A method for synthesizing ambrox

Abstract

The present application relates to a kind of synthesis methods of reducing ambrox, comprising the following steps: ambrinol is dissolved in organic solvent, then adding catalyst aluminum trichloride, quaternary ammonium salt catalyst, then stirring condition is at least divided into 3 times and adds potassium borohydride, control reaction liquid temperature is 20-25 degrees Celsius, the total consumption time of first feeding to reaction end of potassium borohydride is 2-5h, reaction generates reducing ambrox, obtains the reaction liquid containing reducing ambrox;Dilute sulfuric acid is added to the reaction liquid containing reducing ambrox, adjusts the pH of reaction liquid to 3-4, keep 1h, then drop alkali solution, adjust the pH of reaction liquid to 5.2-7.5, keep 1h, filter, filtrate is placed and is layered, organic solvent layer is concentrated to dryness under reduced pressure and obtains reducing ambrox product.The present application process condition is mild, yield is high, product purity is good, raw material cost is low, pollution is small, easy to industrialization.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing ambroxol. Background Technology

[0002] Ambroxol [(-)-Ambrox] is one of the most crucial active ingredients in natural ambergris tincture, possessing a soft, long-lasting, and stable animalic ambergris aroma with a mild woody fragrance. Synthetic ambroxol is often used as a fixative and is one of the excellent substitutes for natural ambergris. In addition, ambroxol can also be used as a food additive.

[0003] Currently, there are two main methods for synthesizing ambroxol: 1) Using perillyl alcohol as raw material, hydrogen peroxide (70%) is used to oxidize the tertiary carbon hydroxyl group of the aliphatic side chain of perillyl alcohol into peroxide, and then Cu(OAc)2 and FeSO4 are used for catalytic degradation to obtain ambroxol. Although this reaction has a short step, the yield is extremely low, with a maximum of no more than 35%. 2) Using perillaldehyde as a raw material, a reduction reaction is first carried out in diethyl ether with lithium aluminum hydride as a reducing agent to generate ambroxol (-)-Ambradiol. Then, ambroxol undergoes a dehydration cyclization reaction in pyridine with sulfonyl chloride to synthesize ambroxol ether. This synthesis reaction is a two-step reaction, which has the following main drawbacks: 1) The required reducing agent is expensive, resulting in high product cost, and the post-treatment after the reduction process generates a large amount of waste liquid, which is difficult to treat; 2) The raw material used, methanesulfonyl chloride, is corrosive and releases toxic gases when it comes into contact with water; 3) The final product, ambroxol ether, has a low yield, many byproducts, and is complicated and difficult to separate and purify, resulting in poor product purity. In addition, the above two methods also have the problems of difficult separation and purification and high impurity content. Since ambroxol ether is a fragrance component, 1% impurity is enough to change the fragrance type of the product, thus making it impossible to obtain the pure fragrance of ambroxol ether.

[0004] Therefore, it is crucial to develop a method for synthesizing ambroxol that features mild process conditions, simple operation, low pollution, low cost, high yield, simple product separation and purification, and good product purity. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for synthesizing ambroxol, which features mild process conditions, simple operation, high yield and high purity, minimal wastewater and waste liquid generation, no use of sulfonyl chlorides, less environmental pollution, and inexpensive reducing agents and catalysts, resulting in low raw material costs.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A method for synthesizing ambroxan includes the following steps:

[0008] Dissolve perillyl lactone in an organic solvent, then add aluminum trichloride and quaternary ammonium salt catalysts, and then add potassium borohydride in at least 3 portions under stirring. Control the temperature of the reaction solution at 20-25 degrees Celsius. The total time from the first addition of potassium borohydride to the end of the reaction is 2-5 hours. The reaction produces ambroxol, and a reaction solution containing ambroxol is obtained.

[0009] As a further technical solution, dilute sulfuric acid is added to the reaction solution containing ambroxol to quench the catalyst, adjusting the pH of the reaction solution to 3-4 and maintaining this state for 1 hour to deactivate the catalyst. Then, alkali solution is added dropwise to adjust the pH of the reaction solution to 5.2-7.5 and maintained for 1 hour. 3+ The process involves converting the aluminum hydroxide into solid aluminum hydroxide, allowing it to precipitate, filtering (to remove the precipitated aluminum hydroxide solid), allowing the filtrate to stand and separate into layers, removing the water layer [to remove water-soluble quaternary ammonium salt catalysts and other water-soluble impurities (mainly ring-opening impurities of the raw material perillaldehyde)], and concentrating the organic solvent layer under reduced pressure to dryness to obtain ambroxol product. When adjusting the pH with alkali solution, if the pH is greater than 7.5, some of the precipitated aluminum hydroxide will dissolve back into the solution; however, if the pH is less than 5.2, the aluminum salt can only be partially converted into solid aluminum hydroxide and precipitate, while some remains dissolved in the solution. Both of these situations result in some Al dissolving in the aqueous phase. 3+ During the static stratification process, although the tetrahydrofuran layer and the water layer separate into layers, a very small amount of water still remains in the tetrahydrofuran layer, thus causing Al... 3+ The product could not be completely removed, resulting in some Al remaining in the product. 3+ Residue; however, this invention, by strictly limiting the addition of alkali solution, maintains a reaction solution pH of 5.2-7.5, which promotes Al... 3+ It transforms into solid aluminum hydroxide precipitation, thereby reducing the Al content in the aqueous phase. 3+ Reduce the Al content in the product 3+ To reduce residue and improve product purity.

[0010] As a further technical solution, the mass concentration of the dilute sulfuric acid is 20%;

[0011] The alkaline solution is a 20% sodium hydroxide aqueous solution.

[0012] As a further technical solution, the molar ratio of the total amount of perilla lactone to potassium borohydride is 1:1-9; preferably 1:3-5;

[0013] As a further technical solution, the time interval between two consecutive additions of potassium borohydride is 0.3-0.7 hours (preferably 0.5 hours);

[0014] The amount of potassium borohydride added in the first two feedings is 1 / 5 to 1 / 3 of the total amount of potassium borohydride;

[0015] The final addition of potassium borohydride should be 1 / 1 to 3 / 5 of the total amount of potassium borohydride.

[0016] As a further technical solution, the potassium borohydride is added in three parts. The first part is 1 / 5 to 1 / 3 of the total amount of potassium borohydride, and the mixture is kept for 0.5 hours. The second part is 1 / 5 to 1 / 3 of the total amount of potassium borohydride, and the mixture is kept for 0.5 hours. The third part is the remaining potassium borohydride, and the mixture is kept for 2 hours until the content of perilla lactone is ≤0.1%.

[0017] As a further technical solution, the molar ratio of perillaldehyde to aluminum trichloride is 1:0.5-1.5; preferably 1:1-1.2.

[0018] As a further technical solution, the amount of the quaternary ammonium salt catalyst added is 2.5-4.0 wt% of perillaldehyde.

[0019] As a further technical solution, the quaternary ammonium salt catalyst includes one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, and hexadecyltrimethylammonium chloride, preferably tetrabutylammonium bromide or benzyltriethylammonium chloride.

[0020] As a further technical solution, the organic solvent is one or more of benzene, toluene, chlorobenzene, ethylbenzene, xylene, acetonitrile, tetrahydrofuran, dioxane, acetone, dichloromethane, and chloroform; preferably tetrahydrofuran or toluene.

[0021] The synthetic route of this invention is as follows:

[0022]

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] 1. This invention uses perilla lactone prepared by microbial fermentation as a raw material to synthesize ambroxol. The raw material is readily available, easy to obtain, has high purity, and produces few byproducts.

[0025] 2. This invention uses perillaldehyde as a raw material and potassium borohydride as a reducing agent under the action of aluminum chloride catalyst and quaternary ammonium salt catalyst to generate ambroxol through a one-step reduction reaction. The reaction conditions are mild, and the synthesis process does not require a stepwise reaction of ring opening and then cyclization, which shortens the reaction steps, reduces the occurrence of side reactions, and improves the reaction yield and purity. Compared with traditional technology, it has a shorter reaction step, higher reaction yield, simpler separation and purification, better product purity, and the catalyst and reducing agent used are inexpensive, reducing raw material costs, less wastewater and waste liquid, and no sulfonyl chloride is used in the reaction process, resulting in less environmental pollution. In addition, this invention is simple to operate and easy to industrialize.

[0026] 3. This invention avoids the ring-opening of the lactone ring of perillaldehyde during synthesis by screening catalysts and reducing agents, adding quaternary ammonium salt catalysts, and controlling the temperature and the method of adding reducing agents during the reaction process. This makes it possible for perillaldehyde to be reduced to ambroxol in one step. All of the above measures are indispensable. In addition, the quaternary ammonium salt catalyst of this invention can promote the reaction equilibrium of the one-step reduction reaction to the forward direction at a lower temperature, which greatly improves the reaction yield. The lower temperature can also reduce the occurrence of side reactions and improve the reaction purity.

[0027] 4. Since diatomaceous earth has poor selective adsorption of aluminum chloride, this invention uses an alkali to adjust the pH of the reaction solution to 5.2-7.5 after acid quenching. By controlling the pH of the solution, aluminum chloride is eventually converted into aluminum hydroxide solid and precipitated. Aluminum is then removed by filtration, thereby achieving product separation and purification. This simplifies the separation and purification steps of ambroxol, reduces aluminum residue in the product, and improves the purity of ambroxol.

[0028] 5. Although tetrahydrofuran and water are miscible, when ambroxol is produced by the reaction, the ambroxol dissolves in the tetrahydrofuran layer, thus achieving the separation of the tetrahydrofuran layer and the water layer. Therefore, this invention uses a static separation method to remove the quaternary ammonium salt catalyst and other water-soluble impurities in the aqueous phase, simplifying the separation and purification steps of ambroxol and improving the purity of ambroxol.

[0029] In summary, this invention uses perillaldehyde as a raw material and potassium borohydride as a reducing agent under the action of aluminum chloride catalyst and quaternary ammonium salt catalyst to generate ambroxol through a one-step reduction reaction. The process conditions are mild, the yield is high, the product purity is good, the raw material cost is low, the pollution is small, and it is easy to industrialize. Detailed Implementation

[0030] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0031] In this invention, the microbial preparation method of the perilla lactone includes the following steps:

[0032] Step 1. Using perillyl alcohol as a substrate, perillyl lactone was synthesized by the Hyphozyma roseonigra strain of microorganisms;

[0033] Step 2. The fermentation broth containing perilla lactone was separated by a ceramic membrane to obtain a slurry, which was then extracted with an ethanol aqueous solution, concentrated, cooled and crystallized, and filtered to obtain a wet crude product.

[0034] Step 3. The wet crude product is recrystallized in a solvent to obtain perilla lactone.

[0035] Unless otherwise specified, all raw materials used in this invention are commercially available.

[0036] Example 1

[0037] A method for synthesizing ambroxan includes the following steps:

[0038] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: the first addition of 8.63 g (1 eq) was maintained for 0.5 h; the second addition of 8.63 g (1 eg) was maintained for 0.5 h; and the final addition of 8.63 g (1 eg) was maintained for 2 h. The process of adding potassium borohydride and the reaction were described. During the reaction, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0. This was maintained for 1 hour, and a solid precipitated. The solution was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated under reduced pressure to dryness to obtain 36.46g of ambroxol product with a purity of 99.48% and a yield of 95.90%.

[0039] Example 2

[0040] A method for synthesizing ambroxan includes the following steps:

[0041] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: 8.63 g (1 eq) was added first and maintained for 0.5 h; 8.63 g (1 eg) was added second and maintained for 0.5 h; and 17.26 g (2 eg) was added last and maintained for 2 h. The process of adding potassium borohydride and the reaction were described. During the process, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0. This was maintained for 1 hour, and a solid precipitated. The solution was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated under reduced pressure to dryness to obtain 36.47g of ambroxol product with a purity of 99.49% and a yield of 95.93%.

[0042] Example 3

[0043] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: the first addition was 8.63 g (1 eq), maintained for 0.5 h; the second addition was 8.63 g (1 eg), maintained for 0.5 h; and the final addition was 25.89 g (3 eg), maintained for 2 h. The potassium borohydride addition process and reaction were recorded. During the reaction process, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 36.45g of ambroxol with a purity of 99.50% and a yield of 95.90%.

[0044] Example 4

[0045] A method for synthesizing ambroxan includes the following steps:

[0046] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 24.56 g (1.15 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: the first addition was 8.63 g (1 eq), maintained for 0.5 h; the second addition was 8.63 g (1 eg), maintained for 0.5 h; and the final addition was 8.63 g (1 eg), maintained for 2 h. The potassium borohydride addition was then completed. During the reaction process, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated under reduced pressure to dryness to obtain 36.48g of ambroxol with a purity of 99.46% and a yield of 95.92%.

[0047] Example 5

[0048] A method for synthesizing ambroxan includes the following steps:

[0049] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 25.63 g (1.2 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: 8.63 g (1 eq) was added first and maintained for 0.5 h; 8.63 g (1 eg) was added second and maintained for 0.5 h; and 8.63 g (1 eg) was added last and maintained for 2 h. The potassium borohydride addition process and reaction were recorded. During the reaction, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 36.47g of ambroxol with a purity of 99.48% and a yield of 95.91%.

[0050] Example 6

[0051] A method for synthesizing ambroxan includes the following steps:

[0052] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1.2 g (3%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: the first addition of 8.63 g (1 eq) was maintained for 0.5 h, the second addition of 8.63 g (1 eg) was maintained for 0.5 h, and the final addition of 8.63 g (1 eg) was maintained for 2 h. The potassium borohydride addition process and reaction were recorded. During the reaction, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated under reduced pressure to dryness to obtain 36.48g of ambroxol with a purity of 99.49% and a yield of 95.95%.

[0053] Example 7

[0054] A method for synthesizing ambroxan includes the following steps:

[0055] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: the first addition was 8.63 g (1 eq), maintained for 0.5 h; the second addition was 8.63 g (1 eg), maintained for 0.5 h; and the final addition was 8.63 g (1 eg), maintained for 1 h. The potassium borohydride addition process and reaction were recorded. During the reaction, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.02wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The aqueous layer was removed, and the organic solvent layer was concentrated under reduced pressure to dryness to obtain 36.33g of ambroxol with a purity of 99.01% and a yield of 95.10%.

[0056] Comparative Example 1

[0057] A method for synthesizing ambroxan includes the following steps:

[0058] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three stages: the first addition of 8.63 g (1 eq) was maintained for 0.5 h; the second addition of 8.63 g (1 eg) was maintained for 0.5 h; and the final addition of 8.63 g (1 eg) was maintained for 2 h. The potassium borohydride addition process and... During the reaction, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 8.0. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 36.54g of ambroxol with a purity of 99.22% and a yield of 95.85%.

[0059] Comparative Example 2

[0060] A method for synthesizing ambroxan includes the following steps:

[0061] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: the first addition of 8.63 g (1 eq) was maintained for 0.5 h, the second addition of 8.63 g (1 eg) was maintained for 0.5 h, and the final addition of 8.63 g (1 eg) was maintained for 2 h. The potassium borohydride addition process was described. During the reaction, the temperature of the reaction solution was controlled at 20-25 degrees Celsius. After the reaction was completed, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 4.5. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The water layer was removed, and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 36.44g of ambroxol with a purity of 99.33% and a yield of 95.71%.

[0062] Comparative Example 3

[0063] A method for synthesizing ambroxan includes the following steps:

[0064] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in two portions: the first addition of 12.3 g (1.5 eq) was maintained for 1 h, and the second addition of 12.3 g (1.5 eq) was maintained for 2 h. The temperature of the reaction solution was controlled during the addition of potassium borohydride and the reaction process. The reaction was carried out at 20-25 degrees Celsius. After completion, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst and the pH was controlled at 3-4. The pH was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0 and maintained for 1 hour. The solid precipitated and was filtered. The filtrate was allowed to stand and separate into layers. The water layer was removed and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 35.70g of ambroxol with a purity of 99.43% and a yield of 93.86%.

[0065] Comparative Example 4

[0066] A method for synthesizing ambroxan includes the following steps:

[0067] 40g (0.16mol) of purified perillaldehyde was dissolved in 1000mL of tetrahydrofuran and stirred to form a solution. Then, 23.50g (1.1eq) of aluminum trichloride catalyst and 1g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst were added. Then, 25.89g (3eq) of potassium borohydride was added at 20-25°C and maintained at 20-25°C for 3h. The perillaldehyde content in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst and the pH was controlled at 3-4. The solution was maintained for 1h to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0 and maintained for 1h. The solid precipitated and filtered. The filtrate was allowed to stand and separate into layers. The aqueous layer was removed and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 34.74g of ambroxol with a purity of 99.38% and a yield of 91.29%.

[0068] Comparative Example 5

[0069] A method for synthesizing ambroxan includes the following steps:

[0070] 40g (0.16mol) of purified perillaldehyde was dissolved in 1000mL of tetrahydrofuran and stirred to form a solution. Then, 23.50g (1.1eq) of aluminum trichloride catalyst was added, followed by 1g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst, and then 25.89g (3eq) of potassium borohydride. The mixture was refluxed at 68-72°C for 2 hours. The perillaldehyde content in the reaction solution was monitored and found to be ≤0.01wt%. Then, 20% dilute sulfuric acid was added to quench the catalyst and the pH was controlled at 3-4 for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.8-6.0 and the solution was maintained for 1 hour. A solid precipitated, which was filtered. The filtrate was allowed to stand and separate into layers. The aqueous layer was removed, and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 35.63g of ambroxol with a purity of 99.37% and a yield of 93.62%.

[0071] Comparative Example 6

[0072] A method for synthesizing ambroxan includes the following steps:

[0073] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 23.50 g (1.1 eq) of aluminum trichloride catalyst was added. Potassium borohydride was then added in three portions: the first addition of 8.63 g (1 eq) was maintained for 0.5 h; the second addition of 8.63 g (1 eq) was maintained for 0.5 h; and the final addition of 8.63 g (1 eq) was maintained for 2 h. The temperature of the reaction solution was controlled at 20-25 degrees Celsius during the addition of potassium borohydride and the reaction process. After the reaction was complete... After completion, the content of perillaldehyde in the reaction solution was monitored and found to be ≤0.30wt% (the content of perillaldehyde no longer decreased when the reaction time was further increased). Then, 20% dilute sulfuric acid was added to quench the catalyst, and the pH was controlled at 3-4. This was maintained for 1 hour to deactivate the catalyst. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 5.2-5.5. This was maintained for 1 hour, and a solid precipitated. The solid was filtered, and the filtrate was allowed to stand and separate into layers. The aqueous layer was removed, and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 34.30g of ambroxol with a content of 92.53% and a yield of 83.92%.

[0074] Comparative Example 7

[0075] A method for synthesizing ambroxan includes the following steps:

[0076] 40 g (0.16 mol) of purified perillaldehyde was dissolved in 1000 mL of tetrahydrofuran and stirred to form a solution. Then, 76.56 g (1.5 eq) of zinc iodide catalyst was added, followed by 1 g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three portions: 8.63 g (1 eq) was added first and held for 0.5 h; 8.63 g (1 eq) was added second and held for 0.5 h; and 8.63 g (1 eq) was added last and held for 2 h. The temperature of the reaction solution was controlled at 20°C during the addition of potassium borohydride and the reaction process. The reaction was completed at -25 degrees Celsius. Central monitoring showed that the content of perillaldehyde in the reaction solution was ≤0.05 wt% (the perillaldehyde content no longer decreased with further increases in reaction time). Then, 20% dilute sulfuric acid was added for quenching, and the pH was controlled at 3-4. This was maintained for 1 hour to decompose excess zinc iodide. Then, 20% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 9.5. This was maintained for 1 hour, causing zinc hydroxide to precipitate. The solution was filtered, and the filtrate was allowed to stand and separate into layers. The aqueous layer was removed, and the organic solvent layer was concentrated to dryness under reduced pressure to obtain 34.60 g of ambroxol, with a purity of 98.62% and a yield of 90.21%.

[0077] Comparative Example 8

[0078] 40g (0.16mol) of purified perillaldehyde and 12g (0.32mol) of NaBH4 were dissolved in 1000mL of tetrahydrofuran. The reaction solution temperature was controlled at 0℃, and 76.56g of zinc iodide was slowly added. After the addition was complete, the reaction solution temperature was raised to room temperature and maintained for 1 hour. Then, the temperature was raised to 68-72℃ and refluxed for 1 hour to end the reaction. The content of perillaldehyde in the reaction solution was ≤0.01wt% as measured by the central control. The reaction solution was then filtered with 50g of diatomaceous earth and washed with 500ml of t-BuOMe. The filtrate and washings were combined and evaporated to obtain 31.99g of ambroxol with a purity of 99.46% and a yield of 84.12%.

[0079] Comparative Example 9

[0080] 40g (0.16mol) of purified perillaldehyde was dissolved in 1000mL of tetrahydrofuran and stirred to form a solution. Then, 23.50g (1.1eq) of aluminum trichloride catalyst was added, followed by 1g (2.5%) of tetrabutylammonium bromide quaternary ammonium salt catalyst. Potassium borohydride was then added in three stages: 8.63g (1eq) was added first and maintained for 0.5h; 8.63g (1eg) was added second and maintained for 0.5h; and 8.63g (1eg) was added last and maintained for 2h. The temperature of the reaction solution was controlled at 20-25°C during the addition of potassium borohydride and the reaction process. After the reaction was completed, the perillaldehyde content in the reaction solution was monitored and found to be ≤0.01wt%. The solution was then filtered with 50g of diatomaceous earth and washed with 500ml of t-BuOMe. The filtrate and washings were combined and evaporated to obtain 39.95g of ambroxol with a purity of 90.59% and a yield of 95.68%.

[0081] Example of effect

[0082] The control results of the reaction solutions of each embodiment and comparative example, as well as the product weight, content (purity) and yield of ambroxan, are summarized in Table 1.

[0083] Among them, the central control method for styracil lactone was TLC;

[0084] The detection conditions were as follows: 1) Thin-layer chromatography silica gel plate model: HSGF254; 2) Developing solvent: petroleum ether: ethyl acetate = 3:1

[0085] The content of ambroxol was determined by gas chromatography, specifically as follows:

[0086] Internal standard solution: 10 mg / mL dibutyl phthalate ethanol solution.

[0087] Standard solution: 10 mg / mL ambroxol standard solution.

[0088] Test solution: 10 mg / mL sample solution.

[0089] Chromatographic conditions: Instrument: Gas chromatograph; Detector: FID detector; Detector temperature: 300℃; Column temperature: 250℃; Injector temperature: 270℃; Split ratio: 1:40; Total flow rate: 45mL / min; Hydrogen: 40mL / min; Air: 400mL / min; Column flow rate: 1.7mL / min; Run time: 5min; Injection volume: 0.5μL; Column: HP-5 (5% phenyl)-methylpolysiloxane); Model: 30m × 0.32mm × 0.25μm;

[0090] System suitability solution: 10 mg / mL internal standard + 10 mg / mL ambroxol standard solution.

[0091] System suitability: The peak area of ​​the internal standard, the peak area of ​​the standard, and the ratio of the peak area of ​​the internal standard to the peak area of ​​the standard are all within ≤0.5%; the resolution between the internal standard and the sample is ≥3.

[0092] Determination method: Accurately measure the test solution and standard solution, inject them separately into the gas chromatograph, and record the chromatograms.

[0093] Formula 1: f = (As / Cs) / (Ar / Cr);

[0094] Formula 2: Cx = f × Ax / (As' / Cs');

[0095] Calculation formula 3: W=Cx×V / m×100;

[0096] In the formula: As: peak area of ​​the internal standard in the reference standard; Ar: peak area of ​​the reference standard; Cs: concentration of the internal standard; Cr: concentration of the reference standard. Ax: peak area of ​​the test sample; Cx: concentration of the test sample; W: content of the test sample; As': peak area of ​​the internal standard in the sample; Cs': concentration of the internal standard; f: correction factor; V: final volume of the sample; m: mass of the sample.

[0097] Table 1

[0098]

[0099]

[0100] From the data in Table 1, we can see that:

[0101] 1) As can be seen from the data in Examples 1-7, the present invention uses potassium borohydride as a reducing agent under the action of aluminum chloride catalyst and quaternary ammonium salt catalyst, and with the addition of potassium borohydride in multiple batches and control of reaction temperature, so that perillaldehyde can be reduced to ambroxol in one step. The reaction conditions are highly selective for the one-step reduction to ambroxol, and the reaction conditions are mild and the method is stable, which greatly reduces the yield of perillaldehyde ring-opening byproducts and greatly improves the product yield, which can reach more than 95%. In addition, with the separation and purification process of acid quenching, alkali addition, filtration, filtrate standing and layering, and vacuum concentration of organic solvent layer, ambroxol product with purity (content) greater than 99% can be prepared, and the product purity is high.

[0102] 2) A comparison of Example 1 and Comparative Examples 1-2 shows that during the separation and purification of ambroxol, when the pH is not within the required range of 5.2-7.5, the purity of the product decreases slightly. This is because when adjusting the pH with alkali, if the pH is greater than 7.5, some of the precipitated aluminum hydroxide will dissolve back into the solution. However, if the pH is less than 5.2, the aluminum salt can only be partially converted into solid aluminum hydroxide and precipitated, while some remains dissolved in the solution. Both situations result in some Al dissolving in the aqueous phase. 3+ During the static stratification process, although the tetrahydrofuran layer and the water layer separate into layers, a very small amount of water still remains in the tetrahydrofuran layer, thus causing Al... 3+ The product could not be completely removed, resulting in some Al remaining in the product. 3+ Residual alkaline residue slightly reduces product purity. Therefore, when adjusting the pH by adding alkali solution, strictly controlling the reaction solution within the range of 5.2-7.5 can reduce the Al content in the product. 3+ Residues improve product purity.

[0103] 3) As can be seen from the comparison between Example 1 and Comparative Examples 3-4: When the number of times potassium borohydride is added is reduced, the amount of potassium borohydride in the early stage of the reaction will be too large, which will cause the ring-opening side reaction of styracil lactone to produce impurity ring-opening products, resulting in a significant decrease in product yield. However, since the impurity ring-opening products can be dissolved in the aqueous phase, they are removed during the separation and purification process, thus not having a significant impact on the purity of the product.

[0104] 4) A comparison between Example 1 and Comparative Example 5 shows that as the reaction temperature increases, the reaction intensity increases, leading to a ring-opening side reaction of styracil lactone, producing impurity ring-opening products, and resulting in a decrease in yield.

[0105] 5) As can be seen from the comparison between Example 1 and Comparative Examples 6-7: when no quaternary ammonium salt catalyst is added or zinc iodide is used instead of aluminum chloride as the catalyst, on the one hand, after the reaction reaches equilibrium, the residue of the raw material perillyl lactone increases, and the separation and purification method of the present invention is insufficient to remove the raw material perillyl lactone, which leads to it entering the product and forming impurities, resulting in a decrease in product purity and yield. On the other hand, it also leads to a decrease in the selectivity of the one-step reduction reaction and an increase in the ring-opening side reaction, thereby generating a large number of ring-opening byproducts, which further reduces the product yield. The above two reasons result in a significant decrease in the purity and yield of the product.

[0106] 6) As can be seen from the comparison between Example 1 and Comparative Example 8: when zinc iodide catalyst and sodium borohydride reducing agent are used to prepare ambergris ether by high temperature reflux reaction, the yield is seriously reduced due to the excessive impurities generated in the reaction. However, the product obtained by pure ambergris still has high purity because diatomaceous earth has a good adsorption effect on impurities and zinc iodide in its separation and purification process.

[0107] 7) From the comparison between Example 1 and Comparative Example 9, it can be seen that when the separation and purification process of Comparative Example 9 is used, since the adsorption effect of diatomaceous earth on quaternary ammonium salt catalyst and AlCl3 is worse than that on zinc iodide, the quaternary ammonium salt catalyst and AlCl3 are not completely adsorbed, resulting in both remaining as impurities in the product, causing the product purity to drop sharply. Therefore, it can be seen that the separation and purification method in Comparative Example 9 is not suitable for removing quaternary ammonium salt catalyst and aluminum chloride catalyst from the reaction solution.

[0108] The embodiments described above are merely preferred embodiments of the present invention, and not an exhaustive list of all possible implementations of the present invention. Any obvious modifications made by those skilled in the art without departing from the principles and spirit of the present invention should be considered to be included within the scope of protection of the claims of the present invention.

Claims

1. A method of synthesizing ambrox, characterized in that, The method comprises the following steps: The sclareolide is dissolved in an organic solvent, and then a catalyst aluminum trichloride and a quaternary ammonium salt catalyst are added, and then potassium borohydride is added in three times under stirring, the temperature of the reaction solution is controlled at 20-25℃, the total time for the first addition of potassium borohydride to the end of the reaction is 2-5h, and ambroxide is generated in the reaction, and the reaction solution containing ambroxide is obtained; Dilute sulfuric acid is added to the reaction solution containing ambroxide, the pH of the reaction solution is adjusted to 3-4, and the pH is maintained for 0.5-1.5h, then lye is added dropwise, the pH of the reaction solution is adjusted to 5.2-7.5, and the pH is maintained for 0.5-1.5h, then filtration is performed, the filtrate is allowed to stand and separate into layers, and the organic solvent layer is concentrated to dryness under reduced pressure to obtain ambroxide product; The molar ratio of the total amount of the sclareolide to the potassium borohydride is 1:1-9; The interval between the addition times of the two adjacent additions of potassium borohydride is 0.3-0.7h; The amount of the potassium borohydride added in the first two times is 1 / 5-1 / 3 of the total amount of the potassium borohydride; The amount of the potassium borohydride added in the last time is 1 / 3-3 / 5 of the total amount of the potassium borohydride; The molar ratio of the sclareolide to the aluminum trichloride is 1:0.5-1.5; The addition amount of the quaternary ammonium salt catalyst is 2.5-4.0wt% of the sclareolide; The organic solvent is one or more of benzene, toluene, chlorobenzene, ethylbenzene, dimethylbenzene, acetonitrile, tetrahydrofuran, dioxane, acetone, dichloromethane, and trichloromethane.

2. The method according to claim 1, wherein The mass concentration of the dilute sulfuric acid is 20%. The lye is a sodium hydroxide aqueous solution with a mass concentration of 20%.

3. The method according to claim 1, wherein The quaternary ammonium salt catalyst comprises one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, and cetyltrimethylammonium chloride.

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