Preparation method of key chiral intermediate for fesoterodine synthesis

Abstract

The invention relates to the technical field of chemical synthesis of medicines, and particularly discloses a preparation method for synthesizing a fesoterodine chiral intermediate. According to the method, commercially available cheap chiral binaphthol (BINOL) or a derivative thereof (such as 3, 3 '-dibromo-BINOL, 3, 3'-dimethyl-BINOL and 3, 3 '-difluoro-BINOL) is used as a chiral ligand, copper chloride, copper bromide, copper acetate or copper nitrate is used as a catalyst, and an asymmetric conjugate addition reaction of arylboronic acid to 4-hydroxymethylcoumarin is realized. And the target chiral center is directly constructed with high enantioselectivity. According to the method, high-risk and high-cost reagents such as a Grignard reagent and lithium aluminum hydride in a traditional method are abandoned, and meanwhile the problems that in the prior art (such as US8530691B2), resolution is carried out through a chiral resolving agent after raceme synthesis is adopted, so that the atom economy is poor, the process steps are tedious, and the resolving agent is expensive are solved. The method is mild in reaction condition, simple and convenient to operate, high in yield (up to 88.1%), excellent in enantioselectivity (up to 99.1% in ee value), simple in post-treatment and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a preparation method of a key chiral intermediate for an anticholinergic drug fesoterodine, and particularly relates to a method for directly constructing the chiral center through an asymmetric catalytic conjugate addition reaction. BACKGROUND

[0002] Fesoterodine is an anticholinergic drug used to treat symptoms such as overactive bladder and urinary incontinence. Its structure Formula is 2-[(R)-3-[bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxymethylphenyl isobutyrate, and it usually exists in the form of fumarate. Fesoterodine has an excellent pharmacological mechanism and can effectively inhibit the overcontraction of bladder smooth muscle, thereby relieving symptoms such as frequent urination, urinary urgency, and incontinence.

[0003]

[0004] The prior art (such as US8530691B2) generally uses a method of first synthesizing a racemate, and then using a chiral acid (such as dibenzoyl tartaric acid, camphor sulfonic acid, etc.) to form a diastereomeric salt for resolution to obtain an optically pure intermediate. This route generally has the following defects: 1) low resolution efficiency, usually requiring multiple recrystallizations, and at least 50% of the non-target enantiomers are wasted, with poor atom economy; 2) use of expensive chiral resolving agents, resulting in high production costs; 3) long process steps, including racemate synthesis, resolution, salt decomposition, etc., with complicated operation and low total yield; 4) environmental pollution: a large amount of waste liquid and waste residue containing resolving agents are generated during production, and the post-treatment is complex, which does not comply with the principles of green chemistry. In addition, in some other synthesis routes, there are serious problems of relying on flammable and explosive Grignard reagent, and water-reactive lithium aluminum hydride, which have high requirements for equipment and operation, and have great safety hazards. Therefore, it is of great significance to develop an economic, safe, efficient and environmentally friendly synthesis method that directly constructs the chiral center from the source. Therefore, it is of great significance to develop an efficient, environmentally friendly and easy-to-industrialize production method for fesoterodine, especially a method that can achieve high yield and high enantioselectivity in the synthesis of key chiral intermediates. This not only can promote the application of fesoterodine in clinical practice, but also can provide patients with more reliable and economical treatment options.

[0005] The prior art related to the present technology includes: [1] Wu, X.; Yue, H.T.; Zuo, X.D.; Yang, X. H.; Yan, P.C.; Xie, J.H.&Zhou, Q.L., Kinetic Resolution of Recamic 4-Substituted Chroman-2-onesthrough Asymmetric Lactone Hydrogenation. CCS Chem. 2024, 6 , 2560–2576.。 SUMMARY

[0006] The present application aims to overcome the deficiencies of the prior art, in particular, to overcome the defects of the traditional racemate resolution route (such as US8530691B2), and to provide an economical, efficient, environmentally friendly and suitable for industrial production method for preparing a key chiral intermediate of fesoterodine.

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows: A preparation method of a key chiral intermediate for fesoterodine synthesis, characterized in that it comprises the following steps: (1) Dissolve chiral binol or its derivative (BINOL) in anhydrous alcohol to prepare solution A; (2) Dissolve copper salt of copper in anhydrous alcohol to prepare solution B; (3) Mix solution A and solution B, and react under the protection of inert atmosphere at -20℃ to room temperature, and the reaction time is 14-28 hours.

[0008] (4) After the reaction is completed, the reaction liquid is extracted, dried and concentrated to obtain a crude product, and the crude product is purified by recrystallization to obtain a target chiral intermediate with high optical purity.

[0009] The present application discards the traditional racemate synthesis-resolution route, and for the first time uses asymmetric conjugate addition reaction to directly and highly enantioselectively construct the target chiral center with commercially available and inexpensive chiral ligand BINOL derivative and metal copper salt as the catalytic system, realizes the control of chirality from the source, and avoids the material waste and purification burden brought by the resolution step, which is a great improvement in the field.

[0010] Preferably, the chiral ligand is (R)- or (S)-binol, (R)- or (S)-3,3'-dibromo-1,1'-binaphthalene-2,2'-diphenol, (R)- or (S)-3,3'-dimethyl-1,1'-binaphthol, or (R)- or (S)-3,3'-difluoro-1,1'-binaphthol, and the structure is any one of the following: .

[0011] Preferably, the copper salt catalyst is copper chloride, copper bromide, copper acetate or copper nitrate.

[0012] Preferably, in steps (1) and (2), the anhydrous alcohol is selected from any one or a combination of anhydrous methanol, anhydrous ethanol, anhydrous propanol, and anhydrous butanol.

[0013] Preferably, in step (3), the molar ratio of the chiral binaphthol derivative to the copper salt is 1:1.5 to 1:3.

[0014] Preferably, in step (3), the molar ratio of the aryl boronic acid to 4-hydroxymethyl coumarin is 1:1 to 1.2:1.

[0015] Preferably, in step (3), the reaction system is cooled to -20℃ to -10℃, and the aryl boronic acid and 4-hydroxymethyl coumarin are sequentially added, first reacting at low temperature for 2-4 hours, and then naturally warming to 20-25℃ for continued reaction for 12-24 hours.

[0016] Preferably, in step (4), the solvent used for recrystallization is a mixed system of diethyl ether / petroleum ether or ethanol / water.

[0017] Compared with the prior art, the present application has the following beneficial effects: The novel catalytic system composed of a chiral binaphthol derivative and copper chloride has made significant technical progress in the asymmetric conjugate addition reaction of aryl boronic acid and 4-hydroxymethyl coumarin compared with the prior art. The catalytic system can obtain the key chiral intermediate of the drug Fesoterodine with high yield and excellent enantioselectivity. Its outstanding performance is due to the unique chiral microenvironment created by the synergistic effect of the chiral binaphthol ligand and the copper center. Specifically, the chiral binaphthol ligand not only forms a rigid "chiral pocket" by coordinating with the copper center, effectively guiding the nucleophilic reagent derived from aryl boronic acid to attack from a specific spatial direction; more importantly, it can use the ligand skeleton to form a key hydrogen bond interaction with the hydroxymethyl group in the 4-hydroxymethyl coumarin substrate, thereby precisely positioning and fixing the electrophilic substrate in the conformation of the active center. This dual stereocontrol of both nucleophilic and electrophilic reactants is the fundamental reason for achieving high enantioselectivity. At the same time, copper chloride, as a highly efficient and economical Lewis acid, significantly activates the coumarin skeleton, ensuring high conversion and yield of the reaction. In summary, the catalytic system provided by the present application has the outstanding advantages of high catalytic efficiency, precise stereocontrol, and low cost, providing an extremely valuable industrial application approach for the green and efficient synthesis of key chiral intermediates. DETAILED DESCRIPTION

[0018] 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. The enantioselectivity of all example products is determined by high performance liquid chromatography (HPLC). It should be further understood that, after reading the content of the present application, those skilled in the art can make various modifications or changes to the present application, and these equivalent forms also fall within the scope of the appended claims.

[0019] Example 1 7.16 g (0.025 mol) of (R)-binol was dissolved in 500 mL of anhydrous ethanol under nitrogen protection, stirred at 25°C for 3 hours to prepare solution A.

[0020] 10.0 g (0.075 mol, molar ratio BINOL:CuCl2=1:3) of anhydrous copper chloride (CuCl2) was dissolved in 500 mL of anhydrous ethanol, stirred for 30 minutes to prepare solution B.

[0021] Solution A and solution B were combined in a 2L three-necked flask and mixed uniformly. The reaction system was cooled and maintained at -20°C, then aryl boronic acid (45.7 g, 0.375 mol) and 4-hydroxymethyl coumarin (66.1 g, 0.375 mol) were added in sequence. The reaction was stirred at this temperature for 3 hours. Then, the reaction mixture was naturally warmed to 25°C and the reaction was continued to stir for 18 hours.

[0022] After the reaction was completed, the reaction liquid was poured into 800 mL of ethyl acetate, washed with water (200 mL x 2) and separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure at 40°C to obtain a crude product in the form of viscous oil. 200 mL of diethyl ether was added to the crude product, which was completely dissolved by warming to 40°C, then 600 mL of petroleum ether was slowly added dropwise to precipitate white solid. The mixture was continuously stirred to crystallize at 0°C for 1 hour. Filtration was performed, and the solid was washed with cold petroleum ether and placed in a vacuum drying oven at 40°C for 6 hours to obtain a white solid product 84.0 g. The yield was 88.1% and the enantiomeric excess rate (ee) was 99.1% by HPLC analysis.

[0023] Example 2 Under nitrogen protection, 7.16 g (0.025 mol) (R)-binol was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C, and prepared into solution A. 6.72 g (0.05 mol, molar ratio BINOL:CuCl2=1:2) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution B. The subsequent operation was the same as Example 1, and 82.39 g of white solid product was obtained. The yield was 86.4% and the enantiomeric excess rate (ee) was 98.7% by HPLC analysis.

[0024] Example 3 Under nitrogen protection, 7.16 g (0.025 mol) (R)-binol was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C, and prepared into solution A. 8.40 g (0.0625 mol, molar ratio BINOL:CuCl2=1:2.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution B. The subsequent operation was the same as Example 1, and 83.53 g of white solid product was obtained. The yield was 87.6% and the enantiomeric excess rate (ee) was 98.9% by HPLC analysis.

[0025] Example 4 Under nitrogen protection, 7.16 g (0.025 mol) (R)-binol was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C, and prepared into solution A. 4.97 g (0.037 mol, molar ratio BINOL:CuCl2=1:1.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution B. The subsequent operation was the same as Example 1, and 81.05 g of white solid product was obtained. The yield was 85.0% and the enantiomeric excess rate (ee) was 98.5% by HPLC analysis.

[0026] Example 5 Under nitrogen protection, 7.16 g (0.025 mol) (R)-binol was dissolved in 500 mL anhydrous ethanol, stirred at 25°C for 3 hours to prepare solution A. 8.40 g (0.0625 mol, molar ratio BINOL:CuCl2=1:2.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes to prepare solution B. Solution A and solution B were combined in a 2L three-necked flask and mixed well. The reaction system was cooled and maintained at -10°C (different from -20°C in Example 1), then arylboronic acid (45.7 g, 0.375 mol) and 4-hydroxymethyl coumarin (66.1 g, 0.375 mol) were added in sequence. The subsequent operation was the same as in Example 1 to obtain white solid product 80.00 g. HPLC analysis showed that the yield was 83.9% and the enantiomeric excess rate (ee) was 98.0%.

[0027] Example 6 Under nitrogen protection, 7.16 g (0.025 mol) (R)-binol was dissolved in 500 mL anhydrous ethanol, stirred at 25°C for 3 hours to prepare solution A. 8.40 g (0.0625 mol, molar ratio BINOL:CuCl2=1:2.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes to prepare solution B. Solution A and solution B were combined in a 2L three-necked flask and mixed well. The reaction system was cooled and maintained at -20°C, then arylboronic acid (45.7 g, 0.375 mol) and 4-hydroxymethyl coumarin (66.1 g, 0.375 mol) were added in sequence. The reaction was stirred at this temperature for 2 hours (different from 3 hours in Example 1). The subsequent operation was the same as in Example 1 to obtain white solid product 78.96 g. HPLC analysis showed that the yield was 82.8% and the enantiomeric excess rate (ee) was 97.8%.

[0028] Example 7 Under nitrogen protection, 7.16 g (0.025 mol) (R)-binol was dissolved in 500 mL anhydrous ethanol, stirred at 25 °C for 3 hours to prepare solution A. 8.40 g (0.0625 mol, molar ratio BINOL:CuCl2=1:2.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes to prepare solution B. Solution A and solution B were combined in a 2L three-necked flask and mixed well. The reaction system was cooled and maintained at -20 °C, then arylboronic acid (45.7 g, 0.375 mol) and 4-hydroxymethyl coumarin (66.1 g, 0.375 mol) were added successively. The reaction was stirred at this temperature for 3 hours. Then the reaction mixture was naturally warmed to 25 °C and the reaction was continued to stir for 12 hours (different from 18 hours in Example 1). The subsequent operation was the same as Example 1 to obtain the product 77.71 g of white solid. The yield was 81.5% and the enantiomeric excess (ee) was 97.5% by HPLC analysis.

[0029] Example 8 Under nitrogen protection, 7.16 g (0.025 mol) (R)-binol was dissolved in 500 mL anhydrous ethanol, stirred at 25 °C for 3 hours to prepare solution A. 8.40 g (0.0625 mol, molar ratio BINOL:CuCl2=1:2.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes to prepare solution B. Solution A and solution B were combined in a 2L three-necked flask and mixed well. The reaction system was cooled and maintained at -20 °C, then arylboronic acid (45.7 g, 0.375 mol) and 4-hydroxymethyl coumarin (66.1 g, 0.375 mol) were added successively. The reaction was stirred at this temperature for 3 hours. Then the reaction mixture was naturally warmed to 25 °C and the reaction was continued to stir for 24 hours (different from 18 hours in Example 1). The subsequent operation was the same as Example 1 to obtain the product 81.72 g of white solid. The yield was 85.7% and the enantiomeric excess (ee) was 99.0% by HPLC analysis.

[0030] Example 9 Under nitrogen protection, 7.16 g (0.025 mol) (S)-BINOL was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C to prepare solution A. 8.40 g (0.0625 mol, molar ratio BINOL:CuCl2=1:2.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes to prepare solution B. The subsequent operation was the same as Example 1, and 80.86 g of white solid product was obtained. HPLC analysis showed that the yield was 84.8%, and the enantiomeric excess rate (ee) was 98.6%. The product was confirmed to be (S)-configuration by chiral HPLC analysis.

[0031] Example 10 Under nitrogen protection, 71.6 g (0.25 mol) (R)-BINOL was dissolved in 5 L anhydrous ethanol, stirred for 3 hours at 25°C to prepare solution A. 55.5 g (0.412 mol, molar ratio BINOL:CuCl2=1:1.65) anhydrous copper chloride (CuCl2) was dissolved in 5 L anhydrous ethanol, stirred for 30 minutes to prepare solution B. Solution A and solution B were combined in a 20 L reaction kettle and mixed well. The reaction system was cooled and maintained at -20°C, and then arylboronic acid (503 g, 4.125 mol) and 4-hydroxymethyl coumarin (726.7 g, 4.125 mol) were added in sequence. The reaction was stirred at this temperature for 3 hours. Then, the reaction mixture was naturally warmed to 25°C and the reaction was continued for 20 hours. After the reaction was completed, the reaction liquid was poured into 8 L ethyl acetate and washed with water (2 L x 2) and separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure at 40°C to obtain a crude product in the form of viscous oil. 2 L diethyl ether was added to the crude product, which was completely dissolved by warming to 40°C, and then 6 L petroleum ether was slowly added dropwise to precipitate white solid. The mixture was continuously stirred at 0°C for 1 hour to crystallize. Filtration was performed, and the solid was washed with cold petroleum ether and placed in a vacuum drying oven at 40°C for 6 hours to obtain 907 g of white solid product. HPLC analysis showed that the yield was 86.5%, and the enantiomeric excess rate (ee) was 98.4%.

[0032] Example 11 Under nitrogen protection, 5.55 g (0.0125 mol) (R)-3,3'-dibromo-1,1'- binaphthalene-2,2'-dihol was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C, and prepared into solution A. 5.58 g (0.025 mol) copper bromide (CuBr2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution B. Solution A and solution B were combined in a 2L three-necked flask and mixed uniformly. The subsequent operation was the same as Example 1, and 82.1 g of white solid product was obtained with a yield of 86.0% and an ee value of 98.8%.

[0033] Example 12 Under nitrogen protection, 3.93 g (0.0125 mol) (R)-3,3'-dimethyl-1,1'- binaphthol was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C, and prepared into solution A. 4.54 g (0.025 mol) copper acetate (CuAc2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution B. The subsequent operation was the same as Example 1. 80.5 g of white solid product was obtained with a yield of 84.4% and an ee value of 98.5%.

[0034] Example 13 Under nitrogen protection, 4.03 g (0.0125 mol) (R)-3,3'-difluoro-1,1'- binaphthol was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C, and prepared into solution A. 4.70 g (0.025 mol) copper nitrate (Cu(NO3)2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution B. The subsequent operation was the same as Example 1. 81.2 g of white solid product was obtained with a yield of 85.1% and an ee value of 98.7%.

[0035] Comparative Example 1 Under nitrogen protection, 8.40 g (0.0625 mol) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution (no chiral binaphthol ligand was added in this comparative example). The catalyst solution was placed in a 2L three-necked flask. The subsequent operation was the same as Example 1, and 69.42 g of white solid product was obtained. The product purity was 92.1% by HPLC analysis, the yield was 72.8%, and the enantiomeric excess rate (ee) was 0%. Chiral HPLC analysis confirmed that the product was a racemate. The results showed that the reaction could not be asymmetrically induced without the presence of a chiral ligand, a mixture without optical activity was obtained, the byproducts increased, and the yield and purity significantly decreased.

[0036] Comparative Example 2 Under nitrogen protection, 7.16 g (0.025 mol) (R)-BINOL was dissolved in 500 mL anhydrous ethanol, stirred for 3 hours at 25°C, and prepared into solution A. 8.40 g (0.0625 mol, molar ratio BINOL:CuCl2=1:2.5) anhydrous copper chloride (CuCl2) was dissolved in 500 mL anhydrous ethanol, stirred for 30 minutes, and prepared into solution B. Solution A and solution B were combined in a 2L three-necked flask and mixed uniformly. The temperature of the reaction system was controlled at 0°C (different from -20°C in Example 1). The subsequent operation was the same as in Example 1, and 74.00 g of light yellow solid product was obtained. HPLC analysis showed that the product purity was 96.5%, the yield was 77.6%, and the enantiomeric excess rate (ee) was 92.0%. Compared with Example 1, the reaction was carried out at a higher temperature, the product color deepened, indicating that the side reaction increased, resulting in a significant decrease in product purity, yield and enantioselectivity, proving that low temperature conditions are crucial for controlling the selectivity and efficiency of the reaction.

[0037] Comparative Example 3 (S)-3,3'-dibromo-BINOL was used as a ligand, copper chloride was used as a catalyst, and the rest of the conditions were the same as in Example 1, but the reaction temperature was 0°C. A light white solid product was obtained, with a yield of 78.2% and an ee value of 91.5%, indicating that low temperature is crucial for the selectivity of the reaction.

[0038] Comparative Example 4 According to the method of reference US8530691B2 Example 2-4, the racemic intermediate was resolved using (+)-2,3-dibenzoyl-D-tartaric acid. After multiple steps such as salting, fractional crystallization, and salt decomposition, the optically pure (R)-configuration intermediate was obtained. The total yield of this process was 45% (based on the racemate), and the enantiomeric excess rate (ee) was 95%. This method not only has a significantly lower yield than the examples of the present application (~88%), but also uses an expensive chiral resolving agent, and the process is complicated and has low atom economy In summary, the present application successfully develops a new method for directly, efficiently and selectively synthesizing a key chiral intermediate of fesoterodine by using cheap and readily available chiral BINOL and copper chloride (CuCl2) as a catalytic system through asymmetric conjugate addition reaction. This method is completely different from the existing racemate resolution method in terms of technical route, and has the advantages of mild conditions, safe operation, high enantioselectivity and yield, and simple work-up, which is significantly superior to the traditional racemate resolution route. It provides a solid technical foundation for the green, economic and large-scale production of fesoterodine, and has a broad industrial application prospect.

Claims

1. A process for the preparation of a chiral intermediate for the synthesis of fesoxodine, characterized in that, The method comprises the following steps: Step 1: preparing a solution of chiral ligand binaphthol or its derivative; Step 2: preparing a solution of copper salt catalyst; Step 3: mixing the solution of chiral ligand with the solution of copper salt catalyst, adding aryl boronic acid and 4-hydroxymethyl coumarin to perform asymmetric conjugate addition reaction; Step 4: after the reaction is completed, extracting, drying, concentrating and recrystallizing to obtain a chiral intermediate, i.e. (R)-6-(hydroxymethyl)-4-phenyl chroman-2-one.

2. The method of claim 1, wherein, The chiral ligand is selected from one of the following structures: (R)- or (S)-binaphthol, (R)- or (S)-3,3'-dibromo-1,1'-binaphthalene-2,2'-diphenol, (R)- or (S)-3,3'-dimethyl-1,1'-binaphthol, (R)- or (S)-3,3'-difluoro-1,1'-binaphthol, and any one of the following structural formulas: ； The chiral ligand is dissolved in anhydrous alcohol solution to form a ligand solution.

3. The method of claim 1, wherein, The copper salt catalyst is selected from one of copper chloride, copper bromide, copper acetate and copper nitrate; the copper salt catalyst is dissolved in anhydrous alcohol solution to form a solution of copper salt catalyst.

4. The method of claim 1, wherein, The molar ratio of the chiral ligand to the copper salt catalyst is 1:2 to 1:

4.

5. The method of claim 1, wherein, The reaction is performed at -20℃ to room temperature, and the reaction time is 14-28 hours.

6. The method of claim 5, wherein, During the reaction, the reaction system is first cooled to -20℃ to -10℃ under the protection of inert atmosphere, aryl boronic acid and 4-hydroxymethyl coumarin are sequentially added, and low-temperature reaction is performed for 2-4 hours, and then the temperature is naturally increased to 20-25℃ to continue the reaction for 12-24 hours.

7. The method of claim 1, wherein, The molar ratio of the aryl boronic acid to 4-hydroxymethyl coumarin is 1:1 to 1.2:

1.

8. The method of claim 1, wherein, The recrystallization solvent is ethanol / petroleum ether or ethanol / water.

9. A chiral intermediate prepared by the method according to any one of claims 1-8, which is used for the synthesis of fumarate salt of fesoterodine.

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