A method for synthesizing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride

Abstract

The application provides a synthesis method of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, and belongs to the technical field of chemical synthesis. The synthesis method realizes synthesis of the molecular building block 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride. The synthesis method uses raw materials with low price and safety, is simple to operate, has high product purity, and has a total yield of more than 30%. The application enriches the preparation method of important intermediates in the field of medicine synthesis, is expected to promote the development of related innovative drugs, brings new treatment schemes and drug selection to the field of medicine, and has good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride. Background Technology

[0002] Novel 3D conformational molecules have attracted widespread interest in the medicinal chemistry community in recent years. Compared with planar molecules, the pharmacophores at each site of the multidimensional rigid structure precisely determine the strength of the drug-target interaction, which can improve the physicochemical properties of the drug, such as lipophilicity, solubility, selectivity and metabolic stability, thereby affecting properties such as efficacy, absorption, distribution, metabolism and excretion.

[0003] 2-Azabicyclo[2.1.1]hexane is a typical 3D rigid molecular building block. Compared with traditional pyrrolidine molecular building blocks, it exhibits similar biodegradability stability, lower lipophilicity, and higher water solubility, and can be used as a water-soluble bioisostere of pyrrolidine for drug development (Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity. Vadym V Levterov, et al. J. Org. Chem. 2018, 83, 14350-14361.). 4-Fluoro-2-azabicyclo[2.1.1]hexane hydrochloride is one such molecular building block and is an important intermediate in pharmaceutical synthesis. For example, in Chinese patent application CN115504967A published by Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd., 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride is used as a key intermediate in the synthesis of compounds with AXL kinase inhibitory activity. In international patent application WO2023049367 published by Xenon Pharmaceuticals, 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride can be used as a key building block in the synthesis of compounds with potential for treating convulsive disorders such as epilepsy.

[0004]

[0005] 4-Fluoro-2-azabicyclo[2.1.1]hexane hydrochloride is a key molecular building block in pharmaceutical synthesis, but its synthetic method has not yet been reported in the literature. Therefore, it is of great significance to study the synthetic method of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride.

[0007] This invention provides a method for preparing intermediate IV of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, comprising the following steps:

[0008]

[0009] Step (1): In the solvent, the reducing agent and compound II react; base A and water are added to the reaction solution to form a solid, and the filtrate is collected by filtration; base B and a compound that provides a leaving group are added to the filtrate to react and obtain compound III;

[0010] Step (2): In the solvent, the compound The base reacts with compound III to give compound IV;

[0011] R1 is selected from leaving groups; R2 is selected from protecting groups.

[0012] Leaving groups, also known as leaving radicals, refer to atoms or groups of atoms that break off from reactant molecules during organic chemical reactions. They are terms used in nucleophilic substitution and elimination reactions.

[0013] A protecting group is a temporarily introduced chemical group that is linked to a functional group or reaction site in a molecule via a chemical bond, thereby temporarily altering the reactivity of that functional group. Its main function is to protect certain functional groups or reaction sites in the molecule, preventing them from undergoing undesirable reactions in subsequent reactions, thus ensuring the smooth progress of the synthesis reaction and the correct formation of the target product.

[0014] Furthermore,

[0015] R1 is selected from p-toluenesulfonyl, methanesulfonyl, or methanesulfonic acid group;

[0016] R2 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenyloxycarbonyl, acetyl, trifluoroacetyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl, benzyl, or benzoyl.

[0017] Preferably,

[0018] R1 is selected from p-toluenesulfonyl group;

[0019] R2 is selected from tert-butyloxycarbonyl.

[0020] Furthermore,

[0021] In step (1), the solvent is an organic solvent;

[0022] And / or, in step (1), the reducing agent is selected from aluminum hydride, lithium aluminum hydride, sodium borohydride or lithium borohydride;

[0023] And / or, in step (1), the base B is selected from organic bases or inorganic bases;

[0024] And / or, in step (1), the compound providing the leaving group is selected from p-toluenesulfonyl chloride, methanesulfonyl chloride, or methanesulfonic anhydride;

[0025] And / or, in step (2), the solvent is an organic solvent;

[0026] And / or, in step (2), the compound Selected from methyl 2-[(tert-Butoxycarbonyl)amino]-3-chloropropionate;

[0027] And / or, in step (2), the base is selected from potassium tert-butoxide, sodium tert-butoxide, or LDA;

[0028] Preferably,

[0029] In step (1), the solvent is selected from diethyl ether;

[0030] And / or, in step (1), the reducing agent is selected from aluminum hydride, which is obtained by reacting lithium aluminum hydride and aluminum chloride;

[0031] Preferably, the equivalence ratio of the lithium aluminum hydride and aluminum chloride reaction is 1:1.

[0032] Preferably, the method for reacting lithium aluminum hydride and aluminum chloride includes the following steps:

[0033] (1-1) Dissolve lithium aluminum hydride and aluminum chloride separately in diethyl ether.

[0034] (1-2) Under the protection of an inert gas, add aluminum chloride solution to lithium aluminum hydride solution and stir at room temperature for 0.1 to 1 h to obtain the solution.

[0035] And / or, in step (1), the base B is selected from triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, DBU, sodium carbonate or potassium carbonate; preferably triethylamine;

[0036] And / or, in step (1), the compound providing the leaving group is selected from p-toluenesulfonyl chloride;

[0037] And / or, in step (2), the solvent is selected from tetrahydrofuran;

[0038] And / or, in step (2), the base is selected from potassium tert-butoxide.

[0039] Furthermore,

[0040] In step (1), the equivalence ratio of compound II, reducing agent, base B and the compound providing the leaving group is 1:(1-3):(1-3):(1-3);

[0041] Preferably, in step (1), the equivalent ratio of compound II, reducing agent, base B and the compound providing the leaving group is 1:1.2:2:1.5.

[0042] Preferably, in step (1), the temperature when compound II is added is -70 to -80°C; the mass-to-volume ratio of compound II to solvent is 1 g: (10 to 50) mL.

[0043] And / or, in step (1), when the reducing agent and compound II react, the reaction temperature is 25-35°C and the reaction time is 10-20h;

[0044] And / or, in step (1), when the base B and the compound providing the leaving group are added to the filtrate for reaction, the reaction temperature is 25-35°C and the reaction time is 10-20h;

[0045] And / or, in step (2), compound III, compound The equivalence ratio of the base is 1:(1-3):(1-3);

[0046] Preferably, in step (2), compound III and compound The equivalence ratio of the base is 1:2.13:2.1.

[0047] Preferably, in step (2), the mass-to-volume ratio of compound III to solvent is 1 g: (10-50) mL.

[0048] And / or, in step (2), the reaction temperature is 25-35°C and the reaction time is 10-20h.

[0049] Furthermore,

[0050] In step (1), the reaction solution is first cooled to 0-4°C, quenched with water, then an aqueous solution of alkali A is added, and then water is added to generate a solid. The filtrate is then collected by filtration.

[0051] And / or, in step (1), before obtaining compound III, purification is performed, and the purification method includes the following steps: adding water to the reaction solution, extracting with ethyl acetate, washing and concentrating the organic phase, and obtaining compound III by column chromatography;

[0052] And / or, in step (2), the compound When a base reacts with compound III, the compound is first... Add it to the solvent, then add the alkali and compound III;

[0053] And / or, in step (2), after the reaction, a saturated sodium bisulfate aqueous solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic phase is washed, dried, concentrated, and then obtained by column chromatography to obtain compound IV.

[0054] Preferably,

[0055] In step (1), the base A is sodium hydroxide;

[0056] And / or, in step (2), the temperature when adding the alkali and compound III is -60 to -90°C.

[0057] The present invention also provides a method for preparing intermediate V of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, which comprises the following steps:

[0058]

[0059] Step (A): Prepare compound IV according to the method described above;

[0060] Step (B): In a solvent, compound IV and a photocatalyst react under light irradiation to obtain compound V;

[0061] Wherein, R1 and R2 are each independently selected from the aforementioned groups;

[0062] Preferably,

[0063] In step (B), the equivalence ratio of compound IV to the photocatalyst is 1:(0.05-0.5);

[0064] Preferably, the mass-to-volume ratio of compound IV to solvent is 1 g: 10-50 mL.

[0065] And / or, in step (B), the photocatalyst is selected from benzophenone, 9-thioxanthone, 2-isopropylthioxanthone or 4,4'-dimethoxybenzophenone;

[0066] And / or, in step (B), the wavelength of the light is 360–390 nm;

[0067] And / or, in step (B), the reaction temperature is 25–35°C and the reaction time is 10–20 h;

[0068] And / or, in step (B), the purification steps before obtaining compound V include: concentrating the reaction solution to remove most of the solvent, adding water, extracting with ethyl acetate, washing, drying and concentrating the organic phase, and finally performing column chromatography.

[0069] More preferably,

[0070] In step (B), the solvent is acetonitrile;

[0071] And / or, in step (B), the equivalence ratio of compound IV to the photocatalyst is 1:0.2;

[0072] And / or, in step (B), the photocatalyst is selected from benzophenone;

[0073] And / or, in step (B), the wavelength of the light is 365 nm.

[0074] Preferably, in step (B), the reaction is purged with an inert gas (such as nitrogen) beforehand.

[0075] The present invention also provides a method for preparing intermediate VI of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, which includes the following steps:

[0076]

[0077] Step (a): Prepare compound V according to the method described above;

[0078] Step (b): In a solvent, compound V reacts with a base to give compound VI;

[0079] Wherein, R1 and R2 are each independently selected from the aforementioned groups;

[0080] Preferably,

[0081] In step (b), the equivalent ratio of compound V to the base is 1:(1-3);

[0082] Preferably, in step (b), the equivalent ratio of compound V to the base is 1:1.5; and in step (b), the mass-to-volume ratio of compound V to the solvent is 1 g: 5-50 mL.

[0083] And / or, in step (b), the reaction temperature is 25–35°C and the reaction time is 10–20 h;

[0084] And / or, in step (b), the purification steps before obtaining compound VI include the following: concentrating the reaction solution to remove most of the solvent, washing the aqueous phase, adjusting the pH of the aqueous phase to 1-2, extracting with DCM, drying and concentrating the organic phase to produce a solid, pulping with petroleum ether, filtering, and drying the filter cake to obtain the compound;

[0085] More preferably,

[0086] In step (b), the solvent is a mixed solution of tetrahydrofuran and methanol, wherein the volume ratio of tetrahydrofuran to methanol is 1:1.

[0087] And / or, in step (b), the base is NaOH. Preferably, the base is an aqueous solution of NaOH with a concentration of 1.2 M.

[0088] The present invention also provides a method for synthesizing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, which includes the following steps:

[0089]

[0090] Step (I): Prepare compound VI according to the method described above;

[0091] Step (II): In a solvent, compound VI, a free radical quenching compound, a ligand, a photoinitiator, and a base are reacted to obtain compound VII;

[0092] Step (III): In a solvent, compound VII reacts with hydrogen chloride solution to obtain compound I;

[0093] Wherein, R1 and R2 are each independently selected from the aforementioned groups;

[0094] Preferably,

[0095] In step (II), the free radical quenching compound is selected from 2,4,6-triisopropylbenzylthiophenol, bis(2,4,6-triisopropylphenyl) disulfide or diphenyl disulfide;

[0096] And / or, in step (II), the ligand is selected from 2,2'-dipyridinemethylamine and trimethylpyridine;

[0097] And / or, in step (II), the photoinitiator is selected from Fe(NO3)3·9H2O, FeCl3 or Fe(OTf)3;

[0098] And / or, in step (II), the base is selected from Na2CO3, K2CO3, NaOH or triethylamine;

[0099] And / or, in step (III), the hydrogen chloride solution is selected from ethyl hydrogen chloride solution, 1,4-dioxane hydrogen chloride solution, diethyl hydrogen chloride ether solution or methyl tert-butyl hydrogen chloride ether solution;

[0100] More preferably,

[0101] In step (II), the free radical quenching compound is selected from 2,4,6-triisopropylbenzylthiophenol;

[0102] And / or, in step (II), the ligand is selected from 2,2'-dipyridinemethylamine;

[0103] And / or, in step (II), the photoinitiator is selected from Fe(NO3)3·9H2O;

[0104] And / or, in step (II), the base is selected from Na2CO3;

[0105] And / or, in step (III), the hydrogen chloride solution is selected from ethyl hydrogen chloride solution.

[0106] Furthermore,

[0107] In step (II), the equivalent ratio of compound VI, the free radical quenching compound, the ligand, the photoinitiator, and the base is 1:(0.1-0.5):(0.1-0.5):(0.1-0.5):(0.5-1);

[0108] Preferably, in step (II), the equivalent ratio of compound VI, free radical quenching compound, ligand, photoinitiator and base is 1:0.2:0.1:0.1:0.5.

[0109] Preferably, in step (II), the mass-to-volume ratio of compound VI to solvent is 1g:10-50mL.

[0110] And / or, in step (II), the reaction is carried out under light irradiation, the wavelength of the light is 350-400 nm, and the reaction time is 40-60 h;

[0111] And / or, in step (III), the equivalent ratio of compound VII and hydrogen chloride in the ethyl hydrogen chloride solution is 1:(8-10);

[0112] Preferably, in step (III), the equivalent ratio of compound VII and ethyl hydrogen chloride is 1:8.1.

[0113] And / or, in step (III), the reaction temperature is 25–35°C and the reaction time is 1–10 h;

[0114] Preferably,

[0115] In step (II), the solvent is a mixed solution of dichloroethane and water, and the volume ratio of dichloroethane to water is 1:1;

[0116] And / or, in step (II), the reaction is bubbled with an inert gas for 10 to 60 minutes before the reaction;

[0117] And / or, in step (II), the wavelength of the light is 390 nm;

[0118] And / or, in step (II), the purification steps before obtaining compound VII include: filtering the reaction solution, extracting the filtrate with DCM, concentrating the organic phase, and performing column chromatography to obtain the compound;

[0119] And / or, in step (III), the solvent is diethyl ether;

[0120] And / or, in step (III), the concentration of the ethyl hydrochloride solution is 1–5 M;

[0121] And / or, in step (III), the purification steps before obtaining compound I include the following: adding diethyl ether to the reaction solution, mixing evenly and filtering, washing the filter cake with diethyl ether, and drying.

[0122] The present invention also provides an intermediate for preparing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, said intermediate being selected from one of the following structures:

[0123]

[0124] R2 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenyloxycarbonyl, acetyl, trifluoroacetyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl, benzyl or benzoyl.

[0125] Preferably,

[0126] R2 is selected from tert-butyloxycarbonyl.

[0127] Preferably, an intermediate for preparing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride is selected from one of the following structures:

[0128]

[0129] The present invention has achieved the following beneficial effects:

[0130] There are no existing reports on the synthesis of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride. This invention provides a method for synthesizing the molecular building block 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, achieving the synthesis of this compound. The synthetic method of this invention uses inexpensive and safe raw materials, is simple to operate, produces high-purity products, and achieves a total yield of over 30%. This invention enriches the preparation methods of important intermediates in the field of pharmaceutical synthesis, and is expected to promote the development of related innovative drugs, bringing new treatment options and drug choices to the pharmaceutical field, with promising application prospects.

[0131] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0132] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0133] Figure 1 The hydrogen nuclear magnetic resonance (H-NMR) spectrum of compound III-1 (400M, CDCl3).

[0134] Figure 2 The fluorine nuclear magnetic resonance (F-NMR) spectrum of compound III-1 (376M, CDCl3).

[0135] Figure 3 The hydrogen nuclear magnetic resonance (H-NMR) spectrum of compound IV-1 (400M, CDCl3).

[0136] Figure 4 The fluorine nuclear magnetic resonance (F-NMR) spectrum of compound IV-1 (376M, CDCl3).

[0137] Figure 5 The hydrogen nuclear magnetic resonance (H-NMR) spectrum of compound V-1 (400 M, CDCl3).

[0138] Figure 6 The fluorine nuclear magnetic resonance (F-NMR) spectrum of compound V-1 (376M, CDCl3).

[0139] Figure 7 The hydrogen nuclear magnetic resonance (H-NMR) spectrum of compound VI-1 (400M, CDCl3).

[0140] Figure 8 The fluorine nuclear magnetic resonance (F-NMR) spectrum of compound VI-1 (376M, CDCl3).

[0141] Figure 9 The hydrogen nuclear magnetic resonance (H-NMR) spectrum of compound VII-1 (400 M, CDCl3).

[0142] Figure 10 The fluorine nuclear magnetic resonance (F-NMR) spectrum of compound VII-1 (376M, CDCl3).

[0143] Figure 11 The hydrogen nuclear magnetic resonance (H-NMR) spectrum of compound I-1 (400M, DMSO-D6).

[0144] Figure 12The fluorine nuclear magnetic resonance (F-NMR) spectrum of compound I-1 (376M, DMSO-D6).

[0145] Figure 13 This is the HPLC chromatogram of compound I-1.

[0146] Figure 14 This is the MS spectrum of compound I-1. Detailed Implementation

[0147] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0148] In this invention, room temperature refers to 25–35°C, and overnight refers to 10–12 hours.

[0149] The abbreviations involved in this invention are: lithium aluminum hydride (LAH), triethylamine (Et3N), p-toluenesulfonyl chloride (TsCl), ethyl acetate (EA), tetrahydrofuran (THF), potassium tert-butoxide (t-BuOK), acetonitrile (MeCN), dichloroethane (DCE), and diethyl ether (Et2O).

[0150] Example 1: Preparation of compound I-1 (4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride)

[0151] The synthetic route for compound I-1 is shown below:

[0152]

[0153] Step 1, Preparation of Compound III-1:

[0154] Add 200 mL of dry diethyl ether to a 1 L three-necked flask, cool to 0 °C, and slowly add LAH (8.75 g, 230.592 mmol, 1.20 equiv). Add 200 mL of dry diethyl ether to another 500 mL three-necked flask, cool to -5 °C, and add AlCl3 (30.74 g, 230.556 mmol, 1.20 equiv). Under nitrogen protection, slowly add the AlCl3 ether solution to the LAH ether solution. Stir at room temperature for 0.5 h, cool the entire system to -78 °C, and add dropwise 100 mL of ether solution of II-1 (20 g, 192.160 mmol, 1 equiv). Allow to rise naturally to room temperature and react overnight. Monitor the reaction for completeness using GC-MS. The reaction solution was cooled to 0°C. Using a lithium aluminum hydride quenching method, 10 mL of water, 10 mL of 15% NaOH aqueous solution, and 30 mL of water were slowly added sequentially. A gray solid was formed. Anhydrous sodium sulfate was added for drying, and the gray solid was removed by filtration. The solid was washed with ether, and the filtrate was collected. The filtrates were combined and transferred to a 1 L three-necked flask. Et3N (38.89 g, 384.320 mmol, 2 equiv) and TsCl (54.95 g, 288.240 mmol, 1.5 equiv) were added. The reaction was allowed to proceed overnight at room temperature under LC-MS monitoring until complete. Water (400 mL) was added, and the mixture was extracted with EA (300 mL × 2). The organic phase was collected, washed with saturated brine (300 mL), concentrated, and column chromatography was performed to obtain colorless oil III-1 (41.20 g, yield 93.16%). The NMR spectrum of compound III-1 is shown below. Figures 1-2 As shown.

[0155] Step 2, Preparation of Compound IV-1:

[0156] Methyl 2-[(tert-Butoxycarbonyl)amino]-3-chloropropionate (90.59 g, 381.134 mmol, 2.13 equiv) and 550 mL of THF were added to a 1 L three-necked flask. The mixture was cooled to -78 °C, and a t-BuOK THF solution (3.76 M, 100 mL, 375.766 mmol, 2.10 equiv) was added. Then, III-1 (41.2 g, 178.936 mmol, 1.00 equiv) was added, and the mixture was reacted overnight at room temperature. The reaction was monitored for completeness by LC-MS. The reaction solution was poured into a saturated sodium bisulfate aqueous solution (400 mL), extracted with EA (400 mL × 2), and the organic phase was collected. The solution was washed with saturated brine (200 mL), dried, concentrated, and subjected to column chromatography to obtain colorless oil IV-1 (31.4 g, yield 67.66%). The NMR spectrum of compound IV-1 is shown below. Figures 3-4 As shown.

[0157] Step 3, Preparation of compound V-1:

[0158] IV-1 (31.3 g, 120.720 mmol, 1 equiv), MeCN (620 mL), and benzophenone (4.4 g, 24.144 mmol, 0.2 equiv) were added to a 1000 mL jacketed reactor. The reactor was purged with nitrogen and irradiated with a 365 nm LED lamp overnight at room temperature. The reaction was monitored by LC-MS until completion. The mixture was concentrated to remove most of the acetonitrile, and water (200 mL) was added. Extraction was performed using EA (150 mL x 2). The organic phase was collected, washed with saturated brine (150 mL), dried, concentrated, and column chromatography was performed to obtain colorless oil V-1 (22.6 g, yield 72.20%). The NMR spectrum of compound V-1 is shown below. Figures 5-6 As shown.

[0159] Step 4, Preparation of compound VI-1:

[0160] In a 500 mL three-necked flask, VI-1 (22.6 g, 87.165 mmol, 1 equiv), THF (110 mL), methanol (110 mL), and NaOH aqueous solution (1.2 M, 110 mL, 132.0 mmol, 1.5 equiv) were added. The reaction was carried out overnight at room temperature under LC-MS monitoring until complete. Most of the THF and MeOH were removed by concentration. The aqueous phase was washed with DCM (20 mL x 3), and the aqueous phase was retained. The pH of the aqueous phase was adjusted to 1-2 with saturated sodium bisulfate aqueous solution. Extraction was performed with DCM (50 mL x 4), and the organic phase was collected, dried, and concentrated. A white solid was produced. 30 mL of petroleum ether was added and the mixture was stirred. The mixture was filtered, and the filter cake was collected and dried to obtain a white solid VI-1 (18.7 g, yield 87.47%). The NMR spectrum of compound VI-1 is shown below. Figures 7-8 As shown.

[0161] Step 5, Preparation of compound VII-1:

[0162] Add VI-1 (15g, 61.162mmol, 1equiv), 2,4,6-triisopropylbenzylthiophenol (2.89g, 12.232mmol, 0.20equiv), 2,2'-dipyridinylmethylamine (1.22g, 6.116mmol, 0.1equiv), DCE (300mL), H2O (300.00mL), Fe(NO3)3·9H2O (2.49g, 6.116mmol, 0.1equiv), and Na2CO3 (3.24g, 30.581mmol, 0.5equiv) to a 1000mL three-necked flask. Bubble with N2 for 20min, irradiate with a 390nm LED lamp at room temperature for 48h, and monitor the reaction with LCMS until the reaction is complete. The reaction solution was filtered, and the filtrate was extracted with DCM (80 mL * 2). The organic phase was concentrated, and column chromatography was used to obtain a white solid VII-1 (10.6 g, yield 86.12%). The NMR spectrum of compound VII-1 is shown below. Figures 9-10As shown.

[0163] Step 6, Preparation of Compound I-1:

[0164] Add VII-1 (8.7 g, 43.232 mmol, 1 equiv) to a 500 mL three-necked flask, add 87 mL of Et₂O, cool to 0 °C, add ethyl hydrochloride solution (4.0 M, 87 mL, 240 mmol, 8.1 equiv), react at room temperature for 4 h, monitored by LC-MS. Once the reaction is complete, add 300 mL of diethyl ether, stir well, filter, wash the filter cake with diethyl ether, and dry to obtain I-1 (5.6 g, purity 99.93%, yield 94.47%). The NMR spectrum of compound I-1 is shown below. Figures 11-12 As shown. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.59 (s, 2H), 4.13 (dt, J = 20.8, 2.5Hz, 1H), 3.22 (d, J = 1.6Hz, 2H), 2.24 (s, 2H), 2.10 (s, J = 5.2, 3.5, 1.6Hz, 2H). The HPLC chromatogram of compound I-1 is shown below. Figure 13 As shown. The MS spectrum of compound I-1 is as follows. Figure 14 As shown.

[0165] The above method, starting from starting material II-1, yielded a total yield of 32.39% for preparing compound I-1.

[0166] Comparative Example 1: This comparative example provides other methods for preparing compound VII-1.

[0167] Add VI-1 (200 mg, 0.815 mmol, 1 equiv), DMSO (5 mL, 70.395 mmol, 86.32 equiv), ammonium persulfate (558.26 mg, 2.445 mmol, 3 equiv), 2,4,6-trimethylpyridine (296.47 mg, 2.445 mmol, 3 equiv), and water (29.38 mg, 1.630 mmol, 2 equiv) to a 20 mL sample tube. Bubble under nitrogen for 5 min, stir at 6 °C for 2 h (the system changes from colorless to dark red). Monitor the reaction by GC-MS and TLC until complete. Add 15 mL of water, extract with methyl ether (2 x 15 mL), wash with saturated sodium bisulfate aqueous solution (15 mL x 3), wash with saturated brine (15 mL), collect the organic phase, dry, concentrate, and column chromatography to obtain a colorless oily substance VII-1 (37 mg, yield: 22.55%).

[0168] Comparative Example 2: This comparative example provides other methods for preparing compound VII-1.

[0169] Add VI-1 (200 mg, 1.631 mmol, 1 equiv, 200%), water (20 mL, 22.204 mmol, 13.61 equiv, 2%), dichloroethane (20 mL, 25.169 mmol, 15.43 equiv, 8%), and cesium hydroxide (220.05 mg, 1.468 mmol, 0.9 equiv) to a 20 mL sample tube. Stir at room temperature for 2 h, then add 2,4,6... -Tri(propyl-2-yl)phenyl-1-thiol (38.56 mg, 0.163 mmol, 0.1 equiv), Ir[dF(CF3)ppy]2(dtbpy))PF6 (18.30 mg, 0.016 mmol, 0.01 equiv), bubbled under nitrogen for 5 min, stirred for 72 h under blue light at room temperature, monitored by ¹H-NMR (starter:product = 1:1.73), further extending the reaction time did not significantly change the reaction ratio. 15 mL of water was added, extracted with methyl ether (2 x 15 mL), washed with saturated sodium bisulfate aqueous solution (15 mL x 3), washed with saturated brine (15 mL), the organic phase was collected, dried, concentrated and column chromatography was performed to give colorless oil VII-1 (63 mg, yield: 38.39%).

[0170] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0171] Experimental Example 1: Screening of Reaction Conditions

[0172] This experimental example, based on Example 1, further screened the reaction conditions for step 3, mainly exploring the effects of different photocatalysts and different wavelengths of light on the reaction yield. Except for the different reaction conditions for step 3 shown in Table 1, the reaction conditions and operations for the other synthesis steps in Examples 2-6 were consistent with those in Example 1 (" / " indicates no reaction or no product detected).

[0173] Table 1: Screening of Reaction Conditions

[0174]

[0175]

[0176] As can be seen from the experimental results in Table 1, under the same light source, compared with different photocatalysts (Examples 1-5), benzophenone showed higher conversion rate and yield. Using benzophenone as a photocatalyst, different light wavelengths were screened, and 365nm light was found to have the best effect (Examples 1, 6-8). Further optimization of the catalyst equivalent (Examples 1, 9-11) yielded the optimal yield of 72.2% under the current conditions when the catalyst equivalent was 0.2.

[0177] In summary, this invention provides a method for synthesizing the molecular building block 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, achieving the synthesis of this compound. The synthetic method of this invention uses inexpensive and safe raw materials, is simple to operate, produces high-purity products, and achieves an overall yield of over 30%. This invention enriches the methods for preparing important intermediates in the field of pharmaceutical synthesis, and is expected to promote the development of related innovative drugs, bringing new treatment options and drug choices to the pharmaceutical field, demonstrating promising application prospects.

Claims

1. A method for preparing 4-fluoro-2-azabicyclic [ 2.1.1] The method for intermediate IV of hexane hydrochloride, characterized in that: It includes the following steps: Step (1): In the solvent diethyl ether, the reducing agent and compound II react; base A sodium hydroxide and water are added to the reaction solution to form a solid, and the filtrate is collected by filtration; base B triethylamine and compound p-toluenesulfonyl chloride, which provides a deionization group, are added to the filtrate to react and obtain compound III; Step (2): In the solvent tetrahydrofuran, the compound The base potassium tert-butoxide reacts with compound III to give compound IV; In step (1), the reducing agent is selected from aluminum hydride, which is obtained by reacting lithium aluminum hydride and aluminum chloride; In step (2), the compound Selected from methyl 2-[(tert-Butoxycarbonyl)amino]-3-chloropropionate; Wherein, R1 is selected from p-toluenesulfonyl; R2 is selected from tert-butyloxycarbonyl; In step (1), the equivalence ratio of compound II, reducing agent, base B and the compound providing the leaving group is 1:(1~3):(1~3):(1~3); In step (1), when the reducing agent and compound II react, the reaction temperature is 25~35℃ and the reaction time is 10~20h; In step (1), when adding base B and the compound that provides leaving groups to the filtrate to react, the reaction temperature is 25~35℃ and the reaction time is 10~20h; In step (2), compound III and compound The equivalence ratio of base to alkali is 1:(1~3):(1~3); In step (2), the reaction temperature is 25~35℃ and the reaction time is 10~20h; In step (1), the reaction solution is first cooled to 0~4℃, quenched with water, then an aqueous solution of alkali A is added, and then water is added to generate a solid. The filtrate is then collected by filtration. In step (1), before obtaining compound III, purification is performed. The purification method includes the following steps: adding water to the reaction solution, extracting with ethyl acetate, washing and concentrating the organic phase, and obtaining compound III by column chromatography. In step (2), the compound When a base reacts with compound III, the compound is first... Add it to the solvent, then add the alkali and compound III; In step (2), after the reaction, a saturated sodium bisulfate aqueous solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic phase is washed, dried, concentrated, and then obtained by column chromatography to obtain compound IV. In step (2), the temperature when adding alkali and compound III is -60~-90℃.

2. A method for preparing intermediate V of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, characterized in that: It includes the following steps: Step (A): Prepare compound IV according to the method of claim 1; Step (B): Compound IV and the photocatalyst benzophenone react in the solvent acetonitrile under light irradiation to obtain compound V; Wherein, R1 and R2 are each independently selected from the groups described in claim 1.

3. The method according to claim 2, characterized in that: In step (B), the equivalence ratio of compound IV to the photocatalyst is 1:(0.05~0.5). And / or, in step (B), the wavelength of the light is 360~390nm; And / or, in step (B), the reaction temperature is 25~35℃ and the reaction time is 10~20h; And / or, in step (B), the purification steps before obtaining compound V include: concentrating the reaction solution to remove most of the solvent, adding water, extracting with ethyl acetate, washing, drying, concentrating the organic phase, and finally performing column chromatography.

4. The method according to claim 3, characterized in that: In step (B), the equivalence ratio of compound IV to the photocatalyst is 1:0.2; And / or, in step (B), the wavelength of the light is 365 nm.

5. A method for preparing intermediate VI of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, characterized in that: It includes the following steps: Step (a): Prepare compound V according to the method described in any one of claims 2 to 4; Step (b): In a solvent, compound V reacts with the base NaOH to obtain compound VI; In step (b), the solvent is a mixed solution of tetrahydrofuran and methanol, wherein the volume ratio of tetrahydrofuran to methanol is 1:

1. Wherein, R1 and R2 are each independently selected from the groups described in claim 1.

6. The method according to claim 5, characterized in that: In step (b), the equivalent ratio of compound V to the base is 1:(1~3). And / or, in step (b), the reaction temperature is 25~35℃ and the reaction time is 10~20h; And / or, in step (b), the purification steps before obtaining compound VI include the following: concentrating the reaction solution to remove most of the solvent, washing the aqueous phase, adjusting the pH of the aqueous phase to 1-2, extracting with DCM, drying and concentrating the organic phase until a solid is produced, pulping with petroleum ether, filtering, and drying the filter cake to obtain the compound.

7. A method for synthesizing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, characterized in that: It includes the following steps: Step (I): Prepare compound VI according to the method of claim 5 or 6; Step (II): In a solvent, compound VI, free radical quenching compound 2,4,6-triisopropylbenzylthiophenol, ligand 2,2'-dipyridinemethylamine, photoinitiator Fe(NO3)3·9H2O and base Na2CO3 are reacted to obtain compound VII; Step (III): Compound VII reacts with hydrogen chloride solution in the solvent diethyl ether to obtain compound I; In step (II), the solvent is a mixed solution of dichloroethane and water, and the volume ratio of dichloroethane to water is 1:1; In step (III), the hydrogen chloride solution is selected from ethyl hydrogen chloride solution, and the concentration of ethyl hydrogen chloride solution is 1~5M; Wherein, R1 and R2 are each independently selected from the groups described in claim 1.

8. The synthesis method according to claim 7, characterized in that: In step (II), the equivalent ratio of compound VI, the free radical quenching compound, the ligand, the photoinitiator, and the base is 1:(0.1~0.5):(0.1~0.5):(0.1~0.5):(0.5~1). And / or, in step (II), the reaction is carried out under light irradiation, the wavelength of the light is 350~400nm, and the reaction time is 40~60h; And / or, in step (III), the equivalent ratio of compound VII and hydrogen chloride in the ethyl hydrogen chloride solution is 1:(8~10). And / or, in step (III), the reaction temperature is 25~35℃ and the reaction time is 1~10h.

9. The synthesis method according to claim 8, characterized in that: In step (II), the reaction is bubbled with an inert gas for 10-60 minutes beforehand; And / or, in step (II), the wavelength of the light is 390 nm; And / or, in step (II), the purification steps before obtaining compound VII include: filtering the reaction solution, extracting the filtrate with DCM, concentrating the organic phase, and performing column chromatography to obtain the compound; And / or, in step (III), the purification steps before obtaining compound I include the following: adding diethyl ether to the reaction solution, mixing evenly and filtering, washing the filter cake with diethyl ether, and drying.

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