Preparation method of levorotatory muscone and muscone product

Abstract

The invention belongs to the field of flavors, fragrances and pharmaceutical engineering, and relates to a preparation method of levorotatory muscone and a muscone product. 4-methyl cyclopentadecanone is used as a raw material, and under the action of sulfur and cyclic secondary amine, levorotatory muscone is prepared through one-step reaction; wherein in a system of the one-step reaction, the atmosphere condition is an inert atmosphere condition, the solvent is an alcohol-water solution, the reaction temperature is 64-120 DEG C, the cyclic secondary amine is a heterocyclic compound, at least one heteroatom of the heterocyclic compound is an N atom, and the N atom is a secondary amine group. According to the preparation method disclosed by the invention, a chiral reagent can be prevented from being used for directly preparing a product mainly containing levo-muscone.

Description

Technical Field

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

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

[0003] Due to the scarcity of natural musk resources, left-handed musk ketone needs to be prepared by synthetic methods. At present, the main strategies for chemically synthesizing left-handed musk ketone are: 1. First prepare the racemic musk ketone, and then obtain it by chiral resolution; however, the separation process of this strategy requires chiral reagents or chiral fillers, which have problems such as high preparation cost and difficulty in recycling, and cause waste of right-handed musk ketone. 2. Use chiral catalysts to control the stereoconfiguration in key steps such as hydrogenation and epoxidation to obtain left-handed musk ketone; however, the chiral catalysts in this strategy usually contain precious metals, which are expensive and difficult to recycle. At the same time, the synthesis of chiral ligands in chiral catalysts itself is cumbersome, which limits the promotion and application of this strategy. Therefore, it is necessary to provide a method for synthesizing left-handed musk ketone that avoids the use of chiral reagents or chiral catalysts. Summary of the invention

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

[0005] The purpose of the present invention is to provide a preparation method of L-musk ketone and a musk ketone product, which can avoid using a chiral reagent or a chiral catalytic agent to prepare L-musk ketone, thereby greatly reducing the production cost of L-musk ketone.

[0006] In order to achieve the above object, the technical solution of the present invention is: In a first aspect, a method for preparing L-musk ketone is provided, wherein 4-methylcyclopentadecanone is used as a raw material and L-musk ketone is prepared by a one-step reaction under the action of sulfur and a cyclic secondary amine; 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.

[0007] The present invention is that 4-methylcyclopentadecanone can be prepared into musk ketone in one step under the action of sulfur and secondary amine. When the secondary amine is a cyclic secondary amine, the steric hindrance thereof is different from that of the chain secondary amine, so the synthesis process has certain stereoselectivity. The prepared musk ketone product is mainly L-musk ketone (the proportion of L-musk ketone is higher), thereby improving the economic benefits of the musk ketone product.

[0008] The reaction formula involved in the synthesis method of the present invention is shown below.

[0009]

[0010] In some embodiments, the cyclic secondary amine is one or more of piperazine, piperidine, tetrahydropyrrole, and morpholine.

[0011] The sulfur described in the present invention includes various allotropes. In some embodiments, the sulfur described is rhombic sulfur and monoclinic sulfur.

[0012] The alcohol aqueous solution of the present invention is a mixed solution of an alcohol organic solvent and water. In some embodiments, in the alcohol aqueous solution, the volume ratio of water to the alcohol organic solvent is 1:18-50, preferably 1:20-40.

[0013] In some embodiments, the alcohol organic solvent used in the alcohol aqueous solution is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, etc.

[0014] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to the secondary amine is 1:0.5 to 4.0. Studies have shown 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 L-musk ketone is higher.

[0015] In some embodiments, the molar ratio of 4-methylcyclopentadecanone to sulfur is 1:0.1 to 1.5. Studies have shown 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 L-musk ketone is higher.

[0016] In some embodiments, the reaction temperature is 80°C to 110°C.

[0017] In some embodiments, the reaction time is 12 to 42 hours, preferably 16 to 32 hours.

[0018] In some embodiments, the material after the reaction 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.

[0019] On the other hand, a musk ketone product is obtained by the above preparation method.

[0020] The musk ketone product of the invention is mainly composed of L-musk ketone and contains a small amount of D-musk ketone. Compared with racemic musk ketone, the product has higher aroma intensity and biological activity and greater economic value.

[0021] The beneficial effects of the present invention are: 1. The present invention uses 4-methylcyclopentadecanone as a raw material to prepare musk ketone under the action of sulfur and secondary amines, further selects the type of secondary amine, and adjusts the spatial configuration of musk ketone in the preparation process through the steric hindrance of the cyclic secondary amine, so as to obtain a product mainly composed of L-musk ketone.

[0022] 2. Compared with racemic musk ketone, the product prepared by the present invention has a higher proportion of L-musk ketone, and its aroma intensity and biological activity are also higher. Therefore, the L-musk ketone prepared by the present invention has a higher economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] 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.

[0024] Figure 1 This is the chiral chromatogram of the commercially available racemic musk ketone; Figure 2 This is the chiral chromatogram of musk ketone prepared in Example 1 of the present invention; Figure 3 This is the chiral chromatogram of musk ketone prepared in Example 2 of the present invention; Figure 4 This is the chiral chromatogram of musk ketone prepared in Example 3 of the present invention; Figure 5 This is the chiral chromatogram of musk ketone prepared in Example 4 of the present invention; Figure 6 This is the chiral chromatogram of musk ketone prepared in Example 5 of the present invention. DETAILED DESCRIPTION

[0025] 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.

[0026] The chiral detection data of the commercially available racemic musk ketone are as follows: Figure 1 And as shown in Table 1.

[0027] Table 1 Chiral detection data of racemic musk ketone

[0028] Among them, the compound with a retention time of about 12.901 is L-musketone, and the compound with a retention time of about 14.288 is D-musketone. Table 1 shows that in the racemic musk ketone, the mass ratio of L-musketone to D-musketone is about 1:1.

[0029] The sulfur used in the following examples is all rhombic sulfur.

[0030] Example 1 4-Methylcyclopentadecanone (10.0 g, 41.94 mmoL), sulfur (2.7 g, 10.52 mmoL), tetrahydropyrrole (3.0 g, 42.18 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 90 °C and kept warm for 16 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase converted to 4-methylcyclopentadecanone was 24.9%. After the reaction, the reaction solution was concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, extracted, and allowed to stand for stratification. The organic phase was concentrated and then purified by DAC50 compression column to obtain musk ketone. The chiral detection results showed that the left-handed ratio was 81.76%. Figure 2 With Table 2.

[0031] Table 2 Chiral detection data of musk ketone

[0032] Example 2 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 the reactor, replaced with nitrogen, and the reaction was heated to 90 ° C. The temperature was kept for 16 hours. The reaction solution was sampled and controlled. The gas phase ratio of musk ketone 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, extracted, and allowed to stand for stratification. The organic phase was concentrated and then purified by DAC50 compression column to obtain musk ketone. The chiral detection results showed that the left-handed ratio was 75.76%, see Figure 3 With Table 3.

[0033] Table 3 Chiral detection data of musk ketone

[0034] Example 3 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 the reactor, replaced with nitrogen, and the reaction was heated to 90 ° C. The temperature was kept for 16 hours. The reaction solution was sampled and controlled. The proportion of musk ketone in the gas phase of 4-methylcyclopentadecanone conversion 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, extracted, and the organic phase was concentrated. Then, it was purified by DAC50 compression column to obtain musk ketone. The chiral detection results showed that the left-handed ratio was 84.53%, see Figure 4 With Table 4.

[0035] Table 4 Chiral detection data of musk ketone

[0036] Example 4 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (10.8 g, 42.1 mmol), tetrahydropyrrole (7.1 g, 99.8 mmol), pure water (3.78 g, 210 mmol) and n-butanol (84 mL) were added to the reactor, replaced with nitrogen, and the reaction was heated to 95 ° C., kept warm for 16 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 by DAC50 compression column to obtain musk ketone (4.07 g) with a yield of 40.7% and a gas phase purity of 99.436%. The chiral detection results showed that the left-handed ratio was 94.53%, see Figure 5 With Table 5.

[0037] Table 5 Chiral detection data of musk ketone

[0038] Example 5 4-Methylcyclopentadecanone (10.0 g, 41.94 mmol), sulfur (10.8 g, 42.1 mmol), tetrahydropyrrole (7.1 g, 99.8 mmol), pure water (3.78 g, 210 mmol) and n-butanol (84 mL) were added to the reactor, replaced with nitrogen, and the reaction was heated to 118 ° C., kept warm for 16 hours, concentrated, methyl tert-butyl ether (60 mL) and water (40 mL) were added, extracted, allowed to stand and stratified, the organic phase was concentrated, and then purified by DAC50 compression column to obtain musk ketone (2.18 g) with a yield of 21.8% and a gas phase purity of 99.515%. The chiral detection results showed that the left-handed ratio was 88.66%, see Figure 6 With Table 6.

[0039] Table 6 Chiral detection data of musk ketone

[0040] 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 L-musk ketone, characterized in that: 4-Methylcyclopentadecanone is used as a raw material to prepare L-musk ketone through a one-step reaction under the action of sulfur and a cyclic secondary amine; 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.

2. The preparation method according to claim 1, characterized in that: The cyclic secondary amine is one or more of piperazine, piperidine, tetrahydropyrrole and morpholine.

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

4. 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.

5. 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.

6. 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.

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

1.

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

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

10. A musk ketone product, characterized in that: Obtained by the preparation method according to any one of claims 1 to 9.

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