Process for the preparation of compounds of formula I and process for the preparation of bicyclic alcohol

Abstract

The application belongs to the field of medicine and specifically relates to a method for preparing a compound shown in formula I, comprising the following steps: mixing a compound shown in formula V, a coupling catalyst, an oxidant and dimethyl sulfoxide, and reacting under the conditions of 50 DEG C-200 DEG C and normal pressure to obtain the compound shown in formula I; wherein the coupling catalyst is selected from one or more of chloro rhodium dimer of norbornadiene, palladium single substance, palladium acetate, tetrakis (triphenylphosphine) palladium and bis (dibenzalacetone) palladium; the oxidant is selected from one or more of manganese dioxide, silver oxide and silver acetate; R1 is selected from C1-C6 alkyl. The application also relates to a method for preparing bicyclic alcohol. The method for preparing the compound shown in formula I has the advantages of high yield, high selectivity, mild reaction conditions and simple operation.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a method for preparing a compound of Formula I, and also to a method for preparing bicyclic alcohols. Background Technology

[0002] Bicyclol (CAS No.: 118159-48-1) is a Class I anti-hepatitis drug in China. It is a compound containing a hexaalkoxybiphenyl structure, obtained through structural modification of schisandrin, an active ingredient from the traditional Chinese medicine Schisandra chinensis, as a lead compound. Studies have shown that bicyclol has a significant protective effect against liver damage caused by various factors, can significantly reduce serum transaminase levels, alleviate liver pathological damage, and also has certain anti-hepatitis virus activity. It can effectively improve clinical symptoms in patients with chronic hepatitis B and C, and has good safety with no obvious toxic side effects. Bicyclol was approved for marketing by the State Drug Administration in 2004 and is used clinically for the treatment of chronic hepatitis and non-viral liver diseases.

[0003] The industrial synthesis routes for bicyclic alcohols both domestically and internationally mainly use gallic acid or methyl gallate as raw materials. After monohydroxy etherification, bromination, and Ullmann coupling, biphenyl diester is obtained. The biphenyl diester is then hydrolyzed under alkaline conditions to produce biphenyl bisacid, which is subsequently dehydrated, reduced, hydrolyzed, and methylated to yield the bicyclic alcohol. Among these, biphenyl bisacid... It is an important intermediate product. However, in the above-mentioned synthesis methods, the preparation process of biphenyl bisacid involves many steps, bromination is prone to pollution, the yield is low, the selectivity is poor, there are many by-products that are difficult to separate, and the Ullmann coupling reaction conditions are harsh, which is not conducive to industrial production.

[0004] Therefore, there is an urgent need for a method to prepare biphenyl bisacrylic acid that has fewer steps, does not involve bromination, has high yield, high selectivity, and mild reaction conditions. Summary of the Invention

[0005] One objective of this invention is to provide a method for preparing the compound shown in Formula I, which features high yield, high selectivity, mild reaction conditions, and simple operation. Furthermore, another objective of this invention is to provide a method for preparing bicyclic alcohols.

[0006] To achieve the above objectives, a first aspect of the present invention provides a method for preparing the compound of formula I, comprising: The compound shown in Formula V, the coupling catalyst, the oxidant, and the solvent dimethyl sulfoxide were mixed and reacted under conditions of 50°C-200°C (e.g., 50°C, 100°C, 150°C, 160°C, 200°C) and atmospheric pressure to obtain the compound shown in Formula I.

[0007] The coupling catalyst is selected from one or more of norbornene rhodium chloride dimer [{Rh(nbd)Cl}2], elemental palladium, palladium acetate, tetra(triphenylphosphine)palladium Pd(PPh3)4, and bis(dibenzylacetone)palladium Pd(dba)2; the oxidant is selected from one or more of manganese dioxide, silver oxide, and silver acetate. R1 is selected from C1-C6 alkyl groups.

[0008] In any embodiment of the first aspect of this invention, "normal pressure" is an abbreviation for "common pressure" or "normal atmospheric pressure," typically referring to one standard atmosphere, which is the atmospheric pressure at 0°C above sea level. Its precise value is 101325 Pa, approximately equal to 101.3 kPa.

[0009] In any embodiment of the first aspect of the present invention, the reaction is carried out under an inert atmosphere, for example, under an argon atmosphere.

[0010] In any embodiment of the first aspect of the present invention, the temperature of the reaction is 100°C - 160°C.

[0011] In any embodiment of the first aspect of the present invention, the reaction time is 5-48 hours, optionally 10-30 hours, for example 5 hours, 10 hours, 15 hours, 20 hours, 25 hours, 28 hours, 30 hours, 32 hours, 35 hours, 40 hours, 45 hours, or 48 hours.

[0012] In any embodiment of the first aspect of the present invention, the coupling catalyst is norbornene rhodium chloride dimer.

[0013] In any embodiment of the first aspect of the present invention, the oxidant is manganese dioxide.

[0014] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula V to the coupling catalyst is 1:0.01 - 1:0.2, for example 1:0.01, 1:0.02, 1:0.022, 1:0.024, 1:0.026, 1:0.03, 1:0.05, 1:0.06, 1:0.08, 1:0.1, 1:0.14, 1:0.15, 1:0.16, 1:0.2.

[0015] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula V to the oxidant is 1:0.01 - 1:0.25, for example 1:0.01, 1:0.02, 1:0.03, 1:0.035, 1:0.038, 1:0.04, 1:0.045, 1:0.05, 1:0.06, 1:0.08, 1:0.1, 1:0.13, 1:0.15, 1:0.17, 1:0.19, 1:0.2, 1:0.21, 1:0.23, 1:0.25.

[0016] In any embodiment of the first aspect of the present invention, the ratio of the compound represented by Formula V to the organic solvent is 0.01:1 g / mL to 0.1:1 g / mL, for example 0.01:1 g / mL, 0.02:1 g / mL, 0.03:1 g / mL, 0.04:1 g / mL, 0.05:1 g / mL, 0.06:1 g / mL, 0.08:1 g / mL, or 0.1:1 g / mL.

[0017] In any embodiment of the first aspect of the present invention, R1 is a methyl group.

[0018] In any embodiment of the first aspect of the present invention, the compound represented by formula V is prepared by the following steps: The compound shown in Formula IV, an alkaline solution, and a first organic solvent are mixed and reacted at 50°C-120°C (e.g., 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C) to obtain the compound shown in Formula V.

[0019] The alkaline solution is selected from one or more solutions of sodium hydroxide and potassium hydroxide; the first organic solvent is selected from one or more solutions of methanol, ethanol, and isopropanol. R1 and R2 are each independently selected from C1-C6 alkyl groups.

[0020] In any embodiment of the first aspect of the present invention, in the step of preparing the compound shown in formula V, the reaction time is 2-10 hours, for example 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

[0021] In any embodiment of the first aspect of the present invention, in the step of preparing the compound of formula V, the reaction is carried out under reflux conditions.

[0022] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula IV to the base in the alkaline solution is 1:9 to 1:12, for example 1:9, 1:10, 1:10.2, 1:10.5, 1:10.7, 1:10.8, 1:10.9, 1:11, 1:11.5, 1:12.

[0023] In any embodiment of the first aspect of the present invention, the molar concentration of the alkaline solution is 1-10 M, for example 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0024] In any embodiment of the first aspect of the present invention, the alkaline solution is an aqueous solution.

[0025] In any embodiment of the first aspect of the present invention, the ratio of the compound represented by Formula IV to the first organic solvent is 1:12 g / mL to 1:18 g / mL, for example 1:12 g / mL, 1:13 g / mL, 1:14 g / mL, 1:15 g / mL, 1:16 g / mL, 1:17 g / mL, 1:18 g / mL.

[0026] In any embodiment of the first aspect of the present invention, R1 and R2 are methyl groups.

[0027] In any embodiment of the first aspect of the present invention, the compound represented by Formula IV is prepared by the following steps: The compound shown in Formula III, the first base, the dihalomethane, the catalyst, and the second organic solvent were mixed and reacted under conditions of 80°C-150°C and in a closed environment to obtain the compound shown in Formula IV.

[0028] Wherein, the first alkali is selected from one or more of potassium carbonate and sodium carbonate; the catalyst is selected from one or more of copper oxide and potassium iodide; and the second organic solvent is N,N-dimethylformamide. R1 and R2 are each independently selected from C1-C6 alkyl groups.

[0029] In any embodiment of the first aspect of the present invention, in the step of preparing the compound of formula IV, the reaction time is 2-10 hours, for example 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, or 10 hours.

[0030] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula III to the first base is 1:1 to 1:2, for example 1:1, 1:1.3, 1:1.5, 1:1.6, 1:1.67, 1:1.7, 1:1.8, 1:1.9, 1:2.

[0031] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula III to the dihalomethane is 1:2 to 1:4, for example 1:2, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.65, 1:2.7, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.5, 1:3.6, 1:3.8, 1:4.

[0032] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula III to the catalyst is 1:0.02 – 1:0.1, for example 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.067, 1:0.07, 1:0.08, 1:0.1.

[0033] In any embodiment of the first aspect of the present invention, the ratio of the compound represented by Formula III to the second organic solvent is 1:8 g / mL – 1:14 g / mL, for example 1:8 g / mL, 1:9 g / mL, 1:10 g / mL, 1:11 g / mL, 1:11.1 g / mL, 1:11.5 g / mL, 1:11.7 g / mL, 1:12 g / mL, 1:13 g / mL, 1:14 g / mL.

[0034] In any embodiment of the first aspect of the present invention, the dihalomethane is selected from one or more of dibromomethane, difluoromethane, and dichloromethane.

[0035] In any embodiment of the first aspect of the present invention, R1 and R2 are methyl groups.

[0036] In any embodiment of the first aspect of the present invention, the compound represented by Formula III is prepared by the following steps: The compound shown in Formula II, the second base, the halo-C1-C6 alkane, trimethyl borate or borax, and the third organic solvent are mixed and reacted at -20°C to 70°C (e.g., -20°C, -10°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 50°C, 60°C, 70°C) to obtain the compound shown in Formula III.

[0037] Wherein, the second base is selected from one or more of sodium hydride, potassium carbonate, and cesium carbonate; the halo-C1-C6 alkane is selected from one or more of iodo-C1-C6 alkane (e.g., CH3I), bromo-C1-C6 alkane, and chlorinated C1-C6 alkane; and the third organic solvent is selected from one or more of N,N-dimethylformamide and acetone. R1 and R2 are each independently selected from C1-C6 alkyl groups.

[0038] In any embodiment of the first aspect of the present invention, in the step of preparing the compound of formula III, the reaction time is 10-24 hours, for example 10 hours, 12 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 20 hours, 22 hours, or 24 hours.

[0039] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula II to the second base is 1:1 to 1:4, for example 1:1, 1:1.5, 1:2, 1:2.3, 1:2.5, 1:3, 1:3.5, or 1:4.

[0040] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula II to the halo-C1-C6 alkane is 1:0.8 to 1:1.2, for example, 1:0.8, 1:0.9, 1:1, 1:1.3, 1:1.5, 1:1.8, or 1:2.

[0041] In any embodiment of the first aspect of the present invention, the molar ratio of the compound represented by Formula II to the trimethyl borate or borax is 1:1 to 1:3, for example 1:1, 1:1.1, 1:1.3, 1:1.5, 1:1.7, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.5, 1:2.7, 1:3.

[0042] In any embodiment of the first aspect of the present invention, the ratio of the compound represented by Formula II to the third organic solvent is 1:11 g / mL to 1:16 g / mL, for example 1:11 g / mL, 1:11.5 g / mL, 1:12 g / mL, 1:12.3 g / mL, 1:12.5 g / mL, 1:12.7 g / mL, 1:13 g / mL, 1:13.5 g / mL, 1:14 g / mL, 1:14.5 g / mL, 1:15 g / mL, or 1:16 g / mL.

[0043] In any embodiment of the first aspect of the present invention, R1 and R2 are methyl groups.

[0044] In any embodiment of the first aspect of the present invention, the method further includes: in the step of preparing compound I, adjusting the reaction product to a pH of 11-13 (e.g., 12), performing a first solid-liquid separation (e.g., vacuum filtration), adjusting the resulting liquid phase to a pH of 1-3 (e.g., 2), concentrating and drying, mixing the dried product with an alcohol solvent (e.g., methanol), performing a second solid-liquid separation (e.g., vacuum filtration), collecting the liquid phase, and washing the solid phase obtained from the two solid-liquid separations with an alcohol solvent (e.g., methanol), combining the collected liquid phase and the washing liquid, concentrating, and then purifying by column chromatography to obtain the compound shown in formula I. Optionally, the column chromatography is silica gel column chromatography; optionally, the eluent used in the column chromatography is a mixed solvent of dichloromethane and methanol, with the volume ratio varying from 100:1 to 100:5.

[0045] In any embodiment of the first aspect of the present invention, the method further includes: in the step of preparing the compound of formula V, drying the reaction product, dissolving the dried product in water, adjusting the pH of the resulting solution to 1-3 (e.g., 2), performing solid-liquid separation, collecting the solid phase and drying it to obtain the compound of formula V. Optionally, the solid phase is evaporated with water using toluene.

[0046] In any embodiment of the first aspect of the present invention, the method further includes: in the step of preparing the compound of formula IV, separating the reaction product into solid and liquid phases (e.g., filtering with diatomaceous earth as a filter aid), collecting the liquid phase, washing the solid phase with dichloromethane, combining the liquid phase and the washing liquid, drying, mixing the dried product with water, extracting the resulting mixture with methyl tert-butyl ether, collecting the organic phase and removing the solvent, mixing the resulting substance with n-hexane and dichloromethane, separating the solid and liquid phases (e.g., vacuum filtration), and collecting the solid phase as the compound of formula IV. Optionally, the extraction is performed 1 to 3 times.

[0047] In any embodiment of the first aspect of the present invention, in the step of preparing the compound of formula III, during mixing, the compound of formula II is first mixed with a portion of the third organic solvent, and the second base is added to the resulting mixture in multiple portions under ice bath conditions. After stirring and mixing for 0.5-2 hours (e.g., 1 hour), the halo-C1-C6 alkane, trimethyl borate or borax and the remaining portion of the third organic solvent are added to the resulting mixture and mixed.

[0048] In any embodiment of the first aspect of the present invention, in the step of preparing the compound of formula III, the second base is provided in the form of a mineral oil containing the second base; optionally, the second base has a mass content of 50%-70%, for example 60%, in the mineral oil.

[0049] In any embodiment of the first aspect of the present invention, the volume ratio of the first portion of the third organic solution to the remaining portion of the third organic solvent added later is 30:1 – 30:10, for example 30:1, 30:2, 30:5, 30:7, 30:8, 30:9, 30:10.

[0050] In any embodiment of the first aspect of the present invention, the method further includes: in the step of preparing the compound of formula III, mixing the reaction product with ice water, adjusting the pH to 2-4 (e.g., 3), extracting with ethyl acetate, collecting the organic phase, removing residual water from the organic phase, concentrating, and purifying by column chromatography to obtain the compound of formula III. Optionally, the extraction is performed 1 to 3 times; optionally, the eluent used for column chromatography is a mixed solvent of petroleum ether and ethyl acetate, with the volume ratio varying from 100:1 to 100:4.

[0051] A second aspect of the present invention relates to a method for preparing bicyclic alcohols, comprising: The compound of formula I was prepared according to the method of the first aspect of the present invention; Bicyclic alcohols were prepared using the compound shown in Formula I as a starting material.

[0052] In the second aspect of the present invention, the steps for preparing bicyclic alcohols from compounds of Formula I are well known to those skilled in the art and will not be described in detail here.

[0053] In this invention, the term "C1-C6 alkane" refers to a straight-chain or branched saturated aliphatic hydrocarbon having 1 to 6 carbon atoms; for example, methane, ethane, propane, etc.

[0054] In this invention, the term "C1-C6 alkyl" refers to a linear or branched group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0055] In this invention, the term "halogenated C1-C6 alkane" refers to a C1-C6 alkyl group substituted with one or more (such as one to five) halogens, such as CH3I, 3,3,3-trifluoro-1-propyl, CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, CHCl2, or -CH2CH2CF3, etc. The term "dihalomethane" refers to a alkyl group substituted with two halogens, such as CH2Br. 2、 CH2Cl2, etc.

[0056] The present invention has achieved at least one of the following beneficial effects: 1. The method of the present invention yields and / or has high selectivity for preparing compounds of formula I.

[0057] 2. The reaction conditions of the method of the present invention are mild and do not require a high-pressure environment.

[0058] 3. The method of the present invention has fewer steps, is simple to operate, and does not require bromination. Detailed Implementation

[0059] The embodiments of the present invention will be clearly and completely described below with reference to examples. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0060] Example

[0061] (1) Synthesis of methyl gallate (III)

[0062] To a 1L three-necked flask, methyl gallate (30.0 g, 163 mmol) and 300 mL N,N-dimethylformamide (DMF) were added. Under ice bath conditions, 15.0 g of mineral oil containing 60% NaH (15.0 g, 375 mmol) was added in batches. After stirring for 1 h, trimethyl borate B(OMe)3 (20 mL, 180 mmol) and 100 mL of DMF solution containing CH3I (10 mL, 163 mmol) were added. The mixture was stirred at 25°C for 16 h. The reaction of the starting material was detected by thin-layer chromatography (TLC) using a 1:1 volume mixture of petroleum ether (PE) and ethyl acetate (EA) as the developing solvent. The reaction solution was poured into ice water, the pH was adjusted to 3 with 3M hydrochloric acid solution, and then extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and subjected to column chromatography (the volume ratio of PE to EA was changed from 100:1 to 100:4) to give 25.4 g of white solid (compound III), with a yield of 77.50%.

[0063] 1H NMR (400 MHz, DMSO-d6): δ 7.15 (s, 1H), 3.81 (s, 3H), 3.74 (s, 3H).

[0064] (2) Synthesis of methyl 7-methoxybenzo[1,3]dioxane-5-carboxylic acid (Ⅳ)

[0065] Compound III (2.70 g, 14.52 mmol), K₂CO₃ (3.35 g, 24.23 mmol), CH₂Br₂ (2.7 mL, 38.47 mmol), CuO (77.2 mg, 0.97 mmol), and 30 mL of DMF were added to a 150 mL sealed tube. The mixture was heated to 110 °C and stirred for 5 h. The reaction was confirmed to be complete by thin-layer chromatography (TLC) using a 3:1 volume ratio of petroleum ether (PE) and ethyl acetate (EA) as the developing solvent. After the reaction solution cooled to room temperature, it was filtered with diatomaceous earth as an aid. The filter cake was washed with dichloromethane (DCM), and the filtrate and washings were combined. The solvent was evaporated to dryness, and the solution was diluted with water. The mixture was extracted three times with methyl tert-butyl ether. The organic phases were combined, the solvent was evaporated to dryness under reduced pressure, and hexane and DCM were added. The mixture was stirred overnight and filtered to give 2.48 g of a pale yellow solid (compound IV), with a yield of 86.2%.

[0066] 1 H NMR (400 MHz, DMSO- d 6): δ 7.24 (s, 1H), 6.05 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H).

[0067] (3) Synthesis of 7-methoxybenzo[1,3]dioxane-5-carboxylic acid (V)

[0068] Compound IV (2.0 g, 2.8 mmol), 5M NaOH solution (6.1 mL, 30.0 mmol), and 30 mL of methanol were added to a 200 mL single-necked flask. The mixture was refluxed at 100 °C for 5 h. The reaction was confirmed to be complete by thin-layer chromatography (TLC) using a mixture of petroleum ether (PE) and ethyl acetate (EA) at a volume ratio of 3:1 as the developing solvent. After the reaction solution was cooled to room temperature, the solvent was evaporated to dryness, and the solution was dissolved in water. The pH was adjusted to 2 with 3M hydrochloric acid solution, and a white solid precipitated. The solid was filtered, and the filter cake was evaporated to dryness with a suitable amount of toluene to obtain 1.72 g of white solid (compound V), with a yield of 93.53%.

[0069] 1 H NMR (400 MHz, DMSO- d 6): δ 7.25 (s, 1H), 6.00 (s, 2H), 3.78 (s, 3H).

[0070] (4) Synthesis of biphenyl bis(I)

[0071] Compound V (1.5 g, 8.4 mmol), coupling catalyst [{Rh(nbd)Cl}2] (100 mg, 0.2 mmol), activated MnO2 (2 g, 0.32 mol), and 50 mL of dimethyl sulfoxide were added to the reaction flask. The mixture was heated to 150 °C and reacted under atmospheric pressure and argon protection for 30 h. The reaction was confirmed to be complete by thin-layer chromatography (TLC) using a mixture of petroleum ether (PE) and ethyl acetate (EA) at a volume ratio of 3:1 as the developing solvent. The pH of the reaction solution was adjusted to 12 using K2CO3 solution, sonicated for 20 min, filtered, and the filter cake was washed with methanol. The pH of the filtrate was adjusted to 2 using 3 M hydrochloric acid solution, concentrated to dryness, and the solid was dissolved in an appropriate amount of methanol. The mixture was filtered, and the filter cake was washed with methanol. The filtrate and washings were combined and concentrated to dryness using silica gel. The mixture was purified by column chromatography (the DCM:MeOH volume ratio was changed from 100:1 to 100:5) to obtain 2.47 g of a pale yellow solid, namely compound I, with a yield of 82.5%.

[0072] 1 H NMR (400 MHz, DMSO- d 6): δ 7.26 (s, 2H), 5.99 (s, 2H), 5.96 (s, 2H), 3.84 (s, 2H); HRMS (ESI-MS) m / z (M+Na) + calcd for C 18 H 14 O 10 Na: 413.0484; Found: 413.0479.

[0073] Comparative example: Compound V (1.5 g, 8.4 mmol), coupling catalyst [{Rh(nbd)Cl}2] (100 mg, 0.2 mmol), and activated MnO2 (2 g, 0.32 mol) were added to a 15 mL sealed tube. The mixture was stirred in 3.5 mL of purified water at 150 °C under air atmosphere for 30 h. The reaction was confirmed to be complete by thin-layer chromatography (TLC) using a mixture of petroleum ether (PE) and ethyl acetate (EA) at a volume ratio of 3:1 as the developing solvent. The pH of the reaction solution was adjusted to 12 using K2CO3 solution, sonicated for 20 min, filtered, and the filter cake was washed with methanol. The pH of the filtrate was adjusted to 2 using 3 M hydrochloric acid solution, concentrated to dryness, and the solid was dissolved in an appropriate amount of methanol. The mixture was filtered, and the filter cake was washed with methanol. The filtrate and washings were combined and concentrated to dryness using silica gel. The mixture was purified by column chromatography (the DCM:MeOH volume ratio was changed from 100:1 to 100:5) to obtain 50 mg of a pale yellow solid, namely compound I, with a yield of 30.2%.

[0074] Comparing the embodiments and comparative examples, it can be seen that the yield and selectivity of the method of the present invention are significantly higher than those of the comparative example method.

[0075] It should be noted that this application is not limited to the above-described embodiments. The above embodiments are merely examples, and any embodiments with the same structure and effect as the technical concept within the scope of this application are included in the technical scope of this application. Furthermore, various modifications that can be conceived by those skilled in the art to the embodiments, and other ways of constructing by combining some of the constituent elements of the embodiments, without departing from the spirit of this application, are also included in the scope of this application.

Claims

1. A method for preparing the compound of formula I, comprising: The compound shown in Formula V, the coupling catalyst, the oxidant and the solvent dimethyl sulfoxide were mixed and reacted at 50℃-200℃ and at atmospheric pressure to obtain the compound shown in Formula I. The coupling catalyst is selected from one or more of norbornene rhodium chloride dimer, elemental palladium, palladium acetate, tetra(triphenylphosphine)palladium, and bis(dibenzylacetone)palladium; the oxidant is selected from one or more of manganese dioxide, silver oxide, and silver acetate. R1 is selected from C1-C6 alkyl groups.

2. The method according to claim 1, wherein, The reaction is carried out under an inert atmosphere; and / or, The reaction temperature is 100℃ - 160℃; and / or, The reaction time is 5-48 hours, optionally 10-30 hours; and / or, The coupling catalyst is norbornene rhodium chloride dimer; and / or The oxidant is manganese dioxide; and / or, The molar ratio of the compound shown in Formula V to the coupling catalyst is 1:0.01 - 1:0.2; and / or, The molar ratio of the compound shown in Formula V to the oxidant is 1:0.01 - 1:0.25; and / or, The ratio of the compound shown in Formula V to the organic solvent is 0.01:1 g / mL - 0.1:1 g / mL; and / or, R1 is a methyl group.

3. The method according to claim 1 or 2, wherein, The compound shown in Formula V is prepared by the following steps: The compound shown in Formula IV, an alkaline solution, and a first organic solvent are mixed and reacted at 50°C-120°C to obtain the compound shown in Formula V. The alkaline solution is selected from one or more solutions of sodium hydroxide and potassium hydroxide; the first organic solvent is selected from one or more solutions of methanol, ethanol, and isopropanol. R1 and R2 are each independently selected from C1-C6 alkyl groups.

4. The method according to claim 3, wherein, In the steps for preparing the compound shown in formula V, the reaction time is 2-10 hours; and / or, In the step of preparing the compound shown in formula V, the reaction is carried out under reflux conditions; and / or, The molar ratio of the compound shown in Formula IV to the base in the alkaline solution is 1:9 - 1:12; and / or, The molar concentration of the alkaline solution is 1-10 M; and / or, The ratio of the compound shown in Formula IV to the first organic solvent is 1:12 g / mL - 1:18 g / mL; and / or, R1 and R2 are methyl groups.

5. The method according to claim 3 or 4, wherein, The compound shown in Formula IV is prepared by the following steps: The compound shown in Formula III, the first base, the dihalomethane, the catalyst, and the second organic solvent are mixed and reacted under conditions of 80°C - 150°C and in a closed environment to obtain the compound shown in Formula IV. Wherein, the first alkali is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; the catalyst is selected from one or more of copper oxide and potassium iodide; and the second organic solvent is N,N-dimethylformamide. R1 and R2 are each independently selected from C1-C6 alkyl groups.

6. The method according to claim 5, wherein, In the steps for preparing the compound of formula IV, the reaction time is 2-10 hours; and / or, The molar ratio of the compound shown in Formula III to the first base is 1:1 to 1:2; and / or, The molar ratio of the compound shown in Formula III to the dihalomethane is 1:2 to 1:4; and / or, The molar ratio of the compound shown in Formula III to the catalyst is 1:0.02 – 1:0.1, for example 1:0.067; and / or, The ratio of the compound shown in Formula III to the second organic solvent is 1:8 g / mL – 1:14 g / mL; and / or, The dihalomethane is selected from one or more of dibromomethane, difluoromethane, and dichloromethane; and / or, R1 and R2 are methyl groups.

7. The method according to claim 5 or 6, wherein, The compound shown in Formula III is prepared by the following steps: The compound shown in Formula II, the second base, the halogenated C1-C6 alkane, trimethyl borate or borax, and the third organic solvent are mixed and reacted at -20°C to 70°C to obtain the compound shown in Formula III. Wherein, the second base is selected from one or more of sodium hydride, potassium carbonate, and cesium carbonate; the halo-C1-C6 alkane is selected from one or more of iodo-C1-C6 alkane, bromo-C1-C6 alkane, and chlorinated C1-C6 alkane; and the third organic solvent is selected from one or more of N,N-dimethylformamide and acetone. R1 and R2 are each independently selected from C1-C6 alkyl groups.

8. The method according to claim 7, wherein, In the step of preparing the compound of formula III, the reaction time is 10-24 hours; and / or, The molar ratio of the compound shown in Formula II to the second base is 1:1 to 1:4; and / or, The molar ratio of the compound shown in Formula II to the haloalkane is 1:0.8 - 1:1.2; and / or, The molar ratio of the compound shown in Formula II to the trimethyl borate or borax is 1:1 – 1:3; and / or, The ratio of the compound shown in Formula II to the third organic solvent is 1:11 g / mL - 1:16 g / mL; and / or, R1 and R2 are methyl groups.

9. The method according to any one of claims 1 to 8, characterized in that... One or more of the following: The method further includes: in the step of preparing compound I, adjusting the reaction product to pH 11-13, performing a first solid-liquid separation, adjusting the obtained liquid phase to pH 1-3, concentrating and drying, mixing the dried product with an alcohol solvent, performing a second solid-liquid separation, collecting the liquid phase, washing the obtained solid phase with an alcohol solvent, combining the collected liquid phase and washing liquid, concentrating, and then purifying by column chromatography to obtain the compound shown in formula I; The method further includes: in the step of preparing the compound shown in formula V, drying the reaction product, dissolving the dried product in water, adjusting the pH of the resulting solution to 1-3, separating the solid and liquid phases, collecting the solid phase and drying it to obtain the compound shown in formula V; The method further includes: in the step of preparing the compound shown in Formula IV, separating the reaction product into solid and liquid phases, collecting the liquid phase, washing the solid phase with dichloromethane, combining the liquid phase and the washing liquid, drying, mixing the dried product with water, extracting the resulting mixture with methyl tert-butyl ether, collecting the organic phase and removing the solvent, mixing the resulting substance with n-hexane and dichloromethane, separating the solid and liquid phases, and collecting the solid phase, which is the compound shown in Formula IV; In the step of preparing the compound shown in Formula III, during mixing, the compound shown in Formula II is first mixed with a portion of the third organic solvent. The second base is added to the resulting mixture in multiple portions under ice bath conditions. After stirring and mixing for 0.5-2 hours, the halo-C1-C6 alkane, trimethyl borate or borax and the remaining portion of the third organic solvent are added to the resulting mixture and mixed. The method further includes: in the step of preparing the compound shown in Formula III, mixing the reaction product with ice water, adjusting the pH to 2-4, extracting with ethyl acetate, collecting the organic phase, removing residual water from the organic phase, concentrating, and purifying by column chromatography to obtain the compound shown in Formula III.

10. A method for preparing bicyclic alcohols, comprising: The compound of formula I is prepared according to the method of any one of claims 1 to 9; Bicyclic alcohols were prepared using the compound shown in Formula I as a starting material.

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