A process for the preparation of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride salt

Abstract

The application provides a preparation method of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy) phenyl] sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and hydrochloride thereof, which optimizes the post-treatment mode of 3-(3-methoxypropoxy) phenylsulfonyl chloride (H2), is high in purity after simple impurity removal to form a sodium sulfonate, and can obtain 3-(3-methoxypropoxy) phenylsulfonyl chloride (H2) which is high in purity and stable in quality after reaction of a chlorinating reagent, and can obtain 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy) phenyl] sulfonyl}-1H-pyrrol-3-methyl formyl (H3) with high reaction conversion rate by adding a small amount of a catalyst under the action of an alkali, and the 1-[5-(2-fluorophenyl)-1-{[3-(3- methoxypropoxy) phenyl] sulfonyl}-1H-pyrrol-3- yl]-N-methylmethanamine and hydrochloride thereof prepared by the method are low in impurity content, high in yield, and suitable for industrial production.

Description

Preparation method of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on November 9, 2023, with patent application number 202311506706.0, entitled “A Method for Preparing Pyrrolyl Sulfonyl Compounds.” The entire contents of the prior application are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride. Background Art

[0003] Keppraxant hydrochloride, whose chemical name is 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride, is a potassium ion competitive acid blocker (P-CAB) with a structure shown in Formula I. Currently, the hydrochloride is clinically used to prevent and treat gastric acid-related diseases, including (but not limited to) gastrointestinal diseases such as peptic ulcer, Zollinger-Ellison syndrome, gastritis, gastric ulcer, duodenal ulcer, ulcers caused by nonsteroidal anti-inflammatory drugs, Helicobacter pylori infection, gastroesophageal reflux disease, and reflux esophagitis.

[0004] Chinese patent CN107879964B discloses a method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine as follows:

[0005] Reagents and conditions: (a) sodium hydride, tetrahydrofuran at -30°C ± 5°C, yield: 66%; (b) methylamine, methanol, sodium triacetoxyborohydride, yield: 88.2%.

[0006] This method reports the conversion of 3-(3-methoxypropoxy)benzenesulfonyl chloride to 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine through sulfonamidation and reductive amination. This route produces numerous byproducts and consumes a lot of energy, making it unsuitable for industrial production.

[0007] The preparation method disclosed in the above-mentioned prior art contains many impurities and cannot meet the drug quality standards and the safety of large-scale production operations. The preparation method needs to be further improved.

[0008] Summary of the Invention

[0009] The invention provides a method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride. The method has low impurity content and high yield, and is suitable for industrial production.

[0010] The technical solutions adopted in the present invention are as follows:

[0011] Step 1: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (H1)

[0012] 5-(2-Fluorophenyl)-1H-pyrrole-3-carbonitrile is dissolved in an organic solvent (HA1), and hydrogen is introduced under the action of Raney nickel catalyst and water. The product is subjected to reduction and hydrolysis under heating conditions until the reaction is complete. After post-treatment and purification, high-purity 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (H1) is obtained.

[0013] Step 2: Preparation of 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2)

[0014] 3-(3-methoxypropoxy)aniline (HB1) is dissolved in acetic acid and reacted with sodium nitrite at low temperature in the presence of hydrochloric acid to obtain a diazotization intermediate. The diazotization intermediate is reacted with sulfur dioxide and acetic acid solution to undergo a chlorosulfonation reaction. The reaction is carried out under controlled temperature for 1 hour under the catalysis of cuprous chloride, and the crude product 3-(3-methoxypropoxy)benzenesulfonyl chloride HB2 is obtained after post-treatment.

[0015] The crude product was dissolved in methanol and reacted with sodium hydroxide under heating conditions for 40 minutes. After post-treatment and purification, sodium 3-(3-methoxypropoxy)benzenesulfonate (HB3) was obtained.

[0016] HB3 is dissolved in an organic solvent and catalyzed by a chlorination reagent. After a low-temperature reaction for 1-3 hours, high-purity 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2) is obtained through post-treatment.

[0017] Step 3: Preparation of 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (H3)

[0018] 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (H1) is dissolved in an organic solvent, and stirred at a certain temperature for 30-40 minutes under the action of an organic base and a catalyst. 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2) is then added to react, and the mixture is post-treated and purified with an organic solvent to obtain high-purity 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxaldehyde (H3).

[0019] Step 4: Preparation of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4)

[0020] 5-(2-Fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (H3) was dissolved in an organic solvent and reacted with a methanol solution of methylamine for 0.5 hours. The mixture was then reduced under the action of sodium triacetylborohydride for 1-2 hours, and post-treated to obtain 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4).

[0021] Step 5: 1-[5-(2-Fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride (H5)

[0022] 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4) is dissolved in an organic solvent, stirred with hydrochloric acid to form a salt, and then post-treated and purified to obtain 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride (H5), which is Keppraxane hydrochloride.

[0023] The reagents, reaction conditions and post-treatment methods used in the preparation steps of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride (kepraxane hydrochloride) are as follows:

[0024] The reaction solvent for the catalytic reduction of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (HA1) in step 1 is an organic weak acid such as formic acid and acetic acid, and a weak base such as pyridine, sodium phosphite, N,N-diphenylethylenediamine is added to passivate Raney Ni, preferably a combination of acetic acid and pyridine; a catalyst wet Raney nickel is used in an amount of 0.05 to 0.3 times the mass of HA1, preferably 0.16 times; Raney nickel is added after mixing with water, and the weight of water added is 1 to 10 times that of Raney nickel, preferably 5 times; the reaction hydrogen pressure is normal pressure (0.1 MPa) to 1.0 MPa, preferably 0.3 to 0.4 MPa; the reaction temperature is 20 to 75° C., preferably 30 to 50° C.

[0025] The post-processing operation of step 1 includes: (1) after the reaction is completed, the reaction solution is added to water for crystallization, and centrifuged to obtain a solid; (2) the solid is dissolved in ethyl acetate, the pH is adjusted to 2-3 with 2 mol / L dilute hydrochloric acid, and extracted to obtain an organic phase; 10% NaHCO3 is added to the organic phase to adjust the pH to 8-9, extract to obtain an organic phase, and concentrate to dryness under reduced pressure; (3) the concentrate is added with organic solvents such as ethanol, tetrahydrofuran, and ethyl acetate for recrystallization or pulping, preferably ethyl acetate is used as the refining solvent; the proportion of ethyl acetate is 0.5 to 2 times the weight of HA1, preferably 0.9 times; the refining conditions are stirring temperature of 50-80°C, preferably 70-80°C, stirring time of 0.5-1 hour; cooling and crystallization temperature of 0-10°C, stirring for 0.5-3 hours, preferably 2 hours, and centrifugal drying to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (H1).

[0026] In step 2, the diazotization reaction temperature of 3-(3-methoxypropoxy)aniline (HB1) is -15°C to 15°C, preferably -5°C to 5°C; the reaction molar ratio of sodium nitrite is 1:1 to 4, preferably 1:1.5; the molar ratio of sulfur dioxide introduced is 1:1.6 to 7.2, preferably 1:4.8; the chlorosulfonation reaction temperature of the preparation method is 0 to 40°C, preferably 20 to 30°C; 3-(3-methoxypropoxy)benzenesulfonyl chloride (HB2) The reaction temperature with sodium hydroxide is 10-65°C, preferably 25-40°C; the reaction molar ratio is 1:1-3, preferably 1:2; the reaction solvent of sodium 3-(3-methoxypropoxy)benzenesulfonate (HB3) and the chlorination reagent is dichloromethane, chloroform, acetonitrile or no solvent; the chlorination reagent is oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, triphosgene, etc., preferably oxalyl chloride; the catalyst is N,N-dimethylformamide, N,N-dimethylaniline, pyridine, etc., preferably N,N-dimethylformamide; the reaction molar ratio of sodium 3-(3-methoxypropoxy)benzenesulfonate and the chlorination reagent is 1:1-3, preferably 1:3; the mass ratio of sodium 3-(3-methoxypropoxy)benzenesulfonate to the catalyst is 1:1-1.2, preferably 1:1; the reaction temperature is -30-0°C, preferably -10-0°C.

[0027] Post-treatment method of HB2: After the reaction is completed, water is added to quench the reaction, and the mixture is extracted twice with methyl tert-butyl ether. The organic phase is washed four times with 10% sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent is removed. The solvent is then removed with toluene twice. The concentrate is hot-extracted four times with petroleum ether, filtered through a filtration apparatus covered with silica gel and anhydrous sodium sulfate, and the filtrate is desolvated to obtain 3-(3-methoxypropoxy)benzenesulfonyl chloride (HB2).

[0028] The post-treatment method of HB3 is as follows: after the reaction is completed, the filtrate is filtered to obtain the filtrate, the solvent is removed from the filtrate, ethyl acetate is added, the mixture is stirred at low temperature, centrifuged, and dried to obtain a crude product; the purification method is as follows: 0.5 times the mass of the crude product is added to the crude product with methanol, the temperature is controlled at 35-45°C, 6 times the mass of the crude product is slowly added with ethyl acetate under stirring, the mixture is stirred for 10 minutes, the temperature is lowered by 5-10°C, the mixture is stirred for 15 minutes, the mixture is centrifuged, the filter cake is washed, and the mixture is dried to obtain sodium 3-(3-methoxypropoxy)benzenesulfonate (HB3).

[0029] Post-treatment method of H2: After the reaction is completed, dichloromethane and water are added for extraction, and the number of dichloromethane extractions is preferably three times. The organic phase is washed with water, dried by adding anhydrous sodium sulfate, and the solvent is removed. Ethyl acetate is added for dissolution, and the phase is washed five times with a saturated sodium chloride solution. After drying, the solvent is removed to obtain 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2).

[0030] In step 3, 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (H1) is dissolved in an organic solvent such as acetonitrile, dichloromethane, N,N-dimethylformamide and N-methylpyrrolidone, preferably acetonitrile, and the amount of solvent is 3.92 times that of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde; the base is triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 2,6-lutidine, sodium hydroxide, cesium carbonate, tetrabutylammonium hydrogen sulfate, etc., preferably N,N-diisopropylethylamine, and 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde. The molar ratio is 1 to 1.6:1, preferably 1.4:1; the catalyst is 4-dimethylaminopyridine (DMAP), pyridine, 4-pyrrolidinylpyridine (PPY), preferably DMAP, and the molar ratio of pyridine to 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is 0.1 to 0.3:1, preferably 0.1:1; the reaction temperature is -5 to 35°C, preferably 25 to 35°C; the reaction molar ratio of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde to 3-(3-methoxypropoxy)benzenesulfonyl chloride is 1:1 to 1.5, preferably 1:1.2.

[0031] The post-processing operation of step 3 includes: after the reaction is completed, the temperature is controlled at 0-10 ° C, the reaction solution is added to drinking water with 2.5 times the mass of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde to quench, and stirred for 15 to 20 minutes; the temperature is controlled at 5 to 15 ° C, and the pH is adjusted with 0.5 mol / L hydrochloric acid. 3-5, stirring for 1 hour; centrifuging, washing the filter cake with drinking water 5 times the mass of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, and air-drying at 35-45°C for 6-8 hours to obtain a crude product; then adding methyl tert-butyl ether 2.5 times the mass of the crude product, stirring at 50-55°C for 10-30 minutes, filtering while hot, cooling to -5-0°C, stirring for 1-2 hours, filtering with suction, and air-drying at 35-45°C to obtain 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxaldehyde (H3).

[0032] In step 4, the molar ratio of 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (H3) to methylamine is 1:2-5, preferably 1:4; the molar ratio to STAB is 1:2-4, preferably 1:2.5; the organic solvent is methanol, and the amount of solvent is 3.95 times that of H3; the imine reaction temperature is 15-25°C; and the reduction reaction temperature is 10-20°C.

[0033] Post-treatment method of step 4: After the reaction is completed, the reaction solution is quenched by adding 10 times the mass of drinking water in H3, the temperature is controlled at 0-15°C, and then 9 times the mass of ethyl acetate in H3 is added each time for extraction three times, the solvent is removed under reduced pressure, and 17.2 times the mass of drinking water in H3 is added to dissolve; the aqueous solution is extracted four times with ethyl acetate, and the amount of ethyl acetate used each time is 3.2 times, 1.9 times, 1.9 times, and 1.4 times the mass of H3, respectively. The ethyl acetate phase is discarded, and the aqueous phase is adjusted to pH with 2 mol / L sodium hydroxide solution To 9-10; dichloromethane was added for extraction three times, each time the mass of dichloromethane was 5 times that of H3, the resulting organic phase was washed three times with a saturated sodium bicarbonate solution, each time the mass of a saturated sodium bicarbonate solution was 4.1 times that of H3, the organic phase was added with 2.8 times the mass of anhydrous sodium sulfate in H3 and dried for 2 hours, filtered, and the solvent was removed under reduced pressure to obtain 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine Preparation (H4).

[0034] In step 5, the weight ratio of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4) to hydrochloric acid is 1:0.23; the salt-forming solvent is ethyl acetate, acetone, tetrahydrofuran, preferably acetone; the dissolved material is filtered through a 0.22 μm PTFE filter element, and the salt-forming temperature is 0 to 30° C., preferably 10 to 15° C.;

[0035] The post-treatment of step 5 is to filtrate the system, wash the filter cake with 2.6 times the weight of acetone in H4, first blow dry at room temperature for 0.5 to 1 hour, and then blow dry at 35 to 45 ° C for 6 to 8 hours to obtain a crude product; the refining method is: add 4 times the weight of acetone to the crude product, stir at 0 to 5 ° C for 1 hour, filter, wash with 1 times the weight of acetone in the crude product, first blow dry at room temperature for 0.5 to 1 hour, and then blow dry at 35 to 45 ° C for 12 to 14 hours to obtain 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethylamine hydrochloride (keprasan hydrochloride).

[0036] The technical effects achieved by the present invention are:

[0037] (1) Preparation of high-purity, process-stable 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2):

[0038] The H2 post-treatment column chromatography purification method in patent CN107879964 B has poor purification effect and a long time (more than 12 hours), making it difficult to scale up for industrial production. The present invention optimizes the H2 post-treatment method for preparation, and after simple impurity removal, the sulfonic acid sodium salt is highly pure, and impurities that affect the quality of the raw material can be effectively removed. After the chloroacylation operation, 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2) with high purity and stable quality can be obtained.

[0039] (2) Preparation of high-purity, process-stable 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxaldehyde (H3):

[0040] Patent CN107879964 B uses sodium hydrogen as a base for the condensation method, which has low safety during the production process; the use of other bases (such as sodium tert-butoxide, or organic bases triethylamine, N,N-diisopropylethylamine) has a low reaction conversion rate, increases the difficulty of compound purification, and is more expensive; the present invention achieves a higher reaction conversion rate by adding a small amount of catalyst (such as 4-dimethylaminopyridine) under the action of an organic base (such as N,N-diisopropylethylamine), and the post-treatment purification process is easy to operate and has a better refining effect. Compared with the original process using ethanol recrystallization, which will cause ethanol to react with the intermediate to produce impurities, the quality of the intermediate is greatly improved, ensuring the quality of the raw material drug.

[0041] (3) The post-treatment process of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4) was improved to enhance production operability.

[0042] The abbreviations of the reaction reagents involved in the instructions are as follows:

[0043] DMF: N,N-dimethylformamide;

[0044] DIEPA: N,N-diisopropylethylamine;

[0045] DCM: dichloromethane;

[0046] DMAP: 4-dimethylaminopyridine;

[0047] 2,6-Lutidine: 2,6-dimethylpyridine;

[0048] Cs2CO3: cesium carbonate. DETAILED DESCRIPTION

[0049] Example 1 Preparation of 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2)

[0050] (1) Preparation of 3-(3-methoxypropoxy)benzenesulfonyl chloride (HB2)

[0051] To a 300L reactor, add 48.0kg of glacial acetic acid, 12.0kg of 3-(3-methoxypropoxy)aniline (HB1), and 20.9kg of hydrochloric acid, stirring until dissolved. Cool the system to -5-5°C. Dissolve 7.0kg of sodium nitrite in 12.0kg of drinking water and add to the reactor. Stir and react for 0.5 hours. Set aside to obtain the diazonium salt solution. Add 60.0kg of glacial acetic acid to a 500L reactor, stirring and controlling the temperature to 10-20°C. Pass 20.4kg of sulfur dioxide through the reactor. After the aeration is complete, add 2.4kg of cuprous chloride, followed by the diazonium salt solution. After the additions are complete, raise the system to 20-30°C and incubate for 1 hour. After the reaction is complete, add 72.0kg of drinking water and extract twice with methyl tert-butyl ether (60.0kg x 2) to obtain the organic phase. The organic phase was washed four times with 10% sodium chloride aqueous solution (72 kg x 4), then stirred and dried with 24.0 kg of anhydrous sodium sulfate for 0.5-1 hour. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and then concentrated under pressure twice with toluene to remove the solvent (24.0 kg x 2) to obtain a concentrate. The concentrate was extracted four times with petroleum ether at 35-45°C (48.0 kg x 4), and filtered through a filter barrel lined with 20.0 kg of silica gel and 6.0 kg of anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain 8.46 kg of a light yellow oil, HB2.

[0052] (2) Preparation of sodium 3-(3-methoxypropoxy)benzenesulfonate (HB3)

[0053] To a 200L reaction tank, 16.84kg of methanol and 8.42kg of crude 3-(3-methoxypropoxy)benzenesulfonyl chloride (HB2) were added in sequence. The temperature was controlled at 25-40°C, and sodium hydroxide / methanol solution (2.69kg / 8.42kg) was slowly added. The reaction was allowed to react for 40 minutes. After the reaction was completed, the mixture was filtered and the filter cake was washed 4 times with methanol (1.68kg*4). The filtrate was concentrated under reduced pressure, and 50.52kg of ethyl acetate was added. After stirring at 30-40°C for 30 minutes, the mixture was cooled to 5-10°C and stirred for 15 minutes. The mixture was centrifuged and the filter cake was washed 4 times with ethyl acetate (6.74kg*4). The mixture was air-dried for 8-10 hours to obtain 8.58kg of a crude white solid. The crude product was added with 4.29 kg of methanol in a 200 L reaction tank and stirred for 10 minutes. The temperature was controlled at 35-45 ° C, and then 51.48 kg of ethyl acetate was slowly added and stirred for 10 minutes. Then the temperature was lowered to 5-10 ° C, stirred for 15 minutes, and centrifuged. The filter cake was washed twice with ethyl acetate (3.43 kg * 2) and dried at 45-55 ° C for 8-10 hours to obtain 7.02 kg of white solid 3-(3-methoxypropoxy)benzenesulfonate sodium (HB3).

[0054] (3) Preparation of 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2)

[0055] Add 27.3 kg of dichloromethane to a 100 L reaction tank. Add 6.5 kg of sodium 3-(3-methoxypropoxy)benzenesulfonate (HB3) and 6.5 kg of N,N-dimethylformamide in sequence while stirring. Cool to -15 to -5°C and dropwise add 9.1 kg of oxalyl chloride. After the addition is complete, control the temperature at -10 to 0°C and stir for 1 to 3 hours. After the reaction is complete, control the temperature at ≤15°C and slowly add 39.0 kg of drinking water to the system. Extract the mixture three times with dichloromethane (13.0 kg x 3). The organic phase is washed with 22.0 kg of drinking water. Add 5.4 kg of anhydrous sodium sulfate to the organic phase, dry it for 1 to 2 hours, filter it, rinse the filter cake with 3.0 kg of dichloromethane, and concentrate the filtrate under reduced pressure. 26.0 kg of ethyl acetate was added, stirred and dissolved, and washed 5 times with saturated sodium chloride aqueous solution (13.0 kg * 5) to obtain an organic phase. 5.4 kg of anhydrous sodium sulfate was added and dried for 1 to 2 hours. The organic phase was filtered and the filter cake was rinsed with 3.0 kg of ethyl acetate and concentrated under reduced pressure to obtain 4.67 kg of light yellow oily H2. Examples and comparative examples of preparing H2 under different reaction conditions are shown in Tables 1 and 2 below:

[0056] Table 1 Examples of preparation of H2 under different reaction conditions

[0057] Table 2 Comparative examples of H2 preparation under different reaction conditions

[0058] As shown in Table 1, when the molar ratio of HB3 to the chlorination reagent is 1:1 to 3, the temperature is -10 to 0°C, and the mass ratio of HB3 to the catalyst is 1 to 1.2, the purity can reach more than 97%. In Example 1.3, when the temperature is -10 to 0°C, the molar equivalent of HB3 to the chlorination reagent is 1:3, and the mass ratio of HB3 to the catalyst is 1:1, the yield and purity are both the highest. It can be seen from Examples 1.1-1.3 that the chlorination reagent equivalent affects the degree of reaction. When the molar ratio of HB3 to the chlorination reagent is 1:1, more raw materials remain and the yield of the finished product is low; when the molar ratio of HB3 to the chlorination reagent is 1:3, the yield and purity are both the highest. It can be seen from Examples 1.5-1.6 that when the reaction temperature is low, the yield will be reduced. In Example 1.11, N,N-dimethylaniline is used as a catalyst, and the yield is not as high as when N,N-dimethylformamide is used as a catalyst.

[0059] As shown in Table 2, when other chlorination reagents are added, when the molar ratio of HB3 to the chlorination reagent is 1:3, the required temperature is higher, the energy consumption is higher, and the reaction yield and purity are not high. When no catalyst is added, the purity of H2 in the reaction solution of Comparative Example 1.14 is significantly reduced.

[0060] Example 2 Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (H1)

[0061] 10.0kg 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (HA1) was added to 10.0kg glacial acetic acid and 20.0kg pyridine, and stirred at room temperature until dissolved; 1.6kg Raney nickel was added to 8.0kg drinking water, and the mixture was sequentially pumped into a 300L nitrogen-substituted hydrogenation kettle, and then hydrogen was replaced, the hydrogen pressure was controlled at 0.3-0.4MPa, the temperature was controlled at 30-50°C, and the reaction was stirred until the hydrogen pressure did not change. After the reaction was completed, the hydrogenation kettle was replaced with nitrogen, the system was filtered, and the filtrate was added to 201.0kg drinking water, the temperature was controlled at 10-20°C, stirred for 1 hour, and then filtered. The filter cake was rinsed with 21.0kg drinking water. 216 kg of ethyl acetate was added to the filter cake to dissolve it, and 2 mol / L hydrochloric acid solution was added to adjust the pH to 2-3. The liquids were separated to obtain an organic phase. 10% aqueous sodium bicarbonate solution was then added to adjust the pH to 8-9. The organic phase was separated and concentrated to dryness under reduced pressure. 9.0 kg of ethyl acetate was added, the temperature was raised to 70-80°C, and the mixture was stirred for 0.5-1 hour. The temperature was lowered to 0-10°C, and the mixture was stirred for 2 hours. The filter cake was filtered and dried in a forced air drying oven at 45-50°C to constant weight to obtain 5.26 kg of the product as a light brown solid H1.

[0062] Example 3 Preparation of 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (H3)

[0063] To a 100L reactor, add 10.93kg of acetonitrile and stir at a temperature of 25-30°C. Then, add 2.79kg of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (H1), 2.65kg of N,N-diisopropylethylamine, and 0.19kg of 4-dimethylaminopyridine in that order. Stir for 30-40 minutes, then dropwise add 4.42kg of 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2). After the addition is complete, stir and maintain the reaction for 13-15 hours. After the reaction is complete, control the temperature at 0-10°C and slowly add the reaction solution to 6.98kg of drinking water, stirring for 15-20 minutes to quench the reaction. Then, control the temperature at 5-15°C and dropwise add 0.5mol / L aqueous hydrochloric acid to adjust the pH to 3-5. Stir for 1 hour. After centrifugation, the filter cake was rinsed with 13.95 kg of drinking water and dried under forced air at 35-45 ° C for 6-8 hours to obtain 4.86 kg of crude product. The crude product was added with 12.13 kg of methyl tert-butyl ether and stirred at 50-55 ° C for 10-30 minutes. The mixture was filtered while hot. The filtrate was placed in another 100L reaction tank, stirred and cooled to -5-0 ° C, and then kept warm and stirred for 1-2 hours. After filtration, the filter cake was dried under forced air at 35-45 ° C for 3-5 hours to obtain an off-white solid, 4.62 kg. Examples and comparative examples of preparing H3 under different reaction conditions are shown in Tables 3 and 4 below:

[0064] Table 3 Examples of preparation of H3 under different reaction conditions

[0065] Table 4 Comparative Examples of Preparation of H3 under Different Reaction Conditions

[0066] Example 3 in Table 3 is the data obtained by recrystallization and purification using methyl tert-butyl ether; Examples 3.1-3.17 and Comparative Examples 3.18-3.20 in Table 4 are the data obtained by recrystallization and purification without using methyl tert-butyl ether.

[0067] In Table 3, when the molar ratio of H1:H2:base:catalyst is 1:1-1.5:1-1.6:0.1-0.3, the yield is above 63% and the purity is above 95%. In Example 3, although the yield is reduced after recrystallization and purification using methyl tert-butyl ether, the pigment is removed and the purity reaches 99.8%. In 3.1, when the molar ratio of H1:base:catalyst:H2 is 1:1.4:0.1:1.2 and the temperature is 25-30°C, the reaction yield is higher. In Examples 3.3-3.4, too much or too little equivalent of the base will affect the yield. The yield is affected, making the yield lower. From the data in Table 3, it can be seen that when the catalyst equivalent is 0.1-0.3, the yield is not greatly affected, and the yield is highest at 0.1. When the temperature is low, it has a certain impact on the reaction yield and purity. At the same time, the excess of H2 relative to H1 will cause a more thorough reaction. When the H2 equivalent is 1.0, there is some residual raw material, which affects the yield and purity. When the H2 equivalent is too much, the reaction by-products will increase and the yield is lower. Using different bases and solvents, it can be seen from the data in the table that when N,N-diisopropylethylamine is used as the base and acetonitrile is used as the solvent, the yield and purity are higher.

[0068] In Table 4, when the reaction solvents were methanol, tetrahydrofuran, and ethyl acetate, a large amount of raw materials remained and did not react.

[0069] Example 4 Preparation of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4)

[0070] To a 100L reactor, add 17.34kg of methanol, 3.95kg of methylamine (methanol solution), and 4.39kg of 5-(2-fluorophenyl)-1-{[3-(3-methoxypropyloxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (H3) in sequence. Stir and react for 0.5 hours at a temperature of 15-25°C. Slowly add 5.53kg of sodium triacetoxyborohydride at a temperature of 10-20°C and keep warm for 1-2 hours. After the reaction is complete, add 43.9kg of drinking water to a 200L reactor. Stir and control the temperature at 0-15°C. Slowly add the reaction mixture to water and stir to quench the mixture for 15-20 minutes. Extract the mixture three times with ethyl acetate (39.51kg x 3). Combine the organic layers and concentrate under reduced pressure. After completion, the concentrate was added with 75.5 kg of drinking water and stirred until dissolved. Ethyl acetate was then added to a 200 L reactor and washed with stirring four times (14.04 kg, 8.34 kg, 8.34 kg, and 6.15 kg) to obtain an aqueous phase. A 2 mol / L sodium hydroxide solution was added dropwise to the aqueous phase at a temperature of 10-20°C to adjust the pH to 9-10. The aqueous phase was then extracted three times with dichloromethane (21.95 kg x 3). The organic phases were combined and then washed three times with saturated sodium bicarbonate solution (18.0 kg x 3). The organic phases were then dried with 12.29 kg of anhydrous sodium sulfate under stirring for 2 hours. The filtrate was filtered and concentrated under reduced pressure to obtain 4.2 kg of an oily product, which was used directly in the next step.

[0071] Example 5 Preparation of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride (H5)

[0072] Add 33.18 kg of acetone to the oily substance 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4) from the previous step and stir until dissolved. Filter through a precision filter (special PTFE filter element, 0.22 μm). Pour the filtrate into a 100 L reaction tank, control the temperature at 10-15°C, add 0.97 kg of hydrochloric acid, and stir for 2 hours. Filter with suction, and rinse the filter cake with 10.92 kg of acetone. Dry the filter cake with forced air at room temperature for 0.5-1 hour, then dry it at 35-45°C for 6-8 hours to obtain 3.16 kg of a crude white solid.

[0073] Add 12.52 kg of acetone and 3.13 kg of crude product to a 100 L reaction tank, control the temperature at 0-5 ° C, and stir for 1 hour. Filter with suction, and rinse the filter cake with 3.13 kg of acetone. Place the filter cake in a hot air circulation oven with air for 0.5-1 hour, then turn on the heat, control the temperature at 35-45 ° C, and dry it for 12-14 hours. After drying, weigh the product and pass it through a 40 mesh sieve to obtain 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethylamine hydrochloride (keprasan hydrochloride).

[0074] Although some components of this patent have been described in detail above, it is obvious to those skilled in the art that such detailed description is only for the purpose of illustrating exemplary embodiments and should not be construed as limiting the scope of this patent. Therefore, the actual scope of this disclosure is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride, in, The preparation method comprises the following steps: Step 1: Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (H1): 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (HA1) is dissolved in an organic solvent, and hydrogen is introduced in the presence of a catalyst and water. After the reaction is completed, 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (H1) is obtained by post-treatment and purification, wherein the catalyst is Raney nickel; Step 2: Preparation of 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2): 3-(3-methoxypropoxy)aniline (HB1) is reacted with hydrochloric acid and sodium nitrite to obtain a diazotization intermediate product, which is then reacted with cuprous chloride and sulfur dioxide acetic acid solution to obtain a crude 3-(3-methoxypropoxy)benzenesulfonyl chloride product; the crude 3-(3-methoxypropoxy)benzenesulfonyl chloride product is reacted with a base to obtain sodium 3-(3-methoxypropoxy)benzenesulfonate, a chlorination agent and a catalyst are added, and post-treatment is performed to obtain 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2); Step 3: Preparation of 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (H3): 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (H1) is dissolved in an organic solvent, reacted with 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2) under the action of a base and a catalyst, and then post-treated to obtain 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxaldehyde (H3), wherein the catalyst is selected from one of 4-dimethylaminopyridine, pyridine and 4-pyrrolidinopyridine; Step 4: Preparation of 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4): 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxaldehyde (H3) is dissolved in an organic solvent, reacted with a methanol solution of methylamine in the presence of sodium triacetylborohydride, and post-treated to obtain 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethylamine (H4); Step 5: 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine Hydrochloride (H5): 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine (H4) is dissolved in an organic solvent, hydrochloric acid is added to react, and post-treatment is performed to obtain 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride (H5).

2. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 1, wherein: In step 3, the base is N,N-diisopropylethylamine, 2,6-lutidine or cesium carbonate.

3. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 1, wherein: In step 3, the molar ratio of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (H1) to 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2), base, and catalyst is 1:1-1.5:1-1.6:0.1-0.

3.

4. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 1, wherein: In step 3, the reaction temperature is -5 to 35°C.

5. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 4, wherein: In step 3, the reaction temperature is 25-35°C.

6. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 1, wherein: In step 3, the organic solvent is acetonitrile, N,N-dimethylformamide or N-methylpyrrolidone.

7. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 1, wherein: In step 3, the post-treatment method is as follows: after the reaction is completed, the reaction solution is added to water for quenching, the pH is adjusted to 3-5 with hydrochloric acid, centrifuged, and dried to obtain a crude product, methyl tert-butyl ether is added for recrystallization, hot filtration is performed to remove the filter residue, the temperature is lowered, centrifuged, and dried to obtain 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxaldehyde (H3).

8. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 1, wherein: In step 2, the base is sodium hydroxide, the catalyst is N,N-dimethylformamide or N,N-dimethylaniline, the chlorination agent is oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or triphosgene, and the reaction temperature is -30 to 0°C.

9. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 8, wherein: In step 2, the chlorination reagent is oxalyl chloride, and the reaction temperature is -10 to 0°C.

10. The method for preparing 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine and its hydrochloride according to claim 1, wherein: In step 2, the reaction molar ratio of sodium 3-(3-methoxypropoxy)benzenesulfonate to the chlorination reagent is 1:1-3, and the mass ratio of sodium 3-(3-methoxypropoxy)benzenesulfonate to the catalyst is 1:1-1.2; the post-treatment method is: after the reaction is completed, dichloromethane and water are added for extraction, the organic phase is washed with water, anhydrous sodium sulfate is added for drying, the solvent is removed, ethyl acetate is added for dissolution, saturated sodium chloride solution is washed, and the solvent is removed after drying to obtain 3-(3-methoxypropoxy)benzenesulfonyl chloride (H2).