Preparation method and detection method of hinokitiol

Abstract

The invention discloses a preparation method and a detection method of hinokitiol, and belongs to the technical field of synthesis of medical intermediates, the preparation method comprises the following steps: S1, carrying out a reaction on cyclopentadiene, ethyl magnesium bromide and isopropyl p-toluenesulfonate to obtain cyclopentadiene; the preparation method comprises the following steps: carrying out an addition reaction on 1-isopropyl cyclopentadiene and dichloroacetyl chloride in a solvent to prepare 7, 7-dichloro-3-isopropyl-bicyclo [3, 2, 0] hept-2-ene-6-one, and carrying out a reaction on the 7, 7-dichloro-3-isopropyl-bicyclo [3, 2, 0] hept-2-ene-6-one and 1-isopropyl cyclopentadiene in the solvent to prepare 7, 7-dichloro-3-isopropyl-bicyclo [3, 2, 0] hept-2-ene-6-one; s3, the 7, 7-dichloro-3-isopropyl-bicyclo [3, 2, 0] hept-2-ene-6-ketone, a mixed solution containing tert-butyl alcohol, acetic acid and water and triethylamine are subjected to a ring expansion reaction, and a crude product of hinokitiol is prepared; and S4, carrying out alkali extraction and acid precipitation on the hinokitiol crude product, and recrystallizing to obtain hinokitiol. The method greatly simplifies the post-treatment process, has the advantages of low cost, high purity, high yield and the like, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, and relates to a method for preparing and detecting juniper alcohol. Background Technology

[0002] Juniperol, also known as juniperol, is a monoterpenoid natural compound with a juniperone structure. It is commonly found in the resins of plants such as juniper and cypress and is a common fragrance ingredient. Studies have shown that juniperol possesses a wide range of biological activities and is widely used in oral care, chemical, pesticide, pharmaceutical, and cosmetic fields, showing broad market prospects and enormous commercial potential.

[0003] Currently, natural juniper alcohol is mainly extracted and prepared from cypress oil. Due to the limited resources of natural juniper alcohol and its very low content in plant tissues, it is not suitable for large-scale development, which limits the application of juniper alcohol. Against this background, the artificial synthesis of juniper alcohol has become a research hotspot. Liu Wei et al. (Liu Wei, Fan Zhen, Li Hongwei. Research on a new synthesis process of juniper alcohol [J]. Shandong Chemical Industry, 2018, 47(12): 33-34.) disclosed a new synthesis process of juniper alcohol, in which cyclopentadiene undergoes an alkylation reaction with isopropyl bromide under the action of metallic sodium to obtain 1-isopropylcyclopentadiene, and then undergoes an addition reaction with dichloroacetyl chloride to obtain 7,7-dichloro-3-isopropyl-bicyclo[3.2.0]hept-2-en-6-one, and finally undergoes a ring expansion reaction to obtain crude juniper alcohol, which is purified to obtain juniper alcohol with a purity of 99.9%. This process requires the use of metallic sodium, which is costly and carries a high risk, making it unsuitable for industrial production.

[0004] CN101602656A discloses a method for preparing physalis alcohol. The method includes generating cyclopentadiene potassium from cyclopentadiene and potassium hydroxide, followed by reacting it with isopropyl bromide to obtain 1-isopropylcyclopentadiene; adding the reaction product of dichloroacetyl chloride and triethylamine to 1-isopropylcyclopentadiene ketene adduct to obtain 1-isopropylcyclopentadiene ketene adduct; and reacting the 1-isopropylcyclopentadiene ketene adduct with acetic acid, sodium hydroxide, and toluene to obtain physalis alcohol. The invention achieves a maximum yield of 80.6% for crude physalis alcohol, but does not disclose the purity and yield of purified physalis alcohol, making it unsuitable for industrial production.

[0005] To address the problems existing in the current technology, it is of great significance to develop a simple, low-cost, and high-yield method for preparing juniper alcohol. Summary of the Invention

[0006] Based on this, the present invention provides a method for preparing and detecting juniper alcohol. The present invention avoids the generation of 2-isopropylcyclopentadiene isomers, improves the purity of intermediates while avoiding isomer conversion processes, and greatly simplifies post-processing processes. It has the advantages of low cost, high purity and high yield, and is suitable for large-scale industrial production.

[0007] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: In a first aspect, the present invention provides a method for preparing juniper alcohol, comprising the following steps: S1, cyclopentadiene reacts with ethyl magnesium bromide and isopropyl p-toluenesulfonate to prepare 1-isopropylcyclopentadiene: S2, 1-isopropylcyclopentadiene and dichloroacetyl chloride undergo an addition reaction in a solvent to prepare 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one; S3,7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one reacts with a mixed solution containing tert-butanol, acetic acid and water, and triethylamine to produce crude juniper alcohol; S4. The crude juniper alcohol is alkali-extracted, acid-precipitated, and recrystallized to obtain juniper alcohol.

[0008] Preferably, the molar ratio of cyclopentadiene, ethyl magnesium bromide and isopropyl p-toluenesulfonate in step S1 is 0.9-1.1:0.9-1.1:0.9-1.2; more preferably 1:0.99:1-1.15.

[0009] Preferably, the reaction in step S1 is as follows: cyclopentadiene and ethyl magnesium bromide are refluxed for 6-10 hours, cooled, and then isopropyl p-toluenesulfonate is added and reacted at a constant temperature for 10-15 hours.

[0010] More preferably, the reflux reaction temperature is 33-37°C; the cooling is to cool to below 4°C, and even more preferably 0-4°C.

[0011] In some embodiments, step S1 further includes the following steps: adding a saturated NH4Cl aqueous solution to the solution after the heat preservation reaction is completed to quench the reaction, extracting with n-hexane, washing the obtained organic phase and removing water to obtain 1-isopropylcyclopentadiene.

[0012] Preferably, the temperature of the saturated NH4Cl aqueous solution is 2-6°C; more preferably, it is 4°C.

[0013] Preferably, the temperature of the n-hexane is 2-6°C; more preferably, it is 4°C.

[0014] In some implementations, step S1 specifically includes the following steps: quenching the reaction by adding a saturated NH4Cl aqueous solution at 2-6°C to the solution after the heat preservation reaction is completed, extracting with n-hexane at 2-6°C, and discarding the aqueous layer; washing the organic phase with a saturated brine aqueous solution, and finally drying with anhydrous sodium sulfate to obtain a solution containing 1-isopropylcyclopentadiene.

[0015] In some embodiments, the solvent in step S2 is n-hexane, and the catalyst for the addition reaction is triethylamine; Preferably, the molar ratio of triethylamine and dichloroacetyl chloride in step S2 is 1:1.

[0016] Preferably, the addition reaction in step S2 is as follows: 1-isopropylcyclopentadiene and n-hexane are mixed, cooled, dichloroacetyl chloride is added, and then triethylamine is added dropwise. After the addition is complete, the mixture is kept at a constant temperature for the reaction.

[0017] More preferably, the cooling is to cool to 0-4°C, the triethylamine is added over a period of 1-2 hours, and the heat preservation reaction is carried out over a period of 0.5-1.5 hours.

[0018] In some implementations, step S2 further includes the following steps: after the reaction is completed, the solution is filtered, the filtrate is collected, the pH of the filtrate is adjusted to neutral, hexane is extracted, and the organic phase is washed to remove the solvent.

[0019] Preferably, the molar ratio of tert-butanol, acetic acid, water and triethylamine in step S3 is 0.65-7:1.4-1.6:5.5-5.7; more preferably, it is 0.69:1.5:5.6.

[0020] Preferably, the ring expansion reaction in step S3 is as follows: 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hepta-2-en-6-one is mixed with a mixed solution containing tert-butanol, acetic acid and water, heated under reflux, and triethylamine is added dropwise. After the addition is complete, the mixture is refluxed and stirred to react.

[0021] More preferably, the reflux temperature in step S3 is 80-100℃; the triethylamine is added dropwise over 1-2 hours; and the reflux stirring reaction time is 1-3 hours.

[0022] In some embodiments, step S3 further includes the following steps: adjusting the pH of the solution to 1-2 after the reaction is completed by reflux and stirring, extracting with ethyl acetate, washing with the organic phase, and removing the solvent.

[0023] Preferably, the alkaline extraction and acid precipitation in step S4 is as follows: crude juniper alcohol is dissolved in diethyl ether, sodium hydroxide solution is added, the mixture is stirred for 1-2 hours, allowed to stand for 1-2 hours, filtered, the filtrate is extracted with dichloromethane, the pH of the organic phase is adjusted to 1-2, and then allowed to stand for separation; dichloromethane extraction is performed, and the organic phase is washed to remove the solvent.

[0024] Preferably, the recrystallization in step S4 is as follows: the solid phase after alkali extraction and acid precipitation is dissolved in a good solvent, ethyl acetate and dichloromethane, heated under reflux, a poor solvent is added, cooled, and juniper alcohol crystals are precipitated. The crystals are then filtered, washed, and dried to obtain juniper alcohol.

[0025] More preferably, the benign solvent is ethyl acetate and / or dichloromethane; the undesirable solvent is petroleum ether and / or n-hexane; the reflux temperature is 40-50°C; and the cooling is performed at a rate of 1-2°C / min to 0°C.

[0026] In some embodiments, the method for preparing the juniper alcohol includes the following steps: S1. Under nitrogen protection, a tetrahydrofuran solution containing ethyl magnesium bromide and cyclopentadiene were mixed evenly and then heated under reflux at 33-37°C for 6-10 hours. After the reaction was completed, the mixture was cooled to 0°C, and isopropyl p-toluenesulfonate was added and stirred and kept at the temperature for 10-15 hours. After the reaction was completed, a saturated NH4Cl aqueous solution was added dropwise to quench the reaction. The mixture was then extracted with n-hexane, the aqueous layer was discarded, and the organic phase was washed with a saturated saline solution. Finally, anhydrous sodium sulfate was added to dry the mixture to obtain 1-isopropylcyclopentadiene. S2. Under nitrogen protection, 1-isopropylcyclopentadiene obtained in step S1 was mixed with n-hexane. The temperature was then adjusted to 0-4℃, dichloroacetyl chloride was added, and then triethylamine was added dropwise. The addition of triethylamine was completed within 1-2 h. The reaction was then continued at this temperature for 0.5-1.5 h. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and hydrochloric acid solution was added to the filtrate to adjust the pH to neutral. Then, n-hexane was used for extraction, and the upper organic phase was collected. The organic phase was washed with saturated brine, and then dried with sodium sulfate solution. The organic phase was then distilled under reduced pressure to remove the solvent, yielding 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one.

[0027] S3. Under nitrogen protection, the 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one obtained in step S2 was dissolved in a mixed solution of tert-butanol, acetic acid and water. The mixture was heated under reflux at 95-100℃, and triethylamine was added dropwise over 0.5-1.5 h. After the addition was complete, the mixture was refluxed and stirred for 0.5-1.5 h. Then, hydrochloric acid solution was added to adjust the pH to 1-2, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried with anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent, yielding crude juniper alcohol.

[0028] S4. Dissolve the crude juniper alcohol obtained in step S3 in diethyl ether, add sodium hydroxide solution and stir for 1-2 h, let stand for 1-2 h, filter the solution to remove insoluble matter, extract the filtrate with dichloromethane, adjust the pH of the organic phase to 1-2 with hydrochloric acid solution, let stand for separation, then extract with dichloromethane, collect the organic phase, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and distill the organic phase under reduced pressure to remove the solvent and obtain solid juniper alcohol; Juniper alcohol solid was dissolved in a good solvent and heated under reflux at 40-50°C. Then, a poor solvent was added, and the mixture was cooled to 0°C at a rate of 1-2°C per minute to precipitate juniper alcohol crystals. The mixture was filtered, the filter cake was washed, collected, and dried to obtain juniper alcohol.

[0029] Secondly, the present invention also provides a method for detecting juniper alcohol obtained by the corresponding preparation method, employing high-performance liquid chromatography (HPLC), wherein the HPLC conditions are as follows: Column: PR-18; Detector: PDA; Detection wavelength: 240nm; Column temperature: 35-40℃; Injection volume: 5-10 μL; Mobile phase A: 0.1-0.2% formic acid aqueous solution; Mobile phase B: acetonitrile; The elution program is as follows: 0-5 min, the volume fraction of mobile phase A decreases from 100% to 75%; 5-10 min, the volume fraction of mobile phase A decreases from 75% to 72%; 10-15 min, the volume fraction of mobile phase A decreases from 72% to 30%, and the running time is 20 min.

[0030] In some embodiments, the conditions for the high-performance liquid chromatography are as follows: Column: PR-18; Detector: PDA; Detection wavelength: 240nm; Column temperature: 40℃; Injection volume: 10 μL; Mobile phase A: 0.1% formic acid aqueous solution; Mobile phase B: acetonitrile; The elution program is as follows: 0-5 min, the volume fraction of mobile phase A decreases from 100% to 75%; 5-10 min, the volume fraction of mobile phase A decreases from 75% to 72%; 10-15 min, the volume fraction of mobile phase A decreases from 72% to 30%, and the running time is 20 min.

[0031] In some embodiments, the method for detecting juniper alcohol obtained by the corresponding preparation method includes the following steps: (1) Preparation of juniper alcohol reference solution: Juniper alcohol reference standard was dissolved in acetonitrile and filtered through a 0.22 μm microporous membrane to obtain juniper alcohol reference solution; (2) Preparation of the test sample: The test sample is dissolved in acetonitrile and filtered through a 0.22 μm microporous membrane to obtain the test sample solution; (3) Chromatographic detection: The juniper alcohol reference solution and the test sample solution were injected into a high-performance liquid chromatograph for detection, wherein the conditions for the high-performance liquid chromatography were: Column: PR-18; Detector: PDA; Detection wavelength: 240nm; Column temperature: 40℃; Injection volume: 10 μL; Mobile phase A: 0.1% formic acid aqueous solution; Mobile phase B: acetonitrile; The elution program is as follows: 0-5 min, the volume fraction of mobile phase A decreases from 100% to 75%; 5-10 min, the volume fraction of mobile phase A decreases from 75% to 72%; 10-15 min, the volume fraction of mobile phase A decreases from 72% to 30%, and the running time is 20 min.

[0032] The beneficial effects of this invention are as follows: (1) The present invention uses cyclopentadiene as raw material to prepare crude juniper alcohol through a three-step reaction. In this step, cyclopentadiene is reacted with ethyl magnesium bromide to generate Grignard reagent, which is then further reacted with isopropyl p-toluenesulfonate to obtain 1-isopropylcyclopentadiene. This avoids the generation of 2-isopropylcyclopentadiene isomer, improves the purity of intermediates, and avoids isomer conversion steps. The addition reaction of 1-isopropylcyclopentadiene with dichloroacetyl chloride to obtain 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one and the ring expansion reaction of 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one with a mixed solution containing tert-butanol, acetic acid and water, and triethylamine are used to obtain crude juniper alcohol. This preparation method only requires alkaline extraction, acid precipitation and recrystallization after the reaction to obtain high-purity juniper alcohol, which greatly simplifies the post-processing steps.

[0033] Compared with existing technologies, the preparation method of the present invention is simple, the reaction conditions are mild, the cost is low, and the yield and purity are high, making it suitable for large-scale industrial production.

[0034] (2) The detection method of the present invention has a short detection time and a wide linear range, and can be used for purity detection and analysis of juniper alcohol. Attached Figure Description

[0035] Figure 1 This is the HPLC chromatogram of juniper alcohol reference standard.

[0036] Figure 2 This is the standard curve graph for Example 1.

[0037] Figure 3 Example 2: Hinoki alcohol 1 1H NMR spectrum (using CDCl3 as solvent).

[0038] Figure 4 Example 2: Hinoki alcohol 13 C10 NMR spectrum (using CDCl3 as solvent). Detailed Implementation

[0039] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0040] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention.

[0041] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0042] The present invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are all commercially available products in this technical field. Unless otherwise specified, the temperatures mentioned are all room temperature (25±2℃). Example 1: Detection method for cypress alcohol (1) Preparation of juniper alcohol reference solution: Accurately weigh 10 mg of juniper alcohol reference standard and place it in a 10 mL volumetric flask. Dissolve it completely in chromatographic acetonitrile and dilute to the mark. Then filter it through a 0.22 μm microporous membrane to obtain a 1 mg / mL juniper alcohol mother liquor. The juniper alcohol mother liquor was then serially diluted to prepare juniper alcohol reference standard solutions with concentrations of 0.5 mg / mL, 0.25 mg / mL, 0.125 mg / mL, 0.0625 mg / mL, and 0.03125 mg / mL.

[0043] (2) Sample solution to be tested Accurately weigh 10 mg of juniper alcohol and place it in a 10 mL volumetric flask. Dissolve it completely in chromatographic acetonitrile and dilute to the mark. Filter the solution using a 0.22 μm microporous membrane to obtain a 1 mg / mL juniper alcohol sample stock solution. Then dilute the solution 8 times to obtain the sample solution to be tested.

[0044] (3) Chromatographic conditions Column: RP-18 (50-2 mm); Mobile phase A: 0.1% formic acid aqueous solution; Mobile phase B: acetonitrile; Flow rate: 0.2 mL / min; Detector: PDA Detector, Detection wavelength: 240 nm; Column temperature: 40℃; Injection volume: 10 μL; Running time: 20 min; Elution program: 0-5 min, the volume fraction of mobile phase A decreases from 100% to 75%; 5-10 min, the volume fraction of mobile phase A decreases from 75% to 72%; 10-15 min, the volume fraction of mobile phase A decreases from 72% to 30%.

[0045] (4) Plotting the standard curve: Under the chromatographic conditions described above, juniper alcohol reference solutions with concentrations of 0.03125 mg / mL, 0.0625 mg / mL, 0.125 mg / mL, 0.25 mg / mL, and 0.5 mg / mL were injected and analyzed. Each sample was tested three times, and the average peak area was recorded.

[0046] The results are as follows Figure 1 As shown in Table 1.

[0047] Table 1. Statistical table of cypress alcohol concentration and peak area

[0048] A standard curve was plotted with juniper alcohol concentration (mg / mL) on the x-axis and peak area (A) on the y-axis. The results are shown below. Figure 2 Therefore, the fitted linear regression equation is y=4*10^8x+3*10^6, R² = 0.997>0.99, indicating that the concentration of juniperol has a good linear relationship with the peak area in the range of 0.03125 mg / mL-0.5 mg / mL.

[0049] (5) Sample purity determination: Under the above chromatographic conditions, the sample solution to be tested was injected and analyzed. The peak area was integrated and substituted into the fitting equation linear equation: y=4*10^8x+3*10^6, and the juniper alcohol content was calculated.

[0050] Example 2: A method for preparing juniper alcohol S1. Under nitrogen protection and at room temperature, 450 mL of tetrahydrofuran (THF) solution containing ethyl magnesium bromide (EtMgBr, 1M) was added to a 1 L three-necked round-bottom flask. Cyclopentadiene (30 g, 0.455 mol) was then added and stirred thoroughly. The mixture was heated under reflux at 35 °C for 8 h. After the reaction, the mixture was slowly cooled to 0 °C, and isopropyl p-toluenesulfonate (IpTS, 97.5 g, 0.455 mol) was added. The mixture was stirred and kept at this temperature for 13 h. After the reaction, 20 mL of saturated NH4Cl aqueous solution pre-cooled to 4 °C was added dropwise to quench the reaction. The mixture was then extracted with 500 mL of n-hexane pre-cooled to 4 °C. The aqueous layer was discarded, and the organic phase was washed three times with saturated saline solution. Finally, anhydrous sodium sulfate was added to dry the solution, yielding a solution containing 1-isopropylcyclopentadiene. S2. Under nitrogen protection, the solution containing 1-isopropylcyclopentadiene obtained in step S1 is added to a container containing 500 mL of n-hexane ( n The mixture was placed in a 2L round-bottom flask containing 7,7-dichloroacetyl chloride (Cl₂CHCOCl, 100.6 g, 0.683 mol) and cooled to 0°C. Then, dichloroacetyl chloride (Cl₂CHCOCl, 100.6 g, 0.683 mol) was added, followed by the slow addition of triethylamine (Et₃N, 69.0 g, 0.683 mol). The triethylamine was added dropwise over 2 h, and the reaction was continued at this temperature for another 1 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was collected. 50 mL of 1M dilute hydrochloric acid solution was added to the filtrate to adjust the pH to neutral. The solution was then extracted with n-hexane, and the upper organic phase was collected. The organic phase was washed three times with saturated brine and dried with anhydrous sodium sulfate. The organic phase was then subjected to vacuum distillation to remove the solvent, yielding 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one.

[0051] S3. Under nitrogen protection, dissolve the 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one obtained in step S2 in tert-butanol ( t A mixed solution of -BuOH (500 g), acetic acid (CH3COOH, 111.3 g), and water (H2O, 111.3 g) was heated to reflux at 100 °C, and then triethylamine (Et3N, 218.5 g, 2.2 mol) was slowly added dropwise over 1 hour. The mixture was stirred under reflux for 1 hour, then the pH was adjusted to 1 with concentrated hydrochloric acid (5 M), and the mixture was extracted with 500 mL of ethyl acetate. The organic phase was collected, washed three times with saturated brine, and dried with anhydrous sodium sulfate. The organic phase was then distilled under reduced pressure to remove the solvent, yielding crude juniper alcohol.

[0052] S4. Dissolve the crude juniper alcohol obtained in step S3 in 50 mL of diethyl ether, add 500 mL of 2 M sodium hydroxide solution, stir for 1 h, and then let stand for 2 h. Filter the solution to remove insoluble matter. Extract the filtrate three times with dichloromethane (50 mL × 3), then add 2 M dilute hydrochloric acid solution to adjust the pH to 1, and let stand for 1 h to separate the layers. Then extract three times with dichloromethane (500 mL × 3), collect the organic phase, wash the organic phase three times with saturated brine, and dry with anhydrous sodium sulfate. Distill the organic phase under reduced pressure to remove the solvent and obtain solid juniper alcohol. The solid juniper alcohol was then dissolved in 10 mL of dichloromethane and heated under reflux at 40 °C. 100 mL of n-hexane was then added to the system, and the mixture was cooled to 0 °C at a rate of 1–2 °C per minute, precipitating juniper alcohol crystals. The mixed solution was filtered, and the filter cake was washed three times with pre-cooled n-hexane solution. The filter cake was collected and dried to obtain 52.1 g of pure juniper alcohol. The overall yield of the three-step reaction was 69.3%, and the purity was 99.7%.

[0053] Subsequent NMR and mass spectrometry analysis were performed to identify hinoki alcohol. 1 H, 13 The C-spectrums are as follows: Figure 3 , Figure 4 As shown.

[0054] Example 2: A method for preparing juniper alcohol S1. Under nitrogen protection and at room temperature, 450 mL of tetrahydrofuran (THF) solution containing ethyl magnesium bromide (EtMgBr, 1M) was added to a 1 L three-necked round-bottom flask. Cyclopentadiene (30 g, 0.455 mol) was then added and stirred thoroughly. The mixture was heated to reflux at 35 °C for 8 h. After the reaction was complete, the mixture was slowly cooled to 0 °C, and isopropyl p-toluenesulfonate (IpTS, 97.5 g, 0.455 mol) was added. The mixture was stirred and kept at this temperature for 13 h. After the reaction was complete, 20 mL of saturated NH4Cl aqueous solution pre-cooled to 4 °C was added dropwise to quench the reaction. The mixture was then extracted with 500 mL of n-hexane pre-cooled to 4 °C. The aqueous layer was discarded, and the organic phase was washed three times with saturated saline solution. Finally, anhydrous sodium sulfate was added to dry the solution, yielding a solution containing 1-isopropylcyclopentadiene.

[0055] S2. Under nitrogen protection, the solution containing 1-isopropylcyclopentadiene obtained in step S1 is added to a container containing 250 mL of n-hexane ( nThe mixture was placed in a 2L round-bottom flask containing 7,7-hexane and cooled to 0°C. Dichloroacetyl chloride (Cl₂CHCOCl, 67.1 g, 0.455 mol) was then added to the system, followed by the slow dropwise addition of triethylamine (Et₃N, 46.0 g, 0.455 mol). The triethylamine was added dropwise over 1.5 h, and the reaction was maintained at this temperature for another 1 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was collected. 50 mL of 1M dilute hydrochloric acid solution was added to the filtrate to adjust the pH to neutral. The solution was then extracted with n-hexane, and the upper organic phase was collected. The organic phase was washed three times with saturated brine and dried with anhydrous sodium sulfate. The organic phase was then subjected to vacuum distillation to remove the solvent, yielding 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one.

[0056] S3. Under nitrogen protection, dissolve the 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one obtained in step S2 in tert-butanol ( t A mixed solution of -BuOH (500 g), acetic acid (CH3COOH, 111.3 g), and water (H2O, 111.3 g) was prepared. The mixture was heated to reflux at 100 °C, and then triethylamine (Et3N, 218.5 g, 2.2 mol) was slowly added dropwise over 1 hour. The mixture was stirred under reflux for 1 hour, and then concentrated hydrochloric acid solution (5 M) was added to adjust the pH to 1. The mixture was extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed three times with saturated brine and then dried with anhydrous sodium sulfate. The organic phase was then distilled under reduced pressure to remove the solvent, yielding crude juniper alcohol.

[0057] S4. Dissolve the crude juniper alcohol obtained in step S3 in 50 mL of diethyl ether, add 500 mL of 2 M sodium hydroxide solution, stir for 1 h, and then let stand for 2 h. Filter the solution to remove insoluble matter. Extract the filtrate three times with dichloromethane (50 mL × 3), then add 2 M dilute hydrochloric acid solution to adjust the pH to 1, and let stand for 1 h to separate the layers. Then extract three times with dichloromethane (500 mL × 3), collect the organic phase, wash the organic phase three times with saturated brine, and dry with anhydrous sodium sulfate. Distill the organic phase under reduced pressure to remove the solvent and obtain solid juniper alcohol. The solid juniper alcohol was then dissolved in 10 mL of ethyl acetate and heated under reflux at 50 °C. 100 mL of petroleum ether was then added to the system, and the mixture was cooled to 0 °C at a rate of 1-2 °C per minute, precipitating juniper alcohol crystals. The mixed solution was filtered, and the filter cake was washed three times with pre-cooled petroleum ether solution. The filter cake was collected and dried to obtain 50.0 g of pure juniper alcohol. The overall yield of the three-step reaction was 67.0%, and the purity was 99.7%. Subsequent NMR and mass spectrometry analysis confirmed the purity of juniper alcohol. 1 H, 13The C-chromatogram is consistent with the cypress alcohol spectrum of Example 2.

[0058] Example 2: A method for preparing juniper alcohol S1. Under nitrogen protection and at room temperature, 450 mL of tetrahydrofuran (THF) solution containing ethyl magnesium bromide (EtMgBr, 1M) was added to a 1 L three-necked round-bottom flask. Cyclopentadiene (30 g, 0.455 mol) was then added and stirred thoroughly. The mixture was heated to reflux at 35 °C for 8 h. After the reaction was complete, the mixture was slowly cooled to 0 °C, and isopropyl p-toluenesulfonate (IpTS, 112.1 g, 0.523 mol) was added. The mixture was stirred and kept at this temperature for 13 h. After the reaction was complete, 20 mL of saturated NH4Cl aqueous solution pre-cooled to 4 °C was added dropwise to quench the reaction. The mixture was then extracted with 500 mL of n-hexane pre-cooled to 4 °C. The aqueous layer was discarded, and the organic phase was washed three times with saturated saline solution. Finally, anhydrous sodium sulfate was added and the mixture was dried to obtain a solution containing 1-isopropylcyclopentadiene.

[0059] S2. Under nitrogen protection, the solution containing 1-isopropylcyclopentadiene obtained in step S1 is added to a container containing 500 mL of n-hexane ( n The mixture was placed in a 2L round-bottom flask containing 7,7-dichloroacetyl chloride (Cl₂CHCOCl, 100.6 g, 0.683 mol) and cooled to 0°C. Then, dichloroacetyl chloride (Cl₂CHCOCl, 100.6 g, 0.683 mol) was added to the system, followed by the slow addition of triethylamine (Et₃N, 69.0 g, 0.683 mol). The triethylamine was added dropwise over 2 hours, and the reaction was maintained at this temperature for another 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was collected. 50 mL of 1M dilute hydrochloric acid solution was added to the filtrate to adjust the pH to neutral. The solution was then extracted with n-hexane, and the upper organic phase was collected. The organic phase was washed three times with saturated brine and dried with anhydrous sodium sulfate. The organic phase was then subjected to vacuum distillation to remove the solvent, yielding 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one.

[0060] S3. Under nitrogen protection, dissolve the 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one obtained in step S2 in tert-butanol ( t A mixed solution of -BuOH (500 g), acetic acid (CH3COOH, 111.3 g), and water (H2O, 111.3 g) was prepared. The mixture was heated to reflux at 80 °C, and then triethylamine (Et3N, 218.5 g, 2.2 mol) was slowly added dropwise over 1 hour. The mixture was stirred under reflux for 3 hours, then concentrated hydrochloric acid solution (5 M) was added to adjust the pH to 1. The mixture was extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed three times with saturated brine and then dried with anhydrous sodium sulfate. The organic phase was then subjected to vacuum distillation to remove the solvent, yielding crude juniper alcohol. S4. Dissolve the crude juniper alcohol obtained in step S3 in 50 mL of toluene solution, add 500 mL of 2 M sodium hydroxide solution, stir for 1 h, and then let stand for 2 h. Filter the solution to remove insoluble matter, extract the filtrate three times with dichloromethane (50 mL × 3), then adjust the pH to 1 with 2 M dilute hydrochloric acid solution, and let stand for 1 h to separate the layers. Then extract three times with dichloromethane (500 mL × 3), collect the organic phase, wash the organic phase three times with saturated brine, and dry with anhydrous sodium sulfate. Distill the organic phase under reduced pressure to remove the solvent and obtain solid juniper alcohol. The solid juniper alcohol was then dissolved in 10 mL of dichloromethane and heated under reflux at 40 °C. 100 mL of n-hexane was then added to the system, and the mixture was cooled to 0 °C at a rate of 1-2 °C per minute, precipitating juniper alcohol crystals. The mixed solution was filtered, and the filter cake was washed three times with pre-cooled n-hexane solution. The filter cake was collected and dried to obtain 47.1 g of pure juniper alcohol. The overall yield of the three-step reaction was 63.0%, and the purity was 99.7%. Subsequent NMR and mass spectrometry analysis confirmed the purity of juniper alcohol. 1 H, 13 C-chromatogram and cypress alcohol spectrum from Example 1 above. Figure 1 To.

[0061] The above description, in conjunction with specific embodiments, further illustrates the present invention. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solutions of the present invention can be made without departing from the spirit and scope of the invention, and all such modifications and substitutions fall within the protection scope of the present invention.

Claims

1. A method for preparing juniper alcohol, characterized in that, Includes the following steps: S1, cyclopentadiene reacts with ethyl magnesium bromide and isopropyl p-toluenesulfonate to prepare 1-isopropylcyclopentadiene: S2, 1-isopropylcyclopentadiene and dichloroacetyl chloride undergo an addition reaction in a solvent to prepare 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one; S3,7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one reacts with a mixed solution containing tert-butanol, acetic acid and water, and triethylamine to produce crude juniper alcohol; S4. The crude juniper alcohol is alkali-extracted, acid-precipitated, and recrystallized to obtain juniper alcohol.

2. The preparation method according to claim 1, characterized in that, The molar ratio of cyclopentadiene, ethyl magnesium bromide and isopropyl p-toluenesulfonate in step S1 is 0.9-1.1:0.9-1.1:0.9-1.

2.

3. The preparation method according to claim 1, characterized in that, The reaction described in step S1 is as follows: cyclopentadiene and ethyl magnesium bromide are refluxed for 6-10 hours, cooled, and then isopropyl p-toluenesulfonate is added and reacted at the same temperature for 10-15 hours. And / or, the reflux reaction temperature is 33-37°C; And / or, the cooling is cooling to 0-4°C.

4. The preparation method according to claim 1, characterized in that, Step S1 also includes the following steps: quenching the reaction by adding a saturated NH4Cl aqueous solution at 2-6℃ to the solution after the heat preservation reaction is completed, extracting with n-hexane at 2-6℃, and discarding the aqueous layer; washing the organic phase with a saturated brine aqueous solution, and finally drying with anhydrous sodium sulfate to obtain a solution containing 1-isopropylcyclopentadiene.

5. The preparation method according to claim 1, characterized in that, The solvent in step S2 is n-hexane, and the catalyst for the addition reaction is triethylamine; And / or the molar ratio of the triethylamine and dichloroacetyl chloride is 1:

1.

6. The preparation method according to claim 1, characterized in that, The addition reaction described in step S2 is as follows: 1-isopropylcyclopentadiene and n-hexane are mixed, cooled, dichloroacetyl chloride is added, and then triethylamine is added dropwise. After the addition is complete, the mixture is kept at a constant temperature for the reaction.

7. The preparation method according to claim 6, characterized in that, In step S2, the cooling is to reduce the temperature to 0-4°C, the triethylamine is added over a period of 1-2 hours, and the heat preservation reaction is carried out over a period of 0.5-1.5 hours.

8. The preparation method according to claim 1, characterized in that, Step S2 also includes the following steps: after the heat preservation reaction is completed, the solution is filtered, the filtrate is collected, the pH value of the filtrate is adjusted to neutral, hexane is extracted, and the organic phase is washed to remove the solvent.

9. The preparation method according to claim 1, characterized in that, The molar ratio of tert-butanol, acetic acid, water and triethylamine in step S3 is 0.65-7:1.4-1.6:5.5-5.

7.

10. The preparation method according to claim 1, characterized in that, The ring expansion reaction described in step S3 is as follows: 7,7-dichloro-3-isopropyl-bicyclo[3,2,0]hept-2-en-6-one is mixed with a mixed solution containing tert-butanol, acetic acid and water, heated to reflux, and triethylamine is added dropwise. After the addition is complete, the mixture is stirred under reflux. And / or, the temperature of the heating reflux in step S3 is 80-100°C; And / or, the triethylamine is added over a period of 1-2 hours; And / or, the reaction time for the reflux stirring is 1-3 hours.

11. The preparation method according to claim 1, characterized in that, Step S3 also includes the following steps: after the reaction is completed by reflux and stirring, the pH of the solution is adjusted to 1-2, extracted with ethyl acetate, washed with organic phase, and the solvent is removed.

12. The preparation method according to claim 1, characterized in that, The alkaline extraction and acid precipitation in step S4 is as follows: crude juniper alcohol is dissolved in diethyl ether, sodium hydroxide solution is added, stirred for 1-2 hours, allowed to stand for 1-2 hours, filtered, the filtrate is extracted with dichloromethane, the pH of the organic phase is adjusted to 1-2, and then allowed to stand for separation; dichloromethane extraction, organic phase is washed and solvent is removed.

13. The preparation method according to claim 1, characterized in that, The recrystallization described in step S4 is as follows: the solid phase after alkali extraction and acid precipitation is dissolved in the good solvent ethyl acetate and dichloromethane, heated to reflux, a poor solvent is added, cooled, and a mixture containing crystals is obtained. The mixture is filtered, washed, and dried to obtain juniper alcohol. And / or, the benign solvent is ethyl acetate and / or dichloromethane; And / or, the undesirable solvent is petroleum ether and / or n-hexane; And / or, the temperature of the heating reflux is 40-50°C, and the cooling is: cooling to 0°C at a rate of 1-2°C / min.

14. A method for detecting juniper alcohol obtained by the preparation method according to any one of claims 1-13, characterized in that, High-performance liquid chromatography (HPLC) was used, and the HPLC conditions were as follows: Column: PR-18; Detector: PDA; Detection wavelength: 240nm; Column temperature: 35-40℃; Injection volume: 5-10 μL; Mobile phase A: 0.1-0.2% formic acid aqueous solution; Mobile phase B: acetonitrile; The elution program is as follows: 0-5 min, the volume fraction of mobile phase A decreases from 100% to 75%; 5-10 min, the volume fraction of mobile phase A decreases from 75% to 72%; 10-15 min, the volume fraction of mobile phase A decreases from 72% to 30%, and the running time is 20 min.

15. The method according to claim 14, characterized in that, Includes the following steps: (1) Preparation of juniper alcohol reference solution: Juniper alcohol reference standard was dissolved in acetonitrile, filtered through a filter membrane to obtain juniper alcohol reference solution; (2) Preparation of the test sample: The test sample is dissolved in acetonitrile, filtered through a filter membrane to obtain the test sample solution; (3) Chromatographic detection: The juniper alcohol reference solution and the sample solution to be tested were injected into the high performance liquid chromatograph for detection; Preferably, the filter membrane is a microporous filter membrane; more preferably, it is a 0.22 μm microporous filter membrane.

16. The method according to claim 15, characterized in that, The conditions for the high-performance liquid chromatography are as follows: Column: PR-18; Detector: PDA; Detection wavelength: 240nm; Column temperature: 40℃; Injection volume: 10 μL; Mobile phase A: 0.1% formic acid aqueous solution; Mobile phase B: acetonitrile; The elution program is as follows: 0-5 min, the volume fraction of mobile phase A decreases from 100% to 75%; 5-10 min, the volume fraction of mobile phase A decreases from 75% to 72%; 10-15 min, the volume fraction of mobile phase A decreases from 72% to 30%, and the running time is 20 min.

Images