Process for the preparation of N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide salt

Abstract

The application discloses a preparation method of N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide salt. The method is simple and easy to operate, has mild conditions, high yield and purity, low energy consumption and low pollution, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for preparing N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Background Technology

[0002] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide, a DRD2 antagonist, has been widely used since its clinical introduction in 1977 due to its good efficacy, few side effects, and low cost. It is primarily used for central motor disorders, such as Huntington's disease, and remains effective even when haloperidol or sulpiride are ineffective. It is also effective for Tourette syndrome. Given that diseases in the elderly are often severe and difficult to treat, and cardiovascular events can occur at any time, only drugs that the patient can tolerate can be used. N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide, with its low toxicity, can be used for senile psychomotor disorders, achieving some improvement in both psychomotor disorders and mental confusion in the elderly. N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide has analgesic effects on intractable headaches, migraines, traumatic headaches, cancer-related pain, shingles pain, painful spasms, joint pain, and pain associated with periarthritis of the shoulder and humerus. Furthermore, it can also improve symptoms in patients with chronic alcoholism.

[0003] It has been reported that N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide can be synthesized in several ways:

[0004] 1. The following is reported in "New Drugs and Clinical Practice", 2(1), 1983, 7-11:

[0005]

[0006] Using salicylic acid as a raw material, the phenolic hydroxyl group is first methylated, then chlorosulfonated, reduced, and methylated, and then oxidized with hydrogen peroxide to obtain 2-methoxy-5-(methanesulfonyl)benzoic acid, which is then reacted with N,N-diethylethylenediamine to obtain N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide.

[0007] 2. The Shandong Pharmaceutical Industry, Volume 22, Issue 1, 2003, reported the following:

[0008]

[0009] 2-Methoxy-5-(methanesulfonyl)benzoic acid is esterified to give methyl 2-methoxy-5-(methanesulfonyl)benzoate, which is then reacted with N,N-diethylethylenediamine to give N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide.

[0010] In the research and development of new drugs, drug quality is a crucial standard for evaluating drug efficacy. The content of related substances (or impurities) in a drug directly affects its therapeutic effect and may lead to toxic side effects. For safe and effective medication, it is necessary to strictly control the purity of the active ingredient and the limits of impurities to provide high-quality drugs. Therefore, the generation of drug impurities must be strictly controlled during the production, storage, and transportation of drugs. Summary of the Invention

[0011] This invention provides a method for preparing N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide salt. The method involves dissolving crude N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide in an organic solvent, adding an acylation reagent, and stirring the reaction for a period of time to protect the secondary amine on the monoethyl impurity, thereby generating an amide structure and converting the monoethyl impurity into a non-saltable compound. Then, an acidic reagent is added to precipitate N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide as a salt. The precipitate is then filtered to obtain the salt of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide. Testing revealed that the content of monoethyl impurities was controlled below 0.03%, which effectively improved the purity of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide salt without affecting its yield.

[0012] A method for preparing N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide salt, characterized in that: crude N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide is dissolved in an organic solvent, an acylation reagent is added first to react, then an acidic reagent is added to adjust the pH to acidic, and the solution is filtered to obtain the salt of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide.

[0013] Further, the crude N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide is obtained by reacting methyl 2-methoxy5-(methanesulfonyl)benzoate with N,N-diethylethylenediamine.

[0014] Furthermore, the organic solvent is selected from one or more of acetone, dichloromethane, ethyl acetate, and ethanol, preferably acetone and dichloromethane.

[0015] Further, the acylation reagent is selected from one or more of ditert-butyl dicarbonate, acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride, butyric anhydride, butyryl chloride, succinic anhydride, phthalic anhydride, benzoyl chloride, trifluoroacetic anhydride, Fmoc-Cl, methyl chloroformate, ethyl chloroformate, and benzyl chloroformate.

[0016] Further, one or more of di-tert-butyl dicarbonate, acetic anhydride, acetyl chloride, succinic anhydride, phthalic anhydride, benzoyl chloride, trifluoroacetic anhydride, Fmoc-Cl, and methyl chloroformate are preferred, and one or more of di-tert-butyl dicarbonate, succinic anhydride, benzoyl chloride, and methyl chloroformate are even more preferred.

[0017] Furthermore, the temperature of the acylation reaction is 10℃-70℃, preferably 20℃-60℃, and more preferably 30-40℃.

[0018] Furthermore, the temperature of the organic solution in which hydrogen chloride is added is 0°C-35°C, preferably 25-30°C.

[0019] Furthermore, the acidic reagent is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid, fumaric acid, succinic acid, acetic acid, trifluoroacetic acid, hydrogen chloride gas, and organic solutions of hydrogen chloride, preferably organic solutions of hydrogen chloride.

[0020] Furthermore, the organic solution of hydrogen chloride is selected from one or more of ethyl acetate solution, ethanol solution of hydrogen chloride, methyl tert-butyl ether solution of hydrogen chloride, isopropanol solution of hydrogen chloride, and acetone solution of hydrogen chloride, preferably isopropanol solution of hydrogen chloride.

[0021] Furthermore, the pH is 1-2.

[0022] Further, the molar ratio of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide to the acylation reagent is 1:0.05 to 1, preferably 1:0.05 to 0.5, and more preferably 1:0.05.

[0023] In some methods, N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide and an organic solvent are added to a reaction vessel, stirred, and then an acylation reagent is added. The reaction is stirred at an appropriate temperature, and the temperature is controlled to a suitable temperature. An acidic reagent is added dropwise to adjust the pH to acidic, and the reaction is maintained at this temperature. After filtration, the salt of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide is obtained.

[0024] This invention provides a method for detecting related substances in the active pharmaceutical ingredient and formulation of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide or its salts, comprising:

[0025] Take the active pharmaceutical ingredient or preparation of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide or its salt, use methanol-water as diluent to prepare the test solution, inject it into the liquid chromatograph, elute with the running gradient according to the table below, and record the chromatogram.

[0026]

[0027]

[0028] The chromatographic conditions were as follows: an octadecylsilane-bonded silica column was used, with potassium dihydrogen phosphate buffer-methanol as mobile phase A and methanol-water as mobile phase B.

[0029] Furthermore, the potassium dihydrogen phosphate buffer solution of the mobile phase A is adjusted to pH 2.0-3.0, preferably 2.5, with phosphoric acid.

[0030] Furthermore, the volume ratio of potassium dihydrogen phosphate buffer to methanol in the mobile phase A is 80-95:5-20, preferably 90:10.

[0031] Furthermore, the volume ratio of methanol to water in the mobile phase B is 70-90:10-30, preferably 80:20.

[0032] Furthermore, the volume ratio of the diluent methanol to water is 70-90:10-30, preferably 80:20.

[0033] Furthermore, the flow rate is 0.5-2 ml per minute, preferably 1 ml.

[0034] Furthermore, the column temperature is 30-50℃, preferably 40℃.

[0035] Furthermore, the detection wavelength is 230-250nm, preferably 240nm.

[0036] Furthermore, the injection volume is 5-15 μl, preferably 10 μl. Detailed Implementation

[0037] The present invention will be further described below with reference to embodiments, but these are not intended to limit the invention.

[0038] Example 1:

[0039] Methyl 2-methoxy-5-(methanesulfonyl)benzoate (680.0 g), ethylene glycol (850 ml), and N,N-diethylethylenediamine (355.8 g) were added to a 5 L reaction flask. The mixture was heated to 80-90 °C and stirred for 8 hours. After the reaction was completed, the temperature was lowered to 45-50 °C, and drinking water (2720 ml) was added. The temperature was further lowered to 0-20 °C, and 10% sodium hydroxide aqueous solution (340 ml) was added. The mixture was stirred at 0-20 °C for 30 minutes, filtered, and the filter cake was washed with drinking water (1360 ml). The mixture was then dried in a forced-air environment at 55-65 °C to obtain 810.5 g of crude N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide. The yield was 88.6%, the purity was 98.578%, and the monoethyl impurity content was 0.302%.

[0040] Example 2:

[0041] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. The mixture was stirred and heated to 30-40 °C for 1 hour. The temperature was then lowered to 25-35 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was then kept at 25-30 °C for 30 minutes. After filtration, 2.13 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride was obtained. The yield was 95.9%, the purity was 99.514%, and the monoethyl impurity content was 0.253%.

[0042] Example 3:

[0043] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and di-tert-butyl dicarbonate (0.13 g, 0.6 mmol, 0.10 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.16 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 97.2%, purity: 99.701%, monoethyl impurity content: 0.029%.

[0044] Example 4:

[0045] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and di-tert-butyl dicarbonate (0.67 g, 3.1 mmol, 0.50 eq) was added. The mixture was heated to 50-60 °C and stirred for 1 hour. The temperature was then controlled at 0-10 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.15 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 96.8%, purity: 99.689%, monoethyl impurity content: 0.027%.

[0046] Example 5:

[0047] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and di-tert-butyl dicarbonate (0.07 g, 0.3 mmol, 0.05 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 25-30 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.18 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 98.1%, purity: 99.732%, monoethyl impurity content: 0.023%.

[0048] Example 6:

[0049] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (13.00 g, 39.6 mmol, 1.0 eq), acetone (91 mL), and dichloromethane (16 mL) were added to a reaction flask. Stirring was started, and acetic anhydride (0.20 g, 2.0 mmol, 0.05 eq) was added. The mixture was stirred at 20-30 °C for 1 hour, and the temperature was controlled at 15-25 °C. An isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2, and the mixture was kept at this temperature for 30 minutes. The mixture was filtered to obtain 14.20 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 98.3%, Purity: 99.682%. Monoethyl impurity content: 0.029%.

[0050] Example 7:

[0051] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and acetyl chloride (0.02 g, 0.3 mmol, 0.05 eq) was added. The mixture was stirred at 40-50 °C for 1 hour, then the temperature was controlled to 30-35 °C. An isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.17 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 97.7%, Purity: 99.670%. Monoethyl impurity content: 0.027%.

[0052] Example 8: N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and di-tert-butyl dicarbonate (0.07 g, 0.3 mmol, 0.05 eq) was added. The mixture was stirred at 0-10 °C for 1 hour, and the temperature was controlled at 25-30 °C. An isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.12 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 95.4%, purity: 99.582%, monoethyl impurity content: 0.131%.

[0053] Example 9:

[0054] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and di-tert-butyl dicarbonate (0.07 g, 0.3 mmol, 0.05 eq) was added. The mixture was stirred at 10-20 °C for 1 hour, and then the temperature was controlled at 25-30 °C. An isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and then filtered to obtain 2.13 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 95.9%, purity: 99.473%, monoethyl impurity content: 0.031%.

[0055] Example 10:

[0056] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and di-tert-butyl dicarbonate (1.34 g, 6.2 mmol, 1.0 eq) was added. The mixture was heated to 50-60 °C and stirred for 1 hour. The temperature was then controlled at 0-10 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.14 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 96.3%, purity: 99.489%, monoethyl impurity content: 0.030%.

[0057] Example 11:

[0058] N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and succinic anhydride (0.06 g, 0.6 mmol, 0.1 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.14 g of N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide hydrochloride. Yield: 96.3%, purity: 99.737%, monoethyl impurity content: not detected.

[0059] Example 12:

[0060] N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and phthalic anhydride (0.09 g, 0.6 mmol, 0.1 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.18 g of N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide hydrochloride. Yield: 98.1%, purity: 99.652%, monoethyl impurity content: 0.036%.

[0061] Example 13:

[0062] N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and benzoyl chloride (0.09 g, 0.6 mmol, 0.1 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.17 g of N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide hydrochloride. Yield: 97.7%, purity: 99.587%, monoethyl impurity content: 0.015%.

[0063] Example 14:

[0064] N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and trifluoroacetic anhydride (0.13 g, 0.6 mmol, 0.1 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.13 g of N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide hydrochloride. Yield: 95.9%, purity: 99.654%, monoethyl impurity content: 0.055%.

[0065] Example 15:

[0066] N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and Fmoc-Cl (0.16 g, 0.6 mmol, 0.1 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.19 g of N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide hydrochloride. Yield: 98.6%, purity: 99.598%, monoethyl impurity content: 0.045%.

[0067] Example 16:

[0068] N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide (2.00 g, 6.1 mmol, 1.0 eq), acetone (14 mL), and dichloromethane (4 mL) were added to a reaction flask. Stirring was started, and methyl chloroformate (0.10 g, 0.6 mmol, 0.1 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.16 g of N-[2-(diethylamino)ethyl]-2-methoxy-5-(methanesulfonyl)benzamide hydrochloride, with a yield of 97.2%, purity of 99.694%, and monoethyl impurity content of 0.024%.

[0069] Example 17:

[0070] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), ethyl acetate (20 mL), and ethanol (20 mL) were added to a reaction flask. Stirring was started, and di-tert-butyl dicarbonate (0.13 g, 0.6 mmol, 0.10 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.10 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 94.5%, purity: 99.696%, monoethyl impurity content: 0.031%.

[0071] Example 18:

[0072] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq), ethyl acetate (14 mL), and dichloromethane (6 mL) were added to a reaction flask. Stirring was started, and succinic anhydride (0.06 g, 0.6 mmol, 0.10 eq) was added. The mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.14 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. Yield: 96.3%, purity: 99.705%, monoethyl impurity content: 0.014%.

[0073] Example 19:

[0074] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq) and acetone (20 mL) were added to a reaction flask, and stirring was started. Di-tert-butyl dicarbonate (0.13 g, 0.6 mmol, 0.10 eq) was added, and the mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 2.18 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. The yield was 98.1%, the purity was 99.688%, and the monoethyl impurity content was 0.032%.

[0075] Example 20:

[0076] N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide (2.00 g, 6.1 mmol, 1.0 eq) and dichloromethane (10 mL) were added to a reaction flask, and stirring was started. Di-tert-butyl dicarbonate (0.13 g, 0.6 mmol, 0.10 eq) was added, and the mixture was heated to 30-40 °C and stirred for 1 hour. The temperature was then controlled at 10-15 °C, and an isopropanol solution of hydrogen chloride was added dropwise to adjust the pH to 1-2. The mixture was kept at this temperature for 30 minutes and filtered to obtain 1.82 g of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride. The yield was 81.9%, the purity was 99.737%, and the monoethyl impurity content was 0.019%.

[0077] Example 21: Detection Method

[0078] An octadecylsilane-bonded silica gel column (YMC-Triart C18 (4.6mm*150mm, 5μm)) or a column of equivalent performance was used. Mobile phase A was 0.005 mol / L potassium dihydrogen phosphate buffer (adjusted to pH 2.50 with phosphoric acid)-methanol (90:10 v / v), and mobile phase B was methanol-water (80:20 v / v). The flow rate was 1 mL / min, the column temperature was 40℃, the detection wavelength was 240 nm, and the injection volume was 10 μL. Elution was performed according to the running gradient in the table below. Accurately measured N-[2-(diethylamino)ethyl... The N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride compound was dissolved and diluted with methanol-water (80:20) to prepare a solution containing 1 mg of the compound per ml. This solution was used as the test solution. The test solution was accurately measured and injected into the liquid chromatograph under the chromatographic conditions in the table below. The chromatogram was recorded. The peak time of N-[2-(diethylamino)ethyl]-5-(methanesulfonyl)-2-methoxybenzamide hydrochloride was approximately 12.529 min, and the peak time of monoethyl impurities was approximately 8.463 min.

[0079] Time (min) Mobile phase A (% by volume) Mobile phase B (% by volume) 0 100 0 25 100 0 50 40 60 60 40 60 61 100 0 70 100 0

[0080] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from its spirit and scope. The scope of the present invention is not limited to the detailed description above, but should be defined by the claims.

Claims

1. A process for the preparation of N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2- methoxybenzamide salt, characterized by: crude N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide is dissolved in an organic solvent, an acylating agent is added first, and an acylation reaction is carried out at a temperature of 10°C to 70°C, then an acidic reagent is added, the pH is adjusted to be acidic, and N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide salt is obtained by filtration; the organic solvent is selected from one or more of acetone, dichloromethane, ethyl acetate, and ethanol; the acylating agent is selected from one or more of di-tert-butyl dicarbonate, acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride, butyric anhydride, butyryl chloride, succinic anhydride, phthalic anhydride, benzoyl chloride, trifluoroacetic anhydride, Fmoc-Cl, methyl chloroformate, ethyl chloroformate, and benzyl chloroformate.

2. A process according to claim 1, characterised in that: the organic solvent is acetone and dichloromethane.

3. The method of claim 1, wherein: The temperature of the acylation reaction is 20°C to 60°C, and the temperature at which the acidic reagent is added is 0°C to 35°C.

4. The method of claim 1, wherein: The temperature of the acylation reaction is 30°C to 40°C, and the temperature at which the acidic reagent is added is 25°C to 30°C.

5. The method of claim 1, wherein: the acidic reagent is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid, fumaric acid, succinic acid, acetic acid, trifluoroacetic acid, hydrogen chloride gas, an ethyl acetate solution of hydrogen chloride, an ethanol solution of hydrogen chloride, a methyl tert-butyl ether solution of hydrogen chloride, an isopropanol solution of hydrogen chloride, and an acetone solution of hydrogen chloride.

6. The method of claim 1, wherein: the acidic reagent is an isopropanol solution of hydrogen chloride.

7. The method of claim 1, wherein: the pH is 1 to 2.

8. The method of claim 1, wherein: the molar ratio of N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide to the acylating agent is 1:0.05 to 1.

9. The method of claim 1, wherein: the molar ratio of N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide to the acylating agent is 1:0.05 to 0.

5.

10. The method of claim 1, wherein: the molar ratio of N-[2-(diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide to the acylating agent is 1:0.05.

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