A preparation method of a pinaverium bromide intermediate with a high content of cis isomers

Abstract

The present invention discloses a method for preparing a pinaverium bromide intermediate having a high content of cis isomers, relating to the technical field of organic synthesis. By introducing an acidic chiral reagent into the system, the content of compound III isomer is significantly increased, and the trans isomer content is controlled to ≤2.0%, thus having advantages for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a method for preparing a pinaverium bromide intermediate with a high content of cis-isomers. Background Art

[0002] Pinaverium bromide is an antispasmodic agent acting on the gastrointestinal tract. It is a calcium ion antagonist that works by inhibiting the influx of calcium ions into intestinal smooth muscle cells. Pinaverium bromide is optically active, and clinical data show that it is the cis-form of pinaverium bromide that is therapeutically effective. Increasing the content of the cis-form of pinaverium bromide can enhance therapeutic efficacy and reduce side effects caused by undesirable components in the drug.

[0003] The optical activity of pinaverium bromide comes from the six-membered ring part with nopol as the skeleton. Existing domestic and foreign technologies mainly use nopol obtained by semi-synthesis of the natural product β-pinene as the starting material for the synthesis of pinaverium bromide. During the quaternization reaction step, it is difficult to effectively control the ratio of cis and trans in the product through recrystallization; therefore, the reduction conditions of the carbon-carbon double bond in nopol are the key link in controlling the cis-trans configuration ratio of pinaverium bromide.

[0004] At present, CN102060807, CN101759666, CN104650005 and FR2429213A1 introduce 6 routes for preparing pinaverium bromide reported at home and abroad, among which 6 routes all use nopol as the starting material: the first route is that nopol is first hydrogenated, condensed with 4-(2-chloroethyl)morpholine, and then quaternized with 2-bromo-4,5-dimethoxybenzyl bromide; the second route is that nopol is first condensed with 4-(2-chloroethyl)morpholine, hydrogenated, and then quaternized with 2-bromo-4,5-dimethoxybenzyl bromide; the third route is that nopol is first hydrogenated, condensed with chloroethanol, and then brominated with 4-(2-chloroethyl)morpholine. The fourth route is to first hydrogenate nopol, condense it with 4-(2-haloacetyl)morpholine, reduce the acetyl group, and then quaternize it with 2-bromo-4,5-dimethoxybenzyl bromide; the fifth route is to first halogenate nopol, condense it with bromoethanol, and then quaternize it with synthetic 4-[(2-bromo-4,5-dimethoxy)methyl]morpholine, and finally hydrogenate it; the sixth route is to first halogenate nopol, condense it with bromoethanol, hydrogenate it, condense it with morpholine, and then quaternize it with 2-bromo-4,5-dimethoxybenzyl bromide.

[0005] Routes 1, 3, and 4 all utilize the preferential hydrogenation of nopol. However, since the hydrogenated product, dihydronopol, is a liquid alkyl alcohol, it is difficult to purify by recrystallization, other than distillation. CN104650005 and CN10531642 report hydrogenation yields of less than 90%, and neither method involves the separation and purification of dihydronopol.

[0006] Both routes 5 and 6 use the method of halogenating nopol first, and dangerous alkali metals are used in the condensation reaction with bromoethanol, which easily produces by-products of excessive condensation with bromoethanol. Since this route uses phosphorus-containing reagents and alkali metals and there are multiple halogenated compounds in the process, this route has problems such as greater environmental pollution, high safety risks, severe corrosion to equipment, and greater harm to the human body, which is not conducive to industrial production.

[0007] The article "Synthesis of Pinaverium Bromide for the Treatment of Irritable Bowel Syndrome," Vol. 20, No. 5, "Chemical Research and Applications," and CN101531642 describe purification methods for the intermediates in Routes 1 and 2. However, both utilize vacuum distillation, requiring controlled temperature and pressure for purification. This purification method requires high equipment requirements and presents challenges such as cumbersome operation, time-consuming and energy-intensive processes, difficult process parameter control, and low yields.

[0008] According to existing reports, the content of the trans isomer of pinaverium bromide raw materials is often required to be no more than 9%. Therefore, how to improve the selectivity of the cis isomer during the hydrogenation step or reduce the difficulty of purifying the hydrogenated product is a key factor in solving the low content of the active ingredient of pinaverium bromide. Summary of the Invention

[0009] The present invention aims to provide a method for preparing a pinaverium bromide intermediate having a high content of cis isomers. After an acidic chiral reagent is introduced into a hydrogenation system, the content of the cis isomer of compound III (4-[2-[2-(6,6-dimethylbicyclo[3.1.1]hept-2-alkyl)ethoxy]ethyl]morpholine) is significantly increased. Furthermore, the content of the trans isomer can be effectively controlled to ≤2.0% through salt formation and resolution, thereby having advantages in industrial production.

[0010] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0011] A method for preparing a pinaverium bromide intermediate having a high content of cis isomers, comprising the following steps:

[0012] An acidic chiral reagent, a solvent, and a catalyst are added to compound II, and the mixture is kept warm under the action of a reducing agent to react. After the reaction is completed, the temperature is lowered and crystallization is carried out to obtain a wet product of compound III after salt formation. The general reaction formula is as follows:

[0013]

[0014] In the preparation method of the present invention, the acidic chiral reagent is crucial for influencing the cis-trans ratio in Compound III. While screening hydrogenation conditions, the inventors unexpectedly discovered that introducing an acidic chiral reagent into the hydrogenation system significantly increased the cis-isomer content of Compound III. Further salt-forming resolution can effectively control the trans-isomer content to ≤2.0%. The cis-form of pinaverium bromide is the active ingredient, and the preparation of the intermediate cis-form of Compound III typically involves vacuum distillation, which requires high equipment. The present invention utilizes a chiral reagent to increase the cis-form content of the intermediate III, significantly improving both yield and cis-isomer content.

[0015] Further, the acidic chiral reagent is selected from one or more of L-(+)-tartaric acid, L-(-)-malic acid, D-(+)-camphoric acid and S-(+)-mandelic acid;

[0016] Furthermore, the mass ratio of the acidic chiral reagent to compound II is 0.1 to 2.0:1.

[0017] Furthermore, the catalyst is selected from one or more of palladium carbon, palladium hydroxide, platinum dioxide or Raney nickel;

[0018] Furthermore, the mass ratio of the catalyst to compound II is 0.2-20:100.

[0019] Furthermore, the solvent is one or more of n-butanol, isopropanol, ethanol, methanol, acetic acid, water, tetrahydrofuran or ethyl acetate.

[0020] Furthermore, the reducing agent is hydrogen, and the temperature of the reduction reaction is 20°C to 80°C;

[0021] Furthermore, the amount of hydrogen used is such as to maintain the pressure of the reaction system at 0.1 MPa to 7 MPa.

[0022] Furthermore, the preparation method of compound II includes the following contents:

[0023] Nopol and compound I or the hydrogen halide salt of compound I undergo condensation reaction under alkaline conditions. After the reaction is complete, acid solution is added, and extraction and separation are performed to obtain an aqueous phase. Alkaline solution is added to the aqueous phase, and the aqueous phase is extracted and separated. The organic phases are combined and concentrated to obtain compound II. The general reaction formula is as follows:

[0024]

[0025] Wherein, X in compound I or its hydrogen halide salt represents one of halogens Cl and Br.

[0026] The inventors discovered that residual nopol in the preparation of Compound II can negatively impact the hydrogenation step and the resolution of Intermediate III. Therefore, the method of salifying Compound II followed by extraction effectively removes nopol.

[0027] Furthermore, the reaction is carried out in the presence of a solvent or in the absence of a solvent;

[0028] Furthermore, the solvent is selected from one or more of 1,4-dioxane, dimethyl sulfoxide, toluene, and tetrahydrofuran.

[0029] The inventors unexpectedly discovered that the preparation reaction effect of Compound II in the absence of solvent is equivalent to the reaction effect in the presence of solvent. Therefore, the present invention can choose to prepare Compound II in the presence or absence of solvent.

[0030] Furthermore, the base of the alkaline condition is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride or sodium amide.

[0031] Furthermore, the molar ratio of nopol to compound I or the hydrogen halide salt of compound I is 1:1 to 1.2, and the reaction temperature is 40°C to 130°C.

[0032] Furthermore, the extractant is selected from one or more of ethyl acetate, dichloromethane, toluene, n-hexane, cyclohexane and chloroform.

[0033] Furthermore, the acid solution is selected from one or more mixed solutions of phosphoric acid, sulfuric acid, hydrochloric acid, and p-toluenesulfonic acid; the alkali solution is selected from one or more mixed solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0034] Furthermore, after adding the acid solution, the pH of the acidic aqueous phase is 1 to 5, and after adding the alkali solution, the pH of the aqueous phase is 6 to 12.

[0035] Furthermore, the treatment method of the wet product of Compound III includes the following:

[0036] The wet product of compound III is added into water, and then an alkaline solution and an extraction solvent are added. After separation, the organic phases are combined and concentrated to obtain high-purity compound III.

[0037] Furthermore, the alkaline solution is selected from one or more mixed solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate;

[0038] Furthermore, the pH of the aqueous phase is 6 to 12 after the addition of the alkali solution.

[0039] Furthermore, the extraction solvent is selected from one of ethyl acetate, toluene or dichloromethane.

[0040] Specifically, the specific steps for preparing compound III of the present invention are:

[0041] (1) In the presence of a solvent or in the absence of a solvent, nopol and a base are added under stirring, and then compound I or its hydrogen halide salt is added, and the reaction is carried out at a temperature of 100°C. After the reaction is completed, the temperature is lowered, and an extractant and water are added and stirred for extraction. Acid is added to the organic phase, and an alkali solution and an extractant are added to the aqueous phase after separation. The organic phase after separation is washed with water until neutral, and the organic phase is concentrated under reduced pressure to obtain oily 4-[2-[2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-alkyl)ethoxy]ethyl]morpholine (Compound II);

[0042] (2) mixing the compound II, an acidic chiral reagent, a solvent, and a catalyst, and reacting the mixture under the action of a reducing agent, filtering the catalyst, cooling the mixture for crystallization, and filtering the mixture to obtain a wet product of the salt-forming compound III;

[0043] (3) The wet product of the salted compound III is added to water, and an alkali solution and an extractant are added. The organic phase after separation is washed with water until it is neutral, and the organic phase is concentrated under reduced pressure to obtain a high-purity compound III.

[0044] The present invention improves the reaction conditions and post-treatment conditions of the second route (selected from "Synthesis of Pinaverium Bromide, a Drug for the Treatment of Irritable Bowel Syndrome" in Volume 20, Issue 5 of "Chemical Research and Application"), introduces an acidic chiral reagent into the process, and then effectively increases the content of the cis-isomer in the intermediate through salt formation and separation, while also avoiding high energy consumption and low efficiency vacuum distillation purification.

[0045] The results of the present invention and the second route are compared in Table 1:

[0046] Table 1 Comparison of results between the present invention and the second route

[0047]

[0048] From the comparative data in Table 1, it can be seen that the yield of compound II in the present invention is ≥93.3%, which is much higher than the yield of compound II in the second route (80%); the yield of compound III in the present invention is ≥76.8%, which is much higher than the yield of compound III in the second route (66%).

[0049] In the second route, the cis isomer of compound III needs to be purified by vacuum distillation. However, the present invention improves the reaction conditions and post-treatment conditions, introduces an acidic chiral reagent induction into the process, and then effectively increases the content of the cis isomer in the intermediate through salt formation and separation, while also avoiding the high energy consumption and low efficiency of vacuum distillation purification.

[0050] The beneficial effects of the present invention are:

[0051] The present invention improves the process of the second route, effectively reducing the content of impurities in the intermediates of each step. In particular, after introducing an acidic chiral reagent into the hydrogenation system, the problem of low content and yield of the cis-isomer in the key intermediate (Compound III) is solved. The compound III with a high content of cis-isomers prepared by the present invention can be used to prepare pinaverium bromide. At the same time, the cis-isomer and yield of the obtained product are significantly improved, which has the advantage of industrial production. DETAILED DESCRIPTION

[0052] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described here are only part of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0053] Detection method of cis-trans isomers of compound III:

[0054] Dissolve compound III in methanol to prepare a solution containing approximately 20 mg per 1 ml. Determine the concentration by gas chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0521, Method 3) using a capillary column. Initially, increase the column temperature from 120°C to 220°C at a rate of 3°C per minute and maintain for 5 minutes. Accurately measure 1.0 μl and inject it into the gas chromatograph. Record the chromatogram; the order of peaks is the trans-isomer followed by the cis-isomer.

[0055] Example 1

[0056] Synthesis of intermediate compound Ⅱ

[0057] 61.1 g of nopol was added to a reaction flask. Under nitrogen protection, 28.1 g of sodium hydride (60%) was slowly added while stirring, followed by 50.0 g of 4-(2-chloroethyl)morpholine. The temperature was raised to 50°C and the reaction was incubated. TLC was performed until the reaction was complete. The reaction solution was cooled to room temperature, 500 ml of toluene was added, and then 200 ml of water was slowly added. The organic phase was separated, and a 3% aqueous sulfuric acid solution was slowly added to the organic phase, and the pH of the aqueous phase was adjusted to 2. The solution was allowed to stand and separated, and 100 ml of toluene was added for extraction. The aqueous phase after separation was slowly added with 10% aqueous sodium hydroxide solution, and the pH of the aqueous phase was adjusted to 8. 100 ml of toluene was added and extracted twice. The organic phase after separation was washed with water until neutral, and the washed organic phase was concentrated under reduced pressure to obtain 87.1 g of compound II with a yield of 93.3% and a compound II content of 98.5%.

[0058] Example 2

[0059] Synthesis of intermediate compound Ⅱ

[0060] 70.4 g of nopol and 300 ml of toluene were added to a reaction flask. Under nitrogen protection, 56.4 g of sodium hydroxide was added under stirring, followed by 75.0 g of 4-(2-chloroethyl)morpholine hydrochloride. The temperature was raised to reflux and the reaction was detected by TLC until complete. The reaction solution was cooled to room temperature, 300 ml of toluene was added, and then 300 ml of water was slowly added. The organic phase was separated and a 3% aqueous sulfuric acid solution was slowly added to adjust the pH of the aqueous phase to 3. The solution was allowed to stand for separation and 150 ml of toluene was added for extraction. A 10% aqueous sodium hydroxide solution was slowly added to the aqueous phase after separation, and the pH of the aqueous phase was adjusted to 8. 150 ml of toluene was added for extraction twice. The organic phase after separation was washed with water until neutral and concentrated under reduced pressure to obtain 106.2 g of compound II with a yield of 94.3% and a compound II content of 98.2%.

[0061] Example 3

[0062] Synthesis of intermediate compound III

[0063] 100.0 g of intermediate compound II, 32.4 g of L-(+)-tartaric acid, 10.1 g of platinum dioxide, 25.4 g of n-butanol, and 475.7 g of purified water were added to a hydrogenation reaction kettle. After replacing the air in the kettle with hydrogen, the pressure of the reactor was increased to 4.5 MPa with hydrogen. The temperature was raised to 65-75° C. with stirring, and the reaction was maintained at this temperature. GC was performed until the reaction was complete. The reaction liquid temperature was lowered to 30-40° C., the catalyst was filtered, and the filtrate was further cooled to 0-5° C. to precipitate a white solid. The solid was stirred for crystallization for more than 1.0 hour, filtered, and the filter cake was quickly washed with 50 ml of ice water to obtain the wet tartrate salt of compound III. The wet product was added to 150 ml of water, and then 500 ml of dichloromethane was added. The pH of the aqueous phase was adjusted to 8 with sodium carbonate. After separation, the organic phase was washed with water until neutral, and then the organic phase was concentrated under reduced pressure to obtain 84.3 g, with a yield of 83.7% and a cis-isomer content of 98.8%.

[0064] Example 4

[0065] Synthesis of intermediate compound III

[0066] 45.6 g of intermediate compound II, 14.4 g of L-(+)-tartaric acid, 4.7 g of platinum dioxide, 11.5 g of n-butanol, and 218.3 g of purified water were added to a hydrogenation reaction kettle. After replacing the air in the kettle with hydrogen, the pressure of the reactor was increased to 4.5 MPa with hydrogen. The temperature was raised to 65-75° C. with stirring, and the reaction was maintained at this temperature. GC was performed until the reaction was complete. The reaction liquid temperature was lowered to 30-40° C., the catalyst was filtered, and sodium carbonate solution was added to adjust the pH of the filtrate to 8. The filtrate was then extracted twice with 500 ml of dichloromethane. The organic phases were combined and washed with water until neutral. The organic phases were concentrated under reduced pressure to obtain 45.0 g of compound III with a yield of 98.0% and a cis-isomer content of 97.2%.

[0067] Example 5

[0068] Synthesis of intermediate compound III

[0069] 104.6 g of intermediate compound II, 33.7 g of L-(+)-tartaric acid, 6.6 g of Raney nickel, 10.7 g of isopropanol, and 500.2 g of purified water were added to a hydrogenation reactor. The air in the reactor was replaced with nitrogen, and then the nitrogen in the reactor was replaced with hydrogen. The pressure of the reactor was increased to 4.6 MPa with hydrogen, and the temperature was raised to 65-75° C. with stirring. The reaction was kept warm and detected by GC until the reaction was complete. The reaction liquid temperature was lowered to 30-40° C., the catalyst was filtered, and the filtrate was further cooled to 0-5° C. to precipitate a white solid. The solid was stirred for crystallization for more than 1.0 hour, filtered, and the filter cake was quickly washed with 50 ml of ice water to obtain the wet product of the tartrate salt of compound III. The wet product was added to 150 ml of water, and then 500 ml of dichloromethane was added. The pH of the aqueous phase was adjusted to 8 with sodium carbonate. After separation, the organic phase was washed with water until neutral, and then the organic phase was concentrated under reduced pressure to obtain 84.6 g, with a yield of 80.3% and a cis-isomer content of 98.1%.

[0070] Example 6

[0071] Synthesis of intermediate compound III

[0072] 40.3 g of intermediate compound II, 11.4 g of L-(-)malic acid, 4.1 g of platinum dioxide, 10.2 g of n-butanol, and 193.0 g of purified water were added to a hydrogenation reaction kettle. After replacing the air in the kettle with hydrogen, the pressure of the reactor was increased to 4.5 MPa with hydrogen. The reaction mixture was stirred and heated to 65-75°C. The reaction was maintained at this temperature and monitored by GC until the reaction was complete. The reaction solution temperature was lowered to 30-40°C, the catalyst was filtered, and the filtrate was further cooled to 0-5°C to precipitate a white solid. The solid was stirred for crystallization for more than 1.0 hour, filtered, and the filter cake was quickly washed with 20 ml of ice water to obtain the wet product of the malate salt of compound III. The wet product was added to 60 ml of water, and 200 ml of dichloromethane was added. The pH of the aqueous phase was adjusted to 8 with sodium carbonate. After separation, the organic phase was washed with water until neutral and then concentrated under reduced pressure to obtain 32.8 g of the malate salt, with a yield of 76.8% and a cis-isomer content of 98.4%.

[0073] Comparative Example 1

[0074] Synthesis of intermediate compound III

[0075] 98.3g of intermediate compound II, 42.25g of acetic acid, 9.8g of platinum dioxide, 25.0g of n-butanol, and 468.5g of purified water were added to a hydrogenation reactor. After replacing the air in the reactor with hydrogen, the pressure of the reactor was increased to 4.5Mpa with hydrogen, and the temperature was raised to 65-75°C with stirring. The reaction was carried out under incubation and detected by GC until the reaction was complete. The reaction liquid temperature was lowered to room temperature, the catalyst was filtered, sodium carbonate solution was added to adjust the pH of the filtrate to 8, and then 500ml of dichloromethane was added and extracted twice. After the organic phases were combined, the organic phases were washed with water until neutral, and the organic phases were concentrated under reduced pressure to obtain 96.3g of compound III with a yield of 97.3% and a cis isomer content of 92.4%. Comparative Example 1 used acetic acid instead of the chiral reagent, and the cis isomer content in the obtained compound III was only 92.4%, which was significantly lower than that of Examples 3-6.

[0076] Comparative Example 2

[0077] Synthesis of intermediate compound Ⅱ

[0078] 65.0 g of nopol and 300 ml of toluene were added to a reaction flask under nitrogen protection. 52.0 g of sodium hydroxide was added under stirring, followed by 69.2 g of 4-(2-chloroethyl)morpholine hydrochloride. The temperature was raised to reflux, and TLC was performed to determine completion of the reaction. The reaction solution was cooled to room temperature, 280 ml of toluene was added, and then 280 ml of water was slowly added. The mixture was allowed to stand for separation, and the organic phase after separation was washed with water until neutral. The washed organic phase was then concentrated under reduced pressure to obtain 102.2 g of Compound II, with a yield of 98.4% and a Compound II content of 91.0%.

[0079] Synthesis of intermediate compound III

[0080] 105.1 g of the intermediate compound II prepared above was used to prepare compound III according to Example 3 to obtain 69.8 g of compound III with a yield of 67.2% and a cis-isomer content of 92.7%.

[0081] In Comparative Example 2, no acid was added during post-treatment of Compound II to form a salt, and organic phase extraction and washing were performed directly. The content of Compound II was only 91.0%, significantly lower than that of Examples 1 and 2. Furthermore, when Compound II synthesized using the comparative example method was used to prepare Compound III, although a chiral reagent was used, the yield and cis-isomer content of Compound III were significantly lower than those of Example 3. This indicates that the absence of an acid-salting step during post-treatment of Compound II would result in an increase in residual nopol in Compound II, hindering the reaction to form Compound III and affecting the resolution of Compound III.

Claims

1. A method for preparing a cis-isomer of Pinaverium bromide intermediate compound III, characterized in that: Includes the following: Compound II, an acidic chiral reagent, a solvent, and a catalyst react under the action of a reducing agent. After the reaction is completed, the temperature is lowered and crystallization is performed to obtain a wet product of compound III after salt formation. The general reaction formula is as follows: ， The acidic chiral reagent is selected from one or more of L-(+)-tartaric acid and L-(-)-malic acid; The catalyst is selected from one or more of palladium carbon, palladium hydroxide, platinum dioxide or Raney nickel; The reducing agent is hydrogen.

2. The preparation method according to claim 1, characterized in that The mass ratio of the acidic chiral reagent to compound II is 0.1-2.0:

1.

3. The preparation method according to claim 1, characterized in that The mass ratio of the catalyst to compound II is 0.2-20:

100.

4. The preparation method according to claim 1, characterized in that The solvent is selected from one or more of n-butanol, isopropanol, ethanol, methanol, acetic acid, water, tetrahydrofuran or ethyl acetate.

5. The preparation method according to claim 1, characterized in that The temperature of the reduction reaction is 20°C~80°C; The amount of hydrogen used is to maintain the pressure of the reaction system at 0.1 MPa~7 MPa.

6. The preparation method according to claim 1, characterized in that The treatment method for wet product of Compound III includes the following: The wet product of compound III is added into water, and then an alkaline solution and an extraction solvent are added. After separation, the organic phases are combined and concentrated to obtain high-purity compound III.

7. The preparation method according to claim 6, characterized in that The alkaline solution is selected from one or more mixed solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; The pH of the aqueous phase after adding alkali solution is 6~12.

8. The preparation method according to claim 6, characterized in that The extraction solvent is selected from one of ethyl acetate, toluene or dichloromethane.

9. The preparation method according to claim 1, characterized in that The preparation method of compound II comprises the following contents: Nopol and compound I or the hydrogen halide salt of compound I undergo condensation reaction under alkaline conditions. After the reaction is complete, acid solution is added, and extraction and separation are performed to obtain an aqueous phase. Alkaline solution is added to the aqueous phase, and the aqueous phase is extracted and separated. The organic phases are combined and concentrated to obtain compound II. The general reaction formula is as follows: ， Wherein, X in compound I or its hydrogen halide salt represents one of halogens Cl and Br.

10. The preparation method according to claim 9, characterized in that The reaction is carried out in the presence of a solvent or in the absence of a solvent; The solvent is selected from one or more of 1,4-dioxane, dimethyl sulfoxide, toluene, and tetrahydrofuran.

11. The preparation method according to claim 9, characterized in that The base of the alkaline condition is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride or sodium amide.

12. The preparation method according to claim 9, characterized in that The molar ratio of nopol to compound I or the hydrogen halide salt of compound I is 1:1-1.2, and the reaction temperature is 40°C-130°C.

13. The preparation method according to claim 9, characterized in that The extractant is selected from one or more of ethyl acetate, dichloromethane, toluene, n-hexane, cyclohexane and chloroform.

14. The preparation method according to claim 9, characterized in that The acid solution is selected from one or more mixed solutions of phosphoric acid, sulfuric acid, hydrochloric acid, and p-toluenesulfonic acid; the alkali solution is selected from one or more mixed solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; The pH of the aqueous phase after adding acid is 1~5, and the pH of the aqueous phase after adding alkali is 6~12.

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