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Chemical Structure| 2022-85-7
Chemical Structure| 2022-85-7
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CAS No. :2022-85-7 MDL No. :MFCD00006035
Formula : C4H4FN3O Boiling Point : -
Linear Structure Formula :- InChI Key :XRECTZIEBJDKEO-UHFFFAOYSA-N
M.W : 129.09 Pubchem ID :3366
Synonyms :
Flucytosine;NSC 103805;Flucytosine, 5-fluorocytosine, Flucytosin, Ancobon, Ancotil;Ancotil;Ancobon;5-FC;Ro 2-9915

Safety of [ 2022-85-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2022-85-7 ]

* 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.

  • Upstream synthesis route of [ 2022-85-7 ]
  • Downstream synthetic route of [ 2022-85-7 ]

[ 2022-85-7 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 71-30-7 ]
  • [ 2022-85-7 ]
YieldReaction ConditionsOperation in experiment
95.7%
Stage #1: at -15 - 0℃; Inert atmosphere
Stage #2: at -20℃; for 4 h; Inert atmosphere
(1) Under nitrogen, the temperature is 0 , the quality of anhydrous hydrogen fluoride was added 1150g 3450g cytosine, at a temperature of -15 deg.] C, into fluorine gas content of 15percent fluorine gas, a mixed gas of nitrogen, flow rate of 40g / h, fluorination reaction; document.write(""); After (2) a reaction for 4 hours in ventilation of nitrogen gas remove excess fluorine gas at -20 reaction of anhydrous hydrogen fluoride was distilled off in vacuo to dryness, water was added 8L, calcium carbonate was added to adjust the pH to 8; document.write(""); (3) The reaction was warmed to 90 deg.] C for 1 hour, filtered hot, 100g activated carbon was added, incubated 90 deg.] C for 0.5 hours and then filtered hot, cooled to 25 deg.] C for 0.5 hours, then cooled to 0 deg.] C, stirred for 1 hour , 5-fluorocytosine was filtered to give a white wet product; document.write(""); (4) the wet product 5-fluorocytosine after 70 deg.] C bake for 16 hours to give 5-fluorocytosine dried. document.write(""); Purity by HPLC and liquid phase titration analysis to analyze the content of 5-fluorocytosine purity and yield the following results: 95.7percent yield, 97.7percent pure.
87.4% at 20℃; Inert atmosphere (Figure 1) corning straight channel module 1 (as premix preheat module), corning "heart" microchannel reaction module 6, corning straight channel module 1 (as quenching module) and heat transfer module 8 , And the continuous flow microchannel reaction system is composed according to the reaction flow shown in Fig. The reaction heat transfer medium is made of heat transfer oil. According to the principle of forced heat transfer of microchannel reactor, only two temperature measurement points are set in the inlet and outlet of the reactor. Before the reaction, the microchannel reaction system and the connecting pipeline were treated by dewatering and degreasing respectively. The system and the connecting line were passivated with 5molpercent fluorine and nitrogen gas mixture to carry out the airtightness check of 1.0MPa. The uracil solution (i.e., a mixture of uracil and anhydrous hydrofluoric acid, and the concentration of uracil 7percent) was continuously added to the microchannel reaction system by the 1-liquid chestnut (Fig. 3). With the gas mass flow meter of Fig. 3, A 20 molpercent fluorine-nitrogen mixed gas was continuously added to the microchannel reaction system.Set the heat exchanger temperature 0 ° C, ie the reaction temperature. Set the reaction pressure 0. IMPa. The molar ratio of fluorine gas to uracil was 1.2: 1, and the molar ratio of fluorine gas to uracil was 1.2: 1. The reaction mixture was heated into the "heart-shaped" microchannel reaction module 4 by the microchannel pre-heating module 3 and the fluorine-nitrogen mixed gas was directly introduced into the "heart-shaped" microchannel reaction module 4 through the gas mass flow meter. Heart-shaped "microchannel reaction module 4-9, the fluorine-nitrogen mixture reacts with uracil. The crude reaction product is separated by a gas-liquid separator after quenching the module 10 and then treated by a system and dried to obtain a 5-fluorouracil product. The reaction product was analyzed by liquid chromatography. The results showed that the purity of 5-fluorouracil reached 98.6percent and the product yield was 86.7percent. The same Corning microchannel reactor was used as in Example 1, and the same connection method and control method were used. This example changes the reaction conditions.Set the heat exchanger temperature 20 ° C, ie the reaction temperature. Set the reaction pressure 0.15MPa. The reaction material 2 is a cytosine solution, that is, a mixture of cytosine and hexafluoroisopropanol, the mass concentration of uracil is 3percent and the feed rate is 80 g / min. The raw material 1 is 20 molpercent of the fluorine-nitrogen mixed gas, and the feed rate is 2.90 L / min. The molar ratio of fluorine to cytosine was 1.2: 1. The raw material 2 cytosine solution was pre-heated by the microchannel preheating module 3 into the "heart-shaped" microchannel reaction module 4. The fluorine-nitrogen mixed gas was directly introduced into the microchannel reaction module 4 through the gas mass flow meter, In the channel reaction module 4-9, the fluorine-nitrogen mixture reacts with cytosine. The crude reaction product is separated by a gas-liquid separator after quenching the module 10 and then treated by a system and dried to obtain a 5-fluorocytosine product. The reaction product was analyzed by liquid chromatography, and the purity of 5-fluorocytosine was 99.3percent and the product yield was 87.4percent.
63% for 1.5 h; Flow reactor; Autoclave 1.0 M cytosine solution in formic acid was introduced at 4.0 mL/h (4.0 mmol/h) while fluorine (10 percent in N2) was introduced at 20 mL/min (5 mmol/h). The reaction was conducted for 90 minutes, the collected fraction was evaporated and the residue was recrystallized from water (7 mL). After filtration, the product was dried under reduced pressure to afford 5-fluorocytosine (0.49 g, 63 percent yield) as a tan powder. M.p.: 295 - 300 °C (decomposes), ([M]+ 129.0337, [M]+ requires: 129.0338); IR (cm"1): 3384, 3092, 2724, 1665, 1624, 1551, 1454, 1216; 1 H NMR (400 MHz, D2O+DCI) 7.83 (1 H, d, 3JHF 4.8 Hz); 19F NMR (400 MHz, D2O+DCI) -169.7 (1 F, d, 3JHF 4.8 Hz); 13C NMR (100 MHz, D2O+DCI): 130.67 (d, 2JCF 29.6 Hz), 135.25 (d, 1JCF 232 Hz), 147.88, 153.65 (d, 2JCF 23.4 Hz); MS (ASAP): 11 1 (37 percent, [M+H-F]+), 129 (8 percent, [M]+), 130 (100 percent, [M+H]+).
Reference: [1] Patent: CN104326990, 2016, B, . Location in patent: Paragraph 0042-0043
[2] Patent: CN106432099, 2017, A, . Location in patent: Paragraph 0028-0031; 0047-0051
[3] Patent: WO2016/30662, 2016, A1, . Location in patent: Paragraph 00251
[4] Patent: CN107089952, 2017, A, . Location in patent: Paragraph 0036; 0037; 0038; 0039; 0040; 0041; 0042; 0043
  • 2
  • [ 1993-63-1 ]
  • [ 2022-85-7 ]
YieldReaction ConditionsOperation in experiment
95% With hydrogenchloride In methanol; water at 40 - 60℃; The 24.0g formula II compound are added 102g30wt percent hydrogen chloride in methanol solution, heating to 40-60°C, stirring reaction 5-7 hours, concentrating the reaction solution under reduced pressure, the concentrated residual liquid cooling to room temperature, add water (the heating volume is residual liquid volume of 2 times), slowly dropping 50 wt percent of sodium hydroxide aqueous solution, the reaction system is adjusted to pH 8.0-8.5, precipitated solid, is continuously stirred for 0.5 hours, filtering, collecting solid, ice water washing, drying, namely type I compound (white solid) 20.6g, molar yield is 95.0percent, HPLC purity of 99.6percent.
Reference: [1] Patent: CN105272922, 2016, A, . Location in patent: Paragraph 0041; 0042; 0043
  • 3
  • [ 945548-37-8 ]
  • [ 2022-85-7 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With acetamide; potassium fluoride In N,N-dimethyl-formamide at 130℃; for 5 h; Inert atmosphere
Stage #2: With ammonia In methanol at 40℃; for 12 h;
The N-acetyl-5-bromocytosin (69.6g, 0 . 3mol) in the reaction bottle into the drying of, under the protection of nitrogen adding anhydrous potassium fluoride (23.2g, 0 . 4mol), acetamide (29.5g, 0 . 5mol), DMF150mL, the temperature is increased to 130 °C reaction 5h, distilling solvent by reduced pressure, cooling to 40 °C by adding 150 ml ammonia methanol and thermal insulation reaction 12h, TLC tracking to intermediate (III) the reaction is complete, the methanol is distilled under reduced pressure, by adding 400 ml water heating to dissolves clear, cooling to 10 °C, filtering, drying to obtain white crystalline solid 5-fluorocytosine (36g, 93percent), the content of the HPLC 99.5percent. This embodiment, with the fluoro reagent is sodium fluoride, cesium fluoride, lithium fluoride, antimony trifluoride, five antimonic fluoride, fluorinated mercury, tachiol, copper fluoride, cobalt fluoride, cerium fluoride, pyridine hydrogen fluoride salt, tetrabutyl ammonium fluoride, tetramethyl ammonium fluoride or carrier potassium fluoride anhydrous potassium fluoride replaced, for non-proton polar solventN, N-dimethylacetamide, DMSO, sulfolanes,N-methylpyrrolidone, acetamide, acetonitrile, benzyl cyanide, crown ether, polyethylene glycol, a hydrogen fluoride mixtureN or replaced, N-dimethyl formamide, can obtain similar technical effects.
Reference: [1] Patent: CN103819412, 2016, B, . Location in patent: Paragraph 0028-0030;0041; 0042
  • 4
  • [ 99429-06-8 ]
  • [ 2022-85-7 ]
YieldReaction ConditionsOperation in experiment
98.1% With ammonia In hydrogenchloride; ethanol; water EXAMPLE 4
Preparation of 5-fluorocytosine from 2,5-difluoro-4-chloropyrimidine
15.05 g (0.1 mole) of 2,5-difluoro-4-chloropyrimidine were stirred in 30 ml of 37percent strength aqueous hydrochloric acid at 50° C. for 2 hours.
After the mixture had cooled, it was neutralized with 33percent strength aqueous ammonia solution.
The mixture was then diluted with 100 ml of ethanol and a further 20 ml of aqueous 33percent strength ammonia solution were added.
The mixture was subsequently stirred at room temperature for 2 hours.
Thereafter, it was concentrated in vacuo, the residue was taken up in 60 ml of water and the solid obtained was filtered off with suction, washed with water and dried.
11.5 g of product with a melting point of 294° to 296° C. were obtained, corresponding to a yield of 98.1percent of theory.
Reference: [1] Patent: US4703121, 1987, A,
  • 5
  • [ 71-30-7 ]
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YieldReaction ConditionsOperation in experiment
66% for 1.5 h; Flow reactor; Sealed tube General procedure: 1.0 M cytosine solution in formic acid was introduced at 4.0 mL/h (4.0 mmol/h) while fluorine (10 percent in N2) was introduced at 20 mL/min (5 mmol/h). The reaction was conducted for 90 minutes, the collected fraction was evaporated and the residue was recrystallized from water (7 mL). After filtration, the product was dried under reduced pressure to afford 5-fluorocytosine (0.49 g, 63 percent yield) as a tan powder. M.p.: 295 - 300 °C (decomposes), ([M]+ 129.0337, [M]+ requires: 129.0338); IR (cm"1): 3384, 3092, 2724, 1665, 1624, 1551, 1454, 1216; 1 H NMR (400 MHz, D2O+DCI) 7.83 (1 H, d, 3JHF 4.8 Hz); 19F NMR (400 MHz, D2O+DCI) -169.7 (1 F, d, 3JHF 4.8 Hz); 13C NMR (100 MHz, D2O+DCI): 130.67 (d, 2JCF 29.6 Hz), 135.25 (d, 1JCF 232 Hz), 147.88, 153.65 (d, 2JCF 23.4 Hz); MS (ASAP): 11 1 (37 percent, [M+H-F]+), 129 (8 percent, [M]+), 130 (100 percent, [M+H]+).
Reference: [1] Patent: WO2016/30662, 2016, A1, . Location in patent: Paragraph 00251; 00273
[2] Organic Process Research and Development, 2017, vol. 21, # 2, p. 273 - 276
  • 6
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Reference: [1] Journal of the American Chemical Society, 1957, vol. 79, p. 4559
[2] Patent: US2802005, 1956, ,
  • 7
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Reference: [1] Journal of Fluorine Chemistry, 1984, vol. 24, p. 355 - 362
  • 8
  • [ 134379-77-4 ]
  • [ 98-00-0 ]
  • [ 2022-85-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 9, p. 2159 - 2162
  • 9
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  • [ 2022-78-8 ]
Reference: [1] Bioscience, biotechnology, and biochemistry, 2002, vol. 66, # 11, p. 2362 - 2366
  • 10
  • [ 2022-85-7 ]
  • [ 147027-09-6 ]
  • [ 764659-72-5 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: at 25 - 130℃; Inert atmosphere
Stage #2: With zirconium(IV) chloride In dichloromethane at 25 - 30℃; for 6 h; Inert atmosphere
Fluorocytosine (22.4 g, 0.173 mol, 1.1 molar equivalents), Hexamethyl disilazane (HMDS) (100 ml, 0.477 mol, 3.1 molar equivalents) and trimethylsilyl chloride (TMSCL), ( 1 1.2 ml) were mixed at 25-30°C under Nitrogen atmosphere. The reaction mixture was heated up to 120- 130°C to get clear solution and excess solvent was distilled out under vacuum at 90- 100°C to get the residue of silylated fluorocytosine. The residue of silylated fluorocytosine was cooled to room temperature and fresh dichlorome thane (100 ml) was added (solution A). In a separate flask L-menthyl-5R-acetoxy- l ,3-oxathiolane-2R-carboxylate (50 g, 0.151 mol, 1.0 molar equivalents), dichloromethane (250 ml) and zirconium tetrachloride (ZrCU) (17.6 g, 0.075 mole, 0.5 molar equivalents) were mixed under nitrogen atmosphere (solution B). Presilylated fluorocytosine solution A was added into solution B at 25-30°C and reaction mixture was stirred at the same temperature for 6 hrs. The reaction was monitored by HPLC or thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 10-20°C and precooled ( 10-20°C) water (250 ml) was added under stirring. pH was adjusted at 8 to 8.5 using triethylamine under stirring. The layers were separated and the organic layer was washed with 250 ml of water. The organic layer was concentrated under vacuum to get the residue. The residue was dissolved in methanol (200 ml) and n- heptane (100 ml) under stirring. The said solution was added into water (200 ml). The isolated solid was filtered and washed with water followed by n-heptane. The solid was dried under vacuum at 40-45°C. Yield: 48.5 g (80 percent). Chiral Purity: 99.94 percent; 0.06 percent undesired isomer. Ή NMR (DMSO-d6) δ (ppm): 0.70-0.99 (m, 10H), 1.02- 1.10 (m, 2H), 1.39- 1.49 8 (m, 2H), 1.63- 1.66 8 (d, 2H), 1.88- 1.95 8 (m, 2H), 3.20-3.24 8 (m, 1H), 3.53-3.57 8 (m, 1H), 4.66-4.72 (m, 1H), 5.71 8 (s, 1H), 6.29- 6.30 8 (d, 1H), 7.69 (s, 1H), 7.94 8 (s, 1H), 8.16-8. 18 8 (d, 1H); i3C NMR (DMSO- d6): 16.5, 20.9, 22.2.3.2, 26.1 , 31.8, 34, 35.8, 46.8, 76, 78.3, 89.5, 125.4, 135.2, 137.6, 153.4, 158, 169.8; IR (KBr) (cm-i): 3323, 3083, 2956, 2869, 1754, 1687, 1640, 1513, 1348, 1287, 1 178, 1090, 940, 774, 678, 498; MS (EI) m/z = 400 (M+ l); [a]D25 = -45.23° (c = 0.2percent, MeOH).
Reference: [1] Organic Letters, 2015, vol. 17, # 11, p. 2626 - 2629
[2] Patent: WO2013/21290, 2013, A1, . Location in patent: Page/Page column 24; 25
  • 11
  • [ 2022-85-7 ]
  • [ 764659-72-5 ]
YieldReaction ConditionsOperation in experiment
50.5%
Stage #1: With thionyl chloride In dichloromethane at 0 - 15℃; for 2 h;
Stage #2: With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In tolueneReflux
Stage #3: at 90℃; Reflux
720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added, 20 mL DMF, Cooled to 0 ~ 5 deg C, A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise. After stirring for 2 hours at 10-15 ° C, Concentrated under reduced pressure, Then add 2.2 L of toluene and cool for use. 324 g of 5-fluorocytosine, 12g ammonium sulfate, 600mL hexamethyldisilazane, 960 mL of toluene was added, Heated to reflux for 1 to 2 hours. Slightly cooled to below 90 deg C, Add dropwise 350 mL of triethylamine, It was heated to reflux, but not vigorous. The chlorinated solution prepared above was added dropwise, Wash with 240 mL of toluene. Reflux for 2 to 3 hours, Cooled to 30 ~ 35 deg C, Dropping a solution of 180 mL triethylamine in water 2.9 L, Cooled to 15 ~ 20 deg C, Stirred for 1 hour, 2.9 L of n-heptane was dropped, Stir for 16 hours, filter, Washed, Emtricitabine Intermediate III was obtained after drying, 504g, Yield 50.5percent HPLC purity 98.17percent.
50.5%
Stage #1: With thionyl chloride In dichloromethane; toluene; N,N-dimethyl-d6-formamide at 10 - 15℃; for 2 h;
Stage #2: With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane; N,N-dimethyl-formamide; tolueneReflux
720 g Emtricitabine Intermediate IV 7.2 L dichloromethane was added,20mLDMF, cooled to 0 ~ 5 ,A solution of 192 mL of thionyl chloride in 1.2 L of dichloromethane was added dropwise.After stirring at 10-15 ° C for 2 hours, concentrated under reduced pressure,Then add 2.2 L of toluene and cool for use.324 g of 5-fluorocytosine, 12 g of ammonium sulfate, 600 mL of hexamethyldisilazane, 960 mL of toluene was added and the mixture was heated to reflux1 ~ 2 hours. Slightly cooled to below 90 , 350mL triethylamine dropwise, heated to reflux but not severe.The chlorinated solution prepared above was added dropwise and washed with 240 mL of toluene. Refluxed for 2 to 3 hours, cooled to 30 to 35 ° C, and added dropwise 2.9 mL of a solution of 180 mL of triethylamine in water, cooled to 15 to 20 ° C and stirred for 1 hour,2.9 L of n-heptane was added dropwise and the mixture was stirred for 16 hours, filtered, washed with water and dried to yield Emtricitabine Intermediate III,504g, yield 50.5percentHPLC purity 98.17percent.
Reference: [1] Patent: CN106496208, 2017, A, . Location in patent: Paragraph 0047; 0048; 0049
[2] Patent: CN106478618, 2017, A, . Location in patent: Paragraph 0048; 0049; 0050
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Reference: [1] Patent: WO2009/84033, 2009, A2, . Location in patent: Page/Page column 8-9
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