtained, and the GC purity was 98.02%.

[0046] (2) (S)-4-fluoropyrrolidin-2-one 92.8 g (0.90 mol) was added into 800 ml tetrahydrofuran, after stirring and dissolving, the temperature was lowered to -10 °C, 44.0 g (1.1 mol) of sodium hydride with a content of 60% was added in batches, after the addition was completed, the stirring was incubated for 0.5 hours, then (S)-1-bromoethylbenzene 183.2 g (0.99 mol) was added, and the temperature was raised to 25 °C for reaction; 2 hours later, TLC detection was performed on the sample, and it was detected that 4-fluoropyrrolidin-2-one was completely reacted; the reaction liquid was lowered to 0 °C, 800 ml water was slowly added to quench the reaction, then 400 ml ethyl acetate was added for extraction, the organic phase was washed with 800 ml saturated brine, and then was dried with anhydrous sodium sulfate; after concentration, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one 171.6 g was obtained, and the HPLC purity was 99.10%.

[0047] (3) Under nitrogen protection, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one 165.8 g (0.8 mol) was added into 829 ml tert-butyl alcohol, potassium tert-butoxide 269.3 g (2.4 mol) was added, after stirring and uniformity, the system was lowered to -10 °C; then p-methylbenzenesulfonylmethyl isocyanate 187.4 g (0.96 mol) was added dropwise; after the dropwise addition was completed, the reaction was incubated, the temperature range was -10 ~ -2 °C, and the whole process was protected by nitrogen; 3 hours later, TLC detection was performed on the sample, and it was detected that (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one and the cyano intermediate state were completely reacted; the reaction liquid was raised to 25 °C, 580 ml water was slowly added dropwise for crystallization, after the solid was precipitated, the stirring was incubated for 1 hour; filtration and drying were performed to obtain (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide 88.8 g, and the HPLC purity was 98.28%.

[0048] (4) (4S, 2S)-4-Fluoro-l-(l-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide 82.7 g (0.35 mol) was added into N, N-dimethylformamide 250 ml, and cooled to -5 °C, and tricyanuric chloride 31.3 g (0.17 mol) was added in batches, ensuring that the temperature of the reaction system did not exceed 5 °C during the addition; after the addition was completed, the reaction was maintained at 0-5 °C; after 2.5 hours, TLC detection showed that the reaction of (4S, 2S)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide was complete; 5% sodium carbonate aqueous solution 250 ml was added to the reaction liquid, and the pH of the reaction liquid was detected to be 10; then 250 ml of ethyl acetate was added for extraction; the organic phase was washed with 250 ml of saturated brine; anhydrous sodium sulfate was added for drying, and the filtrate was concentrated to obtain (4S, 2S)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidine-2-carbonitrile 69.8 g, with an HPLC purity of 98.37%.

[0049] (5) (4S, 2S)-4-Fluoro-l-(l-phenyl-ethyl)-pyrrolidine-2-carbonitrile 65.5 g (0.3 mol) was added into methanol 650 ml, and after stirring and dissolving, ammonium formate 41.3 g (0.6 mol) and palladium hydroxide 6.5 g were added, and the reaction system was heated to reflux; after 2 hours, TLC detection showed that the reaction of (4S, 2S)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidine-2-carbonitrile was complete; filtration was performed, 4 mol / L hydrochloric acid was added, the pH of the reaction liquid was controlled to be 4, the reaction liquid was concentrated, and when the amount of methanol evaporated was 550 ml, the concentration was stopped, methyl tert-butyl ether 150 ml was added, stirring was performed for 0.5 hours, and then the mixture was filtered and dried to obtain (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile hydrochloride 43.0 g, with an HPLC purity of 99.09%.

[0050] Example 2

[0051] For the method of removing isomer by adding water to crystallize in step (3), the optimal amount of crystallization solvent was determined. The amount of raw material (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one was 10.35 g (50 mmol), and the amount of tert-butyl alcohol was 51.8 ml (5 ml / g based on the amount of (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one). After the reaction, different volumes of water were added, and the amount of water was 0.2 ml / ml, 0.4 ml / ml, 0.5 ml / ml, 0.6 ml / ml, 0.7 ml / ml, 0.8 ml / ml, 0.9 ml / ml, 1.0 ml / ml, 1.5 ml / ml and 2.0 ml / ml based on the amount of tert-butyl alcohol. After obtaining solid (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide, the purity of the product was detected to determine the optimal amount of crystallization solvent. If the content of isomer is high, continue to prepare (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carbonitrile to detect the removal effect of the subsequent step on the isomer. The specific results are shown in Table 1 below:

[0052] Table 1 - Crystallization experiment results

[0053]

[0054] In Table 1, IM3 represents (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide, ISO-IM3 represents (4S,2R)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide (isomer of IM3); IM4 represents (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carbonitrile, and ISO-IM4 represents (4S,2R)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carbonitrile (isomer of IM4).

[0055] From the crystallization experiment results of Table 1, it can be seen that by controlling the amount of water used in the crystallization, the two can be separated. When the amount of water used is less than 0.5 ml / ml (based on the amount of tert-butyl alcohol added), (4S,2S)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide can not be crystallized (0.2 ml / ml), or it can not be completely crystallized, and the yield is too low. When the amount of water used is greater than 0.8 ml / ml (based on the amount of tert-butyl alcohol added), the isomer (4S,2R)-4-fluoro-l-(l-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide begins to crystallize in large quantities, and the intermediate obtained in the subsequent reaction and purification cannot be completely removed. Especially when the amount of water added is greater than the amount of tert-butyl alcohol, the isomer almost completely crystallizes, and there is almost no removal effect of the isomer in the subsequent reaction. Therefore, the optimal amount of water used is determined to be 0.6-0.7 ml / ml (based on the amount of tert-butyl alcohol added), at which time the intermediate crystallized almost has no isomer, and the yield is ideal, and when the amount of water used continues to increase, although a small amount of isomer is crystallized, the isomer can be removed in the subsequent reaction. Therefore, the range of the amount of water used is selected to be 0.5-0.8 ml / ml based on the amount of tert-butyl alcohol used.

[0056] Example 3

[0057] A preparation method of a plomirapitant intermediate, the reaction route is as follows:

[0058] ;

[0059] comprising the following steps:

[0060] (1) In a 20 L glass reactor, (S)-4-hydroxy-2-pyrrolidinone 1010 g was added into 5 L dichloromethane, and after dissolution, the system was lowered to -10°C, and DAST (diethylamine sulfur trifluoride) 2095 g was slowly added dropwise, and the temperature of the reaction system was controlled to be not more than 0°C; the dropwise addition time was 60 minutes. After the dropwise addition was completed, the reaction was incubated for 2 hours; after the reaction was completed, the reaction liquid was washed with 5 L water, the organic phase was washed with 5 L 10% sodium carbonate aqueous solution, the organic phase was dried with anhydrous sodium sulfate for 1 hour, and was filtered under suction; after vacuum concentration, (S)-4-fluoropyrrolidin-2-one 946 g was obtained, and the GC purity was 98.47%.

[0061] (2) In a 30L glass reactor, (S)-4-fluoropyrrolidin-2-one 928g was added to 8000L tetrahydrofuran, and after stirring to dissolve, it was cooled to -10°C, and 440g of sodium hydride with a content of 60% was added in batches, and after the addition was completed, it was stirred for 1 hour, then 1832g of (S)-1-bromoethylbenzene was added, and the temperature was raised to 25°C for reaction; 3 hours later, TLC detection showed that the reaction of 4-fluoropyrrolidin-2-one was complete; the reaction liquid was cooled to 0°C, and 8L water was slowly added to quench the reaction, then 4L ethyl acetate was added for extraction, and the organic phase was washed with 8L saturated brine, then dried over anhydrous sodium sulfate; after concentration, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one 1736g was obtained, with an HPLC purity of 98.99%.

[0062] (3) In a 30L glass reactor, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one 1658g was added to 8.3L tert-butyl alcohol under nitrogen protection, and 2693g of potassium tert-butoxide was added, and after stirring, the system was cooled to -10°C; then 1874g of p-methylbenzenesulfonylmethyl isocyanate was added dropwise; after the addition was completed, the reaction was carried out at a temperature range of -10~-5°C, and the whole process was protected by nitrogen; 3 hours later, TLC detection showed that the reaction of (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one and the cyano intermediate was complete, the reaction liquid was warmed to 25°C, and 5.8L water was slowly added to crystallize, and after the solid was precipitated, it was stirred for 1 hour; filtration and drying gave (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide 891g, with an HPLC purity of 98.34%.

[0063] (4) In a 10L five-necked flask, (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide 827g was added to 2.5L N,N-dimethylformamide, and cooled to -5°C, then 313g of tricyanuric chloride was added in batches, ensuring that the temperature of the reaction system did not exceed 5°C during addition; after the addition was completed, the reaction was carried out at 0~5°C; 3 hours later, TLC detection showed that the reaction of (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide was complete; 2.5L of 5% sodium carbonate aqueous solution was added to the reaction liquid, and the pH of the reaction liquid was detected to be 10; then 2.5L of ethyl acetate was added for extraction; the organic phase was washed with 2.5L of saturated brine; dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carbonitrile 702g, with an HPLC purity of 98.46%.

[0064] (5) In a 20L glass reactor, (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile 655g was added into methanol 7L, after stirring and dissolving, ammonium formate 413g and palladium hydroxide 65g were added, the reaction system was heated to reflux; after 2 hours, TLC detection showed that the reaction of (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile was complete; filtration was performed, 4mol / L hydrochloric acid was added, the pH of the reaction liquid was controlled at 4, the reaction liquid was concentrated, the concentration was stopped when the methanol evaporation amount was 6L, methyl tert-butyl ether 2L was added, stirring was performed for 1 hour, suction filtration was performed, and (4S,2S)-4-fluoro-pyrrolidine-2-carbonitrile hydrochloride 434g was obtained by drying, with an HPLC purity of 99.21%.

[0065] Although the present application has been described in detail with reference to the preferred embodiments, it should be understood that the application is not limited to those preferred embodiments. Without departing from the spirit and essential characteristics of the application, one of ordinary skill can make other variations and modifications of the application under the framework of all disclosure and the proper scope of the application. Any variations or modifications based on the technical range disclosed in the present application should be covered in the protection scope of the present application.

Claims

1. A process for the preparation of a plomaril intermediate characterized in that, The reaction route is as follows: ； The method comprises the following steps: (1) (S)-4-hydroxy-2-pyrrolidinone is reacted with DAST to obtain (S)-4-fluoropyrrolidin-2-one; The specific steps are as follows: (S)-4-hydroxy-2-pyrrolidinone is added into dichloromethane, and after being dissolved, the system is lowered to-10~0 ℃, and DAST is added dropwise, and the temperature of the reaction system is controlled to be ≤0 ℃; after the dropwise addition is completed, the reaction is preserved for 2~3 hours; after the reaction is completed, the reaction liquid is washed with water, and the organic phase is washed with 10% sodium carbonate aqueous solution; after being concentrated, (S)-4-fluoropyrrolidin-2-one is obtained; (2) (S)-4-fluoropyrrolidin-2-one is reacted with (S)-1-bromoethylbenzene under the catalysis of sodium hydride to obtain (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one; The specific steps are as follows: (S)-4-fluoropyrrolidin-2-one is added into tetrahydrofuran, and after being stirred and dissolved, the temperature is lowered to-10~-5 ℃, and sodium hydride is added, and after the addition is completed, the stirring is preserved for 0.5 hours, then (S)-1-bromoethylbenzene is added, and the temperature is raised to 20~30 ℃ for reaction; 4-fluoropyrrolidin-2-one is detected by TLC to be completely reacted; after the reaction is quenched by adding water, ethyl acetate is added for extraction, and the organic phase is washed with saturated brine; after being concentrated, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one is obtained; (3) (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one is reacted with p-methylbenzenesulfonylmethyl isocyanide to obtain (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide in t-butanol; The specific steps are as follows: under the protection of nitrogen, (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one is added into t-butanol, and potassium t-butoxide is added, and after being uniformly stirred, the system is lowered to-10~0 ℃; then p-methylbenzenesulfonylmethyl isocyanide is added dropwise; after the dropwise addition is completed, the reaction is preserved, and the whole process is protected by nitrogen; (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-one and the cyanide intermediate are detected by TLC to be completely reacted, the reaction liquid is raised to 20~30 ℃, water is slowly added for crystallization, the amount of water is 0.5~0.8 ml / ml based on the amount of t-butanol; after the solid is precipitated, the stirring is preserved for 1 hour; (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide is obtained by filtration; (4) (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carboxylic acid amide is dehydrated to obtain (4S,2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidin-2-carbonitrile; Specific steps are: (4S, 2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile is added into N, N-dimethylformamide, cooled to -5~5℃, and trichloroisocyanuric acid is added in batches, and the reaction is kept; TLC detection (4S, 2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile reaction is complete; 5% sodium carbonate aqueous solution is added to the reaction solution, and the pH of the reaction solution is controlled at 9~10; then ethyl acetate is added for extraction; the organic phase is washed with saturated brine; and the organic phase is concentrated to obtain (4S, 2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile; (5) (4S, 2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile is reacted with hydrochloric acid after the side chain is removed to obtain (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile hydrochloride; Specific steps are: (4S, 2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile is added into methanol, stirred and dissolved, then ammonium formate and palladium hydroxide are added, and the reaction system is heated to reflux; TLC detection (4S, 2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile reaction is complete; filter, add hydrochloric acid to the filtrate, control the pH of the reaction solution to 3~4, concentrate the reaction solution, then add methyl tert-butyl ether to the concentrate, and filter to obtain (4S, 2S)-4-fluoro-pyrrolidine-2-carbonitrile hydrochloride.

2. A process for the preparation of a plomaril intermediate as claimed in claim 1, wherein, In step (1), the molar ratio of (S)-4-hydroxy-2-pyrrolidinone to DAST is 1:1.2~1.

5.

3. A process for the preparation of a plomaril intermediate as claimed in claim 1, wherein, In step (2), the molar ratio of 4-fluoropyrrolidin-2-one to (S)-1-bromoethylbenzene is 1:1.1~1.2; the molar ratio of 4-fluoropyrrolidin-2-one to sodium hydride is 1:1.2~1.

5.

4. The process for the preparation of a plomirapide intermediate as claimed in claim 1 wherein, In step (3), the molar ratio of (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-one to p-methylbenzenesulfonylmethyl isocyanide is 1:1.1~1.3; the molar ratio of (S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-one to potassium tert-butoxide is 1:3~3.

5.

5. The process for the preparation of a plomirapide intermediate as claimed in claim 1 wherein, In step (4), the molar ratio of (4S, 2S)-4-fluoro-1-(1-phenyl-ethyl)-pyrrolidine-2-carbonitrile to trichloroisocyanuric acid is 1:0.45~0.55.

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