Novel synthesis method of key intermediate of cebrumex

Abstract

The invention discloses a novel synthesis method of a key intermediate of Hibrube, and aims to provide the novel synthesis method of the key intermediate of Hibrube, which is simple and safe to operate, good in stereoselectivity, higher in yield, lower in cost and suitable for industrial mass production. The key points of the technical scheme are as follows: in the process of preparing the key intermediate of the Hibomib, the initial raw materials are easy to obtain, the cost required during preparation is reduced, and a novel reaction route is adopted, so that the total reaction steps are fewer, and the operation difficulty is lower. The method is suitable for the technical field of medical chemistry.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, more particularly, it relates to a novel synthesis method of a key intermediate of hebernicin. BACKGROUND

[0002] Hebernicin (HS-25) is an important cholesterol-lowering drug, and the synthesis efficiency of its core intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid (compound of formula VII) is directly related to the industrial production cost and feasibility of the drug. Its chemical formula is as follows:

[0003]

[0004] Hebernicin, as China's first self-developed cholesterol absorption inhibitor, was approved for marketing in 2021 and is mainly used for the treatment of primary hypercholesterolemia. It can significantly reduce the level of low-density lipoprotein cholesterol (LDL-C) (the reduction can reach 32%) by inhibiting the absorption of cholesterol in the small intestine, and can be used in combination with statins.

[0005] The patent application with publication number WO2011017907A1 provides a preparation method of hebernicin. However, the synthesis route of the above method is too long, and there is no stereoselectivity in the reaction of generating double bond configuration. In addition, many reaction steps are not suitable for industrial production, which limits the application of this route in the commercialization of hebernicin. For changing the synthesis route of hebernicin, the most important thing is to change the synthesis method of the key intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid. This key intermediate affects the difficulty and cost of the whole process.

[0006] The synthesis method of the intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid disclosed in WO2015188727 has the problems of complicated operation, high risk, low yield, and high cost.

[0007] The synthesis method of the intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid disclosed in WO2022262768 has the problems of harsh reaction conditions and easy degradation of the intermediate during post-treatment.

[0008] The synthesis method of the intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid disclosed in CN117186018 makes small-scale modifications to the previous method and introduces cyanogen chloride during the reaction process, which simplifies the post-treatment and reduces the side reactions of subsequent reactions, and finally increases the reaction yield of the key intermediate. Overall, this method is only a small improvement, but it does not fundamentally solve the problem.

[0009] Therefore, it is necessary to develop a new synthetic route for the key intermediate of Harmane (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid to overcome the problems existing in the prior art. SUMMARY

[0010] In view of the deficiencies in the prior art, the purpose of the present application is to provide a new synthetic method for the key intermediate of Harmane, which is simple and safe to operate, has good stereoselectivity, high yield, low cost and is suitable for industrial mass production.

[0011] To achieve the above-mentioned purpose, the present application provides the following technical solution: a compound III,

[0012]

[0013] The synthesis formula of the compound III is as follows:

[0014]

[0015] Among them, X1 is selected from Br, Cl, preferably Br, and X2 is selected from acetoxy OAc, Br, Cl, OC(=O)OCH3, preferably OAc or Cl.

[0016] The method for synthesizing the compound III comprises the following steps: S11, adding 100ml THF solution in a dry three-necked flask, and adding 4-chloro-2-butyn-1-ol with an addition amount of 10.45g, 100.0mmol, and stirring the above-mentioned solution uniformly, and cooling to 0℃ after stirring is completed;

[0017] S12, adding 4-fluorophenyl magnesium bromide with an addition amount of 110mL, 110mmol, 1.0M THF solution into the cooled solution, and dropping into the above-mentioned solution, and controlling the temperature in the range of 0-5℃ during dropping;

[0018] S13, after the dropping is completed, gradually increasing the temperature of the mixture so that the temperature of the mixture is the same as the room temperature, and stirring the mixture for 1h;

[0019] S14, after the stirring is completed, quenching with saturated NH4Cl aqueous solution (500mL), and extracting with ethyl acetate (1L×3);

[0020] S15, after the extraction is completed, washing the combined organic phase with saturated brine, drying with Na2SO4, filtering, and vacuum concentrating to obtain an oily product.

[0021] Preferably, in the above reaction, the temperature of the reaction is set to -10-0°C, preferably 0°C, and the molar ratio of compound I to compound II is 1:1.05-1.3, preferably 1:1.1.

[0022] The compound V is synthesized based on compound III, and the synthesis formula of the compound V is as follows:

[0023]

[0024] wherein R is selected from C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably -CH3 or -CH2CH3.

[0025] Preferably, the synthesis method of the compound V comprises the following steps: S21, tetra-triphenylphosphine palladium (1.16 g, 1.0 mmol) and compound III (10.03 g, 50 mmol) are added to a 70 ml dichloromethane solution and stirred for 5 min;

[0026] S22, after the stirring is completed, diethyl malonate (9.61 g, 60 mmol) and sodium carbonate (6.36 g, 60 mmol) are added to the mixture and stirred at room temperature for 2 h;

[0027] S23, after the required reaction time, the reaction mixture is diluted with ethyl acetate (200 ml), and after the dilution, saturated NH4Cl aqueous solution (800 ml) is added;

[0028] S24, ethyl acetate is added to the mixture formed in step S23 for extraction, the addition times of ethyl acetate are set to 3 times, and the single addition amount is set to 50 ml, after the extraction, MgSO4 is used for drying, and then filtration is performed;

[0029] S25, after the filtration is completed, a mixed solvent of petroleum ether and ethyl acetate is added for crystallization, the ratio of petroleum ether to ethyl acetate is 3:1, and the product is obtained after filtration and vacuum drying.

[0030] The palladium catalyst used in the reaction is selected from Pd(PPh3)4, Pd2(dba)3, Pd(OAc)2, PdCl2, preferably Pd(PPh3)4, the reaction temperature is 10-25°C, preferably 15-25°C, the reaction solvent is dichloromethane, the molar ratio of the palladium catalyst to compound III in the reaction is 1:20-50, preferably 1:50, and the base in the reaction is KOAc, Na2CO3 or K2CO3, preferably Na2CO3.

[0031] The synthesis method of the compound VI is a preparation method of the compound VI, which comprises the following steps that S31, a three-mouth flask is added with prepared compound V (9.73 g, 30 mmol), cesium carbonate (11.73 g, 36 mmol) and deionized water (80 ml);

[0032] S32, the mixture is heated so that the temperature of the mixture is kept at 130 DEG C and stirred for one hour and 30 minutes;

[0033] S33, the mixture in step S32 is poured into saturated sodium bicarbonate (100 ml), extracted with ethyl acetate, and the adding times of ethyl acetate is set to 2 times and the single adding amount is set to 400 ml;

[0034] S34, after the extraction is completed, the mixture is washed with sodium bicarbonate (300 ml) and saturated brine (300 ml) in sequence, dried with sodium sulfate and concentrated under vacuum;

[0035] S35, after the concentration is completed, the mixture is crystallized with a mixed solvent of petroleum ether and ethyl acetate, the ratio of the mixed solvent is 5:1, and the product is obtained after filtration and vacuum drying;

[0036] The base is Li2SO4 or Cs2CO3, preferably Cs2CO3, and the reaction temperature is 130-160 DEG C, preferably 130-140 DEG C.

[0037] The preparation method of the key intermediate of the compound is as follows: S41, a flask is added with prepared compound VI (5.05 g, 20 mmol) and NaOH solution 50 ml (4 g NaOH is dissolved in 50 ml purified water), and the mixture is stirred at 20-30 DEG C for one hour;

[0038] S42, after the reaction is completed, the organic phase is extracted with purified water 20 ml twice, the water phase is combined, adjusted to ph=3-3.5 with dilute hydrochloric acid, extracted with ethyl acetate 30 ml twice, the organic phase is combined, washed with saturated brine 30 ml once, dried with anhydrous sodium sulfate, filtered, concentrated and dried under vacuum to form the product.

[0039] By adopting the technical scheme, beneficial effects are as follows: 1. In the process of preparing the key intermediate of sea horse maca, the starting material is easy to obtain, and the cost required in preparation is reduced. Specifically, in the preparation of compound III, the starting material is 4-chloro-2-butynyl-1-ol (compound I) and 4-fluorophenyl magnesium bromide (compound II), and in the preparation of compound V, malonic acid diethyl ester (compound IV) is added to compound III to form compound V. In the synthesis step, reagent raw materials such as THF solution, NH4Cl aqueous solution, ethyl acetate, brine, Na2SO4, tetraphenylphosphine palladium, sodium carbonate, cesium carbonate, deionized water, sodium bicarbonate, NaOH and dilute hydrochloric acid are all convenient to obtain for the staff, and a new reaction route is adopted to make the total reaction step number less and the operation difficulty lower.

[0040] 2. Further, in the preparation of compound III, the reaction has spatial selectivity by utilizing steric hindrance, so that the double bond of Z configuration can be directly constructed, and no stereoisomer is generated, which avoids the trouble of removing the stereoisomer. In the preparation of compound V, the allyl alkylation also has high regioselectivity due to steric hindrance and other reasons, and less impurities are generated. In the reaction, the relatively inexpensive tetraphenylphosphine palladium catalyst is used, and the cost can be further reduced by recycling. In the preparation of compound VI, decarboxylation reaction is needed, and water is used as the solvent in the decarboxylation reaction, which is relatively environmentally friendly and simple in post-treatment.

[0041] 3. Meanwhile, the total molar yield of the key intermediate of sea horse maca (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid prepared by the above scheme is 67.67%, and the overall yield is high. The present application does not involve high-pressure reaction, and there is no post-treatment step that is easy to cause degradation. The raw materials and reagents selected in the present application are relatively easy to obtain and relatively inexpensive. The reaction conditions are mild, the operation is simple and safe, the stereoselectivity is good, the yield is high, the cost is low, and the present application is suitable for industrial mass production.

[0042] 4. Furthermore, when selecting the catalyst in the reaction process, the example and the comparative example are set, so that the influence of the substrate (compound III) on the yield under the action of different palladium catalysts can be compared intuitively. By adding the same dose of different catalysts and operating in the same steps, different yields of the product are finally obtained. Based on the data judgment, the catalyst with the highest product yield can be obtained, which can further improve the product yield and has better use effect. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 The compound III is a synthesis method flow chart of the compound III of the new type synthesis method example of the key intermediate of sea horse maca.

[0044] Figure 2 Synthesis flow chart of compound V for the embodiment of the novel synthesis method of a key intermediate of Harmane;

[0045] Figure 3 Synthesis flow chart of compound VI for the embodiment of the novel synthesis method of a key intermediate of Harmane;

[0046] Figure 4 Synthesis flow chart of compound VII for the embodiment of the novel synthesis method of a key intermediate of Harmane. DETAILED DESCRIPTION

[0047] REFERENCE Figures 1 to 4 The embodiment of the novel synthesis method of a key intermediate of Harmane is further described.

[0048] For ease of description, spatial relative terms such as "upper", "lower", "left", "right" and the like are used in the embodiments to describe the relationship of one element or feature to another element or feature as shown in the drawings. It should be understood that the spatial terms are intended to include different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, an element described as being "below" or "beneath" other elements or features would then be oriented "above" the other elements or features. Thus, the exemplary term "below" can encompass both an orientation of above and below. The device can be otherwise oriented (rotated 90 degrees or located in any other orientation) and the spatially relative terms used herein interpreted accordingly.

[0049] Moreover, relative terms such as "first" and "second" are used merely to distinguish one from another of a same name, and do not necessarily require or imply any such actual relationship or order between the parts.

[0050] A compound III-1,

[0051]

[0052] The method for synthesizing the compound III-1 comprises the following steps: S11, 100ml THF solution is added in a dry three-necked flask, and 4-chloro-2-butyn-1-ol is added in an amount of 10.45g, 100.0mmol, and the solution is stirred uniformly, and after the stirring is completed, the temperature is lowered to 0℃;

[0053] S12, 4-fluorophenyl magnesium bromide is added into the cooled solution, the addition amount is 110 mL, 110 mmol, 1.0 M THF solution, which is added dropwise into the above solution, and the temperature is controlled in the range of 0-5°C during the dropwise addition;

[0054] S13, after the dropwise addition is completed, the temperature of the mixture is gradually increased to the same as the room temperature, and the mixture is stirred for 1 h;

[0055] S14, after the stirring is completed, saturated NH4Cl aqueous solution (500 mL) is used for quenching, and ethyl acetate (1 L x 3) is used for extraction;

[0056] S15, after the extraction is completed, the combined organic phase is washed with saturated brine, dried with Na2SO4, filtered, and concentrated under vacuum to obtain an oily product.

[0057] Preferably, in the above reaction, the temperature of the reaction is set to -10-0°C, preferably 0°C, and the molar ratio of compound I-1 to compound II-1 is 1:1.05-1.3, preferably 1:1.1.

[0058] The compound V-1 is synthesized based on compound III-1, and the synthesis formula of the compound V-1 is as follows:

[0059]

[0060] Preferably, the synthesis method of the compound V-1 comprises the following steps: S21, tetra-triphenylphosphine palladium (1.16 g, 1.0 mmol) and compound III-1 (10.03 g, 50 mmol) are added into 70 ml dichloromethane solution and stirred for 5 min;

[0061] S22, after the stirring is completed, diethyl malonate (9.61 g, 60 mmol) and sodium carbonate (6.36 g, 60 mmol) are added into the mixture, and the reaction is stirred at room temperature for 2 h;

[0062] S23, after the required reaction time, the reaction mixture is diluted with ethyl acetate (200 ml), and saturated NH4Cl aqueous solution (800 ml) is added after the dilution;

[0063] S24, ethyl acetate is added to the mixture formed in step S23 for extraction, the addition times of ethyl acetate are set to 3 times, and the single addition amount is set to 50 ml, and after the addition is completed, MgSO4 is used for drying, and then filtering;

[0064] S25, after filtration, add petroleum ether and ethyl acetate mixed solvent for crystallization, the ratio of petroleum ether and ethyl acetate is 3:1, after filtration and vacuum drying, the product is obtained.

[0065] The palladium catalyst used in the reaction is selected from Pd(PPh3)4, Pd2(dba)3, Pd(OAc)2, PdCl2, preferably Pd(PPh3)4, the reaction temperature is 10-25℃, preferably 15-25℃, the reaction solvent is dichloromethane, the molar ratio of palladium catalyst to compound III-1 in the reaction is 1:20-50, preferably 1:50, the base in the reaction is KOAc, Na2CO3 or K2CO3, preferably Na2CO3.

[0066] The synthesis formula of the compound VI-1 is as follows:

[0067]

[0068] The preparation method of the compound VI-1 is: S31, adding the prepared compound V-1 (9.73g, 30mmol), cesium carbonate (11.73g, 36mmol) and deionized water (80ml) into a three-necked flask;

[0069] S32, heating the mixture to keep the temperature of the mixture at 130℃ and stirring for 1 hour and 30 minutes;

[0070] S33, pouring the mixture in step S32 into saturated sodium bicarbonate (100ml), extracting with ethyl acetate, and setting the adding times of ethyl acetate to 2 times and the single adding amount to 400ml;

[0071] S34, after extraction, washing with sodium bicarbonate (300ml) and saturated brine (300ml) in sequence, and drying with sodium sulfate, vacuum concentration;

[0072] S35, after concentration, adding petroleum ether and ethyl acetate mixed solvent for crystallization, the ratio of petroleum ether and ethyl acetate mixed solvent is 5:1, and the product is obtained after filtration and vacuum drying;

[0073] The base is Li2SO4 or Cs2CO3, preferably Cs2CO3, and the reaction temperature is 130-160℃, preferably 130-140℃.

[0074] The synthesis formula of the key intermediate (compound VII) of the compound is as follows:

[0075]

[0076] The preparation method of the key intermediate of the above-mentioned Hibimab is as follows: S41, adding the prepared compound VI-1 (5.05 g, 20 mmol) into a flask, then adding NaOH solution 50 ml (4 g NaOH is dissolved in 50 ml purified water), and stirring the mixture at 20-30℃ for one hour;

[0077] S42, after the reaction is completed, the organic phase is extracted twice with purified water 20 ml, the water phase is combined, then diluted with hydrochloric acid to ph=3-3.5, extracted twice with ethyl acetate 30 ml, washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, vacuum concentrated and dried to form the product.

[0078] In the process of preparing the key intermediate of the above-mentioned Hibimab, the starting material is easy to obtain, which reduces the cost required in the preparation. Specifically, in the preparation of compound III-1, the starting material is 4-chloro-2-butyn-1-ol (compound I-1) and 4-fluorophenyl magnesium bromide (compound II-1), and in the preparation of compound V-1, diethyl malonate (compound IV-1) is added to compound III-1 to form compound V-1. In the synthesis step, reagents and raw materials such as THF solution, NH4Cl aqueous solution, ethyl acetate, brine, Na2SO4, tetrakis triphenylphosphine palladium, sodium carbonate, cesium carbonate, deionized water, sodium bicarbonate, NaOH and dilute hydrochloric acid are all convenient to obtain for the staff, and a new reaction route is used to make the total reaction steps fewer and the operation difficulty lower.

[0079] Further, in the preparation of compound III-1, the reaction has spatial selectivity by using steric hindrance, so that the double bond of Z configuration can be directly constructed without the generation of stereoisomers, which avoids the trouble of removing stereoisomers. In the preparation of compound V-1, the allyl alkylation also has high regioselectivity due to steric hindrance and other reasons, and produces less impurities. In the reaction, the relatively inexpensive tetrakis triphenylphosphine palladium catalyst is used, which can further reduce the cost through recycling. In the preparation of compound VI-1, decarboxylation reaction is needed, and water is used as the solvent in the decarboxylation reaction, which is more environmentally friendly and simple in post-treatment.

[0080] Meanwhile, the total molar yield of the key intermediate of the above-mentioned Hibimab (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid prepared by the above-mentioned scheme is 67.67%, which has high overall yield. The present application does not involve high-pressure reaction and post-treatment steps which are prone to degradation. The raw materials and reagents selected in the present application are relatively easy to obtain and relatively inexpensive. The reaction conditions are mild, the operation is simple and safe, the stereoselectivity is good, the yield is high, the cost is low, and it is suitable for industrial mass production.

[0081] And, in the selection of the catalyst in the reaction process, by setting examples and comparative examples, so that the substrate (compound III-1) can be directly compared with the yield under the action of different palladium catalysts, by adding the same dose of different catalysts, and operating in the same steps, the final yield of the product is different, based on the data of judgment, the catalyst with the highest yield of the product can be obtained, which can further improve the processing yield and has better use effect. Specifically, the yield of different palladium catalysts is shown in the following table:

[0082] Palladium catalyst [Pd(PPh3)4] [Pd2(dba)3] [Pd(OAc)2] [PdCl2] Yield 85.7％ 85.1％ 81.3％ 80.9％

[0083] It can be obtained from the table that under the same reaction conditions, the yield of the product obtained by using the catalyst Pd(PPh3)4 is the highest, so Pd(PPh3)4 is selected as the catalyst for the reaction. The meanings of the abbreviations used in the present application are as follows:

[0084] OAc: acetyloxy OC(=O)OCH3: methoxycarbonyloxy

[0085] EA: ethyl acetate

[0086] Pd: palladium

[0087] THF: tetrahydrofuran Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0088] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any change and replacement within the technical scheme range of the present application should be included in the protection scope of the present application.

Claims

1. A compound III, It is characterized by: The synthetic formula of compound III is as follows: Wherein, X1 is selected from Br, Cl, preferably Br, and X2 is selected from acetoxy OAc, Br, Cl, OC(=O)OCH3, preferably OAc or Cl.

2. A method for synthesizing compound III according to claim 1, characterized in that: The following steps are involved: S11. Add 100 ml of THF solution to a dry three-necked flask, and add 4-chloro-2-butyn-1-ol (10.45 g, 100.0 mmol). Stir the solution until uniform. After stirring, cool to 0°C. S12, add 4-fluorophenylmagnesium bromide to the cooled solution, the addition amount is 110 mL, 110 mmol, 1.0 M THF solution, and add it dropwise to the above solution, controlling the temperature in the range of 0-5°C during the addition; S13. After the dropwise addition is completed, gradually increase the temperature of the mixture until the temperature of the mixture is the same as room temperature, and stir the mixture for 1 hour; S14. After stirring, quench with saturated aqueous NH4Cl solution (500 mL), and extract with ethyl acetate (1 L×3); S15. After the extraction is completed, the combined organic phase is washed with saturated brine, dried over Na2SO4, filtered, and concentrated in vacuo to obtain an oily product.

3. The method for synthesizing compound III according to claim 2, characterized in that: In the reaction, the reaction temperature is set to -10-0°C, preferably 0°C, and the molar ratio of compound I to compound II is 1:1.05-1.3, preferably 1:1.

1.

4. A method for synthesizing compound V based on compound III according to claim 1, characterized in that: The synthesis formula of the compound V is as follows: Wherein, R is selected from C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably -CH3 or -CH2CH3.

5. A method for synthesizing compound V according to claim 4, characterized in that: The following steps are involved: S21, tetrakistriphenylphosphine palladium (1.16 g, 1.0 mmol) and compound III (10.03 g, 50 mmol) were added to 70 ml of dichloromethane solution and stirred for 5 min; S22. After stirring, diethyl malonate (9.61 g, 60 mmol) and sodium carbonate (6.36 g, 60 mmol) were added to the mixture and stirred for reaction at room temperature for 2 h. S23. After the desired reaction time, the reaction mixture was diluted with ethyl acetate (200 ml), and saturated aqueous NH4Cl solution (800 ml) was added after dilution; S24, adding ethyl acetate to the mixture formed in step S23 for extraction, the number of additions of ethyl acetate is set to 3 times, and the single addition amount is set to 50 ml. After the extraction is completed, it is dried with MgSO4 and then filtered; S25. After filtration, a mixed solvent of petroleum ether and ethyl acetate was added for crystallization, wherein the ratio of petroleum ether to ethyl acetate was 3:

1. The product was obtained after filtration and vacuum drying.

6. The method for synthesizing compound V according to claim 5, characterized in that: The palladium catalyst used in the reaction is selected from Pd(PPh3)4, Pd2(dba)3, Pd(OAc)2, PdCl2, preferably Pd(PPh3)4, the reaction temperature is 10-25°C, preferably 15-25°C, the reaction solvent is dichloromethane, the molar ratio of the palladium catalyst to compound III in the reaction is 1:20-50, preferably 1:50, and the base in the reaction is KOAc, Na2CO3 or K2CO3, preferably Na2CO3.

7. A method for synthesizing compound VI, characterized in that: The preparation method of the compound VI is as follows: S31, adding the prepared compound V (9.73 g, 30 mmol), cesium carbonate (11.73 g, 36 mmol) and deionized water (80 ml) into a three-necked flask; S32, heating the mixture so that the temperature of the mixture is maintained at 130° C., and stirring for 1 hour and 30 minutes; S33, pouring the mixture in step S32 into saturated sodium bicarbonate (100 ml), and extracting with ethyl acetate, wherein the number of additions of ethyl acetate is set to 2 times, and the single addition amount is set to 400 ml; S34. After the extraction is completed, wash with sodium bicarbonate (300 ml) and saturated brine (300 ml) in sequence, dry with sodium sulfate, and concentrate in vacuo; S35. After the concentration is completed, a mixed solvent of petroleum ether and ethyl acetate is added for crystallization, wherein the ratio of the mixed solvent of petroleum ether and ethyl acetate is 5:1, and the product is obtained after filtration and vacuum drying; The base is Li2SO4 or Cs2CO3, preferably Cs2CO3, and the reaction temperature is 130-160°C, preferably 130-140°C.

8. A method for preparing a key intermediate of Hebombe, characterized in that: The preparation method of the key intermediate of Hebomide is as follows: S41, adding the prepared compound VI (5.05 g, 20 mmol) into a flask, and then adding 50 ml of NaOH solution (4 g of NaOH dissolved in 50 ml of purified water), and stirring the mixture at 20-30° C. for one hour; S42. After the reaction is completed, the organic phase is extracted twice with 20 ml of purified water, the aqueous phases are combined and adjusted to pH = 3-3.5 with dilute hydrochloric acid, and then extracted twice with 30 ml of ethyl acetate. The organic phases are combined, washed once with 30 ml of saturated brine, and then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to form a product.

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