A process for the preparation of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline

Abstract

The application belongs to the field of pharmaceutical chemistry and specifically relates to a preparation method of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, which comprises the following steps: adding a reducing agent in an alkaline aqueous solution, adding a cosolvent under nitrogen protection, controlling the temperature at 10-30 DEG C, slowly adding an aqueous solution of compound 2, and stirring to react, thereby obtaining the product directly. In the application, after compound 2 is prepared, the post-reaction liquid is not concentrated, and the product is extracted with water, thereby solving the problem of unstable product concentration. In the reduction reaction from compound 2 to compound 3, the reducing agent is added in the aqueous solution of sodium hydroxide at one time, the solvent is added to assist dissolution, and then the aqueous solution of compound 2 is added to perform the reduction reaction, the process is mild, the cumbersome batch addition of the reducing agent is avoided, the reaction time is short, the energy consumption is low, the post-treatment is mild, and the obtained product has the advantages of high yield and high purity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and specifically provides a preparation method of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline. BACKGROUND

[0002] Dextromethorphan is a powerful central antitussive drug, which is the right isomer of morphine and is mainly used to inhibit the cough center of the medulla. In 1958, the U.S. Food and Drug Administration approved that dextromethorphan can be sold as an antitussive drug without a doctor's prescription. The effective component of the antitussive drug, dextromethorphan hydrobromide monohydrate, has the following structure:

[0003] .

[0004] 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (see formula III below) is an important intermediate in the synthesis of dextromethorphan, and the conventional process route is as follows:

[0005] .

[0006] Today's pharmacy, 2008, 18 (4), 63-64, discloses a traditional synthesis route of dextromethorphan:

[0007] .

[0008] The route uses p-methoxyphenylacetic acid (1) and 2-(1-cyclohexenyl)ethylamine (2) as raw materials, and 3 is obtained through a high-temperature condensation reaction of xylene; 3 is subjected to Bischler-Napieralski ring closure through phosphorus oxychloride to obtain 4; 4 is subjected to catalytic hydrogenation reduction through Raney nickel to obtain 5, and then 5 is subjected to salt formation through hydrobromic acid; 5 is subjected to methylation through formaldehyde and hydrogenation reduction to obtain 6; 6 is subjected to D-tartaric acid resolution to obtain single configuration 7; compound 7 is subjected to Grewe ring closure through phosphoric acid to obtain 8; and 8 is subjected to methylation through trimethylphenyl ammonium hydroxide to obtain dextromethorphan. In the method, the nitrogen methylation reaction of compound 5 has two Raney nickel hydrogenation processes, and the requirements for equipment and personnel operation are high, and the safety risk of enlargement is high. In addition, trimethylphenyl ammonium hydroxide is used as a methylating agent for the methylation of compound 8, which is expensive, and the by-product of the reaction is N,N-dimethylaniline, which is a genotoxic impurity, and the residue directly affects the quality of the bulk drug.

[0009] CN102977021A discloses a synthesis route of dextromethorphan as follows:

[0010] .

[0011] The route also takes p-methoxybenzene acetic acid (1) and 2-(1-cyclohexenyl) ethylamine (2) as raw materials, compound 3 is obtained by high temperature condensation of xylene, compound 3 is obtained by Bischler-Napieralski ring closure of phosphorus oxychloride and reduction of potassium borohydride, compound 5 is obtained by R-ibuprofen splitting, compound 6 is obtained by formaldehyde, hydrogenation methylation, compound 7 is obtained by aluminum chloride ring closure, and the API is obtained by hydrobromic acid salt of compound 8.

[0012] The ring closure step of the process 3-4, the post-treatment is reduced pressure concentration of toluene, the concentration temperature is too high, the product is unstable, the concentration temperature is too low, and too much toluene is left. Too much residual toluene will affect the reduction reaction of 4-5, the reaction rate is slow, and the raw material is not completely reacted. Therefore, the process stability is poor in the scale-up process. And the reduction needs to be 0℃, and the post-treatment process is relatively violent, the safety risk is high. The splitting step of the process 5 to 6, R-ibuprofen is used as a splitting reagent, which is expensive. In addition, the reduction of 6 to 7 uses Raney nickel catalytic hydrogenation reaction, which has high requirements for equipment and personnel, and high safety risk in scale-up. The ring closure reaction of 7 to 8 uses aluminum chloride Grewe ring closure, which avoids the use of phosphoric acid, but experiments have verified that the method cannot obtain the target product, mainly obtaining isomerization by-product impurity G.

[0013]

[0014] CN106632041A also discloses that p-methoxybenzene acetic acid and 2-(1-cyclohexenyl) ethylamine are used as raw materials, compound II is obtained by high temperature condensation of xylene, compound II is obtained by Bischler-Napieralski ring closure of phosphorus oxychloride and reduction of potassium borohydride. The reaction also has problems such as instability of the reaction product after ring closure, poor process stability, need to be cooled to 0℃, and high safety risk in post-treatment.

[0015] Therefore, based on the defects of the above-mentioned method, the present application still needs to provide a preparation method of dextromethorphan intermediate which is simple in operation, stable in reaction, high in yield and purity, can improve the problems of general existing production technology, improve the product yield and purity, is more practical in production, and has more market competitiveness to meet the increasing market demand. SUMMARY

[0016] The purpose of the present application is to provide a preparation method of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (i.e. compound 3 of the following formula), which overcomes the defects in the prior art, is simple in operation, stable in reaction, high in yield and purity, and is more suitable for industrial production, and has high industrial value.

[0017] The technical problem solved by the present application is to provide a preparation method of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (compound 3), comprising the following steps:

[0018]

[0019] (1) adding a reducing agent in an alkaline aqueous solution, adding a cosolvent under nitrogen protection, controlling the temperature at 10-30℃, slowly adding an aqueous solution of compound 2, and stirring to react;

[0020] (2) after the reaction is completed, the target compound 3 is separated;

[0021] In a further preferred embodiment of the present application, the separation method in step (2) comprises the steps of extracting the reaction system, concentrating the organic phase, and optionally washing the obtained solid after concentration.

[0022] In a further preferred embodiment of the present application, the alkaline aqueous solution is sodium hydroxide aqueous solution and / or potassium hydroxide aqueous solution, and the concentration of the alkaline aqueous solution is 5-30wt%, preferably 10-20wt%, and more preferably 12-15wt%. In a further preferred embodiment of the present application, the temperature is preferably controlled at 10-25℃, and more preferably at 12-20℃.

[0023] In a further preferred embodiment of the present application, the reducing agent is any one or a combination of potassium borohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and borane.

[0024] In a further preferred embodiment of the present application, the reducing agent can be added in batches or at one time, and is preferably added at one time.

[0025] In a further preferred embodiment of the present application, the cosolvent is any one or a combination of methanol, ethanol, propanol, isopropanol, and THF.

[0026] In a further preferred embodiment of the present application, the extraction solvent is any one or a combination of ethyl acetate, isopropyl acetate, and toluene.

[0027] In a further preferred embodiment of the present application, the stirring time is 5-30 minutes, and preferably 10-20 minutes.

[0028] In a further preferred embodiment of the present application, the obtained organic phase is added with a hydrobromic acid solution, heated to 50-60℃, and stirred for 0.5-2h to obtain a hydrobromated compound 3.

[0029] Still another aspect of the present application provides a method for preparing 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (compound 3), comprising the following steps:

[0030]

[0031] (1) adding a dehydrating agent to a solution containing compound 1 to perform a cyclization reaction, and then adding water to the solution after the reaction is completed, stirring and standing to obtain an aqueous solution of compound 2;

[0032] (2) adding a reducing agent to an aqueous base solution, adding a cosolvent under nitrogen protection, slowly adding the aqueous solution of compound 2 while controlling the temperature at 10-30℃, and stirring to react;

[0033] 3) separating the target compound 3 after the reaction is completed.

[0034] In a further preferred embodiment of the present application, the separation method of step 3) comprises the steps of extracting the reaction system and concentrating the organic phase, and optionally further comprises the step of washing the solid obtained by concentration.

[0035] In a further preferred embodiment of the present application, the method for preparing compound 1 comprises the following steps: dissolving p-methoxyphenylacetic acid in an organic solvent, adding N,N-carbonyldiimidazole and controlling the temperature below 40℃ to perform the reaction; then adding a mixture of 2-(1-cyclohexenyl)ethylamine and an organic solvent and controlling the temperature below 50℃ to perform the reaction; and obtaining the product after the reaction is completed and post-treatment.

[0036] In a further preferred embodiment of the present application, the solvent in the solution of compound 1 in step (1) is any one or a combination of toluene, chlorobenzene, nitrobenzene and xylene. Further preferably, the solution containing compound 1 is a toluene solution of compound 1.

[0037] In a further preferred embodiment of the present application, the dehydrating agent in step (1) is selected from any one or a combination of phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and polyphosphoric acid.

[0038] In a further preferred embodiment of the present application, the reaction temperature in step (1) is 70-150℃, preferably 80-130℃, and more preferably 90-120℃; and the reaction time is 3-10h, preferably 4-8h, and more preferably 5-7h.

[0039] In a further preferred embodiment of the present application, the mass ratio of the dehydrating agent to 2-(1-cyclohexenyl)ethylamine in step (1) is (0.1-2):1, preferably (0.5-1.5):1, and more preferably (0.7-1):1.

[0040] In a further preferred embodiment of the present application, the mass ratio of water to 2-(1-cyclohexenyl)ethylamine added in step (1) is (1-10):1, preferably (3-7):1, more preferably (4-5):1.

[0041] In a further preferred embodiment of the present application, after the reaction in step (1) is completed, the feed solution is cooled to 10-20°C, preferably to 15-20°C.

[0042] In a further preferred embodiment of the present application, the aqueous alkaline solution in step (2) is sodium hydroxide solution and / or potassium hydroxide solution, and the concentration of the aqueous alkaline solution is 5-30wt%, preferably 10-20wt%, more preferably 12-15wt%.

[0043] In a further preferred embodiment of the present application, the temperature in step (2) is preferably controlled at 10-25°C, more preferably 12-20°C.

[0044] In a further preferred embodiment of the present application, the reducing agent in step (2) is any one of potassium borohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane, or a combination thereof.

[0045] In a further preferred embodiment of the present application, the reducing agent in step (2) can be added in batches or all at once, preferably all at once.

[0046] In a further preferred embodiment of the present application, the cosolvent in step (2) is any one of methanol, ethanol, propanol, isopropanol, THF, or a combination thereof.

[0047] In a further preferred embodiment of the present application, the mass ratio of reducing agent to 2-(1-cyclohexenyl)ethylamine in step (2) is (0.05-1):1, preferably (0.1-0.5):1, more preferably (0.15-0.25):1.

[0048] In a further preferred embodiment of the present application, the mass ratio of cosolvent to 2-(1-cyclohexenyl)ethylamine in step (2) is (0.1-2):1, preferably (0.5-1.5):1, more preferably (0.7-1):1.

[0049] In a further preferred embodiment of the present application, the extraction solvent is any one of ethyl acetate, isopropyl acetate, toluene, or a combination thereof.

[0050] In a further preferred embodiment of the present application, a hydrobromic acid solution is added to the obtained organic phase, and the temperature is raised to 50-60°C, and the mixture is stirred for 0.5-2h to obtain the hydrobromic acid compound 3.

[0051] Another aspect of the present application provides a preparation method of compound 4, comprising the following steps:

[0052]

[0053] Compound 3 or the hydrobromide salt of compound 3 is subjected to resolution in a solvent under the action of D-mandelic acid to obtain compound 4.

[0054] In a further preferred embodiment of the present application, compound 3 is subjected to resolution in a solvent selected from any one of acetone, acetonitrile, methanol, ethanol or a combination thereof, and D-mandelic acid is further added.

[0055] In a further preferred embodiment of the present application, the resolution reaction is carried out at a temperature of 40-80℃, preferably 50-70℃, more preferably 55-60℃, and the reaction time is 0.5-4h, preferably 1-3h.

[0056] In a further preferred embodiment of the present application, the hydrobromide salt of compound 3 is subjected to resolution after being freed.

[0057] In a further preferred embodiment of the present application, the mass ratio of the hydrobromide salt of compound 3 to D-mandelic acid is (1-10):1, preferably (2-7):1, more preferably (3-4):1.

[0058] In a further preferred embodiment of the present application, after the resolution reaction is completed, the reaction solution is cooled to 50-55℃, and then stirred for 0.5-2h, and then washed and dried after cooling.

[0059] Compared with the prior art, the present application has the following beneficial effects:

[0060] 1. In the present application, after compound 2 is prepared, the post-reaction reaction solution is not concentrated, and the product is extracted with water, thereby solving the problem of unstable product concentration. In the reduction reaction of compound 2 to compound 3, a reducing agent is added in an aqueous solution of sodium hydroxide, a solvent is added for dissolution, and then an aqueous solution of compound 2 is added for reduction reaction. This process is mild, can realize one-time addition of the reducing agent, simplifies the operation steps, has short reaction time, low energy consumption, and mild post-treatment, and can obtain a product with high yield and high purity.

[0061] 2. In the present application, the overall reaction conditions in the preparation process of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline are mild, the product yield and purity are high, the quality of the finished product of the dextromethorphan intermediate is improved, and the process is suitable for industrialized large-scale continuous production.

[0062] 3. In the application, 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline is resolved by D-mandelic acid, and the resolved R-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline has high selectivity and high yield. DETAILED DESCRIPTION

[0063] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. Furthermore, it should be understood that after reading the content of the application, those skilled in the art can make various modifications or changes to the application, and these equivalent forms also fall within the scope of the appended claims.

[0064] The specific conditions not mentioned in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments not mentioned by the manufacturer are all conventional products that can be obtained by purchase.

[0065] The synthetic route of the application is as follows:

[0066]

[0067] Example 1:

[0068] A 5L reaction bottle was added with toluene (1569g), and stirring was started. Then p-methoxyphenylacetic acid (258g) was added, and after the addition was completed, the temperature was increased to 30℃. Then N,N'-carbonyldiimidazole (252g) was added in batches, and after the addition was completed, the temperature was controlled at ≤35℃, and stirring was carried out for 1h. Then a mixture of 2-(1-cyclohexenyl)ethylamine (150g) and toluene (131g) was added. After the addition was completed, the reaction liquid was controlled at 40-50℃, and reaction was carried out for 1h. After the reaction was completed, 10% dilute hydrochloric acid was added, stirring was carried out, and phase separation was carried out after standing. Then 10% sodium carbonate aqueous solution was added to the organic layer, stirring was carried out, and phase separation was carried out after standing. Anhydrous sodium sulfate was dried for 1h, suction filtration was carried out, and the toluene solution of compound 1 was obtained, and the HPLC purity was 99.32%.

[0069] Example 2:

[0070] To the toluene solution of compound 1 in Example 1, phosphorus oxychloride (129g) was slowly added. After the addition was completed, the liquid was heated to 96-110℃, and reaction was carried out for 6h. After the reaction was completed, the liquid was cooled to 15℃, and drinking water (655g) was added. After the addition was completed, stirring was carried out, and phase separation was carried out after standing, and the aqueous solution of compound 2 was obtained, and the HPLC purity was 96.29%.

[0071] Example 3:

[0072] Into a 5L reaction flask, add 983g of drinking water, 144g of sodium hydroxide, and stir. Cool to 15°C, and add 31.5g of sodium borohydride. Slowly add 129g of methanol to assist dissolution under nitrogen protection. After the addition is complete, control the temperature of the solution at 10-20°C, and slowly add the aqueous solution of compound 2 from Example 2. After the addition is complete, stir for 20 minutes. The HPLC purity of the reaction solution is 82.51%. After the reaction is complete, control the temperature of the solution at 20-25°C, add ethyl acetate, stir, and separate the liquid by standing. Then add 10% sodium chloride aqueous solution, stir, and separate the liquid by standing. Slowly add 48% hydrobromic acid (212g) to the organic phase. After the addition is complete, warm to 55-60°C, and stir for 1 h. Continue to cool to 0-10°C, and stir for 2 h. Filter, and dry the obtained solid at 60-70°C under a blast of air for 12 h to obtain 339g of the hydrobromide salt of compound 3, with a yield of 83.7% (calculated based on the amount of 2-(1-cyclohexenyl)ethylamine used in Example 1), and an HPLC purity of 99.07%.

[0073] Example 4:

[0074] Into a 5L reaction flask, add 678g of drinking water, 919g of ethyl acetate, and 339g of the hydrobromide salt of compound 3, and stir. Adjust the pH of the solution to 8-11 with 25%-28% ammonia water, stir, and separate the liquid by standing to obtain the organic phase. Add drinking water, stir, and separate the liquid by standing. Wash the organic phase with drinking water once more. Concentrate the ethyl acetate under reduced pressure below 70°C. Cool the solution to 30-40°C. Add acetone to the above concentrate, stir, and warm to 55-60°C. Slowly add a mixture of 92g of D-mandelic acid and acetone. After the addition is complete, stir at 55-60°C for 1 h. Cool the solution to 50-55°C, stir for 1 h. Cool to 20-30°C, stir for 1 h. Continue to cool the solution to -5-0°C, and stir for 1 h. Filter, and dry the obtained solid at 60-70°C under a blast of air for 8 h to obtain 189g of compound 4, with a yield of 46.1% (calculated based on the amount of compound 3 used), an HPLC purity of 99.0%, and an ee value of 97.2%.

[0075] Example 5:

[0076] To a 5L reaction flask, add drinking water (983g), sodium hydroxide (144g), and stir. Cool to 15°C, and add sodium borohydride (32g). Slowly add methanol (129g) to aid dissolution under nitrogen protection. After the addition is complete, control the temperature of the solution at 10-20°C, and slowly add the aqueous solution of compound 2 from Example 2. After the addition is complete, stir for 20 minutes. The HPLC purity of the reaction solution is 88.59%. After the reaction is complete, control the temperature of the solution at 20-25°C, add ethyl acetate, stir, and separate the liquid by standing, to obtain an organic phase. Then add 10% sodium chloride aqueous solution, stir, and separate the liquid by standing, to obtain an ethyl acetate solution of compound 3. Concentrate the ethyl acetate under reduced pressure below 70°C. After the concentration is complete, cool the solution to 30-40°C.

[0077] To the above concentrate, add acetone, stir, and warm to 55-60°C. Slowly add a mixture of D-mandelic acid (109g) and acetone. After the addition is complete, stir at 55-60°C for 1 h. Cool the solution to 50-55°C, stir for 1 h. Cool to 20-30°C, stir for 1 h. Continue to cool the solution to -5-0°C, and stir for 1 h. Filter, and dry the obtained solid at 60-70°C for 8 h, to obtain 185g of compound 4, with a yield of 37.7% (calculated based on the amount of 2-(1-cyclohexenyl)ethylamine used in Example 1), an HPLC purity of 99.1%, and an ee value of 97.1%.

[0078] Comparative Example 1

[0079] To the toluene solution of compound 1 in Example 1, slowly add phosphorus oxychloride (129g). After the addition is complete, warm the solution to 96-110°C, and react for 6 h. The HPLC purity of the reaction solution is 94.90%. After the reaction is complete, control the temperature below 70°C, and concentrate under reduced pressure, to obtain compound 2, which is unstable, with an HPLC purity of 91.14%.

[0080] To the compound 2, add methanol (1296 g) and stir until dissolved. Cool the solution to 5°C, and add potassium borohydride (6.45 g) in batches, controlling the temperature to be ≤15°C, and the time to be about 1 h. If the reaction is too fast, the reaction will overflow the material. After the addition is complete, control the temperature to be 5-20°C for 2 h. The HPLC purity of the reaction solution is 75.93%. Add drinking water to another 5 L reaction bottle, cool to 2°C, and add the above reaction solution in batches for quenching, controlling the temperature to be ≤30°C, and the addition time to be about 1.5 h. After the quenching is complete, continue to stir for 1 h. Concentrate the methanol under reduced pressure while controlling the temperature to be below 80°C. After the concentration is complete, cool the solution to below 30°C, and add 20% sodium hydroxide aqueous solution and ethyl acetate. After the addition is complete, stir and separate the liquid. Add 10% sodium chloride aqueous solution to the organic phase, stir, and separate the liquid. Slowly add 48% hydrobromic acid (202.5 g) to the organic phase while cooling to 10°C. After the addition is complete, warm to 55-60°C, and stir for 1 h. Continue to cool to 0-10°C, and stir for 2 h. Filter, and dry the obtained solid at 60-70°C with air blowing for 12 h to obtain 315 g of compound 3, with a yield of 77.8% (calculated based on the amount of 2-(1-cyclohexenyl)ethylamine used in Example 1), and an HPLC purity of 98.48%.

[0081] Comparative Example 2

[0082] After obtaining the reaction solution of compound 2 according to the methods of Example 1 and Example 2, the stability of the solution was investigated at different concentrations. The results are shown below.

[0083]

[0084] From the above test results, it can be seen that the purity of compound 2 decreases with the extension of the concentration time at different temperatures, and the higher the concentration temperature, the faster the purity decreases. Since the boiling point of toluene is 110°C, too low a concentration temperature will result in too much residual toluene, which will affect the reaction rate of the next step. If the concentration temperature is too high, the quality risk is large. However, the present application directly adds water after the reaction is complete, extracts the product into the aqueous phase, overcomes the shortcomings of the prior art, saves energy, and the process is easier to control and has higher stability.

[0085] Although the present application has been described in detail above, those skilled in the art will understand that various modifications and improvements can be made to the present application without departing from the spirit and scope of the present application.

Claims

1. A method for preparing a 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline compound 3, comprising the following steps: (1) Add a dehydrating agent to a solution containing compound 1 and carry out a cyclization reaction. After the reaction is completed, add water to the solution, stir and let stand to obtain an aqueous solution of compound 2. (2) Add a reducing agent to an alkaline aqueous solution, add a cosolvent under nitrogen protection, control the temperature at 10-30℃, slowly add the aqueous solution of compound 2, and stir to react. After the reaction is completed, separate to obtain target compound 3. The solvent in the solution of compound 1 in step (1) is toluene and / or xylene. The dehydrating agent in step (1) is selected from any one or a combination of phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride. The alkaline aqueous solution in step (2) is an aqueous solution of sodium hydroxide and / or an aqueous solution of potassium hydroxide. The reducing agent is any one or a combination of potassium borohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and borane.

2. The method of claim 1, wherein the separation method in step (2) includes the steps of extracting the reaction system and concentrating the organic phase, and optionally further includes the step of washing the solid obtained from the concentration.

3. The method according to claim 1, wherein the concentration of the alkaline aqueous solution is 5-30 wt%.

4. The method according to any one of claims 1-3, wherein the reducing agent is added at once; and the co-solvent is any one or a combination of methanol, ethanol, propanol, isopropanol, and THF.

5. The method as described in claim 4, wherein the stirring time in step (2) is 5-30 minutes.

6. The method according to claim 2, wherein hydrobromic acid solution is added to the organic phase obtained by washing in step (2), the temperature is raised to 50-60°C, and the mixture is kept warm and stirred for 0.5-2 hours to obtain the hydrobromide of compound 3.

7. The method of claim 1, wherein the preparation method of compound 1 comprises the following steps: dissolving p-methoxyphenylacetic acid in an organic solvent, adding N,N-carbonyldiimidazole, and reacting at a temperature controlled below 40°C; then adding a mixture of 2-(1-cyclohexenyl)ethylamine and the organic solvent, and reacting at a temperature controlled below 50°C; and obtaining the product after post-treatment after the reaction is completed.

8. The method as described in claim 1, wherein the reaction temperature in step (1) is 70-150°C and the reaction time is 3-10h.

9. The method according to claim 7, wherein the mass ratio of the dehydrating agent to 2-(1-cyclohexenyl)ethylamine in step (1) is (0.1-2):1; and the mass ratio of the water added to the feed liquid in step (1) to 2-(1-cyclohexenyl)ethylamine is (1-10):

1.

10. The method according to claim 9, wherein after the reaction in step (1) is completed, the liquid is cooled to 10-20°C.

11. A method for preparing compound 4, comprising the following steps: Compound 3 or its hydrobromide is prepared by the method according to any one of claims 1-10, and then compound 3 or its hydrobromide is resolved in a solvent under the action of D-mandelic acid to obtain compound 4.

12. The method of claim 11, wherein the solvent is selected from any one or a combination of acetone, acetonitrile, methanol, ethanol.

13. The method as described in claim 11 or 12, wherein the temperature of the splitting reaction is 40-80°C and the reaction time is 0.5-4 h.

14. The method of claim 13, wherein the hydrobromide of compound 3 is freed and then further separated; the mass ratio of the hydrobromide of compound 3 to D-mandelic acid is (1-10):1.

Images