Preparation method of (R)-1-(6-fluoro-2-benzothiazolyl)-ethylamine and preparation intermediate of (R)-1-(6-fluoro-2-benzothiazolyl)-ethylamine
A technology for intermediates and ethylamines, applied in the field of preparing -1--ethylamine salts, can solve the problems of low yield, high price, complicated post-processing and the like
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Embodiment 1
[0045]Add 240g of toluene, 40g of D-alanine, 68g of phthalic anhydride and 1g of triethylamine into the reaction flask, heat and reflux to separate water, react for 2.5-3.5h, add 66g of thionyl chloride dropwise, and control the dropping rate to Keep the temperature in the reaction bottle at 60-65°C. After dropping, raise the temperature to 77°C. After reacting for 5 hours, monitor and confirm the completion of the reaction by thin-layer chromatography, then concentrate at -0.06MPa and 55°C for 2 hours to obtain the formula (III) 106 g of the indicated acid chloride compound.
[0046] Under nitrogen protection, 43g of 2-amino-5-fluorothiophenol was dissolved in 128g of water, and the aqueous solution was added dropwise to 510g of hydrochloric acid with a concentration of 36wt%. After completion, 106 g of the acid chloride compound represented by the formula (III) prepared above was added dropwise, and the rate of addition was controlled so that the temperature was controlled a...
Embodiment 2
[0057] Add 635g of toluene, 61.5g of D-alanine, 102g of phthalic anhydride and 1g of triethylamine into the reaction flask, heat and reflux to separate water, react for 2.5-3.5h, add 82g of thionyl chloride dropwise, and control the dropping rate To keep the temperature in the reaction bottle at 60-65°C, after dropping, raise the temperature to 72°C, react for 5 hours, monitor and confirm the completion of the reaction by thin-layer chromatography, concentrate at -0.09MPa, 60°C for 1 hour, and obtain the formula (III) 164 g of the indicated acid chloride compound.
[0058] Under the protection of nitrogen, 43g of 2-amino-5-fluorothiophenol was dissolved in 85g of water, and the solution was added dropwise to 310g of hydrochloric acid with a concentration of 35wt%, and the dropping rate was controlled so that the temperature was always controlled at 0-10°C. After dropping, add 164 g of the acid chloride compound represented by the above-mentioned formula (III) dropwise, control...
Embodiment 3
[0061] Put 80.0 g of the compound of formula (I) into the reaction flask, add 1276 g of methanol aqueous solution with a concentration of 55 wt %, and 55 g of hydrazine hydrate, and conduct hydrazinolysis reaction at 45-50 ° C for 2.5-3.5 h under the protection of nitrogen, and then add hydrochloric acid to adjust to The pH is acidic, stirred for 1 h, cooled to below 15°C and filtered after the reaction, added 115 g of p-toluenesulfonic acid solution with a concentration of 50 wt % to the filtrate, cooled to 3°C to crystallize for 1.5 h, filtered to obtain the compound of formula (IV) 71.0 g of p-toluenesulfonate salt of (R)-1-(6-fluoro-2-benzothiazolyl)-ethylamine.
[0062] Add the above-prepared (R)-1-(6-fluoro-2-benzothiazolyl)-ethylamine methanesulfonate to an equal mass of water, adjust the pH to 10-12 with sodium hydroxide to dissolve the target compound , extract with dichloromethane, separate the layers, and concentrate the organic phase to obtain the compound of formu...
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