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CN-122010689-A - Preparation method of cycloparaffin

CN122010689ACN 122010689 ACN122010689 ACN 122010689ACN-122010689-A

Abstract

The invention discloses a preparation method of cycloparaffin, which takes methyl salicylate as a starting material, and obtains the cycloparaffin through etherification, alkyl migration rearrangement, weinreb amide preparation, grignard addition, witting reaction and terminal alkene asymmetric original six-step reaction. On the basis of the innovative synthetic route, the process conditions are optimized, the atom economy is improved, the raw material and production cost are reduced, and the method is suitable for industrial production. The invention has simple and efficient synthetic route, high total yield and high product purity, and solves the problems of high raw material cost, more side reactions, low yield, complex process and the like in the existing preparation method.

Inventors

  • FENG YU
  • Feng Qianxi
  • FAN MINGCONG
  • Liao Yizhe
  • CAI QIANG
  • XU YING

Assignees

  • 浙江清华长三角研究院

Dates

Publication Date
20260512
Application Date
20260127

Claims (10)

  1. 1. The preparation method of the cycloparaffin is characterized by comprising the following specific reaction routes: ; Methyl salicylate is used as a raw material, and cycloparaffin is prepared through six steps of reactions of etherification, alkyl migration rearrangement, weinreb amide preparation, grignard addition and asymmetric reduction of Wittig reaction terminal alkene, wherein the specific reaction steps are as follows: S1 etherification reaction, namely directly preparing a compound 2 by nucleophilic substitution reaction of methyl salicylate and isopropyl haloalkane, wherein the yield is 86.2% -91.1%; s2 alkyl migration rearrangement reaction, namely preparing the compound 3 by adopting a gradient heating and phase transfer catalysis synergistic process under an acidic condition, wherein the yield is 85.0% -90.0%; S3 Weinreb amide is prepared by preparing a compound 4 from a compound 3 and Me (OMe) NH-CH (N, O-dimethylhydroxylamine hydrochloride) under the action of a condensing agent and a basic reagent, and the yield is 93.0-98.0%; s4 Grignard addition, namely, reacting the compound 4 with a cyclopropyl Grignard reagent to prepare a compound 5, wherein the yield is 91.0% -96.0%; s5, carrying out a Witting reaction on the compound 5 under the action of alkali to obtain a compound 6 with a yield of 92.3-97.0%; s6 terminal alkene asymmetric reduction, namely, the compound 6 adopts a metal Rh (rhodium) catalyst to carry out chiral catalytic reduction to prepare cycloparaffin, the yield is 87.4% -93.0%, the ee value is more than or equal to 99%, and the total yield of six-step reaction is 56.2% -64.7%.
  2. 2. The preparation method of the cycloparaffin according to claim 1, wherein the etherification reaction in the step S1 adopts a combination of an alkali reagent, i-propyl haloalkane and an aprotic solvent, wherein the alkali reagent is at least one selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, TEA (triethylamine), DIPEA (N, N-diisopropylethylamine), DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), the dosage is 2.0-4.0eq (equivalent) of methyl salicylate, the i-propyl haloalkane is one or more selected from 2-chloropropane, 2-bromopropane and 2-iodopropane, the aprotic solvent is at least one selected from DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), NMP (N-methylpyrrolidone), DMAc (N, N-dimethylacetamide), acetonitrile and 1, 4-dioxane, and the reaction temperature is 20-35 ℃ and the reaction time is 2-12 hours.
  3. 3. The preparation method of cycloparaffin according to claim 1, wherein in the step S2 alkyl migration rearrangement reaction, the compound 2 is added into an acidic mixed solution, a phase transfer catalyst is added and nitrogen is introduced for protection, the temperature is raised by adopting a gentle gradient, the acidic mixed solution is sulfuric acid and acetic anhydride mixed solution, the volume ratio of sulfuric acid to acetic anhydride is 1:1-1:5, the concentration of sulfuric acid solution is less than or equal to 75%, the phase transfer catalyst is at least one of TBAB (tetrabutylammonium bromide), TBAC (tetrabutylammonium chloride), TBAI (tetrabutylammonium iodide), TBAHS (tetrabutylammonium bisulfate), trioctylmethyl ammonium chloride and TEBA (benzyl triethyl ammonium chloride), and the dosage of the phase transfer catalyst is 0.3-0.8mol% of the compound 2 mol%.
  4. 4. The preparation method of cycloparaffin according to claim 1, wherein in the step S2, the temperature is raised to 80-110 ℃ to react for 0.5-2 hours, then the temperature is raised to 120-150 ℃ to reflux, and a water separator is adopted to separate the water in the system in the reflux process.
  5. 5. The method for preparing cycloparaffin according to claim 1, wherein in the preparation of step S3 Weinreb amide, the condensing agent is at least one of EDC (EDC), HCl (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), DCC (N, N '-dicyclohexylcarbodiimide), HATU (O- (7-azabenzotriazol-1-yl) -N, N, N', N '-tetramethylurea), T3P (propylphosphoric anhydride), DIC (N, N' -diisopropylcarbodiimide), the amount of which is 1.0-1.8eq of the compound 3, and 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, the amount of which is 1.0-3.0eq of the compound 3.
  6. 6. The process for preparing cyclopol according to claim 1, wherein in the preparation of step S3 Weinreb amide, me (OMe) NH-HCl is used in an amount of 1.0-1.5eq 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, the amount is 5-15 times (mL/g) the mass of compound 3, namely, 5-15mL of solvent used per gram of compound 3, the base and the condensing agent are slowly added at 0-5 ℃ and reacted at 20-40 ℃ for 1-8h.
  7. 7. The preparation method of the cycloparaffin according to claim 1, wherein in the step S4, a cyclopropyl grignard reagent reacts with the compound 4 in a solvent at a temperature of-10 ℃ to form at least one of cyclopropyl magnesium chloride, cyclopropyl magnesium bromide and cyclopropyl magnesium iodide, the concentration is 0.5-2.0M, the dosage is 1.0-2.5eq of the compound 4, the temperature is controlled to be-10-10 ℃, the solvent is at least one of THF, 2-MeTHF, MTBE, diethyl ether and toluene, and the dosage is 2-20 times (mL/g) of the mass of the compound 4.
  8. 8. The preparation method of the cycloparaffin according to claim 1, wherein in the step S5 Witting reaction, the compound 5 is reacted with a Witting reagent under the action of alkali to generate a compound 6, wherein the Witting reagent is at least one of MTPPB (methyl triphenylphosphine bromide), MTPPC (methyl triphenylphosphine chloride) and ethyl triphenylphosphine bromide, the dosage is 1.0-2.5eq of the compound 5, the alkali reagent is at least one of cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, DBU (1, 8-diazabicyclo undec-7-ene), sodium bis (trimethylsilyl) amide, liHMDS (lithium bis (trimethylsilyl) amide), sodium methoxide and sodium ethoxide, the dosage is 1.0-4.0eq of the compound 5, the solvent is at least one of tetrahydrofuran, 1, 4-dioxane, methyl tetrahydrofuran, acetonitrile and DMSO, and the reaction is carried out for 4-18h at a temperature of 0-80 ℃.
  9. 9. The process for preparing cyclopol according to claim 1, wherein the asymmetric reduction neutralizer at the end of the step S6 is a metal Rh catalyst-chiral ligand, which is one of [ RhCl (COD) ] 2 ((1, 5-cyclooctadiene) rhodium (I) chloride dimer), [ (NBD) 2 Rh] BF 4 (rhodium (I) bis (norbornadiene) tetrafluoroborate) ], [ Rh (acac) (C 2 H 4 ) 2 ] ((acetylacetonate) bis (ethylene) rhodium (I)), and is (R) - (+) -BINAP (R- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine), (R) - (+) -Xyl BINAP ((R) - (-) -1,1' -binaphthyl-2, 2' -bis (3, 5-xylyl) phosphine), (R) -Seg Phos (5, 5' -bis (diphenylphosphoryl) -4,4' -bis-1, 3-biphenyl), (2R, 1' S) -Duan.
  10. 10. The preparation method of the cycloparaffin according to claim 1, wherein in the asymmetric reduction of the terminal alkene in the step S6, the compound 6 is reduced to form the cycloparaffin under the hydrogen pressure of 1.0-4.5MPa and the action of a catalyst, the dosage of the Rh (rhodium) metal catalyst is 0.1-5% of the molar quantity of the 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.

Description

Preparation method of cycloparaffin Technical Field The invention relates to the technical field of organic synthesis, in particular to a preparation method of cycloparaffin. Background The cycloparaffin is a novel short-acting intravenous anesthetic, belongs to gamma ⁃ aminobutyric acid (GABA) receptor agonists, is prepared by introducing cyclopropyl into an isopropyl side chain of propofol to form a novel chiral molecule, increases a space effect, increases affinity to GABA receptors, has the advantages of high potency, quick onset, quick recovery, low accumulation, less adverse reaction and the like, and is suitable for various endoscope diagnosis and treatment operations, ICU sedation, general anesthesia and the like. Has the advantages of quick response, quick recovery, small influence on the cardiovascular system and the like, and has wide application prospect in clinical anesthesia. At present, the synthetic schemes of cycloparaffin are more, but the routes of the prior art all have a plurality of key bottlenecks, and the specific analysis of the routes of the combined references is as follows: The original route patent CN105820040 (shown below) takes 2-isopropyl-6- (1-methylallyl) phenol as a starting material, the cost of the starting material is high, a direct commercial bulk commodity source is not needed, the preparation is carried out through multi-step pre-synthesis, the route is long, the cost of the starting material is high, the process route comprises complex steps such as carbamate, cyclopropanation, chiral resolution and the like, the total yield is only 32.5-42.4%, the Gao Wenke Laisen rearrangement reaction (about 200 ℃) is easy to cause carbonization and polymerization side reactions, more byproducts are needed, the product purity is obviously reduced, diiodomethane/zinc-copper reagent is needed in the cyclopropanation step, diiodomethane is extremely toxic, the zinc-copper reagent is easy to spontaneously combust, the operation fault tolerance rate is low, the requirement on equipment protection is severe, and the large-scale production risk is high. The multi-step serial route is shown as patent CN105384608, which takes 2-isopropyl phenol as a starting material and synthesizes cycloparaffin (shown below) through nine steps of cyclization-hydrolysis-protection-resolution-reduction-oxidation-Wittig reaction-cyclopropanation-deprotection. Long synthesis route, complicated flow, high operation difficulty and low yield, and is not suitable for large-scale industrial production. Journal of MEDICINAL CHEMISTRY, 2017, vol.60, #9, p.3606-3617 (hereinafter referred to as JMC 2017) takes 2-isopropyl phenol as a starting material, and prepares cycloparaffin through phenolic hydroxyl protection-nucleophilic addition and hydrolysis-Grignard reaction-reduction dehydroxy-chiral resolution, so that key problems of complicated raw material pretreatment, high chiral resolution cost, harsh reaction conditions, low yield purity and the like exist, chiral resolution step needs to adopt chiral-HPLC, the other half of the racemate after resolution cannot be effectively utilized, raw material waste is serious, the total yield of the racemic body of the cycloparaffin before resolution is 71.6%, the yield after resolution is less than or equal to 35.8%, further cost is increased, meanwhile, the reactivity of n-BuLi (n-butyllithium) used in the route is extremely high, the requirement on the operation environment is severe, and the industrialized production risk is relatively high. In conclusion, the existing cycloparaffin synthesis route generally has the common problems of harsh reaction conditions, low total yield, high cost, large industrialization difficulty and the like, and is difficult to adapt to the large-scale production requirements. Therefore, the development of a cycloparaffin synthesis route with easily available raw materials, simple steps, high yield and low cost has important significance for promoting the industrialized production and clinical application of the cycloparaffin. Disclosure of Invention The invention aims to solve the defects in the prior art and provides the preparation method of the cycloparaffin, which realizes high yield and low cost through a reaction system and process parameters which are accurately designed. The invention firstly provides a preparation method of cycloparaffin, which comprises the following specific synthetic route: Methyl salicylate is used as a starting material, and the cycloparaffin is finally obtained through six steps of reactions including etherification, alkyl migration rearrangement, weinreb amide preparation, grignard reaction, witting reaction and terminal alkene asymmetric reduction. The specific reaction flow is as follows: S1 etherification reaction, namely, methyl salicylate (compound 1) is taken as a raw material, and reacts for 2-12 hours at 20-35 ℃ in an alkaline reagent, isopropyl haloalkane and an aprotic solvent, and after the reacti