Preparation method of cyclopofol

Abstract

The invention discloses a preparation method of cyclopofol, which comprises the following steps: by taking methyl salicylate as a starting material, carrying out etherification, alkyl migration rearrangement, Weinreb amide preparation, Grignard addition, Witting reaction and terminal alkene asymmetric raw six-step reaction to obtain cyclopofol. On the basis of the innovative synthesis route, the process conditions are optimized, the atom economy is improved, the raw material and production cost is reduced, and the method is suitable for industrial production. The synthetic route is simple and efficient, the total yield is high, the product purity is high, and the problems of high raw material cost, many side reactions, low yield, complex process and the like in the existing preparation method are solved.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing cyclopropanol. Background Technology

[0002] Propofol is a novel, short-acting intravenous anesthetic belonging to the γ-aminobutyric acid (GABA) receptor agonist class. It is produced by introducing a cyclopropyl group into the isopropyl side chain of propofol, forming a new chiral molecule, increasing steric effect, and thus increasing affinity for GABA receptors. It possesses advantages such as high potency, rapid onset of action, rapid recovery, low accumulation, and few adverse reactions, making it suitable for various endoscopic procedures and ICU sedation and general anesthesia. With its rapid onset, rapid recovery, and minimal impact on the cardiovascular system, it has broad application prospects in clinical anesthesia.

[0003] Currently, there are many synthetic routes for propofol, but existing technical routes all have many key bottlenecks. The specific analysis of the routes in the references is as follows: The original research route patent CN105820040 (as shown below) uses 2-isopropyl-6-(1-methylallyl)phenol as the starting material. This raw material is expensive and there is no direct commercial bulk source. It needs to be prepared through multiple pre-synthesis steps, resulting in a long route and high raw material costs. The process route contains complex steps such as carbamate, cyclopropanation, and chiral resolution, with an overall yield of only 32.5-42.4%. Among them, the high-temperature Claisen rearrangement reaction (around 200℃) is prone to carbonization and polymerization side reactions, resulting in more by-products and significantly reducing product purity. The cyclopropanation step requires the use of diiodomethane / zinc-copper reagent. Diiodomethane is highly toxic and zinc-copper reagent is flammable, resulting in low operational error tolerance, strict equipment protection requirements, and high risks for large-scale production.

[0004]

[0005] A multi-step tandem route, as described in patent CN105384608, involves synthesizing cyclopophene from 2-isopropanol via a nine-step reaction process: cyclization, hydrolysis, protection, resolution, reduction, oxidation, Wittig reaction, cyclopropanation, and deprotection (as shown below). This synthetic route is lengthy, complex, and difficult to operate, resulting in low yields and making it unsuitable for large-scale industrial production.

[0006]

[0007] Journal of Medicinal Chemistry, 2017, vol.60, #9, p.3606-3617 (hereinafter referred to as JMC2017) describes the preparation of cyclopropofol from 2-isopropylphenol via a process of "phenolic hydroxyl protection-nucleophilic addition and hydrolysis-Grignard reaction-reductive dehydroxylation-chiral resolution". This process presents several key challenges, including cumbersome raw material pretreatment, high cost of chiral resolution, stringent reaction conditions, and low yield and purity. The chiral resolution step requires chiral-HPLC, and the remaining half of the racemic mixture cannot be effectively utilized, resulting in significant raw material waste. The total yield of the racemic cyclopropofol before resolution was 71.6%, while the yield after resolution was ≤35.8%, further increasing costs. Furthermore, the n-BuLi (n-butyllithium) used in this route exhibits extremely high reactivity and requires a stringent operating environment, posing a high risk for industrial production.

[0008]

[0009] In summary, existing synthetic routes for propofol generally suffer from common problems such as harsh reaction conditions, low overall yield, and high cost, making them difficult to industrialize and thus unsuitable for large-scale production.

[0010] Therefore, developing a synthetic route for cyclopropanol that uses readily available raw materials, involves simple steps, has a high yield, and is inexpensive is of great significance for promoting its industrial production and clinical application. Summary of the Invention

[0011] To address the shortcomings of existing technologies, this invention provides a method for preparing cyclopropanol with high yield and low cost through precisely designed reaction systems and process parameters.

[0012] This invention first provides a method for preparing cyclopropanol, the specific synthetic route of which is as follows:

[0013] Starting with methyl salicylate, cyclopophene was finally obtained through a six-step reaction involving etherification, alkyl migration rearrangement, Weinreb amide preparation, Grignard reaction, Witting reaction, and asymmetric reduction of terminal olefins.

[0014] The specific reaction process is as follows: S1 Etherification Reaction: Using methyl salicylate (compound 1) as a starting material, the reaction is carried out in an alkaline reagent, isopropyl alkyl halide, and aprotic solvent at 20-35℃ for 2-12 h. After the reaction is complete, compound 2 is obtained by water extraction, washing, drying, and vacuum concentration, with a yield of 86.2%-91.1%. Mechanistically, the alkaline reagent reacts with the phenolic hydroxyl group of methyl salicylate to generate a nucleophile, which attacks the alkylating agent through an SN2 substitution reaction to form an ether intermediate. This system has a high yield, and the alkaline reagent and alkylating agent can be flexibly switched according to industrial cost requirements, making it suitable for large-scale production.

[0015] The alkaline reagent is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, TEA, DIPEA, and DBU, and the amount of alkaline reagent used is 2.0-4.0 times the molar amount of methyl salicylate; the isopropyl haloalkane is selected from at least one of 2-iodopropane, 2-bromopropane, and 2-chloropropane, and the amount used is 1.2-2.2 eq of methyl salicylate; the aprotic solvent is selected from at least one of DMF, DMSO, NMP, DMAc, acetonitrile, and 1,4-dioxane, and the amount used is 8-15 times (mL / g) the mass of methyl salicylate.

[0016] S2 Alkyl Migration Rearrangement: Under nitrogen protection and anhydrous conditions (moisture < 0.05%), compound 2 was reacted with a phase transfer catalyst in an acidic mixture of sulfuric acid (concentration ≤ 75%) and acetic anhydride under a protective gas atmosphere via gradient heating and reflux. After cooling, layering, alkaline extraction, neutralization, and feed recovery, rearranged product 3 was obtained, with an overall yield of 85.0%-90.0%. Mechanistically, sulfuric acid provides a protonated environment to form oxonium ions, acetic anhydride inhibits hydrolysis side reactions, and TBAB reduces carbonization byproducts and improves reaction efficiency through phase transfer. Combined with gradient heating, this achieves the directional migration of isopropyl groups, balancing high yield with economic efficiency.

[0017] The acid mixture is composed of sulfuric acid and acetic anhydride in a volume ratio of 1:1 to 1:5, with a sulfuric acid concentration ≤75%. The phase transfer catalyst is at least one of TBAB, TBAC, TBAI, TBAHS, trioctylmethylammonium chloride, and TEBA, with the amount of phase transfer catalyst being 0.3-0.8 mol of 2 moles of the compound. The gradient temperature is first raised to 80-120℃ and reacted for 0.5-2 hours, then raised to 120-150℃ for reflux. During reflux, a water separator is used to separate the water in the system.

[0018] Preparation of S3 Weinreb amide: Compound 3 and Me(OMe)NH·HCl were dissolved in a solvent, and the mixture was cooled to 0-5℃ under nitrogen protection. Then, a solution of alkali and a condensing agent was slowly added dropwise. The mixture was then slowly heated to 20-40℃ at room temperature for 1-8 hours. After the reaction, compound 4 was obtained through post-treatment and purification. The yield of this step was 93.0%-98.0%. This step employed a highly efficient direct condensation strategy to construct the key intermediate of the Weinreb amide. The specific reaction mechanism is as follows: In an alkaline environment, the condensing agent first reacts with the carboxyl group of compound 3 to generate a highly reactive O-acyl isourea intermediate. This intermediate is then subjected to nucleophilic attack by the nitrogen atom of Me(OMe)NH·HCl, and through an addition-elimination process, efficiently forms the Weinreb amide (compound 4), while simultaneously generating an easily removable water-soluble urea byproduct.

[0019] The amount of Me(OMe)NH・HCl used is 1.0-1.5 eq of compound 3; the condensing agent is any one of EDC・HCl, DCC, HATU, T3P, and DIC, and the amount used is 1.0-1.8 eq of compound 3; the base is at least one of TEA, DIPEA, NMM, DMAP, DBU, and 2,6-di-tert-butylpyridine, and the amount used is 1.0-3.0 eq of compound 3; if EDC・HCl is selected as the condensing agent, in addition to the base as an acid-binding agent, DMAP is also required for synergistic reaction. The solvent used in the reaction is at least one of MTBE, THF, 2-MeTHF, and ethyl acetate, and the amount used is 5-15 times the mass of compound 3 (mL / g), that is, 5-15 mL of solvent is used per gram of compound 3.

[0020] S4 Grignard addition: Compound 4 was dissolved in anhydrous (water content ≤ 0.5%) solvent and cooled to -10℃-10℃. Cyclopropyl Grignard reagent was added dropwise over 2-8 hours. After addition, the reaction was maintained at -10℃-10℃. Compound 5 was then purified by quenching, extraction, washing, drying, concentration, and recrystallization. The yield of this step was 91.0%-96.0%. Mechanistically, the nucleophilic reaction of compound 4 with cyclopropyl Grignard reagent selectively generates a ketone through the formation of a stable six-membered ring transition state and a chelate intermediate. This reaction only stops at this stage, without excessive bimolecular nucleophilic addition. Low temperature (-10-10℃) and slow dropwise addition of the reagent suppress side reactions, and the anhydrous solvent ensures the activity of the Grignard reagent.

[0021] The cyclopropyl Grignard reagent is selected from at least one of cyclopropyl magnesium bromide, cyclopropyl magnesium chloride, and cyclopropyl magnesium iodide. The concentration of the cyclopropyl Grignard reagent solution is 0.5-2.0 M, and the amount used is 1.0-2.5 eq of compound 4. The anhydrous solvent is selected from at least one of THF, 2-MeTHF, diethyl ether, and toluene. The water content is ≤0.05%, and the amount used is 2-20 times (mL / g) of the mass of compound 4.

[0022] S5 Witting reaction: Compound 5 was mixed with Wittig reagent in a solvent, and a base reagent was added in portions at 0-15°C. The reaction was carried out at 0-80°C for 4-18 hours. After quenching, pH adjustment, extraction, drying, concentration, and recrystallization, compound 6 was obtained, with a yield of 92.3%-97.0%. Mechanistically, a base reagent such as sodium methoxide can efficiently induce methyltriphenylphosphine bromide to form a ylide intermediate, which attacks the carbonyl group of the addition product to form a transition state and then decomposes to form a carbon-carbon double bond. Adding the base reagent at low temperature and then slowly raising the temperature can reduce side reaction losses. The use of a mixed solvent of n-heptane and ethyl acetate for recrystallization can efficiently remove triphenylphosphine oxide.

[0023] The Witting reagent is at least one of MTPPB, MTPPC, and ethyltriphenylphosphine bromide, and the amount used is 1.0-2.5 eq of compound 5; the base reagent is at least one of cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, DBU (1,8-diazabicycloundec-7-ene), NaHMDS, LiHMDS, sodium methoxide, and sodium ethoxide, and the amount used is 1.0-4.0 eq of compound 5; the solvent is at least one of THF, 1,4-dioxane, 2-MeTHF, acetonitrile, and DMSO, and the amount used is 4-20 times (mL / g) of the mass of compound 5.

[0024] S6 terminal olefin asymmetric reduction: Compound 6 was reacted with Rh metal catalyst at a hydrogen pressure of 1.0-4.5 MPa and at 20-60 °C for 2-24 h, and post-processed to obtain cyclopophene. The catalyst is a Rh metal catalyst with a chiral ligand, used at 0.1%-5% of 6 moles of the compound. The Rh metal catalyst is one of [RhCl(COD)]2 ((1,5-cyclooctadiene)rhodium chloride(I) dimer), [(NBD)2Rh]BF4 (bis(norbornene)rhodium tetrafluoroborate(I)), or [Rh(acac)(C2H4)2] ((acetylacetone)di(ethylene)rhodium(I)). The chiral ligand is (R)-(+)-BINAP (R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine), (R)-(+)-Xyl BINAP ((R)-(-)-1,1'-binaphthyl-2,2'-bis(3,5-dimethylyl)phosphine), or (R)-Seg Phos One of (5,5'-bis(diphenylphospho)-4,4'-di-1,3-biphenyl) and (1S,1′S,2R,2′R)-Duan Phos. The reaction solvent is at least one of methanol, ethanol, dichloromethane, and 2-MeTHF. The enantioselectivity of this step is ≥99%, with a yield of 87.4-93.0%. Mechanistically, the ligand forms a complex with the active metal center, guiding the directional addition of hydrogen to the olefin double bond. The hydrogen pressure and reaction temperature are synergistically controlled to achieve efficient reduction, avoiding over- or incomplete reduction. Post-treatment involves simple filtration, vacuum concentration, and vacuum distillation, followed by recrystallization purification to obtain the target product.

[0025] The theoretical overall yield of the six-step reaction is 50.0%-69.6%, while the actual yield is 56.2%-64.7%. This simple and efficient route determines its technological advantages, eliminating the need for cumbersome pre-activation of functional groups or the use of highly hazardous metal reagents, and achieving direct conversion from key intermediates, resulting in high atom economy. In addition, the reaction is carried out under mild conditions, byproducts are easy to handle, and post-processing is simple and safe, giving it the potential for large-scale production.

[0026] This invention also provides the following optimization scheme: Preferably, in step S1, the etherification reaction, the base reagent is selected from at least one of potassium carbonate, sodium carbonate, TEA, and DIPEA, and the amount of base reagent used is 2.5-3.5 times the molar amount of methyl salicylate; the amount of isopropyl haloalkane used is 1.8-2.5 eq of methyl salicylate, more preferably 2.0 eq; the aprotic solvent is selected from at least one of DMF, DMSO, NMP, DMAc, acetonitrile, and 1,4-dioxane, and the amount used is 8-15 times the mass of methyl salicylate, more preferably 10-12 times (mL / g); the reaction temperature is preferably 20-25℃, and the reaction time is 6-8 h.

[0027] Preferably, in step S2, the alkyl migration rearrangement reaction: the acidic mixture is selected from 65%-75% sulfuric acid with acetic anhydride or 60%-70% sulfuric acid with propionic anhydride, and the volume ratio of acid to anhydride in the acidic mixture is 1:(1.5-2.5); the phase transfer catalyst is selected from at least one of TBAB, TBAC, and TBAI, and the amount of phase transfer catalyst is 0.4%-0.6% of 2 moles of the compound; the gradient temperature reflux conditions are preferably: first reflux at 95-115℃ for 0.5-1h, then reflux at 130-150℃ for 2-4h at a rate of 3-15℃ / min; after the reaction is completed and cooled, ice water is added dropwise to quench the reaction; the resulting oily substance is extracted with an 8%-15% alkaline solution; after extraction, the aqueous phase is controlled at 10-40℃, and 7%-13% sodium hydroxide solution or potassium hydroxide solution is slowly added dropwise to adjust the pH to 6-8; the precipitated oily substance or solid is purified by vacuum distillation.

[0028] Preferably, in step S3, the preparation of Weinreb amide, the amount of Me(OMe)NH・HCl used is 1.0-1.5 eq of compound 3; more preferably, it is 1.1-1.3 eq. The condensing agent is any one of EDC・HCl, DCC, DIC, and HATU, and the amount used is 1.1-1.6 eq of compound 3; more preferably, the condensing agent is EDC・HCl or DCC, and the amount used is 1.1-1.4 eq; the base is at least one of TEA, DIPEA, DMAP, and DBU, and the amount used is 1.2-2.8 eq of compound 3; more preferably, the base is DIPEA, DMAP, or TEA, and the amount used is 1.5-2.2 eq; if EDC・HCl is selected as the condensing agent, in addition to the base as an acid-binding agent, a catalytic amount of DMAP is also required for synergistic reaction; the solvent used in the reaction is one of MTBE and 2-MeTHF, and the amount used is 8-12 times (mL / g) of the mass of compound 3, that is, 8-12 mL of solvent is used per gram of compound 3.

[0029] Preferably, in step S3, the preparation of Weinreb amide includes: quenching with dilute hydrochloric acid aqueous solution, solvent extraction, alkali washing of the organic phase, salt washing, concentration, recrystallization purification, and drying; during quenching, the reaction solution temperature is controlled at 0-10℃, and dilute hydrochloric acid aqueous solution is slowly added dropwise for ≥1h, wherein the concentration of the dilute hydrochloric acid aqueous solution is 1%-10%; alkali washing and back-extraction use at least one of Na2CO3, NaHCO3, NaOH, K2CO3, and NH4Cl aqueous solution.

[0030] Preferably, in step S4 Grignard addition: the cyclopropyl Grignard reagent is selected from cyclopropyl magnesium bromide or cyclopropyl magnesium iodide, and the concentration of the cyclopropyl Grignard reagent solution is 0.5-1.5M, more preferably 0.5-1.0M; the amount used is 1.5-2.5 eq of compound 4, more preferably 1.5-2.0 eq; the anhydrous solvent is at least one of THF, 2-MeTHF, and toluene, the solvent water content is ≤0.03%, and the amount used is 8-12 times (mL / g) of the mass of compound 4; the reaction temperature is -5℃ to 5℃, more preferably -2-2℃; the cyclopropyl Grignard reagent is added dropwise for 2-4 h, and the temperature during the dropwise addition does not exceed the set upper limit of temperature; the reaction time is 2.0-2.5 h; after the reaction is completed, it is quenched with saturated ammonium chloride aqueous solution or saturated sodium chloride aqueous solution at a quenching temperature of 0-15℃.

[0031] Preferably, in step S5, the Witting reaction: the Witting reagent is selected from methyltriphenylphosphine bromide or methyltriphenylphosphine chloride, and the amount used is 2.5-3.5 eq of compound 5, more preferably 2.5-2.8 eq; the base reagent is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, and sodium ethoxide, and the amount used is 2.0-3.8 eq of compound 5, more preferably 2.8-3.2 eq; the solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, and 2-methyltetrahydrofuran; the reaction temperature is preferably 65-75℃, and the reaction time is preferably 8-12 h; the solvent for recrystallization is one of n-heptane-ethyl acetate, cyclohexane-ethyl acetate, or n-hexane-ethyl acetate; the post-treatment also includes filtration to remove triphenylphosphine oxide and concentrating the filtrate.

[0032] Preferably, in step S6 (terminal olefin asymmetric reduction): the Rh metal catalyst is [RhCl(COD)]2 or [(NBD)2Rh]BF4; the chiral ligand is one of (R)-(+)-BINAP, (R)-(+)-Xyl NAP, and (1S,1′S,2R,2′R)-DuanPhos; the catalyst dosage is 0.5-1.5% of 6 moles of the olefin product compound; more preferably, the catalyst is [(NBD)2Rh]BF4-(1S,1′S,2R,2′R)-DuanPhos. Phos, in an amount of 0.5-1.0%; the reaction solvent is selected from at least one of ethanol, methanol, and methanol-dichloromethane mixture (volume ratio 1:1-10-1), and the amount of solvent is 4-8 times the mass of compound 6; the hydrogen pressure is 1.2-3.2 MPa, the reaction temperature is 35-40℃, the reaction time is 6-8 h, and the corresponding fraction is collected to obtain pure cyclopropofol; optionally, it can be purified by recrystallization after distillation.

[0033] This invention provides a novel synthetic route for the synthesis of propofol, which boasts high atom economy and overall yield, low cost, and mild process conditions, making it suitable for industrial production. Specific innovative advantages are as follows: I. Construction of a Novel Synthetic Route: This invention designs a six-step synthetic route: etherification-Fries alkyl migration rearrangement-Weinreb amide preparation-Grignard addition-Wittig reaction-terminal alkene asymmetric reduction. This route eliminates complex steps such as phenolic hydroxyl protection / deprotection, chiral resolution, and cyclopropanation, achieving efficient synthesis of cyclopophenes through the directional transformation of key intermediates. Its core mechanistic advantages are as follows: The etherification reaction constructs an ether intermediate via SN2 substitution, laying the foundation for subsequent reactions; the Fries rearrangement achieves directional migration of the isopropyl group and reduces byproducts through a protonated environment, phase transfer catalysis, and gradient temperature; the Weinreb amide preparation selectively constructs an amide intermediate through carboxyl activation and nucleophilic addition-elimination; Grignard addition forms a stable transition state, generating ketones with high selectivity and no over-addition; the Wittig reaction generates a ylide intermediate, directionally introducing a terminal alkene structure; the terminal alkene asymmetric reduction guides the directional addition of hydrogen through an Rh metal catalyst and a chiral ligand complex, achieving a high enantioselectivity reduction with an ee value ≥99%. This synthetic method solves the problems of redundant steps, poor selectivity, numerous byproducts, and insufficient optical purity of traditional routes (such as CN105820040 and CN105384608), and provides a brand-new technical route for the industrial synthesis of cyclopophenol.

[0034] II. High atom economy, significantly improved overall yield and cost advantages: This invention optimizes the process parameters and material ratios of each reaction step, achieving efficient connection and low loss of reaction links. The yields of each of the six reaction steps remain excellent: etherification reaction 86.2%-91.1%, alkyl migration and rearrangement reaction 85.0%-90.0%, Weinreb amide preparation 93.0%-98.0%, Grignard addition 91.0%-96.0%, Witting reaction 92.3%-97.0%, and terminal olefin asymmetric reduction 87.4%-93.0%, with a final overall yield of 56.2%-64.7%. Compared with the original route's yield of 32.5%-42.4% and the JMC2017 route's yield of ≤35.8% after resolution, this invention significantly improves atom utilization and reduces raw material waste. The raw materials used, such as methyl salicylate and isopropyl halogenated alkyl, are all commercially available commodities that are inexpensive and readily available, and do not require custom synthesis. Compared with the original research route, which requires expensive custom raw materials, and the JMC2017 route, which requires high-cost consumables for chiral resolution, the raw material procurement cost is significantly reduced. In addition, the synthesis route does not require special protective equipment for high-temperature rearrangement and handling of highly toxic reagents. The high yield further reduces raw material consumption and waste treatment costs, comprehensively reducing the overall investment in industrial production and giving it a significant competitive advantage in the market.

[0035] III. Mild Process Conditions and Safe and Controllable Operation: The reaction conditions in each step of this process are mild, with no extreme temperature or pressure conditions. The reaction temperature is concentrated between -10℃ and 80℃, and the hydrogen pressure is controlled between 1.0 and 4.5 MPa. The process is stable and easy to control, and it avoids the complex stepwise purification and functional group protection / deprotection steps in traditional routes. Post-processing only requires conventional operations such as extraction, washing, concentration, and recrystallization. The process is simple and efficient, without highly toxic diiodomethane or flammable zinc and copper reagents. It also does not require the use of highly reactive and demanding reagents such as n-butyllithium, and no special safety protection equipment is needed, making it more suitable for large-scale industrial production. Attached Figure Description

[0036] Figure 1 Compound 2 obtained in Example 1 of this invention 1 H-NMR spectrum; Figure 2 Compound 5 obtained in Example 1 of this invention 1 H-NMR spectrum; Figure 3 Compound 5 obtained in Example 1 of this invention 13 C-NMR spectrum; Figure 4 Compound 6 obtained in Example 1 of this invention 1 H-NMR spectrum; Figure 5 Compound 6 obtained in Example 1 of this invention13 C-NMR spectrum; Figure 6 The cyclopropanol obtained in Example 1 of this invention 1 H-NMR spectrum; Figure 7 The cyclopropanol obtained in Example 1 of this invention 13 C-NMR spectrum; Figure 8 This is a synthetic route diagram for the present invention. Detailed Implementation

[0037] To enable those skilled in the art to better understand the technical solution of the invention, the invention will be further described in detail below with reference to specific embodiments.

[0038] This invention discloses a method for preparing cyclopropanol, the specific synthetic route of which is as follows:

[0039] Starting with methyl salicylate, a six-step reaction process was performed, involving etherification, alkyl migration rearrangement, Weinreb amide preparation, Grignard addition, Witting reaction, and asymmetric chiral reduction of the terminal alkene, to finally obtain cyclopophenol. The above is a brief description of the invention; the following are embodiments of the invention. Example 1:

[0040] S1 etherification reaction:

[0041] In a 50 mL three-necked flask under nitrogen protection, methyl salicylate (compound 1) (1.50 g, 9.86 mmol, 1.0 eq), K₂CO₃ (2.71 g, 19.6 mmol, 2.0 eq), 2-bromopropane (1.50 g, 12.2 mmol, 1.2 eq), and 18 mL of DMF were added. The reaction was carried out with magnetic stirring at a controlled temperature of 25-35 °C for 12 hours.

[0042] After the reaction was complete, 15 mL of purified water was added to the reaction system to quench the reaction, and the mixture was allowed to stand and separate into layers. The aqueous layer was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed once with saturated brine (15 mL), and dried for 3 hours with 1.2 g of anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 2 (1.75 g, yield 91.1%). The results were analyzed... Figure 1 Compound 2 1 H-NMR spectrum, 1 HNMR(400MHz, CDCl3) δ 7.75(dd, J =7.6Hz, 2.0Hz, 1H), 7.42(td,J =7.2Hz, 2.0Hz, 1H), δ 6.99-6.94(m, 2H), δ 4.61-4.5(m, 1H), 3.88 (s,3H), δ 1.37(d, J =6.0Hz, 6H). MS(ESI): m / z [M+H]⁺ calcd for C 11 H 15 O2: 195.10, found: 95.50.

[0043] S2 alkyl migration rearrangement reaction:

[0044] In a nitrogen-protected 50 mL three-necked flask, add compound 2 (1.75 g, 8.97 mmol, 1.0 eq), 7.78 mL of a pre-prepared 70% sulfuric acid:acetic anhydride (v / v 1:5) mixture, and TBAC (0.014 g, 0.044 mmol, 0.5 mol%). After mechanical stirring until homogeneous, purge with nitrogen at a flow rate of 12 mL / min for protection.

[0045] The reaction mixture was first heated to 80-100℃ and reacted for 2 hours, then refluxed at 120-130℃ for 3 hours at a rate of 8℃ / min, separating the water using a water separator during reflux. After the reaction was complete, the reaction solution was cooled to 50℃, and 110 mL of ice water was slowly added to quench the reaction. The mixture was allowed to stand and separate into layers, and the lower layer of waste acid phase was discarded. The upper oily layer was extracted once with 42 mL of 10% sodium hydroxide solution, and the alkaline phase was collected. The alkaline phase was first adjusted to pH=7 by slow dropwise addition of 10% sodium hydroxide solution at 25℃, precipitating an oily product. The oily product was purified by vacuum distillation to obtain compound 3 (1.51 g, yield 87.2%). 1 HNMR (CDCl3) δ: 1.30 (d, J =6.5Hz, 6H), 3.42(septet, J =6.5Hz,1H), 3.96(s,3H), 6.7-7.8(m,3H), 11.5(s,1H). MS (ESI): m / z[M+H]⁺ calcd for C 11 H 15 O2: 195.10, found: 195.10.

[0046] S3 Weinreb amide preparation

[0047] In a 100 mL four-necked flask under a nitrogen atmosphere, compound 3 (1.51 g, 7.74 mmol, 1.0 eq), Me(OMe)NH·HCl (1.24 g, 11.6 mmol, 1.5 eq), DMAP (18.91 mg, 0.15 mmol, 0.2 eq), and anhydrous THF (22.7 mL, 0.03% water content) were added. The flask was cooled to 0–5 °C with mechanical stirring, and 5 mL of THF solutions of DIPEA (3.00 g, 23.3 mmol, 3.0 eq) and EDC·HCl (1.79 g, 9.32 mmol, 1.2 eq) were slowly added dropwise, maintaining the temperature ≤5 °C during the addition process.

[0048] After the addition was complete, the temperature was naturally raised to 20℃, and the mixture was stirred at 250 r / min for 6 hours. After the reaction was complete, 15 mL of 10% hydrochloric acid aqueous solution was slowly added at 0-10℃ to quench the reaction until pH = 3-4, and the mixture was stirred for 10 minutes. The mixture was extracted three times with ethyl acetate (15 mL each time, total 45 mL), and the organic phases were combined. The organic phase was washed once with saturated sodium bicarbonate solution (15 mL) and once with saturated brine (15 mL), and dried for 2 hours with 1.0 g of anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give Weinreb amide compound 4 (1.63 g, yield 94.9%). ¹H NMR (400 MHz, CDCl₃) δ 11.30 (s, 1H), 7.74 (dd, J =1.6, 8.0 Hz, 1H), 7.31 (dd, J =1.6, 8.0 Hz, 1H), 6.80(t, J =8.0Hz, 1H), .64(s, 3H), 3.40(s, 3H), 1.24 (dd, J =6.4, 6.8 Hz, 6H). MS(ESI): m / z [M+H]⁺ calcd forC 12 H 18 NO3: 224.13, found: 224.12.

[0049] S4 Grignard reaction:

[0050] In a nitrogen-protected 100 mL four-necked flask, compound 4 (1.63 g, 7.28 mmol, 1.0 eq) and anhydrous THF (32.6 mL, 0.02% water content) were added. The mixture was cooled to -10 °C with mechanical stirring, and a 0.5 M THF solution of cyclopropyl magnesium chloride (35.5 mL, 17.7 mmol, 2.5 eq) was added dropwise at a rate of 0.5 mL / min, maintaining the temperature at -10 to 0 °C during the addition. After the addition was completed, the mixture was kept at this temperature and stirred for 2 hours.

[0051] After the reaction was complete, 19 mL of saturated ammonium chloride aqueous solution was slowly added at 0-15℃ to quench the reaction, and the mixture was extracted three times with methyl tert-butyl ether. The organic phases were combined, washed once with saturated brine, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 5 (1.42 g, yield 96.0%). The results showed that... Figure 2 Compound 5 1 H-NMR spectrum, 1 HNMR(400MHz, DMSO-d6) δ 12.98 (s, 1H), 8.08(dd, J =1.6, 8.0Hz, 1H), 7.52(dd, J =1.6, 8.0Hz, 1H), 6.98(t, J =8.0Hz, 1H), 3.30(hept, J =6.8Hz, 1H), 3.04-3.01(m, 1H), 1.19 (d, J =6.8Hz, 6H), 1.17-1.10 (m, 4H). Detected... Figure 3 Compound 5 13 CNMR spectrum 13 CNMR (100MHz, CDCl3) δ 205.9, 159.9, 137.7, 132.4, 127.4, 119.5, 118.4, 26.4, 22.4, 16.6, 12.0. MS (ESI): m / z[M+H] + calcd for C 13 H 17 O2: 205.27, found: 205.10.

[0052] S5 Wittig Response

[0053] In a 250 mL four-necked flask under nitrogen protection, compound 5 (1.42 g, 7.0 mmol, 1.0 eq), MTPPC (3.91 g, 12.54 mmol, 1.8 eq), and 55 mL of tetrahydrofuran were added. The mixture was cooled to 0-5 °C with mechanical stirring, and a 2 M NaHMDS THF solution (7.0 mL, 14.0 mmol, 2.0 eq) was slowly added dropwise under controlled temperature.

[0054] After the addition of materials is complete, maintain the temperature at 0-5℃ and stir for 30 minutes, then naturally raise the temperature to 20-25℃ and react for 4 hours. After the reaction is complete, cool to 0-5℃, add 23 mL of purified water to quench the reaction, and slowly add 2M dilute hydrochloric acid solution to adjust the pH to 6.5. Add 22 mL of ethyl acetate and 14 mL of saturated sodium chloride solution, allow to stand for separation, and collect the organic phase. Dry the organic phase with anhydrous magnesium sulfate for 2 hours, filter, and concentrate to dryness to obtain the crude product.

[0055] A mixture of 33.1 mL of n-heptane and 1.7 mL of ethyl acetate (volume ratio 20:1) was added to the crude product. The mixture was stirred and heated to 60 °C for 1 hour. It was then cooled to room temperature at a rate of 2.5 °C / h, allowed to stand for 2 hours, and filtered to remove the solid. The filtrate was concentrated to dryness under reduced pressure to give compound 6 (1.31 g, yield 92.3%). Analysis showed that... Figure 4 Compound 6 1 H-NMR spectrum, 1 HNMR(600MHz, DMSO-d6) δ 7.86 (s, 1H), 7.06(dd, J =7.6, 1.8 Hz, 1H), 6.82 (dd, J =7.4, 1.8 Hz, 1H), 6.76(t, J =7.5Hz, 1H), 5.12(dd, J =1.9, 0.9Hz, 1H), 4.86(d, J =1.8Hz, 1H), 3.30-3.24 (m, 1H), 1.70(d, J =0.8Hz, 1H), 1.15(d, J =6.9Hz, 6H), 0.65(dd, J =8.3, 2.2 Hz, 2H), 0.41-0.35 (m, 2H). Detected... Figure 5 Compound 6 13 C-NMR spectrum, 13C-NMR(101MHz, DMSO-d6) δ 50.5, 148.2, 135.1, 128.9, 126.8, 124.6, 119.1,112.1, 26.2, 22.8, 16.9, 6.3; MS (ESI): m / z[M+H] + calcd for C 15 H 18 O: 203.30, found: 202.41.

[0056] S6-terminated olefin asymmetric reduction:

[0057] Add [(NBD)2Rh]BF4 (10.43 mg, 0.035 mmol, 0.55 mol%) and (1S, 1′S, 2R, 2′R)-Duan Phos ligand (19.8 mg, 0.035 mmol, 0.55 mol%) to a 500 mL high-pressure reactor, followed by 2.0 mL of anhydrous dichloromethane. Activate the solution by stirring at room temperature for 30 minutes until it turns orange-red. Dissolve compound 6 (1.31 g, 6.45 mmol, 1.0 eq) in 25.0 mL of anhydrous methanol and add this solution to the reactor. After sealing the reactor, purge with nitrogen three times, followed by purging with hydrogen three times, maintaining a hydrogen pressure of 3.0 MPa. Control the reaction temperature at 20-30 °C and stir for 12 hours.

[0058] After the reaction was complete, the mixture was cooled to room temperature, and hydrogen gas was slowly released. The reaction solution was filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated under reduced pressure to remove the solvent, and then distilled under reduced pressure (0.01 MPa, 120-130 °C) to collect the fraction. The fraction was recrystallized from n-heptane and ethyl acetate to give 1.17 g of polyphenol, with a yield of 88.6% and an ee value of 99%. The results showed that... Figure 6 Porylphenol 1 H-NMR spectrum, 1 HNMR (400 Hz, DMSO-d6) δ 7.07-7.12 (dd, J = 1.6 Hz, 1H), 7.05 (dd, J =1.6 Hz, 1H), 6.87-6.91(t, J = 5.4 Hz, 1H), 4.90(s, 1H), 3.12-3.17(hept, J =10.2 Hz, 1H), 2.47-2.50 (p, J= 10.8 Hz, 1H), 1.25-1.30 (dd, J = 6.9, 9H), 1.02-1.07(qt, J = 9.6, 6.9 Hz, 1H), 0.52-0.57 (m, 1H), 0.43-0.47 (m, 1H), 0.14-0.23 (m, 2H). Detected... Figure 7 Porylphenol 13 C-NMR spectrum, 13 CNMR(101 MHz, DMSO-d6) δ 50.4,133.8, 131.9, 125.0, 123.6, 120.5, 37.3, 27.1, 26.9, 22.7, 20.0, 17.0, 4.3,3.8. MS(ESI): m / z [M+H]⁺ calcd for C 14 H 21 O: 205.30, found: 204.45.

[0059] The overall yield of this six-step embodiment is 59.2%. Example 2:

[0060] S1 etherification reaction:

[0061] Except for the following specific conditions, the rest of the operation was the same as in Example 1: The S1 etherification reaction was carried out in a 500 mL three-necked flask as the reaction vessel. The amount of methyl salicylate (compound 1) added was (10.0 g, 65.7 mmol, 1.0 eq). Na2CO3 (27.8 g, 262.8 mmol, 4.0 eq) and 2-chloropropane (11.24 g, 143.1 mmol, 2.0 eq) were used as reagents. DMF (100 mL) was used as the solvent. The reaction conditions were controlled at a temperature of 20-30 °C and a time of 10 hours to finally obtain compound 2 (11.0 g, yield 86.2%).

[0062] S2 alkyl migration rearrangement reaction:

[0063] Except for the following specific conditions, the operation was the same as in Example 1: Compound 2 (11.0 g, 56.4 mmol, 1.0 eq) and TBAHS (143.0 mg, 0.441 mmol, 0.8 mol%) were reacted with 43.6 mL of a 70% sulfuric acid:acetic anhydride (volume ratio 1:1) mixture. The reaction conditions were: reflux at 100-105 °C for 0.5 h, followed by reflux at 10 °C / min to 140-150 °C for 2 h; extraction was performed with 12% sodium hydroxide solution, finally yielding Compound 3 (9.90 g, yield 89.9%).

[0064] Preparation of S3 Weinreb amide:

[0065] Except for the following specific conditions, the operation was the same as in Example 1: Compound 3 (9.89 g, 50.7 mmol, 1.0 eq) and Me(OMe)NH·HCl (5.56 g, 50.7 mmol, 1.0 eq) were used as reagents, DBU (7.72 g, 50.7 mmol, 1.0 eq) and DIC (11.53 g, 91.3 mmol, 1.8 eq) were used as reagents, MTBE (48.5 mL, water content 0.04%) was used as solvent, the mixture was stirred at 25-35 °C for 8 hours, and quenched with 10% hydrochloric acid aqueous solution to pH=3-4, finally yielding Compound 4 (10.9 g, yield 97.8%).

[0066] S4 Grignard reaction:

[0067] Except for the following specific conditions, the operation was the same as in Example 1: Compound 4 (10.9 g, 48.4 mmol, 1.0 eq), 0.5 M THF solution of cyclopropyl magnesium bromide (241.5 mL, 120.7 mmol, 2.05 eq), solvent was 2-MeTHF (21.8 mL, water 0.03%), reaction was carried out at 0-10 °C for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution to give Compound 5 (9.0 g, yield 95.0%).

[0068] S5 Wittig response:

[0069] Except for the following specific conditions, the operation was the same as in Example 1: Compound 5 (9.0 g, 44.0 mmol, 1.0 eq), MTPPB (39.11 g, 111.6 mmol, 2.5 eq), sodium methoxide (8.80 g, 176.0 mmol, 4.0 eq) as base, 1,4-dioxane as solvent, reacted at 70-80 °C for 18 hours to obtain Compound 6 (8.1 g, yield 96.8%). S6 terminal ene asymmetric reduction:

[0070] Except for the following conditions, the operation was the same as in Example 1: Compound 6 (8.1 g, 42.9 mmol, 1.0 eq), solvent was 81.0 mL of methanol, [(NBD)2Rh]BF4 (0.181 g, 0.365 mmol, 0.85 mol%), (1S, 1'S, 2R, 2'R)-DuanPhos (0.269 g, 0.403 mmol, 0.94 mol%), hydrogen pressure 3.5 MPa, yielding 7.53 g of polyphenol, yield 92.9%, ee value 100%.

[0071] The overall yield in this embodiment was 64.7%. Example 3:

[0072] S1 etherification reaction:

[0073] Except for the following specific conditions, the rest of the operation was the same as in Example 1 (methyl salicylate was added in 50g increments, and the amounts of related reagents were scaled up proportionally): methyl salicylate (compound 1) (50.0g, 328.6mmol, 1.0eq), DIPEA (90.8g, 657.5mmol, 3.0eq), 2-iodopropane (123.6g, 722.9mmol, 2.2eq), NMP (400mL) was used as the solvent. The reaction temperature was controlled at 25-35℃, and the mixture was stirred for 12h to obtain compound 2 (56.1g, yield 88.0%).

[0074] S2 alkyl migration rearrangement reaction:

[0075] Except for the following specific conditions, the operation was the same as in Example 1: Compound 2 (55.7 g, 286.8 mmol, 1.0 eq) was reacted with 223 mL of a mixture of 70% sulfuric acid and acetic anhydride (volume ratio 1:2), and TBAB (0.28 g, 0.86 mmol, 0.5 mol%) was added. The mixture was first heated to 100 °C and stirred for 1 hour, then heated to 120 °C and refluxed for 3 hours. The mixture was then extracted with 18 mL of 10% sodium hydroxide solution to obtain Compound 3 (48.0 g, yield 86.3%).

[0076] Preparation of S3 Weinreb amide:

[0077] Except for the following specific conditions, the operation was the same as in Example 1: Compound 3 (48.0 g, 247.1 mmol, 1.0 eq), Me(OMe)NH·HCl (27.6 g, 284.2 mmol, 1.15 eq), TEA (46.26 g, 457.1 mmol, 1.85 eq), 50% T3P ethyl acetate solution (106.9 g, 173.2 mmol, 1.0 eq), stirred at 40 °C for 1 hour to obtain Compound 4 (51.3 g, yield 93.1%).

[0078] S4 Grignard reaction:

[0079] Except for the following specific conditions, the other operations were the same as in Example 1: Compound 4 (51.3 g, 227.0 mmol, 1.0 eq) was prepared in 2-MeTHF (513 mL, 0.02% water content) using 2.0 M THF solution of cyclopropyl magnesium bromide (170.3 mL, 340.5 mmol, 1.5 eq) to obtain Compound 5 (45.7 g, 95.5% yield).

[0080] S5 Wittig response:

[0081] Except for the following specific conditions, the operation was the same as in Example 1: Compound 5 (45.7 g, 223.0 mmol, 1.0 eq), Witting reagent MTPPB (79.66 g, 223.0 mmol, 1.0 eq), cooled to 15 °C and potassium tert-butoxide (50.0 g, 442.6 mmol, 2.0 eq), heated to 75-80 °C and reacted for 6 hours to obtain Compound 6 (43.5 g, yield 95.1%).

[0082] S6 terminal ene asymmetric reduction:

[0083] Except for the following conditions, the operation was the same as in Example 1: Compound 6 (42.5 g, 210.5 mmol, 1.0 eq) was reacted with (R)-Xyl-BINAP (1.35 g, 2.21 mmol, 1.05 mol%) under hydrogen pressure of 4.5 MPa and temperature of 50-60°C for 2 h to obtain 40.4 g of polyphenol, with a yield of 93.0% and an ee value of 99%.

[0084] The overall yield of this embodiment is 59.7%. Example 4:

[0085] S1 etherification reaction:

[0086] Except for the following specific conditions, the rest of the operation was the same as in Example 1: methyl salicylate (compound 1) (15.0 g, 98.6 mmol, 1.0 eq), K2CO3 (27.2 g, 197.2 mmol, 2.0 eq), 2-bromopropane (14.9 g, 123.2 mmol, 1.25 eq), DMF as solvent, reaction temperature controlled at 25-35 °C, stirred for 2 h to obtain compound 2 (17.1 g, yield 88.2%).

[0087] S2 alkyl migration rearrangement reaction:

[0088] Except for the following specific conditions, the operation was the same as in Example 1: Compound 2 (17.1 g, 87.7 mmol, 1.0 eq) was reacted with 68.4 mL of a mixture of 70% sulfuric acid and acetic anhydride (volume ratio 1:2), and TBAB (85.0 mg, 0.26 mmol, 0.3 mol%) was added. The mixture was first heated to 100-110 °C and stirred for 1 hour, then heated to 120-130 °C and refluxed for 3 hours. The mixture was then extracted with 10% sodium hydroxide to obtain Compound 3 (14.7 g, yield 86.5%).

[0089] Preparation of S3 Weinreb amide:

[0090] Except for the following specific conditions, the operation was the same as in Example 1: Compound 3 (14.7 g, 75.3 mmol, 1.0 eq), Me(OMe)NH·HCl (9.8 g, 90.4 mmol, 1.2 eq), DIPEA (23.7 g, 183.1 mmol, 2.4 eq), DMAP (0.92 g, 7.5 mmol, 0.1 eq), EDC·HCl (17.3 g, 90.4 mmol, 1.2 eq), stirred at 20-30 °C for 3 hours to obtain Compound 4 (16.1 g, yield 96.0%).

[0091] S4 Grignard reaction:

[0092] Except for the following specific conditions, the other operations were the same as in Example 1: Compound 4 (16.1 g, 71.9 mmol, 1.0 eq) was prepared in 2-MeTHF (161 mL, water content 0.02%) and cyclopropylmagnesium iodide in 1.0 M THF solution (72.0 mL, 71.9 mmol, 1.0 eq) to obtain Compound 5 (13.4 g, yield 91.0%).

[0093] S5 Wittig response:

[0094] Except for the following specific conditions, the operation was the same as in Example 1: Compound 5 (13.4 g, 65.8 mmol, 1.0 eq), Witting reagent MTPPB (47.1 g, 131.6 mmol, 2.0 eq), DBU (20.1 g, 131.6 mol, 2.0 eq) was added at room temperature, stirred at 20-30 °C for 30 min, and then heated to 55-60 °C for 12 h to obtain Compound 6 (12.8 g, yield 96.5%).

[0095] S6 terminal ene asymmetric reduction:

[0096] Except for the following conditions, the operation was the same as in Example 1: compound 6 (12.8 g, 65.3 mmol, 1.0 eq), catalyst [(NBD)2Rh]BF4 (0.97 g, 3.3 mmol, 5.0 mol%), ligand (1S, 1'S, 2R, 2'R)-Duan Phos (2.20 g, 3.3 mmol, 5.0 mol%), hydrogen pressure 1.0 MPa, temperature 50-60°C, reaction for 24 h, yielding 11.3 g of polyphenol, yield 87.4%, ee value 99%.

[0097] The overall yield of this embodiment is 56.2%. The above are merely preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be considered as limitations on the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. For those skilled in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing cyclopophenol, characterized in that, The specific reaction route is as follows: ； Cyclopophenol was prepared from methyl salicylate via a six-step reaction involving etherification, alkyl migration rearrangement, Weinerb amide preparation, Grignard addition, and Wittig reaction-induced asymmetric reduction of terminal olefins. The specific reaction steps are as follows: S1 Etherification reaction: Compound 2 was directly prepared by nucleophilic substitution reaction of methyl salicylate with isopropyl alkyl halides, with yields of 86.2%-91.1%; S2 alkyl migration rearrangement reaction: Compound 3 was prepared under acidic conditions using a gradient temperature increase and phase transfer catalysis synergistic process, with yields of 85.0%-90.0%; Preparation of S3 Weinreb amide: Compound 3 was reacted with Me(OMe)NH・HCl (N,O-dimethylhydroxylamine hydrochloride) in the presence of a condensing agent and a base to prepare compound 4, with yields of 93.0%-98.0%. S4 Grignard addition: Compound 4 was reacted with a cyclopropyl Grignard reagent to prepare compound 5, with yields of 91.0%–96.0%; S5 Witting reaction: Compound 5 undergoes a Witting reaction under the action of a base to give compound 6, with a yield of 92.3%-97.0%; S6 terminal olefin asymmetric reduction: Compound 6 was prepared into cyclopophenol by chiral catalytic reduction using a metal Rh (rhodium) catalyst, with yields of 87.4%-93.0% and ee values ​​≥99%; The overall yield of the six-step reaction was 56.2%-64.7%.

2. The method for preparing cyclopropofol according to claim 1, characterized in that, Step S1, the etherification reaction, employs a combination of a base reagent, isopropyl alkyl halide, and an aprotic solvent. The base reagent is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, TEA (triethylamine), DIPEA (N,N-diisopropylethylamine), and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and is used in an amount of 2.0-4.0 eq (equivalents) of methyl salicylate. The isopropyl alkyl halide is one or more of 2-chloropropane, 2-bromopropane, and 2-iodopropane, and is used in an amount of 1.2-2.2 eq of methyl salicylate. The aprotic solvent is selected from at least one of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), NMP (N-methylpyrrolidone), DMAc (N,N-dimethylacetamide), acetonitrile, and 1,4-dioxane. The reaction temperature is 20-35℃, and the reaction time is 2-12 hours.

3. The method for preparing cyclopophenol according to claim 1, characterized in that, In step S2, the alkyl migration rearrangement reaction, compound 2 is added to an acidic mixture, a phase transfer catalyst is added, and nitrogen gas is introduced for protection. A gentle gradient temperature increase is adopted. The acidic mixture is a mixture of sulfuric acid and acetic anhydride, with a volume ratio of sulfuric acid to acetic anhydride of 1:1 to 1:5, and the concentration of sulfuric acid solution is ≤75%. The phase transfer catalyst is at least one of TBAB (tetrabutylammonium bromide), TBAC (tetrabutylammonium chloride), TBAI (tetrabutylammonium iodide), TBAHS (tetrabutylammonium hydrogen sulfate), trioctylmethylammonium chloride, and TEBA (benzyltriethylammonium chloride), and the amount of phase transfer catalyst used is 0.3-0.8 mol of the molar amount of compound 2.

4. The method for preparing cyclopophenol according to claim 1, characterized in that, In step S2, the temperature is first raised to 80-110℃ and reacted for 0.5-2 hours, then raised to 120-150℃ for reflux; during the reflux process, a water separator is used to separate the water in the system.

5. The method for preparing cyclopophenol according to claim 1, characterized in that, In step S3, the preparation of Weinreb amide, the condensing agent is one of EDC・HCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DCC (N, N'-dicyclohexylcarbodiimide), HATU (hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethylurea), T3P (propylphosphoric anhydride), and DIC (N, N'-diisopropylcarbodiimide), used in an amount of 1.0-1.8 eq of compound 3; the base is at least one of TEA, DIPEA (N, N-diisopropylethylamine), NMM (N-methylmorpholine), DMAP (4-dimethylaminopyridine), DBU (1,8-diazabicycloundec-7-ene), and 2,6-di-tert-butylpyridine, used in an amount of 1.0-3.0 eq of compound 3.

6. The method for preparing cyclopophenol according to claim 1, characterized in that, In step S3, the amount of Me(OMe)NH・HCl used is 1.0-1.5 eq of compound 3. The solvent used in the reaction is at least one of MTBE (methyl tert-butyl ether), THF (tetrahydrofuran), 2-MeTHF (2-methyltetrahydrofuran), and ethyl acetate, and the amount used is 5-15 times (mL / g) of the mass of compound 3, that is, 5-15 mL of solvent is used per gram of compound 3. The base and condensing agent are added slowly at 0-5℃, and the reaction is carried out at 20-40℃ for 1-8 h.

7. The method for preparing cyclopophenol according to claim 1, characterized in that, In step S4, Grignard addition is used to prepare compound 4. Cyclopropyl Grignard reagent reacts with compound 4 in a solvent at -10 to -10°C. The cyclopropyl Grignard reagent is at least one of cyclopropyl magnesium chloride, cyclopropyl magnesium bromide, and cyclopropyl magnesium iodide, with a concentration of 0.5-2.0 M and an amount of 1.0-2.5 eq of compound 4. The addition must be controlled at -10 to -10°C. The solvent is at least one of THF, 2-MeTHF, MTBE, diethyl ether, and toluene, with an amount of 2-20 times (mL / g) of the mass of compound 4.

8. The method for preparing cyclopophenol according to claim 1, characterized in that, In step S5, the Witting reaction, compound 5 reacts with the Witting reagent under the action of a base to generate compound 6. The Witting reagent is at least one of MTPPB (methyltriphenylphosphine bromide), MTPPC (methyltriphenylphosphine chloride), and ethyltriphenylphosphine bromide, and the amount used is 1.0-2.5 eq of compound 5. The base reagent is at least one of cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, DBU (1,8-diazabicycloundec-7-ene), NaHMDS (sodium bis(trimethylsilyl)amino), LiHMDS (lithium bis(trimethylsilyl)amino), sodium methoxide, and sodium ethoxide, and the amount used is 1.0-4.0 eq of compound 5. The solvent is at least one of tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, acetonitrile, and DMSO. The reaction is carried out at a temperature of 0-80°C for 4-18 h.

9. The method for preparing cyclopophenol according to claim 1, characterized in that, In step S6, the neutralizing agent for the asymmetric reduction of the terminal olefin is a metal Rh catalyst with a chiral ligand. The Rh catalyst is one of [RhCl(COD)]2 ((1,5-cyclooctadiene)rhodium chloride(I) dimer), [(NBD)2Rh]BF4 (bis(norbornene)rhodium tetrafluoroborate(I)), or [Rh(acac)(C2H4)2] ((acetylacetone)di(ethylene)rhodium(I)). The chiral ligand is (R)-(+)-BINAP (R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine), (R)-(+)-Xyl BINAP ((R)-(-)-1,1'-binaphthyl-2,2'-bis(3,5-xylyl)phosphine), or (R)-Seg Phos is one of (5,5'-bis(diphenylphospho)-4,4'-bis-1,3-biphenyl) or (1S,1′S,2R,2′R)-Duan Phos.

10. The method for preparing cyclopropofol according to claim 1, characterized in that, In step S6, the asymmetric reduction of the terminal olefin, compound 6 is reduced to cyclopropanol under a hydrogen pressure of 1.0-4.5 MPa and the action of a catalyst; the amount of the Rh (rhodium) metal catalyst is 0.1%-5% of the molar amount of compound 6; the reaction temperature is 20-60℃, the reaction time is 2-24 hours, and the reaction solvent is at least one of methanol, ethanol, dichloromethane, and 2-MeTHF.

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