CN117603117B - Preparation method of chiral 3- (2-haloacetyl) -4-ethylpyrrolidine - Google Patents

Abstract

The invention discloses a method for preparing chiral 3-(2-haloacetyl)-4-ethylpyrrolidine, comprising the following steps: compound 2 undergoes an asymmetric epoxidation reaction with Oxone to obtain compound 3, compound 3 undergoes a cis-ring-opening reaction with ethylmagnesium chloride to obtain compound 4; compound 4 undergoes a chlorination reaction with NCS to obtain compound 5; compound 5 is prepared into a Grignard reagent and then undergoes a Grignard reaction with carbon dioxide to obtain compound 6, compound 6 reacts with acetic anhydride to obtain compound 7, and compound 7 undergoes an α-halogenation reaction with a hydrohalic acid to obtain compound 1. The method uses the inexpensive and readily available compound 2 as a starting material, and prepares compound 1 through six steps; the reaction conditions are mild, the operation is simple, the production cost is low, and it is safe and environmentally friendly; the optical purity of compound 1 prepared by the method can reach more than 98%.

Description

A preparation method of chiral 3-(2-haloacetyl)-4-ethylpyrrolidine

Technical Field

The present invention belongs to the technical field of drug preparation, and relates to a method for preparing chiral 3-(2-haloacetyl)-4-ethylpyrrolidine, and in particular to a method for preparing (3R, 4S)-3-(2-haloacetyl)-4-ethyl-N-PG-pyrrolidine which can be used to prepare upadacitinib.

Background Art

(3R,4S)-3-(2-haloacetyl)-4-ethyl-N-PG-pyrrolidine (Compound 1) contains a halomethyl group, a carbonyl group and a tetrahydropyrrole ring in its molecule and is an important intermediate for the synthesis of drugs, especially upadacitinib (Formula A). The structural formulas of Compound 1 and upadacitinib (Formula A) are:

Upadacitinib is a new JAK1 inhibitor developed by AbbVie. In August 2019, the FDA approved it for marketing in the United States for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have an inadequate response or intolerance to methotrexate.

The preparation of upadacitinib is typically prepared by alkylation of compound 1 with another intermediate 5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine-2-carbamic acid tert-butyl ester followed by ring closure, deprotection, amidation, and re-deprotection. Therefore, compound 1 is a key intermediate in the synthesis of upadacitinib and is of great significance for the preparation of upadacitinib.

For compound 1, there are also many literature reports on its preparation methods, mainly the following:

Method 1: The preparation method reported in patent US2013072470A, which uses ethyl pentynoate as raw material, undergoes reduction, ring closure, debenzylation, Cbz protection group addition and hydrolysis to obtain a racemic pyrrolidine carboxylic acid intermediate, which is then subjected to splitting, acidification, chlorination, diazotization, bromination and other reactions to generate compound 1 (X = Br, PG = Cbz). The synthetic route is:

This method has many steps, and the starting materials are expensive and difficult to obtain; the process requires two palladium-catalyzed hydrogenation steps, and diazo compounds are used as reaction materials, which poses a great safety hazard; in addition, the chiral separation yield is low, and the enantiomers cannot be used, resulting in high costs. Therefore, it is not suitable for industrial production.

Method 2: Preparation method disclosed in US2017129902A and WO2017066775A: This method uses Cbz-glycine ethyl ester as raw material, undergoes ring closure, esterification, coupling, hydrolysis, asymmetric catalytic reduction, salt formation, sulfonylation and bromination to generate compound 1 (X = Br, PG = Cbz). The synthetic route is:

This method also has many steps. The starting material ethyl acrylate is a Class 2B carcinogen; the second step uses expensive trifluorosulfonic anhydride that is extremely unfriendly to the environment and human body; the third step not only uses an expensive palladium catalyst, but also requires strict anhydrous conditions; the fifth step also uses an expensive chiral catalyst S-segphos Ru complex, which also requires strict anhydrous conditions. Therefore, the reaction conditions of this process are relatively harsh and are not conducive to industrial production.

Method 3: Preparation method disclosed in WO2017066775A: This method uses diethyl malonate as raw material, and undergoes condensation, addition, reduction, ring closure, protective group addition, dehydration after reduction, reduction, hydrolysis, and then C protective group addition, chiral separation, acidification, chlorination, diazotization and bromination to generate compound 1 (X = Br, PG = Cbz). The synthetic route is:

Although the starting materials of this method are cheap, there are many reaction steps; palladium catalytic hydrogenation is used twice in the process, and the fifth step reduction reaction needs to be carried out at -35°C, which is very inconvenient to operate. In addition, diazo compounds are used as reaction materials, and the chiral center is also obtained by splitting, which also has some defects of route 1. Therefore, it is not suitable for industrial production.

Method 4: The method disclosed in CN111217819: This method uses compound B as a raw material, and undergoes chlorination, coupling, asymmetric catalytic reduction, salt formation, acidification, acyl chloride, condensation, hydrolysis and chlorination to generate compound 1 (X=Cl, PG=Cbz). The synthetic route is:

The starting material compound B of this method is expensive and difficult to obtain; the phosphorus oxychloride used in the first step of chlorination will produce a large amount of phosphorus-containing acidic wastewater, which is not friendly to the environment, and the generated hydrogen chloride will react with the double bonds in the molecule to produce impurities; the Grignard reagent in the second step will also react with the ester group in the molecule to produce impurities; the expensive chiral catalyst S-segphos Ru complex and expensive chiral phenylethylamine are also used in the third step; in addition, thionyl chloride is used twice in the process, which is easy to produce hydrogen chloride gas that is not friendly to the environment and equipment, so it is difficult to achieve large-scale production. '

Summary of the invention

The technical problem to be solved by the present invention is to overcome the defects of the existing reported technology for preparing compound 1 that are not conducive to industrial-scale production, and to provide an effective method for preparing compound 1, which has short steps, high yield, few impurities, low production cost, safety and environmental protection.

Technical solution: The synthesis method of the compound 1(3R,4S)-3-(2-haloacetyl)-4-ethyl-N-PG-pyrrolidine of the present invention comprises the following steps:

(1) Compound 2 undergoes an asymmetric epoxidation reaction with Oxone (potassium monopersulfate complex salt) in the presence of a chiral catalyst 1 and an additive to obtain a chiral epoxide compound 3;

(2) Compound 3 reacts with ethyl magnesium chloride in the presence of catalyst 2 and an auxiliary agent to undergo a cis-ring-opening reaction to obtain compound 4;

(3) Compound 4 reacts with NCS under the catalysis of thiourea compounds to undergo chlorination reaction to obtain compound 5;

(4) Compound 5 reacts with magnesium metal to firstly form a Grignard reagent, and then reacts with carbon dioxide to undergo a Grignard reaction, followed by hydrolysis to obtain compound 6;

(5) Compound 6 reacts with acetic anhydride in the presence of a base to obtain compound 7;

(6) Compound 7 undergoes α-halogenation reaction with a hydrohalic acid to obtain compound 1. The specific synthesis route is as follows:

Wherein, PG is a protecting group of a nitrogen atom such as Cbz, Boc, Fmoc or trichloroethoxycarbonyl (Troc), trifluoroethylformamide (CF ₃ CH ₂ NHC=O), etc.; X is Cl or Br.

Preferably, _R1 and _R2 in the thiourea catalyst in step (3) are H and C1-C4 alkyl, respectively.

Preferably, in step (1), the catalyst 1 is a D-fructose-derived ketone, which can be easily prepared by referring to the literature and has the structural formula:

Preferably, the amount of catalyst 1 is 10-30% of the amount of compound 2.

Preferably, in step (1), the additive is a tetrabutyl quaternary ammonium salt, specifically selected from tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium acetate, tetrabutylammonium dihydrogen phosphate, tetrabutylammonium hydrogen carbonate, tetrabutylammonium bromide, etc.; and its amount is 2-6% of the amount of compound 2.

Preferably, in step (1), the solvent is one or a mixture of polar compounds such as acetonitrile, dimethoxymethane (DMM), DMA, DMAC, DMF, etc.; a buffer solution is also added to the solvent, more preferably a mixed solvent consisting of a mixture of acetonitrile and DMM and a buffer solution of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/LNa ₂ (EDTA).

Preferably, in step (1), Oxone is dissolved in 4*10 ^-4 mol/L Na ₂ (EDTA) and added dropwise, and the ratio of its mass to the amount of compound 2 is 0.6-0.9 g:1 mmol.

Preferably, in step (1), the reaction temperature is -20 to 0°C.

Preferably, in step (2), the catalyst 2 is an iron trihalide, such as iron trichloride or iron tribromide, more preferably iron trichloride, and its amount is 2-8% of the amount of compound 3.

Preferably, in step (2), the auxiliary agent is tetramethylethylenediamine (TMEDA), and its amount is 2 to 4 times the amount of compound 3.

Preferably, in step (2), the solvent is one or a mixture of compounds such as THF, toluene, diethyl ether, etc., more preferably a mixture of THF and toluene.

Preferably, in step (2), the reaction temperature is -5 to 10°C.

Preferably, in step (2), the molar ratio of compound 3 to Grignard reagent is 1:1.5-2.5.

Preferably, the catalyst in step (3) is a thiourea compound. Using a thiourea compound as a catalyst not only has a high yield of the chlorination reaction, but also can keep the chiral configuration of compound 5 unchanged. N,N′-dimethylthiourea is preferred, and its amount is 30-50% of the amount of compound 4.

Preferably, in step (4), the reaction temperature is -10 to 10°C.

Preferably, in step (5), the base is an organic amine such as pyridine, triethylamine, tributylamine, etc., more preferably pyridine.

Preferably, in step (5), the reaction temperature is 70-100°C.

Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The starting materials and other raw materials used in the method are cheap and easily available, and compound 1 is prepared in six steps, with a high yield in each step; (2) The reaction conditions are mild, the operation is simple, the production cost is low, and it is safe and environmentally friendly. (3) The chemical purity of compound 1 prepared by the method can reach 99%, and the optical purity can reach more than 98%.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

Example 1

Preparation of compound 3 50 mmol of compound 2 (PG=Cbz) and 300 mL of acetonitrile were added to a reaction flask. After stirring and mixing, 300 mL of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/L Na ₂ (EDTA) buffer solution were added. The stirring was continued. Then 2 mmol of tetrabutylammonium hydrogen sulfate and 5 mmol of catalyst 1 were added. After stirring and mixing, the temperature of the reaction system was lowered to -20°C. 30 g of Oxone dissolved in 100 mL of Na ₂ (EDTA) was slowly dripped into the reaction flask. At the same time, 100 mL of an aqueous solution containing 40 g of potassium carbonate was slowly dripped. After the addition was completed, the system temperature was raised to room temperature and stirred for 10 min. Add 200 mL of petroleum ether and 200 mL of water to the reaction flask, stir and stand for stratification, separate the organic layer, extract the water layer with 150 mL of petroleum ether for 3 times, combine the organic layers, wash 3 times with 150 mL of saturated brine, and dry over anhydrous sodium sulfate. Filter to remove the desiccant and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixed solution of petroleum ether and ethanol and dried under reduced pressure to obtain compound 3 (PG = Cbz), with a yield of 60% and an ee value of 83.3%. The structure of the compound was confirmed by MS and ¹ H NMR.

Example 2

Preparation of compound 3 50 mmol of compound 2 (PG=Cbz) and 300 mL of acetonitrile were added to a reaction flask. After stirring and mixing, 300 mL of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/LNa ₂ (EDTA) buffer solution were added. The mixture was stirred continuously. Then 2 mmol of tetrabutylammonium hydrogensulfate and 10 mmol of catalyst 1 were added. After stirring and mixing, the temperature of the reaction system was lowered to -20°C. 30 g of Oxone dissolved in 100 mL of Na ₂ (EDTA) was slowly dripped into the reaction flask. At the same time, 100 mL of an aqueous solution containing 40 g of potassium carbonate was slowly dripped into the solution. After the addition was completed, the temperature of the system was raised to room temperature and stirred for 10 min. Add 200 mL of petroleum ether and 200 mL of water to the reaction flask, stir and stand for stratification, separate the organic layer, extract the water layer with 150 mL of petroleum ether for 3 times, combine the organic layers, wash 3 times with 150 mL of saturated brine, and dry over anhydrous sodium sulfate. Filter to remove the desiccant and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixed solution of petroleum ether and ethanol and dried under reduced pressure to obtain compound 3 (PG=Cbz), with a yield of 73% and an ee value of 92.2%.

Example 3

Preparation of compound 3 50 mmol of compound 2 (PG=Cbz) and 300 mL of acetonitrile were added to a reaction flask. After stirring and mixing, 300 mL of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/L Na ₂ (EDTA) buffer solution were added. The stirring was continued. Then 2 mmol of tetrabutylammonium hydrogen sulfate and 15 mmol of catalyst 1 were added. After stirring and mixing, the temperature of the reaction system was lowered to -20°C. 30 g of Oxone dissolved in 100 mL of Na ₂ (EDTA) was slowly dripped into the reaction flask. At the same time, 100 mL of an aqueous solution containing 40 g of potassium carbonate was slowly dripped. After the addition was completed, the system temperature was raised to room temperature and stirred for 10 min. Add 200 mL of petroleum ether and 200 mL of water to the reaction flask, stir and stand for stratification, separate the organic layer, extract the water layer with 150 mL of petroleum ether for 3 times, combine the organic layers, wash 3 times with 150 mL of saturated brine, and dry over anhydrous sodium sulfate. Filter to remove the desiccant and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixed solution of petroleum ether and ethanol and dried under reduced pressure to obtain compound 3 (PG=Cbz), with a yield of 69% and an ee value of 95.9%.

Example 4

Preparation of compound 3 50 mmol of compound 2 (PG=Cbz) and 300 mL of acetonitrile were added to a reaction flask. After stirring and mixing, 300 mL of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/L Na ₂ (EDTA) buffer solution were added. The mixture was stirred continuously. Then 2 mmol of tetrabutylammonium hydrogen sulfate and 15 mmol of catalyst 1 were added. After stirring and mixing, the temperature of the reaction system was lowered to -20°C. 35 g of Oxone dissolved in 100 mL of Na ₂ (EDTA) was slowly dripped into the reaction flask. At the same time, 100 mL of an aqueous solution containing 40 g of potassium carbonate was slowly dripped into the solution. After the addition was completed, the temperature of the system was raised to room temperature and stirred for 10 min. Add 200 mL of petroleum ether and 200 mL of water to the reaction flask, stir and stand for stratification, separate the organic layer, extract the water layer with 150 mL of petroleum ether for 3 times, combine the organic layers, wash 3 times with 150 mL of saturated brine, and dry over anhydrous sodium sulfate. Filter to remove the desiccant and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixed solution of petroleum ether and ethanol and dried under reduced pressure to obtain compound 3 (PG=Cbz) with a yield of 72% and an ee value of 96.3%.

Example 5

Preparation of compound 3 50 mmol of compound 2 (PG=Cbz) and 300 mL of acetonitrile were added to a reaction flask. After stirring and mixing, 300 mL of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/L Na ₂ (EDTA) buffer solution were added. The stirring was continued. Then 2 mmol of tetrabutylammonium hydrogen sulfate and 15 mmol of catalyst 1 were added. After stirring and mixing, the temperature of the reaction system was lowered to -20°C. 45 g of Oxone dissolved in 100 mL of Na ₂ (EDTA) was slowly dripped into the reaction flask. At the same time, 100 mL of an aqueous solution containing 40 g of potassium carbonate was slowly dripped. After the addition was completed, the system temperature was raised to room temperature and stirred for 10 min. Add 200 mL of petroleum ether and 200 mL of water to the reaction flask, stir and stand for stratification, separate the organic layer, extract the water layer with 150 mL of petroleum ether for 3 times, combine the organic layers, wash 3 times with 150 mL of saturated brine, and dry over anhydrous sodium sulfate. Filter to remove the desiccant and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixed solution of petroleum ether and ethanol and dried under reduced pressure to obtain compound 3 (PG=Cbz), with a yield of 74% and an ee value of 96.6%.

Example 6

Preparation of compound 3 50 mmol of compound 2 (PG=Cbz) and 300 mL of acetonitrile were added to a reaction flask. After stirring and mixing, 300 mL of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/LNa ₂ (EDTA) buffer solution were added and the stirring was continued. Then 3 mmol of tetrabutylammonium hydrogen sulfate and 15 mmol of catalyst 1 were added. After stirring and mixing, the temperature of the reaction system was lowered to -20°C. 45 g of Oxone dissolved in 100 mL of Na ₂ (EDTA) was slowly dripped into the reaction flask. At the same time, 100 mL of an aqueous solution containing 40 g of potassium carbonate was slowly dripped. After the addition was completed, the system temperature was raised to room temperature and stirred for 10 min. Add 200 mL of petroleum ether and 200 mL of water to the reaction flask, stir and stand for stratification, separate the organic layer, extract the water layer with 150 mL of petroleum ether for 3 times, combine the organic layers, wash 3 times with 150 mL of saturated brine, and dry over anhydrous sodium sulfate. Filter to remove the desiccant and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixed solution of petroleum ether and ethanol and dried under reduced pressure to obtain compound 3 (PG=Cbz) with a yield of 75% and an ee value of 97.5%.

Example 7

Preparation of compound 3 50 mmol of compound 2 (PG=Cbz) and 300 mL of acetonitrile were added to a reaction flask. After stirring and mixing, 300 mL of 0.05 mol/L Na ₂ B ₄ O ₇ .10H ₂ O and 4*10 ^-4 mol/L Na ₂ (EDTA) buffer solution were added and stirring was continued. 3 mmol of tetrabutylammonium hydrogen sulfate and 15 mmol of catalyst 1 were added. After stirring and mixing, the temperature of the reaction system was lowered to -10°C. 45 g of Oxone dissolved in 100 mL of Na ₂ (EDTA) was slowly dripped into the reaction flask. At the same time, 100 mL of an aqueous solution containing 40 g of potassium carbonate was slowly dripped. After the addition was completed, the system temperature was raised to room temperature and stirred for 10 min. Add 200 mL of petroleum ether and 200 mL of water to the reaction flask, stir and stand for stratification, separate the organic layer, extract the water layer with 150 mL of petroleum ether for 3 times, combine the organic layers, wash 3 times with 150 mL of saturated brine, and dry over anhydrous sodium sulfate. Filter to remove the desiccant and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixed solution of petroleum ether and ethanol and dried under reduced pressure to obtain compound 3 (PG=Cbz) with a yield of 82% and an ee value of 97.3%.

On the basis of the reaction conditions of Example 7, the additive tetrabutylammonium hydrogen sulfate in the reaction can be replaced by tetrabutylammonium chloride, tetrabutylammonium acetate, tetrabutylammonium dihydrogen phosphate, tetrabutylammonium hydrogen carbonate, and tetrabutylammonium bromide; the temperature of the reaction system can be adjusted between -20°C and 0°C; the solvent acetonitrile can be replaced by one or a mixture of polar compounds such as DMM, DMA, DMAC, and DMF, and other reaction conditions remain unchanged. Some experimental results are shown in Table 1.

Table 1 Conditions and results for preparing compound 3 in Examples 8 to 26

Note: The solvent in Example 26 is 200 mL DMM + 100 mL acetonitrile, and the specific volume of the remaining acetonitrile + DMM is: 100 mL acetonitrile + 200 mL DMM.

Embodiment 27

Preparation of Compound 4 After purging with nitrogen three times, 60mmol of tetrahydrofuran solution of ethylmagnesium chloride and 90mmol of TMEDA dissolved in 100mL of dry tetrahydrofuran were added to the reaction flask, and the reaction flask was placed in an ice-salt bath. When the system temperature dropped to -5°C, 30mmol of compound 3 (PG=Cbz) prepared in Example 17 was added, and after stirring and mixing evenly, 1.5mmol of ferric chloride was added, and the reaction was stirred at about -5°C for 0.5h, and then the ice-salt bath was removed. The temperature was slowly raised to room temperature and stirred for 2.5h. The reaction flask was then placed in an ice-water bath, and 100mL of saturated _NH4Cl solution was dripped into the reaction flask. After the dripping was complete, it was stirred at room temperature for 30min. The organic layer was separated and washed twice with 100mL of saturated brine. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. 60 mL of ethyl acetate was added to the crude product, and 150 mL of petroleum ether was added after stirring to dissolve. The precipitated solid was filtered and dried to obtain compound 4 (PG=Cbz) with a yield of 74% and an ee value of 98.3%. The structure of the compound was confirmed by MS and ¹ H NMR.

Embodiment 28

Preparation of Compound 4 After purging with nitrogen three times, 60mmol of tetrahydrofuran solution of ethylmagnesium chloride and 90mmol of TMEDA dissolved in 100mL of dry tetrahydrofuran were added to the reaction flask, and the reaction flask was placed in an ice-salt bath. When the system temperature dropped to -5°C, 30mmol of compound 3 (PG=Cbz) prepared in Example 17 was added, and after stirring and mixing evenly, 0.6mmol of ferric chloride was added, and the reaction was stirred at about -5°C for 0.5h, and then the ice-salt bath was removed. The temperature was slowly raised to room temperature and stirred for 2.5h. The reaction flask was then placed in an ice-water bath, and 100mL of saturated _NH4Cl solution was dripped into the reaction flask. After the dripping was complete, it was stirred at room temperature for 30min, the organic layer was separated, and washed twice with 100mL of saturated brine. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. To the crude product was added 60 mL of ethyl acetate, stirred to dissolve, and then added 150 mL of petroleum ether. The precipitated solid was filtered and dried to obtain compound 4 (PG=Cbz) with a yield of 45% and an ee value of 98.2%.

Embodiment 29

Preparation of Compound 4 After purging with nitrogen three times, 60mmol of tetrahydrofuran solution of ethylmagnesium chloride and 90mmol of TMEDA dissolved in 100mL of dry tetrahydrofuran were added to the reaction flask, and the reaction flask was placed in an ice-salt bath. When the system temperature dropped to -5°C, 30mmol of compound 3 (PG=Cbz) prepared in Example 17 was added. After stirring and mixing evenly, 2.4mmol of ferric chloride was added. After stirring and reacting at about -5°C for 0.5h, the ice-salt bath was removed, and the temperature was slowly raised to room temperature and stirred for reaction for 2.5h. The reaction flask was then placed in an ice-water bath, and 100mL of saturated NH ₄ Cl solution was dripped into the reaction flask. After dripping, it was stirred at room temperature for 30min. The organic layer was separated and washed twice with 100mL of saturated brine. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. To the crude product was added 60 mL of ethyl acetate, stirred to dissolve, and then 150 mL of petroleum ether was added. The precipitated solid was filtered and dried to obtain compound 4 (PG=Cbz) with a yield of 75% and an ee value of 98.2%.

Based on the reaction conditions of Example 27, the catalyst ferric chloride in the reaction can be replaced by ferric bromide; the temperature of the reaction system can be adjusted between -10°C and 10°C; compound 3 (PG = Cbz) can be replaced by compound 3 (PG = Boc, Fmoc, CF ₃ CH ₂ NHCO, Troc), and the amount of TMEDA is adjusted between 2 and 4 times the amount of compound 3. Other reaction conditions remain unchanged, and some experimental results are shown in Table 2.

Table 2 Conditions and results for preparing compound 4 in Examples 30 to 44

Embodiment 45

Preparation of Compound 5 50 mmol of compound 4 (PG = Cbz) prepared in Example 32, 15 mmol of N, N'-dimethylthiourea and 100 mL of dichloromethane were added to a reaction flask, stirred and dissolved, and 60 mmol of NCS was added. The reaction was stirred and reacted at room temperature for 1 hour. The reaction was stopped, and the reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure. 100 mL of water and 100 mL of dichloromethane were added to the residue. After stirring, the mixture was allowed to stand for stratification. The organic layer was separated, and the aqueous layer was extracted twice with 100 mL of dichloromethane. The organic layers were combined and washed twice with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure to obtain compound 5 (PG = Cbz) with a yield of 76% and an ee value of 98.5%. The structure of the compound was confirmed by MS and ¹ H NMR.

Embodiment 46

Preparation of Compound 5 50 mmol of compound 4 (PG=Cbz) prepared in Example 32, 20 mmol of N,N′-dimethylthiourea and 100 mL of dichloromethane were added to a reaction flask, stirred to dissolve, and then 75 mmol of NCS was added. The reaction was stirred at room temperature for 1 h. The reaction was stopped, and the reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure. 100 mL of water and 100 mL of dichloromethane were added to the residue. After stirring, the mixture was allowed to stand for stratification. The organic layer was separated, and the aqueous layer was extracted twice with 100 mL of dichloromethane. The organic layers were combined, washed twice with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was evaporated under reduced pressure to obtain compound 5 (PG=Cbz) with a yield of 93% and an ee value of 98.7%.

Based on the reaction conditions of Example 46, the catalyst N,N′-dimethylthiourea in the reaction can be replaced by other thiourea compounds; compound 4 (PG=Cbz) can be replaced by compound 4 (PG=Boc, Fmoc, CF ₃ CH ₂ NHCO, Troc), and other reaction conditions remain unchanged. Some experimental results are shown in Table 3.

Table 3 Conditions and results for preparing compound 5 in Examples 47 to 53

Serial number catalyst PG Yield/% ee value/% Embodiment 47 N,N′-Diethylthiourea Cb 89 98.6 Embodiment 48 Thiourea Cb 80 98.3 Embodiment 49 Tetramethylthiourea Cb 86 98.6 Embodiment 50 N,N′-Dimethylthiourea Boc 91 97.6 Embodiment 51 N,N′-Dimethylthiourea Fmoc 89 98.4 Embodiment 52 N,N′-Dimethylthiourea CF ₃ CH ₂ NHCO 86 97.8 Embodiment 53 N,N′-Dimethylthiourea Troc 83 97.1

Embodiment 54

Preparation of Compound 6 After purging with nitrogen three times, 60 mmol of magnesium metal and 50 mL of dry tetrahydrofuran were added to the reaction flask, heated to reflux, and 50 mmol of compound 5 (PG = Cbz) prepared in Example 46 dissolved in 50 mL of dry tetrahydrofuran was dripped into the reaction flask. After the dripping was completed, reflux was continued for 0.5 h. The heating was stopped, and the reaction flask was placed in an ice-salt bath. Dry carbon dioxide gas was slowly introduced into the reaction system. The reaction temperature was controlled at about 0°C, and the carbon dioxide gas was continuously introduced for 0.5 h. , remove the ice-salt bath, slowly warm to room temperature, and stir the reaction for 0.5h, then place the reaction flask in an ice-water bath, drip 50mL1N hydrochloric acid into the reaction flask, stir at room temperature for 30min after dripping, separate the organic layer, wash twice with 100mL saturated salt water, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain a crude product, which is recrystallized from a mixture of ethyl acetate and petroleum ether, and the precipitated solid is filtered and dried to obtain compound 6 (PG＝Cbz), with a yield of 85% and an ee value of 98.7%. The structure of the compound was confirmed by MS and ¹ H NMR.

Based on the reaction conditions of Example 54, compound 5 (PG=Cbz) can be replaced by compound 5 (PG=Boc, Fmoc, CF ₃ CH ₂ NHCO, Troc), and other reaction conditions remain unchanged. Some experimental results are shown in Table 4.

Table 4 Conditions and results for preparing compound 6 in Examples 55 to 58

Serial number PG Yield/% ee value/% Embodiment 55 Boc 83 97.9 Embodiment 56 Fmoc 77 98.5 Embodiment 57 CF ₃ CH ₂ NHCO 74 98.0 Embodiment 58 Troc 71 98.1

Embodiment 59

Preparation of Compound 7 50 mmol of compound 6 (PG = Cbz) prepared in Example 54, 30 mL of triethylamine and 25 mL of acetic anhydride were added to a reaction flask and stirred to mix evenly. The system temperature was raised to 70°C and stirred for 4 hours at this temperature. The heating was stopped and most of the solvent was evaporated under reduced pressure. 60 mL of xylene was added three times and then distilled under reduced pressure to remove the residual solvent. The residual liquid was cooled and neutralized by adding saturated sodium bicarbonate solution. The organic layers were combined, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound 7 (PG = Cbz) with a yield of 56% and an ee value of 97.9%. The structure of the compound was confirmed by MS and ¹ HNMR.

Based on the reaction conditions of Example 59, the base triethylamine in the reaction can be replaced by pyridine or the like; compound 6 (PG=Cbz) can be replaced by compound 6 (PG=Boc, Fmoc, CF ₃ CH ₂ NHCO, Troc); the temperature of the reaction system can be adjusted between 70° C. and 100° C.; other reaction conditions remain unchanged. Some experimental results are shown in Table 5.

Table 5 Conditions and results for preparing compound 7 in Examples 60 to 65

Embodiment 66

Preparation of Compound 1 50 mmol of compound 7 (PG = Cbz) prepared in Example 61 and 200 mL of ethyl acetate were added to a reaction flask and stirred to mix evenly. 150 mL of 6N hydrochloric acid was dripped into the reaction system at room temperature. After dripping within 0.5 h, the reaction was continued to stir for 2 h. The reaction was stopped, and the layers were allowed to stand for stratification. The organic layer was separated, and the water layer was washed three times with 150 mL of ethyl acetate. The organic layers were combined and then washed with 150 mL of saturated salt water and distilled water, respectively. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure to remove the solvent. 200 mL of petroleum ether was added to the residue for pulping, and the precipitated solid was filtered and dried to obtain compound 1 (PG = Cbz, X = Cl) with a yield of 81% and an ee value of 98.6%.

Embodiment 67

Preparation of Compound 1 50 mmol of compound 7 (PG = Cbz) prepared in Example 61 and 200 mL of ethyl acetate were added to a reaction bottle and stirred to mix evenly. 150 mL of 6N hydrobromic acid was dripped into the reaction system at room temperature. After the dripping was completed within 0.5 h, the temperature of the reaction system was raised to 40 ° C. and the reaction was continued to stir for 2 h. The reaction was stopped, and the layers were allowed to stand for stratification. The organic layer was separated, and the water layer was washed three times with 150 mL of ethyl acetate. The organic layers were combined and then washed with saturated brine and distilled water, 150 mL each, respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. 200 mL of petroleum ether was added to the residue for pulping, and the precipitated solid was filtered and dried to obtain compound 1 (PG = Cbz, X = Br) with a yield of 76% and an ee value of 98.4%.

Based on the reaction conditions of Examples 66 and 67, compound 7 (PG=Cbz) can be replaced by compound 7 (PG=Boc, Fmoc, CF ₃ CH ₂ NHCO, Troc), and other reaction conditions remain unchanged. Some experimental results are shown in Table 6.

Table 6 Conditions and results for preparing compound 1 in Examples 68 to 75

Serial number HX PG Temperature/℃ ee value/% Embodiment 68 HCl Boc 79 98.5 Embodiment 69 HCl Fmoc 75 98.3 Embodiment 70 HCl CF ₃ CH ₂ NHCO 73 98.1 Embodiment 71 HCl Troc 74 97.5 Embodiment 72 HBr Boc 73 98.2 Embodiment 73 HBr Fmoc 70 98.0 Embodiment 74 HBr CF ₃ CH ₂ NHCO 68 97.8 Embodiment 75 HBr Troc 65 97.5

The above are all preferred embodiments of the present invention. For ordinary technicians in this technical field, without departing from the principle of the present invention, various equivalent modifications to the present invention belong to the protection scope of the claims attached to this application.

Claims (10)

1. A preparation method of chiral 3- (2-haloacetyl) -4-ethylpyrrolidine is characterized by comprising the following steps: the method comprises the following steps:

(1) The compound 2 and Oxone (potassium monopersulfate compound salt) are subjected to asymmetric epoxidation reaction under the action of a chiral catalyst 1 and an additive to obtain a chiral epoxy compound 3;

(2) The compound 3 and ethyl magnesium chloride undergo cis-opening reaction under the action of a catalyst 2 and an auxiliary agent to obtain a compound 4;

(3) The compound 4 and NCS undergo chlorination reaction under the catalysis of thiourea compounds to obtain a compound 5;

(4) The compound 5 reacts with magnesium metal to prepare a Grignard reagent, then the Grignard reagent reacts with carbon dioxide, and the compound 6 is prepared after hydrolysis;

(5) Reacting the compound 6 with acetic anhydride under the action of alkali to obtain a compound 7;

(6) The compound 7 and halogen acid are subjected to alpha-halogenation reaction to obtain a compound 1; the specific synthetic route is as follows:

；

Wherein PG is a protecting group Cbz, boc, fmoc, troc, CF ₃CH₂ nhc=o of nitrogen atom; x is Cl or Br; r ₁ and R ₂ are H and C1-C4 alkyl respectively;

The chiral catalyst 1 in the step (1) is D-fructose derivative ketone, and the structural formula is as follows:

；

The additive in the step (1) is tetrabutyl quaternary ammonium salt;

The catalyst 2 in the step (2) is ferric trichloride or ferric tribromide;

The auxiliary agent in the step (2) is TMEDA.

2. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the dosage of the catalyst 1 in the step (1) is 10-30% of the amount of the compound 2 substance.

3. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the tetrabutyl quaternary ammonium salt additive in the step (1) is selected from tetrabutyl ammonium bisulfate, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, tetrabutyl ammonium dihydrogen phosphate, tetrabutyl ammonium bicarbonate and tetrabutyl ammonium bromide, and the dosage of the tetrabutyl quaternary ammonium salt additive is 2-6% of the amount of the substance of the compound 2.

4. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the reaction solvent in the step (1) is selected from one or more of acetonitrile and DMM, DMA, DMAC, DMF; meanwhile, buffer solution is added into the solvent, and the buffer solution consists of 0.05 mol/L Na ₂B₄O₇.10H₂ O and 4 x 10 ^-4 mol/L Na₂ (EDTA).

5. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the Oxone in the step (1) is dissolved in 4x 10 ^-4 mol/L Na₂ (EDTA) and is dripped into the mixture, and the mass ratio of the Oxone to the mass of the compound 2 is 0.6-0.9 g:1 mmol.

6. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the reaction temperature in the step (1) is-20-0 ℃.

7. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the reaction temperature in the step (2) is-5-10 ℃.

8. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the consumption of the thiourea compound in the step (3) is 30-50% of the mass of the compound 4.

9. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the reaction temperature in the step (4) is-10 ℃.

10. The method for preparing chiral 3- (2-haloacetyl) -4-ethylpyrrolidine according to claim 1, wherein the method comprises the following steps: the reaction temperature in the step (5) is 70-100 ℃; the base is pyridine, triethylamine or tributylamine.