Synthesis method of α-cyclopentylmandelic acid

Abstract

The invention discloses a method for synthesizing alpha-cyclopentylmandelic acid, and belongs to the technical field of organic chemical synthesis. The method comprises the following steps: dissolving phenylacetic acid ester in an organic solvent containing an alkali, and dripping halogenated cyclopentane under room temperature to obtain an intermediate iii; dissolving the intermediate iii in an organic solvent, adding an alkali, heating the temperature to 60-80 DEG C, reacting for 1h-6h, removing the organic solvent by rotary evaporation, adjusting the pH to be strongly acidic, precipitating a solid, and filtering to obtain an intermediate iv; dissolving the intermediate iv in an organic solvent, adding a chlorination agent, and obtaining an intermediate v; dissolving the intermediate v in an organic solvent, adding an alkali, reacting for 1h-24h, rotary evaporation, adjusting the pH to be strongly acidic, precipitating a solid, filtering to obtain a target crude product, and recrystallizing to obtain a target pure product. The method of the invention has the characteristics of easy availability of initial raw materials and low price, simple production operation, safety and high efficiency, low cost, high yield, and the like.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a process method which avoids the use of flammable and explosive Grignard reagents through conventional substitution, hydrolysis, chlorination and other reactions. Background Art

[0002] α-Cyclopentylmandelic acid (2-cyclopentyl-2-hydroxyphenylacetic acid, CPMA for short) is an important intermediate for the preparation of glycopyrrolate. Glycopyrrolate has the effects of inhibiting gastric juice secretion, saliva secretion and regulating gastrointestinal motility. It is used to treat diseases such as gastric and duodenal ulcers, chronic gastritis, and chronic obstructive pulmonary disease (COPD).

[0003] Non-patent document 1 provides an overview of the synthesis method of α-cyclopentylmandelic acid (as shown in the figure below), and discusses whether it can be applied industrially from the perspective of the properties and safety of the reaction raw materials.

[0004] The yield of the product (α-cyclopentylmandelic acid) (AD) obtained by the reaction of benzoylformic acid with a halogenated cyclopentyl Grignard reagent or by the reaction of benzoylformic acid ester with a halogenated cyclopentyl Grignard reagent followed by hydrolysis ranges from 28% to 53%. During the above reaction (AD), the reaction is highly exothermic, with many by-products and difficult to purify the product; the reaction conditions and temperature vary greatly, and a large amount of Grignard reagent is consumed during the reaction process, and three wastes are generated. It can be seen that it is necessary to develop a safe and efficient synthesis process for α-cyclopentylmandelic acid.

[0005] Non-patent document 1: Allmendinger T et al., Carry Over of Impurities: A Detailed Exemplification for Glycopyrrolate (NVA237), Organic Process Research & Development, 2012, Vol. 16, No. 11, pp. 1754-1769. Summary of the invention

[0006] The main purpose of the present invention is to solve the technical problems in the above-mentioned background technology and to propose a process synthesis method which avoids the use of flammable and explosive Grignard reagents through conventional substitution, hydrolysis, chlorination and other reactions.

[0007] To achieve the above object, the present invention provides a method for synthesizing α-cyclopentylmandelic acid, comprising the following steps:

[0008] Step 1: dissolving phenylacetic acid ester in an organic solvent containing a base, adding halogenated cyclopentane dropwise at room temperature, reacting for 1 h to 5 h, quenching with water, extracting the organic phase, and drying the organic phase to obtain intermediate iii;

[0009] ;

[0010] Where: R is C1~C3; X is halogen element Cl, Br, I;

[0011] Step 2: Dissolve intermediate iii in an organic solvent, add a base, heat to 60-80°C, react for 1h-6h, remove the organic solvent by rotary evaporation, adjust the pH to strong acidity, precipitate the solid, and filter to obtain intermediate iv

[0012] ;

[0013] Step 3: Dissolve the intermediate iv in an organic solvent, heat to reflux for 1 h, cool to room temperature, add a chlorination reagent, heat to reflux for 2.5 h, cool to room temperature, adjust the pH to a strong acid, quench with water, extract, and spin dry the organic layer to obtain the intermediate v

[0014] ;

[0015] Step 4: Dissolve the intermediate v in an organic solvent, add a base, react for 1 h to 24 h, perform rotary evaporation, adjust the pH to a strong acid, precipitate a solid, filter to obtain the target crude product, and recrystallize to obtain the target pure product;

[0016] in:

[0017] The base in step 1 is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bistrimethylsilylamide, and sodium bistrimethylsilylamide;

[0018] The base in step 2 and step 4 is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide;

[0019] The chlorination reagent in step 3 is selected from one or more of sulfonyl chloride, N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid, sodium dichloroisocyanurate, phosphorus trichloride, and phosphorus pentachloride;

[0020] In step 1, the amount of the base added is 1.0 to 3.0 times the equivalent of the phenylacetic acid ester; the amount of the halogenated cyclopentane added is 1.0 to 2.5 times the equivalent of the phenylacetic acid ester;

[0021] In step 3, the amount of the chlorination reagent added is 1.0 to 20.0 times the equivalent of the intermediate v.

[0022] Preferably, the reaction time in step 1 is 2 h to 4 h; the reaction time in step 2 is 3 h to 5 h; and the reaction time in step 4 is 5 h to 20 h.

[0023] Preferably, the reaction time in step 1 is 3 h; the reaction time in step 2 is 4 h; and the reaction time in step 4 is 18 h.

[0024] Preferably, the pH in step 2 is 1-5; the pH in step 3 is 1-5; and the pH in step 4 is 1-5.

[0025] Preferably, the organic solvent in step 1 is selected from one or more of N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, and dioxane; the organic solvent in step 2 is selected from one or more of methanol, ethanol, and n-propanol; the organic solvent in step 3 is selected from thionyl chloride; the organic solvent in step 4 is selected from one or more of tetrahydrofuran, dioxane, methanol, ethanol, n-propanol, and isopropanol.

[0026] The present invention has the following advantages: the present application proposes a method for synthesizing α-cyclopentylmandelic acid, using phenylacetic acid ester as the initial raw material, performing conventional substitution, hydrolysis, chlorination and other reactions, and performing a completely new design and optimization, greatly improving the yield, and avoiding the use of flammable and explosive Grignard reagents. The method of the present invention has the characteristics of readily available and low-priced initial raw materials, simple production operation, safety and efficiency, low cost, high yield, etc., and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is the hydrogen spectrum nuclear magnetic spectrum of intermediate iv in the present invention.

[0028] Figure 2 It is the hydrogen nuclear magnetic spectrum of α-cyclopentylmandelic acid in the present invention.

[0029] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure clearer, the technical solution of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, rather than all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present disclosure.

[0031] The present invention provides a method for synthesizing α-cyclopentylmandelic acid, comprising the following steps:

[0032] Step 1: dissolving phenylacetic acid ester in an organic solvent containing a base, adding halogenated cyclopentane dropwise at room temperature, reacting for 1 h to 5 h, preferably 2 h to 4 h, more preferably 3 h, quenching with water, extracting the organic phase, and drying the organic phase to obtain intermediate iii;

[0033] ;

[0034] Where: R is C1~C3; X is halogen element Cl, Br, I;

[0035] The base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilylamide), and sodium bis(trimethylsilylamide); the organic solvent is selected from one or more of N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, and dioxane; the amount of the base added is 1.0 to 3.0 times the equivalent of phenylacetic acid ester; and the amount of the halogenated cyclopentane added is 1.0 to 2.5 times the equivalent of phenylacetic acid ester.

[0036] Step 2: Dissolve the intermediate iii in an organic solvent, add a base, heat to 60-80°C, react for 1h-6h, preferably 3h-5h, more preferably 4h, remove the organic solvent by rotary evaporation, adjust the pH to a strongly acidic pH, preferably 1-5, precipitate a solid, and filter to obtain the intermediate iv

[0037] ;

[0038] Among them, the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; the organic solvent is selected from one or more of methanol, ethanol, and n-propanol.

[0039] Step 3: Dissolve the intermediate iv in an organic solvent, heat to reflux for 1 h, cool to room temperature, add a chlorination reagent, heat to reflux for 2.5 h, cool to room temperature, adjust the pH to a strong acid, preferably, a pH of 1 to 5, quench with water, extract, and spin-dry the organic layer to obtain the intermediate v

[0040] ;

[0041] Wherein, the organic solvent is thionyl chloride, and the chlorination agent is selected from one or more of sulfonyl chloride, N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid, sodium dichloroisocyanurate, phosphorus trichloride, and phosphorus pentachloride; and the amount of the chlorination agent added is 1.0 to 20.0 times the equivalent of the intermediate v.

[0042] Step 4: Dissolve the intermediate v in an organic solvent, add a base, react for 1 h to 24 h, preferably 5 h to 20 h, more preferably 18 h, rotary evaporation, adjust the pH to a strong acid, preferably 1 to 5, precipitate a solid, filter to obtain the target crude product, and recrystallize to obtain the target pure product

[0043] ;

[0044] Wherein: the organic solvent is selected from one or more of tetrahydrofuran, dioxane, methanol, ethanol, n-propanol, isopropanol; the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide. Example 1

[0045] Step 1: Weigh 115.3g of sodium tert-butoxide and dissolve it in 500mL of N,N-dimethylformamide, add 150.2g of methyl phenylacetate, stir at room temperature for 1h, then dropwise add 178.8g of bromocyclopentane in 100mL of N,N-dimethylformamide at room temperature, continue stirring for 3h, pour the reaction solution into 1.5L of ice water for water quenching, and extract with ethyl acetate three times (500mL×3). Combine the organic layers, wash them with 1L of water and 1L of saturated brine in turn, and spin dry to obtain 230.2g of crude intermediate iii in the form of yellow oil;

[0046] Step 2: Dissolve 230.2 g of the crude intermediate iii obtained in step 1 in 800 mL of methanol, add 80.0 g of sodium hydroxide in 200 mL of aqueous solution at room temperature, heat to 80°C, and react for 4 hours. Cool to room temperature, remove most of the methanol by rotary evaporation, add 500 mL of water to dilute, adjust the pH to 1 with concentrated hydrochloric acid, and a large amount of white solid precipitates, which is filtered off. The solid is washed twice with a methanol / water = 1 / 2 mixed solvent and toluene, and then dried in a vacuum drying oven at 40°C for 3 hours to obtain 185.6 g of intermediate iv as a white solid. The total yield of the two-step reaction is 90.8%; Figure 1 shown.

[0047] 1 H NMR(400 MHz, DMSO-d6) (ppm): δ 7.20-7.34(m,5H),3.22(d, J=11.2Hz,1H),2.39-2.47(m,1H),1.80-1.89(m,1H),1.37-1.64(m,4H),1.19-1.30(m,2H),0.89-0.98(m,1H).

[0048] Step 3: Dissolve 185.6g of intermediate iv obtained in step 2 in 500mL of thionyl chloride, heat to reflux for 1h, cool to room temperature, slowly drop 981.0g of sulfonyl chloride, heat to reflux after the addition is complete, and react for 2.5h. Cool to room temperature, evaporate a large amount of solvent, pour into 2L of ice water for water quenching, and extract with ethyl acetate three times (500mL×3). Combine the organic layers, wash once with 1L of water and 1L of saturated brine, and spin dry to obtain 210.3g of crude intermediate v in the form of yellow oil;

[0049] Step 4: Dissolve 210.3 g of intermediate v obtained in step 3 in 800 mL of methanol, add 109.0 g of sodium hydroxide in 200 mL of aqueous solution at room temperature, and react for 18 h. Remove most of the methanol by rotary evaporation, add 800 mL of water to dilute, adjust the pH to 1 with concentrated hydrochloric acid, and a large amount of white solid precipitates, which is filtered off. Wash the solid twice with a mixed solvent of methanol / water = 1 / 2 to obtain 183.7 g of the crude final product. The crude product is recrystallized with a mixed solvent of methanol and water to finally obtain 138.2 g of pure product with a liquid phase purity of 99.1%, in the form of a white solid, and the total yield of the four-step reaction is 62.7% (see Figure 2 ).

[0050] 1 H NMR (400 MHz, DMSO-d6) (ppm): δ 12.95 (brs,1H), 7.59-7.62(m,2H),7.30-7.34(m,2H),7.21-7.24(m,1H),5.32(brs,1H),2.82-2.90(m,1H),1.34-1.62(m,6H),1.13-1.25(m,2H). Example 2

[0051] Step 1: Weigh 134.7g potassium tert-butoxide and dissolve it in 500mL N,N-dimethylformamide, add 150.2g methyl phenylacetate, stir at room temperature for 1h, then add dropwise 178.8g bromocyclopentane in 100mL N,N-dimethylformamide solution at room temperature, continue stirring for 3h after addition, pour the reaction solution into 1.5L ice water, and extract with ethyl acetate three times (500mL×3). Combine the organic layers, wash with 1L water and 1L saturated brine in turn, and spin dry to obtain 238.8g crude intermediate iii in the form of yellow oil;

[0052] Step 2: Dissolve 238.8g of the crude intermediate iii obtained in step 1 in 800mL of methanol, add 80.0g of sodium hydroxide in 200mL of aqueous solution at room temperature, heat to 80°C, and react for 4h. Cool to room temperature, remove most of the methanol by rotary evaporation, add 500mL of water to dilute, adjust the pH to 1 with concentrated hydrochloric acid, and a large amount of white solid precipitates, which is filtered. The solid is washed twice with a methanol / water = 1 / 2 mixed solvent and toluene, and then dried in a vacuum drying oven at 40°C for 3h to obtain 187.0g of intermediate iv as a white solid. The total yield of the two-step reaction is 91.5%;

[0053] Step 3: Dissolve 187.0g of intermediate iv obtained in step 2 in 500mL of thionyl chloride, heat to reflux for 1h, cool to room temperature, slowly drop 366.7g of N-chlorosuccinimide, heat to reflux after the addition is complete, and react for 2.5h. Cool to room temperature, evaporate a large amount of solvent, pour into 1.5L of ice water, and extract three times with ethyl acetate (500mL×3). Combine the organic layers, wash once with 1L of water and 1L of saturated brine, and spin dry to obtain 206.1g of crude intermediate v in the form of yellow oil;

[0054] Step 4: Dissolve 206.1g of intermediate v obtained in step 3 in 800mL of methanol, add 200mL of aqueous solution of 154.1g of potassium hydroxide at room temperature, and react for 18h. Remove most of the methanol by rotary evaporation, add 800mL of water to dilute, adjust pH=1 with concentrated hydrochloric acid, and a large amount of white solid precipitates, which is filtered by suction. The solid is washed twice with a mixed solvent of methanol / water=1 / 2 to obtain 170.4g of crude final product. The crude product is recrystallized with a mixed solvent of methanol and water to finally obtain 125.7g of pure product with a liquid phase purity of 98.8%, in the form of a white solid, and the total yield of the four-step reaction is 57.1%. Example 3

[0055] Step 1: Weigh 108.0g of sodium methoxide and dissolve it in 500mL of N,N-dimethylformamide, add 150.2g of methyl phenylacetate, stir at room temperature for 1h, then dropwise add 209.2g of chlorocyclopentane in 100mL of N,N-dimethylformamide solution at room temperature, continue stirring for 3h after addition, pour the reaction solution into 1.5L of ice water, and extract with ethyl acetate three times (500mL×3). Combine the organic layers, wash them with 1L of water and 1L of saturated brine in turn, and spin dry to obtain 210.6g of crude intermediate iii in the form of yellow oil;

[0056] Step 2: Dissolve 210.6g of the crude intermediate iii obtained in step 1 in 800mL of methanol, add 80.0g of sodium hydroxide in 200mL of aqueous solution at room temperature, heat to 80°C, and react for 4h. Cool to room temperature, remove most of the methanol by rotary evaporation, add 500mL of water to dilute, adjust the pH to 1 with concentrated hydrochloric acid, and a large amount of white solid precipitates, which is filtered. The solid is washed twice with a methanol / water = 1 / 2 mixed solvent and toluene, and then dried in a vacuum drying oven at 40°C for 3h to obtain 176.5g of intermediate iv as a white solid. The total yield of the two-step reaction is 86.4%;

[0057] Step 3: Dissolve 176.5g of intermediate iv obtained in step 2 in 500mL of dichlorothionyl, heat to reflux for 1h, cool to room temperature, slowly drop 230.7g of N-chlorosuccinimide, heat to reflux after the addition is complete, and react for 2.5h. Cool to room temperature, evaporate a large amount of solvent, pour into 1.5L of ice water, and extract three times with ethyl acetate (500mL×3). Combine the organic layers, wash once with 1L of water and 1L of saturated brine, and spin dry to obtain 192.9g of crude intermediate v in the form of yellow oil;

[0058] Step 4: Dissolve 192.9g of intermediate v obtained in step 3 in 800mL of methanol, add 200mL of aqueous solution of 103.7g of sodium hydroxide at room temperature, and react for 18h. Remove most of the methanol by rotary evaporation, add 800mL of water to dilute, adjust pH=1 with concentrated hydrochloric acid, and a large amount of white solid precipitates, which is filtered by suction. The solid is washed twice with a mixed solvent of methanol / water=1 / 2 to obtain 77.5g of crude final product. The crude product is recrystallized with a mixed solvent of methanol and water to finally obtain 112.4g of pure product with a liquid phase purity of 98.6%, in the form of a white solid, and the total yield of the four-step reaction is 51.0%. Example 4

[0059] The difference between this embodiment and embodiment 1 is that:

[0060] The reaction time of step 1 is 2 h, the amount of base added is 2.0 times the equivalent of phenylacetic acid ester, and the amount of cyclopentane halide added is 1.5 times the equivalent of phenylacetic acid ester;

[0061] The reaction time of step 2 is 3 h and the pH value is 5;

[0062] In step 3, the amount of the chlorination reagent added is 10 times the equivalent of the intermediate v, and the pH value is 5;

[0063] In step 4, the reaction time is 24 h and the pH value is 5;

[0064] The other reaction conditions remained unchanged.

[0065] The total yield of the two-step reaction was 85.1%, the total yield of the four-step reaction was 52.1%, and the liquid phase purity of α-cyclopentylmandelic acid was 98.7%. Example 5

[0066] The difference between this embodiment and embodiment 2 is that:

[0067] The reaction time of step 1 is 4 hours, the amount of base added is 3.0 times the equivalent of phenylacetic acid ester, and the amount of cyclopentane halide added is 2.5 times the equivalent of phenylacetic acid ester;

[0068] The reaction time of step 2 is 5 h, and the pH value is 2;

[0069] In step 3, the amount of the chlorination reagent added is 5 times the equivalent of the intermediate v, and the pH value is 2;

[0070] In step 4, the reaction time is 10 h and the pH value is 2;

[0071] The other reaction conditions remained unchanged.

[0072] The total yield of the two-step reaction was 70.1%, the total yield of the four-step reaction was 50.8%, and the liquid phase purity of α-cyclopentylmandelic acid was 97.0%. Example 6

[0073] The difference between this embodiment and embodiment 1 is that:

[0074] The reaction time of step 1 is 1 h, the amount of base added is 2.5 times the equivalent of phenylacetic acid ester, and the amount of cyclopentane halide added is 1.5 times the equivalent of phenylacetic acid ester;

[0075] The reaction time of step 2 is 1 h, and the pH value is 1;

[0076] In step 3, the amount of chlorination reagent added is 20 times the equivalent of intermediate v, and the pH value is 1;

[0077] In step 4, the reaction time is 1 h and the pH value is 1;

[0078] The other reaction conditions remained unchanged.

[0079] The total yield of the two-step reaction was 64.3%, the total yield of the four-step reaction was 48.6%, and the liquid phase purity of α-cyclopentylmandelic acid was 99.0%.

[0080] Comparative Example 1

[0081] Weigh 15.0g of benzoylformic acid and dissolve it in 200mL of anhydrous tetrahydrofuran, cool it to -5 - 0℃, slowly drop 300mL of 1M tetrahydrofuran solution of cyclopentylmagnesium bromide, control the temperature not to exceed 5℃ during the dropwise addition, slowly warm it to room temperature after the dropwise addition is completed, stir for 18h, pour the reaction solution into 1L of 1M dilute hydrochloric acid to quench, a yellow viscous solid precipitates, and extract it three times with ethyl acetate (500mL×3). Combine the organic layers, wash them once with 1L of water and 1L of saturated brine, and spin dry to obtain 7.9g of crude product of the final product. The crude product is recrystallized with toluene and methanol / water mixed solvents, and finally 2.8g of pure product is obtained, with a liquid phase purity of 98.0%, in the form of a light yellow solid, and the yield is 12.7%.

Claims

1. A method for synthesizing α-cyclopentylmandelic acid, characterized in that: The following steps are involved: Step 1: dissolving phenylacetic acid ester in an organic solvent containing a base, adding halogenated cyclopentane dropwise at room temperature, reacting for 1 h to 5 h, quenching with water, extracting the organic phase, and drying the organic phase to obtain intermediate iii; ； Wherein: R is methyl; X is halogen element Cl, Br, I; Step 2: Dissolve intermediate iii in an organic solvent, add a base, heat to 60-80°C, react for 1h-6h, remove the organic solvent by rotary evaporation, adjust the pH to strong acidity, precipitate the solid, and filter to obtain intermediate iv ； Step 3: Dissolve the intermediate iv in an organic solvent, heat to reflux for 1 h, cool to room temperature, add a chlorination reagent, heat to reflux for 2.5 h, cool to room temperature, adjust the pH to a strong acid, quench with water, extract, and spin dry the organic layer to obtain the intermediate v ； Step 4: Dissolve the intermediate v in an organic solvent, add a base, react for 1 h to 24 h, perform rotary evaporation, adjust the pH to a strong acid, precipitate a solid, filter to obtain the target crude product, and recrystallize to obtain the target pure product; in: The base in step 1 is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bistrimethylsilylamide, and sodium bistrimethylsilylamide; The base in step 2 and step 4 is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; The organic solvent in step 3 is selected from thionyl chloride; the chlorination agent is selected from one or more of sulfonyl chloride, N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid, sodium dichloroisocyanurate, phosphorus trichloride, and phosphorus pentachloride; in step 1, the amount of the base added is 1.0 to 3.0 times the equivalent of phenylacetic acid ester; the amount of the halogenated cyclopentane added is 1.0 to 2.5 times the equivalent of phenylacetic acid ester; In step 3, the amount of the chlorination reagent added is 1.0 to 20.0 times the equivalent of the intermediate v.

2. The method according to claim 1, characterized in that The reaction time in step 1 is 2h~4h; The reaction time in step 2 is 3h~5h; The reaction time in step 4 is 5 h to 20 h.

3. The method according to claim 1, characterized in that The reaction time in step 1 is 3h; The reaction time in step 2 is 4h; The reaction time in step 4 is 18 h.

4. The method according to any one of claims 1 to 3, characterized in that: The pH in step 2 is 1 to 5; The pH in step 3 is 1 to 5; The pH in step 4 is 1-5.

5. The method according to claim 4, characterized in that The organic solvent in step 1 is selected from one or more of N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, and dioxane; The organic solvent in step 2 is selected from one or more of methanol, ethanol and n-propanol; The organic solvent in step 4 is selected from one or more of tetrahydrofuran, dioxane, methanol, ethanol, n-propanol, and isopropanol.

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