A preparation method of (-)-muscone and a muscone product

Abstract

The present invention belongs to the fields of essence and pharmaceutical engineering, and relates to a preparation method of (-)-muscone and a muscone product. Using 4-methylcyclopentadecanone as a raw material, under the action of sulfur and cyclic secondary amine, (-)-muscone is prepared in one step; wherein, in the system of the one-step reaction, the atmosphere condition is an inert atmosphere condition, the solvent is an aqueous alcohol solution, the reaction temperature is 64 °C to 120 °C, the cyclic secondary amine is a heterocyclic compound, at least one heteroatom of the heterocyclic compound is an N atom, and this N atom is a secondary amine group. The preparation method of the present invention can avoid using chiral reagents to directly prepare a product mainly composed of (-)-muscone.

Description

Technical Field

[0001] The present invention belongs to the fields of essence and pharmaceutical engineering, and relates to a preparation method of (R)-3-methylcyclopentadecanone and a muskone product. Background Art

[0002] (R)-3-methylcyclopentadecanone, namely levomuskone, is the main component of natural musk. Compared with dextramuskone, levomuskone has an extremely strong aroma intensity of natural musk, as well as significant anti-inflammatory and neuroprotective biological activities. Therefore, levomuskone has higher research value and a wider application market than dextramuskone.

[0003] Due to the scarcity of natural musk resources, levomuskone needs to be prepared by a synthetic method. Currently, the main strategies for chemically synthesizing levomuskone are as follows: 1. First, prepare racemic muskone, and then obtain it through chiral resolution. However, the separation process of this strategy requires chiral reagents or chiral packing materials, which have problems such as high preparation costs and difficult recovery, and cause waste of dextramuskone. 2. Control the stereoconfiguration in key steps such as hydrogenation and epoxidation through chiral catalysts to obtain levomuskone. However, the chiral catalysts in this strategy usually contain precious metals, which are expensive and difficult to recover. At the same time, the synthesis of chiral ligands in chiral catalysts is itself a cumbersome process, thus limiting the popularization and application of this strategy. Therefore, a synthesis method of levomuskone that avoids the use of chiral reagents or chiral catalysts is needed. Summary of the Invention

[0004] During the production process of muskone, a large amount of by-product 4-methylcyclopentadecanone will be separated and purified. 4-methylcyclopentadecanone is an isomer of muskone. In the preliminary research of the present invention, it was found that 4-methylcyclopentadecanone can be used as a raw material for preparing muskone, and muskone can be prepared in one step, which can reduce the hazardous waste treatment cost of by-products and improve the utilization rate of by-products. However, in subsequent research, it was found that by adjusting the type of amine, the prepared muskone can be mainly levomuskone. Based on this research result, the present invention is proposed.

[0005] The purpose of the present invention is to provide a preparation method of levomuskone and a muskone product, which can avoid using chiral reagents or chiral catalysts to prepare levomuskone, and greatly reduce the production cost of levomuskone.

[0006] In order to achieve the above purpose, the technical solution of the present invention is as follows:

[0007] First aspect, a method for preparing (-)-muscone, using 4-methylcyclopentadecanone as a raw material, reacting in one step to produce (-)-muscone under the action of sulfur and a cyclic secondary amine; wherein, in the system of the one-step reaction, the atmosphere condition is an inert atmosphere condition, the solvent is an aqueous alcohol solution, the reaction temperature is 64°C to 120°C, the cyclic secondary amine is a heterocyclic compound, at least one heteroatom of the heterocyclic compound is an N atom, and this N atom is a secondary amine group.

[0008] The present invention studies and discovers that under the action of sulfur and secondary amine, 4-methylcyclopentadecanone can be made into muscone in one step. When the secondary amine is selected as a cyclic secondary amine, due to its different steric hindrance from that of a linear secondary amine, there is a certain stereoselectivity in the synthesis process, and the prepared muscone product is mainly (-)-muscone (the proportion of (-)-muscone is higher), improving the economic benefits of the muscone product.

[0009] The reaction formula involved in the synthesis method of the present invention is shown as follows.

[0010]

[0011] In some embodiments, the cyclic secondary amine is one or more of piperazine, piperidine, pyrrolidine, morpholine.

[0012] The sulfur described in the present invention includes various allotropes. In some embodiments, the sulfur is rhombic sulfur and monoclinic sulfur.

[0013] The aqueous alcohol solution described in the present invention is a mixed solution of an alcohol organic solvent and water. In some embodiments, in the aqueous alcohol solution, the volume ratio of water to the alcohol organic solvent is 1:18 to 50, preferably 1:20 to 40.

[0014] In some embodiments, the alcohol organic solvent used in the aqueous alcohol solution is one or several of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, etc.

[0015] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to the secondary amine is 1:0.5 to 4.0. Research shows that when the molar ratio of 4-methylcyclopentadecanone to the secondary amine is 1:1.0 to 3.0, the product yield is higher and the proportion of (-)-muscone is higher.

[0016] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.1 to 1.5. Research shows that when the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.9 to 1.1, the product yield is higher and the proportion of (-)-muscone is higher.

[0017] In some embodiments, the reaction temperature is 80°C to 110°C.

[0018] In some embodiments, the reaction time is 12 to 42 hours, preferably 16 to 32 hours.

[0019] In some embodiments, the reaction product is concentrated, methyl tert-butyl ether and water are added for extraction, and the organic phase after extraction is concentrated and purified by a compression column. Specifically, the compression column is a DAC50 compression column.

[0020] On the other hand, a muscone product is obtained by the above preparation method.

[0021] The muscone product of the present invention is mainly composed of levo-muscone, contains a small amount of dextro-muscone, and has higher aroma intensity and biological activity and greater economic value compared with racemic muscone.

[0022] The beneficial effects of the present invention are as follows:

[0023] 1. On the basis of preparing muscone from 4-methylcyclopentadecanone as a raw material under the action of sulfur and secondary amine, the present invention further selects the type of secondary amine, and adjusts the spatial configuration of muscone during the preparation process through the steric hindrance of cyclic secondary amine, so as to obtain a product mainly composed of levo-muscone.

[0024] 2. Compared with racemic muscone, the proportion of levo-muscone in the product prepared by the present invention is higher, and its aroma intensity and biological activity are also higher. Therefore, the levo-muscone prepared by the present invention has higher economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The specification drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments and descriptions of the present invention are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0026] Figure 1 is the chiral chromatogram of commercially available racemic muscone;

[0027] Figure 2 is the chiral chromatogram of the muscone prepared in Example 1 of the present invention;

[0028] Figure 3 is the chiral chromatogram of the muscone prepared in Example 2 of the present invention;

[0029] Figure 4 is the chiral chromatogram of the muscone prepared in Example 3 of the present invention;

[0030] Figure 5 is the chiral chromatogram of the muscone prepared in Example 4 of the present invention;

[0031] Figure 6 is the chiral chromatogram of the muscone prepared in Example 5 of the present invention. Detailed implementation mode

[0032] 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.

[0033] The chiral detection data of commercially available racemic muscone are as Figure 1 shown in Table 1.

[0034] Table 1 Chiral detection data of racemic muscone

[0035]

[0036] Among them, the compound with a retention time of about 12.901 is (-)-muscone, and the compound with a retention time of about 14.288 is (+)-muscone. Table 1 shows that in racemic muscone, the mass ratio of (-)-muscone to (+)-muscone is about 1:1.

[0037] The sulfur used in the following examples is all rhombic sulfur.

[0038] Example 1

[0039] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (2.7 g, 10.52 mmol), pyrrolidine (3.0 g, 42.18 mmol), pure water (3.78 g, 210 mmol) and n-butanol (84 mL) were added to the reactor, purged with nitrogen, the reaction was heated to 90 °C and kept warm for 16 hours. The reaction solution was sampled for on-line control. The gas-phase proportion of muscone in the conversion of 4-methylcyclopentadecanone was 24.9%. After the reaction was completed, the reaction solution was concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, extracted, allowed to stand for phase separation, the organic phase was concentrated, and then purified through a DAC50 compression column to obtain muscone. The chiral detection result showed that the proportion of the left-handed form was 81.76%, as shown in Figure 2 Table 2.

[0040] Table 2 Chiral detection data of muscone

[0041]

[0042] Example 2

[0043] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (2.7 g, 10.52 mmol), morpholine (3.65 g, 41.9 mmol), pure water (3.78 g, 210 mmol) and n-butanol (84 mL) were added to a reactor. After purging with nitrogen, the reaction was heated to 90 °C and held for 16 hours. A sample of the reaction solution was taken for in-process control, and the gas-phase ratio of muscone to 4-methylcyclopentadecanone was 21.8%. After the reaction was completed, the reaction solution was concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, and extraction was carried out. After standing and separating layers, the organic phase was concentrated and then purified through a DAC50 compression column to obtain muscone. The chiral detection results showed that the proportion of the levorotatory form was 75.76%, as shown in Figure 3 Table 3.

[0044] Table 3 Chiral Detection Data of Muscone

[0045]

[0046] Example 3

[0047] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (1.35 g, 5.26 mmol), piperidine (3.6 g, 42.28 mmol), pure water (3.78 g, 210 mmol) and n-butanol (84 mL) were added to a reactor. After purging with nitrogen, the reaction was heated to 90 °C and held for 16 hours. A sample of the reaction solution was taken for in-process control, and the gas-phase ratio of muscone in the conversion of 4-methylcyclopentadecanone was 22.1%. After the reaction was completed, the reaction solution was concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, and extraction was carried out. After standing and separating layers, the organic phase was concentrated and then purified through a DAC50 compression column to obtain muscone. The chiral detection results showed that the proportion of the levorotatory form was 84.53%, as shown in Figure 4 Table 4.

[0048] Table 4 Chiral Detection Data of Muscone

[0049]

[0050] Example 4

[0051] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (10.8 g, 42.1 mmol), pyrrolidine (7.1 g, 99.8 mmol), pure water (3.78 g, 210 mmol) and n-butanol (84 mL) were added to a reactor, purged with nitrogen, the reaction was heated to 95 °C and kept at this temperature for 16 hours. After concentration, methyl tert-butyl ether (60 mL) and water (40 mL) were added for extraction. After standing for phase separation, the organic phase was concentrated and then purified through a DAC50 compression column to obtain muscone (4.07 g), with a yield of 40.7%, a gas-phase purity of 99.436%, and the chiral detection result showed that the proportion of the levorotatory form was 94.53%, see Figure 5 Table 5.

[0052] Table 5 Chiral Detection Data of Muscone

[0053]

[0054] Example 5

[0055] 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (10.8 g, 42.1 mmol), pyrrolidine (7.1 g, 99.8 mmol), pure water (3.78 g, 210 mmol) and n-butanol (84 mL) were added to a reactor, purged with nitrogen, the reaction was heated to 118 °C and kept at this temperature for 16 hours. After concentration, methyl tert-butyl ether (60 mL) and water (40 mL) were added for extraction. After standing for phase separation, the organic phase was concentrated and then purified through a DAC50 compression column to obtain muscone (2.18 g), with a yield of 21.8%, a gas-phase purity of 99.515%, and the chiral detection result showed that the proportion of the levorotatory form was 88.66%, see Figure 6 Table 6.

[0056] Table 6 Chiral Detection Data of Muscone

[0057]

[0058] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. 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 L-musk ketone, characterized in that: Using 4-methylcyclopentadecanone as a raw material, under the action of sulfur and a cyclic secondary amine, a one-step reaction is performed to prepare L-musk ketone; wherein, in the one-step reaction system, the atmosphere condition is an inert atmosphere condition, the solvent is an alcohol aqueous solution, the reaction temperature is 64° C. to 120° C., the cyclic secondary amine is a heterocyclic compound, at least one heteroatom of the heterocyclic compound is a N atom, and the N atom is a secondary amine group; The cyclic secondary amine is one or more of piperidine, tetrahydropyrrole and morpholine.

2. The preparation method according to claim 1, characterized in that: The sulfur described is rhombic sulfur and monoclinic sulfur.

3. The preparation method according to claim 1, characterized in that: In the alcohol aqueous solution, the volume ratio of water to the alcohol organic solvent is 1:20-40.

4. The preparation method according to claim 1, characterized in that: The alcohol organic solvent used in the alcohol aqueous solution is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol.

5. The preparation method according to claim 1, characterized in that: The molar ratio of 4-methylcyclopentadecanone to the secondary amine is 1:1.0-3.

0.

6. The preparation method according to claim 1, characterized in that: The molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.9-1.

1.

7. The preparation method according to claim 1, characterized in that: The reaction temperature is 80°C to 110°C.

8. The preparation method according to claim 1, characterized in that: The reaction time is 16 to 32 hours.

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