A method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3,1,0]hexane hydrochloride and its derivatives

Abstract

The present invention provides a method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives, belonging to the technical field of chemical synthesis. The present invention first provides a method for synthesizing an intermediate of exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives, and then uses this intermediate to synthesize exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives. The synthesis method of the present invention has mild reaction conditions, simple operation, does not require separation of exo and endo forms, and at the same time does not require the use of expensive metal reagents and highly dangerous organic reagents or solvents, with low cost and high safety; moreover, the product obtained by the synthesis method of the present invention has high yield and high purity. The synthesis method of the present invention is easy to scale up, laying a solid foundation for subsequent process scale-up.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives. Background Art

[0002] Exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane is a kind of molecular building block compound and an intermediate for drug synthesis. For example, the US patent application with the publication number US20200054617A1 discloses a possible plasma kallikrein inhibitor, in which this molecular building block is required.

[0003]

[0004] Exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane

[0005] Currently, there is no literature report on the synthesis of exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride. The inventors deduced according to the prior art and the conventional functional group transformation methods in this field that its traditional synthesis method may need to use the following steps:

[0006]

[0007] Among them, the first three steps are methods reported in the prior art, and the last two steps are deduced by the inventors according to the current product and the conventional functional group transformation methods in this field. The first step is the ring closure of N-Boc-3-pyrroline and ethyl diazoacetate (the yield of the patent application with the publication number WO2022198112A1 is 8.62%, the yield of the patent application with the publication number WO202068867A1 is 13%, the yield of the US patent application with the publication number US20140343295A1 is 43.3%, and the yield of the patent application with the publication number WO2014111496A1 is 47%); the second step is hydrolysis (the yield of the patent application with the publication number WO202130711A1 is 88%, and the yield of the US patent application with the publication number US20140343295A1 is 96.5%); the third step is reduction (the yield of the patent application with the publication number WO202130711A1 is 95%); there is no original reference for the fourth step of fluorination and the fifth step of de-Boc. After the inventors conducted experiments according to the designed synthesis route, the product was successfully synthesized, and the yields were 72.4% and 92.9% respectively.

[0008] In the first step of the prior art, it is necessary to use rhodium (II) acetate dimer (1 g / ￥1250) as a catalyst, which is relatively expensive. During the reaction process, two products, endo and exo, will be generated, and column purification is quite difficult. In addition, the flash point of ethyl diazoacetate is only 26 °C, and the fire risk is relatively high, which is not conducive to large-scale synthesis, and the yield is relatively low. According to the experimental results of the inventor repeating the literature, the yield of the first two steps is only 18.9%, and the total yield of the five steps is only 11%. Due to the reasons of the reagents used, the safety risk is high and large-scale production cannot be achieved. Summary of the Invention

[0009] In view of the deficiencies of the prior art, the present invention provides a method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives.

[0010] The present invention provides a method for synthesizing an intermediate of exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives, which comprises the following steps:

[0011]

[0012] Compound 1, copper (I) bromide dimethyl sulfide complex, and vinylmagnesium bromide react in a solvent to obtain Compound 2;

[0013] Among them,

[0014] n is 1 or 2;

[0015] X is selected from NR1 or O;

[0016] R1 is a protecting group.

[0017] Further, R1 is selected from tert-butoxycarbonyl.

[0018] Further, the foregoing synthesis method comprises the following steps:

[0019] Compound 1 and copper (I) bromide dimethyl sulfide complex are added to a solvent, and then vinylmagnesium bromide is added for reaction to obtain Compound 2;

[0020] Preferably,

[0021] The equivalent ratio of Compound 1, copper (I) bromide dimethyl sulfide complex, and vinylmagnesium bromide is 1:0.1-0.5:1-3;

[0022] and / or, the solvent is tetrahydrofuran;

[0023] and / or, the temperature for adding vinylmagnesium bromide is -30 to -40 °C;

[0024] and / or, the reaction is carried out at -30 to -40 °C for 10 to 30 minutes, and then the temperature is raised to 0 to 30 °C for reaction for 0 to 5 hours;

[0025] More preferably, the reaction is carried out under the protection of an inert gas.

[0026] Furthermore, the reaction further includes a purification step: pouring the reaction solution into a saturated aqueous ammonium chloride solution for quenching, filtering, separating the obtained filtrate, extracting the aqueous phase with an organic solvent, combining all organic phases, washing and drying the organic phase, and then concentrating and passing through a column to obtain compound 2;

[0027] Preferably, the organic solvent for extraction is ethyl acetate.

[0028] The present invention also provides a method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives, which comprises the following steps:

[0029]

[0030] (1) Compound 1 is used to obtain Compound 2 according to the aforementioned synthesis method;

[0031] (2) Compound 2 is dissolved in a solvent, and diethylaminosulfur trifluoride is added to react to obtain compound 3;

[0032] in,

[0033] n is 1 or 2;

[0034] X is selected from NR1 or O;

[0035] R1 is a protecting group;

[0036] Preferably, R1 is selected from tert-butyloxycarbonyl.

[0037] Further,

[0038] In step (2), the equivalent ratio of compound 2 to diethylaminosulfur trifluoride is 1:1-5;

[0039] And / or, in step (2), the solvent is dichloromethane;

[0040] And / or, in step (2), the temperature when adding diethylaminosulfur trifluoride is -80 to 20°C;

[0041] And / or, in step (2), the reaction is carried out at 20 to 30° C. for 1 to 16 hours;

[0042] Preferably, the reaction is carried out under the protection of an inert gas.

[0043] Further, in step (2), after the reaction, a purification step is further included: adding the reaction solution into a saturated aqueous solution of sodium bicarbonate, stirring and then separating the liquid, extracting the aqueous phase with an organic solvent, combining all the organic phases, drying the organic phases, and then concentrating, with or without column chromatography, to obtain compound 3;

[0044] Preferably, the organic solvent for extraction is ethyl acetate.

[0045] Further, when X is selected from NR1, the following steps are further included:

[0046]

[0047] Performing a deprotection reaction on compound 3 to obtain compound 4 or its salt;

[0048] Wherein,

[0049] n is 1 or 2;

[0050] X is selected from NR1;

[0051] R1 is a protecting group;

[0052] Preferably,

[0053] When R1 is selected from tert-butoxycarbonyl, an acid compound solution is added to compound 3, and after the reaction, compound 4 or its salt is obtained.

[0054] Further, the equivalent ratio of compound 3 to the acid compound is 1:5 to 10;

[0055] And / or, compound 3 is soluble or insoluble in a solvent;

[0056] And / or, the acid compound solution is trifluoroacetic acid solution, hydrogen chloride solution, sulfuric acid solution;

[0057] And / or, the reaction is carried out at 20 - 30 °C for 1 - 16 h;

[0058] Preferably,

[0059] The solvent in which compound 3 is soluble is dichloromethane, chloroform, dioxane, ethyl acetate, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, toluene, ether, water;

[0060] And / or, when the acid compound solution is hydrogen chloride solution, the hydrochloride salt of compound 4 is obtained The hydrogen chloride solution is a hydrogen chloride solution in dioxane, ethyl acetate, methanol, ether;

[0061] More preferably,

[0062] The solvent in which the compound 3 is dissolved is dichloromethane;

[0063] and / or, the concentration of the hydrogen chloride solution is 1 - 5 M.

[0064] Furthermore, after the reaction, a purification step is included: the reaction solution is concentrated, and it is obtained after washing or without washing.

[0065] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0066] The present invention provides a method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives. The entire synthetic route has only three steps. The first step is the ring-opening of epoxy with vinylmagnesium bromide Grignard reagent, the second step is the ring-closing with diethylaminosulfur trifluoride to form the exo product, and the third step is deprotection. The synthetic method of the present invention has mild reaction conditions, simple operation, does not require the separation of exo and endo forms, and at the same time does not require the use of expensive metal reagents and highly dangerous organic reagents or solvents. It has low cost and high safety; and the product obtained by the synthetic method of the present invention has high yield and high purity. The synthetic method of the present invention is easy to scale up, laying a solid foundation for subsequent process scale-up.

[0067] Obviously, based on the above content of the present invention, according to the common general knowledge and customary means in the art, without departing from the above basic technical idea of the present invention, various other forms of modification, substitution or variation can be made.

[0068] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be understood 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 belong to the scope of the present invention. Description of the Drawings

[0069] Figure 1 It is the H-NMR (CDCl3) spectrum of compound III-1.

[0070] Figure 2 It is the H-NMR (CDCl3) spectrum of compound IV-1.

[0071] Figure 3 It is the H-NMR (CD3OD) spectrum of compound I-1.

[0072] Figure 4 It is the F-NMR (d-DMSO) spectrum of compound I-1.

[0073] Figure 5 It is the H-NMR (CDCl3) spectrum of compound III-2.

[0074] Figure 61H-NMR (CDCl3) spectrum of compound Ⅳ-2.

[0075] Figure 7 1H-NMR (CD3OD) spectrum of compound Ⅰ-2.

[0076] Figure 8 19F-NMR (CD3OD) spectrum of compound Ⅰ-2.

[0077] Figure 9 1H-NMR (CDCl3) spectrum of compound Ⅲ-3.

[0078] Figure 10 1H-NMR (CDCl3) spectrum of compound Ⅳ-3.

[0079] Figure 11 19F-NMR (CDCl3) spectrum of compound Ⅳ-3. Detailed implementation methods

[0080] The raw materials and equipment used in the present invention are all known products, obtained by purchasing commercially available products. Copper(I) bromide dimethyl sulfide complex, 1M solution of vinylmagnesium bromide in tetrahydrofuran, and 4M solution of hydrogen chloride in dioxane are all commercially available products.

[0081] In the present invention, room temperature refers to 20 - 30 °C, and overnight refers to 12 - 16 h.

[0082] Example 1. Preparation of compound Ⅰ-1

[0083]

[0084] Preparation of compound Ⅲ-1:

[0085] Under nitrogen protection, add compound Ⅱ-1 (5 g, 26.99 mmol, 1 eq), tetrahydrofuran (50 mL), and copper(I) bromide dimethyl sulfide complex (1.11 g, 5.40 mmol, 0.2 eq) to a 250 mL three-necked flask; cool down to -35 °C, control the temperature at -35 °C and dropwise add 1M solution of vinylmagnesium bromide in tetrahydrofuran (67 mL, 2.5 eq), react at -35 °C for 10 min, then raise the temperature to 0 °C and continue to react for 1 h. Slowly pour the reaction system into saturated ammonium chloride aqueous solution (100 mL) to quench; filter and collect the filtrate. Separate the layers of the filtrate, extract the aqueous phase with ethyl acetate (2 * 50 mL), combine the organic phases, wash with saturated sodium chloride (3 * 50 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, and pass through a silica gel column (using ethyl acetate and petroleum ether as eluents, the volume ratio of ethyl acetate to petroleum ether is 0 - 15%), to obtain 4.5 g of yellow oil (compound Ⅲ-1). The yield of compound Ⅲ-1 is 78.16%, and the purity is 91.9%. The 1H-NMR (CDCl3) spectrum of compound Ⅲ-1 is as followsFigure 1 as shown

[0086] Preparation of Compound Ⅳ-1:

[0087] At room temperature, under nitrogen protection, Compound Ⅲ-1 (10 g, 47 mmol, 1.0 eq) and dichloromethane (100 mL) were added respectively, and then the temperature was lowered to -78 °C. Diethylaminosulfur trifluoride (22.7 g, 141 mmol, 3.0 eq) was added dropwise. After addition, the temperature was slowly restored to room temperature, and the reaction was carried out overnight. The reaction solution was slowly added to the cooled saturated sodium bicarbonate aqueous solution (200 mL), stirred for 30 min, separated, and the aqueous phase was extracted with dichloromethane (2 x 200 mL). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column (ethyl acetate and petroleum ether as eluents, volume ratio of ethyl acetate to petroleum ether was 0 - 5%), to obtain 8 g of a pale yellow oily liquid (Compound Ⅳ-1). The yield of Compound Ⅳ-1 was 80%, and the purity was greater than 90%. The H-NMR (CDCl3) spectrum of Compound Ⅳ-1 is as Figure 2 as shown

[0088] Preparation of Compound Ⅰ-1:

[0089] At 0 °C, Compound Ⅳ-1 (8 g, 37.2 mmol, 1.0 eq) and dichloromethane (80 mL) were added to a 250 mL three-necked flask, and 4M hydrogen chloride dioxane solution (56 mL, 224 mmol, 6.0 eq) was slowly added. The reaction was carried out overnight at room temperature. Concentrated, washed with anhydrous diethyl ether (10 mL), and filtered to obtain 5.1 g of a white solid (Compound Ⅰ-1). The yield of Compound Ⅰ-1 was 91%, and the purity was 98.75%. The H-NMR (CD3OD) spectrum of Compound Ⅰ-1 is as Figure 3 as shown, and the F-NMR (d-DMSO) spectrum of Compound Ⅰ-1 is as Figure 4 as shown

[0090] Example 2. Preparation of Compound Ⅰ-2

[0091]

[0092] Preparation of Compound Ⅲ-2:

[0093] Under nitrogen protection, add compound II-2 (20 g, 100.38 mmol, 1 eq), tetrahydrofuran (200 mL), and copper(I) bromide dimethyl sulfide complex (4.13 g, 20.08 mmol, 0.2 eq) to a 500 mL three-necked flask; cool the temperature to -35 °C, control the temperature at -35 °C and dropwise add a 1 M tetrahydrofuran solution of vinylmagnesium bromide (150.6 mL, 1.5 eq). After reacting at -35 °C for 10 min, allow the temperature to rise to room temperature naturally and continue the reaction for 4 h. Slowly pour the reaction system into a saturated ammonium chloride aqueous solution (300 mL) to quench the reaction; filter and collect the filtrate. Separate the layers of the filtrate, extract the aqueous phase with ethyl acetate (2 × 200 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column (using ethyl acetate and petroleum ether as eluents, the volume ratio of ethyl acetate to petroleum ether is 0 - 15%) to obtain 20.3 g of a colorless oil (compound III-2). The yield of compound III-2 is 88.97% and the purity is 85.3%. The H-NMR (CDCl3) spectrum of compound III-2 is as shown in Figure 5 shown.

[0094] Preparation of compound IV-2:

[0095] At room temperature, under nitrogen protection, add compound III-2 (10 g, 43.99 mmol, 1.0 eq) and dichloromethane (100 ml) respectively, then cool the temperature to -78 °C, dropwise add diethylaminosulfur trifluoride (14.18 g, 87.99 mmol, 2.0 eq). After adding, slowly restore to room temperature and react overnight. Drop the reaction solution into a cooled saturated sodium bicarbonate aqueous solution (250 mL), stir for 10 min, separate the layers, extract the aqueous phase with dichloromethane (2 × 100 mL), collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column (using ethyl acetate and petroleum ether as eluents, the volume ratio of ethyl acetate to petroleum ether is 0 - 5%) to obtain 3.1 g of a pale yellow oily liquid (compound IV-2). The yield is 30.7% and the purity is 88%. The H-NMR (CDCl3) spectrum of compound IV-2 is as shown in Figure 6 shown.

[0096] Preparation of compound I-2:

[0097] Add compound IV-2 (1.3 g, 5.67 mmol, 1.0 eq) and a 4 M hydrogen chloride dioxane solution (13 mL, 52 mmol, 9.2 eq) to a 100 mL three-necked flask and react overnight at room temperature. Concentrate to obtain 0.9 g of a yellow viscous oil (compound I-2). The yield is 95.73%. The purity is 90%. The H-NMR (CD3OD) spectrum of compound I-2 is as shown in Figure 7 shown, and the F-NMR (CD3OD) spectrum of compound I-2 is as shown in Figure 8 shown.

[0098] Example 3: Preparation of Compound Ⅳ-3

[0099]

[0100] Preparation of Compound Ⅲ-3:

[0101] Under nitrogen protection, add Compound Ⅱ-3 (10 g, 116.16 mmol, 1 eq), tetrahydrofuran (100 mL), and copper(I) bromide dimethyl sulfide complex (4.78 g, 23.23 mmol, 0.2 eq) into a 250 mL three-necked flask; cool down to -35 °C, and dropwise add a 1 M tetrahydrofuran solution of vinylmagnesium bromide (232.3 mL, 2 eq) while maintaining the temperature at -35 °C. After reacting for 30 min at -35 °C, slowly pour the reaction system into a saturated ammonium chloride aqueous solution (100 mL) to quench the reaction; filter and collect the filtrate. Separate the layers of the filtrate, extract the aqueous phase with ethyl acetate (2 * 100 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column (using ethyl acetate and petroleum ether as eluents, and the volume ratio of ethyl acetate to petroleum ether is 0 - 20%), to obtain 7.5 g of a yellow oil (Compound III-3). The yield of Compound III-3 is 56.6%, and the purity is 80.9%. The 1H-NMR (CDCl3) spectrum of Compound Ⅲ-3 is as Figure 9 shown.

[0102] Preparation of Compound Ⅳ-3:

[0103] At room temperature, under nitrogen protection, add Compound Ⅲ-3 (6.5 g, 56.95 mmol, 1.0 eq) and dichloromethane (65 ml) respectively, then cool down to -78 °C, and dropwise add diethylaminosulfur trifluoride (27.54 g, 170.84 mmol, 3.0 eq). After adding, slowly warm up to room temperature and react overnight. Drop the reaction solution into a cooled saturated sodium bicarbonate aqueous solution (250 mL), stir for 10 min, separate the layers, extract the aqueous phase with dichloromethane (2 x 100 mL), collect the organic phase, dry over anhydrous sodium sulfate, and concentrate to obtain 4.8 g of a brown oil (Compound Ⅳ-3). The yield of Compound Ⅳ-3 is 72.58%, and the purity is 79.9%. The 1H-NMR (CDCl3) spectrum of Compound Ⅳ-3 is as Figure 10 shown, and the 19F-NMR (CDCl3) spectrum of Compound Ⅳ-3 is as Figure 11 shown.

[0104] In summary, the present invention provides a method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives. The entire synthetic route has only three steps. The first step is the ring-opening of epoxy with vinylmagnesium bromide Grignard reagent. The second step is the ring-closing with diethylaminosulfur trifluoride to form the exo product. The third step is deprotection. The synthetic method of the present invention has mild reaction conditions, is easy to operate, does not require the separation of exo and endo forms, and at the same time does not require the use of expensive metal reagents and highly dangerous organic reagents or solvents. It has low cost and high safety. Moreover, the product obtained by the synthetic method of the present invention has high yield and high purity. The synthetic method of the present invention is easy to scale up, laying a solid foundation for subsequent process scale-up.

Claims

1. A method for synthesizing exo-6-fluoromethyl-3-azabicyclo[3.1.0]hexane hydrochloride and its derivatives, characterized in that: It includes the following steps: (1) Compound 1, cuprous bromide dimethyl sulfide complex and vinyl magnesium bromide react in a solvent to obtain compound 2; (2) Compound 2 is dissolved in a solvent, and diethylaminosulfur trifluoride is added to react to obtain compound 3; in, n is 1 or 2; X is selected from NR1 or O; R1 is a protecting group.

2. The synthesis method according to claim 1, characterized in that: R1 is selected from tert-butyloxycarbonyl.

3. The synthesis method according to claim 1 or 2, characterized in that: Step (1) includes the following steps: Compound 1 and cuprous bromide dimethyl sulfide complex are added into a solvent, and then vinyl magnesium bromide is added to react to obtain compound 2.

4. The synthesis method according to claim 3, characterized in that: In step (1), the equivalent ratio of compound 1, cuprous bromide dimethyl sulfide complex and vinyl magnesium bromide is 1:0.1-0.5:1-3; And / or, in step (1), the solvent is tetrahydrofuran; And / or, in step (1), the temperature for adding vinyl magnesium bromide is -30 to -40°C; And / or, in step (1), the reaction is carried out at -30 to -40°C for 10 to 30 minutes, and then the temperature is raised to 0 to 30°C for 0 to 5 hours.

5. The synthesis method according to claim 4, characterized in that: In step (1), the reaction is carried out under the protection of an inert gas.

6. The synthesis method according to claim 3, characterized in that: In step (1), the reaction further includes a purification step: pouring the reaction solution into a saturated aqueous ammonium chloride solution for quenching, filtering, separating the obtained filtrate, extracting the aqueous phase with an organic solvent, combining all organic phases, washing and drying the organic phase, and then concentrating and passing through a column to obtain compound 2.

7. The synthesis method according to claim 6, characterized in that: In step (1), the organic solvent for extraction is ethyl acetate.

8. The synthesis method according to claim 1, characterized in that: In step (2), the equivalent ratio of compound 2 to diethylaminosulfur trifluoride is 1:1-5; And / or, in step (2), the solvent is dichloromethane; And / or, in step (2), the temperature when adding diethylaminosulfur trifluoride is -80~20°C; And / or, in step (2), the reaction is carried out at 20-30° C. for 1-16 hours.

9. The synthesis method according to claim 8, characterized in that: In step (2), the reaction is carried out under the protection of an inert gas.

10. The synthesis method according to claim 1, characterized in that: In step (2), the reaction further includes a purification step: adding the reaction solution into a saturated sodium bicarbonate aqueous solution, stirring and then separating the liquids, extracting the aqueous phase with an organic solvent, combining all the organic phases, drying the organic phase, and then concentrating and passing through a column or not to obtain compound 3.

11. The synthesis method according to claim 10, characterized in that: In step (2), the organic solvent for extraction is ethyl acetate.

12. The synthesis method according to claim 1, characterized in that: When X is selected from NR1, the following steps are also included: Performing a deprotection reaction on compound 3 to obtain compound 4 or a salt thereof; in, n is 1 or 2; X is selected from NR1; R1 is a protecting group.

13. The synthesis method according to claim 12, characterized in that: When R1 is selected from tert-butyloxycarbonyl, an acid compound solution is added to compound 3, and after reaction, compound 4 or a salt thereof is obtained.

14. The synthesis method according to claim 13, characterized in that: The equivalent ratio of compound 3 to the acid compound is 1:5~10; and / or, the compound 3 is soluble or insoluble in a solvent; And / or, the acid compound solution is trifluoroacetic acid solution, hydrogen chloride solution, sulfuric acid solution; And / or, the reaction is carried out at 20-30° C. for 1-16 hours.

15. The synthesis method according to claim 14, characterized in that: The solvent in which the compound 3 is dissolved is dichloromethane, chloroform, dioxane, ethyl acetate, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, toluene, ether, and water; and / or, when the acid compound solution is a hydrogen chloride solution, the hydrochloride of compound 4 is obtained; The hydrogen chloride solution is a dioxane solution of hydrogen chloride, an ethyl acetate solution, a methanol solution, or an ether solution.

16. The synthesis method according to claim 15, characterized in that: The solvent in which the compound 3 is dissolved is dichloromethane; And / or, the concentration of the hydrogen chloride solution is 1~5M.

17. The synthesis method according to claim 13, characterized in that: The reaction further includes a purification step: concentrating the reaction solution, and washing or not washing to obtain the product.

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