Preparation method for 3-[2-(dimethylamino)ethly]-N-methylindole-5-methyl sulfonylamine succinate

Abstract

The invention discloses a preparation method for 3-[2-(dimethylamino)ethly]-N-methylindole-5-methyl sulfonylamine succinate (I), which belongs to the field of preparation of medicament intermediates. The preparation method comprises the following steps of: undergoing a condensation reaction on 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide (III) and a methanol aqueous solution in the presence of ammonium carbonate and methanol, and directly reducing an intermediate product by performing palladium / carbon catalytic hydrogen without separating to obtain 3-[2-(dimethylamino)ethly]-N-methylindole-5-methyl sulfonylamine (II); at the end of the reaction, recovering a solvent, performing post-treatment to obtain a crude product (II); and recrystallizing to obtain refined 3-[2-(dimethylamino)ethly]-N-methylindole-5-methyl sulfonylamine (II), undergoing a salt-forming reaction on the refined product and succinic acid in purified water, clarifying the reaction liquid, and adding activecarbon for decolorizing to obtain 3-[2-(dimethylamino)ethly]-N-methylindole-5-methyl sulfonylamine succinate (I). The preparation method has the characteristics of stable process and easiness for controlling.

Description

Technical field

[0001] The invention relates to a preparation method of 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide succinate compound, which belongs to the field of pharmaceutical intermediate preparation. Background technique

[0002] There are several methods for preparing 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide succinate in the existing literature:

[0003] 1. Patent Publication No. CN101092387A provides a method for preparing sodium 4-chlorobutane-1,1-disulfonate by reacting 4-chlorobutanal and sodium metabisulfite, which is heated and reacted in the presence of inorganic acid or organic acid catalyst. Organic solvent extraction to obtain 3-(2-chloroethyl)-N-1H-indole-5-methanesulfonamide addition phase transfer catalyst, which reacts with dimethylamine, extracts, decolorizes, and refines sumatriptan. Prepared after heating with solvent to dissolve into salt. The total yield of this method is 29%.

[0004] 2. Patent WO2004099141 repor...

Examples

Embodiment 1

[0020] Step A: Add 100kg of methanol, 10kg of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide and 3kg of ammonium carbonate into a 200L autoclave equipped with a stirrer and a thermometer. While stirring, slowly add 15 kg of formaldehyde aqueous solution at a temperature of about 10°C. Then add 5% palladium / carbon 0.5kg, ventilate, raise the temperature to 60°C, feed the hydrogen pressure to 0.3Mpa, and control the temperature at 70°C to react for 4 hours. Press filter to remove the catalyst, transfer the filter hydraulic pressure to a 200L glass-lined reactor, reduce to room temperature, adjust the PH value to 6 while stirring, heat up to recover the solvent to the end, adjust the concentrated solution to pH 2~3 with dilute hydrochloric acid, and extract with ethyl acetate As a by-product, compound (II) is freed with an aqueous solution of sodium carbonate, solidified and centrifuged to obtain 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide compound ( ...

Embodiment 2

[0024] Step A: Add 80kg of methanol, 10kg of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide and 3kg of ammonium carbonate into a 200L autoclave equipped with a stirrer and a thermometer. While stirring, slowly add 12 kg of formaldehyde aqueous solution at a temperature of about 10°C. Then add 5% palladium / carbon 0.5kg, ventilate, increase the temperature to 70°C, feed the hydrogen pressure to 0.6Mpa, and control the temperature at 80°C to react for 3 hours. Press filter to remove the catalyst, transfer the filter hydraulic pressure to a 200L glass-lined reactor, reduce to room temperature, adjust the PH value to 6 while stirring, heat up to recover the solvent to the end, adjust the concentrated solution to pH 2~3 with dilute hydrochloric acid, and extract with ethyl acetate As a by-product, compound (II) is freed with an aqueous solution of sodium carbonate, solidified and centrifuged to obtain 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide compound (...

Embodiment 3

[0028] Step A: Add 120kg of methanol, 10kg of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide and 3kg of ammonium carbonate into a 200L autoclave equipped with a stirrer and a thermometer. While stirring, slowly add 13.5 kg of aqueous formaldehyde solution at a temperature of about 15°C. Then add 5% palladium / carbon 0.5kg, ventilate, raise the temperature to 80°C, feed the hydrogen pressure to 0.4Mpa, and control the temperature at 80°C to react for 3 hours. Press filter to remove the catalyst, transfer the filter hydraulic pressure to a 200L glass-lined reactor, reduce to room temperature, adjust the PH value to 6 while stirring, heat up to recover the solvent to the end, adjust the concentrated solution to pH 2~3 with dilute hydrochloric acid, and extract with ethyl acetate As a by-product, compound (II) is freed with an aqueous solution of sodium carbonate, solidified and centrifuged to obtain 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide compound (...

Technical field

[0001] The invention relates to a preparation method of 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide succinate compound, which belongs to the field of pharmaceutical intermediate preparation. Background technique

[0002] There are several methods for preparing 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide succinate in the existing literature:

[0003] 1. Patent Publication No. CN101092387A provides a method for preparing sodium 4-chlorobutane-1,1-disulfonate by reacting 4-chlorobutanal and sodium metabisulfite, which is heated and reacted in the presence of inorganic acid or organic acid catalyst. Organic solvent extraction to obtain 3-(2-chloroethyl)-N-1H-indole-5-methanesulfonamide addition phase transfer catalyst, which reacts with dimethylamine, extracts, decolorizes, and refines sumatriptan. Prepared after heating with solvent to dissolve into salt. The total yield of this method is 29%.

[0004] 2. Patent WO2004099141 repor...

Examples

Embodiment 1

[0020] Step A: Add 100kg of methanol, 10kg of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide and 3kg of ammonium carbonate into a 200L autoclave equipped with a stirrer and a thermometer. While stirring, slowly add 15 kg of formaldehyde aqueous solution at a temperature of about 10°C. Then add 5% palladium / carbon 0.5kg, ventilate, raise the temperature to 60°C, feed the hydrogen pressure to 0.3Mpa, and control the temperature at 70°C to react for 4 hours. Press filter to remove the catalyst, transfer the filter hydraulic pressure to a 200L glass-lined reactor, reduce to room temperature, adjust the PH value to 6 while stirring, heat up to recover the solvent to the end, adjust the concentrated solution to pH 2~3 with dilute hydrochloric acid, and extract with ethyl acetate As a by-product, compound (II) is freed with an aqueous solution of sodium carbonate, solidified and centrifuged to obtain 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide compound ( ...

Embodiment 2

[0024] Step A: Add 80kg of methanol, 10kg of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide and 3kg of ammonium carbonate into a 200L autoclave equipped with a stirrer and a thermometer. While stirring, slowly add 12 kg of formaldehyde aqueous solution at a temperature of about 10°C. Then add 5% palladium / carbon 0.5kg, ventilate, increase the temperature to 70°C, feed the hydrogen pressure to 0.6Mpa, and control the temperature at 80°C to react for 3 hours. Press filter to remove the catalyst, transfer the filter hydraulic pressure to a 200L glass-lined reactor, reduce to room temperature, adjust the PH value to 6 while stirring, heat up to recover the solvent to the end, adjust the concentrated solution to pH 2~3 with dilute hydrochloric acid, and extract with ethyl acetate As a by-product, compound (II) is freed with an aqueous solution of sodium carbonate, solidified and centrifuged to obtain 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide compound (...

Embodiment 3

[0028] Step A: Add 120kg of methanol, 10kg of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide and 3kg of ammonium carbonate into a 200L autoclave equipped with a stirrer and a thermometer. While stirring, slowly add 13.5 kg of aqueous formaldehyde solution at a temperature of about 15°C. Then add 5% palladium / carbon 0.5kg, ventilate, raise the temperature to 80°C, feed the hydrogen pressure to 0.4Mpa, and control the temperature at 80°C to react for 3 hours. Press filter to remove the catalyst, transfer the filter hydraulic pressure to a 200L glass-lined reactor, reduce to room temperature, adjust the PH value to 6 while stirring, heat up to recover the solvent to the end, adjust the concentrated solution to pH 2~3 with dilute hydrochloric acid, and extract with ethyl acetate As a by-product, compound (II) is freed with an aqueous solution of sodium carbonate, solidified and centrifuged to obtain 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide compound (...

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