Synthesis method of chiral 2-aryl substituted pyrrolidine

Abstract

The invention provides a synthetic method of chiral 2-aryl substituted pyrrolidine. The synthetic method comprises the following specific steps: S1, reacting a compound a with a Grignard reagent to prepare a compound b solution; s2, reacting the compound b solution with a compound c to obtain a compound d; s3, preparing a compound e from the compound d under the action of a catalyst; s4, the compound e, triethylamine and Boc2O are subjected to a reaction, and a compound f is prepared; s5, preparing a compound g from the compound f and potassium isopropyl trifluoroborate under the action of a palladium catalyst; s6, performing deprotection on the compound g to prepare a compound h, namely chiral 2-aryl substituted pyrrolidine; wherein X is selected from chlorine, bromine or iodine. According to the synthesis method, the preparation process is simple, the operation process is reduced, the dosage of the chiral catalyst is reduced, the atom utilization rate is increased, the yield is increased, and industrialization is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing chiral 2-aryl substituted pyrrolidine. Background Art

[0002] 2-Aryl-substituted pyrrolidines (e.g., 2-(2-isopropylphenyl)pyrrolidine) are important intermediates for Bcl-2 inhibitors. Currently, the main synthetic routes are as follows:

[0003] Route 1:

[0004] Route 1, first reported in 2019 by patent WO2019210828, describes a method for synthesizing the racemic compound 5. Starting with an aromatic bromo-substituted pyrrolidine, this method involves amino protection and a palladium-catalyzed Suzuki coupling to introduce a propene group. The double bond is then reduced with palladium-carbon hydrogenation to yield the isopropyl group, which is then acidified and deprotected to obtain the racemic compound 5. This scheme's starting materials are difficult to obtain, and palladium catalysis is used twice during the process. The resulting compound is still a racemic compound, requiring further resolution and preparation to obtain chirally pure compound 5.

[0005] Route 2:

[0006] In order to prepare the chiral compound 5, the early scheme needed to be constructed from scratch, such as Route 2, as reported in Patents WO2022140224 and WO2021133817 and similar patents. Using the chiral induction method, starting from the chiral sulfonamide compound 6, the imine intermediate 8 was prepared, and the compound 8 then introduced a hemiacetal group, followed by deprotection and cyclization to obtain the optically pure compound 1. After that, it went through a similar path as Route 1 and introduced an isopropyl group to obtain the target compound 5. The process route of this scheme is cumbersome, involving multiple steps with harsh reaction conditions, poor overall atom economy, low yield, and great difficulty in industrialization.

[0007] Route 3:

[0008] In order to more efficiently prepare chirally pure compound 5, in 2021, Jacek Mlynarski's research group reported the asymmetric catalytic synthesis scheme shown in Route 3 (Advanced Synthesis & Catalysis (2021), 363 (5), 1317-1321). This scheme starts with 2-isopropyl aryl 11, inserts the carbonyl group through the Grignard reagent to form the carboxyl intermediate compound 12, and then esterifies to obtain compound 13, and then prepares the imine intermediate 14 with N-vinyl-2-pyrrolidone, and finally obtains the optically pure compound 5 through organozinc-catalyzed asymmetric hydrosilylation reduction. Although this scheme has been greatly simplified compared to the previous scheme, the amount of chiral catalyst used in the asymmetric catalysis stage reaches 10 mol%, the atom economy is poor, and industrialization is difficult.

[0009] Judging from the above three routes, it is of great significance to develop more efficient synthesis routes. Summary of the Invention

[0010] Based on the deficiencies of the prior art, the present invention discloses a method for synthesizing chiral 2-aryl substituted pyrrolidines, which aims to simplify the preparation process, reduce the operation flow, and reduce the amount of chiral catalyst used. At the same time, it improves the atom utilization rate and the yield, which is conducive to industrialization.

[0011] In a first aspect, the present invention provides a method for synthesizing a chiral 2-aryl substituted pyrrolidine, the specific steps comprising:

[0012]

[0013] Step S1: Compound a reacts with a Grignard reagent to prepare a solution of compound b;

[0014] Step S2: Compound b solution reacts with compound c solution to produce compound d;

[0015] Step S3: Compound d is reacted with a metal catalyst to obtain compound e;

[0016] Step S4: Compound e, triethylamine and di-tert-butyl dicarbonate (Boc2O) react to prepare compound f;

[0017] Step S5: Compound f and potassium isopropyl trifluoroborate react in the presence of palladium catalyst to prepare compound g;

[0018] Step S6: deprotecting compound g to obtain compound h, i.e., a chiral 2-aryl substituted pyrrolidine;

[0019] wherein X is selected from chlorine, bromine or iodine.

[0020] Furthermore, the Grignard reagent in step S1 is isopropylmagnesium chloride lithium chloride.

[0021] Furthermore, in step S1, the molar ratio of compound a to Grignard reagent is 1:1 to 1:1.5, preferably 1:1.2.

[0022] Furthermore, the solution of compound b obtained in step S1 is directly added dropwise to the tetrahydrofuran solution of compound c without purification.

[0023] Furthermore, in S2, the compound b solution is added dropwise to the compound c solution. Furthermore, the compound b solution is added dropwise at a rate of 1 to 5 drops / second, preferably 1 drop / second, 2 drops / second, 3 drops / second, 4 drops / second, or 5 drops / second. Furthermore, the compound c solution is prepared by dissolving compound c in tetrahydrofuran. Furthermore, the molar ratio of compound c to compound b is 1:1 to 1:1.5, preferably 1:1.2.

[0024] Furthermore, in step S2, after the compound c solution is cooled to -60°C, the compound b solution is added dropwise thereto.

[0025] Furthermore, in step S3, the metal catalyst is a chiral iridium metal complex catalyst generated in situ from an iridium metal catalyst precursor and a ligand. Furthermore, the iridium metal catalyst precursor is selected from at least one of [Ir(COD)Cl]2, [Ir(DBCOT)Cl]2, [Ir(COD)OMe]2, dichlorodi(cyclooctene)iridium(I) dimer, and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer. Furthermore, the ligand is selected from one or more of (R,R)-f-spiroPhos, triphenylphosphine, N,N,N',N'-tetramethylethylenediamine, 2,2-bipyridine, 1,10-phenanthroline, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, n-butyldi(1-adamantyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl) ether, bis(diphenylphosphino)methane, 1,3-bis(diphenylphosphino)propane, 1,5-bis(diphenylphosphino)pentane, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl.

[0026] Furthermore, in step S3, the molar ratio of the iridium metal catalyst precursor to the ligand is 1:1 to 1:3, preferably 1:1, 1:1.5, 1:2, 1:2.2, 1:2.5, or 1:3.

[0027] Furthermore, in step S3, the molar ratio of the metal catalyst to compound d is 1:900 to 1:1200, preferably 1:1000, wherein the molar ratio of the metal catalyst is calculated as the metal molar ratio.

[0028] Furthermore, in step S3, trifluoroacetic acid is added dropwise to the solution of compound d to react under nitrogen protection to obtain a deprotected product; the deprotected product is further subjected to asymmetric reduction hydrogenation with a catalyst and hydrogen to obtain compound e. Furthermore, in step S3, the molar ratio of compound d to trifluoroacetic acid is 1:5 to 1:7, preferably 1:6. Furthermore, the rate of addition of trifluoroacetic acid in step S3 is 1 to 5 drops / second, preferably 1 drop / second. Furthermore, during the dropwise addition of trifluoroacetic acid in step S3, the temperature of the reaction system is 0 to 5°C, preferably 0°C. Furthermore, after the dropwise addition of trifluoroacetic acid in step S3 is completed, the temperature is raised to room temperature and the reaction is allowed to react for 0.5 to 1 hour, preferably 1 hour.

[0029] In the present invention, the room temperature is 15 to 40°C, preferably 20 to 35°C, and preferably 25°C.

[0030] Furthermore, in step S3, the pressure of the hydrogen is 1 to 1.5 MPa.

[0031] Furthermore, in step S3, the reaction temperature of the asymmetric reduction hydrogenation is 20-40° C., preferably 30° C., and the reaction time is 30-55 h, preferably 45-50 h, preferably 48 h.

[0032] Furthermore, in step S4, the compound e is dissolved in dichloromethane, and triethylamine and Boc2O are added sequentially at 20-35°C (preferably 25°C), and the reaction is carried out for 1-5 hours to obtain compound f (preferably 3h). Furthermore, in step S4, the molar ratio of the compound e, triethylamine and Boc2O is 1:(2-4):1-2, preferably a molar ratio of 1:3:1.5, 1:2:1 or 1:4:2.

[0033] Furthermore, in step S5, the molar ratio of compound f to potassium isopropyl trifluoroborate is 1:1 to 1:2, preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8 or 1:2.

[0034] Furthermore, the palladium catalyst is selected from at least one of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, Pd(PPh3)4, PdCl2(dppf), Pd2(dba)3, Pd(OAc)2, Pd(dba)2 and Pd2(dba)3.

[0035] Furthermore, the molar ratio of the palladium catalyst to compound f is 1:80 to 1:120, preferably 1:100.

[0036] Furthermore, in S5, potassium carbonate is also added, and the molar ratio of the compound f to potassium carbonate is 1:1 to 1:2, preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8 or 1:2.

[0037] Furthermore, in step S6, the compound g is reacted with a solution of hydrogen chloride in 1,4-dioxane to obtain compound h. Furthermore, in step S6, the molar ratio of compound g to hydrogen chloride in the solution of hydrogen chloride in 1,4-dioxane is 1:5 to 1:10, preferably 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0038] In a second aspect, the present invention provides a method for synthesizing a chiral 2-aryl substituted pyrrolidine, the specific steps of which are as follows:

[0039]

[0040] A1: o-Dibromobenzene was dissolved in tetrahydrofuran. The temperature was lowered to -5°C under a nitrogen atmosphere. A solution of isopropylmagnesium chloride and lithium chloride in tetrahydrofuran was added dropwise. After the addition was complete, the reaction system was stirred at room temperature for 30 minutes. The obtained solution of compound b1 was used directly in the next reaction without further treatment.

[0041] A2: Dissolve 1-(tert-butoxycarbonyl)-2-pyrrolidone in tetrahydrofuran and cool to -60°C under a nitrogen atmosphere. Then slowly add the solution of compound b1 obtained in A1 dropwise to the reaction system. After the addition is complete, stir at this temperature for 30 minutes. After TLC, the reaction is complete. After post-treatment, compound d-1 is obtained, which can be used directly in the next reaction without further purification.

[0042] A3: Compound d-1 was dissolved in dichloromethane. Trifluoroacetic acid was added dropwise under a nitrogen atmosphere in an ice-water bath. After the addition was complete, the mixture was stirred at 25°C for 1 hour. After the disappearance of the starting material by TLC, the mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in tetrahydrofuran and a pre-prepared catalyst solution was added under a nitrogen atmosphere. The entire system was then replaced with hydrogen. After the replacement was complete, a hydrogen pressure of 1.0 MPa was maintained. The mixture was stirred at 30°C for 48 hours. After post-treatment, compound e-1 was obtained. The catalyst solution was prepared by mixing [Ir(COD)Cl]2 and (R,R)-spiroPhos in a molar ratio of 1:2.2.

[0043] A4: Dissolve compound e-1 in dichloromethane. Add triethylamine and di-tert-butyl dicarbonate sequentially at 25°C. Stir and react for 3 hours. After completion of the reaction, monitor the reaction by TLC. Quench the reaction and obtain compound f-1 after post-treatment. Use it directly in the next step without further purification.

[0044] A5: Compound f-1, potassium isopropyl trifluoroborate, potassium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex were added in sequence. Under a nitrogen atmosphere, 1,4-dioxane was added, the temperature was raised to 80°C, and the reaction was stirred for 24 hours. Compound g was obtained after post-treatment.

[0045] A6: Compound g was dissolved in 1,4-dioxane, and a solution of hydrogen chloride in 1,4-dioxane was added, and the mixture was stirred at room temperature for 1 hour. Compound h was obtained after post-treatment.

[0046] Furthermore, the molar ratio of o-dibromobenzene to isopropylmagnesium chloride and lithium chloride is 1:1 to 1:1.5, preferably 1:1.2.

[0047] Furthermore, the solution of compound b-1 obtained in A1 was directly added dropwise to the 1-(tert-butoxycarbonyl)-2-pyrrolidone solution without purification.

[0048] Furthermore, in A2, the compound b-1 solution is added dropwise to the 1-(tert-butoxycarbonyl)-2-pyrrolidone solution. Furthermore, the compound b-1 solution is added dropwise at a rate of 1 to 5 drops / second, preferably 1 drop / second, 2 drops / second, 3 drops / second, 4 drops / second, or 5 drops / second. Furthermore, the molar ratio of 1-(tert-butoxycarbonyl)-2-pyrrolidone to compound b-1 is 1:1 to 1:1.5, preferably 1:1.2.

[0049] Furthermore, in A2, the 1-(tert-butoxycarbonyl)-2-pyrrolidone solution is cooled to -60°C, and then the compound b-1 solution is added dropwise.

[0050] Furthermore, in A3, the metal catalyst is a chiral iridium metal complex catalyst generated in situ from an iridium metal catalyst precursor and a ligand. Furthermore, the iridium metal catalyst precursor is [Ir(COD)Cl]2. Furthermore, the ligand is selected from (R,R)-spiroPhos.

[0051]

[0052] Furthermore, the residue contained intermediates d-1v and d-2v, and the residue was used in the next reaction without further purification.

[0053] Furthermore, the molar ratio of the metal catalyst to compound d-1 is 1:1000, wherein the molar ratio of the metal catalyst is calculated as the metal molar ratio.

[0054] Furthermore, in A3, the molar ratio of compound d-1 to trifluoroacetic acid is 1:6. Furthermore, the trifluoroacetic acid is added dropwise at a rate of 1 to 5 drops / second, preferably 1 drop / second. Furthermore, during the addition of trifluoroacetic acid, the temperature of the reaction system is 0 to 5°C, preferably 0°C.

[0055] Furthermore, the molar ratio of the compound e-1, triethylamine and Boc2O is 1:3:1.5.

[0056] Furthermore, the molar ratio of compound f-1 to potassium isopropyl trifluoroborate is 1:1 to 1:2, preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8 or 1:2.

[0057] Furthermore, the molar ratio of the palladium catalyst [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex to compound f-1 is 1:100.

[0058] Furthermore, in A5, the molar ratio of the compound f-1 to potassium carbonate is 1:1 to 1:2, preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8 or 1:2.

[0059] Furthermore, the molar ratio of compound g-1 to hydrogen chloride in the 1,4-dioxane solution of hydrogen chloride is 1:5 to 1:10, preferably 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0060] Beneficial effects

[0061] Compared with the prior art, a certain embodiment of the present invention has at least one of the following beneficial effects:

[0062] (1) The present invention provides a method for synthesizing chiral 2-aryl substituted pyrrolidines, which is efficient and simple and can obtain products with high optical selectivity.

[0063] (2) Compared with the prior art of splitting and preparing chirally pure compounds, the present invention can directly prepare them with high atom utilization rate.

[0064] (3) Compared with the complicated routes and harsh reaction steps of the prior art, the present invention has a high yield and is simple and easy to operate.

[0065] (4) Compared with the prior art, which uses 10 mol% of chiral catalyst, the present invention only requires 0.1 mol% of catalyst, which has good raw material economy and is easy to industrialize.

[0066] (5) The synthesis method provided by the present invention can achieve continuous addition of S1-S2, without intermediate purification treatment, thus reducing the operation process and allowing the next step to proceed directly. S3-S4 can also achieve continuous addition of S3-S4, without intermediate purification treatment, thus reducing the operation process.

[0067] (6) In the synthesis method provided by the present invention, a conversion rate greater than 99% and an optical selectivity of up to 93% can be achieved by using 0.1 mol% equivalent of catalyst in S3. The catalyst dosage is low, and the precious metal residues can be recovered and converted into cash, so the overall cost is controllable.

[0068] (7) The synthesis method provided by the present invention has a yield of more than 90% in each step. In particular, starting from S3, the chiral compound is synthesized without the chirality of the compound being reversed, and finally a chiral 2-aryl substituted pyrrolidine with an optical purity of 98.5% is obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 is the H NMR spectrum of compound g in Example 1.

[0070] Figure 2 This is the H NMR spectrum of compound h in Example 1.

[0071] Figure 3 This is the chiral liquid phase diagram of compound h in Example 1.

[0072] Terminology

[0073] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0074] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0075] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0076] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", "further", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and features of different embodiments or examples, unless they are contradictory.

[0077] In the following disclosure, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%. Whenever a number having a value of N is disclosed, any number having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% is expressly disclosed, where "+ / -" means plus or minus.

[0078] The term "and / or" should be understood to mean any one of the options or a combination of any two or more of the options.

[0079] The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur.

[0080] "Room temperature" means ambient temperature, which may be 10-40°C, or 10-35°C, or 15-30°C, or 20-35°C, or 20-30°C, or 25°C.

[0081] (R,R)-f-spiroPhos, CAS: 1629646-88-3, chemical name: Ferrocene,1,1′-bis[(11aR)-10,11,12,13-tetrahydro-4H-diindeno[7,1-cd:1′,7′-ef]phosphocin-5(6H)-yl]-(ACI), structural formula is shown below:

[0082] DETAILED DESCRIPTION

[0083] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0084] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0085] The technical solutions of the present invention are illustrated below with examples, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0086] General method:

[0087]

[0088] Step 1: Using o-halogen bromobenzene as the starting material, preferably X=Br, a Grignard exchange reaction is carried out with isopropylmagnesium chloride and lithium chloride to obtain 2-bromophenylmagnesium bromide Grignard reagent compound b, which can be directly used in the next reaction without purification;

[0089] Step 2: The Grignard reagent obtained in the first step reacts with 1-(tert-butoxycarbonyl)-2-pyrrolidone to open the ring to obtain compound d;

[0090] Step 3: The ring-opened intermediate is in situ deprotected under the action of trifluoroacetic acid, and then undergoes an asymmetric reduction hydrogenation reaction catalyzed by a chiral iridium metal complex to obtain chiral compound e;

[0091] Step 4: Compound e is amino protected with Boc2O to obtain compound f;

[0092] Step 5: Compound f undergoes a coupling reaction with potassium isopropyl trifluoroborate in the presence of palladium catalyst to obtain compound g;

[0093] Step 6: Compound g is deprotected using a solution of hydrogen chloride in 1,4-dioxane to obtain the target compound h.

[0094] Chiral chromatography conditions: HPLC with UV detector, Chiralpak IG-34.6*250mm, 3.0μm. Column temperature: 37°C, detection wavelength: 220nm; injection volume: 5μl; flow rate: 1.0ml / min; mobile phase: n-hexane-ethanol (9-1).

[0095] Isocratic elution: 20 minutes.

[0096] Example 1

[0097]

[0098] Step 1: Grignard exchange

[0099] Mix o-dibromobenzene (11.3 g) with dry tetrahydrofuran (100 mL), replace the system with nitrogen three times, and maintain a nitrogen atmosphere. Cool to -5°C, then add a solution of isopropylmagnesium chloride and lithium chloride in tetrahydrofuran (1.3 M, 44.3 mL) dropwise. After the addition is complete, stir the reaction system at room temperature for 30 minutes to obtain Reaction Solution A. This solution can be used directly in the next reaction without further treatment.

[0100] Step 2: Pyrrolidone ring-opening reaction

[0101] 1-(tert-Butoxycarbonyl)-2-pyrrolidone (7.4 g) was mixed with dry tetrahydrofuran (80 mL), and the system was replaced with nitrogen three times, and the nitrogen atmosphere was maintained. The temperature was lowered to -60 ° C, and then the reaction solution A obtained in the first step was slowly added dropwise. After the addition was completed, the mixture was stirred for 30 minutes. After the reaction was completed by TLC detection, a saturated aqueous solution of ammonium chloride (120 mL) was added to the reaction system for quenching. It was then placed at room temperature and stirred for another hour, allowed to stand for separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases after extraction were combined; the combined organic phases were washed with a saturated aqueous sodium chloride solution (250 mL) and concentrated to obtain a crude compound d-1. The crude yield of the two steps was 90%, and it could be directly used in the next reaction without further purification.

[0102] Step 3: Asymmetric reductive amination

[0103] The crude compound d-1 obtained above was mixed with dichloromethane (90 mL), and the atmosphere was replaced with nitrogen three times, maintaining a nitrogen atmosphere. Trifluoroacetic acid (30.6 g) was added dropwise in an ice-water bath. After the addition was complete, the reaction was stirred at 25°C for 1 hour. After the disappearance of the starting material by TLC, the mixture was concentrated under reduced pressure to obtain the crude deprotected intermediates (Intermediates d-1v and d-2v), which were used in the next reaction without further purification.

[0104] In a nitrogen-filled glove box, (1,5-cyclooctadiene)iridium(I) chloride dimer [Ir(COD)Cl]2 and (R,R)-f-spiroPhos were dissolved in dichloromethane at a molar ratio of 1:2.2. The mixture was stirred at 25°C for 0.5 h to obtain an iridium catalyst solution.

[0105] The crude deprotected intermediate was mixed with dry tetrahydrofuran (180 mL). A pre-prepared iridium catalyst solution ([Ir(COD)Cl]2 / (R,R)-f-spiroPhos = 1 / 2.2 (molar ratio, 0.045 mmol)) was then added under a nitrogen atmosphere. The entire system was then purged with hydrogen three times, maintaining a hydrogen pressure of 1.0 MPa. The reaction was then stirred at 30°C for 48 hours.

[0106] After the reaction is completed, the mixture is concentrated and the organic phase is removed. The residual liquid is dissolved in 0.2M dilute hydrochloric acid solution (100mL) and then washed with methyl tert-butyl ether (50mL). The washed aqueous phase is adjusted to pH 10 with 0.2M sodium hydroxide solution (110mL), and then extracted twice with ethyl acetate (120mL×2). The organic phases are combined, and the combined organic phases are washed once with saturated sodium chloride solution (80mL), and then concentrated under reduced pressure to obtain a crude compound e-1. The third step yield is 95.0% and the ee value is 97.0%.

[0107] Step 4: Amino Boc protection

[0108] The crude product of compound e-1 (9.6 g, 1.0 eq.) obtained in step 3 was mixed with dichloromethane (80 mL) in a 250 mL reaction flask. Triethylamine (12.8 g, 3.0 eq.) and BOC anhydride (13.9 g, 1.5 eq.) were then added sequentially at 25°C. The reaction was stirred for 3 hours. After completion of the reaction, water (100 mL) was added to the reaction system to quench the reaction, and the pH of the reaction solution was adjusted to 5 with 0.1 M dilute hydrochloric acid. The mixture was allowed to stand for separation, and the aqueous phase was extracted once with dichloromethane (80 mL). The combined organic phases were washed once with saturated sodium chloride aqueous solution (70 mL) and then concentrated under reduced pressure to obtain the crude product compound f-1. The yield of step 4 was 93%, and the ee value was 97.0%. The product was used directly in the next step without further purification.

[0109] Step 5: Carbon-carbon coupling

[0110] The crude compound f-1 obtained in step 4 was mixed with potassium isopropyltrifluoroborate (7.2 g), followed by the addition of potassium carbonate (10.9 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (323 mg). The system was purged with nitrogen three times, and then the nitrogen atmosphere was maintained. Deoxygenated 1,4-dioxane (110 mL) was then added to the reaction flask. The temperature was raised to 80°C and the reaction was stirred for 24 hours. The reaction was stopped after the disappearance of the starting material by TLC. The mixture was concentrated under reduced pressure, and the residual liquid was mixed with ethyl acetate (120 mL) and washed sequentially with water and saturated sodium chloride aqueous solution. The organic phase was further concentrated under reduced pressure to obtain a concentrated solution, which was then recrystallized from ethanol to obtain the purified compound g with an optical purity of 98.5%, a fifth-step yield of 90%, and an ee value of 97.0%.

[0111] 1 H NMR (600MHz, CDCl3) δ7.39-7.41(3H),7.20-7.23(1H),4.66(1H),3.27-3.32(1H) ),3.20-3.22(2H),2.89-2.91(2H),1.88-1.93(2H),1.44(9H),1.23-1.24(6H).

[0112] Step 6: Deprotection of amino group by Boc

[0113] The fully purified compound g obtained in step 5 was dissolved in 1,4-dioxane (60 mL), followed by the addition of a 4 M solution of hydrogen chloride in 1,4-dioxane (54.0 mL). Stirring was carried out at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was mixed with water (80 mL) and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The aqueous phase was then washed with methyl tert-butyl ether (50 mL) and the pH was adjusted to 10 with 1 M sodium hydroxide. The mixture was extracted twice with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the target compound h. The yield from step 6 was 95% and the optical purity was 98.5%.

[0114] 1 H NMR (600MHz, CDCl3) δ7.48-7.49(1H),7.25-7.26(1H),7.16-7.22(2H),4.45-4.47(1H),3.22-3.32(2H),3. 00-3.03(1H),2.86(1H),2.15-2.21(1H),1.91-1.97(1H),1.84-1.90(1H),1.62-1.68(1H),1.22-1.24(6H).

[0115] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A method for synthesizing a chiral 2-aryl substituted pyrrolidine, characterized in that: The specific steps include: Step S1: Compound a reacts with a Grignard reagent to prepare a solution of compound b; Step S2: Compound b solution reacts with compound c solution to produce compound d; Step S3: Compound d is reacted with a metal catalyst to obtain compound e; Step S4: Compound e, triethylamine and di-tert-butyl dicarbonate are reacted to prepare compound f; Step S5: Compound f and potassium isopropyl trifluoroborate react in the presence of palladium catalyst to prepare compound g; Step S6: deprotecting compound g to obtain compound h, i.e., a chiral 2-aryl substituted pyrrolidine; wherein X is selected from chlorine, bromine or iodine.

2. The synthesis method according to claim 1, wherein The Grignard reagent is isopropylmagnesium chloride and lithium chloride; Further preferably, the molar ratio of compound a to Grignard reagent in step S1 is 1:1 to 1:1.5; Further preferably, the solution of compound b obtained in step S1 is directly added dropwise to the tetrahydrofuran solution of compound c without purification.

3. The synthesis method according to claim 1, wherein In step S2, the solution of compound b is added dropwise to the solution of compound c; Further preferably, the compound b solution is added at a rate of 1 to 5 drops per second; Further preferably, the compound c solution is prepared by dissolving compound c in tetrahydrofuran; Further preferably, the molar ratio of compound c to compound b is 1:1 to 1:1.5; Further preferably, in step S2, the compound c solution is cooled to -60°C, and then the compound b solution is added dropwise thereto.

4. The synthesis method according to claim 1, characterized in that In step S3, the metal catalyst is a chiral iridium metal complex catalyst generated in situ from an iridium metal catalyst precursor and a ligand; Further preferably, the iridium metal catalyst precursor is selected from at least one of [Ir(COD)Cl]2, [Ir(DBCOT)Cl]2, [Ir(COD)OMe]2, dichlorodi(cyclooctene)iridium(I) dimer and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer; Further preferably, the ligand is selected from one or more of (R,R)-f-spiroPhos, triphenylphosphine, N,N,N',N'-tetramethylethylenediamine, 2,2-bipyridine, 1,10-phenanthroline, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, n-butyldi(1-adamantyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl) ether, bis(diphenylphosphino)methane, 1,3-bis(diphenylphosphino)propane, 1,5-bis(diphenylphosphino)pentane, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl.

5. The synthesis method according to claim 4, characterized in that The molar ratio of the iridium metal catalyst precursor to the ligand is 1:1 to 1:3; Further preferably, the molar ratio of the metal catalyst to compound d in step S3 is 1:900 to 1:1200, preferably 1:1000; Further preferably, in step S3, trifluoroacetic acid is added dropwise to the solution of compound d to react under nitrogen protection to obtain a deprotected product; the deprotected product is further subjected to asymmetric reduction hydrogenation with a metal catalyst and hydrogen to obtain compound e; Further preferably, in step S3, the molar ratio of compound d to trifluoroacetic acid is 1:5 to 1:7, preferably 1:6; Further preferably, in step S3, the trifluoroacetic acid is added at a rate of 1 to 5 drops per second; Further preferably, in step S3, when the trifluoroacetic acid is added dropwise, the temperature of the reaction system is 0-5°C; Further preferably, in step S3, after the trifluoroacetic acid is added dropwise, the temperature is raised to room temperature and the reaction is carried out for 0.5 to 1 hour; Further preferably, in step S3, the pressure of the hydrogen is 1 to 1.5 MPa; Further preferably, in step S3, the reaction temperature of the asymmetric reduction hydrogenation is 20-40° C., and the reaction time is 30-55 h.

6. The synthesis method according to claim 1, characterized in that In step S4, the compound e is dissolved in dichloromethane, and triethylamine and di-tert-butyl dicarbonate are added in sequence at 20-35° C., and the reaction is carried out for 1-5 hours to obtain compound f; Further preferably, in step S4, the molar ratio of compound e, triethylamine and di-tert-butyl dicarbonate is 1:(2-4):1-2, preferably 1:3:1.

5.

7. The synthesis method according to claim 1, characterized in that In step S5, the molar ratio of compound f to potassium isopropyl trifluoroborate is 1:1 to 1:2; Further preferably, in step S5, the palladium catalyst is selected from at least one of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, Pd(PPh3)4, PdCl2(dppf), Pd2(dba)3, Pd(OAc)2, Pd(dba)2 and Pd2(dba)3; Further preferably, in step S5, the molar ratio of the palladium catalyst to compound f is 1:80 to 1:120, preferably 1:

100.

8. The synthesis method according to claim 1, characterized in that In step S5, potassium carbonate is further added, and the molar ratio of the compound f to potassium carbonate is 1:1 to 1:

2.

9. The synthesis method according to claim 1, characterized in that In step S6, the compound g reacts with a 1,4-dioxane solution of hydrogen chloride to obtain compound h; Further preferably, in step S6, the molar ratio of compound g to hydrogen chloride in the hydrogen chloride 1,4-dioxane solution is 1:5 to 1:

10.

10. A method for synthesizing chiral 2-aryl substituted pyrrolidines, characterized in that: The steps are as follows: A1: Dissolve o-dibromobenzene in tetrahydrofuran. Cool to -5°C under a nitrogen atmosphere, and add a solution of isopropylmagnesium chloride and lithium chloride in tetrahydrofuran dropwise. After the addition is complete, stir the reaction system at room temperature for 30 minutes. The resulting solution of compound b1 is used directly in the next reaction without further treatment. A2: Dissolve 1-(tert-butoxycarbonyl)-2-pyrrolidone in tetrahydrofuran and cool to -60°C under a nitrogen atmosphere. Then slowly add the solution of compound b1 obtained in A1 dropwise to the reaction system. After the addition is complete, stir at this temperature for 30 minutes. After TLC, the reaction is complete. After post-treatment, compound d-1 is obtained, which can be used directly in the next reaction without further purification. A3: Compound d-1 was dissolved in dichloromethane. Trifluoroacetic acid was added dropwise under a nitrogen atmosphere in an ice-water bath. After the addition was complete, the mixture was stirred at 25°C for 1 hour. After the disappearance of the starting material by TLC, the mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in tetrahydrofuran. A pre-prepared metal catalyst solution was added under a nitrogen atmosphere. The entire system was then replaced with hydrogen. After the replacement was complete, a hydrogen pressure of 1.0 MPa was maintained. The mixture was stirred at 30°C for 48 hours. After post-treatment, compound e-1 was obtained. The metal catalyst solution was prepared by mixing [Ir(COD)Cl]2 and (R,R)-f-spiroPhos in a molar ratio of 1:2.

2. A4: Dissolve compound e-1 in dichloromethane. Add triethylamine and di-tert-butyl dicarbonate sequentially at 25°C. Stir and react for 3 hours. After completion of the reaction, monitor the reaction by TLC. Quench the reaction and obtain compound f-1 after post-treatment. Use it directly in the next step without further purification. A5: Compound f-1, potassium isopropyl trifluoroborate, potassium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex were added in sequence. Under a nitrogen atmosphere, 1,4-dioxane was added, the temperature was raised to 80°C, and the reaction was stirred for 24 hours. Compound g was obtained after post-treatment. A6: Compound g was dissolved in 1,4-dioxane, and a solution of hydrogen chloride in 1,4-dioxane was added, and the mixture was stirred at room temperature for 1 hour. Compound h was obtained after post-treatment.

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