A method for preparing bambuterol hydrochloride

Abstract

This invention provides a method for preparing bambuterol hydrochloride, comprising the following steps: (1) reacting compound 2 with a condensing agent and dimethylamine to obtain compound 3; (2) reacting compound 3 with a brominating agent to obtain compound 4; (3) reacting compound 4 with tert-butylbenzylamine and a catalyst to obtain compound 5; (4) reacting compound 5 with a reducing agent and treating it with hydrochloric acid to obtain compound 6, which is then reacted with a debenzylidene reagent to obtain the bambuterol hydrochloride. The preparation method provided by this invention has low toxicity, leaves no N,N-dimethylcarbamoyl chloride residue, is environmentally friendly, is simple, avoids dangerous high-pressure Pd / C hydrogenation operations, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing bambuterol hydrochloride, and more particularly to a method for preparing bambuterol hydrochloride with high yield. Background Technology

[0002] Bambuterol hydrochloride was first marketed in Sweden in 1990 by Draco, a subsidiary of the Swiss company Astra. It is a prodrug of terbutaline, a selective β2-receptor agonist. After oral absorption, it is metabolized to terbutaline by enzymes. Terbutaline primarily activates β2 receptors in bronchial smooth muscle, thereby relaxing the bronchial smooth muscle. Additionally, bambuterol hydrochloride also inhibits the release of inflammatory mediators from mast cells. The chemical name of bambuterol hydrochloride is (R,S)-1-[bis-3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride, with the following structural formula:

[0003]

[0004] Currently, the methods for preparing bambuterol hydrochloride disclosed in the literature are mainly limited to the following reports:

[0005] The earliest reported synthetic route for bambuterol hydrochloride in European patent EP43807A2 uses 3,5-dihydroxyacetophenone as a starting material, which undergoes esterification, bromination, and reaction with tert-butylbenzylamine to obtain 3,5-bis(N,N-dimethylaminoformyloxy)-ω-N-benzyltert-butylaminoacetophenone. Bambuterol hydrochloride is then obtained by high-pressure hydrogenation under Pd / C conditions. Although this process can produce qualified bambuterol hydrochloride, the overall yield is only 20%. Furthermore, it uses highly toxic and polluting bromine and involves high-pressure hydrogenation under Pd / C conditions, making the process cumbersome, dangerous, and environmentally problematic, unsuitable for industrial production.

[0006]

[0007] The Chinese Journal of New Drugs, Volume 10, Issue 6, pp. 433-434, reports an improvement in the process by using tert-butylamine instead of tert-butylbenzylamine for amination and sodium borohydride instead of palladium on carbon for reduction, thus avoiding pressurized hydrogenation. While this process avoids high-pressure hydrogenation of Pd / C, the reaction of a primary amine with an α-carbonyl bromide results in more side reactions and increased impurities.

[0008]

[0009] Chinese patent CN109942462A discloses another method for synthesizing bambuterol hydrochloride, using 3,5-dihydroxybenzaldehyde as the starting material. The process involves esterification, thioyl ylide reaction, and alkali cyclization, followed by ammonolysis with tert-butylamine to obtain bambuterol hydrochloride. Although this process shortens the reaction steps, it still uses the highly toxic substance N,N-dimethylcarbamoyl chloride. Furthermore, the thioyl ylide reagent trimethylsulfur iodide is expensive, and the reaction requires the introduction of nitrogen gas, making the operation cumbersome. In the final step, tert-butylamine is used for ammonolysis, resulting in a yield of only 68%, which does not offer a significant cost advantage.

[0010] The aforementioned synthetic process for bambuterol hydrochloride has the following shortcomings: The raw material N,N-dimethylcarbamoyl chloride is a controlled substance and is itself a genotoxic impurity in bambuterol hydrochloride, easily remaining in the bambuterol hydrochloride and causing excessive levels of genotoxic impurities; palladium hydrogenation on carbon poses safety hazards; liquid bromine is highly corrosive, genotoxic, has a strong odor during use, and causes significant environmental pollution; the overall yield is low, reagents are expensive, and costs are high. Therefore, providing a synthetic process for bambuterol hydrochloride with high yield, low toxicity, simple preparation method, and low reaction conditions has become an urgent problem to be solved. Summary of the Invention

[0011] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing bambuterol hydrochloride, and more particularly, a method for preparing bambuterol hydrochloride with high yield. The preparation method provided by the present invention has low toxicity, leaves no N,N-dimethylcarbamoyl chloride residue, is environmentally friendly, is simple to implement, avoids dangerous high-pressure Pd / C hydrogenation operations, and is suitable for industrial production.

[0012] To achieve this objective, the present invention adopts the following technical solution:

[0013] This invention provides a method for preparing bambuterol hydrochloride, the method comprising the following steps:

[0014] (1) Compound 2 was reacted with a condensing agent and dimethylamine to obtain compound 3;

[0015] (2) Compound 3 was mixed with a brominating agent and reacted to obtain compound 4;

[0016] (3) Compound 4 was reacted with tert-butylbenzylamine and a catalyst to obtain compound 5;

[0017] (4) Compound 5 was mixed with a reducing agent to obtain compound 6, which was then mixed with a debento reagent and treated with hydrochloric acid to obtain the bambuterol hydrochloride.

[0018] The reaction route is as follows:

[0019]

[0020] The above method uses low-cost condensing agents and dimethylamine as raw materials, which solves the problem of residual genotoxic impurity N,N-dimethylcarbamoyl chloride and reduces production costs; the use of debenzylidene reagent for debenzylidene treatment avoids dangerous high-pressure Pd / C hydrogenation operation, making it suitable for industrial production; the overall synthesis process is environmentally friendly, the preparation method is simple, and the overall yield is high.

[0021] Preferably, the molar ratio of compound 2, condensing agent, and dimethylamine in step (1) is 1:(1.05-1.3):(1.5-2.5), wherein the amount of condensing agent can be 1.05, 1.1, 1.15, 1.2, 1.25, or 1.3, etc., and the amount of dimethylamine can be 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, or 2.5, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0022] Preferably, the condensing agent in step (1) includes CDI (N,N'-carbonyldiimidazole) or DSC (N,N'-disuccinimidyl carbonate).

[0023] Preferably, the reaction in step (1) is carried out in a solvent, which includes any one or a combination of at least two of acetonitrile, ethyl acetate or toluene, preferably toluene.

[0024] The aforementioned specific solvents can effectively promote the reaction and increase the overall yield.

[0025] Preferably, the reaction temperature in step (1) is 10-120℃ and the time is 1-10h. The temperature can be 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, 110℃ or 120℃, etc., and the time can be 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h or 10h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0026] Preferably, the molar ratio of compound 3 to brominating agent in step (2) is 1:(1-1.5), such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0027] Preferably, the brominating agent in step (2) includes copper bromide and / or potassium bromide, with copper bromide and potassium bromide being more preferred.

[0028] The aforementioned specific brominating agents avoid the use of highly toxic bromine in existing technologies, effectively improving production safety and being environmentally friendly; at the same time, the specific brominating agents can also increase the reaction yield.

[0029] Preferably, the reaction in step (2) is carried out in a solvent, which includes any one or a combination of at least two of acetonitrile, dichloromethane, ethyl acetate, chloroform or toluene, preferably a combination of chloroform and ethyl acetate.

[0030] The specific solvent combination described above can effectively improve the reaction yield.

[0031] Preferably, the reaction temperature in step (2) is 60-90℃ and the time is 2-6h. The temperature can be 60℃, 65℃, 70℃, 75℃, 80℃, 85℃ or 90℃, etc., and the time can be 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h or 6h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0032] Preferably, the molar ratio of compound 4 in step (3) to tert-butylbenzylamine and catalyst is 1:(2-4):(0.01-0.1), wherein the amount of tert-butylbenzylamine can be 2, 2.5, 3, 3.5 or 4, and the amount of catalyst can be 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.1, but is not limited to the values ​​listed above. Other values ​​not listed within the above range are also applicable.

[0033] Preferably, the catalyst in step (3) comprises any one or a combination of at least two of potassium iodide, sodium iodide or cuprous iodide, with potassium iodide being preferred.

[0034] The specific catalysts mentioned above can effectively improve the reaction yield.

[0035] Preferably, the reaction temperature in step (3) is 10-80℃ and the time is 1-5h. The temperature can be 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃ or 80℃, etc., and the time can be 1h, 2h, 3h, 4h or 5h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0036] Preferably, the molar ratio of compound 5 to the debenzylidene reagent in step (4) is 1:(1.2-1.7), such as 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6 or 1:1.7, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0037] The reducing agent in step (4) includes sodium borohydride and / or potassium borohydride.

[0038] Preferably, the debenzylidene reagent in step (4) includes trifluoroacetic acid and / or 1-chloroethyl chloroformate, preferably 1-chloroethyl chloroformate.

[0039] The aforementioned specific debenzylidene reagent can effectively remove the benzyl group from the amino group, avoiding the dangerous high-pressure Pd / C hydrogenation operation used in existing technologies, and is suitable for industrial production; at the same time, the specific debenzylidene reagent can further improve the reaction yield.

[0040] Preferably, the temperature of the reaction with the debenzylidene reagent in step (4) is 0-50℃ and the time is 3-5h. The temperature can be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃ or 50℃, etc., and the time can be 3h, 3.5h, 4h, 4.5h or 5h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] This invention provides a method for preparing bambuterol hydrochloride, using a low-cost condensing agent and dimethylamine as raw materials, solving the problem of residual genotoxic impurity N,N-dimethylcarbamoyl chloride and reducing production costs; using a debenzylidene reagent for debenzylidene treatment avoids the dangerous high-pressure Pd / C hydrogenation operation, making it suitable for industrial production; the overall synthesis process is environmentally friendly, the preparation method is simple, and the overall yield is high. Detailed Implementation

[0043] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0044] Example 1

[0045] This embodiment provides a method for preparing bambuterol hydrochloride, the specific steps of which are as follows:

[0046]

[0047] (1) Preparation of 5-acetyl-1,3-phenylene di(dimethylcarbamate) (compound 3)

[0048] 15.2 g of 3,5-dihydroxyacetophenone (compound 2) was added to a four-necked flask, followed by 120 mL of toluene solvent, 19.5 g of CDI, and 9.0 g of dimethylamine. The system was heated to 110 °C and refluxed for 2 hours. After the reaction was complete, the temperature was lowered to 20 °C, 100 mL of purified water was added, and the mixture was stirred. The pH was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was allowed to stand for separation. The organic phase was collected, the solvent was removed by vacuum evaporation, and 84 mL of isopropanol was added to dissolve the solid. The mixture was stirred, and 60 mL of petroleum ether was slowly added. The mixture was cooled to 0 °C and allowed to crystallize for 3 hours. The solid was filtered, washed with 30 mL of petroleum ether, filtered, and dried under vacuum at 50 °C for 8 hours to obtain 24.73 g of solid, with a yield of 84.12%.

[0049] (2) Preparation of 5-(bromoacetyl)-1,3-phenylene di(dimethylcarbamate) (compound 4)

[0050] Compound 3 (58.8 g), chloroform (250 mL), and ethyl acetate (250 mL) were placed in a three-necked flask equipped with a magnetic stirrer, a nitrogen inlet tube, and a reflux condenser. Copper bromide (44.6 g) and potassium bromide (11.9 g) were added over 2 hours. The reaction mixture was maintained at 75°C with nitrogen continuously flowing through the solution. After the addition was complete, the solution was heated for 1.5 hours until the green and dark copper bromide disappeared. The mixture was cooled to 20°C and filtered. The colorless solid copper chloride was washed with 250 mL of chloroform. The combined filtrate and washings were combined, the solvent was evaporated under reduced pressure, and 125 mL of anhydrous ethanol was added. The mixture was stirred for 1 hour, and a solid precipitated at 20°C. The solid was filtered, washed with 80 mL of petroleum ether, and filtered again to obtain the product. The product was then dried naturally under vacuum at 50°C for 8 hours to obtain 63.73 g of white solid, with a yield of 85.47%.

[0051] (3) Preparation of compound 5

[0052] Add 100 mL of butanone, 35 g (0.093 mol, 1.0 eq) of 3,5-(N,N-dimethylaminoformoxy)-2-bromoacetophenone, 48 g (0.29 mol, 3.25 eq) of N-benzyl tert-butylamine, 80 mL of butanone, and 0.75 g of potassium iodide to a three-necked flask. After the addition is complete, heat to 75 °C and reflux for 2.5 hours. After the reaction is complete, cool to 20 °C, filter, and wash twice with 50 mL of butanone each time. After the solvent is removed from the filtrate under reduced pressure, dissolve in 36 mL of ethanol. Then slowly add 70 mL of purified water, stir to precipitate the solid, stir at 0 °C for 3 hours, filter, wash twice with 40 mL of purified water each time, and dry under vacuum at 50 °C to obtain 35.25 g of a pale yellow solid, with a yield of 83.2%.

[0053] (4) Preparation of Bambuterol Hydrochloride

[0054] Add 18 g (0.039 mol, 1.0 eq) of bis-3,5-(N,N-dimethylaminoformoxy)-2-(N-benzyl-N-tert-butyl)aminoacetophenone, 27 mL of water, and 102 mL of anhydrous ethanol to a three-necked flask. Weigh 5.02 g (0.093 mol, 2.3 eq) of sodium borohydride and add it to the reaction system in two batches. Heat to 30 °C, stir for 2 h, and filter. Transfer the filtrate to another four-necked flask, add 52 mL of dichloromethane, stir, and allow to stand for separation. Collect the organic phase. Extract the aqueous phase with 30 mL of dichloromethane, allow to stand for separation, collect, combine the organic phases, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain an oily compound 6, which will be used in the next reaction.

[0055] Compound 6, 150 mL of dichloromethane, and 82 mL of 1-chloroethyl chloroformate were added to a four-necked flask at 20 °C. The mixture was heated to reflux and maintained for 2 hours. After vacuum concentration, 205 mL of methanol was added, and the mixture was refluxed for another 2 hours. The solvent was evaporated under reduced pressure, 25 mL of purified water was added, and the pH was adjusted to 10 with 10% sodium hydroxide solution at low temperature. The mixture was extracted twice with 90 mL of ethyl acetate each time. The organic layers were combined and evaporated under reduced pressure to an oily substance. The oily substance was dissolved in 30 mL of anhydrous ethanol. A mixture of 6.34 g of hydrochloric acid and 26 g of ethanol was slowly added dropwise to the reaction system. After the addition was complete, 90 mL of diethyl ether was added dropwise. The mixture was stirred to induce crystallization for 1 hour, cooled to 0 °C, and stirred for another 3 hours. The mixture was filtered, washed with 30 mL of acetone, dried under vacuum at 50 °C for 8 hours, and a white solid of 13.12 g, namely bambuterol hydrochloride, was obtained, with a yield of 84.5% and a purity of 99.76%. Characterization data are as follows: NMR δppm: 1.236H(t); 2.683H(s); 3.354H(p); 5.452H(t); 7.351H(q); 7.622H(d); (CDCl3, TMS).

[0056] Example 2

[0057] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that toluene is replaced with an equal amount of acetonitrile in step (1).

[0058] Example 3

[0059] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that toluene is replaced with an equal amount of ethyl acetate in step (1).

[0060] Example 4

[0061] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that in step (2), copper bromide is replaced with an equimolar amount of potassium bromide.

[0062] Example 5

[0063] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that potassium bromide is replaced with an equimolar amount of copper bromide in step (2).

[0064] Example 6

[0065] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that chloroform is replaced with ethyl acetate in step (2).

[0066] Example 7

[0067] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that ethyl acetate is replaced with chloroform in step (2).

[0068] Example 8

[0069] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that ethyl acetate is replaced with acetonitrile in step (2).

[0070] Example 9

[0071] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that potassium iodide is replaced with an equimolar amount of sodium iodide in step (3).

[0072] Example 10

[0073] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that potassium iodide is replaced with an equimolar amount of cuprous iodide in step (3).

[0074] Example 11

[0075] This embodiment provides a method for preparing bambuterol hydrochloride. The specific steps are the same as in Example 1, except that in step (4), 1-chloroethyl chloroformate is replaced with an equimolar amount of trifluoroacetic acid.

[0076] Comparative Example 1

[0077] This comparative example provides a method for preparing bambuterol hydrochloride (refer to EP43807A2), the specific steps of which are as follows:

[0078]

[0079] (1) 280 mL of N,N-dimethylcarbamoyl chloride was added to 152 g of 3,5-dihydroxyacetophenone in 700 mL of dry pyridine solution. The mixture was stirred at 70 °C for 18 hours. After vacuum evaporation, the residue was treated with a mixture of diethyl ether and water. The combined ether phases were then washed with water and dried with MgSO4. After evaporation, the residue was recrystallized from isopropanol petroleum ether to give 180.4 g, yield 61.16%.

[0080] (2) A solution of bromine in 200 mL of dioxane was added dropwise to a solution of 180 g of bis-3,5-(N,N-dimethylcarbamoyloxy)-acetophenone obtained in the previous step in 700 mL of dioxane. The mixture was stirred at 35 °C for 1 hour. The residue obtained after vacuum evaporation was recrystallized from isopropanol petroleum ether to give 174 g of solid, with a yield of 76.23%.

[0081] (3) Add 4.9 g of N-benzyl tert-butylamine in 30 mL of acetone to a solution of 5.6 g of the product obtained in the previous step in 75 mL of acetone. Reflux the mixture with stirring for 18 hours, filter, and evaporate under vacuum. Dissolve the residue in diethyl ether, add petroleum ether, and filter out the resulting yellow precipitate. Wash with water and recrystallize with a 1:1 mixture of isopropanol and petroleum ether. 4.6 g of white crystals are obtained, yield 67.29%.

[0082] (4) A solution of 0.3 g of the product obtained in the previous step in 50 mL of methanol was hydrogenated at 20 °C and 345,000 Pa (50 psig) for 18 hours in the presence of 0.1 g Pd / C. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was dissolved in isopropanol, and diethyl ether was added to precipitate the target compound. Yield: 0.18 g, yield 67.67%.

[0083] Test example:

[0084] The overall yields of the preparation methods provided in Examples 1-11 and Comparative Example 1 were calculated and statistically analyzed as follows:

[0085] Group Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Yield (%) 51.09％ 43.2％ 44.5％ 42.6％ 45.2％ 42.4％ Group Example 7 Example 8 Example 9 Example 10 Example 11 Comparative Example 1 Yield (%) 48.3％ 47.5％ 46.2％ 43.6％ 48.6％ 21.2％

[0086] The data above show that the preparation method provided by this invention avoids the use of highly toxic raw materials, is simple, has low reaction conditions, high yield, and is environmentally friendly. Comparative Examples 1-11 show that this invention can effectively improve the overall yield of the reaction by using a specific combination of solvent, brominating agent, and catalyst. Comparative Examples 1 and 1 show that the preparation method provided by this invention avoids the use of highly toxic reagents such as bromine and N,N-dimethylcarbamoyl chloride, reducing production costs. The use of a debenzylidene reagent for debenzylidene treatment avoids the dangerous high-pressure Pd / C hydrogenation operation, making it suitable for industrial production. The overall synthesis process is environmentally friendly, the preparation method is simple, and the overall yield is high.

[0087] The applicant declares that the present invention illustrates the preparation method of bambuterol hydrochloride through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0088] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0089] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing bambuterol hydrochloride, characterized in that, The preparation method includes the following steps: (1) Compound 2 is mixed with a condensing agent and dimethylamine to react and obtain compound 3; the condensing agent is CDI or DSC; (2) Compound 3 is mixed with a brominating agent to react and obtain compound 4; the brominating agent is copper bromide and / or potassium bromide; (3) Compound 4 is reacted with tert-butylbenzylamine and a catalyst to obtain compound 5; the catalyst is any one or a combination of at least two of potassium iodide, sodium iodide or cuprous iodide; (4) Compound 5 is mixed with a reducing agent to obtain compound 6, which is then mixed with a debenzylidene reagent and treated with hydrochloric acid to obtain the bambuterol hydrochloride; the reducing agent is sodium borohydride and / or potassium borohydride, and the debenzylidene reagent is trifluoroacetic acid and / or 1-chloroethyl chloroformate. The reaction route is as follows: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of compound 2 to condensing agent and dimethylamine in step (1) is 1:(1.05-1.3):(1.5-2.5).

3. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out in a solvent, which is any one or a combination of at least two of acetonitrile, ethyl acetate or toluene.

4. The preparation method according to claim 3, characterized in that, The solvent is toluene.

5. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out at a temperature of 10-120℃ for 1-10 h.

6. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of compound 3 to the brominating agent is 1:(1-1.5).

7. The preparation method according to claim 1, characterized in that, The brominating agents are copper bromide and potassium bromide.

8. The preparation method according to claim 1, characterized in that, The reaction in step (2) is carried out in a solvent, which is any one or a combination of at least two of acetonitrile, dichloromethane, ethyl acetate, chloroform or toluene.

9. The preparation method according to claim 8, characterized in that, The solvent is a combination of chloroform and ethyl acetate.

10. The preparation method according to claim 1, characterized in that, The reaction in step (2) is carried out at a temperature of 60-90℃ for 2-6 hours.

11. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of compound 4 to tert-butylbenzylamine and catalyst is 1:(2-4):(0.01-0.1).

12. The preparation method according to claim 1, characterized in that, The catalyst is potassium iodide.

13. The preparation method according to claim 1, characterized in that, The reaction in step (3) is carried out at a temperature of 10-80℃ for 1-5 hours.

14. The preparation method according to claim 1, characterized in that, In step (4), the molar ratio of compound 5 to the debenzylidene reagent is 1:(1.2-1.7).

15. The preparation method according to claim 1, characterized in that, The debenzylidene reagent in step (4) is 1-chloroethyl chloroformate.

16. The preparation method according to claim 1, characterized in that, The reaction in step (4) with the debenzylidene reagent is carried out at a temperature of 0-50℃ for 3-5 h.

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