Method for preparing muscone

Abstract

The invention belongs to the field of flavors, fragrances and pharmaceutical engineering, and relates to a method for preparing muscone. The preparation method comprises the following steps: putting 4-methylcyclopentadecanone, sulfur and secondary amine into a solvent under an inert atmosphere condition, heating to 64-120 DEG C, and reacting for 12-42 hours, thereby obtaining the 4-methylcyclopentadecanone, wherein the secondary amine is an organic matter containing a secondary amine group. According to the method, the byproduct 4-methylcyclopentadecanone can be converted into the 3-methylcyclopentadecanone, namely, the muscone byproduct is converted into the muscone, so that the muscone byproduct can be utilized at a high value, and the cost in the production process of the muscone can be reduced.

Description

Technical Field

[0001] The invention belongs to the field of flavors and fragrances and pharmaceutical engineering, and relates to a method for preparing musk ketone. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Musk ketone, namely 3-methylcyclopentadecanone, is the main aroma component of musk. At present, the methods for synthesizing musk ketone include closed-loop method, ring-expansion method of cyclic compounds, introduction of methyl group at β position, etc., among which closed-loop method is the main one. In the process of preparing musk ketone by closed-loop method, 4-methylcyclopentadecanone will be produced as a by-product. 4-methylcyclopentadecanone and 3-methylcyclopentadecanone are isomers. Although 4-methylcyclopentadecanone has certain physiological activity, its value is currently much lower than that of 3-methylcyclopentadecanone. If 4-methylcyclopentadecanone can be converted into 3-methylcyclopentadecanone, it will help to increase the value of the by-product. Summary of the invention

[0004] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a method for preparing musk ketone, which can convert the by-product 4-methylcyclopentadecanone into 3-methylcyclopentadecanone, that is, convert the musk ketone by-product into musk ketone, which can not only make high-value utilization of the musk ketone by-product, but also reduce the cost in the musk ketone production process.

[0005] In order to achieve the above object, the technical solution of the present invention is:

[0006] A method for preparing musk ketone comprises placing 4-methylcyclopentadecanone, sulfur and a secondary amine in a solvent under an inert atmosphere, heating to 64 to 120° C., and reacting for 12 to 42 hours to obtain the musk ketone; wherein the secondary amine is an organic substance containing a secondary amine group.

[0007] The present invention unexpectedly discovered through experiments that under the above reaction conditions, 4-methylcyclopentadecanone can be converted into 3-methylcyclopentadecanone under the action of sulfur and secondary amine. The reaction formula is shown below.

[0008]

[0009] In some embodiments, the solvent is an alcohol aqueous solution. Studies have shown that in the reaction system of the present invention, using an alcohol aqueous solution as a solvent is conducive to the reaction. Specifically, in the alcohol aqueous solution, the volume ratio of water to alcohol is 1:8 to 50, preferably 1:10 to 30.

[0010] The alcohol used in the alcohol aqueous solution can be ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, etc. Specifically, the alcohol used in the alcohol aqueous solution is n-propanol, isopropanol, n-butanol or tert-butanol. Experiments show that compared with other alcohols, the alcohol aqueous solution prepared by using n-propanol, isopropanol, n-butanol or tert-butanol and water as a solvent has a better reaction effect.

[0011] In some embodiments, the sulfur is rhombic sulfur or monoclinic sulfur, which has a better catalytic effect.

[0012] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.02 to 2.0. The role of sulfur in the present invention is mainly to catalyze the reaction with secondary amines. The added molar amount of the catalyst is generally 0.1 to 10% of the reactants. However, the present invention has found that the amount of catalyst added affects the yield of musk ketone. When the amount of sulfur added is increased, the yield of musk ketone is significantly improved, that is, the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.125 to 2.0, and the yield of musk ketone is significantly improved, especially when the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.5 to 1.0, the yield of musk ketone is further improved.

[0013] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to secondary amine is 1:0.1 to 5.0. In the present invention, the secondary amine reacts with 4-methylcyclopentadecanone to generate a transition intermediate state, and simultaneously performs a synergistic catalytic effect with sulfur. When the amount of secondary amine added is increased, the yield of musk ketone is significantly improved, that is, the molar ratio of 4-methylcyclopentadecanone to secondary amine is 1:0.5 to 2.5, and the yield of musk ketone is significantly improved.

[0014] The secondary amine of the present invention can be piperazine, piperidine, pyrrolidine, morpholine, dipropylamine, dibutylamine, dipentylamine, diethylamine or derivatives thereof. In some embodiments, the secondary amine is dipropylamine or diethylamine. Studies have shown that the type of secondary amine also affects the yield of musk ketone in the reaction system of the present invention. When the secondary amine is dipropylamine or diethylamine, the yield of musk ketone can be increased, especially when the secondary amine is diethylamine, the yield of musk ketone in the reaction system of the present invention is higher.

[0015] In some embodiments, the reaction temperature is 75-90°C.

[0016] In some embodiments, the reaction time is 16 to 32 hours.

[0017] In order to improve the purity of the yield, purification is required. In some embodiments, the reaction is concentrated, extracted with methyl tert-butyl ether and water, and the extracted organic layer is concentrated and then purified by column.

[0018] Specifically, the volume ratio of methyl tert-butyl ether to water is 1.4-1.6:1.

[0019] Specifically, a DAC50 compressed column was used for column purification.

[0020] The beneficial effects of the present invention are:

[0021] 1. The present invention unexpectedly discovered through research that, under inert atmosphere conditions, under the action of sulfur and secondary amines, 4-methylcyclopentadecanone can react to generate 3-methylcyclopentadecanone (i.e., musk ketone). This reaction can convert the by-products produced in the preparation process of musk ketone into the main product. This reaction can be directly used to prepare musk ketone, thereby expanding the preparation method of musk ketone and increasing the types of raw materials for preparing musk ketone. This reaction is used to treat the by-products of musk ketone produced by the closed-loop method, which can increase the atomic economy of the raw materials of the closed-loop method.

[0022] 2. Based on the one-step reaction of 4-methylcyclopentadecanone to produce musk ketone, the present invention further optimizes the amount of catalyst added and the selection of solvents and secondary amine types, thereby significantly improving the yield of musk ketone prepared by the reaction.

[0023] In summary, the present invention utilizes the by-products in the musk ketone production process to prepare musk ketone in one step, which solves the cost problem and waste disposal problem of musk ketone production and is more conducive to the large-scale green industrial production of musk ketone. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0025] Figure 1 is a gas chromatogram of 4-methylcyclopentadecanone of the present invention;

[0026] Figure 2 This is a gas chromatogram of the central control after the reaction of Example 1 of the present invention;

[0027] Figure 3 This is a gas chromatogram of the central control after the reaction of Example 12 of the present invention;

[0028] Figure 4 This is a gas chromatogram of musk ketone after purification in Example 12 of the present invention. DETAILED DESCRIPTION

[0029] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0030] The sulfur used in the following examples is all rhombic sulfur, and the gas chromatographic analysis of the 4-methylcyclopentadecanone used is as follows: Figure 1 And as shown in 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 isopropanol (84 mL) were added into the reactor, replaced with nitrogen, and the reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase converted to 4-methylcyclopentadecanone was 3.39%. Figure 2 And as shown in Table 2.

[0035] Table 2 Gas chromatogram of the central control after the reaction in this embodiment

[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 isopropanol (84 mL) were added into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase of the conversion of 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 isopropanol (84 mL) were added into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase of the conversion of 4-methylcyclopentadecanone was 14.1%.

[0041] Example 4

[0042] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), dipropylamine (4.24 g, 41.9 mmol), pure water (3.78 g, 210 mmol) and isopropanol (84 mL) were added into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction liquid was sampled and controlled. The proportion of musk ketone in the gas phase of the conversion of 4-methylcyclopentadecanone was 13.4%.

[0043] Example 5

[0044] 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 isopropanol (84 mL) were added into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The gas phase ratio of musk ketone to 4-methylcyclopentadecanone was 11.9%.

[0045] Example 6

[0046] 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 tert-butanol (84 mL) were added into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase of the conversion of 4-methylcyclopentadecanone was 12.8%.

[0047] Example 7

[0048] 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) were added into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase of the conversion of 4-methylcyclopentadecanone was 13.7%.

[0049] Example 8

[0050] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (2.7 g, 10.52 mmol), diethylamine (6.2 g, 84.77 mmol), pure water (3.78 g, 210 mmol) and isopropanol (84 mL) were added into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase of the conversion of 4-methylcyclopentadecanone was 23.2%.

[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 into the reactor and replaced with nitrogen. The reaction was heated to 80°C and kept warm for 24 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase of the conversion of 4-methylcyclopentadecanone was 12.6%.

[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), pure water (3.78 g, 210 mmol) and isopropanol (84 mL) were added into the reactor, replaced with nitrogen, and the reaction was heated to 80°C, kept warm for 24 hours, concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, extracted, allowed to stand for stratification, the organic phase was concentrated, and then purified through a DAC50 compression column to obtain musk ketone (3.52 g) with a yield of 35.2% and a gas phase purity of 96.4%.

[0055] Embodiment 11

[0056] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (5.4 g, 21.05 mmol), dipropylamine (8.5 g, 84 mmol), pure water (6 g, 333.3 mmol) and isopropanol (84 mL) were added to the reactor, replaced with nitrogen, and the reaction was heated to 80°C, kept warm for 30 hours, concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, extracted, allowed to stand for stratification, the organic phase was concentrated, and then purified through a DAC50 compression column to obtain musk ketone (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, replaced with nitrogen, and the reaction was heated to 90 ° C and kept warm for 18 hours (see the results of the central control). Figure 3and Table 3), concentrated, added methyl tert-butyl ether (60 mL) and water (40 mL), extracted, allowed to stand for stratification, concentrated the organic phase, and then purified by DAC50 compression column to obtain musk ketone (4.74 g), with a yield of 47.4% and a gas phase purity of 99.591%, as Figure 4 As shown in Table 4. Musk ketone (3-methylcyclopentadecanone) structural characterization: 1 H-NMR (400MHz, CDCl3): 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 (100MHz, CDCl3): 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] Structural characterization of raw material 4-methylcyclopentadecanone: 1 H-NMR (400MHz, CDCl3): 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 (100MHz, CDCl3): 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 central control after the reaction of this embodiment

[0061]

[0062] Table 4 Gas chromatography data of the purified musk ketone in this example

[0063]

[0064]

[0065] Example 13

[0066] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (10.8 g, 42.1 mmol), diethylamine (7.3 g, 99.8 mol), pure water (3.0 g, 166.7 mmol) and n-butanol (84 mL) were added into the reactor, replaced with nitrogen, and the reaction was heated to 118°C, kept warm for 18 hours, concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, extracted, allowed to stand for stratification, the organic phase was concentrated, and then purified through a DAC50 compression column to obtain musk ketone (3.35 g) with a yield of 33.5% and a gas phase purity of 95.4%.

[0067] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing musk ketone, characterized in that Under inert atmosphere, 4-methylcyclopentadecanone, sulfur and secondary amine are placed in a solvent, heated to 64-120° C., and reacted for 12-42 hours to obtain the product; wherein the secondary amine is an organic compound containing a secondary amine group.

2. The method for preparing musk ketone according to claim 1, characterized in that: The solvent is an alcohol aqueous solution, in which the volume ratio of water to alcohol is 1:8-50, preferably 1:10-30.

3. The method for preparing musk ketone as claimed in claim 2, characterized in that: The alcohol used in the alcohol aqueous solution is n-propanol, isopropanol, n-butanol or tert-butanol.

4. The method for preparing musk ketone according to claim 1, characterized in that: The sulfur is rhombic sulfur or monoclinic sulfur.

5. The method for preparing musk ketone according to claim 1, characterized in that: The molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.02 to 2.0, preferably 1:0.125 to 2.0, and more preferably 1:0.5 to 1.

0.

6. The method for preparing musk ketone according to claim 1, characterized in that: The molar ratio of 4-methylcyclopentadecanone to the secondary amine is 1:0.1 to 5.0, preferably 1:0.5 to 2.

5.

7. The method for preparing musk ketone according to claim 1, characterized in that: The secondary amine is dipropylamine or diethylamine.

8. The method for preparing musk ketone according to claim 1, characterized in that: The reaction temperature is 75-90°C; Alternatively, the reaction time is 16 to 32 hours.

9. The method for preparing musk ketone according to claim 1, characterized in that: After the reaction, the product was concentrated and extracted with methyl tert-butyl ether and water. The extracted organic layer was concentrated and then purified by column.

10. The method for preparing musk ketone according to claim 1, characterized in that: The volume ratio of methyl tert-butyl ether to water is 1.4-1.6:1.

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