Preparation method of irisone
Through the methods of citral condensation, cyclopropanation and intramolecular cyclic reaction, the existing iris ketone synthesis process and low yield are solved, and efficient and stable iris ketone preparation is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411736913.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-29
- Publication Date
- 2025-03-07
AI Technical Summary
The existing iris ketone synthesis methods have complex processes, long routes, difficult to separate products, low yields, and low α-iris ketone content, which is not suitable for industrial production.
The condensation reaction of citral and acetone is used to obtain pseudoionone, and then cyclopropaned with diethyl zinc and diiodomethylane under the action of a catalyst to obtain compound IV, and irisone is obtained through intramolecular cyclic reaction, which improves the stability and selectivity of the process through specific reaction conditions and treatment steps.
It has achieved efficient preparation of irisone, with a high proportion of α-irisone, with a yield of up to 78%, which is suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing irone. Background Art
[0002] Irisone is a precious spice, a colorless to pale yellow oily liquid with an aroma similar to iris and violet. Irisone has three isomers, including α-irone, β-irone, and γ-irone, of which α-irone accounts for a larger proportion and has a higher economic value. The main methods for synthesizing irone are chemical synthesis and natural product extraction.
[0003] The synthesis study of irone (Liu Xiaogeng, Chen Meimei, Xiong Youfa, et al. Synthesis study of irone [C] / / Proceedings of the 2000 China Flavor and Fragrance Academic Symposium.: China Flavor and Fragrance Cosmetics Industry Association, 2000: 115-118.) specifically discloses the following synthesis route:
[0004]
[0005] Citral is prepared from litsea cubeba oil extracted from litsea cubeba, and pseudoionone is synthesized from citral, and pseudoirone is synthesized by a methylation reagent. Microwave radiation technology is used to obtain α-irone and β-irone through a cyclization reagent. The synthesis process is complicated, the route is long, the product is difficult to separate, the yield is low, the α-irone content is low, and it is not suitable for industrial production.
[0006] The natural extraction method mainly uses the rhizomes of plants such as iris root, raspberry, and pittosporum as raw materials for extraction, but due to the limited plant resources, it is difficult to meet the large market demand. The biotechnology method is to use microbial fermentation to produce irone. Fragrance-producing bacteria are screened from iris rhizomes and fermented with fresh root powder as substrate. This method can prepare irone under mild conditions, but the screening of stable strains is the main problem currently faced. Summary of the invention
[0007] Purpose of the invention: The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art and provide a method for preparing irone.
[0008] To achieve the above purpose, the technical solution provided by the present invention is as follows:
[0009] A method for preparing irone, comprising:
[0010]
[0011] Wherein, in the step of preparing compound IV from compound III, the catalyst is trifluoroacetic acid or pyridine hydrogen fluoride; in the step of preparing compound I from compound IV, the catalyst is fluoroboric acid or phosphoric acid.
[0012] The preparation method comprises:
[0013]
[0014] In the step of preparing compound III from compound II, the base is potassium hydroxide or sodium hydroxide; wherein the molar ratio of compound II:base is in the range of 1:0.5-1.
[0015] In the step of preparing compound III from compound II, the reaction solvent is dichloromethane or acetone, and the reaction temperature is 30°C to 40°C.
[0016] In the preparation of compound IV from compound III, the molar ratio of compound III: diethylzinc: diiodomethane: catalyst is in the range of 1:1-2:1-2:1-2.
[0017] In the preparation of compound IV from compound III, the reaction solvent is dichloromethane or cyclohexane, and the reaction temperature is 10°C to 15°C.
[0018] In the preparation of compound I from compound IV, the molar ratio of compound IV to catalyst is in the range of 1:0.1-0.2.
[0019] In the preparation of compound I from compound IV, the reaction solvent is dichloromethane and the reaction temperature is -70°C to -10°C.
[0020] In the preparation of compound I from compound IV, the post-reaction treatment steps are: adding saturated ammonium chloride solution to the reaction solution, standing to separate the layers, washing the organic phase with water, adding anhydrous sodium sulfate to dry, distilling, and collecting the 130-150° C. fraction to obtain compound I.
[0021] The vacuum degree of the distillation is 1 mmHg.
[0022] Beneficial effects: The invention discloses a method for preparing irone, comprising the following steps: using citral (compound II) as a raw material, subjecting it to a condensation reaction with acetone to obtain pseudoionone (compound III); then, under the action of a catalyst, subjecting it to a cyclopropanation reaction with diethylzinc and diiodomethane to obtain compound IV, subjecting compound IV to an intramolecular ring-closing reaction under the action of a catalyst, and subjecting it to post-treatment to obtain compound I. The route has mild reaction conditions, is simple to operate, has a stable process, and has good reaction selectivity. The proportion of α-irone in the crude compound I is relatively high, and the yield can reach 78%, which is suitable for large-scale industrial production.
[0023] The abbreviations of the reaction reagents involved in the instructions are as follows:
[0024] NaOH: sodium hydroxide;
[0025] KOH: potassium hydroxide. DETAILED DESCRIPTION
[0026] The present invention is further illustrated below in conjunction with specific embodiments. The embodiments are implemented based on the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.
[0027] Example 1
[0028] Synthesis of compound III:
[0029]
[0030] Add 500mL 1N NaOH solution to a 2L four-necked bottle, then add 500mL dichloromethane, add 152g (1mol, 1eq) of citral under stirring, and then add 69.6g (1.2mol, 1.2eq) of acetone with a constant pressure dropping funnel. There is a slight exotherm during the addition, and the addition is completed in about 0.5h. Then place the four-necked bottle in an oil bath and heat it to an internal temperature of 30°C for 1h to stop the reaction. The reaction solution is allowed to stand and separate into dichloromethane phases, and the aqueous phase is extracted once with 500mL dichloromethane. After combining the dichloromethane phases, extract once with 300mL of water, dry with anhydrous sodium sulfate, and then spin dry to obtain 138.6g of compound III with a yield of 72%.
[0031] Synthesis of compound IV:
[0032]
[0033] Add 300mL of dichloromethane to a 3L four-necked bottle, then replace with nitrogen and use nitrogen to protect the reaction. Place the 3L four-necked bottle in an ice-water bath. When the internal temperature is 5°C, add 600mL of diethylzinc in n-hexane solution (1mol / L, 0.6mol, 2eq) using a constant pressure dropping funnel. Prepare a dichloromethane solution by dissolving 160.7g (0.6mol, 2eq) of dichloromethane in 300mL of dichloromethane and stirring evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution into the reaction solution. During the dropping process, heat is released significantly. Control the dropping speed so that the internal temperature does not exceed 10°C. After about 2 hours of dropping, remove the ice-water bath, and after the internal temperature rises to 20°C, continue stirring and reacting for 1 hour. Prepare a dichloromethane solution of trifluoroacetic acid, dissolve 34.2g of trifluoroacetic acid (0.3mol, 1eq) in 300mL of dichloromethane and stir evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution of trifluoroacetic acid into the reaction solution. No heat is released during the dropwise addition, and the addition is completed in about 1h. Then cool the reaction solution with an ice water bath. When the internal temperature is 5°C, 57.8g (0.3mol, 1eq) of compound III is dissolved in 300mL of dichloromethane and added to the reaction solution with a constant pressure dropping funnel. The reaction is obviously exothermic. Control the dropping speed so that the internal temperature does not exceed 10°C and the addition is completed in about 3h. Continue the reaction at an internal temperature of 10-15°C for 3h, take samples for detection, GC shows that the raw material disappears, and GC-MS shows that the product compound IV is generated. Add 500mL of saturated ammonium chloride solution to the reaction solution, stir for 0.5h, and then stand for stratification. The dichloromethane phase was washed once with 500 mL of water, and then dried over anhydrous sodium sulfate. After spin drying, 25.8 g of a crude product of compound IV was obtained with a yield of 42%.
[0034] 1 HNMR (400MHz, CDCl3), δ: 7.49-7.30 (m, 1H), 6.17-5.82 (m, 2H), 2.30-2.01 (m, 6H), 1.85- 1.75 (m, 3H), 1.65-1.58 (m, 3H), 1.50-1.35 (m, 1H), 1.04-0.95 (m, 4H), 0.48-0.38 (m, 1H).
[0035] GC-MS; 206(8), 191(18), 163(30), 135(30.0), 122(45), 109(100), 91(25).
[0036] Synthesis of Compound I:
[0037]
[0038] Under nitrogen protection, 0.6L dichloromethane and 61.8g (0.3mol, 1eq) of compound IV were added to a 1L four-necked bottle, and then the four-necked bottle was placed in a low-temperature cooling circulation bath, the internal temperature was cooled to -70°C, and 2.6g (0.03mol, 0.1eq) of fluoroboric acid was added dropwise with a constant pressure dropping funnel, and the internal temperature was kept at -70°C for 1h before sampling and testing. GC showed that the raw material disappeared, and GC-MS showed that the product was generated. 50mL of saturated ammonium chloride solution was added dropwise to the reaction solution and stirred for 0.5h. After the reaction solution was allowed to stand for stratification, the dichloromethane phase was washed once with 50mL of water, and then dried over anhydrous sodium sulfate, and 56g of crude compound I was obtained after being spin-dried. The crude compound I was purified by distillation (130-150° C., 1 mmHg, reflux ratio 10 / 1) to obtain 48.2 g of irone with a yield of 78%, of which the α-irone content was 71% (GC, peak area normalization method).
[0039] 1 H NMR (400MHz, CDCl3), δ: 6.60 (dd, J=15.7, 11.0, 1H), 6.13 (d, J=15.7, 1H), 5.50 (m, 1H), 2.55 (m, 1H), 2.28 (s, 3H), 2.10 (m, 1H), 1.53 (m, 3H), 0.88 (d, J=7, 3H), 0.86 (s, 3H), 0.71 (s, 3H).
[0040] GC-MS; 206(12), 191(21.5), 137(50.0), 122(100), 93(57.6).
[0041] Example 2
[0042] Synthesis of compound III:
[0043]
[0044] Add 500mL 1N NaOH solution to a 2L four-necked bottle, then add 500mL dichloromethane, add 152g (1mol, 1eq) of citral under stirring, and then add 87g (1.5mol, 1.5eq) of acetone with a constant pressure dropping funnel. There is a slight exotherm during the addition, and the addition is completed in about 0.5h. Then place the four-necked bottle in an oil bath and heat it to an internal temperature of 30°C for 1h to stop the reaction. The reaction solution is allowed to stand and separate into dichloromethane phases, and the aqueous phase is extracted once with 500mL dichloromethane. After combining the dichloromethane phases, extract once with 300mL of water, dry with anhydrous sodium sulfate, and then spin dry to obtain 140.2g of compound III with a yield of 73%.
[0045] Synthesis of compound IV:
[0046]
[0047] Add 300mL of dichloromethane to a 3L four-necked bottle, then replace with nitrogen and use nitrogen to protect the reaction. Place the 3L four-necked bottle in an ice-water bath. When the internal temperature is 5°C, add 600mL of diethylzinc in n-hexane solution (1mol / L, 0.6mol, 2eq) using a constant pressure dropping funnel. Prepare a dichloromethane solution by dissolving 160.7g (0.6mol, 2eq) of dichloromethane in 300mL of dichloromethane and stirring evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution into the reaction solution. During the dropping process, heat is released significantly. Control the dropping speed so that the internal temperature does not exceed 10°C. After about 2 hours of dropping, remove the ice-water bath, and after the internal temperature rises to 20°C, continue stirring and reacting for 1 hour. Prepare a dichloromethane solution of trifluoroacetic acid, dissolve 68.4g of trifluoroacetic acid (0.6mol, 2eq) in 300mL of dichloromethane and stir evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution of trifluoroacetic acid into the reaction solution. No heat is released during the dropping process, and the dropping is completed in about 1h. Then cool the reaction solution with an ice water bath. When the internal temperature is 5°C, 57.8g (0.3mol, 1eq) of compound III is dissolved in 300mL of dichloromethane and added to the reaction solution with a constant pressure dropping funnel. The reaction is obviously exothermic. Control the dropping speed so that the internal temperature does not exceed 10°C and the dropping is completed in about 3h. Continue the reaction at an internal temperature of 10-15°C for 3h, take samples for detection, GC shows that the raw material disappears, and GC-MS shows that the product compound IV is generated. Add 500mL of saturated ammonium chloride solution to the reaction solution, stir for 0.5h, and then stand for stratification. The dichloromethane phase was washed once with 500 mL of water, and then dried over anhydrous sodium sulfate. After spin drying, 48.2 g of a crude product of compound IV was obtained with a yield of 78%.
[0048] Synthesis of Compound I:
[0049]
[0050] Under nitrogen protection, 1.2L dichloromethane and compound IV 123g (0.6mol, 1eq) were added to a 2L four-necked bottle, and then the four-necked bottle was placed in a low-temperature cooling circulation bath, the internal temperature was cooled to -50°C, and 5.2g (0.06mol, 0.1eq) of fluoroboric acid was added dropwise with a constant pressure dropping funnel, and the internal temperature was kept at -50°C for 1h before sampling and testing. GC showed that the raw material disappeared, and GC-MS showed that the product was generated. 200mL of saturated ammonium chloride solution was added dropwise to the reaction solution and stirred for 0.5h. After the reaction solution was allowed to stand for stratification, the dichloromethane phase was washed once with 200mL of water, then dried over anhydrous sodium sulfate, and 106g of crude compound I was obtained after being spin-dried. The crude compound I was purified by distillation (130-150° C., 1 mmHg, reflux ratio 10 / 1) to obtain 92.6 g of irone with a yield of 75%, of which the α-irone content was 69% (GC, peak area normalization method).
[0051] Example 3
[0052] Synthesis of compound III:
[0053]
[0054] Add 500mL 1N KOH solution to a 2L four-necked bottle, add 152g (1mol, 1eq) of citral under stirring, and then add 200g of acetone with a constant pressure dropping funnel. There is a slight exotherm during the addition, and the addition is completed in about 0.5h. Then place the four-necked bottle in an oil bath and heat it to an internal temperature of 30°C for 4h to stop the reaction. The reaction solution is allowed to stand and stratify to obtain an organic phase, and the aqueous phase is extracted once with 500mL of ethyl acetate. After combining the ethyl acetate phase, extract once with 300mL of water, dry with anhydrous sodium sulfate, and then spin dry to obtain 163.2g of compound III with a yield of 85%.
[0055] Synthesis of compound IV:
[0056]
[0057] Add 300mL of dichloromethane to a 3L four-necked bottle, then replace with nitrogen and use nitrogen to protect the reaction. Place the 3L four-necked bottle in an ice-water bath. When the internal temperature is 5°C, add 600mL of diethylzinc in n-hexane solution (1mol / L, 0.3mol, 1eq) using a constant pressure dropping funnel. Prepare a dichloromethane solution by dissolving 80.3g (0.3mol, 1eq) of dichloromethane in 150mL of dichloromethane and stirring evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution into the reaction solution. During the dropping process, heat is released significantly. Control the dropping speed so that the internal temperature does not exceed 10°C. After about 2 hours of dropping, remove the ice-water bath, and after the internal temperature rises to 20°C, continue stirring and reacting for 1 hour. Prepare a dichloromethane solution of trifluoroacetic acid, dissolve 34.2g of trifluoroacetic acid (0.3mol, 1eq) in 300mL of dichloromethane and stir evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution of trifluoroacetic acid into the reaction solution. No heat is released during the dropwise addition, and the addition is completed in about 1h. Then cool the reaction solution with an ice-water bath. When the internal temperature is 5°C, 57.8g (0.3mol, 1eq) of compound III is dissolved in 300mL of dichloromethane and added to the reaction solution with a constant pressure dropping funnel. The reaction is obviously exothermic. Control the dropping speed so that the internal temperature does not exceed 10°C and the addition is completed in about 3h. Continue the reaction at an internal temperature of 10-15°C for 3h, take samples for detection, GC shows that the raw material disappears, and GC-MS shows that the product compound IV is generated. Add 500mL of saturated ammonium chloride solution to the reaction solution, stir for 0.5h, and then stand for stratification. The dichloromethane phase was washed once with 500 mL of water, and then dried over anhydrous sodium sulfate. After spin drying, 25.8 g of a crude product of compound IV was obtained with a yield of 42%.
[0058] Synthesis of Compound I:
[0059]
[0060] Under nitrogen protection, add 1.2L dichloromethane and 124g (0.6mol, 1eq) of compound IV to a 2L four-necked bottle, then place the four-necked bottle in a low-temperature cooling circulation bath, cool the internal temperature to -30°C, and add 5.2g (0.06mol, 0.1eq) of fluoroboric acid with a constant pressure dropping funnel. Keep the internal temperature at -30°C for 1h, then take samples for testing. GC shows that the raw material disappears, and GC-MS shows that the product is generated. 200mL of saturated ammonium chloride solution is added to the reaction solution and stirred for 0.5h. After the reaction solution is allowed to stand for stratification, the dichloromethane phase is washed once with 200mL of water, then dried over anhydrous sodium sulfate, and spin-dried to obtain 110g of the crude product of compound I. The crude compound I was purified by distillation (130-150° C., 1 mmHg, reflux ratio 10 / 1) to obtain 86.4 g of irone with a yield of 70%, of which the α-irone content was 64% (GC, peak area normalization method).
[0061] Example 4
[0062] Synthesis of compound III:
[0063]
[0064] Add 500mL 2N NaOH solution to a 2L four-necked bottle, then add 500mL dichloromethane, add 152g (1mol, 1eq) of citral under stirring, and then add 69.6g (1.2mol, 1.2eq) of acetone with a constant pressure dropping funnel. There is a slight exotherm during the addition, and the addition is completed in about 0.5h. Then place the four-necked bottle in an oil bath and heat it to an internal temperature of 40°C for 1h to stop the reaction. The reaction solution is allowed to stand and stratify to obtain a dichloromethane phase, and the aqueous phase is extracted once with 500mL dichloromethane. After combining the dichloromethane phases, extract once with 300mL of water, dry with anhydrous sodium sulfate, and then spin dry to obtain 172.9g of compound III with a yield of 89%.
[0065] Synthesis of compound IV:
[0066]
[0067] Add 300mL of cyclohexane to a 3L four-necked bottle, then replace with nitrogen and use nitrogen to protect the reaction. Place the 3L four-necked bottle in an ice-water bath. When the internal temperature is 5°C, add 600mL of diethylzinc in n-hexane solution (1mol / L, 0.6mol, 2eq) using a constant pressure dropping funnel. Prepare a cyclohexane solution of diiodomethane, dissolve 160.7g of diiodomethane (0.6mol, 2eq) in 300mL of cyclohexane, and stir evenly. Use a constant pressure dropping funnel to drop diiodomethane into the reaction solution. During the dropwise addition, heat is released significantly. Control the dropwise addition speed so that the internal temperature does not exceed 10°C. After about 2 hours of dropwise addition, remove the ice-water bath, and continue stirring the reaction for 1 hour after the internal temperature rises to 20°C. Use a constant pressure dropping funnel to drop 68.4g of trifluoroacetic acid (0.6mol, 2eq) into the reaction solution. No heat is released during the dropwise addition, and the dropwise addition is completed in about 1 hour. The reaction solution was then cooled with an ice-water bath. When the internal temperature was 5°C, 57.8 g (0.3 mol, 1 eq) of compound III was dissolved in 300 mL of cyclohexane and added dropwise to the reaction solution using a constant pressure dropping funnel. The reaction was exothermic and the dropping speed was controlled so that the internal temperature did not exceed 10°C. The addition was completed in about 3 hours. The reaction was continued for 3 hours at an internal temperature of 10-15°C. Sampling was performed and the GC showed that the raw material disappeared and the GC-MS showed that the product compound IV was generated. 500 mL of saturated ammonium chloride solution was added dropwise to the reaction solution, stirred for 0.5 h, and then allowed to stand for stratification. The cyclohexane phase was washed once with 500 mL of water, then dried with anhydrous sodium sulfate, and 48.2 g of crude compound IV was obtained after spin drying with a yield of 78%.
[0068] Synthesis of Compound I:
[0069]
[0070] Under nitrogen protection, 600mL of dichloromethane and 61.8g (0.3mol, 1eq) of compound IV were added to a 1L four-necked bottle, and then the four-necked bottle was placed in a low-temperature cooling circulation bath, the internal temperature was cooled to -30°C, and 5.9g (0.06mol, 0.2eq) of phosphoric acid was added dropwise with a constant pressure dropping funnel. After the internal temperature was kept at -30°C for 1h, sampling was performed. GC showed that the raw material disappeared, and GC-MS showed that the product was generated. 100mL of saturated ammonium chloride solution was added dropwise to the reaction solution and stirred for 0.5h. After the reaction solution was allowed to stand for stratification, the dichloromethane phase was washed once with 100mL of water, then dried over anhydrous sodium sulfate, and 55g of crude compound I was obtained after being spin-dried. The crude compound I was purified by distillation (130-150° C., 1 mmHg, reflux ratio 10 / 1) to obtain 40.2 g of irone with a yield of 65%, of which the α-irone content was 27% (GC, peak area normalization method).
[0071] Example 5
[0072] Synthesis of compound III:
[0073]
[0074] Add 500mL1N NaOH solution to a 2L four-necked bottle, then add 500mL dichloromethane, add 152g (1mol, 1eq) of citral under stirring, and then use a constant pressure dropping funnel to drop 69.6g (1.2mol, 1.2eq) of acetone. There is a slight exotherm during the dropwise addition, and the addition is completed in about 0.5h. Then place the four-necked bottle in an oil bath and heat it to an internal temperature of 40°C for 5h to stop the reaction. The reaction solution is allowed to stand and separate into dichloromethane phases, and the aqueous phase is extracted once with 500mL dichloromethane. After combining the dichloromethane phases, extract once with 300mL of water, dry with anhydrous sodium sulfate, and then spin dry to obtain 168.4g of compound III with a yield of 88%.
[0075] Synthesis of compound IV:
[0076]
[0077] Add 300mL of dichloromethane to a 3L four-necked bottle, then replace with nitrogen and use nitrogen to protect the reaction. Place the 3L four-necked bottle in an ice-water bath. When the internal temperature is 5°C, add 600mL of diethylzinc in n-hexane solution (1mol / L, 0.6mol, 2eq) using a constant pressure dropping funnel. Prepare a dichloromethane solution by dissolving 160.7g (0.6mol, 2eq) of dichloromethane in 300mL of dichloromethane and stirring evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution into the reaction solution. During the dropping process, heat is released significantly. Control the dropping speed so that the internal temperature does not exceed 10°C. After about 2 hours of dropping, remove the ice-water bath, and after the internal temperature rises to 20°C, continue stirring and reacting for 1 hour. Use a constant pressure dropping funnel to drop 84.8g of hydrogen fluoride pyridine solution (70%, 0.6mol, 2eq) into the reaction solution. No heat is released during the dropping process. The dropping is completed in about 1h. Then the reaction solution is cooled with an ice-water bath. When the internal temperature is 5°C, 57.8g of compound III (0.3mol, 1eq) is dissolved in 300mL of dichloromethane and added to the reaction solution with a constant pressure dropping funnel. The reaction is obviously exothermic. The dropping speed is controlled so that the internal temperature does not exceed 10°C. The dropping is completed in about 3h. The internal temperature is 10-15°C and the reaction is continued for 3h. Samples are taken for detection. GC shows that the raw material disappears, and GC-MS shows that the product compound IV is generated. 500mL of saturated ammonium chloride solution is added to the reaction solution, stirred for 0.5h, and then allowed to stand for stratification. The dichloromethane phase is washed once with 500mL of water, then dried with anhydrous sodium sulfate, and spin-dried to obtain 49.2g of crude compound IV with a yield of 79.6%.
[0078] Synthesis of Compound I:
[0079]
[0080] Under nitrogen protection, 3L dichloromethane and 310g (1.5mol, 1eq) of compound IV were added to a 5L four-necked bottle, and then the four-necked bottle was placed in a low-temperature cooling circulation bath, the internal temperature was cooled to -50 ° C, and 13g (0.15mol, 0.1eq) of fluoroboric acid was added dropwise with a constant pressure dropping funnel. After the internal temperature was kept at -50 ° C for 1h, sampling was performed. GC showed that the raw material disappeared, and GC-MS showed that the product was generated. 500mL of saturated ammonium chloride solution was added dropwise to the reaction solution and stirred for 0.5h. After the reaction solution was allowed to stand for stratification, the dichloromethane phase was washed once with 500mL of water, and then dried over anhydrous sodium sulfate, and 530g of crude compound I was obtained after being spin-dried. The crude product of compound I was distilled (130-150° C., 1 mmHg, reflux ratio 10 / 1) to obtain 450.2 g of irone with a yield of 72.8%, of which the α-irone content was 70.1% (GC, peak area normalization method).
[0081] Example 6
[0082] Synthesis of Compound I:
[0083]
[0084] Under nitrogen protection, 600 mL of dichloromethane and 61.8 g (0.3 mol, 1 eq) of compound IV were added to a 1 L four-necked bottle, and then the four-necked bottle was placed in a low-temperature cooling circulation bath, the internal temperature was cooled to -10°C, and 2.6 g (0.03 mol, 0.1 eq) of fluoroboric acid was added dropwise using a constant pressure dropping funnel, and the internal temperature was kept at -10°C for 1 hour before sampling and testing. GC showed that the raw material disappeared, and there were many small peaks, and GC-MS showed that the product was generated.
[0085] Comparative Example 7
[0086] Synthesis of Compound I:
[0087]
[0088] Under nitrogen protection, 600 mL of dichloromethane and 61.8 g (0.3 mol, 1 eq) of compound IV were added to a 1 L four-necked bottle, and then the four-necked bottle was placed in a low-temperature cooling circulation bath, and the internal temperature was cooled to -70°C. 4.3 g (0.03 mol, 0.1 eq) of boron trifluoride etherate was added dropwise using a constant pressure dropping funnel, and the internal temperature was maintained at -70°C for 1 hour before sampling and testing. GC showed that the raw material disappeared, and GC-MS showed that no product was generated.
[0089] Comparative Example 8
[0090] Synthesis of Compound I:
[0091]
[0092] Under nitrogen protection, 600 mL of dichloromethane and 61.8 g (0.3 mol, 1 eq) of compound IV were added to a 1 L four-necked bottle, and then the four-necked bottle was placed in a low-temperature cooling circulation bath, and the internal temperature was cooled to -70°C. 4.5 g (0.03 mol, 0.1 eq) of trifluoromethanesulfonic acid was added dropwise using a constant pressure dropping funnel, and the internal temperature was kept at -70°C for 1 hour before sampling and testing. GC showed that the raw material disappeared, and GC-MS showed that no product was generated.
[0093] Comparative Example 9
[0094] Synthesis of compound IV:
[0095]
[0096] Add 300mL of dichloromethane to a 3L four-necked bottle, then replace with nitrogen and use nitrogen to protect the reaction. Place the 3L four-necked bottle in an ice-water bath. When the internal temperature is 5°C, add 600mL of diethylzinc in n-hexane solution (1mol / L, 0.6mol, 2eq) using a constant pressure dropping funnel. Prepare a dichloromethane solution by dissolving 160.7g (0.6mol, 2eq) of dichloromethane in 300mL of dichloromethane and stirring evenly. Use a constant pressure dropping funnel to drop the dichloromethane solution into the reaction solution. During the dropping process, heat is released significantly. Control the dropping speed so that the internal temperature does not exceed 10°C. After about 2 hours of dropping, remove the ice-water bath, and after the internal temperature rises to 20°C, continue stirring and reacting for 1 hour. The reaction solution was then cooled with an ice-water bath. When the internal temperature was 5°C, 57.8 g (0.3 mol, 1eq) of compound III was dissolved in 300 mL of dichloromethane and added dropwise to the reaction solution using a constant pressure dropping funnel. The reaction was obviously exothermic. The dropping speed was controlled so that the internal temperature did not exceed 10°C. The addition was completed in about 3 hours. The reaction was continued at an internal temperature of 10-15°C for 3 hours. Sampling was performed for detection. GC showed that the raw material disappeared, and GC-MS showed that no product compound IV was generated.
[0097] The above specific implementation methods further illustrate the purpose, technical solutions and beneficial effects of the present application in detail. It should be understood that the above are only specific implementation methods of the present application and are not used to limit the protection scope of the present application. Any modifications, equivalent substitutions, improvements, etc. made on the basis of the technical solutions of the present application should be included in the protection scope of the present application.
Claims
1. A method for preparing irone, characterized in that: include: Wherein, in the step of preparing compound IV from compound III, the catalyst is trifluoroacetic acid or pyridine hydrogen fluoride; in the step of preparing compound I from compound IV, the catalyst is fluoroboric acid or phosphoric acid.
2. The preparation method according to claim 1, characterized in that: include:
3. The preparation method according to claim 2, characterized in that: In the step of preparing compound III from compound II, the base is potassium hydroxide or sodium hydroxide; The molar ratio of compound II to base is in the range of 1:0.5-1.
4. The preparation method according to claim 2 or 3, characterized in that: In the step of preparing compound III from compound II, the reaction solvent is dichloromethane or acetone, and the reaction temperature is 30°C to 40°C.
5. The preparation method according to claim 1 or 2, characterized in that: In the preparation of compound IV from compound III, the molar ratio of compound III: diethylzinc: diiodomethane: catalyst is in the range of 1:1-2:1-2:1-2.
6. The preparation method according to claim 5, characterized in that: In the preparation of compound IV from compound III, the reaction solvent is dichloromethane or cyclohexane, and the reaction temperature is 10°C to 15°C.
7. The preparation method according to claim 1 or 2, characterized in that: In the preparation of compound I from compound IV, the molar ratio of compound IV to catalyst is in the range of 1:0.1-0.
2.
8. The preparation method according to claim 7, characterized in that: In the preparation of compound I from compound IV, the reaction solvent is dichloromethane and the reaction temperature is -70°C to -10°C.
9. The preparation method according to claim 8, characterized in that: In the preparation of compound I from compound IV, the post-reaction treatment steps are: adding saturated ammonium chloride solution to the reaction solution, standing to separate the layers, washing the organic phase with water, adding anhydrous sodium sulfate to dry, distilling, and collecting the 130-150° C. fraction to obtain compound I.
10. The preparation method according to claim 9, characterized in that: The vacuum degree of the distillation is 1 mmHg.