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CN-121990892-A - Preparation method of cycloparaffin intermediate

CN121990892ACN 121990892 ACN121990892 ACN 121990892ACN-121990892-A

Abstract

The invention discloses a preparation method of a cycloparaffin intermediate (5-bromo-2-hydroxy-3-isopropylphenyl cyclopropyl ketone), which uses p-bromophenol as a starting material, and obtains a compound 5 through four-step directional reaction of etherification, alkyl migration rearrangement, esterification and Fries rearrangement, thereby solving the problems of harsh process conditions, more side reactions, low yield and high cost in the prior art. According to the invention, through the systematic optimization strategy of the process, a high-yield cycloparaffin intermediate synthesis route (90.0-95.0% etherification, 92.0-97.0% alkyl migration, 95.0-99.0% esterification and 88.0-93.0% Fries rearrangement) is realized, the total yield of four steps reaches 69.2% -82.2%, a key technical support is provided for efficient cycloparaffin synthesis, the economical efficiency of industrial production is obviously improved, and the method has important significance in promoting the upgrade of the cycloparaffin synthesis process and reducing the drug cost.

Inventors

  • FENG YU
  • Feng Qianxi
  • XU YING
  • ZHU YIN
  • LU JUAN
  • Liao Yizhe

Assignees

  • 浙江清华长三角研究院

Dates

Publication Date
20260508
Application Date
20260114

Claims (10)

  1. 1. A preparation method of a cycloparaffin intermediate is characterized in that the intermediate is 5-bromo-2-hydroxy-3-isopropylphenyl cyclopropyl ketone (compound 5), the method takes p-bromophenol (compound 1) as a starting material, and the compound 5 is directionally synthesized through four-step reaction, wherein the specific synthetic route is as follows: r 1 is selected from one of hydroxyl (-OH), p-toluenesulfonate (-OTs), methanesulfonate (-OMS); r 2 is selected from hydroxyl (-OH) or chlorine (-Cl); The preparation method comprises the following synthesis steps: Step 1), etherification reaction, namely reacting p-bromophenol with an isopropylation reagent in a solvent to obtain a compound 2 (yield 90.0-95.0%); step 2), alkyl migration rearrangement reaction, namely, carrying out reflux reaction on the compound 2 under the synergistic catalysis of an acid mixed solution and a phase transfer catalyst to obtain a compound 3 (the yield is 92.0-97.0%); Step 3) esterification reaction, namely, acylating the compound 3 and a cyclopropyl acylating reagent in a solvent under the condition of a catalyst and an alkali reagent to prepare a compound 4 (the yield is 95.0-99.0%); Step 4) Fries rearrangement reaction, namely, the compound 4 reacts in an acid and solvent system to prepare the compound 5 (the yield is 88.0-93.0%), and the total yield of the four steps is 69.2-82.2%.
  2. 2. The preparation method of the cycloparaffin intermediate according to claim 1, wherein in the step 1, the bromophenol and an isopropylation reagent undergo a Mitsunobu nucleophilic substitution reaction under the action of a phosphine reagent-azo reagent, wherein the isopropylation reagent is selected from one of isopropanol, isopropyl methanesulfonate or isopropyl P-toluenesulfonate, the phosphine reagent is one or more of Bu 3 P (tributylphosphine), PPh 3 (triphenylphosphine) and Me 3 P (trimethylphosphine), and the azo reagent is DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate).
  3. 3. The preparation method of the cycloparaffin intermediate according to claim 1 or 2, wherein the isopropylation reagent in the step 1 is 1.0-1.4 eq of p-bromophenol, the phosphorus reagent is 1.1-2.0 eq of p-bromophenol, the azo reagent is 1.1-2.0 eq of p-bromophenol, the reaction solvent is one or more of THF, 1, 4-dioxane, toluene, xylene and methylene dichloride, the reaction temperature is 30-60 ℃, and the reaction time is 6-30 h.
  4. 4. The preparation method of the cycloparaffin intermediate according to claim 1, wherein the reaction condition of the step 2 is that the acid mixed solution is a mixed solution of 70% sulfuric acid and acetic anhydride or a mixed solution of concentrated sulfuric acid and glacial acetic acid, and the phase transfer catalyst is one or more of TBAB (tetrabutylammonium bromide), TBAC (tetrabutylammonium chloride) and TBAI (tetrabutylammonium iodide) and the dosage is 0.5-1.5mol%.
  5. 5. The preparation method of the cycloparaffin intermediate according to claim 1, wherein the reaction in the step 2 adopts gradient heating, namely, firstly, the reaction is carried out at 95-115 ℃ and then the temperature is raised to the gradient heating of 115-150 ℃ for reflux, and the compound 3 is obtained after the reaction is finished and the post-treatment is carried out.
  6. 6. The preparation method of the cycloparaffin intermediate according to claim 1, wherein in the step 3, the cyclopropylating reagent is cyclopropylcarboxylic acid or cyclopropylchloride, the dosage is 1.0-2.0 eq of the compound 3, the catalyst is DMAP (4-dimethylaminopyridine) or 4-PPY (4-pyrrolidinylpyridine), the dosage is 0.05-0.25 eq of the compound 3, and the alkali reagent is one or more of DIPEA (N, N-diisopropylethylamine), triethylamine, pyridine and 4-methylmorpholine, and the dosage is 1.8-5.0 eq of the compound 3.
  7. 7. The method for preparing a cycloparaffin intermediate according to claim 6, wherein the cyclopropylating reagent in the step 3 is cyclopropylcarboxylic acid, and a condensing agent is added, wherein the condensing agent is one or more of edc·hcl (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), HATU (N, N '-tetramethyl-O- (7-azabenzotriazole-1-yl) hexafluoro-urea phosphate), DIC (N, N' -diisopropylcarbodiimide), and the amount of the condensing agent is 1.5 to 3.0eq of the compound 3.
  8. 8. The method for preparing the cycloparaffin intermediate according to claim 1, wherein in the esterification reaction of the step 3, the solvent is one or more of dichloromethane, chloroform, tetrahydrofuran and ethyl acetate, and the reaction temperature is 0-35 ℃.
  9. 9. The method for preparing a cycloparaffin intermediate according to claim 1, wherein the acid in step 4 is selected from one or more of trifluoromethanesulfonic acid, methanesulfonic acid, a mixed solution of trifluoromethanesulfonic acid and methanesulfonic acid, concentrated sulfuric acid, and polyphosphoric acid.
  10. 10. The preparation method of the cycloparaffin intermediate according to claim 1, wherein the reaction temperature in the step 4 is 40-80 o ℃, and the compound 5 is obtained by low-temperature quenching (0-25 ℃) and purification after the reaction.

Description

Preparation method of cycloparaffin intermediate Technical Field The invention relates to the technical field of medicine and intermediate synthesis, in particular to a preparation method of a cycloparaffin intermediate, which is especially optimized for the synthesis process of a compound 5 (5-bromo-2-hydroxy-3-isopropylphenyl cyclopropyl ketone, CAS: 1552982-39-4). The intermediate is used as a core precursor for synthesizing cycloparaffin drugs, and the preparation efficiency and purity of the intermediate directly influence the industrialized progress of subsequent drug synthesis. Background Cycloparaffin (Ciprofol), a third generation of short-acting intravenous anesthetics, is known under the chemical name 2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenol, is a gamma-aminobutyric acid type a (GABAa) receptor agonist, and produces an anesthetic effect by enhancing GABA-mediated chloride ion influx and inhibiting central nervous system excitability. Compared with the traditional anesthetic propofol, the cycloparaffin has remarkable clinical advantages, the official specification of the cycloparaffin injection of the national drug administration shows that the incidence rate of the injection pain of the cycloparaffin injection is reduced by more than 60 percent, the influence on the cardiovascular system is smaller, the respiratory inhibition risk is reduced by 35 percent, the postoperative wake-up time is shortened by 20 to 30 percent, the metabolite has no accumulated toxicity, and the cycloparaffin injection has wide application prospect in the scenes of operation anesthesia, intensive care sedation and the like. The data of the first leopard institute, panoramic atlas of the national intravenous anesthetic industry in 2023, and Frost & Sullivan, global Intravenous ANESTHETICS MARKET Report 2023 show that the global intravenous anesthetic market size in 2023 exceeds 180 hundred million dollars. The annual compound growth rate of the cycloparaffin is expected to reach 12% -18%, so that along with the continuous increase of clinical demands, the industrial production of the cycloparaffin becomes a research hotspot in the field of medicines. The synthesis core of the cycloparaffin depends on the efficient preparation of a key intermediate (5-bromo-2-hydroxy-3-isopropylphenyl cyclopropyl ketone, CAS: 1552982-39-4), and the process condition, synthesis yield and cost control of the intermediate directly determine the industrialization feasibility and market competitiveness of the cycloparaffin. At present, many reports exist on the synthesis research of cycloparaffin and intermediates thereof, and the prior art still has a certain optimization space in the aspects of raw material and auxiliary material selection, yield level, operation flow and the like, so that the requirement of large-scale production is difficult to meet. According to the report of original research route document CN105820040, the disclosed synthetic route uses 2-isopropyl phenol as a starting material, and prepares cycloparaffin through multi-step reactions such as etherification, gao Wenke Laisen rearrangement, cyclopropanation and the like; secondly, the Gao Wenke Laisen rearrangement step is easy to produce paraisomer, a complex refining process is required to be matched, the single-step yield is only 60%, thirdly, the cyclopropanation reaction depends on metal reagents such as zinc-copper reagents, the operation is required to be strictly controlled to Wen Biguang, the production operation requirement is high, and waste liquid containing heavy metals is produced by post-reaction treatment, so that the treatment load is increased. Although the patent US2016060197 describes the core reaction mechanism of cycloparaffin synthesis in detail, the corresponding process scheme adopts complicated steps of group protection and deprotection, the synthesis route adopts a multi-step route of phenolic hydroxyl protection-nucleophilic substitution-deprotection-grignard reaction-dealcoholization hydroxyl, redundant protection/deprotection steps are included, and the process is chain-length and difficult to operate. According to the patent example, the total yield of the whole process is only 48.6%. And the 3, 4-dihydro-2H-pyran reagent used for protecting the phenolic hydroxyl group is expensive, so that the total raw material is increased. In the document org. Process Res. Dev. 2025,29,5,1291-1298, a rearrangement synthesis method of a cycloparaffin intermediate is reported, the Process also uses isopropyl phenol as a starting material, the raw material cost is high, bromine atoms are required to be introduced by liquid bromine in the subsequent functional group modification stage, the liquid bromine has strong corrosiveness and strong oxidability, the selectivity is poor, polybrominated byproducts are easy to generate, impurities can be removed by repeated recrystallization and purification, and the operation is complex and the yield is low. In