CN115108957B

CN115108957B - Synthesis method of chiral 2-phenylpyrrolidine

Info

Publication number: CN115108957B
Application number: CN202210706377.3A
Authority: CN
Inventors: 丁宇洋; 左联; 唐昌华; 王廷春
Original assignee: Shenzhen Borui Pharmaceutical Technology Co ltd
Current assignee: Shenzhen Borui Pharmaceutical Technology Co ltd
Priority date: 2022-06-21
Filing date: 2022-06-21
Publication date: 2023-12-29
Anticipated expiration: 2042-06-21
Also published as: CN115108957A

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of chiral 2-phenylpyrrolidine, in particular to a synthesis method of chiral (R) -2- (2, 5-difluorophenyl) pyrrolidine. According to the synthesis method of chiral 2-phenylpyrrolidine, halogenated aromatic hydrocarbon is used as a raw material, schiff base is generated by the halogenated aromatic hydrocarbon and bromobutyronitrile for cyclization reaction, imine is reduced by reduction reaction, and chiral reagent is used for resolution, so that chiral 2-phenylpyrrolidine with high chemical purity and high optical purity can be obtained. The synthesis method is simpler, the process steps are shorter, and the reaction yield is higher; the noble metal catalyst and the metal organic compound are avoided, the reaction raw materials are cheap and easy to obtain, and the process safety is better; in particular, the chiral 2-phenylpyrrolidine product has better chiral purity and is easier to split, and the generated chiral halogenated 2-arylpyrrole can be derived into more chemical intermediates.

Description

Synthesis method of chiral 2-phenylpyrrolidine

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of chiral 2-phenylpyrrolidine, in particular to a synthesis method of chiral (R) -2- (2, 5-difluorophenyl) pyrrolidine.

Background

The tetrahydropyrrole derivative is a component or chemical intermediate of a plurality of medicines and has wide application in the fields of foods, medicines, pesticides, coatings, printing and dyeing, papermaking, textiles, photosensitive materials, daily chemicals, high polymer materials and the like. Compounds containing a tetrahydropyrrole moiety have been found to have antifungal, antitumor, antipsychotic, analgesic, antileprosy, and therapeutic activity against cardiovascular and cerebrovascular diseases, only in the pharmaceutical industry. Therefore, the synthesis of the compounds and the research on the biological activity thereof are more and more focused and paid attention to.

The Bayer company announced that the accurate therapeutic drug of the tumor under the flag, larotectanib, obtained the marketing approval of the European Union at day 23 of 9 in 2019. Larotrectinib, as the first oral TRK inhibitor, is specifically used for treating tumors with TRK gene fusion, and is the first approved anticancer drug of European Union without distinguishing tumor types. The biggest difference between Larotrectinib and the previous targeting drug is that Larotrectinib is not aimed at tumors at a certain anatomical position, but is developed as a broad-spectrum antitumor drug for treating all adult or child solid tumor patients carrying VTRK fusion genes. TRK gene fusion refers to fusion of a NTRK gene family member (NTRK 1, NTRK2, NTRK 3) with another unrelated gene due to chromosomal variation, resulting in a conformationally activated aberrant TRK fusion protein. The TRK fusion protein acts as a tumor driving factor and can drive the diffusion and growth of TRK fusion tumors. It has been studied that NTRK gene fusion can occur in any part of the body, resulting in the possibility of TRK fusion tumors occurring in a variety of adult and pediatric solid tumors. It is shown by market-related people that NTRK mutations occur in less than 1% of most solid tumor types, but are quite common in some rare cancers such as adult saliva cancers and infant fibrosarcoma. Larotrectinib, a potent, oral, selective Tropomyosin Receptor Kinase (TRKs) inhibitor, aims to target TRKs (including TRKA, TRKB, and TRKC) directly, thereby closing the signaling pathway that leads to growth of TRK-fused tumors. At present, larotrectinib has been demonstrated to have durable anti-tumor activity and good tolerance in TRK fusion cancers of a wide range of ages and tumor types, has positive effects on 17 tumors including lung cancer, thyroid cancer, melanoma, GIST, colon cancer, soft tissue sarcoma, salivary gland tumor, and infant fibrosarcoma, and the like, and has a therapeutic effective rate of up to 75%.

In Larotrectinib synthesis, (R) -2- (2, 5-difluorophenyl) pyrrolidine of the following structure is the most important intermediate in the synthesis process and the highest cost ratio.

In the prior art, the conventional synthetic route for chiral 2-phenylpyrrolidine represented by (R) -2- (2, 5-difluorophenyl) pyrrolidine is as follows:

however, this synthetic method is not only too long in process route, but also the selectivity of chiral reduction is not ideal.

In addition, in the following synthetic route, diazoacetoacetic acid ethyl ester is used for carrying out addition reaction on toluene sulfonyl imide, and then the process of preparing the 2-aryl pyrrolidine through the steps of protecting group replacement, ring closure, decarboxylation and the like is carried out:

however, the synthesis method still has the problem of long reaction steps, and a very dangerous diazonium reagent is used in the synthesis process, so that the method is not beneficial to industrial popularization.

At present, the synthesis methods of chiral 2-phenylpyrrolidine including (R) -2- (2, 5-difluorophenyl) pyrrolidine all have the problem of relatively long reaction routes, and the production cost is affected to be higher due to the conditions of more used reagents, difficult obtainment and the like, which is not beneficial to industrial popularization.

Disclosure of Invention

Therefore, the technical problem to be solved by the invention is to provide a synthesis method of chiral 2-phenylpyrrolidine, which has the advantages of simple synthesis route, higher chiral synthesis rate, lower cost, simple separation and easily obtained raw materials;

the second technical problem to be solved by the invention is to provide a synthesis method of chiral (R) -2- (2, 5-difluorophenyl) pyrrolidine.

In order to solve the technical problems, the invention discloses a synthesis method of chiral 2-phenylpyrrolidine as shown in formula (I),

wherein n=1 or 2, said R being independently from each other selected from halogen, C1-C3 alkyl, cyano or ester groups;

the synthesis method comprises the following steps:

(1) Taking halogenated aromatic hydrocarbon with a structure shown in a formula (a), and adding bromoxynil to perform ring closure reaction to obtain a compound shown in a formula (b);

(2) Carrying out reduction reaction on the compound shown in the formula (b) under the action of a reducing agent to obtain a compound shown in the formula (c);

(3) Adding a chiral resolving agent into the compound shown in the formula (c) to carry out chiral resolution, thus obtaining the chiral 2-phenylpyrrolidine shown in the formula (I).

Specifically, in the step (1), the ring closing reaction comprises the steps of adding n-butyllithium into the halogenated aromatic hydrocarbon and then adding bromoxynil in a first organic solvent system to perform the ring closing reaction;

preferably, the reaction ratio of the halogenated aromatic hydrocarbon, the n-butyl lithium and the bromoxynil is 1: (1-1.02): (1-1.2) equivalent.

Specifically, in the step (1),

the cyclization reaction comprises the step of forming a format reagent by the halogenated aromatic hydrocarbon and magnesium powder in a first organic solvent system, and the step of adding bromoxynil to perform the cyclization reaction;

preferably, the reaction ratio of the halogenated aromatic hydrocarbon to bromoxynil is 1: (1-1.2) equivalent.

Specifically, in the step (1), the first organic solvent includes anhydrous diethyl ether and/or tetrahydrofuran, and preferably anhydrous diethyl ether.

Preferably, in the step (1), the temperature of the ring closing reaction is-75 to-80 ℃, preferably-78 ℃.

Specifically, in the step (2), the reducing agent includes at least one of sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

Specifically, in the step (2), the reaction ratio of the compound shown in the formula (b) to the reducing agent is 1:1.2-3 equivalents.

Specifically, in the step (2), the solvent system of the reduction reaction includes a mixed solvent of an alcohol solvent and an acidic solvent. The alcohol solvent is preferably methanol and/or ethanol, the acid solvent is preferably acetic acid, and more preferably, the volume ratio of the alcohol solvent to the acid solvent is 3-5:1, more preferably 4:1.

preferably, in the step (2), the temperature of the reduction reaction is-75 to-80 ℃, preferably-78 ℃.

Specifically, in the step (3), the chiral resolving agent includes an acidic resolving agent;

preferably, the chiral resolving agent comprises D-tartaric acid, D-malic acid and/or D-mandelic acid.

Specifically, in the step (3), the reaction ratio of the compound shown in the formula (c) and the chiral resolving agent is 1: (1-1.1) equivalent.

Specifically, in the step (3), the chiral resolution step includes a step of reacting the compound represented by the formula (c) with the chiral resolving agent in a second organic solvent to form a chiral salt, and a step of neutralizing and purifying the chiral salt in a third organic solvent.

Specifically, the second organic solvent and the third organic solvent are selected from alcohol solvents independently of each other;

preferably, the second organic solvent and the third organic solvent are selected from methanol and/or ethanol independently of each other.

Preferably, in the step (3), the reaction temperature of the resolution step is 0-30 ℃.

According to the synthesis method of chiral 2-phenylpyrrolidine, halogenated aromatic hydrocarbon is used as a raw material, schiff base is generated by the halogenated aromatic hydrocarbon and bromobutyronitrile for cyclization reaction, imine is reduced by reduction reaction, and chiral reagent is used for resolution, so that chiral 2-phenylpyrrolidine with high chemical purity and high optical purity can be obtained. Compared with the chiral synthesis process reported in the prior art, the synthesis method is simpler, the process steps are shorter, and the reaction yield is higher; the noble metal catalyst and the metal organic compound are avoided, the reaction raw materials are cheap and easy to obtain, and the process safety is better; in particular, the chiral 2-phenylpyrrolidine product has better chiral purity and is easier to split, and the generated chiral halogenated 2-arylpyrrole can be derived into more chemical intermediates.

According to the synthesis method of chiral (R) -2- (2, 5-difluorophenyl) pyrrolidine, the selected structure halogenated aromatic hydrocarbon is used for cyclization, reduction and chiral resolution reaction, so that chiral products with higher optical purity can be obtained, the reaction basically can be subjected to simple post-treatment to directly feed materials, the reaction conversion rate is high, and the synthesis cost of the compounds can be reduced; the whole synthesis process has the advantages of high reactant yield, low cost, simple and easy separation process, easily available raw materials and mild process conditions, and is suitable for large-scale synthesis of (R) -2- (2, 5-difluorophenyl) pyrrolidine. The intermediate synthesized by the method can be used for processing and preparing the 2-phenylpyrrolidine parent nucleus structural compound with low cost, high efficiency and high speed, and has high industrial popularization value.

Drawings

In order that the invention may be more readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings, in which,

FIG. 1 is a graph showing the results of the dissolution of 400MHz deuterated chloroform in nuclear magnetic resonance (H-NMR) spectrum of target compound 5 in example 1;

FIG. 2 is a graph showing the results of chiral purity EE detection of target compound 5 in example 1, wherein (a) is a racemate HPLC profile and (b) is a pure HPLC profile;

FIG. 3 is a graph showing the results of the dissolution of 400MHz deuterated chloroform in nuclear magnetic resonance (H-NMR) spectrum of target compound 11 in example 3;

FIG. 4 is a graph showing the results of chiral purity EE detection of target compound 11 in example 3, wherein (a) is a racemate HPLC profile and (b) is a pure HPLC profile.

Detailed Description

The following describes the invention in further detail with reference to examples.

The raw materials and the reaction conditions involved in the synthesis reaction are all conventional reagents and control modes in the field.

Example 1

This example scheme was used to synthesize (R) -2- (2, 5-difluorophenyl) pyrrolidine, the reaction scheme of the synthesis method was as follows:

the synthetic method of (R) -2- (2, 5-difluorophenyl) pyrrolidine comprises the following steps:

(1) Dissolving compound 1 (1.92 g,10 mmol) in 20mL of anhydrous diethyl ether, dropwise adding n-butyllithium (7.7 mL,10mmol (1.3M in THF)) at-80 ℃, and reacting for 1 hour at-80 ℃ after the dropwise adding; dissolving 4-bromobutyronitrile (1.47 g,10 mmol) in 5mL anhydrous tetrahydrofuran, dropwise adding into the reaction solution at-80deg.C, and reacting at room temperature for 1 hr; after the completion of TLC detection reaction, saturated ammonium chloride solution was added to quench the reaction, 20mL of ethyl acetate was taken to extract the organic phase 2 times, anhydrous sodium sulfate was dried to remove anhydrous sodium sulfate, and the organic phase was evaporated to dryness to give 1.7g of crude compound 2, which was identified as the target compound by LCMS-ESI (m/z), and the crude product was directly used for the next reaction.

(2) Dissolving the compound 2 obtained in the above in 10mL of a mixed solvent of anhydrous methanol and acetic acid (v: v=4:1), adding sodium borohydride (15 mmol,570 mg) in portions at the temperature of-78 ℃, and gradually heating the reaction solution to room temperature after the addition is completed, so as to perform a reaction for 1 hour; after completion of the TLC detection reaction, 1mL of water was added to quench the reaction, the reaction solvent was evaporated to dryness, 2mL of water, 5mL of ethyl acetate extract aqueous solution were added, the organic phase was combined, dried over anhydrous sodium sulfate, the anhydrous sodium sulfate was filtered off, the organic phase was evaporated to dryness, and the crude product was subjected to a flash silica gel column (dichloromethane: methanol=50:1) to give 1.68g of a white solid as a compound with a yield of 92%. Identified as target compound 3 by LCMS-ESI (m/z).

¹ H NMR(600MHz,CDCl3)δ7.26–7.23(m,1H),6.96–6.92(m,1H),6.87–6.83(m,1H),4.41–4.38(m,1H),3.17–3.14(m,1H),3.07–3.03(m,1H),2.27–2.23(m,2H),1.91–1.82(m,2H),1.63–1.56(m,1H).MS(ESI):[M+H]+found 184.1. The product was identified to be structurally correct.

(3) Compound 3 (1.84 g,10 mmol) was added to 100mL of absolute ethanol, D-malic acid (0.78 g,10 mmol) was added, heated to reflux until the sample was completely dissolved, the stirring was lowered to room temperature, stirred at room temperature for 3 hours, filtered to give (R, R) -2, 5-difluorobenzopyrrolidine malate, and washed 3 times with cold ethanol to give 1.38g of a white crystal, i.e., malate compound 4.

1.38g of the compound 4 is added with 30mL of methanol, 20mL of 1N aqueous sodium hydroxide solution is added dropwise, the mixture is stirred for 2 hours, the solvent is evaporated, the ethyl acetate is extracted for 3 times, the organic phases are combined, the mixture is washed with saturated saline water, dried with anhydrous sodium sulfate and evaporated to dryness, and yellow oily matters are obtained, namely 1.02g of chiral compound 5 (R) -2, 5-difluorobenzopyrrolidine, and the yield is 96%.

¹ H NMR(600MHz,CDCl3)δ7.26–7.23(m,1H),6.96–6.92(m,1H),6.87–6.83(m,1H),4.41–4.38(m,1H),3.17–3.14(m,1H),3.07–3.03(m,1H),2.27–2.23(m,2H),1.91–1.82(m,2H),1.63–1.56(m,1H)。MS(ESI):[M+H]+found 184.1. The product was identified to be structurally correct.

The nuclear magnetic resonance hydrogen spectrum (H-NMR) 400MHz deuterated chloroform of the compound 5 prepared in the embodiment is shown in the figure 1, and the chiral purity EE of the compound 5 is shown in the figure 2, wherein (a) is a raceme HPLC spectrum, and (b) is a pure HPLC spectrum. It can be seen that the product structure is correct.

Example 2

This example scheme was used to synthesize (R) -2- (3-bromophenyl) pyrrolidine, the reaction scheme of the synthesis was as follows:

compound 6 (2.35 g,10 mmol) was dissolved in 20mL of anhydrous diethyl ether, and n-butyllithium (7.7 mL,10mmol (1.3M in THF)) was added dropwise at-80℃and reacted at-80℃for 1 hour. 4-bromobutyronitrile (1.47 g,10 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and the mixture was added dropwise to the reaction mixture at-80℃for 1 hour. After the TLC detection reaction is completed, saturated ammonium chloride solution is added to quench the reaction, 20mL of ethyl acetate is used for extracting the organic phase for 2 times, anhydrous sodium sulfate is dried on the organic phase, anhydrous sodium sulfate is filtered off, the organic phase is evaporated to dryness, and the compound 7 is obtained, and is identified as a target compound through LCMS-ESI (m/z), and the crude product is directly used for the next reaction.

The obtained compound 7 was dissolved in 10mL of a mixed solvent of anhydrous methanol and acetic acid (v: v=9:1), sodium borohydride (20 mmol,760 mg) was added in portions at-78 ℃, and after the addition was completed, the reaction mixture was gradually warmed to room temperature and reacted for 1 hour. After completion of TLC detection, 1mL of water was added to quench the reaction. The reaction solvent was evaporated to dryness, 2mL of water, 5mL of ethyl acetate extract aqueous solution were added, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, anhydrous sodium sulfate was filtered off, the organic phase was evaporated to dryness, and the crude product was subjected to a flash silica gel column (dichloromethane: methanol=50:1) to obtain 2.04g of compound 8, and the yield in two steps was calculated to be 91%. The target compound was identified by LCMS-ESI (m/z).

Using the compound 8 obtained above as a starting material, chiral compound resolution was performed according to the procedure in step (3) of example 1, to obtain 1.93g of a white solid compound 10, and a yield of 95% was calculated.

¹ H-NMR(500MHz,CDCl3)δ7.37(s,1H),7.20-7.08(m,2H),6.99-6.95(m,1H),4.11(t,J＝7.5Hz,1H),3.18(m,2H),2.21-2.14(m,1H) 1.95-1.80 (m, 2H), 1.65-1.57 (m, 1H). The product was identified to be structurally correct.

Example 3

This example scheme was used to synthesize methyl 3- (pyrrolidin-2-yl) benzoate, the reaction scheme of the synthesis method was as follows:

compound 10 was prepared according to the procedure described in example 2.

Compound 10 (225 mg,1 mmol) was dissolved in 2mL of methanol and 2mL of triethylamine (303 mg,3 mmol) was added, along with Pd (dppf) Cl ₂ (0.1 mmol,72.5 mg) was reacted at 100℃under a pressure of 1bar of carbon monoxide gas for 10 hours. After completion of the TLC detection, the solvent was evaporated off and the crude product was passed through a flash silica gel column (dichloromethane: methanol=50:1) to give 202mg of compound 11, calculated 92% yield. Identified as target compound 11 by LCMS-ESI (m/z).

¹ H NMR (400 mhz, cdcl 3) delta 8.05 (s, 1H), 7.92 (d, j=7.7 hz, 1H), 7.59 (d, j=7.7 hz, 1H), 7.40 (t, j=7.7 hz, 1H), 4.20 (t, j=7.7 hz, 1H), 3.93 (s, 3H), 3.23 (ddd, j=10.1, 7.7,5.4hz, 1H), 3.06 (ddd, j=10.1, 8.2,6.8hz, 1H), 2.29-2.18 (m, 1H), 1.97-1.81 (m, 2H), 1.69 (ddd, j=17.0, 12.3,8.1hz, 1H). The product was identified to be structurally correct.

The nuclear magnetic resonance hydrogen spectrum (H-NMR) 400MHz deuterated chloroform of the target compound 11 is shown in FIG. 3, and the chiral purity EE of the compound 11 is shown in FIG. 4, wherein (a) is a racemate HPLC spectrum and (b) is a pure HPLC spectrum. It can be seen that the product structure is correct.

Example 4

The synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine described in this example is identical to that of example 1, except that the procedure for synthesizing compound 2 is different.

2-bromo-1, 4-difluorobenzene (1.92 g,10 mmol) and magnesium powder (240 mg,10 mmol) are prepared into a 1M Grignard reagent in diethyl ether, the Grignard reagent solution is dissolved in 5mL of anhydrous tetrahydrofuran at-80 ℃, and the solution is dropwise added into the reaction solution at-80 ℃ and then the reaction is carried out for 1 hour at room temperature after the dropwise addition; after completion of TLC detection, the reaction was quenched by adding saturated ammonium chloride solution, the organic phase was extracted 2 times with 20mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered off, and evaporated to dryness to give 1.02g of Compound 2 as a crude product, which was identified as Compound 2 by LCMS-ESI (m/z).

It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.

Claims

1. A synthesis method of chiral 2-phenylpyrrolidine as shown in formula (I) is characterized in that,

wherein n=1 or 2, said R being independently from each other selected from halogen, C1-C3 alkyl or cyano;

the synthesis method comprises the following steps:

(1) Taking halogenated aromatic hydrocarbon with a structure shown in a formula (a), and adding bromobutyronitrile to carry out a ring closure reaction to obtain a compound shown in a formula (b);

2. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 1, wherein in the step (1), the ring closing reaction is performed by adding n-butyllithium to the halogenated aromatic hydrocarbon in a first organic solvent system _， Then the reaction with bromobutyronitrile is carried out for ring closure reaction.

3. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 2, wherein the reaction ratio of the halogenated aromatic hydrocarbon, n-butyllithium and bromobutyronitrile is 1: (1-1.02): (1-1.2) equivalent.

4. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 1, wherein in the step (1), the ring closure is performed by adding bromobutyronitrile, wherein in the first organic solvent system, the halogenated aromatic hydrocarbon and magnesium powder form a formatting reagent.

5. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 4, wherein the reaction ratio of the halogenated aromatic hydrocarbon to bromobutyronitrile is 1: (1-1.2) equivalent.

6. The method for synthesizing chiral 2-phenylpyrrolidine according to any of claims 2 to 5, wherein in the step (1), the first organic solvent is anhydrous diethyl ether and/or tetrahydrofuran.

7. The method for synthesizing chiral 2-phenylpyrrolidine according to any of claims 1 to 5, wherein in the step (2), the reducing agent is at least one of sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

8. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 7, wherein the reaction ratio of the compound represented by formula (b) and the reducing agent is 1:1.2-3 equivalents.

9. The method according to any one of claims 1 to 5, wherein in the step (2), the solvent system for the reduction reaction is a mixed solvent of an alcohol solvent and an acidic solvent.

10. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 9, wherein the alcohol solvent is methanol and/or ethanol, and the acidic solvent is acetic acid.

11. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 10, wherein a volume ratio of the alcohol solvent to the acidic solvent is 3 to 5:1.

12. the method for synthesizing chiral 2-phenylpyrrolidine according to any of claims 1 to 5, wherein in the step (3), the chiral resolving agent is an acidic resolving agent.

13. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 12, wherein the chiral resolving agent is D-tartaric acid, D-malic acid and/or D-mandelic acid.

14. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 13, wherein the reaction ratio of the compound represented by formula (c) and the chiral resolving agent is 1: (1-1.1) equivalent.

15. The method according to any one of claims 1 to 5, wherein in the step (3), the chiral resolution step is a step of reacting the compound represented by the formula (c) with the chiral resolving agent in a second organic solvent to form a chiral salt, and a step of neutralizing and purifying the chiral salt in a third organic solvent.

16. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 15, wherein the second organic solvent and the third organic solvent are selected from alcohol solvents independently of each other.

17. The method for synthesizing chiral 2-phenylpyrrolidine according to claim 16, wherein the second organic solvent and the third organic solvent are selected from methanol and/or ethanol independently of each other.

18. The method for synthesizing chiral 2-phenylpyrrolidine according to any of claims 1 to 5, wherein:

in the step (1), the temperature of the ring closing reaction is-75 to-80 ℃;

in the step (2), the temperature of the reduction reaction is-75 to-80 ℃;

in the step (3), the reaction temperature of the resolution step is 0-30 ℃.