Method for preparing pentazocine intermediate
Through the new synthesis route, the problem of insufficient purity of pentazocin intermediate compound 3 and the safety risk of high-pressure reaction is solved, the high purity and high yield of compound 3 are achieved, the yield of three wastes is reduced, and it is suitable for industrial production.
Patent Information
- Application Number
- CN202411442724.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-16
- Publication Date
- 2025-02-07
AI Technical Summary
In the existing pentazocin synthesis route, the purity of intermediate compound 3 is insufficient, resulting in low yields in subsequent steps, difficulty in purification, and high-pressure reactions are used, which increases safety risks and three waste yields.
Compound 3 is prepared through a new synthetic route, including methylation, ring opening, hydroxyl protection, reaction and elimination, and hydrazine dissolution of compound SM, to avoid high-pressure reactions and improve the purity and overall yield of compound 3.
The overall yield of Compound 3 was significantly improved, from 30% to 46%, and the yield of subsequent cyclosynthesis reaction was improved, from 30% to about 70%, reducing the yield of three wastes, and suitable for industrial production.
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Figure CN119390584A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a pentazocine intermediate. Background Art
[0002] Pentazocine was developed and successfully marketed by the Sterling Winslobber Group in the UK in 1967. Pentazocine is a derivative of benzomorphane, which has a mixture of agonist and antagonist effects on opioid receptors, mainly agonists of opioid κ receptors, and can agonize σ receptors at higher doses, and has partial agonist or weak antagonist effects on μ receptors. Pentazocine is suitable for analgesia of moderate to severe pain and has a wide range of clinical applications. For example, it can be used for intraoperative auxiliary analgesia, postoperative analgesia, chronic pain treatment, cancer pain treatment, etc. Oral pentazocine tablets are currently the only oral opioid receptor agonist and antagonist analgesics.
[0003] The main synthetic routes of pentazocine are as follows:
[0004]
[0005] The synthetic route uses cyanoacetic acid as a raw material, and reacts with butanone to obtain a mixture of compounds 1 and 2 (ratio of about 1:1), and then undergoes a high-pressure (5-6 MPa) hydrogenation reaction to obtain an intermediate compound 3 (3-methyl-3-pentenylamine), and also produces an isomer compound 4. Then, compound 5 is cyclized to obtain compound 5. Since the step of generating compound 5 is difficult to purify, after obtaining compound 5, it is reacted in the form of a mixture, and a key intermediate 6 is obtained through a cyclization reaction. Intermediate 6 reacts with 4-bromo-2-methyl-butene to obtain pentazocine 7.
[0006] In this route, since all intermediates are mixtures, the yield of each step is relatively low, resulting in a higher unit consumption of raw and auxiliary materials and increasing the difficulty of purification in subsequent steps.
[0007] Therefore, it is necessary to optimize the existing process to adapt to industrial production. Summary of the invention
[0008] The purpose of the present invention is to solve the problem that the intermediate compound 3 (3-methyl-3-pentenylamine) is not sufficiently pure, resulting in low yield in subsequent steps and difficult purification, and avoid the use of high pressure to reduce the output of three wastes.
[0009] To achieve the purpose of the present invention, the present invention provides a method for preparing compound 3, which comprises the following synthetic route:
[0010]
[0011] Wherein, R is selected from:
[0012] The method comprises the following steps:
[0013] (1) Methylating compound SM to obtain compound 6;
[0014] (2) In an acid solution, compound 6 is subjected to ring opening to obtain compound 7;
[0015] (3) using a hydroxyl protecting agent to convert compound 7 into compound 8;
[0016] (4) reacting compound 8 with a dicarboximide salt to obtain compound 9; wherein the dicarboximide salt is selected from potassium phthalamide, sodium phthalamide, sodium dicarboxamide and sodium succinimide;
[0017] (5) in the presence of methanesulfonyl chloride and lithium bromide, converting compound 9 into compound 10 via elimination reaction;
[0018] (6) Under alkaline conditions, compound 10 is reacted with water to undergo hydrazinolysis to obtain a hydrazinolysis product, namely compound 3.
[0019] According to an embodiment of the method of the present invention, in step (1), the methylating agent used in the methylation is selected from one of methyl iodide and dimethyl sulfate. The post-treatment of methyl iodide as a methylating agent is simple and can be put into the next step of reaction. When dimethyl sulfate is used as a methylating agent, the dimethyl sulfate needs to be quenched and washed after the reaction is completed.
[0020] According to one embodiment of the method of the present invention, in step (2), the acid solution is selected from hydrochloric acid solution and sulfuric acid solution.
[0021] According to an embodiment of the method of the present invention, in step (2), the concentration of the acid solution is 20-30%.
[0022] According to an embodiment of the method of the present invention, in step (2), it also includes adding a water-soluble inorganic chloride to the reaction system; preferably, the water-soluble inorganic chloride is selected from sodium chloride, potassium chloride, lithium chloride, calcium chloride, aluminum chloride, ammonium chloride, magnesium chloride, and hydrogen chloride. The inventors of the present invention have found that the increase in chloride ion concentration is conducive to significantly increasing the reaction rate, shortening the reaction time, and accelerating the reaction process. In addition, the concentration of the inorganic chloride in the reaction system is related to their saturated solubility in the reaction system. After experiments, it is found that the preferred concentration of the water-soluble inorganic chloride in the reaction system is 10 to 30 wt%.
[0023] According to one embodiment of the method of the present invention, in step (3), the hydroxyl protecting agent is selected from trimethylsilyl chloride (TMSCl) and 2-tetrahydropyran (THP). Considering that the removal of TMS is more convenient, TMSCl is preferred.
[0024] According to one embodiment of the method of the present invention, in step (4), the phthalamide salt is potassium phthalamide or sodium phthalamide, sodium diphthalamide, or sodium succinimide.
[0025] According to one embodiment of the method of the present invention, in step (5), the elimination reaction is carried out under alkaline conditions. The inventors also tried to carry out the elimination reaction under acidic conditions, but found that the selectivity of the elimination reaction under acidic conditions was poor.
[0026] According to one embodiment of the method of the present invention, in step (6), the alkaline condition is provided by a sodium hydroxide solution or a potassium hydroxide solution.
[0027] According to an embodiment of the method of the present invention, the method further comprises: in step (6), reacting compound 3 with an acid solution to obtain an acid salt of compound 3; wherein the acid salt of compound 3 is a hydrochloride or a sulfate. The salt formation of compound 3 can remove most impurities, bring about a better purification effect, and provide a more easily obtained and higher purity reaction material for the next reaction.
[0028] The present invention also provides a method for preparing a pentazocine intermediate compound 5 using compound 3, the method comprising the following synthetic route:
[0029]
[0030] Wherein, the preparation method of compound 3 is as described above.
[0031] After obtaining compound 3, the acid salt of compound 3 is reacted with 3-(4-ethylphenyl)ethylene oxide-2-carboxylate to obtain compound 5.
[0032] According to one embodiment of the method of the present invention, in step (7), 3-(4-ethylphenyl)ethylene oxide-2-carboxylate is 3-(4-ethylphenyl)ethylene oxide-2-carboxylic acid methyl ester, 3-(4-ethylphenyl)ethylene oxide-2-carboxylic acid ethyl ester, or 3-(4-ethylphenyl)ethylene oxide-2-carboxylic acid propyl ester.
[0033] According to one embodiment of the method of the present invention, in step (7), the reaction conditions are pH=4 and the reaction temperature is 85°C-100°C.
[0034] Beneficial Effects of the Invention
[0035] The present invention uses 2-acetylbutyric acid lactone as a starting material, and obtains compound 3 through methylation, ring opening, reduction protection, substitution, elimination, and hydrazinolysis. Although the reaction steps are increased relative to the existing method, the overall yield of preparing compound 3 is significantly improved, which can be increased from 30% to 46%, which is a significant optimization for industrial production. In addition, the method of the present invention can prepare compound 3 with higher purity, which is conducive to improving the yield of subsequent cyclization reaction, from a yield of about 30% to a yield of about 70%.
[0036] Each step of the method of the present invention avoids high-pressure reaction, has a high safety factor, further improves the overall route yield, reduces the output of three wastes, and is more suitable for industrial production of pentazocine raw materials. BRIEF DESCRIPTION OF THE DRAWINGS
[0037] Figure 1 is the compound 8 prepared in Example 5 of the present invention 1 H NMR spectrum.
[0038] Figure 2 is the compound 10 prepared in Example 8 of the present invention 1 H NMR spectrum.
[0039] Figure 3 The hydrochloride of compound 3 prepared in Example 9 of the present invention 1 H NMR spectrum.
[0040] Figure 4 It is the HPLC spectrum of compound 5 prepared in Example 10 of the present invention.
[0041] Figure 5 is the compound 5 prepared in Example 10 of the present invention 1 H NMR spectrum. DETAILED DESCRIPTION
[0042] The present invention will be further described below by means of specific examples.
[0043] Example 1
[0044] Synthesis of compound 6
[0045] The synthetic route of compound 6 is as follows:
[0046]
[0047] Add 300 g of compound SM, 1.5 L of acetone, 387.8 g of K2CO3 and 63.2 g of water into a 5 L four-necked bottle, stir evenly, add 399.1 g of iodomethane dropwise, control the internal temperature not to exceed 35 °C, add dropwise for about 1.5 h, after the addition is complete, keep warm for about 3 h, take a sample to detect the completion of the reaction.
[0048] The reaction solution was cooled to 0-5°C in an ice bath, filtered, the filter cake was rinsed with a small amount of acetone, and the filtrate was concentrated under reduced pressure at 40°C to obtain compound 6 as an oil (calculated according to the theoretical amount), which was directly used in the next step.
[0049] Example 2
[0050] Synthesis of compound 6
[0051] The synthetic route of compound 6 is as follows:
[0052]
[0053] Add 20g SM, 100ml DMF and 25.5g K2CO3 into a 500ml four-necked bottle, and add 23.6g dimethyl sulfate dropwise while stirring. Control the internal temperature not to exceed 10-20℃, and add dropwise for about 1.5h. After the addition is complete, keep the temperature for about 1h to complete the reaction.
[0054] Methyl tert-butyl ether (MTBE) and water were added to the reaction solution, stirred for 20 min, allowed to stand for separation, the aqueous phase was extracted again with methyl tert-butyl ether, the organic phases were combined, washed once with saturated brine, and the organic phases were concentrated under reduced pressure to obtain 20.4 g of compound 6 (oil) with a yield of 91.5%. The oil was directly fed to the next step.
[0055] Example 3
[0056] Synthesis of compound 7
[0057] The synthetic route of compound 7 is as follows:
[0058]
[0059] Add 470 g of concentrated hydrochloric acid (concentration of about 37 wt%) to a 2 L reaction bottle, then add 670 ml of saturated sodium chloride solution, heat to 50 ° C, add 333 g of compound 6 oil dropwise, add for about 1 hour, after the addition is complete, keep at 50 ° C for about 3 hours, and take samples to detect the completion of the reaction;
[0060] The reaction liquid was distilled at normal pressure (external temperature 140°C / top temperature about 100°C) to obtain a mixture of the product and water, which was separated to obtain 255.1 g of a yellow-green oil; the aqueous phase was extracted once more with DCM, and the organic phase was concentrated under reduced pressure to obtain 10 g, which was combined with the previously distilled product to obtain a total of 260.5 g of compound 7 (oil), which was stored in a refrigerator at 0°C with a yield of 82.5%.
[0061] Example 4
[0062] Synthesis of compound 7
[0063] The synthetic route of compound 7 is as follows:
[0064]
[0065] Add 50g of concentrated hydrochloric acid (concentration is about 37wt%) to a 250ml reaction bottle, heat to 50℃, add 20g of compound 6, and add for about 15 minutes. After the addition is complete, keep warm at 50℃ for 8h. Sampling and TLC detection showed that the reaction was basically unchanged and the raw materials disappeared. Judging from the depth of the color of the spots on the TLC plate, the reaction product contained two components in a ratio of about 1:1. Subsequently, the inventors tried to increase the sodium chloride solution to increase the chloride ion concentration in the reaction system, and found that the proportion of one product in the reaction product decreased and the other product increased. The ratio shift value R detected by TLC f It shows that after increasing the chloride ion concentration in the reaction system, the amount of compound 7 increases significantly, while the amount of another product decreases gradually. Based on the reaction mechanism and TLC test results, it is speculated that its structure is the intermediate chlorinated product in the ring-opening process - compound 7a.
[0066] Based on the influence of chloride ion concentration in the reaction system on the reflux velocity and the reaction product, the applicant conducted experiments on the influence of various chlorides and the concentration of chlorides in the system on the reaction. The experimental feed amount and reaction conditions refer to Example 3, and the experimental results are shown in Table 1 below.
[0067] Table 1
[0068]
[0069] Example 5
[0070] Synthesis of compound 8
[0071] The synthetic route of compound 8 is as follows:
[0072]
[0073] Add 470ml of water to a 1L three-necked flask, add 6.4g of sodium borohydride in batches, keep it at about 0℃, add 57g of compound 7 dropwise, after the addition is complete, keep warm for about 2h, take a sample TLC to detect that the raw material has reacted completely, then adjust the pH to 4-5 with 2N dilute hydrochloric acid, add 400ml of dichloromethane to extract once, and after stratification, dry the organic phase with anhydrous sodium sulfate (note that the color will gradually darken during storage). After drying, cool to 0-5℃ in an ice bath, then add 94g of triethylamine dropwise, after the addition is complete, slowly add 55.7g of TMSCl dropwise, control the temperature at about 0℃, after the addition is complete, keep warm at 0-5℃ for 2h, take a sample TLC to detect that the raw material has reacted completely, filter to remove the triethylamine hydrochloride solid, concentrate the filtrate under reduced pressure, add n-hexane to pulp once, filter to remove the insoluble matter, and concentrate the filtrate to obtain 69g of red oil, which is compound 8, with a yield of 78%. Compound 8 1 H NMR Figure 1 .
[0074] Example 6
[0075] Synthesis of compound 9
[0076] The synthetic route of compound 9 is as follows:
[0077]
[0078] In a 500ml three-necked flask, 57.3g of potassium phthalamide, 6.8g of tert-butylammonium bromide (TBAB), 270ml of dimethylformamide (DMF) and 68g of compound 8 were added in sequence, heated to 60°C for overnight reaction, and the raw materials were sampled for TLC detection to determine if the reaction was complete. The reaction was cooled to room temperature, methyl tert-butyl ether (MTBE) and water were added, stirred for 20min, and allowed to stand for separation. The aqueous phase was extracted once with MTBE, the organic phases were combined, 40g of concentrated hydrochloric acid was added, and stirred at room temperature for 2h, and the trimethylsilane (TMS) protective group was sampled for TLC detection to determine if the removal was complete. After the TMS protective group was completely removed by TLC detection, the mixture was washed with water once and saturated sodium chloride twice, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 9, about 72g of crude oil, with a yield of 89.6%.
[0079] Example 7
[0080] Synthesis of compound 9a
[0081] The synthetic route of compound 9a is as follows:
[0082]
[0083] In a 100 ml three-necked flask, 4.8 g sodium diformamide, 1 g tetrabutylammonium bromide (TBAB), 50 ml toluene and 10 g compound 8 were added in sequence and stirred. The mixture was heated to 80 ° C for 3 h, and a sample was taken for TLC detection to confirm that the raw material reaction was complete. The reaction system was cooled to room temperature, water was added and stirred for 20 min, and the mixture was allowed to stand for separation. The aqueous phase was extracted once with toluene, the organic phases were combined, 1 g hydrochloric acid was added and stirred at room temperature for 2 h, and then washed once with sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 9a, about 7.2 g of oil, with a yield of 87%.
[0084] Example 8
[0085] Synthesis of compound 10
[0086] The synthetic route of compound 10 is as follows:
[0087]
[0088] In a 2L reaction bottle, add 72g of compound 9, 725ml of DMF, and then add 57g of K2CO3. Slowly add 40.3g of methanesulfonyl chloride at room temperature. After the addition is complete, react for 3h, then add 23.8g of LiBr, heat to 80℃, keep warm for 3h, and then the intermediate state I is converted into intermediate state II. Keep warm for 2h, and the intermediate state II basically disappears and is converted into compound 10. After the reaction is completed, add water to dilute, extract twice with 900ml of MTBE, combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 58.7g of oil, with a yield of 88%. Compound 10 1 H NMR Figure 2 .
[0089] Example 9
[0090] Synthesis of compound 3
[0091] The synthetic route of compound 3 is as follows:
[0092]
[0093] In a 1L reaction bottle, add 55g of compound 10, 550ml of ethanol, drop 15.5g of 80% hydrazine hydrate, heat to 80°C and react overnight. After the reaction is completed, cool to about 0°C, add 300ml of 20% NaOH solution (adding alkali solution can make the by-product phthalic acid hydrazide salt, so that the by-product phthalic acid hydrazide salt is better dissolved in the aqueous phase, which is convenient for washing and removal, and reduces the by-product content in the organic phase), extract twice with methyl tert-butyl ether, combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter, drop 90ml of 4mol / L HCl / EtOH in the filtrate, concentrate under reduced pressure to obtain compound 3 hydrochloride, add n-hexane and beat at room temperature for 1h, filter, and dry to obtain 30.2g product with a yield of 93%.
[0094] Compound 3 hydrochloride 1 H NMR Figure 3 .
[0095] Example 10
[0096] Synthesis of compound 5
[0097] The synthetic route of compound 5 is as follows:
[0098]
[0099] Add 9g of compound 3 and 90ml of purified water to a 250ml reaction bottle, adjust the pH to about 4 with hydrochloric acid, then add 19.2g of ether ester, raise the temperature to about 95℃ and react for about 48h. When compound 3 disappears by TLC detection, stop the reaction. Cool down to 60℃, add 2.7g of activated carbon, stir for 2h and filter while hot, adjust the pH of the filtrate to above 10 with 20% NaOH solution, extract twice with DCM, combine the organic phases, wash with semi-saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain 14.1g of crude product. Add 15ml of isopropyl ether to the crude product, beat at room temperature for about 1h, filter with suction, and dry to obtain 11.8g of off-white solid, which is compound 5, with a yield of 71% and a purity of 97.4%. HPLC spectrum of compound 5 and 1 H NMR spectra are shown in Figure 4 and Figure 5 .
[0100] Embodiment 11
[0101] Synthesis of compound 3
[0102] The synthetic route of compound 3 is as follows:
[0103]
[0104] Referring to Examples 9 and 10, the operations of Examples 9 and 10 were repeated.
[0105] In a 1L reaction bottle, add 55g of compound 10, 550ml of ethanol, dropwise add 15.5g of 80% hydrazine hydrate, heat to 80°C and react overnight. After the reaction is completed, cool to about 0°C, add 300ml of 20% NaOH solution (adding alkali solution can make the by-product phthalic acid hydrazide salt, so that the by-product phthalic acid hydrazide salt can be better dissolved in the water phase, which is convenient for washing and removal, and reduces the by-product content in the organic phase), extract twice with methyl tert-butyl ether, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to obtain 23g of compound 3 as an oil.
[0106]
[0107] 9g of compound 3 and 90ml of purified water were added to a 250ml reaction bottle, and the pH was adjusted to about 4 with hydrochloric acid. Then, 19.2g of internal ether ester was added, and the temperature was raised to about 95°C for reaction for about 48h. The compound 3 disappeared after TLC detection, and the reaction was stopped. The temperature was lowered to 60°C, 2.7g of activated carbon was added, and the mixture was stirred for 2h and filtered while hot. The filtrate was adjusted to pH 10 or above with 20% NaOH solution, extracted twice with DCM, and the organic phases were combined, washed with half-saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 10.2g of crude product. 10ml of isopropyl ether was added to the crude product, and the mixture was slurried at room temperature for about 1h, filtered, and dried to obtain 8.1g of off-white solid, which was compound 5, with a yield of 49%.
[0108] Example 12
[0109] Synthesis of compound 5
[0110] The synthetic route of compound 5 is as follows:
[0111]
[0112] 9g of compound 3 and 90ml of purified water were added to a 250ml reaction bottle, and the pH was adjusted to about 4 with hydrochloric acid. Then, 20.5g of internal ether ester was added, and the temperature was raised to about 95°C for reaction for about 48h. The compound 3 disappeared after TLC detection, and the reaction was stopped. The temperature was lowered to 60°C, 2.7g of activated carbon was added, and the mixture was stirred for 2h and filtered while hot. The filtrate was adjusted to pH 10 or above with 20% NaOH solution, extracted twice with dichloromethane, the organic phases were combined, washed with half-saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain 14g of crude product. 15ml of isopropyl ether was added to the crude product, and the mixture was slurried at room temperature for about 1h, filtered, and dried to obtain 11.4g of compound 5 as an off-white solid with a yield of 69%.
[0113] Each step of the method of the present invention avoids high-pressure reaction, has a high safety factor, further improves the overall route yield, reduces the output of three wastes, and is more suitable for industrial production of pentazocine raw materials.
Claims
1. A method for preparing a pentazocine intermediate, the method comprising the following synthetic route: in, R is selected from: The method comprises the following steps: (1) Methylating compound SM to obtain compound 6; (2) In an acid solution, compound 6 is subjected to ring opening to obtain compound 7; (3) using a hydroxyl protecting agent to convert compound 7 into compound 8; (4) reacting compound 8 with a dicarboximide salt to obtain compound 9; wherein the dicarboximide salt is selected from potassium phthalamide, sodium phthalamide, sodium dicarboxamide and sodium succinimide; (5) in the presence of methanesulfonyl chloride and lithium bromide, converting compound 9 into compound 10 via elimination reaction; (6) Under alkaline conditions, compound 10 is subjected to hydrazinolysis reaction to obtain a hydrazinolysis product, namely compound 3.
2. The method according to claim 1, wherein in step (1), the methylating agent used in the methylation is selected from one of methyl iodide and dimethyl sulfate.
3. The method according to claim 1, in step (2), the acid solution is selected from hydrochloric acid solution and sulfuric acid solution; preferably, the concentration of the acid solution is 20-30%.
4. The method according to claim 1, in step (2), further comprises adding a water-soluble inorganic chloride to the reaction system; preferably, the water-soluble inorganic chloride is selected from sodium chloride, potassium chloride, lithium chloride, calcium chloride, aluminum chloride, ammonium chloride, magnesium chloride, and hydrogen chloride; preferably, the concentration of the water-soluble inorganic chloride in the reaction system is 10 to 30 wt%.
5. The method according to claim 1, wherein in step (3), the hydroxyl protecting agent is selected from trimethylsilyl chloride and 2-tetrahydropyran.
6. The method according to claim 1, wherein in step (5), the elimination reaction is carried out under alkaline conditions.
7. The method according to claim 1, wherein in step (6), the alkaline condition is provided by a sodium hydroxide solution or a potassium hydroxide solution.
8. The method according to claim 1, further comprising: In step (6), compound 3 is reacted with an acid solution to obtain an acid salt of compound 3; wherein the acid salt of compound 3 is a hydrochloride or a sulfate.
9. A method for preparing a pentazocine intermediate, the method comprising the following synthetic route: in, R is selected from: The method comprises the following steps: (1) Methylating compound SM to obtain compound 6; (2) In an acid solution, compound 6 is subjected to ring opening to obtain compound 7; (3) using a hydroxyl protecting agent to convert compound 7 into compound 8; (4) reacting compound 8 with a dicarboximide salt to obtain compound 9; wherein the dicarboximide salt is selected from potassium phthalamide, sodium phthalamide, sodium dicarboxamide and sodium succinimide; (5) in the presence of methanesulfonyl chloride and lithium bromide, converting compound 9 into compound 10 via elimination reaction; (6) Under alkaline conditions, compound 10 is subjected to a hydrazinolysis reaction to obtain a hydrazinolysis product; the hydrazinolysis product is then reacted with an acid solution to obtain an acid salt of compound 3; (7) The acid salt of compound 3 is reacted with 3-(4-ethylphenyl)oxirane-2-carboxylate to obtain compound 5.
10. The method according to claim 9, wherein in step (7), 3-(4-ethylphenyl)ethylene oxide-2-carboxylate is 3-(4-ethylphenyl)ethylene oxide-2-carboxylic acid methyl ester, 3-(4-ethylphenyl)ethylene oxide-2-carboxylic acid ethyl ester, or 3-(4-ethylphenyl)ethylene oxide-2-carboxylic acid propyl ester; Preferably, in step (7), the reaction conditions are pH=4 and the reaction temperature is 85°C-100°C.