CN107337658A - A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to a synthesis method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid. The present invention takes p-aminosalicylic acid as starting raw material, obtains 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester through esterification, acylation, twice halogenation, and then with 1 , 2-dibromoethane undergoes a substitution reaction to obtain 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester, and then undergoes cyclization and hydrolysis to obtain the final product. The invention has easy-to-obtain raw materials, simple and mild operation, short production cycle, high purity, good safety, low cost and is suitable for industrialized production.

Description

A kind of synthetic method of prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid Law

technical field

The invention belongs to the technical field of medicine and relates to a synthesis method of prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid.

Background technique

Chronic constipation is a common disease caused by a variety of factors and is related to the movement of the digestive tract. Constipation is characterized by reduced bowel movements, hard stools, incomplete defecation and straining. Colonic movements in normal healthy people include short-term contractions, long-term contractions, tension contractions, and giant transitional contractions. Patients with functional constipation are mainly divided into two types: delayed colon transit time and normal colon transit time. In the former patients, the frequency, duration, and amplitude of huge transitional contractions may decrease, and the gastrocolic reflexes may weaken or disappear, while the local phasic non-propelling contractions may increase, making the movement of the entire colon uncoordinated, and a small number of patients may experience weakened small bowel motility. Patients with normal passage times mainly had abnormal anal sphincter function and decreased rectal sensory function. In recent years, with the impact of factors such as living standards, lifestyles, and dietary structure, coupled with serious aging, the incidence of constipation in my country is on the rise.

Prucalopride succinate was licensed by Movetis Company in accordance with the authorization of Janssen Company. After being approved in Europe in October 2009, it was launched in Germany in January 2010 and in the UK in March 2010. Prucalopride succinate is a benzofuran derivative with the chemical name 4-amino-5-chloro-2,3-dihydro-N[1-(3-methoxypropyl)-4-piperidinyl ]-7-benzofuran carboxamide is a newly discovered drug that promotes intestinal motility. The drug has a good effect on promoting lower gastrointestinal motility and can effectively relieve the symptoms of constipation patients. After taking prucalopride in healthy people, the operation of colonic contents was significantly promoted, and the emptying time of the proximal colon was accelerated, while the gastric emptying and small intestinal transit time did not change. , the proportion of loose stools increased. Treatment studies in patients with constipation have found that colon transit time is shortened, bowel frequency is increased, and rectal sensitivity to distension and electrical stimulation is increased. Prucalopride has no serious side effects on normal people or patients with constipation, has high safety and good tolerance, and has a good market prospect.

Prucalopride succinate is a 5-HT4 receptor agonist, which has little effect on the secretion of the gastrointestinal tract and does not excite other receptors. For healthy people, prucalopride can shorten the transit time of the upper gastrointestinal tract and colon, and for patients with constipation, prucalopride can increase the frequency of defecation and reduce the hardness of stool. Compared with cisapride, it has higher selectivity, better effect, and less adverse reactions. It is a new type of effective drug for patients with chronic constipation.

Contents of the invention

The technical problem to be solved by the present invention is to provide a synthesis method of prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid.

The present invention adopts following technical scheme:

Using p-aminosalicylic acid as the starting material, under the action of a catalyst, undergoes methylation reaction with methanol to obtain 4-amino-2-hydroxybenzoic acid methyl ester; then undergoes acetylation reaction with acetylating reagent to obtain 4-acetamide Methyl-2-hydroxybenzoate, 4-acetamido-5-chloro-2-hydroxybenzoate was obtained by chlorination, and 4-acetamido-3-bromo-5-chloro was obtained by bromination -2-Hydroxybenzoic acid methyl ester, bromoethylation to obtain 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester, and then cyclization and hydrolysis to obtain Intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid of prucalopride succinate.

The whole process includes the following steps:

(1) 4-amino-2-hydroxybenzoic acid methyl ester described in preparation formula (II)

Add p-aminosalicylic acid, methanol, and catalyst in a molar ratio of 1:(4~8):(1.5~4), preferably 1:(5~6.5):(1.8~2.8), and add the catalyst dropwise at low temperature , the reaction temperature is the reflux temperature. After the reaction is terminated, the pH is adjusted to 4-5 with an aqueous alkali solution, and the off-white solid 4-amino-2-hydroxybenzoic acid methyl ester is obtained by suction filtration.

The catalyst used in the above preparation method includes but not limited to concentrated sulfuric acid, p-toluenesulfonic acid, tetrabutyl titanate, thionyl chloride or concentrated hydrochloric acid, preferably the catalyst is concentrated sulfuric acid.

(2) 4-acetamido-2 hydroxybenzoic acid methyl ester described in preparation formula (Ⅲ)

The prepared 4-amino-2-hydroxybenzoic acid methyl ester, glacial acetic acid, and acylating agent are in a molar ratio of 1: (3.5-9): (0.5-2), preferably in a ratio of 1: (4-6.5) : (0.7～1.3), reaction temperature 25 ℃～55 ℃, preferred temperature is 35 ℃～45 ℃, dropwise add acylating reagent during reaction temperature, after reaction terminates, add water, suction filtration, obtain white solid 4-acetamido - Methyl 2-hydroxybenzoate.

The acylating reagent used in the above preparation method includes but not limited to acetic anhydride and acetyl chloride, preferably the acylating reagent is acetic anhydride.

(3) 4-acetamido-5-chloro-2-hydroxybenzoic acid methyl ester described in preparation formula (Ⅳ)

The prepared 4-acetylamino-2-hydroxybenzoic acid methyl ester and the chlorination reagent are added to the reaction reagent according to the molar ratio of 1: (0.8～2), preferably 1: (1.1～1.5), and the reaction temperature The temperature is -10°C to 20°C, preferably -6°C to 5°C. After the reaction is terminated, add water, adjust the pH to 4 to 5 with aqueous sodium hydroxide solution, filter with suction, extract the filtrate to separate the organic phase, and spin to dry the solvent. A filter cake and spin-dried white solid methyl 4-acetamido-5-chloro-2-hydroxybenzoate were obtained.

The chlorinated reagent used in the above-mentioned preparation method includes but not limited to N-chlorosuccinimide, sulfonyl chloride, thionyl chloride, phosphorus trichloride or phosphorus pentachloride, preferably chlorinated reagent sulfonyl chloride, the reaction used The solvent includes but not limited to dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, toluene or carbon tetrachloride, and the preferred reaction solvent is ethyl acetate.

(4) 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester described in preparation formula (Ⅴ)

The prepared 4-acetamido-5-chloro-2-hydroxybenzoic acid methyl ester and the brominating reagent are in a molar ratio of 1: (0.5 to 1.8), preferably in a ratio of 1: (1 to 1.3). In the reaction solvent, react at room temperature. After the reaction is terminated, add water, filter with suction, and wash the filter cake with water to obtain white solid 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester .

The brominated reagent used in the above-mentioned preparation method includes but not limited to N-bromosuccinimide, dibromohydantoin or bromine, preferably brominated reagent N-bromosuccinimide, and the reaction reagent is N, N-dimethylformamide, tetrahydrofuran, a mixed reagent of acetic acid and water, ethanol, the preferred reagent is N,N-dimethylformamide.

(5) 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester described in preparation formula (Ⅵ)

The prepared 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester, 1,2-dibromoethane, and acid-binding agent are in a molar ratio of 1: (1.3 to 2.4): (0.6～1.4), the preferred ratio is 1:(1.6～2):(1.8～1.2), added to the reaction solvent, the reaction temperature is 25°C～65°C, the preferred temperature is 35°C～45°C, after the reaction is terminated, add Cool warm water to room temperature, stir overnight for crystallization, suction filtration, recrystallization with toluene, suction filtration while hot, and crystallization of the filtrate to obtain white solid 4-acetamido-3-bromo-2-(2-bromoethoxy) - Methyl 5-chlorobenzoate.

The acid-binding agent used in the above preparation method includes but not limited to potassium carbonate, triethylamine, pyridine, sodium carbonate, preferably the acid-binding agent is potassium carbonate, and the reaction solvent is N,N-dimethylacetamide, N,N - Dimethylformamide, acetone, toluene, preferably the reagent N,N-dimethylacetamide.

(6) Preparation of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-methyl carboxylate described in formula (VII)

The prepared 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester and zinc powder are 1: (0.9～2.1) according to the molar ratio, and the preferred ratio is 1: (1.05~1.5), added to the reaction solvent, under the protection of nitrogen, stirred at room temperature for 2 hours, heated to a reaction temperature of 35°C to 70°C, preferably at a temperature of 45°C to 60°C, reacted for about 24h, monitored the reaction by TLC, and terminated the reaction Afterwards, drop hydrochloric acid, isopropanol, water according to molar ratio (0.3～0.8): (0.25～0.75): (0.5～1.0), preferred ratio (0.45～0.6): (0.4～0.6): (0.7～0.9 ), the dropwise addition was completed and the temperature was raised, the reaction liquid was clarified, added cold water to stir and cool to crystallize, and suction filtered to obtain white solid 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester.

Reagents used in the above preparation method include but not limited to N,N-dimethylacetamide, N,N-dimethylformamide, acetone, tetrahydrofuran, preferably N,N-dimethylacetamide.

(7) Preparation of 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid described in formula (Ⅷ)

The prepared 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester and 50% aqueous sodium hydroxide solution are in a molar ratio of 1: (2 to 4), preferably in a ratio of 1: (2.5 ~ 3.8), added to the reaction solvent, and an appropriate amount of water, the reaction temperature is 65 ° C ~ 100 ° C, the preferred temperature is 80 ° C ~ 95 ° C, TLC monitors the reaction, after the reaction is terminated, cool to 5 ° C and stir to analyze crystallization, suction filtration, the filter cake was added to the mixed solvent of propylene glycol monomethyl ether and water, the temperature was raised to 80 ℃ ~ 95 ℃ and stirred, and dilute hydrochloric acid was added dropwise to adjust the pH to about 3, and the solid precipitated, cooled to room temperature, stirred and precipitated crystallized, filtered with suction to obtain 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as a white solid.

The reaction reagents used in the above preparation method include but are not limited to the reaction solvent is a mixed solvent of ethanol and water, propylene glycol monomethyl ether or propylene glycol monomethyl ether and water mixed solvent, the preferred reaction solvent is a mixed solvent of propylene glycol monomethyl ether and water, used for hydrolysis The base is sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably sodium hydroxide, and is made into a 50% aqueous solution.

The invention has easy-to-obtain raw materials, simple and mild operation, short production cycle, high purity, good safety, low cost and is suitable for industrialized production.

detailed description

The prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid to be synthesized in the present invention can be carried out according to the following steps:

The synthesis of embodiment 1 4-amino-2 hydroxybenzoic acid methyl esters

Add p-aminosalicylic acid (50g, 0.327mol) and methanol (300mL) into a 1L three-necked flask, stir well and add concentrated sulfuric acid (100mL) dropwise under ice-bath conditions. During the dropwise addition, ensure that the temperature is controlled at 0 Between ~5°C, after the dropwise addition, transfer to an oil bath and raise the temperature to 80°C for reflux reaction for 6h. TLC monitors the end of the reaction, cools to room temperature, adds 10mol/L sodium hydroxide solution (about 200mL) to adjust to pH 4-5, a large amount of solid precipitates, suction filters, washes with water, and dries to obtain 50.3g of product, yield 92.1%, purity 99.6%, ESI-MS m/z: 168 [M+H] ⁺ , 190 [M+Na] ⁺ .

Example 2 Synthesis of 4-acetamido-2-hydroxybenzoic acid methyl ester

Add 2 (108g, 0.65mol) and glacial acetic acid (540mL) into a 2L three-necked flask, stir well, heat up to 40°C, add acetic anhydride (79.2g, 0.78mol) dropwise, and the reaction solution gradually becomes clear. After dropping, monitor by TLC and react for about 1 hour. Water (1000 mL) was added and a large amount of solid precipitated out. After cooling to room temperature, filter with suction, wash the filter cake with water and dry to obtain 125 g of white solid, yield 92.4%, purity 99.9%, ESI-MS m/z: 210[M+H] ⁺ , 232[M+Na] ⁺ , 207.8[MH] ⁻ , 418.9[2M+H] ⁺ , 440.9[2M+Na] ⁺ .

Example 3 Synthesis of 4-acetamido-5-chloro-2-hydroxybenzoic acid methyl ester

Add 3 (160g, 0.776mol) and ethyl acetate (1100mL) into a 2L three-necked flask, add sulfuryl chloride (134.5g, 0.995mol) dropwise at -5 to 0°C, and control the temperature at -5 to 0°C for about 1h The inner drop is complete. After the dropwise addition, the stirring reaction was continued for 1 h, and the reaction was monitored by TLC. After the reaction is completed, pour the reaction liquid into water, adjust the pH to 4-5 with 10mol/L sodium hydroxide solution, filter with suction, extract the filtrate to separate the organic layer, and spin the organic layer to dry to obtain a large amount of solids, which are combined with the filter cake solids , beat with 5 times the amount of ethanol for 30 minutes, filter with suction, and dry the filter cake to obtain 151.1 g of white solid, with a yield of 80%, a purity of 98.7%, ESI-MS m/z: 244[M+H] ⁺ , 266[M +Na] ⁺ , 242[MH] ^- . Example 4 Synthesis of 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester

Add 4 (64g, 0.263mol) and N,N-dimethylformamide (510mL) into a 50mL three-necked flask, add NBS (61g, 0.342mol) at room temperature under stirring conditions, and continue the reaction under these conditions , TLC monitored the reaction. After the reaction was completed, add 400 mL of water, filter with suction, wash the filter cake with water several times, collect 67.5 g of white solids dried on the filter cake, yield 79.5%, purity 92.4%, ESI-MS m/z: 324 [M+H] ⁺ ,

345.9 [M+Na] ⁺ , 322 [MH] ^- .

Example 5 Synthesis of 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester

Add 5 (90g, 0.28mol), potassium carbonate (42g, 0.30mol) and N,N-dimethylacetamide (450mL) sequentially into a 1L three-necked flask, and stir at room temperature for 0.5h. 1,2-Dibromoethane (104.6 g, 0.56 mol) was added, and the reaction was stirred at 50° C. for 5 h. FeCl ₃ monitors the reaction. After the reaction is complete, add warm water (300 mL) at 60° C., keep stirring to precipitate solids, then add 150 mL warm water, cool down to room temperature, add 150 mL cold water, and stir overnight for crystallization. The next day, about 100 g of off-white solid was obtained by suction filtration, dried, recrystallized with 5 times the amount of toluene, heated by suction, and the filtrate was placed to crystallize, and the white solid was dried by suction filtration. The yield was 106.6 g, the yield was 89.8%, and the purity was 97.4%. , ESI-MSm/z: 429[M+H] ⁺ , 451[M+Na] ⁺ , 427[MH] ^- .

Example 6 Synthesis of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester

Add 6 (80g, 0.187mol), zinc powder (14.9g, 0.229mol) and N,N-dimethylacetamide (160mL) into a 1L three-necked flask, stir at room temperature for 2h and heat up to 50°C for reaction under nitrogen protection , TLC monitored the reaction, and the reaction was completed in 20 h. After the reaction was completed, hydrochloric acid (43 mL), water (60 mL) and isopropanol (40 mL) were added dropwise, and the temperature was raised to 70° C. and stirred for 0.5 h, and the solution was clear. Add cold water (300mL), cool to room temperature, stir overnight, filter with suction, and recrystallize the crude filter cake with propylene glycol monomethyl ether, yield 43.1g, yield, 85.5%, purity 98.8%, ESI-MS m/z: 270[ M+H] ⁺ , 292[M+Na] ⁺ , 562[2M+Na] ⁺ .

Example 7 Synthesis of 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid

Add the obtained intermediate 7 (30g, 0.11mol), water (150mL), propylene glycol monomethyl ether (36mL) and 50% sodium hydroxide solution (90mL) into a 500mL single-necked bottle, and slowly heat up to 90°C under stirring, and Warm reaction for 8h, TLC monitoring the reaction. After the reaction was completed, cool in an ice bath to 5°C and stir for 2 h, suction filter, wash the filter cake with an appropriate amount of water and add it to a 500 mL single-necked bottle, add water (210 mL) and propylene glycol monomethyl ether (35 mL), and heat the reaction solution to 80 °C, the reaction solution became homogeneous. Dilute hydrochloric acid was added dropwise to adjust the pH to about 3, and a solid precipitated. After dropping, cool to 10°C and continue stirring for 2h. Suction filtration, the filter cake was washed with an appropriate amount of water, and dried to obtain an off-white solid, yield 20.8g, yield 89.8%, purity 99%, ESI-MS m/z: 214.1[M+H] ⁺ , 236.1[M+Na] ⁺ , 448[2M+Na] ⁺ . ¹ H-NMR (400MHz, DMSO) δ: 12.065(s, 1H), 7.436(s, 1H), 5.993(s, 2H), 4.603(t, J=8.87Hz, 2H), 2.982(t, J= 8.87Hz, 2H).

Claims (10)

1. a synthetic method of prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, characterized in that: starting with p-aminosalicylic acid The starting material, under the action of a catalyst, undergoes a methyl esterification reaction with methanol to obtain methyl 4-amino-2-hydroxybenzoate, and then reacts with an acetylating reagent to obtain methyl 4-acetamido-2-hydroxybenzoate. Chlorinating reagent Chlorination gives methyl 4-acetamido-5-chloro-2-hydroxybenzoate, bromination gives methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate, bromo Ethylating to get 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester, then cyclization and hydrolysis. 2. the synthetic method of a kind of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1, is characterized in that, comprises the steps : (1) 4-amino-2-hydroxybenzoic acid methyl ester described in preparation formula (II) Using p-aminosalicylic acid as the starting material, under the action of a catalyst, it can be obtained through methylation reaction with methanol; (2) 4-acetamido-2-hydroxybenzoic acid methyl ester described in preparation formula (Ⅲ) 4-Amino-2-hydroxybenzoic acid methyl ester is prepared by acetylation reaction with acetylating reagent; (3) 4-acetamido-5-chloro-2-hydroxybenzoic acid methyl ester described in preparation formula (Ⅳ) 4-Acetamido-2-hydroxybenzoic acid methyl ester is prepared by chlorination reaction of chlorination reagent; (4) 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester described in preparation formula (Ⅴ) 4-acetamido-5-chloro-2-hydroxybenzoic acid methyl ester is prepared by bromination reaction; (5) 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester described in preparation formula (Ⅵ) 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester prepared by reaction with 1,2-dibromoethane; (6) Preparation of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-methyl carboxylate described in formula (VII) Preparation of 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester through cyclization reaction; (7) Preparation of 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid described in formula (Ⅷ) 4-Acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester can be prepared by hydrolysis reaction. 3. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1 or 2, is characterized in that, 4-acetyl In the synthetic method of amino-2 hydroxybenzoic acid methyl ester, described catalyzer is the concentrated sulfuric acid, p-toluenesulfonic acid, tetrabutyl titanate, sulfur oxychloride or concentrated hydrochloric acid, is preferably the concentrated sulfuric acid; , methanol, catalyst molar ratio is 1: (4～8): (1.5～4), preferred ratio is 1: (5～6.5): (1.8～2.8). 4. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1 or 2, is characterized in that, 4-acetyl In the synthetic method of amino-2-hydroxybenzoic acid methyl ester, acetylating reagent is acetic anhydride or acetyl chloride, and preferred acetylating reagent is acetic anhydride; 4-amino-2-hydroxybenzoic acid methyl ester, glacial acetic acid, acylating reagent are according to The molar ratio is 1:(3.5～9):(0.5～2), the preferred ratio is 1:(4～6.5):(0.7～1.3), the reaction temperature is 25°C～55°C, the preferred temperature is 35°C～45°C . 5. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1 or 2, is characterized in that, 4-B In the synthetic method of amido-5-chloro-2-hydroxybenzoic acid methyl ester, the chlorination reagent is N-chlorosuccinimide, sulfonyl chloride, thionyl chloride, phosphorus trichloride or pentachloro Phosphate, the preferred chlorination reagent is sulfonyl chloride; the mol ratio of 4-acetylamino-2-hydroxybenzoic acid methyl ester to the chlorination reagent is 1: (0.8～2), and the preferred ratio is 1: (1.1～1.5), the reaction reagent Dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, toluene or carbon tetrachloride, the preferred reaction solvent is ethyl acetate, the reaction temperature is -10°C to 20°C, the preferred temperature is -6°C ~5°C. 6. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1 or 2, is characterized in that, 4-B In the synthetic method of amido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester, the bromination reagent is bromine, dibromohydantoin, copper bromide or N-bromosuccinimide, The preferred bromination reagent is N-bromosuccinimide, the reagent is a mixed reagent of N,N-dimethylformamide, tetrahydrofuran, acetic acid and water, ethanol, and the preferred reagent is N,N-dimethyl The molar ratio of formamide, 4-acetamido-5-chloro-2-hydroxybenzoic acid methyl ester and brominating reagent is 1: (0.5-1.8), preferably 1: (1-1.3). 7. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1 or 2, is characterized in that, 4-B In the synthesis of amido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester, the reaction solvent is N,N-dimethylacetamide, N,N-dimethylform Amide, acetone, toluene, preferably N,N-dimethylacetamide, the acid-binding agent used is potassium carbonate, triethylamine, pyridine, sodium carbonate, preferably the acid-binding agent is potassium carbonate, the reaction temperature is 25 ° C ~ 65 ° C, The preferred temperature is 35°C to 45°C, and the molar ratio of 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester, 1,2-dibromoethane, and acid-binding agent is 1:(1.3 ~2.4):(0.6~1.4), the preferred ratio is 1:(1.6~2):(1.8~1.2), added to the reaction solvent. 8. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1 or 2, is characterized in that, 4-B In the synthesis of amido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester, the reaction solvent is N,N-dimethylacetamide, N,N-dimethylformamide, acetone , the preferred reaction solvent is N,N-dimethylacetamide, the catalyst is zinc powder, the reaction temperature is 35°C to 70°C, the preferred temperature is 45°C to 60°C, 4-acetamido-3-bromo-2-(2 -Bromoethoxy)-5-chlorobenzoic acid methyl ester, zinc powder molar ratio is 1: (0.9～2.1), preferably 1: (1.05～1.5). 9. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 8, is characterized in that, after reaction terminates, drop Add hydrochloric acid, isopropanol, water, dropwise finish and heat up, the reaction solution is clear, add cold water to stir, cool and crystallize, the molar ratio of hydrochloric acid, isopropanol, water is (0.3～0.8):(0.25～0.75):(0.5 ~1.0), preferably (0.45~0.6):(0.4~0.6):(0.7~0.9). 10. the synthetic method of prucalopride intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as claimed in claim 1 or 2, is characterized in that, 4-amino -In the synthesis of 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, the reaction solvent is ethanol and water mixed sodium solvent, propylene glycol monomethyl ether or propylene glycol monomethyl ether and water mixed solvent, preferably the reaction solvent It is a mixed solvent of propylene glycol monomethyl ether and water. The alkali used for hydrolysis is sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably sodium hydroxide, and it is made into a 50% aqueous solution. The reaction temperature is 65°C to 100°C, preferably 80℃～95℃, 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester, 50% sodium hydroxide aqueous solution according to the molar ratio of 1: (2～4), preferably The ratio is 1: (2.5-3.8).