Preparation method of 1-(aryl sulfonyl) bicyclo [1.1. 0] butane compound

Abstract

The invention discloses a preparation method of a 1-(aryl sulfuryl) bicyclo [1.1. 0] butane compound, which comprises the following steps: reacting a compound 1 serving as a raw material with trisubstituted propane and an alkaline reagent in a reaction solvent in an air-isolated environment under the action of an organic catalyst and a metal catalyst at the temperature of-78 to 200 DEG C for 1 to 48 hours to obtain the 1-(aryl sulfuryl) bicyclo [1.1. 0] butane compound. And obtaining a compound 2 after complete reaction. The key raw materials in the synthesis route are cheap and easy to obtain, the reaction conditions are mild, the operation is convenient, the process safety is high, the selectivity is high, the yield is high, the product purity is high, the production cost is greatly reduced, and the production requirement of the product at the ton level or above can be fully met.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical engineering, and in particular to a method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds. Background Art

[0002] Functionalized cyclobutane is known for its rigid conformational skeleton, which provides a solid foundation for building complex molecules. Compared with drug molecules such as cyclohexane and cyclopropane that are widely available on the market, cyclobutane compounds are relatively less used in drug development, which brings huge exploration potential to the field of drug research. Through rapid and direct alkylation reactions, the application range of cyclobutane in drug development can be significantly expanded.

[0003] The bicyclo[1.1.0]butane (BCB) skeleton has a ring strain energy of up to 64 kcal / mol, which gives it unique reactivity. It can form a cyclobutane structure through a "stress release" mechanism, making it an ideal starting material for the synthesis of cyclobutane drug molecules. The C1-C3 bond of bicyclo[1.1.0]butane exhibits a wide range of reactivity, and can achieve high-energy bond ring-opening reactions through a variety of catalytic methods such as nucleophiles, free radicals, electrophiles, and transition metal catalysts, thereby constructing a variety of cyclobutane molecular structures.

[0004] 1-(Phenylsulfone)bicyclo[1.1.0]butane (CAS No.: 80989-84-0) is a leader among 1-(arylsulfone)bicyclo[1.1.0]butane compounds, and its synthesis method has attracted widespread attention from professionals in the pharmaceutical industry. The synthesis of this compound not only represents the progress of cyclobutane drug molecule synthesis technology, but also indicates the broad prospects for the application of cyclobutane skeletons in drug development in the future.

[0005]

[0006] There are two main synthetic routes of 1-(arylsulfone)bicyclo[1.1.0]butane compounds that have been reported to be of practical value: The first is the following route reported by Justin M. Lopchuk et al. in J. Am. Chem. Soc. 2017, 139, 8, 3209–3226:

[0007] This route adopts a 6-step synthesis method, with benzenesulfonyl chloride as the starting material, and is synthesized through 6 steps of reactions, including sodium thiosulfate reduction, 4-bromo-2-butene substitution, epoxidation, cyclopropane ring closure reaction, mesylation, and bicyclo[1.1.0]butane ring closure reaction. This method has three serious problems when it is scaled up to kilogram level or above: first, the steps are lengthy, the operation is cumbersome, the yield is extremely low, and the total yield of the 6-step reaction is 9.3%, which is extremely economical; second, two steps of the reaction require the use of the extremely dangerous and expensive reagent butyl lithium, which must be reacted at an ultra-low temperature of -78°C, which is highly dangerous, inconvenient to operate, and has high power consumption; third, the third step requires the use of highly dangerous ozone, and the power consumption is also extremely high when ozone is generated. In general, this route requires the use of a large amount of dangerous reagents, involves multiple steps of extremely dangerous redox reactions, ultra-low temperature reactions, and strong alkaline reactions, has a large amount of three wastes, and is highly dangerous to operate, which does not meet the requirements of green production.

[0008] The second route is the following route reported by Myunggi Jung et al. in J. Am. Chem. Soc. 2022, 144, 11, 4764–4769.

[0009]

[0010] This route adopts a three-step synthesis method, using mesyl aromatics as the starting material, and synthesizing through three steps of cyclobutane ring closure reaction, benzenesulfonic acid esterification, and bicyclo[1.1.0]butane ring closure. When this method is scaled up to kilogram level or above, there are also three serious problems: first, the steps are long, the operation is cumbersome, the yield is low, and the total yield of the three-step reaction is 60-70%, which is poor in economy; second, two steps of the reaction require the use of extremely dangerous and expensive reagents dibutyl magnesium and butyl lithium, which must be reacted at an ultra-low temperature of -78°C, which is highly dangerous, inconvenient to operate, and has high power consumption. In general, this route requires the use of a large amount of dangerous reagents, involves multiple steps of extremely dangerous ultra-low temperature reactions and strong alkaline reactions, has a large amount of three wastes, and is highly dangerous to operate, which does not meet the requirements of green production.

[0011] In order to solve the problems of high risk of reaction reagents, poor process safety, large amount of three wastes, and operator-unfriendlyness in the existing process routes of 1-(arylsulfone)bicyclo[1.1.0]butane compounds, it is of great significance to find a method for synthesizing 1-(arylsulfone)bicyclo[1.1.0]butane compounds with reasonable route design, safe and easy-to-obtain raw materials, high process safety, less three wastes, and operator-friendlyness. Summary of the invention

[0012] In view of the problems existing in the above-mentioned prior art, the present invention develops a method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds, which has safe and easily available raw materials, high process safety, less waste and high product purity.

[0013] One of the technical problems to be solved by the present invention is to provide a method for preparing a 1-(arylsulfone)bicyclo[1.1.0]butane compound, comprising the following steps: Compound 1 is used as a raw material, and a trisubstituted propane and an alkaline reagent are reacted in a reaction solvent in an air-tight environment, under the action of an organic catalyst and a metal catalyst, the reaction temperature is -78-200°C, the reaction time is 1-48h, and compound 2 is obtained after the reaction is complete, wherein the trisubstituted propane is 1,2,3-trichloropropane, 1,2,3-tribromopropane, 1,2,3-triiodopropane, 1,2,3-triphenylsulfonyloxypropane, 1,2,3-tri The alkaline reagent is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium ethoxide, sodium ethoxide, lithium ethoxide, potassium methoxide, sodium methoxide, lithium methoxide, sodium hydride, potassium hydride or lithium hydride, and the reaction solvent is n-hexane, n-heptane, ethyl ether, propyl ether, isopropyl ether, butyl ether, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane , one or more of chlorobenzene, nitrobenzene or o-dichlorobenzene, the organic catalyst is one or more of 18-crown-6, 15-crown-5, 12-crown-4, benzo-18-crown-6, dibenzo-18-crown-6, benzo-15-crown-5 or benzo-12-crown-4, the metal catalyst is sodium trifluoroacetate, potassium trifluoroacetate, lithium trifluoroacetate, iron trifluoroacetate, manganese trifluoroacetate, cadmium trifluoroacetate, cobalt trifluoroacetate, trifluoroacetic acid, one or more of zinc trifluoroacetate, magnesium trifluoroacetate or aluminum trifluoroacetate, wherein Ar is selected from phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-pyridyl, 2-furyl and 2-thienyl, and X is selected from chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy, .

[0014] In a preferred embodiment of the present invention, the molar ratio of the tri-substituted propane to compound 1 is 0.5-2:1.

[0015] In a preferred embodiment of the present invention, the molar ratio of the tri-substituted propane to compound 1 is 0.9-1.1:1.

[0016] In a preferred embodiment of the present invention, the molar ratio of the alkaline reagent to compound 1 is 2.5-7.5:1.

[0017] In a preferred embodiment of the present invention, the molar ratio of the alkaline reagent to compound 1 is 3.0-3.5:1.

[0018] In a preferred embodiment of the present invention, the molar ratio of the organic catalyst to compound 1 is 0.0001-0.1:1.

[0019] In a preferred embodiment of the present invention, the molar ratio of the organic catalyst to compound 1 is 0.001-0.01:1.

[0020] In a preferred embodiment of the present invention, the molar ratio of the metal catalyst to compound 1 is 0.0001-0.1:1.

[0021] In a preferred embodiment of the present invention, the molar ratio of the metal catalyst to compound 1 is 0.0001-0.001:1.

[0022] In a preferred embodiment of the present invention, the reaction temperature is 20-40°C. Beneficial Effects

[0023] Compared with the prior art, the key raw materials in the synthesis route adopted by the present invention are cheap and easy to obtain, the reaction conditions are relatively mild, the operation is convenient, the process is safe, the operator is friendly, the reaction selectivity is high, the reaction yield is high, the product purity is high, the production cost is greatly reduced, and the production demand of products above the ton level can be fully met. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention. Example 1

[0025] Preparation of 1-(phenylsulfonyl)bicyclo[1.1.0]butane

[0026] Keeping nitrogen slightly positive pressure, add 2L tetrahydrofuran, 156.20 g (1.0 mol) methyl phenyl sulfone, 162.18 g (1.1 mol) 1,2,3-trichloropropane, 0.03g (0.0001 mol) 18-crown ether-6, 0.02g (0.001mol) potassium trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0 ℃, and 297.91g (3.1 mol) sodium tert-butoxide is added in batches, and the temperature is controlled at 0-5℃. After the addition is completed, the reaction solution is naturally heated to room temperature for 48 hours to complete the reaction.

[0027] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 179.29 g of a white solid product.

[0028] Yield: 92.3%, product purity: 98.13% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ 7.98 (dd, J = 8.4, 1.5 Hz, 2H), 7.68-7.63 (m, 1H), 7.61-7.55 (m, 2H), 2.60-2.56 (m, 1H), 2.56-2.50 (m, 2H), 1.44-1.38 (m, 2H). Example 2

[0029] Preparation of 1-(4-methoxyphenylsulfone)bicyclo[1.1.0]butane

[0030] Keeping nitrogen slightly positive pressure, add 2L of n-hexane, 186.23g (1.0 mol) of 1-methoxy-4-methylsulfonylbenzene and 140.39g (0.5 mol) of 1,2,3-tribromopropane, 0.11g (0.0005mol) of 15-crown ether-5, and 0.04g (0.0004mol) of sodium trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0℃, and 240.25g (2.5mol) of potassium tert-butoxide is added in batches, and the temperature is controlled at 0-5℃. After the addition is completed, the reaction solution is naturally heated to room temperature for 24 hours, and the reaction is completed.

[0031] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 102.83 g of a white solid product.

[0032] Yield: 91.7%, product purity: 98.57% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ 7.86 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 2.50-2.46 (m, 3H), 1.37-1.33 (m, 2H). Example 3

[0033] Preparation of 1-(3-methoxyphenylsulfonyl)bicyclo[1.1.0]butane

[0034] Keeping nitrogen slightly positive pressure, add 2L isopropyl ether, 186.23g (1.0 mol) 1-methoxy-3-methylsulfonylbenzene and 253.07g (0.6 mol) 1,2,3-triiodopropane, 0.18g (0.001 mol) 12-crown ether-4, 0.1g (0.0006mol) ferric trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0 ℃, and 252.48g (3.0mol) potassium ethoxide is added in batches, and the temperature is controlled at 0-5℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 30 ℃ for reaction, and kept warm for 36 hours, and the reaction is completed.

[0035] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 122.05 g of a white solid product.

[0036] Yield: 90.7%, product purity: 99.05% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ7.55-7.50 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.45-7.42 (m, 1H), 7.17-7.12 (m,1H), 3.88 (s, 3H), 2.59-2.54 (m, 1H), 2.54-2.47 (m, 2H), 1.43-1.35 (m, 2H). Example 4

[0037] Preparation of 1-(2-methoxyphenylsulfonyl)bicyclo[1.1.0]butane

[0038] Keeping nitrogen slightly positive pressure, add 2L of butyl ether, 186.23g (1.0 mol) of 1-methoxy-2-methylsulfonylbenzene and 410.05g (0.8 mol) of 1,2,3-triphenylsulfonyloxypropane, 1.56g (0.005 mol) of benzo-18-crown-6, and 0.32g (0.0008 mol) of manganese trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0 ℃, and 182g (3.5 mol) of lithium ethoxide is added in batches, and the temperature is controlled at 0-5 ℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 40 ℃ for reaction, and kept warm for 18 hours, and the reaction is completed.

[0039] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 164.88 g of a white solid product.

[0040] Yield: 91.9%, product purity: 98.68% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ 7.93 (dd, J = 7.8, 1.8 Hz, 1H), 7.57-7.53 (m, 1H), 7.08-7.01 (m, 2H), 3.94 (s, 3H), 2.59-2.50 (m, 3H), 1.38-1.35 (m, 2H). Example 5

[0041] Preparation of 1-(4-trifluoromethylphenylsulfonyl)bicyclo[1.1.0]butane

[0042] Keeping nitrogen slightly positive pressure, add 2L ethylene glycol diethyl ether, 224.2g (1.0 mol) 1-trifluoromethyl-4-methylsulfonylbenzene and 250.52g (0.9 mol) 1,2,3-trimethylsulfonylpropane, 3.6g (0.01 mol) dibenzo-18-crown ether-6, 0.40g (0.001mol) cobalt trifluoroacetate to the 5L reaction bottle, stir and dissolve. The reaction solution is cooled to 0℃, and 280.48g (4 mol potassium methoxide is added in batches, and the temperature is controlled at 0-5℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 40℃ for reaction, and kept warm for 12 hours. The reaction is complete.

[0043] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 211.24 g of a white solid product.

[0044] Yield: 89.5%, product purity: 98.45% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ 8.08 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 2.72-2.68(m, 1H), 2.60-2.54 (m,2H), 1.46-1.42 (m, 2H). Example 6

[0045] Preparation of 1-(4-fluorophenylsulfone)bicyclo[1.1.0]butane

[0046] Keeping nitrogen slightly positive pressure, add 2L ethylene glycol dimethyl ether, 174.19g (1.0 mol) 1-fluoro-4-methylsulfonylbenzene and 557.67g (1.0 mol) 1,2,3-tri-p-toluenesulfonyloxypropane, 13.42g (0.05 mol) benzo-15-crown ether-5, 1.46g (0.005 mol) zinc trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0 ℃, and 170.87g (4.5 mol) lithium methoxide is added in batches, and the temperature is controlled at 0-5 ℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 60℃ for reaction, and kept warm for 12 hours, and the reaction is completed.

[0047] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 191.86 g of a white solid product.

[0048] Yield: 90.4%, product purity: 98.27% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ7.99-7.93 (m, 2H), 7.26-7.20 (m, 2H), 2.62-2.57 (m, 1H), 2.54-2.51 (m, 2H), 1.41-1.37 (m, 2H). Example 7

[0049] Preparation of 1-(3,5-difluorophenylsulfonyl)bicyclo[1.1.0]butane

[0050] Keeping nitrogen slightly positive pressure, add 2L 2-methyltetrahydrofuran, 192.18g (1.0mol) 1,3-difluoro-5-methylsulfonylbenzene and 176.93g (1.2mol) 1,2,3-trichloropropane, 22.43g (0.1mol) benzo-12-crown-4, 2.50g (0.01mol) magnesium trifluoroacetate to the 5L reaction bottle, stir and dissolve. The reaction solution is cooled to 0℃, and 120g (5.0mol) sodium hydride is added in batches, and the temperature is controlled at 0-5℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 60℃ for reaction, kept warm for 10 hours, and the reaction is completed.

[0051] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 204.21 g of a white solid product.

[0052] Yield: 88.7%, product purity: 98.57% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ7.53-7.49 (m, 2H), 7.12-7.05 (m, 1H), 2.75-2.70 (m, 1H), 2.60-2.56 (m, 2H), 1.50-1.47 (m, 2H). Example 8

[0053] Preparation of 1-(2-fluorophenylsulfone)bicyclo[1.1.0]butane

[0054] Keeping nitrogen slightly positive pressure, add 2L of dioxane, 174.19g (1.0 mol) 1-fluoro-2-methylsulfonylbenzene and 421.17g (1.5mol) 1,2,3-tribromopropane, 1.85g (0.007 mol) 18-crown ether-6, 2.16g (0.015 mol) aluminum trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0 ℃, and 220g (5.5 mol) potassium hydride is added in batches, and the temperature is controlled at 0-5 ℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 80 ℃ for reaction, and kept warm for 8 hours, and the reaction is completed.

[0055] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 187.20 g of a white solid product.

[0056] Yield: 88.20%, product purity: 98.75% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ7.98-7.90 (m, 1H), 7.65-7.61 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.26-7.21 (m,1H), 2.69-2.66 (m, 1H), 2.63-2.59 (m, 2H), 1.48-1.45 (m, 2H). Example 9

[0057] Preparation of 2-(Bicyclo[1.1.0]butyl-1-sulfonyl)thiophene

[0058] Keeping nitrogen slightly positive pressure, add 2L tetrahydrofuran, 162.22g (1.0 mol) 2-methylsulfonylthiophene and 505.40g (1.8 mol) 1,2,3-tribromopropane, 1.59g (0.009 mol) 12-crown ether-4, 7.61g (0.05mol) potassium trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0 ℃, and 47.70g (6.0 mol) lithium hydride is added in batches, and the temperature is controlled at 0-5 ℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 80 ℃ for reaction, and kept warm for 8 hours, and the reaction is completed.

[0059] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 175.44 g of a white solid product.

[0060] Yield: 87.6%, product purity: 98.04% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ7.74-7.61 (m, 2H), 7.16-7.09 (m, 1H), 2.53 (t, J = 3.4 Hz, 1H), 2.51 (d, J =3.5Hz, 2H), 1.45-1.38 (m, 2H). Example 10

[0061] Preparation of 2-(Bicyclo[1.1.0]butyl-1-sulfone)pyridine

[0062] Keeping nitrogen slightly positive pressure, add 2L tetrahydrofuran, 157.19 g (1.0 mol) 2-methylsulfonylpyridine and 843.58g (2.0 mol) 1,2,3-triiodopropane, 15.42g (0.07 mol) 15-crown ether-5, 12.00g (0.1 mol) lithium trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. The reaction solution is cooled to 0 ℃, and 600.38g (7.5 mol) lithium tert-butoxide is added in batches, and the temperature is controlled at 0-5 ℃. After the addition, the reaction solution is naturally heated to room temperature for 1 hour, then heated to 40 ℃ for reaction, and kept warm for 12 hours, and the reaction is completed.

[0063] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 170.25 g of a white solid product.

[0064] Yield: 87.2%, product purity: 98.89% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ8.81-8.76 (m, 1H), 8.10-8.04 (m, 1H), 7.97-7.94 (m, 1H), 7.56-7.49 (m, 1H), 2.68-2.66 (m, 1H), 2.62-2.54 (m, 2H), 1.51-1.44 (m, 2H). Comparative Example 1

[0065] Preparation of 1-(phenylsulfonyl)bicyclo[1.1.0]butane

[0066] Keeping nitrogen slightly positive pressure, add 2L tetrahydrofuran, 156.20 g (1.0 mol) methyl phenyl sulfone, 162.18 g (1.1 mol) 1,2,3-trichloropropane, 0.02g (0.001 mol) potassium trifluoroacetate to the 5L reaction bottle in sequence, stir and dissolve. Cool the reaction solution to 0℃, add 297.91g (3.1 mol) sodium tert-butoxide in batches, control the temperature at 0-5℃, and after adding, naturally heat the reaction solution to room temperature for 18 hours to complete the reaction.

[0067] The reaction solution was cooled to 0°C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 9.95 g of a white solid product.

[0068] Yield 5.12%, product purity: 98.73% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ 7.98 (dd, J = 8.4, 1.5 Hz, 2H), 7.68-7.63 (m,1H), 7.61-7.55 (m, 2H), 2.60-2.56 (m,1H), 2.56-2.50 (m, 2H), 1.44-1.38 (m, 2H). Comparative Example 2

[0069] Preparation of 1-(phenylsulfonyl)bicyclo[1.1.0]butane

[0070] Keeping nitrogen slightly positive pressure, add 2L tetrahydrofuran, 156.20 g (1.0 mol) methyl phenyl sulfone, 162.18 g (1.1 mol) 1,2,3-trichloropropane, 0.03g (0.0001 mol) 18-crown ether-6 to the 5L reaction bottle in turn, stir and dissolve. The reaction solution is cooled to 0 ℃, and 297.91g (3.1 mol) sodium tert-butoxide is added in batches, and the temperature is controlled at 0-5 ℃. After the addition is completed, the reaction solution is naturally heated to room temperature and reacted for 18 hours, and the reaction is completed.

[0071] The reaction solution was cooled to 0 °C, and 200 g of pure water was added dropwise to quench the reaction. The reaction solution was extracted with toluene (1 L x 3). The organic phases were combined and the solvent was recovered by rotary evaporation. The residue was recrystallized with n-heptane-ethyl acetate (v / v, 5:1) to obtain 12.70 g of a white solid product.

[0072] Yield: 6.54%, product purity: 99.12% (HPLC); NMR data: 1H NMR (400MHz, CDCl3): δ 7.98 (dd, J = 8.4, 1.5 Hz, 2H), 7.68-7.63 (m, 1H), 7.61-7.55 (m, 2H), 2.60-2.56 (m, 1H), 2.56-2.50 (m, 2H), 1.44-1.38 (m, 2H).

[0073] It can be seen from comparative examples 1 and 2 that when the catalysts in steps S1 and S2 of the examples are replaced with other catalysts, the reaction yields drop sharply. The experimental results prove that the catalysts used in the present technical solution are unique and highly efficient.

[0074] The above examples are only for illustrating the technical concept and features of the present invention. Their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a 1-(arylsulfone)bicyclo[1.1.0]butane compound, characterized in that: The steps include: Compound 1 is used as a raw material, and a trisubstituted propane and an alkaline reagent are reacted in a reaction solvent in an air-tight environment, under the action of an organic catalyst and a metal catalyst, the reaction temperature is -78-200°C, the reaction time is 1-48h, and compound 2 is obtained after the reaction is complete, wherein the trisubstituted propane is 1,2,3-trichloropropane, 1,2,3-tribromopropane, 1,2,3-triiodopropane, 1,2,3-triphenylsulfonyloxypropane, 1,2,3-tri The alkaline reagent is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium ethoxide, sodium ethoxide, lithium ethoxide, potassium methoxide, sodium methoxide, lithium methoxide, sodium hydride, potassium hydride or lithium hydride, and the reaction solvent is n-hexane, n-heptane, ethyl ether, propyl ether, isopropyl ether, butyl ether, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane , one or more of chlorobenzene, nitrobenzene or o-dichlorobenzene, the organic catalyst is one or more of 18-crown-6, 15-crown-5, 12-crown-4, benzo-18-crown-6, dibenzo-18-crown-6, benzo-15-crown-5 or benzo-12-crown-4, the metal catalyst is sodium trifluoroacetate, potassium trifluoroacetate, lithium trifluoroacetate, iron trifluoroacetate, manganese trifluoroacetate, cadmium trifluoroacetate, cobalt trifluoroacetate, trifluoroacetic acid, one or more of zinc trifluoroacetate, magnesium trifluoroacetate or aluminum trifluoroacetate, wherein Ar is selected from phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-pyridyl, 2-furyl and 2-thienyl, and X is selected from chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy, .

2. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 1, characterized in that: The molar ratio of the trisubstituted propane to compound 1 is 0.5-2:

1.

3. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 2, characterized in that: The molar ratio of the trisubstituted propane to compound 1 is 0.9-1.1:

1.

4. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 1, characterized in that: The molar ratio of the alkaline reagent to compound 1 is 2.5-7.5:

1.

5. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 4, characterized in that: The molar ratio of the alkaline reagent to compound 1 is 3.0-3.5:

1.

6. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 1, characterized in that: The molar ratio of the organic catalyst to the compound 1 is 0.0001-0.1:

1.

7. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 6, characterized in that: The molar ratio of the organic catalyst to compound 1 is 0.001-0.01:

1.

8. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 1, characterized in that: The molar ratio of the metal catalyst to compound 1 is 0.0001-0.1:

1.

9. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 8, characterized in that: The molar ratio of the metal catalyst to compound 1 is 0.0001-0.001:

1.

10. The method for preparing 1-(arylsulfone)bicyclo[1.1.0]butane compounds according to claim 1, characterized in that: The reaction temperature is 20-40°C.

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