* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Heating step 1) made of a compound represented by the formula B N - amino -5 - methylthiomethyl -2 - oxazolidinone reaction liquid, into the step 2) made of a compound represented by the formula D 5 - nitro-furfural reaction solution, to carry out dehydration condensation reaction, the control temperature is 25 °C, after dripping in 15 °C -40 °C reaction under 5h; TLC monitoring, a compound represented by the formula B N - amino -5 - methylthiomethyl -2 - oxazolidinone the reaction is complete the end of the reaction, a compound represented by the refractory fettling [...] E; 4) preparation of a compound represented by the formula E micromolecule The above-mentioned step 3) after the reaction, cooling to room temperature filtration, the filter cake is washed with methanol washing, the centrifugal spin-dry methanol, and then the cake is washed by pure water, until the washing water after PH>6; then methanol pulping for 1 time, drying after drying centrifugally refractory fettling micromolecule a compound represented by the formula E 135.9 kg.
3) a mixture of nifuratel (0.4percent) and Polysorbate 80 (1percent) is prepared in water. The mixture is stirred until it becomes homogeneous.
0.4%
3)a mixture of nifuratel (0.4percent) and Polysorbate 80 (1percent) is prepared in water.The mixture is stirred until it becomes homogeneous.
2
[ 698-63-5 ]
[ 25517-72-0 ]
[ 4936-47-4 ]
Yield
Reaction Conditions
Operation in experiment
95.3%
for 2h;
In the 2000ml reaction flask,To the product obtained in Example 6, 122.20 g of N-amino-5-methylthiomethyl-2-oxazolidone obtained in Example 4 was added in portions.Gradually yellow solids precipitated,After completion of the incubation 2h,After suction filtration, filter cake was rinsed with methanol and dried.The yellow solid is 204.60g,The purity of the gas phase was 99.1%, which is the product nifuratel.Calculated according to 5-nitrofurfural diethyl ester, the yield was 95.30%.
85.2%
In ethanol; at 20 - 25℃; for 2h;
was charged with 60 L of ethanol, 50 kg of 5-nitro-furfural (compound l), 20 kg (82.25 mol), and 10% of sulfuric acid (^ (3) (4.11111, 111):Heated to 78 to 85 C, reacted for 1 and 5 h, concentrated under reduced pressure to remove ethanol to give a concentrate; the concentrate was dissolved in methylene chloride and washed three times with saturated sodium chloride to collect the methylene chloride layer; The crude product was purified by silica gel column chromatography (eluent PE: EA = 5: 1). The crude product was collected and the residue was purified by solidification on silica gel. Concentrated to give 5 - nitro - furfural pure product, the yield was 89.2%.[0077] If the preparation of nitramine too Seoul, then the reaction of the product without purification separation, directly used for the preparation of Nasisi Taier.[0078] (2) Preparation of nitrofurant crude[0079] In the dark conditions, 3-amino-5-methylthiomethyl-2-oxazolidinone (compound3) 14. 7 kg (90.66 mil) in ethanol (20 L) was added to the reaction solution (60 L) of step (1) cooled to 15 to 25 C of 5-nitro-furfural (compound 2) After precipitation, the reaction was carried out at 20 to 25 C for 2 hours. The solid was filtered and the residue was filtered. The filter cake was washed with cold ethanol (5 to 10 C) and dried to obtain crude nitrofurant.(3) refinement of nitrofurant[0081] in the dark conditions, take nitrofurant crude 5kg, add 95% ethanol 60L, heated to reflux, hot filter to get the filtrate; the filtrate to stand, precipitate solid, filter, filter cake with a small amount of 95% ethanol , The solvent was removed and dried to constant weight to give a light yellow nitrofurant extract with a yield of 95% and a total yield of 85.2%.
285 g
In ethanol; at 0 - 20℃; for 2h;
Between 0 C, a solution of intermediate 7 was added aqueous ethanol three-necked flask, mechanical stirring was added dropwise a solution of Intermediate 5 in ethanol, to produce a yellow precipitate. After the addition was complete, naturally returned to room temperature, stirred 1h, place 2h, filtration, washed with water until neutral to give crude Nifuratel 348 grams. The crude product was N, N- dimethylformamide to give 285 g product was recrystallized Nifuratel 1.
at 25 - 30℃; for 2h;
N-amino-5-methylthiomethyl-2-oxazolidinone obtained in the step (3) was reacted with 5-nitrofurfural obtained in the step (4) at a molar ratio of 1: 1.1, mixing, stirring at 25 ~ 30 for 2 hours, standing, filtration, washing, drying, the nitrofurant crude; take nitrofurant crude, according to g / ml, adding 10 times the volume of ice Acetic acid, reflux, activated carbon adsorption, filter hot, the filtrate static crystallization, cooling to room temperature after filtration, the filter cake washed with ethanol to the product without red, then water, ethanol, dried and dried to nitrofurant Pure product, high performance liquid chromatography external standard method for the determination of 99.8%.
114 g
The macroporous resin adsorbing the cyclized product is placed in a 1000 ml reaction flask, and 300 ml of ethanol is added.The hydrolysis product of nitrofurfural diethyl ester was added dropwise at 8 C, and the dropping time was controlled for about 2 hours.The reaction has a large amount of yellow solids formed. After the dropwise addition was completed, the reaction was carried out at 22 C for 3 hours.After the completion of the reaction, filtration was carried out to obtain about 1.0 kg of a mixed solid of the product and the macroporous resin.The mixed solid was added to a 2000 ml four-necked flask, 800 g of acetic acid was added, and heated to 100 C. Stir at 100 C for 1 hour, filter to obtain the mother liquor, and cool to 0 C and stir for 1 hour.Recrystallization of N,N-dimethylformamide,Filtration again gave 114 g of nifuratel product.The purity of the liquid phase detection is 100%, and other indicators are superior to the pharmacopoeia standards.
Heating step 1) made of a compound represented by the formula B N - amino -5 - methylthiomethyl -2 - oxazolidinone reaction liquid, into the step 2) made of a compound represented by the formula D 5 - nitro-furfural reaction solution, to carry out dehydration condensation reaction, the control temperature is 25 °C, after dripping in 15 °C -40 °C reaction under 5h; TLC monitoring, a compound represented by the formula B N - amino -5 - methylthiomethyl -2 - oxazolidinone the reaction is complete the end of the reaction, a compound represented by the refractory fettling [...] E; 4) preparation of a compound represented by the formula E micromolecule The above-mentioned step 3) after the reaction, cooling to room temperature filtration, the filter cake is washed with methanol washing, the centrifugal spin-dry methanol, and then the cake is washed by pure water, until the washing water after PH>6; then methanol pulping for 1 time, drying after drying centrifugally refractory fettling micromolecule a compound represented by the formula E 135.9 kg.
With sulfuric acid; In ethanol; water; at 80℃; for 1h;
90 ml of water, 20 ml of ethanol and 10 ml of sulfuric acid were placed in a 500 ml three-necked flask.51 g (0.2 mol) of 5-nitrofurfural diethyl ester and 32.4 g (0.2 mol) of N-amino-5-methylthiomethyl-2-oxazolidinone, and the mixture was heated to 80 C for 1 hour, cooled and filtered. Washed with water and washed with ethanol to obtain 52.1 g of yellow powder, with a yield of 91.4%.MP184 ~ 185 C.
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