Refining method of dextroborneol crude product

Abstract

The invention relates to the technical field of organic synthesis, in particular to a refining method of a crude product of dextroborneol, which comprises the following steps: sequentially carrying out a rearrangement reaction, an esterification reaction, a salt forming reaction, an alkaline hydrolysis reaction and post-treatment refining on the crude product of dextroborneol in the presence of a solvent and a catalyst on the basis of a reaction product to obtain a refined product of dextroborneol, in the refined dextroborneol product, the content of dextroborneol is greater than or equal to 98.0%, the content of L-borneol is less than or equal to 1.0%, the content of isoborneol is less than or equal to 0.15%, the content of natural camphor is less than or equal to 0.15%, and the content of other impurities is less than or equal to 0.10%. The method has the advantages that the isoborneol structure can be selectively destroyed under mild conditions, impurities are effectively removed through the esterification-salification-alkaline hydrolysis three-step reaction, and the purity and yield of dextroborneol are remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for purifying crude dextromethorphanol. Background Technology

[0002] Borneol, also known as natural borneol or dextrorotatory borneol, is an important natural organic compound with unique aroma and pharmacological activity. It has wide applications in pharmaceuticals, daily chemicals, fragrances, agrochemicals, and new materials. High-purity borneol is widely used in compound traditional Chinese medicine preparations, topical anti-inflammatory and analgesic preparations, transdermal absorption enhancers, and the preparation of cerebrovascular active drugs.

[0003] According to the provisions of the Pharmacopoeia of the People's Republic of China (2025 Edition), dextrorotatory borneol extracted from the fresh branches and leaves of the camphor tree (Cinnamomum camphora) must contain no less than 95.0% dextrorotatory borneol and no more than 3.0% camphor, as determined by gas chromatography. Because the purity of naturally extracted dextrorotatory borneol is low, purification is also required to meet the pharmacopoeia's pharmaceutical standards. Furthermore, synthetic borneol contains levorotatory borneol, dextrorotatory borneol, and isoborneol, mostly in racemic forms. The content of dextrorotatory borneol in synthetic borneol is relatively low, and its efficacy and properties are far inferior to those of natural borneol. Therefore, synthetic borneol prepared by traditional chemical methods cannot meet the pharmacopoeia's pharmaceutical grade standards and requires further purification.

[0004] However, due to the extremely similar physicochemical properties of dexborneol and isoborneol, traditional physical separation methods such as vacuum distillation, extraction, or multiple crystallization are often ineffective. For example, dexborneol and isoborneol have very similar boiling points, and the fractions tend to overlap during distillation purification. Simple distillation under conventional industrial conditions often fails to achieve the pharmacopoeia-level purity. Currently, some purification techniques for crude dexborneol are summarized below: Patent CN102746121A discloses a method of obtaining the final borneol product by recrystallizing crude borneol (content 80%) twice with acetone. The dextroborneol content of the purified product obtained in this invention is above 99.5%, but the yield is too low, only 40-45%.

[0005] Patent CN119039107A discloses a method for purifying dexborneol using a silane protection-deprotection process, based on the difference in steric hindrance between dexborneol and isochorol in their hydroxyl groups. The resulting dexborneol has a purity of ≥99.7%, meeting pharmaceutical-grade standards. However, this process uses a large amount of organochlorosilanes (such as trimethylchlorosilane and tert-butyldimethylchlorosilane), which readily react with water to generate HCl, exhibiting strong corrosiveness and an irritating odor. Especially under low-temperature (-40°C) dropwise addition conditions, the equipment cost and safety risks are high. Furthermore, desilication requires acidic conditions, but acid hydrolysis easily generates siloxane byproducts or silica gel precipitates, making complete removal of residual silica particles difficult.

[0006] Patent CN118239823A discloses a method for obtaining high-purity dexborneol through a multi-step reaction involving sulfonation, resolution, and desulfonation. Although the purity is high, the steps are cumbersome and the column chromatography reaction cycle is long, which is not conducive to large-scale production.

[0007] Patent CN103739448A discloses a method for reacting a mixture of borneol with aluminum alkoxide and an alcohol to generate aluminum dexborneol and aluminum isoborneol. Under high temperature conditions, aluminum isoborneol undergoes dehydration and rearranges to form camphene. Subsequently, dexborneol and camphene are obtained by steam distillation, followed by column chromatography to obtain high-purity dexborneol. This invention suffers from cumbersome post-processing using aluminum reagents, safety risks associated with high-temperature closed reactions, long column chromatography purification cycles, high solvent consumption, high production costs, and low product purity (not meeting pharmaceutical grade standards).

[0008] In summary, the existing technologies for the purification of dextroborneol generally suffer from the following problems: Incomplete removal of isomers such as isoborneol makes it difficult for the purity of dexborneol to meet the standards of natural borneol; the catalytic system often relies on strong acids, strong bases or special catalysts, which cause severe corrosion to equipment; the purification process involves many steps and has high energy consumption, making it difficult to achieve continuous industrial production. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a purification method for crude dexborneol, which can selectively remove isoborneol under mild conditions and achieve high-purity and high-yield dexborneol preparation by simplifying the reaction steps.

[0010] This invention is achieved through the following technical solution: On one hand, a method for purifying crude dexborneol is provided. This method involves sequentially subjecting crude dexborneol to a rearrangement reaction, an esterification reaction, a salt formation reaction, an alkaline hydrolysis reaction, and post-treatment in the presence of a solvent and a catalyst to obtain refined dexborneol. The refined dexborneol has a dexborneol content ≥98.0%, a levorotatory borneol content ≤1.0%, an isoborneol content ≤0.15%, a natural camphor content ≤0.15%, and other impurities ≤0.10%.

[0011] Through the above technical solution, dexborneol and isoborneol have similar structures and polarities, making them difficult to separate using traditional physical purification methods. This invention introduces a catalyst to selectively destroy isoborneol, converting it into the dehydration rearrangement product camphene, thus preventing its coexistence with dexborneol. Subsequently, an esterification reaction is carried out with dexborneol using an anhydride reagent, followed by alkaline salt formation and alkaline hydrolysis steps to efficiently convert it into dexborneol, achieving the transformation of dexborneol from crude to high-purity product.

[0012] Furthermore, the specific process of this method is as follows: Step 1) Rearrangement reaction The crude dexborneol and catalyst I were reacted in solvent I to cause the isoborneol to undergo a rearrangement reaction. The reaction solution was then quenched with an alkaline aqueous solution and washed with water to obtain organic phase M. Step 2) Esterification reaction The organic phase M was subjected to an esterification reaction with an acid anhydride reagent under the action of catalyst II to obtain the dextroborneol esterified organic phase; Step 3) Salt formation reaction The organic phase of the dexborneol ester was reacted with an alkaline reagent to form a salt, and the solution of the ester salt was obtained by separation. Step 4) Alkali hydrolysis reaction The aqueous solution of the obtained esterified salt was subjected to alkaline hydrolysis with an alkaline reagent to obtain the reaction solution; Step 5) Post-processing The reaction solution was extracted, dried, and concentrated using solvent II to obtain solid A; After mixing the solid A with solvent III, the mixture is decolorized, filtered, crystallized, and dried to obtain the high-quality dextromethorphanol.

[0013] Further, catalyst 1 is selected from p-toluenesulfonic acid and concentrated sulfuric acid; the molar ratio of isoborneol in crude dextroborneol to catalyst 1 is 1:0.05~2; and / or, solvent 1 is selected from toluene, xylene and N,N-dimethylformamide.

[0014] Further, the anhydride reagent is selected from one of 2,3-pyrazinic anhydride, glutaric anhydride, succinic anhydride and phthalic anhydride; and / or, the catalyst II is selected from one of triethylamine and 4-dimethylaminopyridine.

[0015] Furthermore, based on the amount of dexborneol in the crude dexborneol, its molar ratio with that of the acid anhydride reagent and catalyst II is 1:0.5~5:0.5~5.

[0016] Furthermore, in steps 3) and 4), the alkaline reagent is selected from one or more of sodium bicarbonate, potassium carbonate, sodium hydroxide, and sodium carbonate.

[0017] Further, in step 3), the molar ratio of dexborneol in crude dexborneol to the alkaline reagent is 1:1 to 8; and / or, in step 4), the molar ratio of dexborneol in crude dexborneol to the alkaline reagent is 1:1 to 5.

[0018] Further, in step 5), the solvent II is selected from toluene, dichloromethane, methyl tert-butyl ether, ethyl acetate and n-heptane; the mass ratio of solid A to solvent II is 1:1~10.

[0019] Further, in step 5), the solvent III is selected from one of n-hexane, n-heptane, ethyl acetate and ethanol; the mass ratio of solid A to solvent III is 1:1~10.

[0020] Furthermore, in step 5), the crystallization temperature is -20~5℃; the time is 0.5~7h.

[0021] Beneficial effects The catalyst used in this invention selectively destroys impurities while having virtually no effect on the target compound, dexborneol. The combined esterification-saltification-alkali hydrolysis reaction significantly improves purity; after decolorization and recrystallization, the purity of dexborneol can reach over 99.0%, with a dexborneol content of not less than 98.0% and an isoborneol content of not more than 0.15%, comparable to the quality of natural borneol.

[0022] The process of this invention is simple and suitable for industrial production; the purification process of crude dextromethorphan is carried out using conventional equipment without special separation equipment; the reaction system generates no organic waste gas, which is environmentally friendly. Attached Figure Description

[0023] Figure 1 The gas chromatogram of dextromethorphan prepared in Example 1 of this invention. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0025] Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of this invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0026] Unless otherwise specified, the reagents and raw materials used in the embodiments and comparative examples of this invention are commercially available.

[0027] Example 1 A method for purifying crude dexborneol, comprising the following steps: reordering reaction, esterification reaction, salt formation reaction, alkaline hydrolysis reaction, and post-treatment, in the presence of a solvent and a catalyst, to obtain purified crude dexborneol; specifically including the following steps: Step 1) Rearrangement reaction The crude dexborneol and catalyst I were reacted in solvent I to cause the isoborneol to undergo a rearrangement reaction. The reaction solution was then quenched with an alkaline aqueous solution and washed with water to obtain organic phase M. Specifically, 100g of crude dexborneol (72% dexborneol, 22% isoborneol) (0.47mol dexborneol, 0.14mol isoborneol) was added to 1L of toluene and stirred to dissolve. 1.2g of p-toluenesulfonic acid (6.97mmol, 0.05eq) was slowly added, and the reaction was heated at 60℃ for 6 hours. Gas chromatography (GC) was used for monitoring; the reaction was stopped when the isoborneol concentration dropped below 1.0%. After cooling, 10% sodium hydroxide solution was added to quench the reaction, and the mixture was allowed to stand for phase separation. The aqueous layer was discarded, and the organic layer was washed with purified water until neutral to obtain organic phase M, which was used directly in the next step.

[0028] Step 2) Esterification reaction The organic phase M was subjected to an acid anhydride reagent for esterification under the action of catalyst II to obtain the dextroborneol esterified organic phase; Specifically, organic phase M, 23.6 g (0.23 mol, 0.5 eq) of triethylamine, and 26.6 g (0.23 mol, 0.5 eq) of glutaric anhydride were added to the reaction flask (the amounts of triethylamine and glutaric anhydride were based on the amount of dexborneol in the crude dexborneol product). The mixture was stirred to dissolve, heated to 50 °C, and refluxed for 6 h. When the concentration of dexborneol was monitored by HPLC to be <0.5%, the reaction was stopped to obtain the organic phase of dexborneol esterification.

[0029] Step 3) Salt formation reaction The organic phase of dexborneol ester was reacted with an alkaline reagent to form a salt, and the aqueous solution of the ester salt was obtained after separation. Specifically, after cooling the obtained dexborneol ester organic phase to room temperature, 190 mL (0.47 mol, 1 eq) of 10% sodium hydroxide solution was added to form a salt. After the salt formation was completed, the liquid was separated and the organic phase was discarded to obtain an aqueous solution of dexborneol ester sodium salt. Step 4) Alkali hydrolysis reaction The aqueous solution of the obtained esterified salt was subjected to alkaline hydrolysis with an alkaline reagent to obtain an alkaline hydrolysis reaction solution; Specifically, an aqueous solution of sodium salt of dexborneol ester was mixed with 49.5 g (0.47 mol, 1 eq) of sodium carbonate and heated to 50 °C for 6 h for further alkaline hydrolysis. The reaction was stopped when the ester content was monitored by HPLC to be <0.5%, and the alkaline hydrolysis reaction solution was obtained.

[0030] Step 5) Post-processing The resulting alkaline hydrolysis reaction solution was extracted with solvent II, dried, and concentrated to obtain solid A; Specifically, the alkaline hydrolysis reaction solution was extracted twice with 75 mL of toluene, the organic layers were combined, washed with water and dried, and the solvent was removed by rotary evaporation under reduced pressure to obtain solid A (62.7 g, 0.41 mol), with a dextroborneol content of 99.8% and a yield of 86.5%.

[0031] After mixing the obtained solid A with solvent III, the mixture is decolorized, filtered, crystallized, and dried to obtain the high-quality dextromethorphanol.

[0032] Specifically, solid A was mixed with 85 mL of ethyl acetate-n-heptane (volume ratio 1:2), and 0.6 g of activated carbon was added. The mixture was heated under reflux for at least 1 hour, and then filtered while hot to remove the carbon. The filtrate was cooled to -20 °C to crystallize for 0.5 hours, filtered, and the filter cake was dried under vacuum at 50-60 °C to obtain 53.0 g of pure dexborneol, with a yield of 86.6%. The product was a white crystalline powder with a purity of 99.35%, a dexborneol content of 102.2%, a levonorhalil content ≤1.0%, and an isoborneol content ≤0.15%.

[0033] Example 2 A method for purifying crude dexborneol, comprising the following steps: reordering reaction, esterification reaction, salt formation reaction, alkaline hydrolysis reaction, and post-treatment, in the presence of a solvent and a catalyst, to obtain purified crude dexborneol; specifically including the following steps: Step 1) Rearrangement reaction The crude dexborneol and catalyst I were reacted in solvent I to cause the isoborneol to undergo a rearrangement reaction. The reaction solution was then quenched with an alkaline aqueous solution and washed with water to obtain organic phase M. Specifically, 50 g of crude dexborneol (74% dexborneol, 21% isoborneol) (0.24 mol dexborneol, 68.07 mmol isoborneol) was dissolved in 500 mL of N,N-dimethylformamide. 23.4 g (136.1 mmol, 2 eq) of p-toluenesulfonic acid was slowly added dropwise. The mixture was heated to 120 °C and reacted for 5 h. The reaction was stopped when the isoborneol content dropped to 1.0% according to GC analysis. After cooling, 10% NaOH solution was added to quench the reaction, and the mixture was allowed to stand and separate into layers. The aqueous layer was discarded, and the organic layer was washed with purified water until neutral to obtain organic phase M, which was used directly in the next step.

[0034] Step 2) Esterification reaction The organic phase M was subjected to an acid anhydride reagent for esterification under the action of catalyst II to obtain the dextroborneol esterified organic phase; Specifically, organic phase M, 146.6 g (1.2 mol, 5 eq) of 4-dimethylaminopyridine, and 177.7 g (1.2 mol, 5 eq) of phthalic anhydride were added to the reaction flask (the amounts of 4-dimethylaminopyridine and phthalic anhydride were based on the amount of dexborneol in the crude dexborneol). The mixture was heated to 110 °C and refluxed for 4 h. When HPLC monitoring showed that dexborneol was <0.5%, the reaction was stopped, yielding the dexborneol esterified organic phase.

[0035] Step 3) Salt formation reaction The organic phase of dexborneol ester was reacted with an alkaline reagent to form a salt, and the aqueous solution of the ester salt was obtained after separation. Specifically, after cooling the obtained dexborneol ester organic phase to room temperature, 1.07 L (1.92 mol, 8 eq) of 15% sodium bicarbonate solution was added to form a salt. After salt formation was completed, the liquid was separated, and the organic phase was discarded to obtain an aqueous solution of dexborneol ester sodium salt.

[0036] Step 4) Alkali hydrolysis reaction The aqueous solution of the obtained esterified salt was subjected to alkaline hydrolysis with an alkaline reagent to obtain the reaction solution; Specifically, the sodium salt aqueous solution of dexborneol ester was mixed with 48.0 g (1.2 mol, 5 eq) of sodium hydroxide and heated to 100 °C for 4 h for alkaline hydrolysis. When the ester content was monitored by HPLC to be <0.5%, the reaction was stopped to obtain the alkaline hydrolysis reaction solution.

[0037] Step 5) Post-processing The resulting alkaline hydrolysis reaction solution was extracted with solvent II, dried, and concentrated to obtain solid A; Specifically, the alkaline hydrolysis reaction solution was extracted twice with 430 mL of methyl tert-butyl ether, the organic layers were combined, washed with water and dried, and the solvent was removed by rotary evaporation under reduced pressure to obtain solid A (31.6 g, 0.2 mol), with a dextroborneol content of 99.2% and a yield of 84.7%.

[0038] After mixing the obtained solid A with solvent III, the mixture is decolorized, filtered, crystallized, and dried to obtain the high-quality dextromethorphanol.

[0039] Specifically, solid A was mixed with 480 mL of n-hexane, and 3.2 g of activated carbon was added. The mixture was heated under reflux for more than 1 h, filtered to remove carbon, and the filtrate was cooled to 5 °C to crystallize for 7 h. After filtration, the filter cake was dried under vacuum at 50-60 °C to obtain 27.8 g of purified dexborneol, with a yield of 87.5%. The purity was 99.79%, the dexborneol content was 98.7%, the L-borneol content was ≤1.0%, and the isoborneol content was ≤0.15%.

[0040] Example 3 A method for purifying crude dexborneol, comprising the following steps: reordering reaction, esterification reaction, salt formation reaction, alkaline hydrolysis reaction, and post-treatment, in the presence of a solvent and a catalyst, to obtain purified crude dexborneol; specifically including the following steps: Step 1) Rearrangement reaction The crude dexborneol and catalyst I were reacted in solvent I to cause the isoborneol to undergo a rearrangement reaction. The reaction solution was then quenched with an alkaline aqueous solution and washed with water to obtain organic phase M, which was directly used in the next step. Specifically, 200g of crude dexborneol (75% dexborneol, 21% isoborneol) (0.97mol dexborneol, 0.27mol isoborneol) was added to 2L of N,N-dimethylformamide and stirred to dissolve. Then, 23.4g of p-toluenesulfonic acid (135.9mol, 0.5eq) was added, and the mixture was reacted at 100℃ for 4h. GC monitoring showed that the isoborneol content dropped below 1.0%, at which point 10% sodium hydroxide was added to quench the reaction. The mixture was allowed to stand and separate into layers. The aqueous layer was discarded, and the organic layer was washed with purified water until neutral to obtain organic phase M, which was used directly in the next step.

[0041] Step 2) Esterification reaction The organic phase M was subjected to an acid anhydride reagent for esterification under the action of catalyst II to obtain the dextroborneol esterified organic phase; Specifically, organic phase M, 147.5 g (1.46 mol, 1.5 eq) of triethylamine, and 408.5 g (2.72 mol, 2.8 eq) of 2,3-pyrazine dianhydride were added to the reaction flask (the amounts of triethylamine and 2,3-pyrazine dianhydride were based on the amount of dexborneol in the crude dexborneol product). The mixture was stirred until homogeneous, heated to 80 °C and refluxed for 5 h. When the concentration of dexborneol was monitored by HPLC to be <0.5%, the reaction was stopped, yielding the organic phase of dexborneol esterification.

[0042] Step 3) Salt formation reaction The organic phase of dexborneol ester was reacted with an alkaline reagent to form a salt, and the aqueous solution of the ester salt was obtained after separation. Specifically, after cooling the obtained dexborneol ester organic phase to room temperature, 4.03 L (2.92 mol, 3 eq) of 10% potassium carbonate solution was added to form a salt. After salt formation, the liquid was separated, the organic phase was discarded, and an aqueous solution of dexborneol ester potassium salt was obtained.

[0043] Step 4) Alkali hydrolysis reaction The aqueous solution of the obtained esterified salt was subjected to alkaline hydrolysis with an alkaline reagent to obtain the reaction solution; Specifically, the aqueous solution of the potassium salt of the esterified compound was mixed with 77.8 g (1.95 mol, 2 eq) of sodium hydroxide, heated to 80 °C and continued alkaline hydrolysis for 4 h. When the esterified compound was monitored by HPLC to be <0.5%, the reaction was stopped to obtain the alkaline hydrolysis reaction solution.

[0044] Step 5) Post-processing The resulting alkaline hydrolysis reaction solution was extracted with solvent II, dried, and concentrated to obtain solid A; Specifically, the alkaline hydrolysis reaction solution was extracted twice with 680 mL of ethyl acetate, the organic layers were combined, washed with water and dried, and the solvent was removed by rotary evaporation under reduced pressure to obtain solid A (136.5 g, 0.87 mol), with a dextroborneol content of 98.5% and a yield of 90%.

[0045] Solid A was mixed with 780 mL of ethanol, and 6.2 g of activated carbon was added. The mixture was heated under reflux for more than 1 hour, filtered to remove the carbon, and the filtrate was cooled to -5 °C to crystallize for 4 hours. The filter cake was then dried under vacuum at 55 °C to obtain 116.6 g of pure dexborneol, with a yield of 85.8%. The purity was 99.73%, the dexborneol content was 98.9%, the L-borneol content was ≤1.0%, and the isoborneol content was ≤0.15%.

[0046] Comparative Example 1 The difference from Example 1 is that column chromatography was used to purify the crude dextroborneol. The purification method is as follows: The crude dextroborneol (9.22 g) was purified by column chromatography by elution with hexane, 100:1, 80:1, 50:1, and 20:1 (hexane / ethyl acetate, w / w), and the eluent was collected in fractions.

[0047] Test results: Before refining: the purity of crude dexborneol was 69.19%; isoborneol was 16.04%; and natural camphor was 14.77%. After refining: dextroborneol purity 95.27%; isoborneol 1.12%; natural camphor 2.98%; Test results: Low purity, high impurity content.

[0048] Comparative Example 2 The difference from Example 1 is that column chromatography was used to purify the concentrate of organic phase M. The purification method is as follows: The concentrate (18.0 g) of organic phase M was purified by column chromatography by eluting sequentially with n-hexane, 100:1, 80:1, 60:1, 40:1, and 20:1 (n-hexane / ethyl acetate, w / w), and the eluent was collected in fractions.

[0049] Test results: Before refining: Purity 27.303%; Isobath 0.13%; Natural camphor 2.2%; After refining: purity 98.98%; isoborneol 0.05%; camphor 0.03%, maximum single impurity 0.6%; content 91.6%; isoborneol content 0.05%; Test results: Low content; high content of other impurities.

[0050] Comparative Example 3 The difference from Example 1 is that the crude dextroborneol was purified by recrystallization, and the purification method is as follows: Dissolve crude dexborneol (5.0 g) in acetone (6 mL), heat to 40 °C until dissolved, add activated carbon (0.05 g), continue heating to 56 °C and reflux, hot filter, cool the filtrate to allow crystals to precipitate, filter, and collect the filter cake.

[0051] Before refining: Purity 76.26%; Isobath 21.95%; Natural camphor 1.74%; Content 75.4%; After refining: Purity 80.70%; Isobath 19.09%; Natural camphor 0.18%; Content 80.4%; Test results: Low purity, low content; yield was 37.5%.

[0052] Effect Example To verify the technical effect of the method of the present invention, Example 1 was compared with Comparative Example 3, and the detection conditions were as follows: This invention uses GC to determine the purity and content of dextroborneol. The chromatographic conditions are as follows: Column: Cyclosil B (0.25 mm × 30 m, DF = 0.25 µm); Detector: FID; Inlet temperature: 200℃; Vaporization chamber temperature: 220℃; Incubator temperature: 100℃ (0-7min) → 3℃ / min → 150℃ → 10℃ / min → 220℃ (30.667-37.667min); Flow rate: 1.0 mL / min (N2); Injection volume: 1µL; Analysis time: 37.667 min; Retention time: 20.9 min; The purity, content, and yield of the two products were determined under the same testing conditions. The comparison results are shown in Table 1 below: Table 1:

[0053] The results showed that the purity of the dexborneol product prepared in Comparative Example 3 was only 80.70%, containing a large amount of impurities such as isoborneol and natural camphor, which did not meet the requirements for pharmaceutical use. Furthermore, the yield was low and material loss was significant. Compared to the purification method in Comparative Example 3, the dexborneol product prepared in Example 1 achieved a purity of 99.35% and a content of 102.2%, with extremely low levels of impurities such as levoborneol, isoborneol, and natural camphor, demonstrating a better purification effect.

[0054] In summary, the crude dexborneol refining process used in the embodiments of the present invention yields dexborneol with high purity and content, and isoborneol content ≤0.15%. The product quality is similar to that of natural borneol and can meet the requirements for pharmaceutical-grade applications.

[0055] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for purifying crude dextromethorphanol, characterized in that, The method involves sequentially refining crude dexborneol through rearrangement, esterification, salt formation, alkaline hydrolysis, and post-treatment in the presence of a solvent and catalyst to obtain refined dexborneol. The refined dexborneol contains ≥98.0% dexborneol, ≤1.0% levoborneol, ≤0.15% isoborneol, ≤0.15% natural camphor, and ≤0.10% other impurities.

2. The purification method for crude dextromethorphanol according to claim 1, characterized in that, The specific process of this method is as follows: Step 1) Rearrangement reaction The crude dexborneol and catalyst I were reacted in solvent I to cause the isoborneol to undergo a rearrangement reaction. The reaction solution was then quenched with an alkaline aqueous solution and washed with water to obtain organic phase M. Step 2) Esterification reaction The organic phase M was subjected to an esterification reaction with an acid anhydride reagent under the action of catalyst II to obtain the dextroborneol esterified organic phase; Step 3) Salt formation reaction The organic phase of the dexborneol ester was reacted with an alkaline reagent to form a salt, and the solution of the ester salt was obtained by separation. Step 4) Alkali hydrolysis reaction The aqueous solution of the obtained esterified salt was subjected to alkaline hydrolysis with an alkaline reagent to obtain the reaction solution; Step 5) Post-processing The reaction solution was extracted, dried, and concentrated using solvent II to obtain solid A; After mixing the solid A with solvent III, the mixture is decolorized, filtered, crystallized, and dried to obtain the high-quality dextromethorphanol.

3. The method for purifying crude dextromethorphanol according to claim 2, characterized in that, In step 1), catalyst 1 is selected from p-toluenesulfonic acid and concentrated sulfuric acid; the molar ratio of isoborneol in crude dextroborneol to catalyst 1 is 1:0.05~2; and / or, solvent 1 is selected from toluene, xylene and N,N-dimethylformamide.

4. The purification method for crude dextromethorphanol according to claim 2, characterized in that, In step 2), the anhydride reagent is selected from one of 2,3-pyrazine anhydride, glutaric anhydride, succinic anhydride and phthalic anhydride; and / or, the catalyst II is selected from one of triethylamine and 4-dimethylaminopyridine.

5. The method for purifying crude dextromethorphanol according to claim 2 or 4, characterized in that, Based on the amount of dexborneol in crude dexborneol, its molar ratio with that of acid anhydride reagent and catalyst II is 1:0.5~5:0.5~5.

6. The method for purifying crude dextromethorphanol according to claim 2, characterized in that, In steps 3) and 4), the alkaline reagent is selected from one or more of sodium bicarbonate, potassium carbonate, sodium hydroxide, and sodium carbonate.

7. The method for purifying crude dextromethorphanol according to claim 6, characterized in that, In step 3), the molar ratio of dexborneol in crude dexborneol to the alkaline reagent is 1:1 to 8; and / or, in step 4), the molar ratio of dexborneol in crude dexborneol to the alkaline reagent is 1:1 to 5.

8. The method for purifying crude dextromethorphanol according to claim 2, characterized in that, In step 5), solvent II is selected from toluene, dichloromethane, methyl tert-butyl ether, ethyl acetate and n-heptane; the mass ratio of solid A to solvent II is 1:1~10.

9. The method for purifying crude dextromethorphanol according to claim 2, characterized in that, In step 5), solvent III is selected from one of n-hexane, n-heptane, ethyl acetate and ethanol; the mass ratio of solid A to solvent III is 1:1~10.

10. The method for purifying crude dextromethorphanol according to claim 2, characterized in that, In step 5), the crystallization temperature is -20~5℃; the time is 0.5~7h.

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