Synthesis method of muscone intermediate and catalyst adopted by synthesis method
By using phase transfer nucleophilic ionic liquid catalyst, the problem of insimplicity and efficiency of synthesis of musk ketone intermediates in the prior art is solved, high yield and economical synthesis are achieved, and the catalyst can be reused.
Patent Information
- Application Number
- CN202510426893.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-07
- Publication Date
- 2025-05-30
AI Technical Summary
The prior art is difficult to achieve simple, efficient and economical synthesis of musk ketone intermediates, and the reusability of the catalyst is poor.
The phase transfer nucleophilic ionic liquid catalyst is used to achieve efficient synthesis of musk ketone intermediates through specific synthesis routes and catalyst structure design, and the catalyst can be reused.
It improves the yield and reaction efficiency of musk ketone intermediates, simplifies the synthesis process, reduces costs, and realizes the reuse of catalysts, with broad application prospects.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a synthesis method of a musk ketone intermediate and a catalyst used therein. Background Art
[0002] Natural musk is a dried product of the glandular sac secretion between the navel and genitals of male musk deer. It is in block or granular form and is a high-grade natural fragrance with high medicinal value. It can also be used in the preparation of high-grade daily chemical fragrances. From ancient times to the present, in order to obtain natural musk, people have hunted musk animals wantonly, causing these animals to be on the verge of extinction.
[0003] Musk ketone, 3-methylcyclopentadecanone, is the main component of musk and can now be synthesized artificially. Natural musk ketone is the left-handed isomorph, while synthetic musk ketone is generally the right-handed isomorph. Musk ketone is a very precious Chinese medicinal material and also a very valuable spice with a wide range of uses. Since the yield of musk ketone is very low and the price is expensive, it is mainly used in the pharmaceutical industry. Since the source of natural musk is small and expensive. Therefore, studying a simple and efficient method for synthesizing musk ketone has important economic value, and the industrial synthesis of musk ketone is a research project that researchers have long paid attention to. Summary of the invention
[0004] The invention aims to provide a synthesis method of a musk ketone intermediate and a catalyst used therein. The synthesis method is simple, the conditions are mild, the yield is high, the catalyst can be reused, and the invention has broad application prospects.
[0005] The technical solution of the present invention is achieved in this way:
[0006] The present invention provides a phase transfer nucleophilic ionic liquid catalyst having a structure as shown in Formula I:
[0007]
[0008] Where R = C3-C12 alkyl chain, X is HSO 4 or CH 3 SO 3 .
[0009] The present invention further protects a method for preparing the above-mentioned phase transfer nucleophilic ionic liquid catalyst, comprising the following steps:
[0010] S1. Diphenylphosphine chloride is reacted with alkyl glycol to obtain intermediate 1, the structure of which is as follows:
[0011] S2. The intermediate 1 is reacted with thionyl chloride to obtain the intermediate 2, the structure of which is as follows:
[0012] S3. React imidazole with 1,3 - propanesultone to obtain intermediate 3, whose structure is as follows:
[0013] S4. React intermediate 3 with intermediate 2, and then add the product to sulfuric acid or methanesulfonic acid and stir to obtain the phase - transfer nucleophilic ionic liquid catalyst.
[0014] As a further improvement of the present invention, in step S1, the molar ratio of diphenylphosphine chloride to alkyl diol is 1:1 - 1.1, and the alkyl diol is selected from at least one of 1,3 - propanediol, 1,4 - butanediol, 1,5 - pentanediol, 1,6 - hexanediol, 1,7 - heptanediol, 1,8 - octanediol, 1,9 - nonanediol, 1,10 - decanediol, 1,11 - undecanediol, 1,12 - dodecanediol.
[0015] As a further improvement of the present invention, in step S2, the molar ratio of intermediate 1 to thionyl chloride is 1:1.2 - 1.5.
[0016] As a further improvement of the present invention, in step S3, the molar ratio of imidazole to 1,3 - propanesultone is 1:0.9 - 1.1.
[0017] As a further improvement of the present invention, in step S4, the molar ratio of intermediate 3 to intermediate 2 is 1:0.9 - 1.1.
[0018] The present invention further protects a method for synthesizing a muscone intermediate, comprising the following steps:
[0019] (1) Mix 1,10 - decanediol and hydrobromic acid solution evenly, dropwise add concentrated sulfuric acid, heat under reflux for reaction, separate the liquid of the reaction solution, wash, dry, and distill under reduced pressure to collect the product 1,10 - dibromodecane;
[0020] (2) Add alkali to ethanol, add the above - mentioned phase - transfer nucleophilic ionic liquid catalyst, add 1,10 - dibromodecane and ethyl acetoacetate, heat under reflux for reaction, remove the excessive ethyl acetoacetate and ethanol under reduced pressure, add dilute alkali solution, heat for hydrolysis reaction, cool to room temperature, filter, wash the solid, and dry to obtain the muscone intermediate 2,15 - hexadecanedione.
[0021] As a further improvement of the present invention, in step (1), the concentration of the hydrobromic acid solution is 35 - 45 wt%, the solid - liquid ratio of 1,10 - decanediol to the hydrobromic acid solution is 10 - 15:45 - 60 g / mL, the addition amount of concentrated sulfuric acid is 30 - 40 wt% of the mass of 1,10 - decanediol, and the time of the heat - reflux reaction is 15 - 20 h.
[0022] As a further improvement of the present invention, the base is selected from at least one of potassium carbonate, sodium carbonate, triethylamine, diethylamine, NaOH or KOH.
[0023] As a further improvement of the present invention, in step (2), the addition amount of the phase transfer nucleophilic ionic liquid catalyst is 5-10 wt% of 1,10-dibromodecane, the molar ratio of the base, 1,10-dibromodecane and ethyl acetoacetate is 3-5:1:2.1-2.2, the time for the heating reflux reaction is 15-20 h, the dilute base solution is a NaOH or KOH solution with a concentration of 10-15 wt%, the temperature for the heating hydrolysis reaction is 75-85 °C, and the time is 10-15 h.
[0024] The present invention has the following beneficial effects:
[0025] The present invention prepares a phase transfer nucleophilic ionic liquid catalyst, and the synthesis route is as follows:
[0026]
[0027] Using an ionic liquid as a phase transfer catalyst, it has high catalytic activity, good solubility in both aqueous and organic phase solvents, and is also easy to recycle. Due to its relatively complex cation, which is both lipophilic and hydrophilic, it can be dissolved in both the aqueous and organic phases simultaneously. When it encounters salts distributed in the aqueous phase, the anions in the aqueous phase exchange with the cations in the catalyst, and the exchanged ions can react with the reagents in the organic phase. The cations of the ionic liquid can form ion pairs with the reactants, and the anions can stabilize the reaction intermediates, thereby reducing the reaction activation energy and increasing the reaction rate.
[0028] During the synthesis of the muscone intermediate, the added base can provide a basic environment. In addition, a nucleophilic catalyst structure trisubstituted organophosphine is also connected to the phase transfer nucleophilic ionic liquid catalyst prepared in the present invention, and there is a lone pair of electrons on its phosphorus atom, which can participate in the reaction as a nucleophilic reagent, thus greatly catalyzing the reaction. Compared with adding a nucleophilic reaction catalyst and a phase transfer catalyst separately, the present invention reduces the addition amount of the catalyst, and can realize the synchronous process of phase transfer and catalytic reaction, shortening the reaction distance, thereby accelerating the reaction process, increasing the reaction conversion rate, and reducing the reaction activation energy.
[0029] The phase transfer nucleophilic ionic liquid catalyst prepared in the present invention has low solubility in organic esters. By adding ethyl acetate to the reaction solution, the phase transfer nucleophilic ionic liquid catalyst can be separated by filtration, thus realizing recycling. Specific embodiments
[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.
[0031] Preparation Example 1 Preparation Method of Phase Transfer Nucleophilic Ionic Liquid Catalyst
[0032] It includes the following steps:
[0033] S1. Add 20 mmol of diphenylphosphine chloride, 60 mmol of triethylamine, and 20 mmol of 1,3-propanediol into 50 mL of dichloromethane, heat under reflux for 4 h, add the product into 50 mL of saturated sodium carbonate solution, wash, separate the liquid, collect the organic phase, dry, filter, remove the solvent under reduced pressure, and separate by column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain Intermediate 1; ESI-MS calculated value: C 15 H 18 O 2 P(M+H) + 261.27, measured value: 261.3, and the yield is 87%.
[0034] NMR results of Intermediate 1: 1 H NMR (300 MHz, CDCl 3 ) δ 7.42 (m, 10H), 3.57 (t, 4H), 2.0 (br, 1H), 1.72 (m, 2H).
[0035] S2. Add 20 mmol of Intermediate 1 into 50 mL of dichloromethane, dropwise add 20 mL of dichloromethane solution containing 24 mmol of thionyl chloride, stir and react at 0 °C for 30 min, remove the solvent and excess thionyl chloride under reduced pressure, wash and dry the product to obtain Intermediate 2; ESI-MS calculated value: C 15 H 17 OClP(M+H) + 279.71, measured value: 279.7, and the yield is 96%.
[0036] NMR results of Intermediate 1: 1 H NMR (300 MHz, CDCl 3 ) δ 7.4 (m, 10H), 3.52 (t, 2H), 3.27 (t, 2H), 1.79 (m, 2H).
[0037] S3. Dissolve 20 mmol of imidazole in 50 mL of absolute ethanol, add 18 mmol of 1,3 - propane sultone, stir and react at 0 °C for 30 min, then raise the temperature to 50 °C, stir and react for 12 h, filter, wash, and dry to obtain intermediate 3; the product is analyzed by infrared spectrum, and characteristic peaks appear at 3110 cm -1 and 3159 cm -1 , which are the stretching vibrations of the -N-H bond in imidazole, and 1585 cm -1 and 1608 cm -1 are the stretching vibration peaks of C=N in the imidazole ring skeleton.
[0038] S4. Add 20 mmol of intermediate 3, 60 mmol of triethylamine, and 18 mmol of intermediate 2 to 50 mL of acetonitrile, heat under reflux and stir for 4 h, filter, wash, and dry. Add the product to 50 mL of an aqueous solution containing 20 mmol of methanesulfonic acid, stir at room temperature for 12 h, remove water under reduced pressure, wash with ethyl acetate, and dry to obtain the phase - transfer nucleophilic ionic liquid catalyst. The product is analyzed by infrared spectrum, and a characteristic absorption peak of the benzene ring appears at 775 cm -1 .
[0039] Preparation method of the phase - transfer nucleophilic ionic liquid catalyst in Preparation Example 2
[0040] Comprises the following steps:
[0041] S1. Add 20 mmol of diphenylphosphine chloride, 60 mmol of triethylamine, and 22 mmol of 1,5 - pentanediol to 50 mL of dichloromethane, heat under reflux and react for 5 h. Add the product to 50 mL of saturated sodium carbonate solution, wash, separate the liquid, collect the organic phase, dry, filter, remove the solvent under reduced pressure, and separate by column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain intermediate 1;
[0042] S2. Add 20 mmol of intermediate 1 to 50 mL of dichloromethane, dropwise add 20 mL of a dichloromethane solution containing 30 mmol of thionyl chloride, stir and react at 0 °C for 40 min, remove the solvent and excess thionyl chloride under reduced pressure, wash and dry the product to obtain intermediate 2;
[0043] S3. Dissolve 20 mmol of imidazole in 50 mL of absolute ethanol, add 22 mmol of 1,3 - propane sultone, stir and react at 0 °C for 30 min, then raise the temperature to 55 °C, stir and react for 10 h, filter, wash, and dry to obtain intermediate 3;
[0044] S4. Add 20 mmol of intermediate 3, 60 mmol of triethylamine, and 22 mmol of intermediate 2 to 50 mL of acetonitrile, heat under reflux and stir for reaction for 5 h, filter, wash, and dry. Add the product to 50 mL of an aqueous solution containing 20 mmol of sulfuric acid, stir at room temperature for 12 h, remove water under reduced pressure, wash with ethyl acetate, and dry to obtain the phase transfer nucleophilic ionic liquid catalyst.
[0045] Preparation Example 3 Preparation method of phase transfer nucleophilic ionic liquid catalyst
[0046] It includes the following steps:
[0047] S1. Add 20 mmol of diphenylphosphine chloride, 60 mmol of triethylamine, and 21 mmol of 1,6 - hexanediol to 50 mL of dichloromethane, heat under reflux for reaction for 5 h. Add the product to 50 mL of saturated sodium carbonate solution, wash, separate the liquid, collect the organic phase, dry, filter, remove the solvent under reduced pressure, and separate by column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain intermediate 1;
[0048] S2. Add 20 mmol of intermediate 1 to 50 mL of dichloromethane, dropwise add 20 mL of a dichloromethane solution containing 27 mmol of thionyl chloride, stir at 0 °C for reaction for 30 min, remove the solvent and excess thionyl chloride under reduced pressure, wash the product, and dry to obtain intermediate 2;
[0049] S3. Dissolve 20 mmol of imidazole in 50 mL of absolute ethanol, add 20 mmol of 1,3 - propane sultone, stir at 0 °C for reaction for 30 min, then raise the temperature to 55 °C, stir for reaction for 12 h, filter, wash, and dry to obtain intermediate 3;
[0050] S4. Add 20 mmol of intermediate 3, 60 mmol of triethylamine, and 20 mmol of intermediate 2 to 50 mL of acetonitrile, heat under reflux and stir for reaction for 5 h, filter, wash, and dry. Add the product to 50 mL of an aqueous solution containing 20 mmol of sulfuric acid, stir at room temperature for 12 h, remove water under reduced pressure, wash with ethyl acetate, and dry to obtain the phase transfer nucleophilic ionic liquid catalyst.
[0051] Comparative Preparation Example 1
[0052] Compared with Preparation Example 3, the difference is that steps S1 and S2 are not carried out, and there is no reaction with intermediate 2 in step S4.
[0053] Specifically as follows:
[0054] S1. Dissolve 20 mmol of imidazole in 50 mL of absolute ethanol, add 20 mmol of 1,3 - propane sultone, stir at 0 °C for reaction for 30 min, then raise the temperature to 55 °C, stir for reaction for 12 h, filter, wash, and dry to obtain intermediate 3;
[0055] S2. Add 20 mmol of intermediate 3 to 50 mL of an aqueous solution containing 20 mmol of sulfuric acid, stir at room temperature for 12 h, remove water under reduced pressure, wash with ethyl acetate, and dry to obtain a phase transfer ionic liquid catalyst.
[0056] Example 1
[0057] This example provides a method for synthesizing a muscone intermediate, comprising the following steps:
[0058] (1) Mix 10 g of 1,10-decanediol and 45 mL of a 35 wt% hydrobromic acid solution evenly, dropwise add concentrated sulfuric acid, the addition amount of the concentrated sulfuric acid is 30 wt% of the mass of 1,10-decanediol, heat under reflux for 15 h, separate the liquid of the reaction solution, wash, dry, and distill under reduced pressure to collect the product 1,10-dibromodecane; ESI-MS calculated value: C 10 H 21 Br 2 (M + H) + 301.07, measured value: 301.1.
[0059] The NMR results of 1,10-dibromodecane: 1 H NMR (300 MHz, CDCl 3 ) δ 3.42 (m, 4H), 1.82 (m, 4H), 1.27 - 1.35 (m, 12H).
[0060] (2) Add 0.3 mol of sodium carbonate to 200 mL of ethanol, add the phase transfer nucleophilic ionic liquid catalyst prepared in Preparation Example 1, the addition amount of the phase transfer nucleophilic ionic liquid catalyst is 5 wt% of 1,10-dibromodecane, add 0.1 mol of 1,10-dibromodecane and 0.21 mol of ethyl acetoacetate, heat under reflux for 15 h, remove the excessive ethyl acetoacetate and ethanol under reduced pressure, add the product to a 10 wt% NaOH solution, heat to 75 °C, carry out a hydrolysis reaction for 10 h, cool to room temperature, filter, wash the solid, and dry to obtain the muscone intermediate 2,15-hexadecanedione. ESI-MS calculated value: C 16 H 31 O 2 (M + H) + 255.41, measured value: 255.4.
[0061] The NMR results of 2,15-hexadecanedione: 1 H NMR (300 MHz, CDCl 3 ) δ 2.52 (t, 4H), 2.15 (s, 6H), 1.62 (m, 4H), 1.30 - 1.37 (m, 16H).
[0062] Example 2
[0063] This example provides a method for synthesizing a muskone intermediate, comprising the following steps:
[0064] (1) Mix 15 g of 1,10-decanediol and 60 mL of a 45 wt% hydrobromic acid solution evenly, and dropwise add concentrated sulfuric acid. The addition amount of the concentrated sulfuric acid is 40 wt% of the mass of 1,10-decanediol. Heat under reflux for 20 h, separate the reaction solution by liquid separation, wash, dry, and distill under reduced pressure to collect the product 1,10-dibromodecane;
[0065] (2) Add 0.5 mol of potassium carbonate to 200 mL of ethanol, add the phase-transfer nucleophilic ionic liquid catalyst prepared in Preparation Example 2. The addition amount of the phase-transfer nucleophilic ionic liquid catalyst is 10 wt% of 1,10-dibromodecane. Add 0.1 mol of 1,10-dibromodecane and 0.22 mol of ethyl acetoacetate, heat under reflux for 20 h, remove the excessive ethyl acetoacetate and ethanol under reduced pressure. Add the product to a 15 wt% KOH solution, heat to 85 °C, carry out hydrolysis reaction for 15 h, cool to room temperature, filter, wash the solid, and dry to obtain the muskone intermediate 2,15-hexadecanedione.
[0066] Example 3
[0067] This example provides a method for synthesizing a muskone intermediate, comprising the following steps:
[0068] (1) Mix 12 g of 1,10-decanediol and 55 mL of a 40 wt% hydrobromic acid solution evenly, and dropwise add concentrated sulfuric acid. The addition amount of the concentrated sulfuric acid is 35 wt% of the mass of 1,10-decanediol. Heat under reflux for 17 h, separate the reaction solution by liquid separation, wash, dry, and distill under reduced pressure to collect the product 1,10-dibromodecane;
[0069] (2) Add 0.4 mol of sodium carbonate to 200 mL of ethanol, add the phase-transfer nucleophilic ionic liquid catalyst prepared in Preparation Example 3. The addition amount of the phase-transfer nucleophilic ionic liquid catalyst is 7 wt% of 1,10-dibromodecane. Add 0.1 mol of 1,10-dibromodecane and 0.215 mol of ethyl acetoacetate, heat under reflux for 17 h, remove the excessive ethyl acetoacetate and ethanol under reduced pressure. Add the product to a 12 wt% NaOH solution, heat to 80 °C, carry out hydrolysis reaction for 12 h, cool to room temperature, filter, wash the solid, and dry to obtain the muskone intermediate 2,15-hexadecanedione.
[0070] Comparative Example 1
[0071] Compared with Example 3, the difference is that the phase transfer nucleophilic ionic liquid catalyst is prepared by Comparative Preparation Example 1, and triphenylphosphine is added in an amount of 1 wt % of 1,10-dibromodecane.
[0072] Comparative Example 2
[0073] Compared with Example 3, the difference is that the phase transfer nucleophilic ionic liquid catalyst is replaced by tetrabutylammonium bromide, and triphenylphosphine is added in an amount of 1 wt % of 1,10-dibromodecane.
[0074] Test Example 1
[0075] The yields of the reactions in Example 1-3 and Comparative Example 1-2 were compared, and the results are shown in Table 1.
[0076] Table 1
[0077] Group Total yield of muscone intermediate 2,15-hexadecanedione (%) Example 1 86.5 Example 2 85.9 Example 3 87.2 Comparative Example 1 72.1 Comparative Example 2 66.7
[0078] It can be seen from the above table that the total yield of the musk ketone intermediate 2,15-hexadecanedione obtained by the method in Examples 1-3 of the present invention is relatively high.
[0079] Test Example 2
[0080] Ethyl acetate was added to the filtrate after filtration in step (2) of Example 3, the mixture was stirred and mixed, precipitated, filtered, and separated to obtain a phase transfer nucleophilic ionic liquid catalyst, which was then re-added to the reaction. The other conditions were the same as those of Example 3. The product 2,15-hexadecanedione was tested and the total yield was 84.2%.
[0081] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims
1. A phase transfer nucleophilic ionic liquid catalyst, characterized in that: Having the structure shown in Formula I: Wherein, R=C3-C12 alkyl chain, X is HSO4 or CH3SO3.
2. A method for preparing a phase transfer nucleophilic ionic liquid catalyst as claimed in claim 1, characterized in that: The following steps are involved: S1. Diphenylphosphine chloride is reacted with alkyl glycol to obtain intermediate 1, the structure of which is as follows: S2. The intermediate 1 is reacted with thionyl chloride to obtain the intermediate 2, the structure of which is as follows: S3. Reaction of imidazole with 1,3-propane sultone to obtain intermediate 3, the structure of which is as follows: S4. Intermediate 3 is reacted with intermediate 2, and then the product is added into sulfuric acid or methanesulfonic acid and stirred to obtain a phase transfer nucleophilic ionic liquid catalyst.
3. The preparation method according to claim 2, characterized in that: The molar ratio of diphenylphosphine chloride to alkyl glycol in step S1 is 1:1-1.1, and the alkyl glycol is selected from at least one of 1,3-propylene glycol, 1,4-butylene glycol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, and 1,12-dodecanediol.
4. The preparation method according to claim 2, characterized in that: The molar ratio of the intermediate 1 to thionyl chloride in step S2 is 1:1.2-1.
5.
5. The preparation method according to claim 2, characterized in that: The molar ratio of imidazole to 1,3-propane sultone in step S3 is 1:0.9-1.
1.
6. The preparation method according to claim 2, characterized in that: The molar ratio of intermediate 3 to intermediate 2 in step S4 is 1:0.9-1.
1.
7. A method for synthesizing a musk ketone intermediate, characterized in that: The following steps are involved: (1) 1,10-decanediol and hydrobromic acid solution are uniformly mixed, concentrated sulfuric acid is added dropwise, heated under reflux for reaction, the reaction solution is separated, washed, dried, and the product 1,10-dibromodecane is collected by vacuum distillation; (2) adding a base to ethanol, adding the phase transfer nucleophilic ionic liquid catalyst according to claim 1, adding 1,10-dibromodecane and ethyl acetoacetate, heating to reflux reaction, removing excess ethyl acetoacetate and ethanol under reduced pressure, adding a dilute alkali solution, heating to hydrolyze reaction, cooling to room temperature, filtering, washing the solid, and drying to obtain the musk ketone intermediate 2,15-hexadecanedione.
8. The synthesis method according to claim 7, characterized in that The concentration of the hydrobromic acid solution in step (1) is 35-45wt%, the solid-liquid ratio of the 1,10-decanediol to the hydrobromic acid solution is 10-15:45-60g / mL, the amount of concentrated sulfuric acid added is 30-40wt% of the mass of 1,10-decanediol, and the heating reflux reaction time is 15-20h.
9. The synthesis method according to claim 7, characterized in that The base is selected from at least one of potassium carbonate, sodium carbonate, triethylamine, diethylamine, NaOH or KOH.
10. The synthesis method according to claim 7, characterized in that The amount of the phase transfer nucleophilic ionic liquid catalyst added in step (2) is 5-10wt% of 1,10-dibromodecane, the molar ratio of the base, 1,10-dibromodecane and ethyl acetoacetate is 3-5:1:2.1-2.2, the heating reflux reaction time is 15-20h, the dilute alkali solution is a NaOH or KOH solution with a concentration of 10-15wt%, the heating hydrolysis reaction temperature is 75-85°C, and the time is 10-15h.