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

A technology of sulfonamide succinate and methane sulfonamide, which is applied in the field of pharmaceutical intermediate preparation, can solve the problems of difficulty in realizing industrialized production, low total yield, complicated operation, etc., and achieves easy control of reaction conditions, good product quality, and high post-processing efficiency. Handling easy effects

Active Publication Date: 2012-05-02
SHANDONG XINHUA PHARMA CO LTD
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Problems solved by technology

There are many shortcomings in the above several methods, wherein method 2 prepares compound 4-(N, N-dimethylamino) butyraldehyde diethyl acetal, needs strict anhydrous Grignard reaction, and the compound has a high boiling point and is difficult to purify The total yield of this route is less than 15%
Though method 1 total yield is higher than method 2, the starting material 4-chlorobutyraldehyde unstable that this method uses is difficult to buy, and prepares 4-chlorobutane-1, and the process of 1-sodium disulfonate produces relatively A lot of waste water, in the process of preparing 3-(2-chloroethyl)-N-1H-indole-5-methanesulfonamide, a large amount of dilute hydrochloric acid, ammonia water, sodium chloride aqueous solution and sodium sulfate, etc. are used, and there are many steps. And produce a large amount of three wastes, the 3-(2-chloroethyl)-N-1H-indole-5-methanesulfonamide content and yield of its preparation are lower
In its preparation of 3-[2-(dimethylamino)ethyl[-N-methylindole-5-methanesulfonamide, a large amount of dimethylamine aqueous solution and precious potassium iodide are used, and the resulting 3-[2-(di Methylamino) ethyl]-N-methylindole-5-methanesulfonamide crude product content and yield are also lower
And 3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide reacts with succinic acid using an organic solvent, and the residual solvent in the final product is difficult to remove, seriously affecting the safety of product use , the method has a long route, complex operation, a large amount of three wastes, high total cost, poor product safety, and low yield, making it difficult to realize industrial production

Method used

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

Examples

Experimental program
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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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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14
Inventor 朱连博郑忠辉赵帅杜培亮徐雪梅
Owner SHANDONG XINHUA PHARMA CO LTD
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