A process for the preparation of dextromethorphan hydrobromide

Abstract

The application belongs to the field of pharmaceutical chemistry and particularly relates to a preparation method of dextromethorphan hydrobromide. The method comprises the following steps: adding a reducing agent to a solution containing a compound of formula 3, adding an acid, performing a reduction reaction, obtaining a boron-containing intermediate state, and performing acid hydrolysis on the boron-containing intermediate state to obtain dextromethorphan. In the reduction reaction process for preparing dextromethorphan, sodium borohydride and an acid system are adopted, and compared with a sodium borohydride and zinc chloride system, the reaction is more complete, and the yield and purity of dextromethorphan are greatly improved. In the process for preparing dextromethorphan hydrobromide, butanone is used as a solvent, and compared with other solvents, butanone has the best refining effect, and related impurities can be effectively removed.

Description

[0001] This application is a divisional application of the application filed on October 21, 2025, with application number 202511505399.3 and invention title "A method for preparing dextromethorphan hydrobromide". Technical Field

[0002] This invention belongs to the field of pharmaceutical chemistry, and specifically provides a method for preparing dextromethorphan hydrobromide. Background Technology

[0003] Dextromethorphan is the dextrorotatory isomer of levomorphine methyl ether, a potent centrally acting antitussive that primarily inhibits the cough center in the medulla oblongata. The U.S. Food and Drug Administration approved dextromethorphan for sale as an antitussive without a prescription in 1958. The active ingredient, dextromethorphan hydrobromide monohydrate, has the following structure: .

[0004] Today's Pharmacy, 2008, 18(4), 63-64, discloses the traditional synthetic route of dextromethorphan: .

[0005] This route uses p-methoxyphenylacetic acid (1) and 2-(1-cyclohexenyl)ethylamine (2) as raw materials. The reaction proceeds via high-temperature condensation with xylene to obtain compound 3; compound 3 undergoes Bischler-Napieralski cyclization with phosphorus oxychloride to obtain compound 4; compound 4 undergoes Raney nickel-catalyzed hydrogenation reduction and hydrobromic acid salt formation to obtain compound 5; compound 5 undergoes formaldehyde and hydrogenation reduction methylation to obtain compound 6; compound 6 undergoes D-tartaric acid resolution to obtain compound 7 with a single configuration; compound 7 undergoes Grewe cyclization with phosphate to obtain compound 8; and compound 8 undergoes trimethylphenylammonium hydroxide methylation to obtain dextromethorphan. In this method, the nitrogen methylation reaction of compound 5 involves two Raney nickel hydrogenation processes, which places high demands on equipment and personnel, resulting in high safety risks during scale-up. Furthermore, the methylation of compound 8 uses trimethylphenylammonium hydroxide as the methylating agent, which is expensive, and the byproduct of this reaction is N,N-dimethylaniline, a genotoxic impurity whose residue directly affects the quality of the active pharmaceutical ingredient.

[0006] The synthetic route for dextromethorphan disclosed in CN102977021A is as follows: .

[0007] This route also uses p-methoxyphenylacetic acid (1) and 2-(1-cyclohexenyl)ethylamine (2) as raw materials. Compound 3 is obtained by high-temperature condensation with xylene. Compound 3 is cyclized with phosphorus oxychloride by Bischler-Napieralski and reduced with potassium borohydride to obtain compound 5. Compound 5 is resolved with R-ibuprofen to obtain compound 6 with a single configuration. Compound 6 is cyclized with formaldehyde and hydrogen methylation to obtain compound 7. Compound 7 is cyclized with aluminum trichloride to obtain dextromethorphan base 8. 8 is salted with hydrobromic acid to obtain API.

[0008] In the cyclization steps 3-4 of this process, the product is unstable after vacuum concentration. In the reduction steps 4-5, the reaction is violent, requiring ice bath cooling to 0-10℃, and the reaction is incomplete. In the resolution steps 5-6, R-ibuprofen is used as the resolving agent, which is expensive. Furthermore, the reduction steps 6-7 employ Raney nickel-catalyzed hydrogenation, which requires sophisticated equipment and personnel, posing a high safety risk during scale-up. The cyclization reaction 7-8 uses aluminum chloride (Grewe) to avoid the use of phosphoric acid; however, experimental verification shows that this method cannot yield the target product, mainly producing the isomerization byproduct impurity G.

[0009] The synthetic route for dextromethorphan, as disclosed in Tetrahedron Letters 1987, 28:4829-4832, is as follows: This route uses p-methoxyphenylacetic acid ((1)) and 2-(1-cyclohexenyl)ethylamine ((2)) as raw materials, which are condensed to obtain 3; 3 is cyclized by Bischler-Napieralski under the action of phosphorus oxychloride to obtain 4; 4 is cyclized by a mixture of formic acid and neopentyl acid to obtain a formylated enamine 5; 5 is selectively hydrogenated by Ru(OCOCF3)2(R)-tolbinap catalysis to obtain a single configuration 6; 6 is cyclized by acid-catalyzed Grewe to obtain 7; 7 is reduced to obtain dextromethorphan. The metal catalyst used in the hydrogenation reduction process of this method has a high production cost, and the hydrogenation process has high requirements for equipment and personnel operation, resulting in high safety risks during scale-up.

[0010] Therefore, based on the shortcomings of the above methods, there is a need in the art to provide a method for preparing dextromethorphan that is simple to operate, has a stable reaction, high yield, and high purity. This method can improve the problems of general existing production technologies, increase product yield and purity, make it more practical for production, and make it more competitive in the market to meet the growing market demand. Summary of the Invention

[0011] The purpose of this invention is to provide a method for preparing dextromethorphan hydrobromide, overcoming the shortcomings of existing technologies. The preparation method provided by this invention is simple to operate, has stable reaction, high yield, and high purity, making it more suitable for industrial production and possessing significant industrial application value.

[0012] One of the technical problems to be solved by the present invention is to provide a method for preparing dextromethorphan (compound of formula 4), comprising the following steps: (1) Add a reducing agent and acid to a solution containing compound of formula 3 to carry out a reduction reaction to obtain a boron-containing intermediate; (2) The boron-containing intermediate is then hydrolyzed with acid to obtain dextromethorphan.

[0013] In a further preferred embodiment of the present invention, the reducing agent is any one or a combination of potassium borohydride, sodium borohydride, lithium borohydride, and calcium borohydride.

[0014] In a further preferred embodiment of the present invention, the acid in step (1) can be glacial acetic acid or trifluoroacetic acid.

[0015] In a further preferred embodiment of the present invention, the acid used for acid hydrolysis in step (2) is an aqueous solution of hydrochloric acid or sulfuric acid, wherein the concentration of the aqueous solution of hydrochloric acid or sulfuric acid is 5-20%, preferably 8-15%, and more preferably 10-12%.

[0016] In a further preferred embodiment of the present invention, the organic solvent used in the preparation of compound 4 from compound 3 is selected from any one or a combination of toluene, tetrahydrofuran, 2-methyltetrahydrofuran.

[0017] In a further preferred embodiment of the present invention, during the reaction process, the mixture is first stirred at -10℃ to 20℃ for 0.2-1h, then heated to 20℃ to 50℃ and stirred for 0.5-2h, and finally heated to 50℃ to 80℃ and stirred for 2-6h; preferably, the mixture is first stirred at 0℃ to 10℃ for 0.3-0.8h, then heated to 20℃ to 30℃ and stirred for 0.7-1.5h, and finally heated to 55℃ to 65℃ and stirred for 3-5h.

[0018] In a further preferred embodiment of the present invention, the molar ratio of the reducing agent and the compound of formula 3 in step (1) is (1-6):1, preferably (2-5):1; more preferably (3-4):1.

[0019] In a further preferred embodiment of the present invention, the molar ratio of the acid and the compound of formula 3 in step (1) is (1-6):1, preferably (2-5):1; more preferably (3-4):1.

[0020] In a further preferred embodiment of the present invention, sodium borohydride is added to a solution containing the compound of formula 3, followed by the addition of glacial acetic acid to carry out a reduction reaction.

[0021] In a further preferred embodiment of the present invention, the molar ratio of glacial acetic acid and sodium borohydride in step (1) is 1:1.

[0022] Another aspect of the present invention is to provide a method for preparing dextromethorphan (compound of formula 4), wherein the compound of formula 3 is subjected to a reduction reaction in the presence of red aluminum and an organic solvent, and the reaction is carried out at a controlled temperature of 30-40°C for 1-3 hours. After the reaction is completed, the mixture is filtered and washed to obtain dextromethorphan.

[0023] In a further preferred embodiment of the present invention, the molar ratio of the red aluminum and the compound of formula 3 is (2-4):1, preferably 3:1.

[0024] Another aspect of the present invention is to provide a method for preparing dextromethorphan hydrobromide, comprising the following steps: The compound of formula 4 is dissolved in a solution of butanone, and then acidified with hydrobromic acid solution to obtain dextromethorphan hydrobromide.

[0025] In a further preferred embodiment of the present invention, the concentration of the hydrobromic acid solution is 30-60%, preferably 40-50%, and more preferably 45-48%.

[0026] In a further preferred embodiment of the present invention, the weight ratio of the butanone solution to the compound of formula 4 is (1.0-10.0):1, preferably (2-8):1, more preferably (3-6):1, and even more preferably (4-5):1.

[0027] In a further preferred embodiment of the present invention, the molar ratio of the hydrobromic acid and the compound of formula 4 is (0.5-1.5):1, preferably (0.8-1.2):1, and more preferably 1:1.

[0028] In a further preferred embodiment of the present invention, the reaction temperature is 20-60℃, preferably 25-55℃, preferably 30-50℃, preferably 40-50℃, preferably 30-45℃, preferably 30-35℃; the reaction time is 1-10h, preferably 2-8h, preferably 3-6h; after the reaction is completed at the above temperature, the temperature is lowered to -5-0℃ and stirred for 1-3h.

[0029] In a further preferred embodiment of the present invention, after the reaction is completed, the sample is filtered and dried to obtain dextromethorphan hydrobromide.

[0030] Another aspect of the present invention is to provide a method for preparing a compound of formula 3, comprising the following steps: Compound of Formula 2 is cyclized to produce compound of Formula 3.

[0031] In a further preferred embodiment of the invention, the cyclization reaction is carried out in the presence of 85% phosphoric acid and phosphorus pentoxide.

[0032] In a further preferred embodiment of the present invention, the solvent used for the cyclization reaction is toluene.

[0033] In a further preferred embodiment of the present invention, the cyclization reaction temperature is 40-70°C, preferably 50-60°C.

[0034] In a further preferred embodiment of the present invention, the mass ratio of the compound of formula 2 to 85% phosphoric acid is (4-11):1, preferably (5-10):1, and more preferably (6-8):1.

[0035] In a further preferred embodiment of the present invention, the mass ratio of phosphorus pentoxide to compound of formula 2 is (1-6):1, preferably (2-5):1, and more preferably (3-4):1.

[0036] Another aspect of the present invention is to provide a method for preparing a compound of formula 2, comprising the following steps: Compound of Formula 1 undergoes a formylation reaction to produce compound of Formula 2.

[0037] In a further preferred embodiment of the present invention, the formylation reaction is carried out at a reflux temperature, preferably at 90-110°C for 4-6 hours.

[0038] In a further preferred embodiment of the present invention, the molar ratio of the compound of Formula 1 to formic acid is 1:(2-4), preferably 1:3.

[0039] In a further preferred embodiment of the invention, formic acid and a compound of formula 1 are used for a formylation reaction.

[0040] In a further preferred embodiment of the present invention, the solvent used for the formylation reaction is toluene.

[0041] In a further preferred embodiment of the invention, the compound of Formula 1 is freed prior to the formylation reaction.

[0042] Compared with the prior art, the present invention has the following advantages: 1. In the reduction reaction process for preparing dextromethorphan, this invention uses a sodium borohydride and preferably glacial acetic acid system, which, compared to the sodium borohydride and zinc chloride system, results in a more thorough reaction and greatly improves the yield and purity of dextromethorphan.

[0043] 2. In the preparation of dextromethorphan hydrobromide, this invention uses butanone as a solvent. Compared with other solvents, butanone has the best purification effect, and all related impurities can be effectively removed. This invention scientifically screens parameters such as reaction temperature, crystallization temperature, and feed ratio, which improves the removal effect of impurities while ensuring the yield.

[0044] 3. In the process of preparing dextromethorphan hydrobromide according to the present invention, the overall reaction conditions are mild, the product yield and purity are high, the quality of the finished product is improved, and it is suitable for large-scale industrial production. Detailed Implementation

[0045] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0046] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0047] The reaction route of this invention is as follows: .

[0048] Example 1: Preparation of compound 2 Add 294 g of 10% sodium hydroxide aqueous solution to the reaction flask, stir, add toluene (393 g) and compound 1 (150 g), stir for 1.5 h, allow to stand and separate the liquid to obtain the organic phase. Add toluene (393 g) to the aqueous phase, stir, allow to stand and separate the liquid to obtain the organic phase. Combine the organic phases, add drinking water (150 g), stir, allow to stand and separate the liquid to obtain the organic phase.

[0049] Add 51g of 99% formic acid to the above organic phase. After the addition is complete, heat the solution to reflux and separate the water. React at 100-110℃ for 5 hours. After the reaction is complete, cool to 20-30℃. Add 10% sodium hydroxide aqueous solution, stir, and allow to stand for separation. Add 10% sodium chloride aqueous solution to the organic phase, stir, and allow to stand for separation. Dry the organic phase with anhydrous sodium sulfate for 1 hour. Filter to obtain the filtrate. Concentrate toluene under reduced pressure at a temperature below 100℃ to obtain 103.1g of oily substance with an HPLC purity of 99.78%.

[0050] Example 2: Preparation of compound 3 Add 562g of 85% phosphoric acid to the reaction flask, stir, and add 268g of phosphorus pentoxide in batches while maintaining the temperature. After the addition is complete, stir for 4-5 hours. Then add a mixed solution of 83.6g of compound 2 and 110g of toluene. Maintain the temperature at 55-65℃ and react for 24 hours. After the reaction is complete, add 219g of toluene to the reaction solution, stir, cool to 10℃, and add drinking water while maintaining the temperature ≤40℃. After the addition is complete, stir, let stand, and separate the liquid to obtain the organic phase. Add 10% sodium hydroxide aqueous solution to the organic phase to adjust the pH to 8-12, stir, let stand, and separate the liquid. Add 10% sodium chloride aqueous solution to the organic phase, stir, let stand, and separate the liquid. Dry the organic phase with anhydrous sodium sulfate for 1 hour. Filter to obtain a toluene solution of compound 3, concentrate to dryness under reduced pressure below 100℃ to obtain 82.7g of oily substance with an HPLC purity of 87.36%.

[0051] Example 3: Preparation of compound 4 To 69.7g of compound 3, add toluene (422g), tetrahydrofuran (497g), and sodium borohydride (36.3g), and cool to 0-5℃. Under nitrogen protection, slowly add a mixed solution of glacial acetic acid (57.6g) and tetrahydrofuran (63g) at a controlled temperature of ≤10℃. After addition, stir at 0-10℃ for 0.5h, then raise the temperature to 20-30℃ and stir for 1h. Raise the reaction solution to 55-65℃ and react for 4h. After timing, cool to 5℃ and slowly add 479g of 10% dilute sulfuric acid under nitrogen protection to quench the reaction. After quenching, add 48g of concentrated sulfuric acid and 32ml of drinking water to the reaction flask. After addition, raise the temperature to 70-75℃ and stir for 1h.

[0052] After the reaction was complete, the temperature was lowered to 20-30℃. A 20% sodium hydroxide aqueous solution was added, stirred, allowed to stand, and the mixture was separated. An 18% sodium chloride aqueous solution was added to the organic phase, stirred, allowed to stand, and the mixture was separated. The organic phase was dried over anhydrous magnesium sulfate for 1 hour. The mixture was filtered, and the temperature was controlled below 100℃. The toluene was concentrated to dryness under reduced pressure to give 58.1 g of a white solid with an HPLC purity of 87.74%.

[0053] Example 4: Preparation of compound 5 Butanone (281g) was added to 58.1g of compound 4 and the mixture was heated to 35°C to dissolve it. 48% hydrobromic acid (36.1g) was then slowly added. After the addition was complete, the temperature was maintained at 30-45°C and stirred for 1 hour. The temperature was then lowered to -5 to 0°C and stirred for 2 hours. The mixture was filtered, and the resulting solid was dried under vacuum at 60±5°C for 10 hours to obtain 58.9g of dextromethorphan hydrobromic acid, with a yield of 74.3% and an HPLC purity of 99.1%.

[0054] Comparative Example 1: Preparation of Compound 4 Zinc chloride (1.06 g), sodium borohydride (0.29 g), and anhydrous tetrahydrofuran (20 ml) were added to the reaction flask. After the addition was complete, the mixture was stirred, and then a mixture of compound 3 (2.2 g) and anhydrous tetrahydrofuran (12 ml) was added dropwise. After the addition was complete, a large number of bubbles were generated. The mixture was heated to reflux temperature of approximately 68 °C and reacted for 24 h. TLC monitoring showed that a small amount of starting material compound 3 remained. 35 ml of 10% sodium hydroxide aqueous solution was added, and the mixture was heated to 60 °C and reacted for 3 h. The mixture was cooled, and 20 ml of tetrahydrofuran was added. The mixture was stirred and allowed to stand to separate into layers. The aqueous phase was extracted once more with 20 ml of tetrahydrofuran. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 1.89 g of a yellow solid with an HPLC purity of 65.32%.

[0055] Example 5 and Comparative Example 2: The preparation method in Example 4 remained unchanged. The amounts of compound 4, butanone, and hydrobromic acid were adjusted to form Example 5. No solvent was added to form Comparative Example 2-1. Butanone was replaced with acetone, ethyl acetate, toluene, isopropyl acetate, and methyl tert-butyl ether, respectively, to form Comparative Examples 2-2, 2-3, 2-4, 2-5, and 2-6. The contents of impurity G and impurity RRT0.95 were determined, as shown in the table below.

[0056] The structure of impurity G described in the table: .

[0057] The structure of the RRT0.95 impurity in the table is as follows: .

[0058] As can be seen from the table above, the purification effect of methyl ethyl ketone (MEK) is the best, and all related impurities can be effectively removed.

[0059] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and improvements can be made to the present invention without departing from the spirit and scope thereof.

Claims

1. A method for preparing dextromethorphan hydrobromide, comprising the following steps: The compound of formula 4 was dissolved in a solution of butanone, and then acidified with hydrobromic acid solution to give dextromethorphan hydrobromic acid.

2. The method according to claim 1, wherein the molar ratio of the hydrobromic acid and the compound of formula 4 is (0.5-1.5):1; and the concentration of the hydrobromic acid solution is 30-60%.

3. The method according to claim 1 or 2, wherein the weight ratio of the butanone solution to the compound of formula 4 is (1.0-10.0):

1.

4. The method according to claim 3, wherein the reaction temperature for acidification of hydrobromic acid solution is 20-60℃ and the reaction time is 1-10h; after the reaction is completed at the above temperature, the temperature is lowered to -5-0℃ and stirred for 1-3h.

5. The method of claim 1, wherein the preparation method of the compound of formula 4 comprises the following steps: (1) Add a boron-based reducing agent to a solution containing compound 3, add glacial acetic acid, and carry out a reduction reaction to obtain a boron-containing intermediate; (2) The boron-containing intermediate is then hydrolyzed with acid to obtain dextromethorphan.

6. The method according to claim 5, wherein the boron reducing agent is any one or a combination of potassium borohydride, sodium borohydride, lithium borohydride, and calcium borohydride.

7. The method according to claim 5, wherein the acid used for acid hydrolysis in step (2) is an aqueous solution of hydrochloric acid or sulfuric acid, and the concentration of the aqueous solution of hydrochloric acid or sulfuric acid is 5-20%.

8. The method of claim 5, wherein the organic solvent used in the preparation of compound 4 from compound 3 is selected from any one or a combination of toluene, tetrahydrofuran, 2-methyltetrahydrofuran.

9. The method according to claim 5, wherein during the reduction reaction, the mixture is first stirred at -10℃ to 20℃ for 0.2-1h, then heated to 20℃ to 50℃ and stirred for 0.5-2h, and finally heated to 50℃ to 80℃ and stirred for 2-6h.

10. The method of claim 5, wherein the molar ratio of the reducing agent and the compound of formula 3 in step (1) is (1-6):1; and the molar ratio of the acid and the compound of formula 3 in step (1) is (1-6):1.

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