A one-pot two-step process for the preparation of ambrox

Abstract

The application discloses a method for synthesizing ambrox, relates to the field of daily chemicals and fragrances, and provides a one-pot two-step method for preparing ambrox by using sclareolide as raw material. The same solvent is used in the whole reaction process, a catalytic stabilizer is first added into the solvent, then a reducing agent is added, and finally the sclareolide is added, the catalytic stabilizer is used as a reagent for the second step reaction after the first step reaction, and then an acid methyl ester reagent is added to carry out the second step reaction, so that the whole reaction process is continuous and carried out in the same reactor, the operation steps are simplified, the reaction efficiency is improved, and the production cost is reduced.

Description

Technical Field

[0001] This invention relates to the fields of daily chemicals and fragrances, and in particular to a green, efficient, and low-cost method for preparing ambroxan. Background Technology

[0002] Natural ambergris is a secretion from the digestive tract of sperm whales, a grayish-brown waxy substance. Due to its elegant animalic aroma, smooth texture, and strong fixative properties, it has been highly valued since ancient times for its tonic, aphrodisiac, anti-inflammatory, and analgesic effects, almost equivalent to gold. It was used as a high-grade fragrance in the high-end perfume industry for a long time. Because sperm whales are endangered, natural ambergris is now very difficult to obtain, and synthetic products are often used as substitutes. Among the many synthetic ambergris fragrances, ambroxol is recognized as the best alternative to natural ambergris.

[0003] Ambroxol possesses a strong, distinctive ambergris aroma and is used in high-end perfumes and cosmetic fragrances. Because it is non-irritating to humans and does not cause allergic reactions in animals, it is well-suited for adding fragrance to skin, hair, and fabrics. Ambroxol is also widely used in the cigarette industry as a flavoring agent, harmonizing with the characteristic aroma of tobacco and masking off-flavors. Even in small amounts, it can improve the aroma quality of tobacco, making it particularly suitable for flavoring blended cigarettes and enhancing the flavor of oriental tobaccos. Ambroxol is also permitted for use as a food additive in the food industry and is listed in my country's food additive usage standards.

[0004] Currently, production technologies generally employ lithium aluminum hydride, sodium hydride, and borohydrides as reducing agents to reduce perillaldehyde to ambroxol. Subsequently, under the action of organic acids, sulfonyl chlorides, or Lewis acids, a water molecule is removed, leading to ambroxol ether. The main problems with this method are: the reducing agents such as lithium aluminum hydride and sodium hydride pose significant safety risks during the reduction process, requiring large amounts of borohydride to compensate for their consumption in the solvent; and the dehydration and cyclization process involves detrimental reaction conditions and environmental pollution.

[0005] In order to synthesize higher quality ambroxol and reduce production costs and environmental pollution, we have invented an ambroxol preparation method that is more cost-effective, environmentally friendly, and has convenient post-processing, making it more suitable for industrial production, based on the above-mentioned shortcomings. Summary of the Invention

[0006] One objective of this invention is to provide a method for preparing ambroxol that simplifies reaction steps, shortens reaction time, and reduces production costs.

[0007] Another objective of this invention is to address the shortcomings and deficiencies of existing technologies, and to solve the technical problems of high cost of auxiliary raw materials, poor safety, serious environmental pollution, and low product yield in current technologies, by providing a method for preparing ambroxol.

[0008] The present invention addresses the technical problem of overcoming the shortcomings of the above-mentioned methods for synthesizing ambroxol, and provides a method for synthesizing ambroxol that is simple, has few process steps, short reaction time, high product yield and purity, low product cost, and no environmental pollution.

[0009] The technical solution adopted to solve the above technical problems is:

[0010] The "one-pot, two-step method" for preparing ambroxol involves mixing perillaldehyde, a catalytic stabilizer, and a reducing agent in a specific mass ratio. First, the catalytic stabilizer is added to an organic solvent, followed by the reducing agent. Finally, perillaldehyde is added, and the mixture is heated and stirred under reflux for approximately 3 hours until the first reaction stage ends. Immediately afterward, reagents for the second reaction stage are added, including an alcohol metal salt and an ester reagent. The mixture is heated under reflux for approximately 5 hours until the second reaction stage ends. After removing the reaction solvent, water and non-water-soluble solvents are added for extraction three times. The aqueous phases are then combined for further extraction. Finally, the organic phases are combined, and the organic solvent is removed to obtain the crude ambroxol product. The crude product is recrystallized from 95% ethanol to obtain a high-quality ambroxol product.

[0011] Preferably, the water-soluble organic solvent is one or more of the following solvents: methanol, ethanol, n-propanol, isopropanol, tert-butanol, tetrahydrofuran, acetonitrile, 1,4-dioxane; and the non-water-soluble organic solvent is one or more of the following solvents: toluene, xylene, n-hexane, cyclohexane, petroleum ether.

[0012] Preferably, the catalytic stabilizer is an alkali metal salt of alcohol, including at least one of sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0013] Preferably, the reducing agent borohydride of the present invention includes at least one of potassium borohydride or sodium borohydride.

[0014] Preferably, the ester reagent of the present invention includes at least one of dimethyl carbonate, diethyl carbonate, dimethyl oxalate, ethyl acetate, ethyl formate, and methyl acetate.

[0015] Preferably, in the reaction process, the mass ratio of perilla lactone is 1, the mass ratio of water-soluble organic solvent is 2-10, the mass ratio of alcohol alkali metal salt is 0.01-2, the mass ratio of reducing agent borohydride is 0.25-0.5, the mass ratio of ester reagent is 1-10, and the mass ratio of non-water-soluble organic solvent is 3-15.

[0016] Preferably, in this invention, the reaction reagent is first dissolved in a water-soluble organic solvent at a temperature of 40℃ to 110℃, and then styracil lactone is added to form a reaction system. The reaction system is then heated, stirred, and refluxed at a temperature close to the boiling point.

[0017] Preferably, after the reaction is completed, the water-soluble solvent is recovered, and water, acid, alkali and other non-water-soluble solvents are added for extraction to remove irrelevant components. The organic phase is removed to obtain a crude product, which is then recrystallized with solvents such as ethanol, petroleum ether, and cyclohexane to obtain a high-quality product.

[0018] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0019] This invention employs a "one-pot, two-step method" that uses inexpensive and readily available reagents. The entire reaction process is characterized by mild reaction conditions, simple operation, convenient post-processing, and low environmental pollution, making it suitable for industrial production. Attached Figure Description

[0020] Figure 1 The chemical reaction formula for preparing ambroxol using perillaldehyde as a raw material in a preferred embodiment of the present invention is shown below. Detailed Implementation

[0021] To make the purpose, technical solution, and advantages of the invention clearer, the following embodiments are provided to illustrate the content of the invention. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of the invention.

[0022] It should be noted that, unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used in the following examples are commercially available unless otherwise specified.

[0023] like Figure 1 As shown, the "one-pot two-step method" for preparing ambroxol is described in this invention.

[0024] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings, but the scope of protection of the present invention is not limited to the following description.

[0025] Example 1

[0026] 63 mg sodium methoxide and 6 mL methanol were dissolved in a 100 mL two-necked flask and stirred until dissolved. 425 mg sodium borohydride was then added and stirred for 5 min. 1.25 g (5 mmol) of succinyl lactone was added and dissolved. The mixture was heated to 70 °C and stirred under reflux for about 3 h. The reaction endpoint was monitored by TLC. After the reaction was complete, 4 mL of methanol, 1.25 g of sodium methoxide, and 3 mL of dimethyl carbonate were added, and the mixture was stirred under reflux for another 5 h. The reaction endpoint was monitored by TLC. After the reaction was complete, the methanol was removed and the mixture was extracted three times with 10 mL of water and 10 mL of toluene, respectively. The toluene phase was then removed by rotary evaporation to obtain 1.07 g of crude ambroxol, with a yield of 85.6%.

[0027] Example 2

[0028] 160 mg sodium ethoxide and 13 mL ethanol were dissolved in a 100 mL two-necked flask by stirring. 875 mg sodium borohydride was then added and stirred for 5 min. 2.5 g (10 mmol) of succinyl lactone was added and dissolved. The mixture was heated to 80 °C and stirred under reflux for about 2 h. The reaction endpoint was monitored by TLC. After the reaction was complete, 10 mL ethanol, 3.1 g sodium ethoxide, and 5 mL diethyl carbonate were added, and the mixture was stirred under reflux for about 4 h. The reaction endpoint was monitored by TLC. After the reaction was complete, the ethanol was removed, and the mixture was extracted three times with 20 mL water and 20 mL toluene, respectively. The toluene phase was then removed by rotary evaporation to obtain 2.16 g of crude ambroxol, with a yield of 86.4%.

[0029] Example 3

[0030] 220 mg of sodium tert-butoxide and 15 mL of tert-butoxide were dissolved in a 100 mL two-necked flask by stirring. 875 mg of sodium borohydride was then added and stirred for 5 min. 2.5 g (10 mmol) of styracil lactone was added and dissolved. The mixture was then heated to 85 °C and refluxed with stirring for about 2 h. The reaction endpoint was monitored by TLC. After the reaction was complete, 20 mL of tert-butoxide, 4.5 g of sodium tert-butoxide, and 5 mL of dimethyl carbonate were added, and the mixture was refluxed with stirring for another 4 h. The reaction endpoint was monitored by TLC. After the reaction was complete, ethanol was removed, and the mixture was extracted three times with 20 mL of water and 20 mL of toluene, respectively. The toluene phase was then removed by rotary evaporation to obtain 2.13 g of crude ambroxol, with a yield of 85.2%.

[0031] Example 4

[0032] 250 mg of sodium methoxide and 25 mL of methanol were dissolved in a 250 mL three-necked flask by stirring. 2.35 g of potassium borohydride was added and stirred for 5 min. Then, 5 g (20 mmol) of styracil lactone was added and dissolved. The mixture was heated to 70 °C and refluxed with stirring for about 3 h. The reaction endpoint was monitored by TLC. After the reaction was complete, 20 mL of methanol, 5 g of sodium methoxide, and 10 mL of dimethyl carbonate were added, and the mixture was refluxed with stirring for another 5 h. The reaction endpoint was monitored by TLC. After the reaction was complete, the methanol was removed, and the mixture was extracted three times with 50 mL of water and 50 mL of cyclohexane, respectively. The organic phase was then removed by rotary evaporation to obtain 4.34 g of crude ambroxol, with a yield of 86.8%. After multiple recrystallizations with 95% ethanol, a total of 4.16 g of high-quality ambroxol was obtained, with an overall yield of 83.2%.

[0033] Example 5

[0034] 500 mg sodium methoxide and 50 mL methanol were dissolved in a 500 mL three-necked flask by stirring. 3.4 g sodium borohydride was then added and stirred for 5 min. 10 g (40 mmol) of styracil lactone was added and dissolved. The mixture was heated to 70 °C and refluxed with stirring for approximately 3 h. The reaction endpoint was monitored by TLC. After complete reaction, 50 mL of methanol, 9 g of sodium methoxide, and 18 mL of dimethyl carbonate were added, and the mixture was refluxed with stirring for another 5 h. The reaction endpoint was monitored by TLC. After the reaction was complete, the methanol was removed, and the mixture was extracted three times with 100 mL of water and 100 mL of toluene, respectively. The toluene phase was removed by rotary evaporation to obtain 8.65 g of crude ambroxol, with a yield of 86.5%. After multiple recrystallizations with 95% ethanol, a total of 8.39 g of high-quality ambroxol was obtained, with an overall yield of 83.9%.

[0035] Example 6

[0036] 1 g of sodium methoxide and 100 mL of methanol were dissolved in a 1000 mL three-necked flask by stirring. Then, 9.5 g of potassium borohydride was added and stirred for 5 min. Next, 20 g (80 mmol) of styracil lactone was added and dissolved. The mixture was then heated to 70 °C and refluxed with stirring for about 3 h. The reaction endpoint was monitored by TLC. After the reaction was complete, 20 g of sodium methoxide and 38 mL of dimethyl carbonate were added, and the mixture was refluxed with stirring for another 4 h. The reaction endpoint was monitored by TLC. After the reaction was complete, methanol was removed, and the mixture was extracted three times with 200 mL of water and 200 mL of cyclohexane, respectively. The organic phase was then removed by rotary evaporation to obtain 17.22 g of crude ambroxol, with a yield of 86.1%. After multiple recrystallizations with 95% ethanol, 16.7 g of high-quality ambroxol was obtained, with an overall yield of 83.5%.

[0037] The above description is merely a preferred embodiment of the present invention. It should be understood that the present invention is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the concept described herein through the above teachings or related technologies or knowledge. Modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the present invention should be within the protection scope of the appended claims.

[0038] The above description is only a preferred embodiment of the present invention, but it does not mean that the content of the present invention is limited to the embodiments described. Any non-essential modifications, equivalent substitutions, and improvements to the present invention should be included within the protection scope of the present invention.

Claims

1. A method for one-pot two-step preparation of ambrox, characterized in that: The sclareolide is mixed with a catalytic stabilizer alcohol alkali metal salt and a reducing agent in a certain mass ratio, the catalytic stabilizer alcohol alkali metal salt is first put into a water-soluble organic solvent, then the reducing agent is put in, and finally the sclareolide is put in, heated, stirred and refluxed for 2-3 hours to end the first reaction stage, then an alcohol alkali metal salt and an ester reagent are put in and heated and refluxed for 4-5 hours to end the second reaction stage, after the reaction solvent is removed, water and a non-water-soluble organic solvent are added and extracted three times, the water phase is extracted, finally the organic phase is combined, the organic solvent is removed, and the crude product ambrox is obtained, the crude product is recrystallized with 95% ethanol to obtain the ambrox product; the alcohol alkali metal salt is at least one of sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the reducing agent is at least one of potassium borohydride and sodium borohydride; and the ester reagent includes at least one of dimethyl carbonate, diethyl carbonate, dimethyl oxalate, ethyl acetate, ethyl formate and methyl acetate.

2. The one-pot two-step process for the preparation of ambrox according to claim 1, characterized in that: The water-soluble organic solvent is one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, tetrahydrofuran, acetonitrile and 1,4-dioxane; and the non-water-soluble organic solvent is one or more of toluene, xylene, n-hexane and cyclohexane.

3. The one-pot two-step process for the preparation of ambrox according to claim 1, characterized in that: During the reaction, the mass ratio of the sclareolide, the water-soluble organic solvent, the alcohol alkali metal salt, the reducing agent, the ester reagent and the non-water-soluble organic solvent is 1:2-10:0.01-2:0.25-0.5:1-10:3-15.

4. The one-pot two-step process for the preparation of ambrox according to claim 1, characterized in that: The reaction reagent is first dissolved in the water-soluble organic solvent, then the sclareolide is added to form a reaction system, and the reaction system is heated, stirred and refluxed under the condition that the reaction system is close to the boiling point.

5. The one-pot two-step process for the preparation of ambrox according to claim 1, characterized in that: After the reaction is completed, the water-soluble organic solvent is recovered, water, acid, base and a non-water-soluble solvent are added and extracted to remove irrelevant components, the organic phase is removed to obtain the crude product, and the product is obtained after recrystallization with ethanol, petroleum ether and cyclohexane solvent.

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