2-azabicyclo [3.1. 1] heptene derivative as well as synthesis method and application thereof

Abstract

The invention discloses a 2-azabicyclo [3.1. 1] heptene derivative as well as a synthesis method and application of the 2-azabicyclo [3.1. 1] heptene derivative. The 2-azabicyclo [3.1. 1] heptene derivative provided by the invention is obtained by exciting a rhodium complex by visible light to catalyze bicyclo [1.1. 0] butane to perform cycloaddition reaction. The 2-azabicyclo [3.1. 1] heptene derivative constructed by the method can be applied to the aspects of simulating bioisosteres and the like, is expected to obtain more innovative achievements in the field of organic synthesis methodology, and also can provide a brand new thought and a structural basis for developing novel drug molecules; and the medicine with better curative effect and less side effect can be designed.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemistry, and in particular relates to a 2-azabicyclo[3.1.1]heptene derivative and a synthesis method and application thereof. Background Art

[0002] 2-Azabicyclo[3.1.1]heptene derivatives can act as bioisosteres of pyridine, sharing similar physical and chemical properties and exhibiting similar physiological activities. They are synthesized by cycloaddition of bicyclo[1.1.0]butane (BCB). BCB is the smallest cyclic compound with extremely high ring strain energy. Over 90% of its bridging bent σ bonds are composed of two p orbitals, resulting in p orbital-like properties. BCB exhibits high reactivity in a variety of chemical reactions, enabling reactions difficult for conventional compounds, providing new pathways and methods for organic synthesis.

[0003] 2-Azabicyclo[3.1.1]heptene derivatives are a class of promising bioisosteres that have attracted widespread attention in the field of organic synthesis due to their unique structure and biological activity. However, there are relatively few methods for constructing azabicyclo derivatives. Existing methods for synthesizing azabicyclo derivatives include: 1) Azabicyclo structures are obtained by reducing spirooxetane nitriles, but two catalysts must be used at the same time, the synthesis steps are cumbersome, and subsequent reactions require N-tert-butyloxycarbonyl protection. Please refer to the literature (Angewandte Chemie International Edition., 2023, 62, e202304246.); 2) Azabicyclo derivatives are prepared by silver-catalyzed BCB and isonitrile, but this method requires a large amount of silver catalyst, which may increase metal residues. Please refer to the literature (Angewandte Chemie International Edition., 2023, 62, e202304246.); 3). The strain-release cycloaddition reaction of BCB with vinyl azide catalyzed by pyridine-boryl radicals, however, requires a high catalyst dosage and is therefore limited in its substrate applicability. For reference, see (Chem. 2024, 10, 3699). 4). The cyclization reaction of BCB with vinyl azide via a single-electron reduction catalyzed by trivalent titanium, however, requires a high catalyst dosage and requires the addition of other reactants such as manganese and triethylamine hydrochloride to ensure the reaction occurs. For reference, see (Journal of the American Chemical Society, 2024, 146, 18565).

[0004] At present, the synthesis of 2-azabicyclo[3.1.1]heptene derivatives needs further research and optimization. Therefore, the efficient synthesis of 2-azabicyclo[3.1.1]heptene derivatives remains a huge challenge in organic synthetic chemistry. Summary of the Invention

[0005] In light of the shortcomings of the aforementioned prior art, the present invention aims to provide a 2-azabicyclo[3.1.1]heptene derivative, its synthesis method, and its application. The present invention's method for synthesizing 2-azabicyclo[3.1.1]heptene derivatives from the highly reactive bicyclo[1.1.0]butane provides a novel approach for the synthesis of bioisosteres of pyridine, potentially having applications in drug development, such as improving drug activity, optimizing pharmacokinetic properties, and reducing toxic side effects.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] One of the technical solutions of the present invention provides a 2-azabicyclo[3.1.1]heptene derivative, wherein the 2-azabicyclo[3.1.1]heptene derivative is selected from any one of compounds I, II, and III, and the structures of compounds I, II, and III are shown below:

[0008]

[0009] The second technical solution of the present invention provides a method for synthesizing the above-mentioned 2-azabicyclo[3.1.1]heptene derivative, comprising the following steps:

[0010] (1) adding a bicyclo[1.1.0]butane substrate, (1-azidovinyl)benzene, and a catalyst to a reaction vessel in sequence, and adding a solvent under an inert gas atmosphere to obtain a reaction mixture;

[0011] (2) The reaction mixture was stirred overnight at room temperature under LED light;

[0012] (3) After the reaction is completed, the solvent is removed by concentration under reduced pressure to obtain a crude product; the crude product is purified by column chromatography to obtain a 2-azabicyclo[3.1.1]heptene derivative.

[0013] The reaction formula is as follows:

[0014]

[0015] Wherein, R1 is any one of hydrogen, chlorine or methyl.

[0016] Furthermore, the bicyclo[1.1.0]butane substrate in step (1) is selected from compound IV, V or VI; the structural formulas of compound IV, V or VI are shown in formula IV, V and VI respectively; wherein the product corresponding to compound IV is compound I, the product corresponding to compound V is compound II, and the product corresponding to compound VI is compound III.

[0017]

[0018] Furthermore, the ratio of the amount of the bicyclo[1.1.0]butane substrate, (1-azidovinyl)benzene, catalyst and solvent used in step (1) is 1 mmol:(1-3.5) mmol:(0.02-0.1) mmol:(2-20) mL, preferably 1 mmol:3 mmol:0.02 mmol:10 mL.

[0019] Furthermore, the catalyst in step (1) is any one of RhS, Ga(OTf)3, Eu(OTf)3, and BF3·Et2O, preferably RhS; and the solvent is any one of acetonitrile, acetone, dichloromethane, and tetrahydrofuran, preferably acetonitrile.

[0020] Furthermore, the wavelength range of the LED light in step (2) is 420-500 nm, preferably 455 nm.

[0021] Furthermore, the eluent for the column chromatography in step (3) is a petroleum ether / ethyl acetate mixed solution, wherein the volume ratio of petroleum ether to ethyl acetate is (5-20):1, preferably 10:1.

[0022] The third technical solution of the present invention provides a use of the above-mentioned 2-azabicyclo[3.1.1]heptene derivative in the preparation of drugs, wherein the 2-azabicyclo[3.1.1]heptene derivative is used to prepare analogs of drug molecules such as antihypertensive drugs, antihistamines or leukotriene antagonists.

[0023] Compared with the prior art, this application has at least the following improvements and beneficial effects:

[0024] The present invention uses an octahedral rhodium complex as an efficient Lewis acid catalyst to catalyze the photocycloaddition reaction of acyl imidazole-substituted bicyclo[1.1.0]butane with vinyl azide, thereby obtaining a series of 2-azabicyclo[3.1.1]heptene derivatives. In this method, the rhodium complex coordinates to the bicyclo[1.1.0]butane substrate in a bidentate manner, significantly reducing the energy required for the substrate to reach a triplet excited state, and the reaction can occur at room temperature and under visible light excitation. Compared with the prior art using metal trifluoromethanesulfonate as a catalyst, the method of the present invention requires a significantly reduced amount of catalyst. In summary, the prior art has problems such as a large amount of catalyst, a limited scope of substrate application, and poor functional group tolerance; the present invention has the advantages of simple operation, mild conditions, a small amount of catalyst, a wide scope of substrate application, and strong functional group tolerance. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the structural formula of compound I, II, and III;

[0026] Figure 2 is the structural formula of compounds IV, V, and VI;

[0027] Figure 3 The NMR hydrogen spectrum of IV (CDCl3, 298K);

[0028] Figure 4 The NMR carbon spectrum of IV (CDCl3, 298K);

[0029] Figure 5 This is the I H NMR spectrum (CDCl3, 298K);

[0030] Figure 6 The NMR carbon spectrum of I (CDCl3, 298K);

[0031] Figure 7 The H NMR spectrum of V (CDCl3, 298K);

[0032] Figure 8 The NMR carbon spectrum of V (CDCl3, 298K);

[0033] Figure 9 This is the H NMR spectrum of II (CDCl3, 298K);

[0034] Figure 10 This is the NMR carbon spectrum of II (CDCl3, 298K);

[0035] Figure 11 This is the H NMR spectrum of VI (CDCl3, 298K);

[0036] Figure 12This is the NMR carbon spectrum of VI (CDCl3, 298K);

[0037] Figure 13 The H NMR spectrum of III (CDCl3, 298K);

[0038] Figure 14 This is the NMR carbon spectrum of III (CDCl3, 298K). DETAILED DESCRIPTION

[0039] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is described in detail below with reference to specific embodiments. It should be noted that the following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0040] All raw materials of the present invention are not particularly limited in their sources and can be purchased from the market or prepared according to conventional methods well known to those skilled in the art.

[0041] Compounds I, II, and III in this patent are all new compounds, with structures such as Figure 1 As shown, the structures of the corresponding substrate compounds IV, V, and VI are as follows Figure 2 The above embodiments are described in more detail below with reference to specific examples.

[0042] Example 1: Preparation process of compound I.

[0043] (1) Preparation of Compound IV:

[0044] A 250 mL round-bottom flask was placed in a magnetic bar, backfilled three times with noble gas under vacuum, and sealed. Bromobenzene (22 mmol) and THF (32 mL) were added. A 1.6 mol / L solution of n-butyllithium in n-hexane (13.8 mL, 22 mmol) was slowly added dropwise at -78°C. After 1 hour of reaction, a solution of 3-oxocyclobutane-1-carboxylic acid (1.14 g, 10 mmol) in THF (10 mL) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours and then quenched with saturated ammonium chloride solution (16 mL) and water (10 mL). The reaction mixture was diluted with 50 mL of n-pentane and transferred to a separatory funnel. The organic layer was extracted with water (3 × 20 mL). The pH of the aqueous layer was carefully adjusted to 1-2 with aqueous NaHSO₄, and the remaining acid was extracted with tert-butyl methyl ether (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 3-hydroxy-3-arylcyclobutane-1-carboxylic acid. 10 mL of concentrated hydrochloric acid was slowly added dropwise to a 10 mL toluene solution of 3-hydroxy-3-arylcyclobutane-1-carboxylic acid. After 12 hours of reaction, the layers were separated, and the hydrochloric acid layer was washed once with 5 mL of toluene. The organic layer was washed with saturated brine (50 mL). The remaining acid in the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were concentrated under reduced pressure to yield 3-chloro-3-arylcyclobutane-1-carboxylic acid. To a solution of 3-chloro-3-arylcyclobutane-1-carboxylic acid (1.05 g, 5 mmol) in dichloromethane (0.3 M, 15 mL) were added N-phenylimidazole (0.865 g, 6 mmol) and DMAP (0.611 g, 5 mmol). After stirring for 5 minutes, EDC-HCl (1.15 g, 6 mmol) was added at 0°C. After reacting at room temperature for 12 hours, the reaction was quenched with 10mL of ammonium chloride solution, and the aqueous layer was extracted with dichloromethane (3×20mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was placed in a 50mL round-bottom flask, a magnetic bar was placed, backfilled three times with a noble gas under vacuum and sealed, and THF (10mL) was added. The reaction mixture was cooled to 0°C, and a 2mol / L THF solution of NaHMDS (3.1mL) was slowly added dropwise. After reacting for 3 hours, the reaction was quenched with 10mL of ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate (3×20mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound IV (whose nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum are as follows Figure 3 and Figure 4 The structural formula of compound IV is as follows:

[0045]

[0046] (2) Preparation of Compound I:

[0047] A magnetic bar was placed in a 10 mL Schlenk tube, and compound IV (0.1 mmol), (1-azidovinyl)benzene (0.1 mmol), and RhS catalyst (0.002 mmol, 2.0 mol%) were added. The Schlenk tube was backfilled twice with nitrogen under vacuum. Subsequently, acetonitrile (1 mL) was added under nitrogen atmosphere. The reaction mixture was illuminated by a blue LED light (λ max =455nm) and stirred overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain product I (its H NMR spectrum and C NMR spectrum are as follows Figure 5 and Figure 6 As shown). Yield % = actual yield / theoretical yield × 100% to calculate: Yield 98%. The structural formula of compound I is as follows:

[0048]

[0049] 1 H NMR (600MHz, CDCl3) δ7.91–7.79(m,2H),7.53–7.31(m,11H),7.29–7.19(m,5H),3.25(s,2H),2.69(dd,J=6.6,2.5Hz,2H),2.26(dd,J=6.6,2.5Hz,2H). 13 CNMR(151MHz, CDCl3)δ190.38,166.19,146.48,142.11,138.55,137.62,130.30,130.06,129.07 ,128.81,128.63,128.28,126.67,126.38,126.23,125.87,125.04,67.47,45.73,41.66,41.25.

[0050] Example 2: Preparation process of compound II.

[0051] (1) Preparation of Compound V:

[0052] The preparation method of compound IV in Example 1 is similar, except that bromobenzene is replaced by 4-bromochlorobenzene. The obtained compound V (its H NMR spectrum and C NMR spectrum are as follows Figure 7 and Figure 8 The structural formula of (shown) is as follows:

[0053]

[0054] (2) Preparation of Compound II:

[0055] A magnetic bar was placed in a 10 mL Schlenk tube, and compound V (0.1 mmol), (1-azidovinyl)benzene (0.1 mmol), and RhS catalyst (0.002 mmol, 2.0 mol%) were added. The Schlenk tube was backfilled twice with nitrogen under vacuum. Subsequently, acetonitrile (1 mL) was added under nitrogen atmosphere. The reaction mixture was illuminated by a blue LED light (λ max =455nm) and stirred overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain product II (its H NMR and C NMR spectra were as follows Figure 9 and Figure 10 The yield is 88%. The structural formula of compound II is as follows:

[0056]

[0057] 1 H NMR (600MHz, CDCl3) δ7.89–7.82(m,2H),7.51–7.30(m,11H),7.22(d,J=1.0Hz,1H),7. 19–7.13(m,2H),3.22(s,2H),2.66(dd,J=6.7,2.5Hz,2H),2.24(dd,J=6.7,2.5Hz,2H). 13 C NMR (151MHz, CDCl3) δ190.09,165.99,144.92,142.01,138.51,137.47,132.46,130.40,130.10 ,129.07,128.96,128.66,128.31,126.54,126.37,126.33,125.87,67.30,45.49,41.64,40.89.

[0058] Example 3: Preparation process of compound III.

[0059] (1) Preparation of Compound VI:

[0060] The preparation method of compound IV in Example 1 is similar, except that bromobenzene is replaced by p-bromotoluene. The obtained compound VI (its H NMR spectrum and C NMR spectrum are as follows Figure 11 and Figure 12 The structural formula of (shown) is as follows:

[0061]

[0062] (2) Preparation of Compound III:

[0063] A magnetic bar was placed in a 10 mL Schlenk tube, and compound VI (0.1 mmol), (1-azidovinyl)benzene (0.1 mmol), and RhS catalyst (0.002 mmol, 2.0 mol%) were added. The Schlenk tube was backfilled twice with nitrogen under vacuum. Subsequently, acetonitrile (1 mL) was added under nitrogen atmosphere. The reaction mixture was illuminated by a blue LED light (λ max =455nm) and stirred overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain product III (its H NMR spectrum and C NMR spectrum are as follows Figure 13 and Figure 14 The yield is 85%. The structural formula of compound III is as follows:

[0064]

[0065] 1 H NMR (600MHz, CDCl3) δ7.90–7.82(m,2H),7.51–7.31(m,10H),7.24–7.12(m,5H),3 .23(s,2H),2.67(dd,J=6.6,2.5Hz,2H),2.36(s,3H),2.23(dd,J=6.7,2.5Hz,2H). 13 CNMR(151MHz, CDCl3)δ190.45,166.22,143.52,142.12,138.56,137.65,136.29,130.27,130.05,12 9.46,129.06,128.61,128.27,126.38,126.20,125.86,124.95,67.51,45.71,41.74,40.91,21.13.

[0066] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A 2-azabicyclo[3.1.1]heptene derivative, characterized in that The 2-azabicyclo[3.1.1]heptene derivative is selected from any one of compounds I, II, and III, and the structures of compounds I, II, and III are shown below:

2. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 1, wherein: The following steps are involved: (1) adding bicyclo[1.1.0]butane substrate, (1-azidovinyl)benzene and catalyst sequentially to a mixture, and adding a solvent under an inert gas atmosphere to obtain a reaction mixture; (2) The reaction mixture was stirred overnight at room temperature under LED light; (3) After the reaction is completed, the solvent is removed by concentration under reduced pressure to obtain a crude product; the crude product is purified by column chromatography to obtain a 2-azabicyclo[3.1.1]heptene derivative.

3. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 2, wherein: The bicyclo[1.1.0]butane substrate in step (1) is selected from compound IV, V or VI; the structural formulas of compound IV, V or VI are shown in formula IV, V and VI respectively; Among them, the product corresponding to compound IV is compound I, the product corresponding to compound V is compound II, and the product corresponding to compound VI is compound III.

4. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 2, wherein: The ratio of the amount of the bicyclo[1.1.0]butane substrate, (1-azidovinyl)benzene, catalyst and solvent used in step (1) is 1 mmol: (1-3.5) mmol: (0.02-0.1) mmol: (2-20) mL.

5. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 2, characterized in that: The catalyst in step (1) is any one of RhS, Ga(OTf)3, Eu(OTf)3, and BF3·Et2O.

6. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 2, characterized in that: The solvent in step (1) is any one of acetonitrile, acetone, dichloromethane and tetrahydrofuran.

7. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 2, characterized in that: The wavelength range of the LED light in step (2) is 420 to 500 nm.

8. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 2, characterized in that: The eluent for the column chromatography in step (3) is a petroleum ether / ethyl acetate mixed solution.

9. The method for synthesizing a 2-azabicyclo[3.1.1]heptene derivative according to claim 8, characterized in that: The volume ratio of petroleum ether and ethyl acetate is (5-20):

1.

10. Use of a 2-azabicyclo[3.1.1]heptene derivative according to claim 1 in the preparation of a drug, characterized in that: The drugs include: antihypertensive drugs or antihistamines.

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