A preparation method of bupavaquinone

Abstract

The invention provides a method for preparing bupavaquinone, and relates to the field of bupavaquinone. The method for preparing bupavaquinone uses substituted 1,4-naphthoquinone as a raw material, and obtains bupavaquinone through a C-C coupling reaction. The method for preparing bupavaquinone of the invention avoids using p-tert-butylcyclohexylacetic acid or p-tert-butylcyclohexylacetaldehyde as a raw material, simplifies the process, reduces production costs, reduces wastewater generation in the production process, and improves environmental friendliness; the yield of the prepared bupavaquinone can reach 68%, and the purity can reach more than 99.9%, which is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the field of bupavaquin, and in particular to a preparation method of bupavaquin. Background Art

[0002] Bupavaquin is a drug for the treatment of bovine Theileriasis. It competitively inhibits the energy metabolism and mitochondrial respiration of the pathogen by blocking the Q cycle of the cytochrome bc1 complex on the inner membrane of the mitochondria in the pathogenic parasite cells, leading to the collapse of the mitochondrial inner membrane potential in the pathogenic parasite cells, and then leading to the death of the parasite. In the chemical structure of Bupavaquin, the substituents on both sides of the cyclohexyl group are in a trans configuration with each other. The specific chemical structure is as follows:

[0003] .

[0004] At the same time, bupavaquin can also improve cattle immunity and animal production performance, so bupavaquin has a high application value. At present, the global bupavaquin API is mainly produced by India. Although relevant domestic manufacturers have conducted research and development, due to its complex synthesis process, especially the difficulty in controlling the product configuration, the production cost is high and there is no competitive advantage. With the gradual expansion of the global annual consumption of bupavaquin and the increase in the current price of production raw materials, the price of bupavaquin has increased year by year; in addition, due to the constraints of import conditions, domestic preparation manufacturers often cannot purchase bupavaquin API.

[0005] The traditional synthesis method of bupavaquinone has the problems of low yield, high pollution and high loading of precious metal catalyst. EU patent EP0077550B1 discloses a production method of bupavaquinone, which uses chloronaphthoquinone as a starting material, and undergoes oxidative decarboxylation coupling with trans-configuration p-tert-butylcyclohexylacetic acid under the catalysis of silver nitrate and ammonium persulfate as an oxidant, and then hydrolyzes under alkaline conditions to obtain bupavaquinone; the specific process route is as follows:

[0006] .

[0007] However, the yield of the oxidative decarboxylation coupling step in this method is less than 40%, and the amount of silver nitrate used is large; the final product separation total yield is less than 15%; therefore, the overall production cost of this production method is high, and the amount of wastewater generated during the production process is large, and the environmental friendliness is poor. At the same time, although there are other related information disclosures of the synthesis routes of bupavaquin in the prior art (such as Chemical Bulletin 2021, Vol. 84, No. 9, pp. 952-957), the raw materials all use tert-butylcyclohexyl acetic acid or tert-butylcyclohexyl acetaldehyde. The use of these two compounds as raw materials to prepare bupavaquin has problems such as long synthesis routes and high production costs.

[0008] Therefore, with the gradual expansion of the global annual consumption of bupavaquin and the continuous increase in the current price of raw materials for production, it is urgent to optimize the synthesis process of bupavaquin and provide a preparation method of bupavaquin to avoid using 4-tert-butylcyclohexylacetic acid or 4-tert-butylcyclohexylacetaldehyde as raw materials, simplify the process, reduce production costs, reduce wastewater generation in the production process, improve environmental friendliness, and simultaneously improve product yield. Summary of the invention

[0009] In order to solve the technical problems existing in the prior art, the present invention provides a method for preparing bupavaquinone, which avoids the use of p-tert-butylcyclohexylacetic acid or p-tert-butylcyclohexylacetaldehyde as a raw material, simplifies the process, reduces production costs, reduces wastewater generation in the production process, improves environmental friendliness, and simultaneously improves product yield.

[0010] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0011] A method for preparing bupavaquinone, using substituted 1,4-naphthoquinone as a raw material, and obtaining bupavaquinone through the following CC coupling reaction, wherein the reaction route is:

[0012] ;

[0013] Wherein, X is one of the following: hydrogen, halogen, hydroxyl, or other groups that can be converted into hydroxyl;

[0014] X' is one of the following: hydrogen, halogen;

[0015] Y is one of the following: halogen, benzenesulfonyloxy, substituted benzenesulfonyloxy, alkanesulfonyloxy;

[0016] A is one of the following: cyclohexane, cyclohexene, or other cyclic compounds that can be converted into cyclohexane.

[0017] Preferably, X is hydroxyl; X' is hydrogen; Y is p-toluenesulfonyloxy; and A is cyclohexane.

[0018] Furthermore, 2-hydroxy-1,4-naphthoquinone and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate are used as raw materials, and a heating reaction is carried out under alkaline conditions and with the catalysis of 4-dimethylaminopyridine to obtain bupavaquinone.

[0019] Preferably, the molar ratio of 2-hydroxy-1,4-naphthoquinone to (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate is 0.9-1.1:1;

[0020] The heating reaction temperature is 35-45°C, and the heating reaction time is 10-15h.

[0021] Preferably, the amount of 4-dimethylaminopyridine added does not exceed 5% of the total weight of 2-hydroxy-1,4-naphthoquinone and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate.

[0022] Furthermore, the preparation method of (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate is as follows: 4-tert-butylcyclohexanone and nitromethane are used as raw materials, and 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene is obtained by heating under alkaline conditions; 4-tert-butylcyclohexylmethylamine is then obtained by catalytic hydrogenation, and then contacted with hydrogen chloride-ethanol solution to obtain 4-tert-butylcyclohexylmethylamine hydrochloride; 4-tert-butylcyclohexylmethylamine hydrochloride is reacted at high temperature in the presence of strong base potassium hydroxide to obtain (4-(tert-butyl)cyclohexyl)methanol; (4-(tert-butyl)cyclohexyl)methanol is reacted with p-toluenesulfonyl chloride to obtain (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate.

[0023] Preferably, in the preparation of 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene, the molar ratio of 4-tert-butylcyclohexanone to nitromethane is 1:27-30;

[0024] The heating reaction temperature is 100-102°C.

[0025] Preferably, in the preparation of 4-tert-butylcyclohexylmethylamine hydrochloride, the hydrogenation temperature is 10-35° C. and the hydrogenation pressure is 760-780 Torr.

[0026] Preferably, in the preparation of (4-(tert-butyl)cyclohexyl)methanol, the high temperature reaction temperature is 205-215°C, and the high temperature reaction time is 2-4h;

[0027] The molar ratio of 4-tert-butylcyclohexylmethylamine hydrochloride to potassium hydroxide is 1:8-10.

[0028] Preferably, in the preparation of (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate, the molar ratio of (4-tert-butylcyclohex-1-enyl)methanol to p-toluenesulfonyl chloride is 1:0.9-1.2.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The method for preparing bupavaquin of the present invention avoids the use of p-tert-butylcyclohexylacetic acid or p-tert-butylcyclohexylacetaldehyde as a raw material and does not require the use of silver nitrate, thereby avoiding the problem of extremely difficult product decolorization caused by the use of silver nitrate; the method for preparing bupavaquin has readily available raw materials, mild reaction conditions in the preparation process, effectively simplifies the process, reduces production costs, reduces wastewater generation in the production process, improves environmental friendliness, and simultaneously improves product yield.

[0031] (2) The preparation method of bupavaquinone of the present invention effectively overcomes the problem of slow reaction of (4-(tert-butyl)cyclohex-1-en-1-yl)methyl-4-methylbenzenesulfonate and 2-hydroxy-1,4-naphthoquinone in an alkaline environment by using 4-dimethylaminopyridine as a catalyst, and can shorten the reaction time, improve the reaction efficiency, and ensure that the reaction is carried out efficiently and controllably under mild conditions.

[0032] (3) The preparation method of bupavaquinone of the present invention uses 2-hydroxy-1,4-naphthoquinone as a starting material and reacts it with (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate under alkaline conditions to obtain bupavaquinone with a yield of up to 68% and a purity of more than 99.9wt%. The preparation process has mild reaction conditions, a simple process flow, can reduce the amount of wastewater generated, has good environmental friendliness, and is suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of bupavaquinone prepared in Example 5.

[0034] Figure 2 This is the liquid chromatogram of bupavaquin prepared in Example 5. DETAILED DESCRIPTION

[0035] In order to have a clearer understanding of the technical features, purposes and effects of the present invention, the specific implementation methods of the present invention are now described.

[0036] The present invention provides a method for preparing bupavaquinone, and the specific steps are as follows: using substituted 1,4-naphthoquinone as a raw material, and obtaining it through the following CC coupling reaction; the specific reaction route is:

[0037] .

[0038] Wherein, X is hydrogen, halogen, hydroxyl or other groups that can be converted into hydroxyl;

[0039] X' is hydrogen or halogen;

[0040] Y is halogen, benzenesulfonyloxy, substituted benzenesulfonyloxy or alkanesulfonyloxy;

[0041] A is cyclohexane, cyclohexene or other cyclic compounds that can be converted into cyclohexane.

[0042] Preferably, X is hydroxyl; X' is hydrogen; Y is p-toluenesulfonyloxy; and A is cyclohexane.

[0043] Specifically, 2-hydroxy-1,4-naphthoquinone and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate are used as raw materials, and under alkaline conditions and catalyzed by 4-dimethylaminopyridine, a heating reaction is performed to obtain bupavaquinone; the specific reaction route is:

[0044] .

[0045] Further, the (4-(tert-butyl)cyclohexyl)methyl toluenesulfonate is prepared by the following method: 4-tert-butylcyclohexanone and nitromethane are used as raw materials, and 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene is obtained by heating under alkaline conditions; then 4-tert-butylcyclohexylmethylamine is obtained by catalytic hydrogenation; the inventors found that 4-tert-butylcyclohexylmethylamine is very unstable as a free amine during the research and development process, which hinders the subsequent reaction; in order to overcome the above-mentioned defects, the inventors converted it into a hydrochloride to obtain 4-tert-butylcyclohexylmethylamine hydrochloride; 4-tert-butylcyclohexylmethylamine hydrochloride is reacted at high temperature in the presence of strong base potassium hydroxide to obtain (4-(tert-butyl)cyclohexyl)methanol; (4-(tert-butyl)cyclohexyl)methanol is reacted with p-toluenesulfonyl chloride to obtain (4-(tert-butyl)cyclohexyl)methyl toluenesulfonate. The specific reaction route is:

[0046] .

[0047] Furthermore, the preparation method of bupavaquine specifically comprises the following steps:

[0048] Step 1, preparation of 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene: a mixture of 4-tert-butylcyclohexanone, nitromethane and ethylenediamine is heated to reflux, and then nitromethane is recovered by vacuum distillation. The residue of the vacuum distillation is subjected to column chromatography (n-hexane: dichloromethane = 9:1) to obtain 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene;

[0049] Step 2, preparation of 4-tert-butylcyclohexylmethylamine hydrochloride: 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene is dissolved in ethanol, hydrogenated in the presence of a Pd-C catalyst, and then the Pd-C catalyst is filtered off. The filtrate is concentrated under reduced pressure, and HCl-EtOH is added to the residue after reduced pressure concentration, and the mixture is concentrated under reduced pressure and washed with n-hexane to obtain 4-tert-butylcyclohexylmethylamine hydrochloride;

[0050] Step 3, preparation of (4-(tert-butyl)cyclohexyl)methanol: a mixture of 4-tert-butylcyclohexylmethylamine hydrochloride, KOH and diethylene glycol was heated to reflux at 210°C for reaction, then cooled to room temperature, dichloromethane and deionized water were added, the organic phase was separated, the aqueous layer was extracted twice with dichloromethane, the organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated by column chromatography (n-hexane: EtOAc = 5:1), and recrystallized with n-hexane / ether to obtain 4-tert-butylcyclohexylmethanol;

[0051] Step 4, (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate: (4-(tert-butyl)cyclohexyl)methanol, p-toluenesulfonyl chloride, 4-dimethylaminopyridine, anhydrous dichloromethane and triethylamine were stirred at room temperature for reaction, and the reaction mixture was washed with HCl, deionized water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate;

[0052] Step 5. Preparation of bupavaquinone: A mixture of 2-hydroxy-1,4-naphthoquinone, triethylamine and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate is stirred in DMF for reaction, cooled to room temperature, HCl is added, the solution and water are poured into a separation funnel, dichloromethane is added, and the organic layer is separated from the aqueous layer; the organic layer is collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and then recrystallized using methanol to obtain bupavaquinone.

[0053] Preferably, in step 1, the molar ratio of 4-tert-butylcyclohexanone, nitromethane and ethylenediamine is 1:(27-30):(0.11-0.15), and the heating reflux temperature is 100-102°C.

[0054] Preferably, in step 2, the added weight of the Pd-Cd catalyst is 1-10% of the weight of 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene.

[0055] Preferably, in step 2, the hydrogenation temperature is 10-35° C., the hydrogenation pressure is 760-780 Torr, and rapid stirring is performed during the hydrogenation process.

[0056] Preferably, in step 3, the heating reflux reaction temperature is 205-215° C., and the heating reflux reaction time is 2-4 h.

[0057] Preferably, in step three, the molar ratio of 4-tert-butylcyclohexylmethylamine hydrochloride, KOH and diethylene glycol is 1:(8-10):(85-95).

[0058] Preferably, in step 4, the molar ratio of (4-tert-butylcyclohex-1-enyl)methanol, p-toluenesulfonyl chloride, 4-dimethylaminopyridine, anhydrous dichloromethane and triethylamine is 1:(0.9-1.2):(0.15-0.17):(29-33):(0.9-1.2).

[0059] Preferably, in step 5, the molar ratio of 2-hydroxy-1,4-naphthoquinone, triethylamine and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate is (0.9-1.1):(0.9-1.2):1, the stirring reaction temperature is 35-45°C, and the stirring reaction time is 10-15h.

[0060] Preferably, in step five, the amount of 4-dimethylaminopyridine added does not exceed 5% of the total weight of 2-hydroxy-1,4-naphthoquinone and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate.

[0061] It should be noted that in step five, the reaction between (4-(tert-butyl)cyclohex-1-en-1-yl)methyl-4-methylbenzenesulfonate and 2-hydroxy-1,4-naphthoquinone has not been reported in the literature. Although it can react under alkaline conditions, the reaction is very slow. The inventors have found that by adding 4-dimethylaminopyridine as a catalyst, the reaction efficiency is effectively improved, the reaction time is shortened, and the reaction can be carried out stably and controllably under mild conditions.

[0062] Example 1

[0063] This embodiment provides the preparation of 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene, specifically:

[0064] The structure of the 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene is shown below:

[0065] .

[0066] A mixture of 4-tert-butylcyclohexanone (10 g, 64.8 mmol), nitromethane (100 ml, 1.86 mol) and ethylenediamine (0.6 ml, 9.0 mmol) was heated to reflux at 101 °C for 3 h, and the nitromethane was recovered by vacuum distillation. The residue was subjected to column chromatography (n-hexane: dichloromethane = 9:1) to obtain a colorless oil (10.23 g, yield 80%).

[0067] The NMR data of the 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene prepared above:

[0068] 1 H NMR(400MHz, CDCl3) δ 5.90(brt,1H),4.85(s,2H),2.33-2.22(m,2H),2.12-1.92(m,2H),1.56-1.52(m,2H),1.36-1.32(m,1H),0.95(s,9H).

[0069] Example 2

[0070] This embodiment provides the preparation of 4-tert-butylcyclohexylmethylamine hydrochloride, specifically:

[0071] The structure of the 4-tert-butylcyclohexylmethylamine is as follows:

[0072] .

[0073] 4-(tert-Butyl)-1-(nitromethyl)cyclohex-1-ene (10.0 g, 50.0 mmol) was dissolved in ethanol (250 mL), and 10 wt% Pd-C catalyst (1.0 g) was added. After hydrogenation with stirring at room temperature and a hydrogen pressure of 770 Torr, the Pd-C catalyst was filtered out, and the filtrate was concentrated under reduced pressure to obtain a concentrate; HCl-EtOH (20 ml) with a volume concentration of 20% was added to the concentrate, and after concentration under reduced pressure, it was washed with n-hexane to obtain a white solid (8.04 g, yield 95%).

[0074] The NMR data of the 4-tert-butylcyclohexylmethylamine hydrochloride prepared above:

[0075] 1 H NMR(400MHz,D2O) δ 2.92(d,2H),1.72-1.62(m,4H),1.42-1.31(m,5H),1.14-1.12(m,1H),0.87(s,9H).

[0076] Example 3

[0077] This embodiment provides the preparation of (4-(tert-butyl)cyclohexyl)methanol, specifically:

[0078] The (4-(tert-butyl)cyclohexyl)methanol has the following structure:

[0079] .

[0080] A mixture of 4-tert-butylcyclohexylmethylamine hydrochloride (4.1 g, 20 mmol), KOH (10.0 g, 175 mmol) and diethylene glycol (160 mL) was placed in a round-bottom flask equipped with a reflux condenser, heated at 210 ° C for 3 h, cooled to room temperature, added with dichloromethane (200 mL) and H2O (150 mL), separated the organic phase, and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated by column chromatography (n-hexane: EtOAc = 5:1), and then recrystallized in n-hexane / diethyl ether to obtain a white solid (2.42 g, yield 71%).

[0081] The NMR data of the (4-(tert-butyl)cyclohexyl)methanol prepared above:

[0082] 1H NMR (400MHz, CDCl3) δ 4.23(brs,1H),3.47(dd,2H),1.70-1.52(m,4H),1.41-1.30(m,5H),1.12-1.10(m,1H),0.86(s,9H).

[0083] Example 4

[0084] This embodiment provides the preparation of (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate, specifically:

[0085] The (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate has the following structure:

[0086] .

[0087] To a 200 ml round-bottom flask containing (4-(tert-butyl)cyclohexyl)methanol (3.41 g, 20 mmol), p-toluenesulfonyl chloride (4.2 g, 22 mmol), 4-dimethylaminopyridine (0.4 g, 3.3 mmol), anhydrous dichloromethane (40 mL) and triethylamine (3 mL, 22 mmol) were added in sequence, and the resulting solution was stirred at room temperature overnight to obtain a reaction mixture; the reaction mixture was washed once with 1 mol / L HCl, water and saturated brine, respectively, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a light yellow solid (6.04 g, yield 93%).

[0088] The NMR data of the (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate prepared above:

[0089] 1 H NMR (400MHz, CDCl3) δ7.77(d,J=8.2Hz,2H),7.33(d,J=8.1Hz,2H),3.81(d,J=6.2Hz,2H),2.44(s ,3H),1.72-1.58(m,5H),1.52-1.42(m,4H),1.14-1.02(m,1H),0.83(s,9H).

[0090] Example 5

[0091] This embodiment provides the preparation of bupavaquinone, specifically:

[0092] A mixture of 2-hydroxy-1,4-naphthoquinone (0.50 g, 2.87 mmol), triethylamine (0.32 g, 3.16 mmol), (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate (0.93 g, 2.87 mmol), and 4-dimethylaminopyridine (5 mg, catalyst) was stirred in DMF (5 mL) at 40 °C for 12 h, cooled to room temperature, and 10 mL of 1N HCl was added. The resulting solution and water were poured into a separation funnel, and dichloromethane was added to separate the organic layer from the aqueous layer; the organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and then recrystallized from methanol to obtain bupavaquinone as a yellow solid (0.64 g, HPLC purity 99.96%, yield 68%).

[0093] The NMR data of the above-prepared bupavaquinone:

[0094] 1 H NMR (400 MHz, CDCl3) δ 8.13(dd,J=15.3,7.6Hz,2H),7.78(t,J=7.5Hz,1H),7.72(d,J=7.5Hz,1H),7.34(brs,1H),2.54(d,J=7 .2Hz,2H),1.78(t,J=13.9Hz,4H),1.60(ddd,J=11.2,10.0,6.3Hz,1H),1.19–0.91(m,5H),0.84(s,9H).

[0095] Comparative Example 1

[0096] This comparative example provides the preparation of bupavaquinone, which is different from Example 5 in that: no 4-dimethylaminopyridine is added as a catalyst; specifically:

[0097] A mixture of 2-hydroxy-1,4-naphthoquinone (0.50 g, 2.87 mmol), triethylamine (0.32 g, 3.16 mmol), and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate (0.93 g, 2.87 mmol) was stirred in DMF (5 mL) at 40 °C for 24 h, cooled to room temperature, and 10 mL of 1N HCl was added. The resulting solution and water were poured into a separation funnel, and dichloromethane was added to separate the organic layer from the aqueous layer; the organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and then recrystallized from methanol to obtain bupavaquinone as a yellow solid (0.52 g, yield 55%).

[0098] The NMR data of the above-prepared bupavaquinone:

[0099] 1H NMR (400MHz, CDCl3) δ8.13-8.07(m,1H),8.09(m,1H),7.79-7.77(m,1H),7.71-7.69(m,1H),7.39-7.27(m,1H),2.70-2.52( m,2H),1.82-1.68(m,3H),1.62(d,1H),1.60-1.55(m,1H),1.48-1.30(m,1H),0.90(m,4H),0.84(s,9H).

[0100] It can be seen that compared with Example 5, in the preparation of bupavaquin in Comparative Example 1, the catalyst 4-dimethylaminopyridine was not added, the required reaction time was greatly prolonged, and the yield of the prepared bupavaquin was significantly reduced.

[0101] Unless otherwise specified, all percentages used in the present invention are by mass.

[0102] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing bupavaquin, characterized in that: Bupavaquinone was obtained by heating 2-hydroxy-1,4-naphthoquinone and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate as raw materials under alkaline conditions and with the catalysis of 4-dimethylaminopyridine.

2. The method for preparing bupavaquinone according to claim 1, characterized in that: The molar ratio of 2-hydroxy-1,4-naphthoquinone to (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate is 0.9-1.1:1; The heating reaction temperature is 35-45°C, and the heating reaction time is 10-15h.

3. The method for preparing bupavaquinone according to claim 1, characterized in that: The amount of 4-dimethylaminopyridine added does not exceed 5% of the total weight of 2-hydroxy-1,4-naphthoquinone and (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate.

4. The method for preparing bupavaquinone according to claim 1, characterized in that: The preparation method of (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate is as follows: 4-tert-butylcyclohexanone and nitromethane are used as raw materials, and 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene is obtained by heating reaction under alkaline conditions; then 4-tert-butylcyclohexylmethylamine is obtained by catalytic hydrogenation, and then contacted with hydrogen chloride-ethanol solution to obtain 4-tert-butylcyclohexylmethylamine hydrochloride; 4-tert-butylcyclohexylmethylamine hydrochloride is reacted at 205-215° C. in the presence of strong base potassium hydroxide to obtain (4-(tert-butyl)cyclohexyl)methanol; (4-(tert-butyl)cyclohexyl)methanol is reacted with p-toluenesulfonyl chloride to obtain (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate.

5. The method for preparing bupavaquinone according to claim 4, characterized in that: In the preparation of 4-(tert-butyl)-1-(nitromethyl)cyclohex-1-ene, the molar ratio of 4-tert-butylcyclohexanone to nitromethane is 1:27-30; The heating reaction temperature is 100-102°C.

6. The method for preparing bupavaquinone according to claim 4, characterized in that: In the preparation of 4-tert-butylcyclohexylmethylamine hydrochloride, the hydrogenation temperature is 10-35° C. and the hydrogenation pressure is 760-780 Torr.

7. The method for preparing bupavaquinone according to claim 4, characterized in that: In the preparation of (4-(tert-butyl)cyclohexyl)methanol, the reaction time is 2-4h at 205-215°C; The molar ratio of 4-tert-butylcyclohexylmethylamine hydrochloride to potassium hydroxide is 1:8-10.

8. The method for preparing bupavaquinone according to claim 4, characterized in that: In the preparation of (4-(tert-butyl)cyclohexyl)methyl p-toluenesulfonate, the molar ratio of (4-(tert-butyl)cyclohexyl)methanol to p-toluenesulfonyl chloride is 1:0.9-1.2.

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