A process for the preparation of muscone
By reacting 4-methylcyclopentadecanone with sulfur and secondary amines in an aqueous alcohol solution under an inert atmosphere, and by optimizing the catalyst and solvent, the byproduct of muscone was successfully converted into the main product. This solved the problem of high production cost of muscone and achieved efficient preparation and high-value utilization of muscone resources.
Patent Information
- Application Number
- CN202510048860.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-13
- Publication Date
- 2026-01-09
- Estimated Expiration
- 2045-01-13
AI Technical Summary
In existing technologies, the byproduct 4-methylcyclopentadecanone produced during the production of musk ketone is difficult to convert into the high-value 3-methylcyclopentadecanone, resulting in high production costs and resource waste in the production of musk ketone.
Under inert atmosphere, 4-methylcyclopentadecanone was reacted with sulfur and a secondary amine in an aqueous alcohol solution. By optimizing the amount of catalyst added and the type of solvent, the conversion of 4-methylcyclopentadecanone to 3-methylcyclopentadecanone was achieved.
This method improves the yield and purity of muscone, reduces production costs, expands the preparation methods of muscone, realizes the high-value utilization of muscone by-products, and promotes the green industrial production of muscone.
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Figure CN119841719B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the field of essence and fragrance and pharmaceutical engineering, and relates to a method for preparing muscone. BACKGROUND
[0002] The information disclosed in this Background section is only for the purpose of increasing an understanding of the general context of the present application and does not necessarily constitute an acknowledgement or any form of suggestion that this information forms part of the prior art already known to a person of ordinary skill in the art.
[0003] Muscone, i.e. 3-methylcyclopentadecanone, is the main flavor component of musk. At present, the methods for synthesizing muscone include ring closure method, ring expansion method of cyclic compound, and introduction of methyl at β position, etc., wherein the ring closure method is mainly used. In the process of preparing muscone by the ring closure method, a by-product, i.e. 4-methylcyclopentadecanone, is produced. 4-methylcyclopentadecanone and 3-methylcyclopentadecanone are isomers. Although 4-methylcyclopentadecanone has certain physiological activity, its value is much lower than that of 3-methylcyclopentadecanone. If 4-methylcyclopentadecanone can be converted into 3-methylcyclopentadecanone, the value of the by-product can be improved. SUMMARY
[0004] In order to solve the problems in the prior art, the present application aims to provide a method for preparing muscone, which can convert the by-product 4-methylcyclopentadecanone into 3-methylcyclopentadecanone, i.e. convert the muscone by-product into muscone, so as to not only make high-value use of the muscone by-product, but also reduce the cost in the production process of muscone.
[0005] In order to achieve the above-mentioned purpose, the technical scheme of the present application is as follows:
[0006] A method for preparing muscone, wherein 4-methylcyclopentadecanone and sulfur and a secondary amine are placed in a solvent under inert atmosphere, heated to 64-120℃, and reacted for 12-42 hours to obtain the product; wherein the secondary amine is an organic compound containing a secondary amine group.
[0007] The present application accidentally found that under the above-mentioned reaction conditions, 4-methylcyclopentadecanone can be converted into 3-methylcyclopentadecanone under the action of sulfur and a secondary amine. The reaction formula is shown as follows.
[0008]
[0009] In some embodiments, the solvent is an alcohol aqueous solution. Studies have shown that in the reaction system of the present application, using an alcohol aqueous solution as the solvent is beneficial to the reaction. Specifically, in the alcohol aqueous solution, the volume ratio of water to alcohol is 1:8-50, preferably 1:10-30.
[0010] The alcohol used in the alcohol aqueous solution can be ethanol, n-propanol, isopropanol, n-butanol, t-butanol, isobutanol, etc. Specifically, the alcohol used in the alcohol aqueous solution is n-propanol, isopropanol, n-butanol or t-butanol. Experiments show that the reaction effect of the alcohol aqueous solution prepared by using n-propanol, isopropanol, n-butanol or t-butanol and water as solvents is better than that of other alcohols.
[0011] In some embodiments, the sulfur is rhombohedral sulfur or monoclinic sulfur. The catalytic effect of using such sulfur is better.
[0012] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.02-2.0. The role of sulfur in the present application is mainly to catalyze the reaction with secondary amine. The molar amount of the catalyst added is generally 0.1-10% of the reactants. However, the present application research shows that the amount of catalyst added affects the yield of muscone. When the amount of sulfur added is increased, the yield of muscone is significantly improved, i.e. the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.125-2.0, and the yield of muscone is significantly improved. Especially when the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.5-1.0, the yield of muscone is further improved.
[0013] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to secondary amine is 1:0.1-5.0. In the present application, the secondary amine reacts with 4-methylcyclopentadecanone to form a transition intermediate, and at the same time, it performs a synergistic catalytic effect with sulfur. When the amount of secondary amine added is increased, the yield of muscone is significantly improved, i.e. the molar ratio of 4-methylcyclopentadecanone to secondary amine is 1:0.5-2.5, and the yield of muscone is significantly improved.
[0014] The secondary amine in the present application can be piperazine, piperidine, pyrrolidine, morpholine, dipropylamine, dibutylamine, dipentylamine, diethylamine or derivatives thereof, etc. In some embodiments, the secondary amine is dipropylamine or diethylamine. Research shows that the type of secondary amine also affects the yield of muscone in the reaction system of the present application. When the secondary amine is dipropylamine or diethylamine, the yield of muscone can be improved. Especially when the secondary amine is diethylamine, the yield of muscone in the reaction system of the present application is higher.
[0015] In some embodiments, the reaction temperature is 75-90°C.
[0016] In some embodiments, the reaction time is 16-32 hours.
[0017] In order to improve the purity of the yield, purification is needed. In some embodiments, after the reaction, concentration is performed, extraction is performed using methyl tert-butyl ether and water, and the organic layer after extraction is concentrated and then column purification is performed.
[0018] Specifically, the volume ratio of methyl tert-butyl ether to water is 1.4-1.6:1.
[0019] Specifically, the DAC50 compression column is used for column purification.
[0020] The present application has the following advantages:
[0021] 1. The present application surprisingly found that under the action of sulfur and secondary amine, 4-methylcyclopentadecanone can react to form 3-methylcyclopentadecanone (i.e. muscone) under the condition of inert atmosphere, which can convert the by-products generated in the preparation of muscone into main products, and directly use the reaction for preparing muscone, expand the preparation method of muscone, and increase the raw material types of muscone; the reaction is used for treating the by-products of muscone produced by the closed loop method, which can increase the atomic economy of the raw material of the closed loop method.
[0022] 2. Based on the one-step reaction of 4-methylcyclopentadecanone to form muscone, the present application further optimizes the addition amount of the catalyst, and selects the solvent and the type of secondary amine, which significantly provides the yield of muscone prepared by the reaction.
[0023] In summary, the present application uses the by-products in the production process of muscone to prepare muscone in one step, solves the cost problem and waste treatment problem of muscone production, and is more conducive to the large-scale green industrialized production of muscone. BRIEF DESCRIPTION OF DRAWINGS
[0024] The drawings accompanying the specification of the present application serve to provide a further understanding of the present application, and the illustrative embodiments of the present application and their descriptions serve to explain the present application, and do not constitute an improper limitation on the present application.
[0025] Figure 1 is the gas chromatogram of 4-methylcyclopentadecanone of the present application;
[0026] Figure 2 is the gas chromatogram of the middle control after reaction of example 1 of the present application;
[0027] Figure 3 is the gas chromatogram of the middle control after reaction of example 12 of the present application;
[0028] Figure 4 is the gas chromatogram of muscone after purification of example 12 of the present application. DETAILED DESCRIPTION
[0029] In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific examples.
[0030] The sulfur used in the following examples is all rhombic sulfur, and the gas chromatogram of 4-methylcyclopentadecanone is shown in Figure 1 and Table 1.
[0031] Table 1 Gas chromatography data of 4-methylcyclopentadecanone
[0032]
[0033] Example 1
[0034] 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (0.27 g, 1.05 mmol), pyrrolidine (0.6 g, 8.44 mmol), pure water (3.78 g, 210 mmol) and isopropyl alcohol (84 mL) were added into the reactor, replaced by nitrogen, the reaction was heated to 80°C, and kept for 24 hours. The reaction liquid was sampled for control, and the proportion of musk ketone in the gas phase converted from 4-methylcyclopentadecanone was 3.39%, as shown in Table 1 and Table 2. Figure 2
[0035] Table 2 Gas chromatogram of the reaction after control in this example
[0036]
[0037] Example 2
[0038] 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), pyrrolidine (3.0 g, 42.18 mmol), pure water (3.78 g, 210 mmol) and isopropyl alcohol (84 mL) were added into the reactor, replaced by nitrogen, the reaction was heated to 80°C, and kept for 24 hours. The reaction liquid was sampled for control, and the proportion of musk ketone in the gas phase converted from 4-methylcyclopentadecanone was 12.7%.
[0039] Example 3
[0040] 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), diethylamine (3.1 g, 42.38 mmol), pure water (3.78 g, 210 mmol) and isopropyl alcohol (84 mL) were added into the reactor, replaced by nitrogen, the reaction was heated to 80°C, and kept for 24 hours. The reaction liquid was sampled for control, and the proportion of musk ketone in the gas phase converted from 4-methylcyclopentadecanone was 14.1%.
[0041] Example 4
[0042] Into a reactor was placed 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), diethylamine (3.1 g, 42.38 mmol), pure water (3.78 g, 210 mmol), and n-butanol (84 mL), purged with nitrogen, and heated to 80 °C for 24 hours. The reaction was sampled and analyzed, and the ratio of muscone to 4-methylcyclopentadecanone conversion was 13.7% by gas chromatography.
[0043] Example 5
[0044] Into a reactor was placed 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), morpholine (3.65 g, 41.9 mmol), pure water (3.78 g, 210 mmol), and isopropyl alcohol (84 mL), purged with nitrogen, and heated to 80 °C for 24 hours. The reaction was sampled and analyzed, and the ratio of muscone to 4-methylcyclopentadecanone conversion was 11.9% by gas chromatography.
[0045] Example 6
[0046] Into a reactor was placed 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), diethylamine (3.1 g, 42.38 mmol), pure water (3.78 g, 210 mmol), and n-butanol (84 mL), purged with nitrogen, and heated to 80 °C for 24 hours. The reaction was sampled and analyzed, and the ratio of muscone to 4-methylcyclopentadecanone conversion was 13.7% by gas chromatography.
[0047] Example 7
[0048] Into a reactor was placed 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), diethylamine (3.1 g, 42.38 mmol), pure water (3.78 g, 210 mmol), and n-butanol (84 mL), purged with nitrogen, and heated to 80 °C for 24 hours. The reaction was sampled and analyzed, and the ratio of muscone to 4-methylcyclopentadecanone conversion was 13.7% by gas chromatography.
[0049] Example 8
[0050] Into a reactor was placed 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), diethylamine (3.1 g, 42.38 mmol), pure water (3.78 g, 210 mmol), and n-butanol (84 mL), purged with nitrogen, and heated to 80 °C for 24 hours. The reaction was sampled and analyzed, and the ratio of muscone to 4-methylcyclopentadecanone conversion was 13.7% by gas chromatography.
[0051] Example 9
[0052] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (2.7 g, 10.52 mmol), diethylamine (6.2 g, 84.77 mmol), pure water (10 g, 556 mmol), and isopropanol (84 mL) were added to the reactor, purged with nitrogen, heated to 80 °C, and kept at that temperature for 24 hours. Samples of the reaction solution were taken for monitoring. Muscone accounted for 12.6% of the gas phase in the conversion of 4-methylcyclopentadecanone.
[0053] Example 10
[0054] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (5.4 g, 21.05 mmol), diethylamine (6.2 g, 84.77 mmol), purified water (3.78 g, 210 mmol), and isopropanol (84 mL) were added to a reactor. The reactor was purged with nitrogen, heated to 80 °C, and maintained at that temperature for 24 hours. The mixture was concentrated, and methyl tert-butyl ether (60 mL) and water (40 mL) were added. The mixture was extracted, allowed to stand for separation, and the organic phase was concentrated. The organic phase was then purified by a DAC50 compression column to obtain muscone (3.52 g), with a yield of 35.2% and a gas phase purity of 96.4%.
[0055] Example 11
[0056] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (5.4 g, 21.05 mmol), dipropylamine (8.5 g, 84 mmol), purified water (6 g, 333.3 mmol), and isopropanol (84 mL) were added to a reactor. The reactor was purged with nitrogen, heated to 80 °C, and held at that temperature for 30 hours. The mixture was concentrated, and methyl tert-butyl ether (60 mL) and water (40 mL) were added. The mixture was extracted, allowed to stand for separation, and the organic phase was concentrated. The organic phase was then purified by a DAC50 compression column to obtain muscone (3.28 g), with a yield of 32.8% and a gas phase purity of 97.8%.
[0057] Example 12
[0058] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (10.8 g, 42.1 mmol), diethylamine (7.3 g, 99.8 mmol), pure water (3.0 g, 166.7 mmol), and n-butanol (84 mL) were added to the reactor, purged with nitrogen, and the reaction was heated to 90 °C and maintained at that temperature for 18 hours (see [link to control results]). Figure 3and water (40 mL), the organic phase was concentrated, then purified by DAC 50 compression column to obtain muscone (3-methylcyclopentadecanone) (4.74 g), with a yield of 47.4%, a gas chromatography purity of 99.591%, as shown in Table 4, and a structure characterization as shown in Table 3. Figure 4 and Table 4. Muscone (3-methylcyclopentadecanone) structure characterization: 1 H-NMR (400 MHz, CDC13): δ = 0.930 ~ 0.947 (3H, d), 1.216 ~ 1.305 (20H, m), 1.578 ~ 1.687 (2H, m), 2.041 ~ 2.056 (1H, m), 2.160 ~ 2.210 (1H, m), 2.392 ~ 2.447 (3H, m). 13 C-NMR (100 MHz, CDC13): δ = 21.048, 22.972, 24.987, 26.112, 26.212, 26.464, 26.514, 26.555, 26.688, 27.072, 27.522, 28.971, 35.520, 42.007, 50.335, 211.824.
[0059] Raw material 4-methylcyclopentadecanone structure characterization: 1 H-NMR (400 MHz, CDC13): δ = 0.886 ~ 0.902 (3H, d), 1.132 ~ 1.147 (1H, m), 1.302 ~ 1.308 (17H, m), 1.436 ~ 1.496 (1H, m), 1.518 ~ 1.595 (2H, m), 1.612 ~ 1.680 (2H, m), 2.339 ~ 2.520 (4H, m). 13 C-NMR (100 MHz, CDC13): δ = 20.415, 23.664, 24.379, 26.188, 26.385, 26.462, 26.566, 26.708, 27.002, 27.457, 29.962, 31.186, 34.198, 40.048, 41.930, 212.464.
[0060] Table 3 Gas chromatography data of the intermediate control after reaction in this embodiment
[0061]
[0062] Table 4 Gas chromatography data of purified muscone in this embodiment
[0063]
[0064]
[0065] Example 13
[0066] Into a reactor was added 4-methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (10.8 g, 42.1 mmol), diethylamine (7.3 g, 99.8 mmol), pure water (3.0 g, 166.7 mmol) and n-butanol (84 mL), nitrogen was purged, the reaction was heated to 118 °C for 18 hours, concentrated, added methyl tert-butyl ether (60 mL) and water (40 mL), extracted, allowed to separate into layers, the organic phase was concentrated, then purified through a DAC50 compression column to obtain muscone (3.35 g), a yield of 33.5%, gas phase purity 95.4%.
[0067] The preferred embodiments of the present application have been described above with the purpose of not limiting the present application, and for those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims
1. A process for the preparation of muscone, characterized in that 4-methylcyclopentadecanone is placed in a solvent with sulfur and a secondary amine under an inert atmosphere, heated to 64-120 ℃, and reacted for 12-42 hours to obtain the product; wherein the secondary amine is an organic compound containing a secondary amine group; The solvent is an alcohol aqueous solution, and the volume ratio of water to alcohol in the alcohol aqueous solution is 1:8-50; The alcohol used in the alcohol aqueous solution is n-propanol, isopropanol, n-butanol, or t-butanol; The secondary amine is dipropylamine or diethylamine; The molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.5-1.0; The molar ratio of 4-methylcyclopentadecanone to the secondary amine is 1:0.1-5.
0.
2. The method of claim 1, wherein the preparation of muscone is characterized by, The volume ratio of water to alcohol is 1:10-30.
3. The method for preparing muscone as described in claim 1, characterized in that, The sulfur is rhombohedral sulfur or monoclinic sulfur.
4. The method of claim 1, wherein the preparation of muscone is characterized by, The molar ratio of 4-methylcyclopentadecanone to the secondary amine is 1:0.5-2.
5.
5. The method for preparing muscone as described in claim 1, characterized in that, The reaction temperature is 75-90 ℃; Or, the reaction time is 16-32 hours.
6. The method of claim 1, wherein the preparation of muscone is characterized by, After the reaction, concentrate, extract with methyl tert-butyl ether and water, and concentrate the extracted organic layer and then perform column purification.
7. The method for preparing muscone as described in claim 6, characterized in that, The volume ratio of methyl tert-butyl ether to water is 1.4-1.6:1.