| CPC C07D 405/04 (2013.01) [C07B 2200/13 (2013.01)] | 8 Claims |
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1. Synthesis method for Formula III compound, comprising a synthesis reaction formula as shown below:
 wherein Formula I is a starting composition, Formula II is an intermediate composition, and Formula III is the Formula III compound, and wherein the method comprises the steps of:
a first synthesis step wherein trimethyliodosilane is dropped into a mixture of a Formula I compound and dichloromethane at 0±3° C. under protection of inert gas, mixed to react for 2.5±0.5 h, then hexamethyldisilazane and N4-acetylcytosine is added, and mixed to react for 3.5±0.5 h and produce a first reaction system;
a first purification step wherein temperature of the first reaction system is increased to 22±3° C., sodium thiosulfate is dropped in, and diatomaceous earth is added, followed by mixing and filtration to produce a filter cake and a filtrate;
washing the filter cake, adding dichloromethane at 27±3° C., followed by mixing and filtration to produce a first solid and a first solvent;
separating the first solvent from the first solid;
combining the filtrate and the first solvent to form a mixture;
separating an organic phase from the mixture and drying after washing;
removing solvent from the filtrate to obtain residues; and
mixing the residues with acetone and isopropyl acetate to make a residue mixture;
heating the residue mixture to reflux, mixing and reducing temperature to 22±3° C. to provide a reduced temperature mixture;
filtrating the reduced temperature mixture, drying and obtaining a second solid;
combining the first solid and the second solid to form a solids mixture;
adding isopropyl acetate and acetone to the solids mixture, and refluxing to heat;
mixing, reducing the temperature to 22±3° C. and filtrating to obtain a further solid; washing and drying the further solid to obtain a Formula II compound;
a second synthesis step wherein the Formula II compound and methanol are combined, mixed, dropped in sodium methoxide-methanol solution and sit to react at 22.5±2.5° C. for 5 h to produce a second reaction system;
a second purification step wherein the second reaction system is adjusted to a pH of 6.5±0.5 at 0±3° C., loaded on to a silica gel column, and eluted, and a liquid is collected which contains a produced Formula III compound;
evaporating the liquid to dryness, adding dehydrated alcohol and mixing;
heating to reflux, reducing temperature to below room temperature and mixing for 12±2 h;
further reducing temperature to 2.5±2.5° C., mixing for 4.5±0.5 h and filtrating to obtain a further filter cake; performing suction filtration of the further filter cake and drying to obtain the Formula III compound; and
further including at least one crystallization step selected from the group consisting of:
(a) heat the Formula III compound on a baking oven to 80° C., maintain for 10 min and cool down to room temperature;
(b) dissolve the Formula III compound in water, volatilize in a fume hood with top open for 3 days, transfer into a vacuum drying oven and volatilize with top open for 1 day; and
(c) add methanol and acetone to the Formula III compound, with volume ratio of methanol to acetone being 1:9, mix the suspension for 3 days, and centrifugate for 3 min at a rate of 10000 rpm, and precipitate and vacuum dry for 1 h.
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