Chiral 2-azabicyclo [3.1. 1] heptane derivative and synthesis method thereof

Abstract

The invention discloses a chiral 2-azabicyclo [3.1. 1] heptane derivative and a synthesis method of the chiral 2-azabicyclo [3.1. 1] heptane derivative. According to the method, bicyclo [1.1. 0] butane is taken as a raw material and is subjected to a cycloaddition reaction with N-allyl carbonate under the catalysis of Lewis acid and a chiral iridium complex, a series of chiral 2-azabicyclo [3.1. 1] heptane compounds with various structures are synthesized with excellent chemical selectivity, and the product can be further derivatized. The method has the advantages of easily available raw materials, simple operation, mild reaction conditions, and diversity of functional groups.

Description

Technical Field

[0001] The invention belongs to the field of bicyclo[3.1.1]heptane synthesis, and particularly relates to a method for preparing chiral 2-azabicyclo[3.1.1]heptane derivatives by co-catalysis of Lewis acid and metal. Background Art

[0002] In recent years, the strategy of using three-dimensional bicyclic skeletons as bioisosteres to replace aromatic rings has become a hot topic in the field of drug research (Nat. Rev. Chem. 2024, 8, 605–627). Azabicyclo[3.1.1]heptane is an important bioisostere of ortho- or meta-substituted nitrogen aromatic rings. Its application in drug development is expected to improve the physicochemical properties and pharmacokinetic properties of drug-like molecules. Especially since medicinal chemists discovered that replacing the pyridine group in Rupatadine with 3-azabicyclo[3.1.1]heptane greatly improved the water solubility of the drug, reduced lipophilicity, and significantly improved metabolic stability in human liver microsomes (Angew. Chem. Int. Ed. 2023, 62, e202304246.), this research has attracted more and more attention from medicinal chemists and organic synthetic chemists. For example, the Studer team applied chiral 2-azabicyclo[3.1.1]heptane to the modification of a new type of active molecule with antiproliferative activity against HT-29, HeLa and 16MCF-7 (J.Am.Chem.Soc.2024,146,272045–27212); Li Xiaoxun's team also followed this idea and obtained a derivative of the local anesthetic Bupivacaine containing a 3-azabicyclo[3.1.1]heptane skeleton (J.Am.Chem.Soc.2024,146,21069–21077). These practices provide a novel research idea for drug development. Therefore, the construction of a new azabicyclo[3.1.1]heptane skeleton has important research significance.

[0003] So far, although 3-azabicyclo[3.1.1]heptane has made some progress, how to obtain 2-azabicyclo[3.1.1]heptane, especially chiral 2-azabicyclo[3.1.1]heptane, is still a huge challenge. At present, there is only one synthetic route for the synthesis of chiral 2-azabicyclo[3.1.1]heptane starting from a chiral substrate (J.Am.Chem.Soc.2024,146,27204–27212). This limits the structural diversity of nitrogen-aromatic bioisosteres. Therefore, developing catalytic asymmetric methods to construct chiral 2-azabicyclo[3.1.1]heptane is an important scientific problem that needs to be solved urgently. The obtained chiral 2-azabicyclo[3.1.1]heptane can be used as a bioequivalent of nitrogen-aromatic rings in the modification of drugs, active molecules and natural products, providing new chemical entities for drug research and development. In particular, it replaces the planar symmetrical nitrogen aromatic ring with a chiral three-dimensional bicyclic skeleton. The introduction of chiral elements will bring new opportunities for drug research and development. Summary of the invention

[0004] The purpose of the present invention is to use bicyclo[1.1.0]butane 2 as a raw material to undergo a cycloaddition reaction with N-allyl carbonate 3 to construct a chiral 2-azabicyclo[3.1.1]heptane compound 1. The present invention uses bicyclo[1.1.0]butane as a raw material, and undergoes a cycloaddition reaction with N-allyl carbonate under the catalysis of Lewis acid and chiral iridium complex, and synthesizes a series of chiral 2-azabicyclo[3.1.1]heptane derivatives with diverse structures with excellent chemical selectivity, and the products can be further derivatized.

[0005] In order to achieve the above object, the technical solution of the present invention is as follows:

[0006] In one aspect, the present invention provides a chiral 2-azabicyclo[3.1.1]heptane derivative, whose molecular structure 1 is as follows:

[0007]

[0008] R 1 is hydrogen; a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms; the group can be further substituted, and the substituent is selected from hydroxyl, amino, halogen, nitro (-NO 2 ), cyano (-CN) or a C1-C4 alkyl group;

[0009] R 2 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms;

[0010] R 3is a C1-C10 straight chain or branched alkyl group; a substituted or unsubstituted aryl group; an acyl group or a sulfonyl group.

[0011] Another aspect of the present invention provides a method for synthesizing the chiral 2-azabicyclo[3.1.1]heptane derivative, wherein a Lewis acid and a chiral iridium complex are used as catalysts, a solvent and a base are added, and a cycloaddition reaction of bicyclo[1.1.0]butane 2 and N-allyl carbonate ester 3 is carried out at 0°C to room temperature to generate a chiral 2-azabicyclo[3.1.1]heptane derivative 1.

[0012] After the reaction is completed, the product is separated and characterized by conventional separation and purification methods to obtain the target product.

[0013]

[0014] Substituents R in Bicyclo[1.1.0]butane 2 1 , R 2 , the substituent R of N-allyl carbonate 3 3 Same as above: R 1 is hydrogen; a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms; the group can be further substituted, and the substituent is selected from hydroxyl, amino, halogen, nitro (-NO 2 ), cyano (-CN) or a C1-C4 alkyl group;

[0015] R 2 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms;

[0016] R 3 is a C1-C10 straight chain or branched alkyl group; a substituted or unsubstituted aryl group; an acyl group or a sulfonyl group.

[0017] Based on the above technical solution, preferably, the Lewis acid catalyst is Ga(OTf) 3 、Yb(OTf) 3 、In(OTf) 3 and Sc(OTf) 3 The iridium complex catalyst is one of [Ir]-A, [Ir]-B and [Ir]-C, and the base is one of LiHMDS, NaHMDS, KHMDS and KOtBu; wherein the reaction is carried out with In(OTf) 3 and [Ir]-A as catalyst, NaHMDS as base has the best effect, the molar ratio of N-allyl carbonate 3 to catalyst is 1:0.01-1:0.5, preferably N-allyl carbonate 3 and In(OTf) 3The molar ratios of [Ir]-A and [Ir]-A were 1:0.02 and 1:0.04, respectively, and the molar ratio of N-allyl carbonate 3 to NaHMDS was 1:1.5.

[0018] Based on the above technical scheme, preferably, the solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylformamide or tetrahydrofuran; the reaction effect is best when the reaction solvent is tetrahydrofuran.

[0019] Based on the above technical scheme, the preferred reaction temperature is 0-130°C; the reaction time is 4-24 hours; the optimal reaction time is 8 hours; the optimal reaction temperature is 0-25°C, wherein a base is added at 0°C and the temperature is raised to 25°C for reaction.

[0020] Based on the above technical solution, preferably, the molar ratio of bicyclo[1.1.0]butane 2 to N-allyl carbonate 3 is 5:1-1:5, more preferably 1.3:1.

[0021] The present invention uses bicyclo[1.1.0]butane as a raw material, and reacts with N-allyl carbonate under the catalysis of Lewis acid and chiral iridium complex to undergo a cycloaddition reaction, thereby synthesizing a series of chiral 2-azabicyclo[3.1.1]heptane derivatives with diverse structures with excellent chemical selectivity, and the products can be further derivatized. Compared with the existing synthesis method of chiral azabicyclo[3.1.1]heptane, the present invention has easy-to-obtain raw materials, simple operation, and the reaction can efficiently modularly synthesize chiral 2-azabicyclo[3.1.1]heptane derivatives with potential biological activity.

[0022] Beneficial Effects

[0023] 1) The synthon bicyclo[1.1.0]butane 2 is easy to prepare in large quantities and can be used to synthesize chiral 2-azabicyclo[3.1.1]heptane derivatives 1 of different types and structures.

[0024] 2) The synthon N-allyl carbonate 3 is easy to prepare in large quantities and can conveniently construct the structurally unique and biologically active 2-azabicyclo[3.1.1]heptane skeleton.

[0025] 3) The present invention utilizes bicyclo[1.1.0]butane 2 to synthesize structurally diverse chiral 2-azabicyclo[3.1.1]heptane derivatives 1 with excellent chemical selectivity, and the raw materials are readily available, the operation is simple, the yield of the target product is high, and further derivatization is possible. DETAILED DESCRIPTION

[0026] The chemical reagents used were all commercially available and used directly without further treatment; bicyclo[1.1.0]butane 2 and N-allyl carbonate 3 were synthesized according to the method reported in the literature (Angew. Chem. Int. Ed. 2024, 63, e202318476; ACS Catal., 2021, 11, 3810-3821.)

[0027] The present invention uses simple bicyclo[1.1.0]butane 2 and N-allyl carbonate 3 as raw materials, and carries out a cycloaddition reaction (reaction formula (1)) under the action of Lewis acid and chiral iridium complex.

[0028]

[0029] The specific process is as follows: under nitrogen atmosphere, bicyclo[1.1.0]butane 2a (60.9 mg, 0.26 mmol) and N-allyl carbonate 3a (52.6 mg, 0.20 mmol) were added sequentially into a Schlenk tube equipped with a magnetic stirrer, and the tube was evacuated and backfilled with nitrogen five times. Then, anhydrous THF (2.0 mL) was added sequentially through a syringe. Then, In(OTf) was added 3 (0.004mmol), stirred at 25°C until N-allyl carbonate was consumed. Then, [Ir]-A (0.008mmol) was added and the mixture was cooled to 0°C. Subsequently, NaHMDS (0.30mmol, 1.5equiv.) was added dropwise. The reaction mixture was warmed to 25°C and stirred for 4h. After the reaction was complete, the mixture was quenched with water and extracted three times with ethyl acetate. The filtrate was separated, the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether (60-90°C) / ethyl acetate: 20:1, v / v) to obtain the target product 1. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0030] The following examples are helpful to further understand the present invention, but the contents of the present invention are not limited thereto.

[0031] Example 1

[0032]

[0033] The specific process is as follows: under nitrogen atmosphere, bicyclo[1.1.0]butane 2a (60.9 mg, 0.26 mmol) and N-allyl carbonate 3a (52.6 mg, 0.20 mmol) were added sequentially into a Schlenk tube equipped with a magnetic stirrer, and the tube was evacuated and backfilled with nitrogen five times. Then, anhydrous THF (2.0 mL) was added sequentially through a syringe. Then, In(OTf) was added 3(0.004mmol), stirred at 25℃ until N-allyl carbonate was consumed. Then, [Ir]-A (0.008mmol) was added and the mixture was cooled to 0℃. Subsequently, NaHMDS (0.30mmol, 1.5equiv.) was added dropwise. The reaction mixture was warmed to 25℃ and stirred for 4h. After the reaction was complete, the mixture was quenched with water and extracted three times with ethyl acetate. The filtrate was separated, the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether (60-90℃) / ethyl acetate: 20:1, v / v) to obtain the target product 1a (59.2mg, yield 80%, 94%ee). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0034] Example 2

[0035]

[0036] The reaction steps and operations were the same as those in Example 1, except that the bicyclo[1.1.0]butane added to the reaction system was 2b (68.7 mg, 0.26 mmol). The reaction was stopped and the target product 1b (63.8 mg, 78% yield, 93% ee) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0037] Example 3

[0038]

[0039] The reaction steps and operations were the same as those in Example 1, except that the bicyclo[1.1.0]butane added to the reaction system was 2c (65.5 mg, 0.26 mmol). The reaction was stopped and the target product 1c (58.0 mg, 73% yield, 96% ee) was obtained by post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0040] Example 4

[0041]

[0042] The reaction steps and operations were the same as those in Example 1, except that the cyclo[1.1.0]butane added to the reaction system was 2d (57.7 mg, 0.26 mmol). The reaction was stopped and post-treated to obtain the target product 1d as a white solid (66.9 mg, yield 81%, 94% ee). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0043] Example 5

[0044]

[0045] The reaction steps and operations were the same as those in Example 1, except that the bicyclo[1.1.0]butane added to the reaction system was 2e (65.5 mg, 0.26 mmol). The reaction was stopped and the target product 1e (61.2 mg, 77% yield, 95% ee) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0046] Example 6

[0047]

[0048] The reaction steps and operations were the same as those in Example 1, except that the bicyclo[1.1.0]butane added to the reaction system was 2f (78.5 mg, 0.26 mmol). The reaction was stopped and the target product 1f (67.1 mg, 75% yield, 96% ee) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0049] Example 7

[0050]

[0051] The reaction steps and operations were the same as those in Example 1, except that 2 g (44.7 mg, 0.26 mmol) of bicyclo[1.1.0]butane was added to the reaction system. The reaction was stopped and 1 g (36.2 mg, 57% yield, 84% ee) of the target product as a white solid was obtained after post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0052] Example 8

[0053]

[0054] The reaction steps and operations were the same as those in Example 1, except that the bicyclo[1.1.0]butane added to the reaction system was 2h (68.67 mg, 0.26 mmol). The reaction was stopped and the target product 1h (46.6 mg, yield 71%, 99% ee) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0055] Example 9

[0056]

[0057] The reaction steps and operations were the same as those in Example 1, except that the bicyclo[1.1.0]butane added to the reaction system was 2i (65.5 mg, 0.26 mmol). The reaction was stopped and the target product 1 (65.9 mg, 83% yield, 94% ee) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0058] Example 10

[0059]

[0060] The reaction steps and operations were the same as those in Example 1, except that N-allyl carbonate 3b (55.4 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped and the target product 1j (64.5 mg, 82% yield, 94% ee) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0061] Embodiment 11

[0062]

[0063] The reaction steps and operations were the same as those in Example 1, except that N-allyl carbonate 3c (59.4 mg, 0.20 mmol) was added to the reaction system. The reaction was stopped and the target product 1k (56.2 mg, 68% yield, 94% ee) was obtained by post-treatment as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0064] Example 12

[0065]

[0066] The reaction steps and operations were the same as those in Example 1, except that N-(2-bromoethyl)aniline 3d (39.8 mg, 0.20 mmol) was added to the reaction system, and [Ir]-A was not added. The reaction was stopped, and the target product 11 (50.2 mg, yield 71%) was obtained as a white solid after post-treatment. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0067] The present invention uses bicyclo[1.1.0]butane as a raw material, and reacts with N-allyl carbonate under the catalysis of Lewis acid and chiral iridium complex to undergo cycloaddition reaction, thereby synthesizing a series of chiral 2-azabicyclo[3.1.1]heptane derivatives with diverse structures with excellent chemical selectivity, and the products can be further derivatized, for example, reacting with benzaldehyde oxime chloride to generate chiral 2-azabicyclo[3.1.1]heptane derivatives 4a and 4b.

[0068]

[0069] The specific process is as follows: a dry Schlenk tube was loaded with chiral 2-azabicyclo[3.1.1]heptane derivative 1a (75.9 mg, 0.20 mmol) and then purged with nitrogen. CH 2 Cl 2 (1.0 mL). A second dry Schlenk tube was charged with benzaldehyde oxime chloride (155.6 mg, 1.00 mmol, 5.0 equiv.) and CH 2 Cl 2 (2.0 mL) and purged with nitrogen. Add triethylamine (139.0 μL, 1.00 mmol, 5.0 equiv.) to the second tube and stir at room temperature for 15 minutes. Then transfer the chlorinated oxime solution to the test tube containing 1a using a syringe. The mixture is stirred at room temperature for 12 hours. After the reaction is completed, the reaction solution is quenched with water and quenched with CH 2 Cl 2 Extract 3 times. Combine the organic phases, wash with brine, and 2 SO 4 The crude product was purified by silica gel column chromatography (petroleum ether (60-90°C) / acetone = 20:1) to obtain white solid product 4a (2.8 mg, yield 23%, 93% ee) and white solid product 4b (77.0 mg, yield 57%, 93% ee). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0070] The product can be introduced into drug molecules as a bioisostere of nitrogen heteroaromatic rings, for example, in the synthesis of a Rupatadine homologue 6.

[0071]

[0072] The specific process is as follows: 1a (379.5 mg, 1.0 mmol) was added to a dry Schlenk tube and purged with nitrogen. Anhydrous MeOH (10.0 mL) was added to the reaction tube using a syringe. The mixture was stirred at 0°C (ice-water bath) for 5.0 minutes. Then, NaBH 4 (45.3 mg, 1.2 mmol). The resulting solution was continued to react at 0°C and stirred for 30 minutes. After the reaction was completed, the reaction mixture was quenched with water and then quenched with CH 2 Cl 2 Extract 3 times. The combined organic phases were washed with brine, Na 2 SO 4 Dry and concentrate under reduced pressure. 3(262.3 mg, 1.0 mmol) was placed in a dry Schlenk tube and purged with nitrogen. 10.0 mL of anhydrous CH 2 Cl 2 The temperature was lowered to 0°C (ice-water bath), and NBS (178.0 mg, 1.0 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted three times with DCM. The combined organic phases were washed with brine and purified by Na 2 SO 4 The mixture was dried and concentrated under reduced pressure. The crude mixture 5 was obtained by flash column chromatography (petroleum ether / ethyl acetate = 50:1). The crude product was directly loaded into a flame-dried Schlenk tube and purged with nitrogen. Anhydrous DMF (10.0 mL) was added to the reaction tube via a syringe. Desloratadine (310.8 mg, 1.0 mmol) and K 2 CO 3 (138.2 mg, 1.0 mmol), heated to 50 ° C, stirred for 8 hours, quenched with water after the reaction, extracted with ethyl acetate three times, combined the organic phases, washed with brine, Na 2 SO 4 The residue was dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol / formic acid = 95:5:1) to give the corresponding compound 6 as a white solid. The total yield was 29% (197.0 mg).

[0073] Further studies have shown that compound 6 exhibits better water solubility than Rupatadine (6: 198 μM vs Rupatadine: 29 μM), and reduced lipophilicity (6: logD = 3.8 vs Rupatadine: logD: > 4.5). We also compared the metabolic stability of compound 6 with that of Rupatadine. Based on its metabolic stability in human liver microsomes, its half-life is significantly prolonged compared with Rupatadine (6: t1 / 2 (min) = 31.6 vs Rupatadine: t1 / 2 (min) = 3.2). This fully demonstrates the application prospects of this skeleton in drug development.

[0074] Characterization data of typical compounds

[0075] (S)-2-Azabicyclo[3.1.1]heptane derivative (1a), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.95–7.82(m,2H),7.58–7.49(m,1H),7.46–7.40(m,2H),7.38–7.33(m,2H),7.27–7.21(m,2H),7. 19–7.12(m,1H),7.11–7.02(m,2H),6.76–6.58(m,3H),5.63(ddd,J=17.0,10.2,9.0Hz,1H),4.85(dd, J=10.3,1.6Hz,1H),4.72(dd,J=16.9,1.8Hz,1H),4.15–3.96(m,2H),3.41(q,J=8.3Hz,1H),3.16(d,J =9.6Hz,1H),3.03(dd,J=11.0,8.1Hz,1H),2.84(dd,J=9.6,8.1Hz,1H),2.48(dd,J=11.1,1.2Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ201.8,149.1,144.0,136.0,135.4,133.0,129.0(2C),128.6(2C),128.6(2C),128.4(2C),126.7, 125.3(2C),119.6(2C),118.7,117.7,63.1,53.2,51.9,48.3,42.6,39.6; HRMS(ESI-TOF,m / z):calcd for C 27 H 25 NONa[M+Na] + :402.1829, found:402.1823; HPLC (Chiralpak OD-H, n-hexane / ethanol=98 / 2, 1.0mL / min, 254nm)t R =8.789min(major),13.137min(minor);[α] D 25 =-171.0(c 0.05,CH 2 Cl 2 ,94%ee).

[0076] (S)-2-Azabicyclo[3.1.1]heptane derivative (1b), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.96–7.79(m,2H),7.58–7.48(m,1H),7.42(t,J=7.6Hz,2H),7.16(t,J=7.9Hz,1H),7.07(dd,J=8. 5,7.1Hz,2H),6.99–6.87(m,2H),6.76–6.60(m,4H),5.62(ddd,J=16.8,10.2,9.0Hz,1H),4.84(dd,J= 10.3,1.6Hz,1H),4.77–4.62(m,1H),4.20–3.95(m,2H),3.71(d,J=1.1Hz,3H),3.46–3.32(m,1H),3.1 2(d,J=9.6Hz,1H),3.01(dd,J=11.0,8.0Hz,1H),2.82(dd,J=9.6,8.0Hz,1H),2.47(d,J=11.0Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ201.8,160.0,149.1,145.9,136.0,135.5,133.0,129.7,128.9(2C),128.6(2C),128.4(2C),119.4(2C ),118.7,117.7(2C),111.9,111.3,63.1,55.3,53.2,51.9,48.3,42.7,39.5; HRMS(ESI-TOF,m / z):calcd for C 27 H 25 NO 2 Na[M+Na]+:432.1934, found:432.1934; HPLC (ChiralpakOD-H, n-hexane / ethanol=90 / 10, 1.0mL / min, 254nm)t R =6.472min(major),9.121min(minor);[α]D 25 =-156.0(c 0.05,CH 2 Cl 2 ,93%ee).

[0077] (S)-2-Azabicyclo[3.1.1]heptane derivative (1c), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.94–7.82(m,2H),7.59–7.49(m,1H),7.47–7.38(m,2H),7.25–7.02(m,5H),6.89–6.79(m,1H ),6.77–6.69(m,1H),6.68–6.62(m,2H),5.62(ddd,J=17.0,10.3,9.0Hz,1H),4.85(dd,J=10.3, 1.6Hz,1H),4.72(dd,J=17.0,1.5Hz,1H),4.13–3.93(m,2H),3.45–3.35(m,1H),3.11(d,J=9.7H z,1H),3.01(dd,J=11.0,8.1Hz,1H),2.84(dd,J=9.6,8.0Hz,1H),2.46(dd,J=11.1,1.2Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ201.6,163.3(d,J=245.6Hz),148.8,146.9(d,J=6.9Hz),135.9,135.2,133.1,130.2(d,J=8.3Hz),128.9(2C),128.7(2C),128.5(2C), 120.8(d,J=2.7Hz),119.5(2C),118.9,117.9,113.7(d,J=21.2Hz),112.5(d,J=22.3Hz),62.8(d,J=1.9Hz),53.2,51.8,48.2,42.6,39.6; 19 F NMR (376 MHz, CDCl 3 )δ-112.76; HRMS(ESI-TOF,m / z):calcd for C 27 H 24 FNONa[M+Na] + :420.1735, found:420.1746; HPLC (Chiralpak OD-H, n-hexane / ethanol=85 / 15, 1.0mL / min, 254nm)t R =4.687min(major),6.507min(minor);[α] D 25 = +88.0 (c 0.05, CH 2 Cl 2 ,96%ee).

[0078] (S)-2-Azabicyclo[3.1.1]heptane derivative (1d), white solid.1 H NMR (400 MHz, CDCl 3 )δ7.88(dd,J=8.2,1.5Hz,2H),7.58–7.48(m,1H),7.47–7.36(m,2H),7.29(d,J=8.4Hz,2H),7.20(d,J =8.5Hz,2H),7.12–7.03(m,2H),6.77–6.68(m,1H),6.63(d,J=8.1Hz,2H),5.61(ddd,J=16.8,10.2,9.0 Hz,1H),4.85(dd,J=10.3,1.5Hz,1H),4.72(d,J=17.0Hz,1H),4.11–3.94(m,2H),3.45–3.35(m,1H),3. 10(d,J=9.6Hz,1H),3.01(dd,J=11.0,8.0Hz,1H),2.84(dd,J=9.6,8.1Hz,1H),2.45(d,J=11.0Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ201.6,148.9,142.6,135.9,135.3,133.1,132.4,128.9(2C),128.8(2C),128.7(2C),128.5(2C), 126.8(2C),119.7(2C),119.0,117.8,62.7,53.3,51.9,48.2,42.6,39.6; HRMS(ESI-TOF,m / z):calcd for C 27 H 24 ClNONa[M+Na] + :436.1439, found:436.1442; HPLC (Chiralpak OD-H, n-hexane / ethanol=90 / 10, 1.0mL / min, 254nm)t R =5.391min(major),9.812min(minor);[α] D 25 =-108.0(c 0.05,CH 2 Cl 2 ,94%ee).

[0079] (S)-2-Azabicyclo[3.1.1]heptane derivative (1e), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.92–7.83(m,2H),7.57–7.49(m,1H),7.47–7.38(m,2H),7.35–7.28(m,2H),7.11–7.04(m,2H),6. 96–6.88(m,2H),6.75–6.67(m,1H),6.67–6.60(m,2H),5.62(ddd,J=17.0,10.3,9.0Hz,1H),4.85(dd ,J=10.3,1.6Hz,1H),4.72(dd,J=17.0,1.6Hz,1H),4.11–3.95(m,2H),3.45–3.35(m,1H),3.11(d,J= 9.6Hz,1H),3.01(dd,J=11.0,8.0Hz,1H),2.85(dd,J=9.6,8.1Hz,1H),2.45(dd,J=11.0,1.1Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ201.7,161.6(d,J=245.2Hz),149.0,139.8(d,J=3.3Hz),135.9,135.4,133.0,128.9(2C),128.7(2C),128.4(2C ),127.0(d,J=8.0Hz)(2C),119.8(2C),118.9,117.8,115.4(d,J=21.4Hz)(2C),62.7,53.3,51.9,48.2,42.8,39.6; 19 F NMR (376 MHz, CDCl 3 )δ-116.29; HRMS(ESI-TOF,m / z):calcd for C 27 H 24 FNONa[M+Na] + :420.1735, found:420.1731; HPLC (Chiralpak OD-H, n-hexane / ethanol=90 / 10, 1.0mL / min, 254nm)t R =5.299min(major),8.634min(minor);[α] D 25 = +94.0 (c 0.10, CH 2 Cl 2 ,95%ee).

[0080] (S)-2-Azabicyclo[3.1.1]heptane derivative (1f), white solid. 1H NMR (400 MHz, CDCl 3 )δ7.94–7.85(m,2H),7.59–7.39(m,7H),7.14–7.04(m,2H),6.78–6.69(m,1H),6.67–6 .57(m,2H),5.62(ddd,J=17.0,10.3,9.0Hz,1H),4.86(dd,J=10.3,1.5Hz,1H),4.73(d d,J=17.0,1.5Hz,1H),4.14–3.97(m,2H),3.48–3.37(m,1H),3.17(d,J=9.7Hz,1H),3. 03(dd,J=11.0,8.1Hz,1H),2.87(dd,J=9.7,8.0Hz,1H),2.47(dd,J=11.1,1.2Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ201.4,148.7,148.0,135.8,135.1,133.1,128.9(d,J=32.5Hz)(2C),128.9,128.7(2C),128.6(2C),125.7(3)(q, J=3.7Hz)(2C),125.6(5)(2C),124.4(q,J=287.8Hz),119.5(2C),119.0,118.0,62.8,53.3,51.9,48.3,42.6,39.6; 19 F NMR (376 MHz, CDCl 3 )δ-62.37; HRMS(ESI-TOF,m / z):calcd for C 28 H 25 F 3 NO[M+H] + :448.1883, found:448.1901; HPLC (Chiralpak OD-H, n-hexane / ethanol=90 / 10, 1.0mL / min, 254nm)t R =4.983min(major),10.694min(minor);[α] D 25 =-152.0(c 0.05,CH 2 Cl 2 ,96%ee).

[0081] (S)-2-Azabicyclo[3.1.1]heptane derivative (1 g), white solid. 1 H NMR (600 MHz, CDCl3 )δ7.89–7.80(m,2H),7.55–7.46(m,1H),7.46–7.37(m,2H),7.32–7.24(m,2H),6.98(d,J =8.0Hz,2H),6.91(t,J=7.3Hz,1H),5.61–5.52(m,1H),4.79(dd,J=10.3,1.6Hz,1H),4.6 5(d,J=17.4Hz,1H),3.80(dd,J=13.7,9.0Hz,1H),3.72(dd,J=13.7,7.1Hz,1H),3.35–3. 24(m,1H),2.88–2.74(m,2H),2.36(d,J=9.0Hz,1H),2.26(d,J=10.2Hz,1H),1.44(s,3H); 13 C NMR (150 MHz, CDCl 3 )δ202.1,149.9,136.2,135.7,132.8,128.9(2C),128.7(2C),128.5(2C),121.4(2C) ,120.2,117.4,57.9,54.7,52.5,48.0,45.4,37.3,25.2; HRMS(ESI-TOF,m / z):calcd for C 22 H 23 NONa[M+Na] + :340.1672, found:340.1672; HPLC (Chiralpak IC, n-hexane / ethanol=90 / 10, 1.0mL / min, 254nm)t R =5.624min(minor),6.243min(major); [α] D 25 = +121.0 (c 0.10, CH 2 Cl 2 ,84%ee).

[0082] (S)-2-Azabicyclo[3.1.1]heptane derivative (1h), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.94–7.84(m,2H),7.40–7.28(m,2H),7.27–7.20(m,2H),7.18–7.12(m,1H),7.10–7.01(m,2H), 6.99–6.85(m,2H),6.76–6.56(m,3H),5.64(ddd,J=17.0,10.2,8.9Hz,1H),4.85(dd,J=10.3,1.6Hz ,1H),4.75(dd,J=17.1,1.6Hz,1H),4.12–3.96(m,2H),3.86(s,3H),3.44–3.32(m,1H),3.14(d,J=9 .6Hz,1H),3.02(dd,J=11.0,8.0Hz,1H),2.80(dd,J=9.6,8.0Hz,1H),2.45(dd,J=11.0,1.1Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ200.3,163.4,149.1,144.1,135.6,131.3(2C),128.8,128.6(2C),128.4(2C),126.7,125.3(2C),119 .5(2C),118.6,117.5,113.8(2C),63.1,55.6,53.2,51.7,48.5,42.6,39.8; HRMS(ESI-TOF,m / z):calcd for C 28 H 27 NO 2 Na[M+Na] + :432.1934, found:432.1954; HPLC (Chiralpak AD-H, n-hexane / ethanol=90 / 10, 1.0mL / min, 254nm)t R =9.815min(major),0.555min(minor);[α] D 25 = +107.0 (c 0.10, CH 2 Cl 2 ,99%ee).

[0083] (S)-2-Azabicyclo[3.1.1]heptane derivative (1i), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.97–7.89(m,2H),7.40–7.30(m,2H),7.30–7.21(m,2H),7.20–7.01(m,5H),6.76–6 .59(m,3H),5.61(ddd,J=17.0,10.2,9.1Hz,1H),4.85(dd,J=10.2,1.6Hz,1H),4.73(d d,J=17.0,1.5Hz,1H),4.12–3.96(m,2H),3.42–3.31(m,1H),3.16(d,J=9.6Hz,1H),3. 03(dd,J=11.1,8.1Hz,1H),2.80(dd,J=9.6,8.0Hz,1H),2.46(dd,J=11.1,1.2Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ200.2,165.6(d,J=254.9Hz),149.0,143.9,135.3,132.3(d,J=2.9Hz),131.6(d,J=9.2Hz)(2C),128.7(2C),128 .4(2C),126.8,125.2(2C),119.6(2C),118.7,117.8,115.8(d,J=21.8Hz)(2C),63.1,53.2,51.8,48.4,42.5,39.6; 19 F NMR (376 MHz, CDCl 3 )δ-105.07; HRMS(ESI-TOF,m / z):calcd for C 27 H 24 FNONa[M+Na] + :420.1735, found:420.1746; HPLC (Chiralpak AD-H, n-hexane / ethanol=98 / 2, 1.0mL / min, 254nm)t R =12.017min(major),13.609min(minor);[α] D 25 =-90.0(c 0.05,CH 2 Cl 2 ,94%ee).

[0084] (S)-2-Azabicyclo[3.1.1]heptane derivative (1j), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.92–7.85(m,2H),7.56–7.48(m,1H),7.45–7.38(m,2H),7.38–7.30(m,2H),7.30–7.20(m,2H),7.19 –7.11(m,1H),6.95–6.81(m,2H),6.63–6.48(m,2H),5.62(ddd,J=17.0,10.3,9.0Hz,1H),4.83(dd,J=10 .2,1.6Hz,1H),4.71(dd,J=17.1,1.5Hz,1H),4.08–3.91(m,2H),3.45–3.35(m,1H),3.12(d,J=9.6Hz,1H ),3.02(dd,J=11.0,8.0Hz,1H),2.83(dd,J=9.6,8.0Hz,1H),2.46(dd,J=11.0,1.2Hz,1H),2.18(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ201.9,146.8,144.2,136.0,135.6,132.9,128.9(9)(2C),128.9(5)(2C),128.6(0)(2C),128.5(9)(2C),128 .0,126.7,125.4(2C),119.8(2C),117.6,63.2,53.4,52.0,48.2,42.4,39.5,20.5; HRMS(ESI-TOF,m / z):calcd for C 28 H 28 NO[M+H] + :394.2166, found:394.2159; HPLC (Chiralpak OD-H, n-hexane / ethanol=90 / 10, 1.0mL / min, 254nm)t R =4.819min(major),6.304min(minor);[α] D 25 = +267.0 (c 0.10, CH 2 Cl 2 ,94%ee).

[0085] (S)-2-Azabicyclo[3.1.1]heptane derivative (1k), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.91–7.85(m,2H),7.58–7.50(m,1H),7.47–7.39(m,2H),7.36–7.29(m,2H),7.29–7.20(m,2H),7. 20–7.12(m,1H),7.03–6.96(m,2H),6.60–6.53(m,2H),5.63(ddd,J=17.0,10.3,8.9Hz,1H),4.86(dd ,J=10.3,1.5Hz,1H),4.74(dd,J=17.0,1.6Hz,1H),4.09–3.93(m,2H),3.44–3.34(m,1H),3.12(d,J= 9.7Hz,1H),2.99(dd,J=11.0,8.0Hz,1H),2.80(dd,J=9.7,8.1Hz,1H),2.50(dd,J=11.1,1.2Hz,1H); 13 C NMR (100 MHz, CDCl 3 )δ201.7,147.7,143.5,135.9,135.3,133.1,128.9(2C),128.8(2C),128.7(2C),128.3(2C),126.9, 125.2(2C),123.6,120.6(2C),117.9,63.2,53.2,51.9,48.2,42.6,39.3; HRMS(ESI-TOF,m / z):calcd for C 27 H 24 ClNONa[M+Na] + :436.1439, found:436.1432; HPLC (Chiralpak OD-H, n-hexane / ethanol=95 / 5, 1.0mL / min, 254nm)t R =6.624min(major),10.682min(minor);[α] D 25 =-109.0(c 0.05,CH 2 Cl 2 ,99%ee).

[0086] 2-Azabicyclo[3.1.1]heptane derivative (11), white solid. 1 H NMR (400 MHz, CDCl 3)δ7.96–7.85(m,2H),7.59–7.51(m,1H),7.49–7.41(m,2H),7.41–7.34(m,2H),7.29–7.19(m,2H),7.20–7.10(m,1H ),7.05(dd,J=8.5,7.1Hz,2H),6.84–6.59(m,3H),4.20(t,J=6.5Hz,2H),2.99–2.76(m,4H),2.34(t,J=6.5Hz,2H); 13 C NMR (100 MHz, CDCl 3 )δ203.0,149.4,144.3,135.1,133.1,129.1(2C),128.7(2C),128.6(2C),128.3(2C),126.7, 125.4(2C),119.9(2C),118.7,63.4,48.4,47.2,42.1(2C),34.2; HRMS(ESI-TOF,m / z):calcd for C 25 H 23 NONa[M+Na] + :376.1672,found:376.1670.

[0087] (S,S)-2-Azabicyclo[3.1.1]heptane derivative (4a), white solid. 1 H NMR of (400MHz, CDCl 3 )δ7.97–7.90(m,2H),7.59–7.50(m,3H),7.49–7.41(m,2H),7.40–7.31(m,5H), 7.28–7.19(m,2H),7.18–7.10(m,1H),7.08–7.00(m,2H),6.73–6.63(m,3H),4. 69–4.58(m,1H),4.26(dd,J=13.9,6.9Hz,1H),3.97(dd,J=13.9,7.4Hz,1H),3. 43–3.34(m,1H),3.32–3.06(m,2H),3.02–2.89(m,3H),2.70(d,J=10.3Hz,1H); 13 C NMR (100 MHz, CDCl 3)δ202.4,156.7,149.1,143.6,135.8,133.0,130.3,129.4,128.9(2C),128.8(2C),128.8(2C),128.7(2C),128.5(2C),126.8 (3),126.7(7)(2C),125.3(2C),119.6(2C),119.0,80.7,63.2,50.7,48.7,46.7,44.5,38.9,36.8; HRMS(ESI-TOF,m / z):calcd for C 34 H 30 N 2 O 2 Na[M+Na] + :521.2200, found:521.2187; HPLC (Chiralpak IC, n-hexane / ethanol=80 / 20, 1.0mL / min, 254nm)t R =18.229min(major),26.112min(minor);[α] D 25 =-69(c 0.10,CH 2 Cl 2 ,93%ee).

[0088] (S,R)-2-Azabicyclo[3.1.1]heptane derivative (4b), white solid. 1 H NMR (400 MHz, CDCl 3 )δ8.06–7.96(m,2H),7.63–7.54(m,1H),7.53–7.42(m,4H),7.42–7.29(m,5H) ,7.26–7.18(m,2H),7.18–7.11(m,1H),7.09–7.00(m,2H),6.73–6.63(m,3H),4 .75–4.63(m,1H),4.42–4.22(m,2H),3.25–3.14(m,2H),3.14–3.00(m,2H),2.8 8(dd,J=9.8,8.1Hz,1H),2.70(dd,J=16.7,9.9Hz,1H),2.57(d,J=11.1Hz,1H); 13 C NMR (100 MHz, CDCl 3)δ203.3,157.0,149.1,143.8,135.7,133.6,130.3,129.3,129.1(2C),129.0(2C),128.8(2C),128.7(2C),128.4(2C),12 6.8,126.7(2C),125.3(2C),119.7(2C),118.9,81.3,63.1,50.9,49.4,48.3,43.8,40.4,39.1; HRMS(ESI-TOF,m / z):calcd for C 34 H 30 N 2 O 2 Na[M+Na] + :521.2200, found:521.2187; HPLC (Chiralpak IC, n-hexane / ethanol=80 / 20, 1.0mL / min, 254nm)t R =10.579min(major),12.743min(minor);[α] D 25 = +133 (c 0.10, CH 2 Cl 2 ,93%ee).

[0089] Rupatadine homologue (6), white solid. 1 H NMR (400 MHz, CDCl 3)δ8.53(dd,J=4.4,2.2Hz,1H),7.78(dd,J=7.9,2.2Hz,1H),7.37–7.34(m,1H),7.32–7.22(m,13H),7.18(d,J=8.9Hz,1H),7.15–7.11(m,1H),6.93–6.88(m,1H),6.80(dd,J=6.5,1.4Hz,2H),5.80–5.71(m,1H),5.10–5.04(m,1H),5.03–4.96(m,1H),4.06(dd,J=12.4,1.7Hz,1H),3.64(dd,J=12.4,4.5Hz,1H),3.61–3.57(m,1H),3.38–3.14(m,2H),2.97–2.79(m,2H),2.71(dd,J=5.1,2.4Hz,2H),2.65(dd,J=5.1,2.4Hz,2H),2.53(dd,J=5.2,2.4Hz,2H),2.48–2.43(m,1H),2.42–2.37(m,3H),2.35(d,J=12.4Hz,1H),2.21(d,J=12.3Hz,1H),2.09(d,J=12.4Hz,1H); 13 C NMR(100MHz,CDCl 3 )δ156.6,148.1,146.3,140.6,139.5,139.0,138.3,138.1,136.4,136.4,134.4,134.3,134.0,129.4(2C),129.1,129.0(2C),128.8(2C),128.0(3),128.0(1)(2C),128.0,126.7,126.2,126.0(2C),123.3,118.8,117.8(2C),116.4,72.6,61.8,51.1,49.3,45.5,44.2,42.5,39.9,38.1,30.1,30.0,29.8,29.6;HRMS(ESI-TOF,m / z):calcd for C 46 H 44 ClN 3 Na[M+Na] + :696.3116,found:696.3111。

Claims

1. A chiral 2-azabicyclo[3.1.1]heptane derivative, whose molecular structure 1 is as follows: R 1 is hydrogen; a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocycle having 1 to 4 nitrogen, oxygen or sulfur atoms; the group can be further substituted, and the substituents are selected from hydroxyl, amino, halogen, nitro (-NO2), cyano (-CN) or a C1-C4 alkyl group; R 2 is a C1-C10 straight or branched alkyl group; a substituted or unsubstituted aryl group; a heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms; R 3 is a C1-C10 straight chain or branched alkyl group; a substituted or unsubstituted aryl group; an acyl group or a sulfonyl group.

2. A method for synthesizing the chiral 2-azabicyclo[3.1.1]heptane derivative according to claim 1, characterized in that: Using bicyclo[1.1.0]butane 2 as a raw material, N-allyl carbonate 3 as a ternary synthon, Lewis acid and chiral iridium complex as catalysts, adding solvent and base, and undergoing a cycloaddition reaction at 0°C to room temperature to generate the chiral 2-azabicyclo[3.1.1]heptane compound 1; The molecular structure of bicyclo[1.1.0]butane 2 is as follows, The molecular structure of N-allyl carbonate 3 is as follows, The synthetic route is shown in the following reaction formula:

3. The synthesis method according to claim 2, characterized in that: The Lewis acid catalyst is one of Ga(OTf)3, Yb(OTf)3, In(OTf)3 and Sc(OTf)3, the iridium complex catalyst is one of [Ir]-A, [Ir]-B and [Ir]-C, the base is one of LiHMDS, NaHMDS, KHMDS and KOtBu, and the molar ratio of bicyclo[1.1.0]butane 2 to N-allyl carbonate 3 is 5:1-1:5; The molar ratio of N-allyl carbonate 3 to the catalyst is 1:0.01-1:0.5; the molar ratio of N-allyl carbonate 3 to the base is 5:1-1:

5.

4. The synthesis method according to claim 3, characterized in that: The solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylformamide or tetrahydrofuran; the reaction temperature is 0-25° C.; and the reaction time is 4-8 hours.

5. The synthesis method according to claim 3, characterized in that: The catalyst is In(OTf)3 and [Ir]-A, and the molar ratios of N-allyl carbonate 3 to In(OTf)3 and [Ir]-A are 1:0.02 and 1:0.04 respectively.

6. The synthesis method according to claim 3, characterized in that: The base is NaHMDS, and the molar ratio of N-allyl carbonate 3 to NaHMDS is 1:1.

5.

7. The synthesis method according to claim 4, characterized in that: The solvent is tetrahydrofuran.

8. The synthesis method according to claim 4, characterized in that: The reaction time is 8 hours.

9. The synthesis method according to claim 4, characterized in that: The reaction temperature is 0-25°C, wherein the base is added at 0°C and the temperature is raised to 25°C for reaction.

10. The synthesis method according to claim 3, characterized in that: The molar ratio of the bicyclo[1.1.0]butane 2 to N-allyl carbonate 3 is 1.3:1.

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