CN119431242A

CN119431242A - A chiral 2-azabicyclo[3.1.1]heptane derivative and a synthesis method thereof

Info

Publication number: CN119431242A
Application number: CN202411580023.4A
Authority: CN
Inventors: 邓卫平; 张键; 苏嘉懿
Original assignee: Zhejiang Normal University CJNU
Current assignee: Zhejiang Normal University CJNU
Priority date: 2024-11-07
Filing date: 2024-11-07
Publication date: 2025-02-14

Abstract

本发明公开了一种手性2‑氮杂二环[3.1.1]庚烷衍生物及其合成方法。以双环[1.1.0]丁烷为原料，在路易斯酸和手性铱络合物的催化下，与N‑烯丙基碳酸酯发生环加成反应，以优异的化学选择性合成了一系列结构多样的手性2‑氮杂二环[3.1.1]庚烷化合物，产物能够进一步衍生化。该方法原料易得、操作简便、反应条件温和，其官能团具有多样性。The invention discloses a chiral 2-azabicyclo[3.1.1]heptane derivative and a synthesis method thereof. Bicyclo[1.1.0]butane is used as a raw material, and a cycloaddition reaction is carried out with N-allyl carbonate under the catalysis of Lewis acid and chiral iridium complex, and a series of chiral 2-azabicyclo[3.1.1]heptane compounds with diverse structures are synthesized with excellent chemical selectivity, and the products can be further derivatized. The method has easy raw materials, simple operation, mild reaction conditions, and its functional groups are diverse.

Description

Chiral 2-aza-bicyclo [3.1.1] heptane derivative and synthesis method thereof

Technical Field

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

Background

In recent years, strategies using three-dimensional bicyclic frameworks as bioisosteres to replace aromatic rings have become a hotspot in the field of pharmaceutical research (Nat. Rev. Chem.2024,8, 605-627). While azabicyclo [3.1.1] heptane is an important bioisostere of ortho-or meta-substituted azaaromatic ring, and is expected to improve physicochemical property and pharmacokinetic property of quasi-drug molecules when being applied to drug development. In particular, since the discovery by pharmaceutical chemists that substitution of 3-azabicyclo [3.1.1] heptane for the pyridine group in Rupatadine greatly increases the water solubility of the drug, decreases the lipophilicity, and significantly increases the metabolic stability in human liver microsomes (angel. Chem. Int. Ed.2023,62, e 202304546.), this study has gained increased attention from pharmaceutical chemists and organic synthetic chemists. For example, the Studier group applies chiral 2-azabicyclo [3.1.1] heptane to a novel modification of the active molecules with antiproliferative activity on HT-29, heLa and 16MCF-7 (J.Am. Chem. Soc.2024,146, 272045-27212) and the Li Xiaoxun group also follows this approach to obtain derivatives of local anesthetic Bupivacaine containing 3-azabicyclo [3.1.1] heptane backbone (J.Am. Chem. Soc.2024,146, 21069-21077). These practices provide a novel research concept for drug development. Therefore, the construction of a novel azabicyclo [3.1.1] heptane skeleton is of great research importance.

Although 3-azabicyclo [3.1.1] heptanes have been developed to date, how to obtain 2-azabicyclo [3.1.1] heptanes, especially chiral 2-azabicyclo [3.1.1] heptanes, remains a significant challenge. At present, there is only one example of synthesis route report for chiral 2-azabicyclo [3.1.1] heptane from chiral substrates (J.Am.chem.Soc.2024, 146, 27204-27212). This limits the structural diversity of the azaaromatic bioisostere. Thus, the development of a catalytic asymmetric process to build chiral 2-azabicyclo [3.1.1] heptanes is an important scientific problem that needs to be resolved urgently. The obtained chiral 2-azabicyclo [3.1.1] heptane can be used as biological equivalent of an azaaromatic ring for modification of medicines, active molecules and natural products, and provides a new chemical entity for medicine research and development. In particular, the planar symmetrical aza-aromatic ring is replaced by a chiral three-dimensional double-ring skeleton, and the introduction of chiral elements brings new opportunities for drug development.

Disclosure of Invention

The invention aims at constructing chiral 2-aza-bicyclo [3.1.1] heptane compound 1 by cycloaddition reaction of bicyclo [1.1.0] butane 2 serving as a raw material and N-allyl carbonate 3. The invention takes bicyclo [1.1.0] butane as raw material, and under the catalysis of Lewis acid and chiral iridium complex, the bicyclo [1.1.0] butane and N-allyl carbonate undergo cycloaddition reaction, a series of chiral 2-aza bicyclo [3.1.1] heptane derivatives with various structures are synthesized with excellent chemical selectivity, and the products can be further derivatized.

In order to achieve the above object, the technical scheme of the present invention is as follows:

In one aspect, the invention provides a chiral 2-azabicyclo [3.1.1] heptane derivative, which has the following molecular structural formula 1:

R ¹ is hydrogen, C1-C10 linear or branched alkyl, substituted or unsubstituted aryl, heterocyclic ring having 1 to 4 nitrogen, oxygen or sulfur atoms, the groups being further substituted, the substituents being selected from hydroxy, amino, halogen, nitro (-NO ₂), cyano (-CN) or C1-C4 alkyl groups;

r ² is a C1-C10 linear 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 linear or branched alkyl group, a substituted or unsubstituted aryl group, an acyl group or a sulfonyl group.

In another aspect, the present invention provides a method for synthesizing the chiral 2-azabicyclo [3.1.1] heptane derivative, wherein lewis acid and chiral iridium complex are used as catalysts, a solvent and a base are added, and cycloaddition reaction of bicyclo [1.1.0] butane 2 and N-allyl carbonate 3 is performed at a temperature of 0 ℃ to room temperature, so as to generate chiral 2-azabicyclo [3.1.1] heptane derivative 1.

And after the reaction is finished, carrying out product separation and characterization according to a conventional separation and purification method to obtain a target product.

The substituents R ¹、R², R ³ of the N-allyl carbonate 3 of bicyclo [1.1.0] butane 2 are as defined above, R ¹ is hydrogen, C1-C10 linear or branched alkyl, substituted or unsubstituted aryl, heterocycle having from 1 to 4 nitrogen, oxygen or sulfur atoms, the radicals being able to be further substituted, the substituents being selected from the group consisting of hydroxy, amino, halogen, nitro (-NO ₂), cyano (-CN) or C1-C4 alkyl radicals;

Based on the above technical scheme, preferably, 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, and the alkali is one of LiHMDS, naHMDS, KHMDS and KOtBu, wherein the reaction uses In (OTf) ₃ and [ Ir ] -A as the catalyst, the NaHMDS is the best alkali effect, the molar ratio of N-allyl carbonate 3 to the catalyst is 1:0.01-1:0.5, preferably the molar ratio of N-allyl carbonate 3 to In (OTf) ₃ to [ Ir ] -A is 1:0.02 and 1:0.04, and the molar ratio of N-allyl carbonate 3 to NaHMDS is 1:1.5, respectively.

Based on the technical scheme, the solvent is preferably one or more than two of 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N-dimethylformamide or tetrahydrofuran, and the reaction effect is the best when the reaction solvent is tetrahydrofuran.

Based on the technical scheme, the preferable reaction temperature is 0-130 ℃, the reaction time is 4-24 hours, the optimal reaction time is 8 hours, and the optimal reaction temperature is 0-25 ℃, wherein alkali is added at 0 ℃ and the reaction is carried out until the temperature reaches 25 ℃.

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

The invention takes bicyclo [1.1.0] butane as raw material, and under the catalysis of Lewis acid and chiral iridium complex, the bicyclo [1.1.0] butane and N-allyl carbonate undergo cycloaddition reaction, a series of chiral 2-aza bicyclo [3.1.1] heptane derivatives with various structures are synthesized 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 method has the advantages of easily available raw materials, simple and convenient operation, and high-efficiency modularized synthesis of chiral 2-azabicyclo [3.1.1] heptane derivatives with potential bioactivity.

Advantageous effects

1) The synthon bicyclo [1.1.0] butane 2 is easy to prepare in large quantities and can be used for synthesizing chiral 2-aza-bicyclo [3.1.1] heptane derivatives 1 with different types and structures.

2) The synthon-allyl carbonate 3 is easy to prepare in large scale, and can conveniently construct a 2-aza-bicyclo [3.1.1] heptane skeleton with unique structure and biological activity.

3) The invention utilizes bicyclo [1.1.0] butane 2 to synthesize chiral 2-azabicyclo [3.1.1] heptane derivative 1 with various structures by excellent chemical selectivity, has easily obtained raw materials, simple and convenient operation and high target product yield, and can be further derivatized.

Detailed Description

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

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

The procedure was followed by sequentially adding bicyclo [1.1.0] butane 2a (60.9 mg,0.26 mmol) and N-allyl carbonate 3a (52.6 mg,0.20 mmol) to a Schlenk tube equipped with a magnetic stirrer under nitrogen atmosphere, evacuating the tube and backfilling five times with nitrogen. Then, anhydrous THF (2.0 mL) was added sequentially via syringe. In (OTf) ₃ (0.004 mmol) was then added and stirred at 25 ℃ until the N-allyl carbonate was consumed. Then [ Ir ] -A (0.008 mmol) was added and the mixture was cooled to 0 ℃. Subsequently, naHMDS (0.30 mmol,1.5 equiv.) was added dropwise. The reaction mixture was warmed to 25 ℃ and stirring was continued for 4h. After completion of the reaction, the mixture was quenched with water, extracted three times with ethyl acetate, the resulting filtrate was separated, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent petroleum ether (60-90 ℃ C.)/ethyl acetate: 20:1, v/v) to give the objective product 1. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

The present invention will be further understood by the following examples, but the content of the present invention is not limited thereto.

Example 1

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

Example 2

The procedure was as in example 1, except that bicyclo [1.1.0] butane was 2b (68.7 mg,0.26 mmol) as added to the reaction system. The reaction was stopped, and the desired product 1b (63.8 mg, yield 78%,93% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 3

The procedure and operation were as in example 1, except that bicyclo [1.1.0] butane was 2c (65.5 mg,0.26 mmol) as fed to the reaction system. The reaction was stopped, and the desired product 1c (58.0 mg, yield 73%,96% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 4

The procedure and the operation were the same as in example 1 except that 2d (57.7 mg,0.26 mmol) of bicyclo [1.1.0] butane was added to the reaction system. The reaction was stopped, and the desired product 1d (66.9 mg, yield 81%,94% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 5

The procedure and operation were as in example 1, except that bicyclo [1.1.0] butane was 2e (65.5 mg,0.26 mmol) as fed to the reaction system. The reaction was stopped, and the desired product 1e (61.2 mg, yield 77%,95% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 6

The procedure and operation were as in example 1, except that bicyclo [1.1.0] butane was 2f (78.5 mg,0.26 mmol) as fed to the reaction system. The reaction was stopped, and the desired product 1f (67.1 mg, yield 75%,96% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 7

The procedure was as in example 1, except that 2g (44.7 mg,0.26 mmol) of bicyclo [1.1.0] butane was added to the reaction system. The reaction was stopped, and the desired product (1 g, 36.2mg, yield 57%,84% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 8

The procedure was as in example 1, except that bicyclo [1.1.0] butane was added to the reaction system for 2 hours (68.67 mg,0.26 mmol). The reaction was stopped, and the desired product was obtained as a white solid by working up for 1h (46.6 mg, yield 71%,99% ee). The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 9

The procedure and operation were as in example 1, except that bicyclo [1.1.0] butane was 2i (65.5 mg,0.26 mmol) as fed to the reaction system. The reaction was stopped, and the desired product 1 (65.9 mg, yield 83%,94% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 10

The procedure and the operation were the same as 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 desired product 1j (64.5 mg, yield 82%,94% ee) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 11

The procedure and the operation were the same as 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 desired product 1k (56.2 mg, yield 68%,94% ee) was obtained as a white solid by work-up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

Example 12

The procedure was as 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 desired product 1l (50.2 mg, yield 71%) was obtained as a white solid by working up. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

The invention takes bicyclo [1.1.0] butane as raw material, and under the catalysis of Lewis acid and chiral iridium complex, the bicyclo [1.1.0] butane and N-allyl carbonate undergo cycloaddition reaction, a series of chiral 2-aza bicyclo [3.1.1] heptane derivatives with various structures are synthesized with excellent chemical selectivity, and the products can be further derivatized. For example with benzaldoxime chloride to chiral 2-azabicyclo [3.1.1] heptane derivatives 4a and 4b.

The procedure was followed by charging chiral 2-azabicyclo [3.1.1] heptane derivative 1a (75.9 mg,0.20 mmol) in a dry Schlenk tube followed by a nitrogen purge. CH ₂Cl₂ (1.0 mL) was added to the reaction tube via syringe. A second dry Schlenk tube was purged with benzaldehyde oxime chloride (155.6 mg,1.00mmol,5.0 equiv.) and CH ₂Cl₂ (2.0 mL) with nitrogen. Triethylamine (139.0. Mu.L, 1.00mmol,5.0 equiv.) was added to the second tube and stirred at room temperature for 15 minutes. The oxime chloride solution was then transferred to a test tube containing 1a using a syringe. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted 3 times with CH ₂Cl₂. The combined organic phases were washed with brine, dried over Na ₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether (60-90 ℃)/acetone=20:1) to give product 4a (2.8 mg, yield 23%,93% ee) as a white solid and product 4b (77.0 mg, yield 57%,93% ee) as a white solid. The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

The product can be introduced into the drug molecule as a bioisostere of the aza aromatic ring. For example for the synthesis of homolog 6 of Rupatadine.

The procedure was 1a (379.5 mg,1.0 mmol) in a dry Schlenk tube and purged with nitrogen. Anhydrous MeOH (10.0 mL) was added to the reaction tube with a syringe. The mixture was stirred at 0 ℃ for 5.0 minutes (ice water bath). Then NaBH ₄ (45.3 mg,1.2 mmol) was added slowly. The resulting solution was further reacted at 0 ℃ with stirring for 30 minutes. After the reaction was completed, the reaction mixture was quenched with water and extracted 3 times with CH ₂Cl₂. The combined organic phases were washed with brine, dried over Na ₂SO₄ and concentrated under reduced pressure. The crude product was charged with PPh ₃ (262.3 mg,1.0 mmol) to a dry Schlenk tube and purged with nitrogen. 10.0mL of anhydrous CH ₂Cl₂ was added to the reaction tube via syringe. Cooled to 0℃in an ice-water bath, 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, dried over Na ₂SO₄ and concentrated under reduced pressure. Crude mixture 5 was obtained by flash column chromatography (petroleum ether/ethyl acetate=50:1). The crude product was directly charged to a flame-dried Schlenk tube and purged with nitrogen. Anhydrous DMF (10.0 mL) is added to the reaction tube via syringe. Desloratadine (310.8 mg,1.0 mmol) and K ₂CO₃ (138.2 mg,1.0 mmol) were then added sequentially, heated to 50℃and stirred for 8 hours, quenched with water after the reaction was completed, extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried over Na ₂SO₄, concentrated under reduced pressure, and the crude product purified by silica gel column chromatography (dichloromethane/methanol/formic acid=95:5:1) to give the corresponding compound 6 as a white solid in 29% overall yield (197.0 mg).

Further studies showed that compound 6 exhibited better water solubility than Rupatadine (6:198 μ M vs Rupatadine:29 μM), reduced lipophilicity (6:log d= 3.8vs Rupatadine:logD: > 4.5), and we also compared the metabolic stability of compound 6 to Rupatadine. Based on its metabolic stability in human liver microsomes, its half-life comparison Rupatadine is significantly prolonged (6:t1/2 (min) = 31.6vs Rupatadine:t1/2 (min) =3.2). The application prospect of the skeleton in drug development is fully shown.

Typical compound characterization data

(S) -2-azabicyclo [3.1.1] heptane derivative (1 a), white solid .¹H NMR(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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 C₂₇H₂₅NONa[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,CH₂Cl₂,94％ee).

(S) -2-azabicyclo [3.1.1] heptane derivative (1 b), white solid .¹H NMR(400MHz,CDCl₃)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),3.12(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);¹³C NMR(100MHz,CDCl₃)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 C₂₇H₂₅NO₂Na[M+Na]+:432.1934,found:432.1934;HPLC(Chiralpak OD-H,n-hexane/ethanol＝90/10,1.0mL/min,254nm)t_R＝6.472min(major),9.121min(minor);[α]D²⁵＝-156.0(c 0.05,CH₂Cl₂,93％ee).

(S) -2-azabicyclo [3.1.1] heptane derivative (1 c), white solid .¹H NMR(400MHz,CDCl₃)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＝9.7Hz,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);¹³C NMR(100MHz,CDCl₃)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;¹⁹F NMR(376MHz,CDCl₃)δ-112.76;HRMS(ESI-TOF,m/z):calcd for C₂₇H₂₄FNONa[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,CH₂Cl₂,96％ee).

(S) -2-azabicyclo [3.1.1] heptane derivative (1 d), white solid .¹H NMR(400MHz,CDCl₃)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＝16.8,10.2,9.0Hz,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);¹³C NMR(100MHz,CDCl₃)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 C₂₇H₂₄ClNONa[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,CH₂Cl₂,94％ee).

(S) -2-azabicyclo [3.1.1] heptane derivative (1 e), white solid .¹H NMR(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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;¹⁹F NMR(376MHz,CDCl₃)δ-116.29;HRMS(ESI-TOF,m/z):calcd for C₂₇H₂₄FNONa[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,CH₂Cl₂,95％ee).

(S) -2-azabicyclo [3.1.1] heptane derivative (1 f), white solid .¹H NMR(400MHz,CDCl₃)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(dd,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);¹³C NMR(100MHz,CDCl₃)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;¹⁹F NMR(376MHz,CDCl₃)δ-62.37;HRMS(ESI-TOF,m/z):calcd for C₂₈H₂₅F₃NO[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,CH₂Cl₂,96％ee).

(S) -2-azabicyclo [3.1.1] heptane derivatives (1 g), white solid .¹H NMR(600MHz,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),4.65(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);¹³C NMR(150MHz,CDCl₃)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 C₂₂H₂₃NONa[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,CH₂Cl₂,84％ee).

(S) -2-azabicyclo [3.1.1] heptane derivatives (1 h), white solid .¹H NMR(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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 C₂₈H₂₇NO₂Na[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,CH₂Cl₂,99％ee).

(S) -2-azabicyclo [3.1.1] heptane derivative (1 i), white solid .¹H NMR(400MHz,CDCl₃)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(dd,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);¹³C NMR(100MHz,CDCl₃)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;¹⁹F NMR(376MHz,CDCl₃)δ-105.07;HRMS(ESI-TOF,m/z):calcd for C₂₇H₂₄FNONa[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,CH₂Cl₂,94％ee).

(S) -2-azabicyclo [3.1.1] heptane derivative (1 j), white solid .¹H NMR(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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 C₂₈H₂₈NO[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,CH₂Cl₂,94％ee).

(S) -2-azabicyclo [3.1.1] heptane derivatives (1 k), white solid .¹H NMR(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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 C₂₇H₂₄ClNONa[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,CH₂Cl₂,99％ee).

2-Azabicyclo [3.1.1] heptane derivatives (1 l), white solid .¹H NMR(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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 C₂₅H₂₃NONa[M+Na]⁺:376.1672,found:376.1670.

(S, S) -2-azabicyclo [3.1.1] heptane derivative (4 a), white solid .¹H NMR of(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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 C₃₄H₃₀N₂O₂Na[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,CH₂Cl₂,93％ee).

(S, R) -2-azabicyclo [3.1.1] heptane derivative (4 b), white solid .¹H NMR(400MHz,CDCl₃)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),2.88(dd,J＝9.8,8.1Hz,1H),2.70(dd,J＝16.7,9.9Hz,1H),2.57(d,J＝11.1Hz,1H);¹³C NMR(100MHz,CDCl₃)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),126.8,126.7(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 C₃₄H₃₀N₂O₂Na[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,CH₂Cl₂,93％ee).

Rupatadine homolog (6), white solid .¹H NMR(400MHz,CDCl₃)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);¹³C NMR(100MHz,CDCl₃)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 C₄₆H₄₄ClN₃Na[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 (-NO ₂ ), cyano (-CN) or a C1-C4 alkyl group;

^R2 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 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: bicyclo[1.1.0]butane 2 is used as a raw material, N-allyl carbonate 3 is used as a ternary synthon, Lewis acid and a chiral iridium complex are used as catalysts, a solvent and a base are added, and a cycloaddition reaction occurs 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, the molar ratio of bicyclo[1.1.0]butane 2 and N-allyl carbonate 3 is 5:1-1:5; the molar ratio of N-allyl carbonate 3 and the catalyst is 1:0.01-1:0.5; and the molar ratio of N-allyl carbonate 3 and 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 is characterized in that: the catalyst is In(OTf) ₃ and [Ir]-A, and the molar ratio of N-allyl carbonate 3 to In(OTf) ₃ and [Ir]-A is 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.