Preparation method of cyclopofol intermediate

Abstract

The invention discloses a preparation method of a cyclopofol intermediate (5-bromo-2-hydroxy-3-isopropyl phenyl cyclopropyl ketone), which comprises the following steps: by taking p-bromophenol as an initial raw material, carrying out four-step directional reaction of etherification, alkyl migration rearrangement, esterification and Fries rearrangement to obtain a compound 5; the problems of harsh process conditions, more side reactions, low yield and high cost in the prior art are solved. Through the systematic optimization strategy of the process, a high-yield cyclopofol intermediate synthesis route (etherification is 90.0-95.0%, alkyl migration is 92.0-97.0%, esterification is 95.0-99.0%, and Fries rearrangement is 88.0-93.0%) is realized, the total yield of the four steps reaches 69.2-82.2%, key technical support is provided for efficient synthesis of cyclopofol, the economical efficiency of industrial production is remarkably improved, and the method is suitable for industrial production. The important significance is realized on promoting the upgrading of the cyclopoise synthesis process and reducing the medication cost.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and intermediate synthesis technology, specifically a method for preparing a cyclopropofol intermediate, with particular optimization of the synthesis process for compound 5 (5-bromo-2-hydroxy-3-isopropylphenylcyclopropyl methyl ketone, CAS: 1552982-39-4). This intermediate, as a core precursor in the synthesis of cyclopropofol drugs, directly affects the industrialization process of subsequent drug synthesis due to its preparation efficiency and purity. Background Technology

[0002] Ciprofol, a third-generation short-acting intravenous anesthetic, chemically named 2-[(1R)-1-cyclopropylethyl]-6-isopropylphenol, is a gamma-aminobutyric acid type A (GABAa) receptor agonist. It produces an anesthetic effect by enhancing GABA-mediated chloride ion influx and inhibiting central nervous system excitability. Compared to the traditional anesthetic propofol, ciprofol has significant clinical advantages. The official instructions for ciprofol injection from the National Medical Products Administration show that it reduces the incidence of injection pain by more than 60%, has less impact on the cardiovascular system, reduces the risk of respiratory depression by 35%, shortens postoperative recovery time by 20%-30%, and its metabolites have no cumulative toxicity. It shows broad application prospects in surgical anesthesia, intensive care sedation, and other scenarios.

[0003] According to data from Toubao Research Institute's "2023 China Intravenous Anesthetics Industry Panorama" and Frost & Sullivan's "Global Intravenous Anesthetics Market Report 2023," the global intravenous anesthetics market exceeded US$18 billion in 2023. Cycloprophenol's compound annual growth rate is projected to reach 12%-18%, thus, with the continued growth in clinical demand, the industrial production of cycloprophenol has become a research hotspot in the pharmaceutical field. The synthesis of cycloprophenol relies heavily on the efficient preparation of a key intermediate (5-bromo-2-hydroxy-3-isopropylphenylcyclopropyl methyl ketone, CAS: 1552982-39-4). The process conditions, synthesis yield, and cost control of this intermediate directly determine the industrialization feasibility and market competitiveness of cycloprophenol.

[0004] Currently, there are numerous reports on the synthesis of propofol and its intermediates. However, existing technologies still have room for optimization in terms of raw material selection, yield levels, and operational procedures, making it difficult to meet the needs of large-scale production. According to the original research route document CN105820040, the disclosed synthetic route uses 2-isopropylphenol as the starting material and prepares propofol through multiple steps including etherification, high-temperature Claisen rearrangement, and cyclopropanation. The technical characteristics of this route are: firstly, it uses specialized reagents such as crotonol and diiodomethane, resulting in relatively high raw material procurement costs; secondly, diiodomethane has a certain degree of toxicity, requiring strict storage and transportation conditions; thirdly, the high-temperature Claisen rearrangement step easily generates side isomers, requiring complex purification processes, resulting in a single-step yield of only 60%; and fourthly, the cyclopropanation reaction relies on metallic reagents such as zinc and copper, requiring strict temperature and light control, placing high demands on production operations, and the post-reaction treatment generates waste liquid containing heavy metals, increasing the treatment load.

[0005] While patent US2016060197 details the core reaction mechanism of cyclopropanol synthesis, its corresponding process also employs cumbersome steps of group protection and deprotection. The synthetic route follows a multi-step process of "phenolic hydroxyl protection - nucleophilic substitution - deprotection - Grignard reaction - removal of alcoholic hydroxyl groups," containing redundant protection / deprotection steps, resulting in a long process chain and high operational difficulty. According to the patent's embodiments, the overall yield is only 48.6%. Furthermore, the expensive 3,4-dihydro-2H-pyran reagent used for phenolic hydroxyl protection increases the overall cost of raw materials.

[0006] A rearrangement synthesis method for a cycloprophenol intermediate was reported in Org. Process Res. Dev. 2025, 29, 5, 1291–1298. This process, also using isopropylphenol as the starting material, suffers from high raw material costs. In the subsequent functional group modification stage, liquid bromine is required to introduce bromine atoms. However, liquid bromine is highly corrosive and oxidizing, exhibits poor selectivity, and easily generates polybrominated byproducts, necessitating multiple recrystallization purifications to remove impurities. This process is cumbersome and results in low yields. Furthermore, the rearrangement step in this process must be carried out at high temperatures of 180–200 °C, which easily leads to carbonization of the starting material, further reducing the yield.

[0007] In summary, existing synthetic techniques for propofol intermediates generally suffer from problems such as lengthy synthetic routes, use of hazardous reagents, harsh reaction conditions, and low yields, which restrict the large-scale production and clinical application of propofol. Therefore, developing a simplified synthetic route, readily available raw materials, mild reaction conditions, and high-yield preparation process for key propofol intermediates has become an urgent technical challenge. Summary of the Invention

[0008] In order to solve the defects of existing technologies such as high cost, numerous side reactions, low yield, and complex operation, this invention provides a preparation method that is easy to obtain, has a high yield, and is simple to operate, making it suitable for industrial production.

[0009] To achieve the above objectives, the present invention adopts the following technical solution: The purpose of this invention is to provide an efficient method for preparing a cycloprophenol intermediate. This method uses p-bromophenol (compound 1) as the starting material and involves four steps: etherification, alkyl migration rearrangement, esterification, and Fries rearrangement, to directionally synthesize the target intermediate compound 5. The specific synthetic route is shown below: R1 is selected from one of the following: hydroxyl (-OH), p-toluenesulfonate (-OTs), or methanesulfonate (-OMS); R2 is selected from hydroxyl (-OH) or chlorine (-Cl); This invention first involves an etherification reaction, in which p-bromophenol (compound 1) is reacted with an isopropylating agent, defined as an agent capable of introducing an isopropyl group (-) into the substrate molecule. i The reagent (Pr) is specifically selected from isopropanol and isopropyl sulfonate, and is used in a phosphine reagent-azo reagent activation system to undergo a Mitsunobu reaction to synthesize compound 2. Compound 2 then undergoes alkyl migration rearrangement in an acid-catalyzed system to generate compound 3. Further, compound 3 reacts with a cyclopropyl acylation reagent (cyclopropylformic acid or cyclopropylformyl chloride) under the action of a base reagent and a catalyst to generate compound 4. When the cyclopropyl acylation reagent is cyclopropylformic acid, a condensing agent is also required to promote the reaction. Finally, compound 4 undergoes Fries rearrangement in a mixed acid system to generate compound 5.

[0010] Step 1: Etherification reaction to prepare compound 2

[0011] Under inert gas protection, p-bromophenol (compound 1) was dissolved in a solvent, and an isopropylating agent was added sequentially: one of isopropanol, isopropyl p-toluenesulfonate, and isopropyl methanesulfonate, in an amount of 1.0–1.4 eq of p-bromophenol; a phosphine reagent was one or more of Bu3P (tributylphosphine), PPh3 (triphenylphosphine), and Me3P (trimethylphosphine), in an amount of 1.1–2.0 eq of p-bromophenol; after stirring until homogeneous, an azo reagent DEAD (diethyl azodicarbonate) or DIAD (diisopropyl azodicarbonate) was slowly added dropwise, in an amount of 1.0–1.6 eq of p-bromophenol; the mixture was stirred at 30–60 °C for 6–30 h; the solvent used for the reaction was one or more of THF, 1,4-dioxane, toluene, xylene, and dichloromethane; after the reaction was completed, the mixture was concentrated under reduced pressure, washed at low temperature, and recrystallized to obtain compound 2.

[0012] Isopropanol or isopropyl sulfonate forms an active intermediate with an azo reagent via a phosphine reagent, activating the phenolic hydroxyl group of p-bromophenol into a leaving group. The isopropylating agent (isopropanol, isopropyl p-toluenesulfonate, or isopropyl methanesulfonate) then acts as a nucleophile, attacking the activated oxygen atom to achieve a nucleophilic substitution reaction and construct an ether bond. This mechanism does not require a strong base, avoiding side reactions such as excessive reaction of the phenolic hydroxyl group and elimination reaction of the isopropylating agent under strong base conditions. This etherification route has a yield of 90.0%–95.0%, which is significantly higher than the traditional etherification process that depends on a strong base.

[0013] Preferably, the isopropylating agent is selected from isopropanol or isopropyl p-toluenesulfonate, more preferably isopropanol, and the amount used is 1.0~1.2 eq; the phosphine reagent is Bu3P or PPh3, and the amount used is 1.1~1.5 eq of p-bromophenol, more preferably 1.2~1.4 eq; the azo dye is used in an amount of 1.2~1.6 eq of p-bromophenol, more preferably 1.2~1.4 eq; the reaction solvent is one or more of THF, 1,4-dioxane, and toluene, and the amount used is 8~12 mL / g p-bromophenol; the reaction temperature is 30~45℃, and the reaction time is 6~20 hours.

[0014] Step 2: Alkyl migration rearrangement reaction to prepare compound 3

[0015] Under an inert gas atmosphere, compound 2 was added to a pre-prepared acid mixture: either a mixture of 70% sulfuric acid and acetic anhydride, or a mixture of concentrated sulfuric acid and glacial acetic acid. The protons in the acid mixture combined with the oxygen atoms of the ether bond in compound 2 to form oxonium ions, promoting α-migration of the alkyl group. Then, one of the phase-transfer catalysts—tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), or tetrabutylammonium iodide (TBAI)—was added at a rate of 0.5–1.5 mol%. A gradient heating mode was used: the reaction system was first heated to 95–115 °C to achieve homogeneity and initiate rearrangement, then refluxed to 115–150 °C to promote complete alkyl migration and rearrangement. Simultaneously, the phase-transfer catalyst enhanced the mass transfer efficiency between the acid and organic phases, reducing byproducts such as para-isomers. After the reaction was complete, compound 3 was obtained through post-treatment including ice-water quenching, separation, and vacuum distillation purification, with a yield of 92.0–97.0%.

[0016] Preferably, in step 2, compound 2 is added to a pre-prepared acid mixture, wherein the acid mixture is 70% sulfuric acid plus acetic anhydride (volume ratio 1:0.8~1:3.5) or concentrated sulfuric acid plus glacial acetic acid (volume ratio 1:1.5~1:4.5), and the total amount is 0.8~2.5 times that of compound 2 (g / ml); the phase transfer catalyst is one of tetrabutylammonium bromide (TBAB) or tetrabutylammonium chloride (TBAC), and the amount is 0.05~1.0 mol%; the gradient heating conditions are: react at 100~105℃ for 0.5~1.5 hours, and then reflux at 120~130℃ for 1.5~4 hours.

[0017] Step 3: Esterification reaction to prepare compound 4 Under an inert gas atmosphere, compound 3, a cyclopropyl acylation reagent, a catalyst, and a base reagent are dissolved in a haloalkanes solvent. The cyclopropyl acylation reagent is cyclopropylformic acid or cyclopropylformyl chloride, used in an amount of 1.0–2.0 eq of compound 3; the catalyst is DMAP (4-dimethylaminopyridine) or 4-PPY (4-pyrrolidinylpyridine), used in an amount of 0.05–0.25 eq; the base reagent is one or more of DIPEA, triethylamine, pyridine, and 4-methylmorpholine, used in an amount of 1.8–5.0 eq of compound 3.

[0018] When cyclopropylformic acid is used as the cyclopropyl acylation reagent, a condensing agent is required. First, compound 3 is dissolved in a solvent, then a base reagent and a catalyst are added. Next, a condensing agent solution is slowly added dropwise. The condensing agent can be one of EDC·HC, DCC, HATU, or DIC, and the amount used is 1.2–4.0 eq of compound 3. The condensing agent first reacts with cyclopropylformic acid to form an active ester intermediate. The catalyst enhances the electrophilicity of the active ester intermediate by forming a complex with it, and then undergoes a nucleophilic substitution reaction with the phenolic hydroxyl group of compound 3 to form an ester bond.

[0019] When cyclopropylformyl chloride is used as the cyclopropyl acylation reagent, under the action of a catalyst such as DMAP, the nitrogen atom in the highly nucleophilic DMAP molecule rapidly attacks the carbonyl carbon of the acyl chloride, generating a highly reactive acyl-DMAP onium salt intermediate. This intermediate efficiently esterifies with the phenolic hydroxyl group, increasing the reaction rate. The base reagent is only used to neutralize the acidic byproducts generated in the reaction. Both of the above reactions are performed under mild conditions, at 0–35°C, with yields consistently between 95.0% and 99.0%.

[0020] Preferably, in step 3, the amount of cyclopropyl acylation reagent is 1.0~1.3 eq; the catalyst is DMAP, the amount is 0.05~0.15 eq, more preferably 0.08~0.10 eq; the base reagent is one of DIPEA, triethylamine, and pyridine, the amount is 1.8~3.5 eq of compound 3, more preferably 2.0~2.8 eq; the solvent is one of dichloromethane, tetrahydrofuran, and chloroform, and the solvent volume to compound 3 mass ratio is 8~15 mL / g, that is, the amount of solvent used per gram of compound 3 is 8~15 ml.

[0021] Preferably, in step 3, when cyclopropylformic acid is used as the cyclopropyl acylation reagent, the condensing agent is EDC·HCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) or DCC (dicyclohexylcarbodiimide), and the amount used is 1.2~3.0 eq of 2-isopropyl-4-bromophenol; the reaction temperature is 25-30℃, and the reaction time is 2~24 hours; the post-treatment is to concentrate the reaction solution and purify it by recrystallization with ethanol-water or ethyl acetate-n-hexane.

[0022] Preferably, in step 3, when cyclopropylformyl chloride is used as the cyclopropyl acylation reagent, the condensing agent is omitted, and cyclopropylformyl chloride is added dropwise directly after the catalyst is added; the reaction temperature is 0~15℃, the reaction time is 2~8 hours, and the post-treatment is to concentrate the reaction solution and purify it by recrystallization with ethanol-water or ethyl acetate-n-hexane.

[0023] Step 4: Fries rearrangement reaction to prepare compound 5

[0024] Compound 4 was dissolved in an acid-catalyzed system under an inert gas atmosphere, and Fries rearrangement was carried out at a controlled reaction temperature (40-80°C). The acid was selected from one or more of trifluoromethanesulfonic acid, methanesulfonic acid, a mixture of trifluoromethanesulfonic acid and methanesulfonic acid, concentrated sulfuric acid, and polyphosphoric acid. After the reaction was completed, the mixture was quenched under low temperature conditions (0-25°C) using an ice-water-ethyl acetate / dichloromethane system. The resulting compound was purified by extraction, washing, drying, concentration, and recrystallization to obtain the target compound 5.

[0025] After protonation, the carbonyl group of compound 4 forms a resonance-stable carbocation intermediate, which then undergoes an intramolecular electrophilic substitution reaction of the aromatic ring, causing the acyl group to migrate from the oxygen atom to the ortho position of the benzene ring. When using a TfOH-MSA mixed acid system, the proton-donating ability of MSA synergistically works with TfOH, enhancing catalytic activity while reducing the corrosiveness of TfOH alone. Simultaneously, it suppresses side reactions such as para-migration of the acyl group, resulting in rearrangement yields of 88.0–93.0%.

[0026] Preferably, in step 4, the acid catalytic system is a mixture of TfOH and MSA with a volume ratio of 1:0.3 to 1:1, and the volume ratio of the acid used to the mass of compound 4 is 3 to 10 mL / g, that is, the amount of acid used per gram of compound 4 is 3 to 10 mL.

[0027] Preferably, in step 4, the reaction temperature is 45~65℃, the reaction time is 1~12 hours, the quenching temperature is 0~20℃, and a quenching system of cold water and ethyl acetate is used; the post-treatment includes separation, organic phase washing, drying and concentration, recrystallization and purification.

[0028] This invention has the following three core innovative features: 1. The fundamental innovation of this invention lies in constructing a streamlined and efficient directed synthesis route, abandoning the lengthy routes in existing technologies that use 2-isopropylphenol as a starting material and involve redundant steps such as protection / deprotection. This invention uses p-bromophenol as a starting material, precisely matching the functional group construction requirements, and directionally synthesizes the target intermediate through four core reactions: etherification, alkyl migration rearrangement, esterification, and Fries rearrangement. The Mitsunobu nucleophilic substitution reaction avoids side reactions under strong base conditions, alkyl migration rearrangement achieves precise group positioning, and Fries rearrangement directionally constructs the target structure, ultimately yielding the cyclopophene intermediate product. This fundamentally solves the problems of lengthy reaction routes, poor directionality, and numerous byproducts in existing processes, significantly improving synthesis efficiency.

[0029] 2. This invention possesses excellent atom economy, with significant advantages in yield and cost. Through systematic optimization of each reaction step, the yield of each single step remains at a high level: etherification 90.0~95.0%, alkyl migration rearrangement 92.0~97.0%, esterification 95.0~99.0%, and Fries rearrangement 88.0~93.0%. The theoretical total yield of the four steps can reach 69.2~84.8%, and the actual yield is 76.5~82.2%, far exceeding the 40%~51% total yield level of existing technologies. The raw materials are inexpensive and readily available industrially produced basic chemical raw materials such as p-bromophenol, isopropanol, and cyclopropionic acid. The auxiliary materials and solvents are all conventional chemicals, eliminating the need for expensive special reagents such as diiodomethane and 3,4-dihydro-2H-pyran used in traditional processes, significantly reducing the cost of raw materials and auxiliary materials. At the same time, the high yield greatly improves atom utilization, reduces waste generation, and further reduces the unit product production cost, giving it a strong competitive advantage in the market.

[0030] 3. The process conditions of this invention are mild and simple to operate, making it suitable for industrial scale-up. Each reaction step of this invention operates within the conventional chemical production temperature range and does not require harsh conditions such as high pressure, strict temperature control, or light avoidance. The synthetic route involves only four core reactions, and post-processing requires only conventional operations such as vacuum concentration, low-temperature washing, and recrystallization. It does not use hazardous organometallic reagents such as zinc or copper reagents and only requires general-purpose reaction vessels, eliminating reliance on specialized equipment. The overall operational threshold is low, safety is high, and the difficulty of industrial scale-up is significantly reduced, possessing the potential for large-scale continuous production.

[0031] This invention addresses the core pain points of existing polyphenol intermediate synthesis processes, such as lengthy routes, low yields, and complex operations. It innovatively designs a four-step directional synthesis scheme using p-bromophenol as the starting material. Through innovative reaction mechanisms, optimized raw material selection, and optimized process conditions, it achieves a comprehensive breakthrough in synthesis efficiency, cost-effectiveness, and industrial adaptability. Compared with existing technologies, it has significant technological improvements and provides a new process route for the large-scale production of polyphenol. Attached Figure Description

[0032] Figure 1 Compound 2 of Example 1 of the present invention 1 HNMR spectrum; Figure 2 Compound 2 of Example 1 of the present invention 13 CNMR spectrum; Figure 3 Compound 3 of Example 1 of the present invention 1 HNMR spectrum; Figure 4 Compound 3 of Example 1 of the present invention 13 CNMR spectrum; Figure 5 Compound 4 of Example 1 of the present invention 1 HNMR spectrum; Figure 6 Compound 4 of Example 1 of the present invention 13 CNMR spectrum; Figure 7 Compound 5 of Example 1 of the present invention 1 HNMR spectrum; Figure 8 Compound 5 of Example 1 of the present invention 13 CNMR spectrum; Figure 9 This is a synthetic route diagram of the present invention. Detailed Implementation

[0033] 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. Example 1:

[0034] Step 1: Etherification reaction to prepare compound 2

[0035] In a 500 mL three-necked flask under nitrogen protection, p-bromophenol (compound 1) (6.92 g, 40.0 mmol, 1.0 eq) and 120 mL THF were added and stirred until completely dissolved. Then, isopropanol (3.3 mL, 44.0 mmol, 1.1 eq) and TBUP (11.90 g, 58.8 mmol, 1.47 eq) were added sequentially, and the mixture was stirred for 30 minutes until homogeneous. DEAD (52.0 mmol, 23.6 mL of 2.2 M toluene solution, 1.3 eq) was added dropwise to the system over 1 hour, and the reaction was maintained at 30 °C for 18 hours. After the reaction, the solvent was removed under reduced pressure, and the mixture was washed twice with petroleum ether at 0–5 °C. The mixture was then purified by recrystallization from a petroleum ether:ethanol mixture (10:1 v / v) to give compound 2 (8.17 g, 95.0% yield). Compound 2 was detected... Figure 1 of 1 HNMR spectrum 1 H-NMR (400MHz, CDCl3) δ: 7.36 (d, J =9.0Hz, 2H), 6.77 (d, J =9.0Hz, 2H), 4.52–4.46 (m, 1H), 1.33 (d, J =6.0 Hz, 6H). Compound 2 was detected. Figure 2 of 13 CNMR spectrum 13 C-NMR (100MHz, CDCl3) δ: 157.1, 132.4, 117.8, 112.7, 70.4, 22.1. MS (ESI): m / z [M+H]⁺ calcd for C9H 11 BrO: 215.00, found: 215.01.

[0036] Step 2: Alkyl migration rearrangement reaction to prepare compound 3

[0037] To a 500 mL three-necked flask under nitrogen protection, compound 2 (8.17 g, 38.0 mmol, 1.0 eq) prepared in the first step, 57 mL of a pre-prepared 70% sulfuric acid-acetic anhydride mixture (volume ratio 1:2), and TBAB (0.06 g, 0.19 mmol, 0.5 mol%) were added. The mixture was slowly heated to 110–115 °C and reacted for 1 hour, then refluxed at 120–125 °C for 3 hours. After cooling the reaction solution to 50 °C, 190 mL of ice water was added. The mixture was allowed to stand and separate into layers, and the waste acid phase was discarded. The upper oily layer was extracted with 10% sodium hydroxide solution. The extracted liquid phase was neutralized to pH 6–7 with 10% sodium hydroxide solution. The precipitated oily product was purified by vacuum distillation (0.08 MPa, 120–125 °C) to obtain compound 3 (7.65 g, yield 93.6%). Compound 3 was analyzed to obtain… Figure 3 of 1 HNMR spectrum 1 HNMR (300MHz, CDCl3) δ: 7.27 (d, J =2.0Hz, 1H), 7.15 (dd, J =2.5, 8.5Hz, 1H), 6.62 (d, J =8.4Hz, 1H), 4.88 (s, 1H), 3.21–3.11 (m, 1H), 1.23 (d, J =7.0 Hz, 6H). Compound 3 was detected. Figure 4 of 13 CNMR spectrum 13 CNMR (125MHz, CDCl3) δ: 151.8, 136.9, 129.4, 129.3, 116.9, 113.1, 27.1, 22.3. MS (ESI): m / z [M+H]⁺ calcd for C9H 11 BrO: 215.09, found: 215.00.

[0038] Step 3: Esterification reaction to prepare compound 4

[0039] In a 500 mL three-necked flask under nitrogen protection, compound 3 (7.65 g, 35.6 mmol, 1.0 eq) prepared in step two, cyclopropionic acid (6.10 g, 71.2 mmol, 2.0 eq), DMAP (0.22 g, 1.78 mmol, 0.05 eq), DIPEA (15.99 g, 123.8 mmol, 3.5 eq), and 171 mL of dichloromethane were added. The mixture was stirred at 25–35 °C until homogeneous. EDC·HCl (20.50 g, 107.0 mmol, 3.0 eq) was dissolved in 114 mL of dichloromethane and slowly added dropwise to the reaction mixture over 1 hour. The mixture was stirred at 25–35 °C for 12 hours. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure. An ethanol:water mixture (3:1, v / v) was added, and the mixture was dissolved at 60 °C. The solution was then cooled to 0–5 °C for 2 hours to crystallize. The crystals were filtered and dried to obtain compound 4 (9.83 g, yield 97.1%). Compound 4 was analyzed and found to be... Figure 5 of 1 HNMR spectrum 1 HNMR (400MHz, DMSO-d) 6 δ: 7.52 (d, J =2.4Hz, 1H), 7.40 (dd, J =8.6, 2.4Hz, 1H), 7.02 (d, J =8.5Hz, 1H), 2.93 (p, J =6.9Hz, 1H), 2.00−1.87 (m, 1H), 1.16 (s, 3H), 1.14 (s, 3H), 1.08 (d, J =8.0 Hz, 2H), 1.05−1.00 (m, 2H). Compound 4 was detected. Figure 6 of 13 CNMR spectrum 13 CNMR (101MHz, DMSO-d) 6 ) δ: 172.8, 147.0, 142.6, 129.6, 129.5, 124.9, 118.7, 27.1, 22.4, 12.5, 8.9; MS (ESI): m / z [M+H]⁺ calcd for C 13 H 15 BrO2: 284.17, found: 284.04.

[0040] Step 4: Fries rearrangement reaction to prepare compound 5

[0041] In a 250 mL three-necked flask under nitrogen protection, compound 4 (9.83 g, 34.6 mmol, 1.0 eq) prepared in step 3 was added. After cooling to 0 °C, 20 mL of a TfOH:MSA mixture (volume ratio 1:0.5) was slowly added, and the mixture was heated to 60–70 °C and maintained at this temperature for 3 hours. After cooling the reaction solution to 0–5 °C, 173 mL of ice water and 100 mL of ethyl acetate were added to quench the reaction. After standing and separating the layers, the organic phase was washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine. After drying with anhydrous magnesium sulfate, the mixture was filtered and concentrated, and then purified by recrystallization (n-heptane-ethyl acetate) to obtain compound 5 (8.72 g, yield 89.0%). Compound 5 was detected to be... Figure 7 of 1 H-NMR spectrum, 1 HNMR (600MHz, DMSO-d) 6 ): δ12.92 (s, 1H), 8.25 (d, J =2.4Hz, 1H), 7.61 (d, J =2.4 Hz, 1H), 3.06–3.33 (m, 1H), 3.05–3.06 (m, 1H), 1.15–1.19 (m, 6H), 1.14–1.15 (m, 4H). Compound 5 was detected... Figure 8 of 13 C-NMR spectrum, 13 CNMR (101MHz, DMSO-d) 6 ) δ: 205.9, 158.0, 139.5, 135.1, 130.2, 120.5, 110.4, 26.1, 21.8, 16.8, 12.8; MS (ESI): m / z [M+H]⁺ calcd forC 13 H 15 BrO2: 284.17, found: 284.05.

[0042] The overall yield of Example 1 was 76.9%. Example 2:

[0043] Step 1: Etherification reaction to prepare compound 2

[0044] In a 500 mL three-necked flask under nitrogen protection, p-bromophenol (compound 1) (17.30 g, 100.0 mmol, 1.0 eq) and 1,4-dioxane (200 mL) were added and stirred until completely dissolved. Then, isopropyl p-toluenesulfonate (22.5 mL, 140.0 mmol, 1.4 eq) and TBP (43.39 g, 206.6 mmol, 1.6 eq) were added sequentially, and the mixture was stirred for 30 minutes until homogeneous. DEAD (200.0 mmol, 90.9 mL of 2.2 M toluene solution, 2.0 eq) was added dropwise to the system at a uniform rate over 1 hour, and the reaction was maintained at 40–45 °C for 30 hours. Compound 2 (19.37 g, yield 90.1%) was obtained.

[0045] Step 2: Alkyl migration rearrangement reaction to prepare compound 3

[0046] Except for the following conditions, the operation was the same as in Example 1: Compound 2 was added (19.35 g, 90.0 mmol, 1.0 eq), the mixed acid was concentrated sulfuric acid-glacial acetic acid (1:3, 135 mL), and the phase transfer catalyst was TBAC (0.44 g, 1.35 mmol, 1.5 mol%). The mixture was stirred at 95-105 °C for 1 h, and then refluxed at 115-125 °C for 2.5 h. Compound 3 (18.73 g, yield 96.8%) was finally obtained.

[0047] Step 3: Esterification reaction to prepare compound 4

[0048] In a 1L three-necked flask under nitrogen protection, compound 3 (18.73 g, 87.12 mmol, 1.0 eq) prepared in step two, triethylamine (44.12 g, 435.6 mmol, 5.0 eq), DMAP (4-dimethylaminopyridine) (1.06 g, 8.71 mmol, 0.1 eq), and 436 mL of chloroform were added. After cooling to 0–5 °C, cyclopropylformyl chloride (11.0 mL, 121.97 mmol, 1.4 eq) was slowly added dropwise over 1 hour. After the addition was complete, the mixture was kept at 0–5 °C and stirred for 24 hours. After the reaction was completed, the mixture was filtered to remove solid impurities. The filtrate was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized in an ethyl acetate-n-hexane mixed solvent (60 mL, volume ratio 1:4) to give compound 4 (24.47 g, yield 98.8%).

[0049] Step 4: Fries rearrangement reaction to prepare compound 5

[0050] In a nitrogen-protected 500 mL three-necked flask, compound 4 (24.46 g, 86.1 mmol, 1.0 eq) prepared in step 3 was added. After cooling to 0 °C, trifluoromethanesulfonic acid (75.3 mL, 592.6 mmol, 7.0 eq) was added. The mixture was stirred until homogeneous, and then heated to 40–50 °C and maintained at this temperature for 12 hours. After cooling the reaction solution to 20–25 °C, 250 mL of ice water and 150 mL of ethyl acetate were added to quench the reaction. After separation, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by recrystallization (n-heptane-ethyl acetate) to give compound 5 (22.75 g, yield 93.0%).

[0051] The overall yield of Example 2 was 80.1%. Example 3:

[0052] Step 1: Etherification reaction to prepare compound 2

[0053] The procedure was the same as in Example 1, except for the following reaction conditions, which were scaled up to a 100.0 g feed ratio for p-bromophenol: phosphine reagent was PPh3 (166.8 g, 635.9 mmol, 1.1 eq), azo reagent was DIAD (124.5 mL, 635.3 mmol, 1.1 eq), and the reaction temperature was 50–60 °C for 6 hours. Compound 2 (114.8 g, yield 92.4%) was obtained.

[0054] Step 2: Alkyl migration rearrangement reaction to prepare compound 3

[0055] The procedure was the same as in Example 1, except that the following reaction conditions were changed and scaled up proportionally: Compound 2 was added in an amount of 114.8 g (534.0 mmol, 1.0 eq); the mixed acid was a 70% sulfuric acid:acetic anhydride mixture (800 mL, volume ratio 1:1.5); the catalyst was tetrabutylammonium iodide (1.01 g, 2.73 mmol, 0.51 mol%); the mixture was refluxed at 125 °C for 2 hours, followed by quenching with 180 mL of ice water. Compound 3 (106.9 g, yield 93.1%) was obtained.

[0056] Step 3: Esterification reaction to prepare compound 4

[0057] The procedure was the same as in Example 1, except that the following reaction conditions were changed and the rest were scaled up proportionally: the amount of compound 3 added was 106.9 g, 497.2 mmol, 1.0 eq; cyclopropylformic acid was 86.1 g, 994.2 mmol, 2.0 eq; DMAP was 26.7 g, 218.5 mmol, 0.25 eq; the condensing agent was EDC・HCl (142.9 g, 745.8 mmol, 1.5 eq); the reaction was carried out at 10-15 °C for 6 hours to obtain compound 4 (138.6 g, yield 98.1%).

[0058] Step 4: Fries rearrangement reaction to prepare compound 5

[0059] The procedure was the same as in Example 1, except that the following reaction conditions were changed and the rest were scaled up proportionally: the amount of compound 4 was changed (138.6 g, 487.7 mmol, 1.0 eq), and the mixed acid was replaced with trifluoromethanesulfonic acid:methanesulfonic acid (1:1, 488 mL); the reaction was carried out at 40~50 °C for 6 h, and finally compound 5 (125.6 g, yield 90.6%) was obtained.

[0060] The overall yield of Example 3 was 76.5%. Example 4:

[0061] Step 1: Etherification reaction to prepare compound 2

[0062] The procedure was the same as in Example 1, except that the following conditions were applied to scale up the reaction by adding 100.0 g of p-bromophenol: p-bromophenol (compound 1) (100.0 g, 578.0 mmol, 1.0 eq), 1,4-dioxane 300 mL, isopropanol (61.8 mL, 809.2 mmol, 1.4 eq), and PPh3 (227.4 g, 867.0 mmol, 1.5 eq), DEAD (601.0 mmol, 273.2 mL of 2.2 M toluene solution, 1.5 eq) were added dropwise to the system at a uniform rate over 1 hour. The temperature was controlled at 45-50 °C and the reaction was maintained for 12 hours to obtain compound 2 (118.1 g, yield 95.0%).

[0063] Step 2: Alkyl migration rearrangement reaction to prepare compound 3

[0064] The procedure was the same as in Example 1, except for the following changes: the amount of compound 2 (118.1 g, 549.3 mmol, 1.0 eq), the mixed acid was replaced with 70% sulfuric acid-acetic anhydride (824 mL, volume ratio 1:1.5), the reaction was first carried out at 115-125 °C for 1.5 h, and then the temperature was raised to 145-150 °C and refluxed for 3 h, finally yielding compound 3 (114.1 g, yield 96.5%).

[0065] Step 3: Esterification reaction to prepare compound 4

[0066] The procedure was the same as in Example 2, except that the amounts of the reactants were changed: compound 3 (114.0 g, 530.2 mmol, 1.0 eq), cyclopropylformyl chloride (60.69 g, 583.2 mmol, 1.1 eq), TEA (150.23 g, 1.48 mol, 2.8 eq), and DMAP (6.75 g, 53.0 mmol, 0.1 eq), finally yielding compound 4 (147.0 g, yield 97.5%).

[0067] Step 4: Fries rearrangement reaction to prepare compound 5

[0068] The procedure was the same as in Example 1, except that the following reaction conditions were changed and the rest were scaled up proportionally: the amount of compound 4 was changed (147.0 g, 517.3 mmol, 1.0 eq) and the mixed acid was changed to 35 mL of trifluoromethanesulfonic acid:methanesulfonic acid (volume ratio 1:0.3). The reaction was carried out at 70~80℃, and compound 5 (135.2 g, yield 92.0%) was finally obtained.

[0069] The overall yield of Example 4 was 82.2%. Example 5:

[0070] Step 1: Etherification reaction to prepare compound 2

[0071] The procedure was the same as in Example 1, except that the following reaction conditions were changed: the isopropylating reagent was replaced with isopropyl methanesulfonate (5.0 mL, 40.0 mmol, 1.0 eq); the phosphine reagent and the azo reagent were replaced with PPh3 and DIAD, respectively, in the same equivalent amounts as in Example 1; 120 mL of toluene was used instead of the original reagents; the reaction was carried out at 30-45 °C for 24 hours; and the mixture was recrystallized from petroleum ether-ethanol (11:1); to obtain compound 2 (8.06 g, yield 93.7%).

[0072] Step 2: Alkyl migration rearrangement reaction to prepare compound 3

[0073] The procedure was the same as in Example 1, except that the following reaction conditions were changed: the mixed acid was replaced with 56.2 mL of concentrated sulfuric acid-glacial acetic acid (volume ratio 1:2.5), and the phase transfer catalyst was tetrabutylammonium iodide (0.07 g, 0.19 mmol, 0.5 mol%), and compound 3 (7.52 g, yield 93.3%) was finally obtained.

[0074] Step 3: Esterification reaction to prepare compound 4

[0075] The procedure was the same as in Example 1, except that the following reaction conditions were changed: compound 3 (7.52 g, 35.0 mmol, 1.0 eq), cyclopropylformic acid (3.50 g, 35.5 mmol, 1.0 eq), (the catalyst and condensing agent were changed to 4-pyrrolidinylpyridine (0.38 g, 3.08 mmol, 0.09 eq) and HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea) (23.93 g, 62.95 mmol, 1.8 eq), and the base was DIPEA (8.14 g, 63.0 mmol, 1.8 eq), finally yielding compound 4 (9.66 g, yield 97.2%).

[0076] Step 4: Fries rearrangement reaction to prepare compound 5

[0077] The procedure was the same as in Example 1, except that the following reaction conditions were changed: Compound 4 (9.66 g, 34.00 mmol, 1.0 eq) was changed to a mixture of trifluoromethanesulfonic acid and methanesulfonic acid (34.0 mL, volume ratio 1:0.8). After reacting at 45-55 °C for 3 h, the mixture was quenched with ice water-ethyl acetate, washed, dried, concentrated, and recrystallized to obtain Compound 5 (8.92 g, yield 92.3%).

[0078] The overall yield of Example 5 was 78.4%.

[0079] 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 a cyclopropanol intermediate, characterized in that, The intermediate is 5-bromo-2-hydroxy-3-isopropylphenylcyclopropyl methyl ketone (compound 5); the method uses p-bromophenol (compound 1) as the starting material and synthesizes compound 5 through four steps of directional reaction. The specific synthetic route is as follows: R1 is selected from one of the following: hydroxyl (-OH), p-toluenesulfonate (-OTs), and methanesulfonate (-OMS); R2 is selected from hydroxyl (-OH) or chlorine (-Cl); The preparation method includes the following synthesis steps: Step 1) Etherification reaction: p-bromophenol reacts with an isopropylating agent in a solvent to prepare compound 2 (yield 90.0~95.0%). Step 2) Alkyl migration rearrangement reaction: Compound 2 was reacted under reflux in an acid mixture with a phase transfer catalyst to prepare compound 3 (yield 92.0~97.0%). Step 3) Esterification reaction: Compound 3 reacts with a cyclopropyl acylation reagent in a solvent under the presence of a catalyst and a base to give compound 4 (yield 95.0~99.0%). Step 4) Fries rearrangement reaction: Compound 4 was reacted in an acid and solvent system to give compound 5 (yield 88.0~93.0%); the overall yield of the four steps was 69.2~82.2%.

2. The method for preparing the cyclopropofol intermediate according to claim 1, characterized in that, In step 1, p-bromophenol reacts with an isopropylating agent in the presence of a phosphine reagent and an azo reagent to undergo a Mitsunobu nucleophilic substitution reaction to obtain compound 2. The isopropylating agent is selected from isopropanol, isopropyl methanesulfonate, or isopropyl p-toluenesulfonate. The phosphine reagent is one or more of Bu3P (tributylphosphine), PPh3 (triphenylphosphine), and Me3P (trimethylphosphine). The azo reagent is DEAD (diethyl azodicarbonate) or DIAD (diisopropyl azodicarbonate).

3. The method for preparing the cyclopropofol intermediate according to claim 1 or 2, characterized in that, The amount of isopropylating reagent used in step 1 is 1.0~1.4 eq of p-bromophenol; the amount of phosphorus reagent used is 1.1~2.0 eq of p-bromophenol; the amount of azo reagent used is 1.1~2.0 eq of p-bromophenol; the reaction solvent is one or more of THF, 1,4-dioxane, toluene, xylene, and dichloromethane; the reaction temperature is 30~60℃, and the reaction time is 6~30h.

4. The method for preparing the cyclopropofol intermediate according to claim 1, characterized in that, The reaction conditions for step 2 are as follows: the acid mixture is a mixture of 70% sulfuric acid and acetic anhydride, or a mixture of concentrated sulfuric acid and glacial acetic acid; the phase transfer catalyst is one or more of TBAB (tetrabutylammonium bromide), TBAC (tetrabutylammonium chloride), and TBAI (tetrabutylammonium iodide), and the amount used is 0.5~1.5 mol.

5. The method for preparing the cyclopropofol intermediate according to claim 1, characterized in that, Step 2 involves a gradient temperature increase: the reaction is first carried out at 95~115℃, and then the temperature is increased to 115~150℃ for reflux. After the reaction is completed, compound 3 is obtained through post-processing.

6. The method for preparing the cyclopophenol intermediate according to claim 1, characterized in that, In step 3, the cyclopropyl acylation reagent is cyclopropylformic acid or cyclopropionyl chloride, and the amount used is 1.0~2.0 eq of compound 3; the catalyst is DMAP (4-dimethylaminopyridine) or 4-PPY (4-pyrrolidinylpyridine), and the amount used is 0.05~0.25 eq of compound 3; the base reagent is one or more of DIPEA (N,N-diisopropylethylamine), triethylamine, pyridine, and 4-methylmorpholine, and the amount used is 1.8~5.0 eq of compound 3.

7. The method for preparing the cyclopophenol intermediate according to claim 6, characterized in that, In step 3, the cyclopropyl acylation reagent is cyclopropylformic acid, and a condensing agent is added. The condensing agent is one or more of EDC·HCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate), and DIC (N,N'-diisopropylcarbodiimide). The amount of condensing agent is 1.5~3.0 eq of compound 3.

8. The method for preparing the cyclopophenol intermediate according to claim 1, characterized in that, In the esterification reaction of step 3, the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, and ethyl acetate; the reaction temperature is 0~35℃.

9. The method for preparing the cyclopophenol intermediate according to claim 1, characterized in that, The acid mentioned in step 4 is selected from one or more of trifluoromethanesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid-methanesulfonic acid mixture, concentrated sulfuric acid, and polyphosphoric acid.

10. The method for preparing the cyclopropofol intermediate according to claim 1, characterized in that, The reaction temperature in step 4 is 40~80°C. o C; After the reaction was completed, the compound was purified by a low-temperature quenching step (0~25℃) to obtain compound 5.

Images