Synthesis method of 4-fluoro-2-azabicyclo [2.1. 1] hexane hydrochloride

Abstract

The invention provides a synthesis method of 4-fluoro-2-azabicyclo [2.1. 1] hexane hydrochloride, and belongs to the technical field of chemical synthesis. According to the invention, the synthesis of the molecular building block 4-fluoro-2-azabicyclo [2.1. 1] hexane hydrochloride is realized. The raw materials used in the synthesis method are low in price and safe, operation is easy and convenient, the product purity is high, and the total yield reaches 30% or above. The preparation method of important intermediates in the field of medicine synthesis is enriched, development of related innovative medicines is expected to be promoted, new treatment schemes and medicine choices are brought to the field of medicine, and the preparation method has good application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride. Background Art

[0002] In recent years, 3D conformational molecules with novel structures have attracted extensive interest in the field of medicinal chemistry. Compared with planar molecules, the pharmacophoric groups at each site of the multi-dimensional rigid structure precisely determine the strength of the interaction between the drug and the target, and 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 biodegradation stability, lower lipophilicity, and higher water solubility, and can be used as a water-soluble bioisostere of pyrrolidine for drug research and 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 of such molecular building blocks and is an important intermediate in pharmaceutical synthesis. For example, in the Chinese patent application with the publication number CN115504967A by Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd., 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, as a key intermediate, can be used to synthesize compounds with AXL kinase inhibitory activity. In the international patent application with the publication number WO2023049367 by Xenon Pharmaceuticals, 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride can be used as a key molecular building block to synthesize compounds that have the potential to treat convulsive diseases such as epilepsy.

[0004]

[0005] As a key molecular building block in pharmaceutical synthesis, there is currently no literature report on the synthesis method of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride. Therefore, it is of great significance to study the synthesis method of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride. Summary of the Invention

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

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

[0008]

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

[0010] Step (2): In a solvent, the compound a base and compound III are reacted to obtain compound IV;

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

[0012] A leaving group, also known as a leaving group, refers to an atom or atomic group that detaches from the reactant molecule during an organic chemical reaction and is a term in nucleophilic substitution reactions and elimination reactions.

[0013] A protecting group is a temporarily introduced chemical group that is connected to the functional group or reaction site in the molecule that needs to be protected through a chemical bond, thereby temporarily changing the reactivity of the functional group. Its main function is to protect certain functional groups or reaction sites in the molecule to prevent them from undergoing undesired reactions during subsequent reaction processes, thereby ensuring the smooth progress of the synthesis reaction and the correct formation of the target product.

[0014] Furthermore,

[0015] R1 is selected from tosyl group, mesyl group, methylsulfonic acid group;

[0016] R2 is selected from tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, acetyl group, trifluoroacetyl group, tosyl group, 4-nitrobenzenesulfonyl group, benzyl group or benzoyl group.

[0017] Preferably,

[0018] R1 is selected from tosyl group;

[0019] R2 is selected from tert-butoxycarbonyl group.

[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, methylsulfonyl chloride or methylsulfonic anhydride;

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

[0026] And / or, in step (2), the compound is 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, and the aluminum hydride is obtained by reacting lithium aluminum hydride with aluminum chloride;

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

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

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

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

[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 equivalent ratio of compound II, reducing agent, base B and the compound providing a 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 a leaving group is 1:1.2:2:1.5.

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

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

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

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

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

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

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

[0049] Furthermore,

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

[0051] And / or, in step (1), before obtaining compound III, purification is carried out. 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), when the compound base reacts with compound III, first the compound Add it to a solvent, then add a base and Compound III;

[0053] And / or, in step (2), after the reaction, add an aqueous solution of saturated sodium bisulfate to the reaction solution, extract with ethyl acetate, wash, dry, and concentrate the organic phase, and then obtain Compound IV by column chromatography;

[0054] Preferably,

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

[0056] And / or, in step (2), the temperature when adding the base 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 aforementioned method;

[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 equivalent ratio of Compound IV to the photocatalyst is 1:(0.05 - 0.5);

[0064] Preferably, the mass-volume ratio of Compound IV to the 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 temperature of the reaction is 25 - 35 °C, and the reaction time is 10 - 20 h;

[0068] And / or, before obtaining Compound V in step (B), the following purification steps are included: 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 equivalent ratio of the 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), before the reaction, it is replaced with an inert gas (such as nitrogen).

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

[0076]

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

[0078] Step (b): In a solvent, compound V reacts with a base to obtain 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 the compound V to the base is 1:(1-3);

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

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

[0084] And / or, before obtaining compound VI in step (b), the following purification steps are included: 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, slurrying with petroleum ether, filtering, and drying the filter cake to obtain;

[0085] More preferably,

[0086] In step (b), the solvent is a mixed solution of tetrahydrofuran and methanol, and 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 NaOH solution 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 comprises the following steps:

[0089]

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

[0091] Step (II): React compound VI, a radical quenching compound, a ligand, a photoinitiator, and a base in a solvent to obtain compound VII;

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

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

[0094] Preferably,

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

[0096] And / or, in step (II), the ligand is selected from 2,2'-dipyridylmethylamine, 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 a hydrogen chloride ethyl acetate solution, a hydrogen chloride 1,4-dioxane solution, a hydrogen chloride ether solution, or a hydrogen chloride methyl tert-butyl ether solution;

[0100] More preferably,

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

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

[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 hydrogen chloride ethyl acetate solution.

[0106] Furthermore,

[0107] In step (II), the equivalent ratio of the compound VI, the compound for quenching free radicals, 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 the compound VI, the compound for quenching free radicals, the ligand, the photoinitiator and the base is 1:0.2:0.1:0.1:0.5.

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

[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 the compound VII and hydrogen chloride in the hydrogen chloride ethyl acetate solution is 1:(8 - 10);

[0112] Preferably, in step (III), the equivalent ratio of the compound VII and ethyl acetate hydrochloride 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, before the reaction in step (II), an inert gas is bubbled for 10 - 60 min;

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

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

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

[0120] And / or, in step (III), the concentration of the ethyl acetate solution of hydrogen chloride is 1 - 5 M;

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

[0122] The present invention also provides intermediates for preparing 4 - fluoro - 2 - azabicyclo[2.1.1]hexane hydrochloride, and the intermediates are selected from one of the following structures:

[0123]

[0124] Among them, R2 is selected from tert - butoxycarbonyl, benzyloxycarbonyl, 9 - fluorenylmethoxycarbonyl, acetyl, trifluoroacetyl, p - toluenesulfonyl, 4 - nitrophenylsulfonyl, benzyl or benzoyl.

[0125] Preferably,

[0126] R2 is selected from tert - butoxycarbonyl.

[0127] Preferably, the 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 is no report on the synthesis method of 4 - fluoro - 2 - azabicyclo[2.1.1]hexane hydrochloride in the prior art. The present invention provides a synthesis method of the molecular building block 4 - fluoro - 2 - azabicyclo[2.1.1]hexane hydrochloride, realizing the synthesis of this compound. The raw materials used in the synthesis method of the present invention are inexpensive, safe, easy to operate, the product has high purity, and the total yield reaches more than 30%. The present invention enriches the preparation methods of important intermediates in the field of pharmaceutical synthesis, is expected to promote the development of related innovative drugs, bring new treatment plans and drug options to the pharmaceutical field, and has good application prospects.

[0131] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can also be made.

[0132] The following is a further detailed description of the above content of the present invention in the form of specific embodiments by way of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. Brief Description of the Drawings

[0133] Figure 1 It is the hydrogen nuclear magnetic resonance (H-NMR) spectrum (400M, CDCl3) of Compound III-1.

[0134] Figure 2 It is the fluorine nuclear magnetic resonance (F-NMR) spectrum (376M, CDCl3) of Compound III-1.

[0135] Figure 3 It is the hydrogen nuclear magnetic resonance (H-NMR) spectrum (400M, CDCl3) of Compound IV-1.

[0136] Figure 4 It is the fluorine nuclear magnetic resonance (F-NMR) spectrum (376M, CDCl3) of Compound IV-1.

[0137] Figure 5 It is the hydrogen nuclear magnetic resonance (H-NMR) spectrum (400M, CDCl3) of Compound V-1.

[0138] Figure 6 It is the fluorine nuclear magnetic resonance (F-NMR) spectrum (376M, CDCl3) of Compound V-1.

[0139] Figure 7 It is the hydrogen nuclear magnetic resonance (H-NMR) spectrum (400M, CDCl3) of Compound VI-1.

[0140] Figure 8 It is the fluorine nuclear magnetic resonance (F-NMR) spectrum (376M, CDCl3) of Compound VI-1.

[0141] Figure 9 It is the hydrogen nuclear magnetic resonance (H-NMR) spectrum (400M, CDCl3) of Compound VII-1.

[0142] Figure 10 It is the fluorine nuclear magnetic resonance (F-NMR) spectrum (376M, CDCl3) of Compound VII-1.

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

[0144] Figure 1219F-NMR spectrum (376M, DMSO-D6) of Compound I-1.

[0145] Figure 13 HPLC spectrum of Compound I-1.

[0146] Figure 14 MS spectrum of Compound I-1. Detailed implementation mode

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

[0148] In the present invention, room temperature refers to 25 - 35 °C, and overnight refers to 10 - 12 h.

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

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

[0151] The synthetic route of Compound I-1 is shown as follows:

[0152]

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

[0154] Add 200 mL of dry ether to a 1 L three-necked flask, cool it to 0 °C, and slowly add LAH (8.75 g, 230.592 mmol, 1.20 equiv). Add 200 mL of dry ether to another 500 mL three-necked flask, cool it to -5 °C, and add AlCl3 (30.74 g, 230.556 mmol, 1.20 equiv). Under nitrogen protection, slowly add the ether solution of AlCl3 to the ether solution of LAH, stir at room temperature for 0.5 h, cool the whole system to -78 °C, and dropwise add the ether solution (100 mL) of II-1 (20 g, 192.160 mmol, 1 equiv). Let it rise to room temperature naturally and react overnight, and monitor the reaction by GCMS until it is complete. Cool the reaction solution to 0 °C, and use the lithium aluminum hydride quenching method to slowly add 10 mL of water, 10 mL of 15% NaOH aqueous solution, and 30 mL of water to the reaction solution in sequence. A gray solid is formed in the system. Add anhydrous sodium sulfate for drying, filter to remove the gray solid, wash the solid with ether, collect the filtrate, combine the filtrates, transfer the filtrate to a 1 L three-necked flask, add Et3N (38.89 g, 384.320 mmol, 2 equiv), TsCl (54.95 g, 288.240 mmol, 1.5 equiv), react at room temperature overnight, monitor by LCMS, when the reaction is complete, add water (400 mL), extract with EA (300 mL × 2), collect the organic phase, wash with saturated brine (300 mL), concentrate, and obtain colorless oil III-1 (41.20 g, yield 93.16%) by column chromatography. The NMR spectrum of compound III-1 is as shown in Figures 1 - 2 shown.

[0155] Step 2: Preparation of compound IV-1:

[0156] Add methyl 2-[(tert-butoxycarbonyl)amino]-3-chloropropionate (90.59 g, 381.134 mmol, 2.13 equiv) and 550 mL of THF to a 1 L three-necked flask, cool it to -78 °C, add the THF solution of t-BuOK (3.76 M, 100 mL, 375.766 mmol, 2.10 equiv), then add III-1 (41.2 g, 178.936 mmol, 1.00 equiv), react at room temperature overnight, and monitor the reaction by LCMS until it is complete. Pour the reaction solution into a saturated aqueous solution of sodium bisulfate (400 mL), extract with EA (400 mL × 2), collect the organic phase, wash with saturated brine (200 mL), dry, concentrate, and obtain colorless oil IV-1 (31.4 g, yield 67.66%) by column chromatography. The NMR spectrum of compound IV-1 is as shown in Figures 3 - 4 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. After purging with nitrogen, the mixture was irradiated with 365 nm LED light at room temperature overnight while monitoring by LCMS. After the reaction was completed, most of the acetonitrile was removed by concentration. Then, water (200 mL) was added, and the mixture was extracted with EA (150 mL × 2). The organic phase was collected, washed with saturated brine (150 mL), dried, concentrated, and purified by column chromatography to obtain colorless oil V-1 (22.6 g, yield 72.20%). The NMR spectrum of compound V-1 is shown as Figures 5 - 6 shown below.

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

[0160] V-1 (22.6 g, 87.165 mmol, 1 equiv), THF (110 mL), methanol (110 mL), and an aqueous NaOH solution (1.2 M, 110 mL, 132.0 mmol, 1.5 equiv) were added to a 500 mL three-necked flask. The reaction was carried out at room temperature overnight while monitoring by LCMS. After the reaction was complete, most of the THF and MeOH were removed by concentration. The aqueous phase was washed with DCM (20 mL × 3), and the aqueous phase was retained. The pH of the aqueous phase was adjusted to 1 - 2 with saturated aqueous sodium bisulfate, and then the mixture was extracted with DCM (50 mL × 4). The organic phase was collected, dried, concentrated, and a white solid was obtained. 30 mL of petroleum ether was added for pulping, and then the mixture was filtered. The filter cake was collected and dried to obtain white solid VI-1 (18.7 g, yield 87.47%). The NMR spectrum of compound VI-1 is shown as Figures 7 - 8 shown below.

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

[0162] VI-1 (15 g, 61.162 mmol, 1 equiv), 2,4,6-triisopropylbenzenethiol (2.89 g, 12.232 mmol, 0.20 equiv), 2,2'-dipyridylmethylamine (1.22 g, 6.116 mmol, 0.1 equiv), DCE (300 mL), H2O (300.00 mL), Fe(NO3)3·9H2O (2.49 g, 6.116 mmol, 0.1 equiv), and Na2CO3 (3.24 g, 30.581 mmol, 0.5 equiv) were added to a 1000 mL three-necked flask. N2 was bubbled through the mixture for 20 min, and then the mixture was irradiated with a 390 nm LED light at room temperature for 48 h while monitoring the reaction by LCMS. After the reaction was complete, the reaction mixture was filtered. The filtrate was extracted with DCM (80 mL × 2), and the organic phase was concentrated. Purification by column chromatography gave white solid VII-1 (10.6 g, yield 86.12%). The NMR spectrum of compound VII-1 is shown as 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 the temperature to 0 °C, add ethyl acetate solution of hydrogen chloride (4.0 M, 87 mL, 240 mmol, 8.1 equiv), react at room temperature for 4 h, monitor by LCMS. When the raw materials react completely, add 300 mL of ether, stir evenly, filter, wash the filter cake with ether, and dry to obtain I-1 (5.6 g, purity 99.93%, yield 94.47%). The NMR spectrum of Compound I-1 is as Figures 11 - 12 as shown 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 2H), 4.13 (dt, J = 20.8, 2.5 Hz, 1H), 3.22 (d, J = 1.6 Hz, 2H), 2.24 (s, 2H), 2.10 (s, J = 5.2, 3.5, 1.6 Hz, 2H). The HPLC spectrum of Compound I-1 is as Figure 13 as shown. The MS spectrum of Compound I-1 is as Figure 14 as shown

[0165] Starting from the starting material II-1, the total yield of preparing Compound I-1 by the above method is 32.39%.

[0166] Comparative Example 1: This comparative example provides another method 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), water (29.38 mg, 1.630 mmol, 2 equiv) to a 20 mL sample tube, bubble with nitrogen for 5 min, stir at 6 °C for 2 h (the system changes from colorless to dark red), monitor by GCMS and TLC. When the reaction is complete, add 15 mL of water, extract with methyl tert-butyl ether (2X 15 mL), wash with saturated aqueous sodium bisulfate solution (15 mL X 3), wash with saturated brine (15 mL), collect the organic phase, dry, concentrate and perform column chromatography to obtain a colorless oil VII-1 (37 mg, yield: 22.55%).

[0168] Comparative Example 2: This comparative example provides another method for preparing Compound VII-1

[0169] Add VI-1 (200 mg, 1.631 mmol, 1 equiv, 200%) into a 20 mL sample tube, water (20 mL, 22.204 mmol, 13.61 equiv, 2%), dichloroethane (20 mL, 25.169 mmol, 15.43 equiv, 8%), cesium hydroxide (220.05 mg, 1.468 mmol, 0.9 equiv), stir at room temperature for 2 h, add 2,4,6-tris(prop-2-yl)benzenethiol (38.56 mg, 0.163 mmol, 0.1 equiv) and Ir[dF(CF3)ppy]2(dtbpy))PF6 (18.30 mg, 0.016 mmol, 0.01 equiv) again, bubble with nitrogen for 5 min, under blue light irradiation at room temperature, stir for 72 h, monitor by 1H-NMR (starting material: product = 1:1.73), continue to extend the time, and the reaction ratio does not change significantly. Add 15 mL of water, extract with methyl tert-butyl ether (2 × 15 mL), wash with saturated aqueous sodium bisulfate solution (15 mL × 3), wash with saturated brine (15 mL), collect the organic phase, dry, concentrate and perform column chromatography to obtain a colorless oil VII-1 (63 mg, yield: 38.39%).

[0170] The beneficial effects of the present invention are demonstrated by the following specific test examples.

[0171] Test Example 1. Screening of reaction conditions

[0172] Based on Example 1, the reaction conditions in Step 3 were further screened in this test example, mainly exploring the effects of different photocatalysts and light of different wavelengths on the reaction yield. Among them, except for the different reaction conditions in Step 3 shown in Table 1, the reaction conditions and operations of other synthesis steps in Examples 2-6 were the same as those in Example 1 (" / " indicates no reaction or no product detected).

[0173] Table 1: Screening of reaction conditions

[0174]

[0175]

[0176] It can be seen from the experimental results in Table 1 that under the same light source, compared with different photocatalysts (Examples 1-5), the conversion rate and yield of benzophenone are higher; using benzophenone as the photocatalyst and screening different light wavelengths, it is found that the light of 365 nm has the best effect (Examples 1, 6-8). Further optimize the equivalent of the catalyst (Examples 1, 9-11), and when the equivalent of the catalyst is 0.2, the best yield of 72.2% under the current conditions is obtained.

[0177] In summary, the present invention provides a method for synthesizing the molecular building block 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, realizing the synthesis of this compound. The raw materials used in the synthesis method of the present invention are inexpensive, safe, easy to operate, with high product purity, and the total yield reaches over 30%. The present invention enriches the preparation methods of important intermediates in the field of pharmaceutical synthesis, is expected to promote the development of related innovative drugs, brings new treatment options and drug choices to the pharmaceutical field, and has good application prospects.

Claims

1. A method for preparing intermediate IV of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, characterized in that: It comprises the following steps: Step (1): In a solvent, a reducing agent and Compound II react; a base A and water are added to the reaction solution to form a solid, and the filtrate is collected by filtration; a base B and a compound providing a leaving group are added to the filtrate to react to obtain Compound III; Step (2): In a solvent, compound reacts with a base and compound III to obtain compound IV; Wherein, R1 is selected from leaving groups; R2 is selected from protecting groups.

2. The method according to claim 1, wherein: R1 is selected from p-toluenesulfonyl, methylsulfonyl, methylsulfonic acid group; R2 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, trifluoroacetyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl, benzyl or benzoyl.

3. The method according to claim 2, wherein: In step (1), the solvent is an organic solvent; and / or, in step (1), the reducing agent is selected from aluminum hydride, lithium aluminum hydride, sodium borohydride or lithium borohydride; and / or, in step (1), the base B is selected from organic bases or inorganic bases; and / or, in step (1), the compound providing a leaving group is selected from p-toluenesulfonyl chloride, methylsulfonyl chloride or methylsulfonic anhydride; and / or, in step (2), the solvent is an organic solvent; and / or, in step (2), the compound is selected from methyl 2-[(tert-butoxycarbonyl)amino]-3-chloropropionate; and / or, in step (2), the base is selected from potassium tert-butoxide, sodium tert-butoxide or LDA; Preferably, in step (1), the solvent is selected from diethyl ether; and / or, in step (1), the reducing agent is selected from aluminum hydride, and the aluminum hydride is obtained by reacting lithium aluminum hydride and aluminum chloride; and / or, in step (1), the base B is selected from triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, DBU, sodium carbonate or potassium carbonate; preferably triethylamine; and / or, in step (1), the compound providing a leaving group is selected from p-toluenesulfonyl chloride; and / or, in step (2), the solvent is selected from tetrahydrofuran; and / or, in step (2), the base is selected from potassium tert-butoxide.

4. The method according to any one of claims 1 to 3, wherein: In step (1), the equivalent ratio of Compound II, the reducing agent, base B and the compound providing a leaving group is 1:(1-3):(1-3):(1-3); 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 10-20 h; and / or, in step (1), when base B and the compound providing a leaving group are added to the filtrate to react, the reaction temperature is 25-35 °C and the reaction time is 10-20 h; and / or, in step (2), the equivalent ratio of the compound III, the compound and the base is 1:(1-3):(1-3); and / or, in step (2), the reaction temperature is 25-35 °C and the reaction time is 10-20 h.

5. The method according to any one of claims 1 to 3, wherein: In step (1), the reaction solution is first cooled to 0-4 °C, quenched with water, then an aqueous solution of base A is added, and then water is added to form a solid, and the filtrate is collected by filtration; and / or, in step (1), purification is carried out before obtaining Compound III, and the purification method comprises the following steps: water is added to the reaction solution, extracted with ethyl acetate, the organic phase is washed, concentrated, and then Compound III is obtained by column chromatography; And / or, in step (2), the compound When the base and compound III react, first add the compound to a solvent, and then add the base and compound III; And / or, in step (2), after the reaction, an aqueous solution of saturated sodium bisulfate is added to the reaction solution, and extraction is carried out with ethyl acetate. After washing, drying, and concentrating the organic phase, compound IV is obtained by column chromatography; Preferably, in step (1), the base A is sodium hydroxide; and / or, in step (2), the temperature when adding the base and compound III is -60 to -90 °C.

6. A method for preparing intermediate V of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, characterized in that: It comprises the following steps: Step (A): Prepare compound IV according to the method described in any one of claims 1 to 5; Step (B): In a solvent, compound IV and a photocatalyst react under light irradiation to obtain compound V; wherein, R1 and R2 are each independently selected from the groups described in any one of claims 1 to 5; Preferably, in step (B), the equivalent ratio of compound IV to the photocatalyst is 1:(0.05 - 0.5); and / or, in step (B), the photocatalyst is selected from benzophenone, 9-thioxanthone, 2-isopropylthioxanthone, or 4,4'-dimethoxybenzophenone; and / or, in step (B), the wavelength of the light is 360 - 390 nm; and / or, in step (B), the temperature of the reaction is 25 - 35 °C, and the reaction time is 10 - 20 h; and / or, before obtaining compound V in step (B), the following purification steps are included: 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; More preferably, in step (B), the solvent is acetonitrile; and / or, in step (B), the equivalent ratio of compound IV to the photocatalyst is 1:0.2; and / or, in step (B), the photocatalyst is selected from benzophenone; and / or, in step (B), the wavelength of the light is 365 nm.

7. A method for preparing intermediate VI of 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, characterized in that: It comprises the following steps: Step (a): Prepare compound V according to the method described in claim 6; Step (b): In a solvent, compound V and a base react to obtain compound VI; wherein, R1 and R2 are each independently selected from the groups described in any one of claims 1 to 5; Preferably, in step (b), the equivalent ratio of compound V to the base is 1:(1 - 3); and / or, in step (b), the temperature of the reaction is 25 - 35 °C, and the reaction time is 10 - 20 h; and / or, before obtaining compound VI in step (b), the following purification steps are included: 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, triturating with petroleum ether, filtering, and drying the filter cake to obtain; More preferably, in step (b), the solvent is a mixed solution of tetrahydrofuran and methanol, and the volume ratio of tetrahydrofuran to methanol is 1:1; and / or, in step (b), the base is NaOH.

8. A method for synthesizing 4-fluoro-2-azabicyclo[2.1.1]hexane hydrochloride, characterized in that: It comprises the following steps: Step (I): Prepare compound VI according to the method described in claim 7; Step (II): In a solvent, react compound VI, a compound for quenching free radicals, a ligand, a photoinitiator, and a base to obtain compound VII; Step (III): In a solvent, compound VII reacts with a hydrogen chloride solution to obtain compound I; wherein, R1 and R2 are each independently selected from the groups described in any one of claims 1 to 5; Preferably, in step (II), the compound for quenching free radicals is selected from 2,4,6-triisopropylbenzenethiol, bis(2,4,6-triisopropylphenyl) disulfide or diphenyl disulfide; and / or, in step (II), the ligand is selected from 2,2'-dipyridylmethylamine, trimethylpyridine; and / or, in step (II), the photoinitiator is selected from Fe(NO3)3·9H2O, FeCl3 or Fe(OTf)3; and / or, in step (II), the base is selected from Na2CO3, K2CO3, NaOH or triethylamine; and / or, in step (III), the hydrogen chloride solution is selected from ethyl acetate solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, diethyl ether solution of hydrogen chloride or methyl tert-butyl ether solution of hydrogen chloride; More preferably, in step (II), the compound for quenching free radicals is selected from 2,4,6-triisopropylbenzenethiol; and / or, in step (II), the ligand is selected from 2,2'-dipyridylmethylamine; and / or, in step (II), the photoinitiator is selected from Fe(NO3)3·9H2O; and / or, in step (II), the base is selected from Na2CO3; and / or, in step (III), the hydrogen chloride solution is selected from ethyl acetate solution of hydrogen chloride.

9. The synthesis method according to claim 8, wherein: in step (II), the equivalent ratio of compound VI, the compound for quenching free radicals, 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 - 400 nm, and the reaction time is 40 - 60 h; and / or, in step (III), the equivalent ratio of compound VII to hydrogen chloride in the ethyl acetate solution of hydrogen chloride is 1:(8 - 10); and / or, in step (III), the reaction temperature is 25 - 35 °C, and the reaction time is 1 - 10 h; Preferably, in step (II), the solvent is a mixed solution of dichloroethane and water, and the volume ratio of dichloroethane to water is 1:1; and / or, in step (II), the reaction is preceded by bubbling with an inert gas for 10 - 60 min; 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; and / or, in step (III), the solvent is diethyl ether; and / or, in step (III), the concentration of the ethyl acetate solution of hydrogen chloride is 1 - 5 M; And / or, in step (III), before obtaining compound I, the following purification step is included: adding ether to the reaction solution, filtering after mixing evenly, washing the filter cake with ether, and drying it to obtain the product.

10. Preparation of 4-fluoro-2-azabicyclo 2.1.1] Intermediate of hexane hydrochloride, characterized in that: The intermediate is selected from one of the following structures: Wherein, R2 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, trifluoroacetyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl, benzyl or benzoyl.

Images