Thiamine compound, preparation method and pharmaceutical composition thereof
A compound, thiamine technology, applied in the field of medicinal chemistry, can solve the problem of no research reports on phosphothiamine compounds, and achieve the effect of outstanding inhibitory effect
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[0061] The present invention also provides a preparation method of thiamine compounds, which is prepared by reacting thiamine phosphate represented by formula (1a) with acid chloride represented by formula (1b);
[0062]
[0063] Among them, R 1 hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amino group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, alkoxy group, substituted alkoxy group, acyl group, or amide base;
[0064] R 2 hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amino group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, alkoxy group, substituted alkoxy group, acyl group, or amide base;
[0065] R 3 hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amino group, carboxyl group, ...
Embodiment 1
[0084] (E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl) 3-phenylprop-2-enethioate, (E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5- (Phosphonooxy)pent-2-en-3-yl)thio 3-phenylprop-2-enoate 1-1 Synthesis:
[0085]
[0086] Dissolve 10.9 g of thiamine phosphate 1a in 12.0 g of water, stir to dissolve, add dropwise sodium hydroxide solution (30%) to adjust the pH to 10-12, stir for 1 hour, retest the pH, and adjust the pH to 10-12 until it becomes stable. Change, keep below 10°C and add the compound of formula 1-1b (dissolved in dichloromethane) dropwise, the dropwise addition is completed, keep the temperature for 8 hours, distill off the dichloromethane under reduced pressure, adjust the pH of the water phase to 4, a large amount of solids are produced, Filter, wash the filter cake with ethyl acetate, beat the filter cake with a small amount of methanol, filter, and dry the filter cake to obtain product 1...
Embodiment 2
[0091] (E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl) 3-(2-fluorophenyl)prop-2-enethioate, (E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide Base)-5-(phosphoryloxy)pent-2-en-3-yl)thio 3-(2-fluorophenyl)prop-2-enoate 1-2 Synthesis:
[0092]
[0093] Add 3.3g of 2-fluorocinnamic acid to 30mL of dichloromethane, add 0.5g of dimethylformamide and 4.8g of thionyl chloride, heat to 60°C and reflux for 1 hour to remove thionyl chloride and dichloride by distillation under reduced pressure methane to obtain the compound of formula 1-2b, add 30 mL of dichloromethane for later use. Dissolve 6.2g of thiamine phosphate 1a in 12g of water, stir to dissolve, start to dropwise add sodium hydroxide solution (30%) to adjust the pH to 10-12, stir for 10.5 hours, retest the pH, and adjust the pH to 10-12 until it becomes stable. Change, stir for 0.5 hours, keep below 10°C and add dropwise the compound of formula 1-2b prepar...
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