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Name: 2022-85-7|6-Amino-5-fluoropyrimidin-2(1H)-one|97%
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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	Chemical Name :	6-Amino-5-fluoropyrimidin-2(1H)-one

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 ]

Yield	Reaction Conditions	Operation 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, ³J_HF 4.8 Hz); ¹⁹F NMR (400 MHz, D₂O+DCI) -169.7 (1 F, d, ³J_HF 4.8 Hz); ¹³C NMR (100 MHz, D₂O+DCI): 130.67 (d, ²J_CF 29.6 Hz), 135.25 (d, ¹J_CF 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 ]

Yield	Reaction Conditions	Operation 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 ]

Yield	Reaction Conditions	Operation 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 ]

Yield	Reaction Conditions	Operation 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 ]
[ 2022-85-7 ]

Yield	Reaction Conditions	Operation 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, ³J_HF 4.8 Hz); ¹⁹F NMR (400 MHz, D₂O+DCI) -169.7 (1 F, d, ³J_HF 4.8 Hz); ¹³C NMR (100 MHz, D₂O+DCI): 130.67 (d, ²J_CF 29.6 Hz), 135.25 (d, ¹J_CF 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
[ 701-87-1 ]
[ 2022-85-7 ]

Reference： [1] Journal of the American Chemical Society, 1957, vol. 79, p. 4559
[2] Patent: US2802005, 1956, ,

7
[ 71-30-7 ]
[ 2022-85-7 ]

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
[ 2022-85-7 ]
[ 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 ]

Yield	Reaction Conditions	Operation 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 ]

Yield	Reaction Conditions	Operation 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

12
[ 2022-85-7 ]
[ 764659-72-5 ]

Reference： [1] Patent: WO2009/84033, 2009, A2, . Location in patent: Page/Page column 8-9

[ 2022-85-7 ] Synthesis Path-Downstream 1~25

1
[ 2022-85-7 ]
[ 27821-07-4 ]
[ 161599-46-8 ]

Yield	Reaction Conditions	Operation in experiment
88.6%	With titanium tetrachloride; In dichloromethane; at 10 - 20℃; for 4h;	5-Fluorocytosine (200.0 g, 1.55 mol) was suspended in 2 L of dichloromethane.1,2,3-Tri-O-acetyl-5-deoxyribose (403.0 g, 1.55 mol) was added at room temperature.Control temperature 10 to 20 C,Titanium tetrachloride (403.0 g, 1.55 mol) was added dropwise to a 1 L solution of dichloromethane under rapid stirring.After the completion of the dropwise addition, the reaction was continued at 10 to 20 C for 4 hours.Add sodium bicarbonate (781.0 g, 9.3 mol),Slowly add 100g of water,Stirring was continued for 3 hours after the completion of the dropping.After filtration, the filter cake was washed with dichloromethane (0.4 L×2), and the filtrate was washed once with saturated aqueous sodium hydrogencarbonate (2.0 L) and the organic phase was dried over anhydrous sodium sulfate (200 g) for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to syrup.The residue was recrystallized from 2.0 L of isopropanol to afford 452 g of capecitabine intermediate as a white powder.The yield was 88.6%, the purity was 99.7%, and the maximum single impurity was 0.11%. The alpha-isomer was not detected.Figure 5 is a HPLC analysis of the capecitabine intermediate obtained in Example 5.
83.6%		Under nitrogen atmosphere, 1.80 kg of toluene, 125 g of compound of formula III, 2 g of ammonium sulfate and 247 g of HMDS were charged into the reaction vessel. After the addition was completed, the mixture was heated to reflux under warming and the mixture was refluxed for 3 hours. The solvent was concentrated under reduced pressure and the residue was dissolved with 1.40 Kg of CH2Cl2. 225 g of the compound of formula II was added and protected by nitrogen. The mixture was cooled to -5 C and 255 g of SnCl4 / 200 g of CH2Cl2 solution was added dropwise. Natural warming reaction to the point of disappearance of raw materials. Cool to about 5 , add 400g sodium bicarbonate, stirring, dropping 187.5g purified water, stirring at room temperature. Feed filtration, the filter cake was washed with 500g CH2Cl2 beating, drained. The filtrate was washed twice with 840 g of 5% aqueous sodium bicarbonate and once with 840 g of saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was concentrated under reduced pressure to give a white solid. Add 500g of anhydrous ethanol to dissolve, filter, and dry to give a white solid (242.3g, 0.736mol, 83.6%), HPLC content of 98.39%.
80%		Example 1 A Process for Producing and Purification of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (I) To a vessel is added of 5-fluorocytosine (1.2 kg, 9.30 mol), triflic acid (5.0 g), hexamethyldisilazane (1.06 kg, 6.57 mol) and acetonitrile (4.3 kg). The mixture is heated to reflux and keeps reflux for about 2 hours. The solution is cooled to room temperature and added of beta-acetylfuranoside (2.528 kg, 9.71 mol) and triflic acid (0.832 kg, 5.54 mol). The resultant mixture is heated and stirred at 45-55 C. for about 20 hours. After completion of the reaction, the solution is cooled to 20-30 C. and worked up with saturated sodium bicarbonate solution. After phase separation with methylene chloride, the organic layer is collected and subsequently swapped with isopropanol (7.76 kg) to an appropriate volume. The resulting isopropanol solution is heated to reflux until dissolved. The solution is cloud after seeding with 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine at 50-70 C. The slurry is cooled to room temperature and n-heptane is charged with stirring for another 0.5 hrs. The solution is cooled to less than 10 C. The resulting solid is filtered, washed with cold isopropanol and dried under vacuum, to afford 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine. The purity is >=99.5% and related alpha-form impurity is <=0.2%. Yield: 80%. 1H NMR (CDCl3, 400 MHz) delta 7.85 (s, 1H), 7.84 (b, NH), 7.09 (b, NH), 5.87 (m, 1H), 5.50 (m, 1H), 5.17 (m, 1H), 4.15 (m, 1H), 2.07 (s, 6H), 1.43 (d, J=6.4 Hz, 3H).

72%		Synthesis of 2',3'-Di-O-acetyl-5'-deoxy-5-fluorocytidine (5) 5-Fluorocytosine (2.42g, 18.8mmol) was suspended in toluene (10ml) and hexyamethyl-disilazane (3.03g, 18.8mmol). The mixture was heated at 100C overnight. After concentrating the reaction mixture under reduced pressure, methylene chloride (30ml) and 5-deoxy-1,2,3-tri-O-Acetyl-beta-D-ribofuranoside (4) (5.16g, 18.8mmol) were added to the residue. Then, anhydrous stannic chloride (4.90g, 18.8mmol) was added dropwise to the ice-cooled reaction mixture over a period of 20min. After stirring the mixture at room temperature for an additional 2h, sodium bicarbonate (10g) was added, followed by the dropwise addition of water (20ml). After stirring the resulting mixture at room temperature overnight, 4% sodium bicarbonate solution was poured into the reaction mixture and stirred for additional 1h. The mixture was then extracted with water-methylene chloride. The organic layer was collected, dried with Na2SO4, the solvent was removed under reduced pressure to give brown syrup. The residue was then partially purified by silica gel chromatography using CH2Cl2:MeOH (5:1) as an eluent to yield crude target compound (5) (4.455g, 13.5mmol, 72%). 1H NMR in DMSOd6: delta 1.34 (d, 3H, J=6.4Hz, H-5), 2.05, 2.06 (2s, each 3H, OMe), 4.14 (q, 1H, J=5.0Hz, H-4), 5.10 (t, 1H, J=6.4Hz, H-2), 5.43 (dd, 1H, J=6.31 Hz, H-3), 5.77 (dd, 1H, J=1.0Hz, H-1), 7.71 (br s, 1H, N-CH=C-F), 7.97 (brs, 1H, NH), 8.02 (d, 1H, J=7.0Hz, NH).
48.7%		5-fluorocytosine (1.32g, 10 . 0mmol) suspended in anhydrous toluene (25 ml) in, adding HMDS (2.40 ml, 5 . 0mmol), heating reflux reaction 3h. 60 C the following concentrate under reduced pressure to dry, the residue is added in 5-deoxy three acetyl ribose (2.4g, 9 . 0mmol) and anhydrous 1,2-dichloroethane (20 ml, 5mmol), -5 C lower dropwise anhydrous tin tetrachloride (1.2 ml, 9 . 5mmol) of anhydrous 1,2-dichloroethane (5 ml) solution, drop Bi Yu 0 C reaction 2h. The above-mentioned solution is dripped slowly into the -5 C of sodium bicarbonate solution, stirring the mixture at room temperature for 5h. Filtering, with 1,2-dichloroethane washing, and combining the filtrate, with 5% sodium bicarbonate solution (20 ml) washing, dry anhydrous sodium sulfate, filtered, filtrate concentrated to dry, the residue by silica gel column chromatography (dichloromethane/methanol =15/1 as eluant) purification, eluant is concentrated to dry, the remaining types of white foam solid recrystallized with isopropyl alcohol, to obtain white crystal 2 ', 3' -di-O-acetyl-5'-deoxy-5-fluorocytidine(1.44g, 48.7%), HPLC: 99.3%
		Example 1 Compound (2a)2.62 g of 5-fluorocytosine was added to 33 ml of CH2Cl2 and 5.93 g 5-deoxy-1,2,3-tri-O-acetyl-beta-d-ribofuranose was added. The suspension was stirred and cooled to 0-4 C. in an ice-bath. 6.25 g of stannic chloride was added dropwise in about 10 minutes. The mixture was allowed to heat up to room temperature and stirred for 1 hour. An almost clear solution was obtained. 10.1 g of sodium bicarbonate was added and 3.5 ml of water was added dropwise (gas formation). The mixture was stirred at room temperature overnight. The insoluble material was filtered off. The filtrate was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried on Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was co-evaporated with 5 ml of 2-Propanol and a solid was obtained.Yield: 6.4 gThe solid was recrystallized from 16 ml of 2-propanol, stirred after cooling to room temperature for 16 hours.Melting Point: 190.1-191.2 C.NMR confirmed the structure.HPLC purity: higher than 99.5%.; Example 4 Capecitabine by ?One Pot? Process2.58 g of 5-fluorocytosine and 5.93 g of 5-deoxy-1,2,3,-tri-O-acetyl-beta-D-furanoside were added to 33 ml of dichloromethane, the mixture was cooled to 0-4 C., stirred and 6.25 g of stannic chloride was added dropwise in about 10 minutes. The mixture was allowed to heat up to room temperature and stirred for about 2.5 hours. 10.1 g of sodium bicarbonate was added. 35 ml of water was added dropwise over a period of 20 minutes. (CO2 formation) The reaction mixture was stirred overnight. About 2 g of Na2SO4 was added to the organic phase and stirred for 30 minutes. The solid was filtered off, washed with 10 ml of dichloromethane. The combined filtrates were reduced in volume to about 20 ml. by reduced pressure. To the resulting solution was added 3.9 ml of pyridine. The mixture was cooled to 0-4 C. (ice-bath). 4.9 ml n-pentylchloroformate was added dropwise. The ice-bath was removed and after 40 minutes 13 ml of methanol was added. The mixture was cooled on an ice bath. A solution of 4.68 g of NaOH in 6.5 ml of water was added dropwise in 10 minutes. Then 9.8 ml of concentrated HCl was added dropwise. After addition the pH was about 5 (pH-paper). 65 ml of dichloromethane and 13 ml water was added. The layers were mixed and allowed to separate. The organic layer was washed with 13 ml of water, dried on Na2SO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The oily residue was dissolved in 8.6 ml of ethyl acetate and 17 ml n-hexane was added. A solid was formed. After stirring overnight, the solid was isolated by filtration and washed with a mixture of 8.6 ml ethyl acetate and 17 ml n-hexane. Dried in a vacuum oven at 40 C.Yield: 4.3 g (60%), purity HPLC: 98.7%
		Example 1 Synthesis of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (Compound 2) 5-Fluorocytosine (5 g, 39 mmol) was suspended in toluene (20 mL), to which hexyamethyl disilazane (3.6 g, 39 mmol) was then added. The mixture was heated at 105 C. for 2 hours. After the reaction mixture was concentrated under reduced pressure, methylene chloride (80 mL) and 5-deoxy-1,2,3-tri-O-acetyl-beta-D-ribofuranoside (11.1 g, 43 mmol) were added, followed by addition of anhydrous stannic chloride (13.1 g, 50 mmol) dropwise at 0-10 C. over a period of 30 min. After 3 hours at room temperature, the reaction mixture was treated with sodium bicarbonate (15 g) and then water (8 mL) was added dropwise over a period of 45 min. Finally, the mixture was stirred at room temperature for 2 hours, and the precipitate was then removed by filtration and the filtrate was washed with 4% sodium bicarbonate solution (40 mL). The resultant solution was subjected to evaporation under reduced pressure, and the residue was crystallized from isopropanol (40 mL) to obtain crude compound 2 (yield: 8.7 g). mp 190+-192 C.; MASS: m/z 352.11 [m+Na+]; 1H NMR (DMSO-d6): delta 1.34 (3H, d), 2.04 (3H, s), 2.05 (3H, s), 4.04 (1H, dq), 5.09 (1H, t), 5.43 (1H, dd), 5.76 (1H, d), 7.67 (1H, br s), 7.94 (1H, br s), 8.01 (1H, d).

Reference： [1]Patent: CN108440623,2018,A .Location in patent: Paragraph 0037-0046
[2]Patent: CN106478751,2017,A .Location in patent: Paragraph 0020; 0061; 0062
[3]Patent: US2011/21769,2011,A1 .Location in patent: Page/Page column 3; 5
[4]Bioorganic and Medicinal Chemistry,2000,vol. 8,p. 1697 - 1706
[5]Patent: EP2393472,2019,B1 .Location in patent: Paragraph 0142; 0151; 0152
[6]Patent: CN105566418,2016,A .Location in patent: Paragraph 0008
[7]Patent: US2008/300399,2008,A1 .Location in patent: Page/Page column 4-5
[8]Patent: US2013/184451,2013,A1 .Location in patent: Paragraph 0028; 0029

2
[ 2022-85-7 ]
[ 2022-78-8 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2002,vol. 66,p. 2362 - 2366

3
[ 2022-85-7 ]
[ 14215-97-5 ]
[ 53294-73-8 ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 4172 - 4173

4
[ 2022-85-7 ]
[ 60410-16-4 ]
[ 1034172-16-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: Flucytosine With triphenylphosphine; sodium t-butanolate In N,N-dimethyl-formamide at 60℃; Stage #2: (1R,4S)-4-hydroxy-2-cyclopentene-1-yl acetate In tetrahydrofuran; N,N-dimethyl-formamide at 70℃; for 12h;	5.1 To a mixture of (lS,4R)-cis-4-acetoxy-2-cyclopenten-l-ol (10.8 g, 76.0 mmol) dipalladium-tris-dibenzylideneacetone (1.7O g, 1.90 mmol) and triphenylphosphine (1.00 g, 3.8 mmol) was added anhydrous tetrahydrofuran (100 mL). The slurry was degassed with nitrogen at room temperature for about 15 minutes. In a 1 L 3-neck round bottomed flask equipped with reflux condenser, a mixture of 5-fluorocytosine (9.80 g, 76.0 mmol) and triphenylphosphine (1.00 g, 3.8 mmol) was suspended in anhydrous dimethylformamide (200 mL). The vigorously stirred slurry of 5-F-cytosine was heated to 6O0C and treated with sodium t-butoxide (7.20 g, 75.0 mmol), which afforded a white precipitate. The resulting thick slurry of anion was treated with the solution of acetate/catalyst via cannula over 10 minutes. The resulting dark green heterogeneous mixture was stirred under nitrogen at 7O0C for 12 hours, and the solvent was removed in vacuo. The residue was dry- loaded onto 40Og silica gel. Silica gel plug filtration (6 x 10 cm SiO2) followed by trituration with acetonitrile/ethyl acetate afforded the title compound as an off- white solid (12.65 g, 80 %).
80%	Stage #1: Flucytosine With sodium t-butanolate In N,N-dimethyl-formamide Stage #2: (1R,4S)-4-hydroxy-2-cyclopentene-1-yl acetate With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; triphenylphosphine In tetrahydrofuran

Reference： [1]Current Patent Assignee: LEXICON PHARMACEUTICALS INC - WO2008/76778, 2008, A1 Location in patent: Page/Page column 22
[2]Location in patent: scheme or table Jessop, Theodore C.; Tarver, James E.; Carlsen, Marianne; Xu, Amy; Healy, Jason P.; Heim-Riether, Alexander; Fu, Qinghong; Taylor, Jerry A.; Augeri, David J.; Shen, Min; Stouch, Terry R.; Swanson, Ronald V.; Tari, Leslie W.; Hunter, Michael; Hoffman, Isaac; Keyes, Philip E.; Yu, Xuan-Chuan; Miranda, Maricar; Liu, Qingyun; Swaffield, Jonathan C.; David Kimball; Nouraldeen, Amr; Wilson, Alan G.E.; Foushee, Ann Marie DiGeorge; Jhaver, Kanchan; Finch, Rick; Anderson, Steve; Oravecz, Tamas; Carson, Kenneth G. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 23, p. 6784 - 6787]

5
[ 2022-85-7 ]
[ 21740-23-8 ]
[ 2353-75-5 ]
C₂₃H₁₈Cl₂FN₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 3; A mixture of 5-fluoro-cytosine (1.0 g, 9.0 mmol), ammonium sulfate (0.12 g, 0.91 mmol), and hexamethyldisilazane (8.1 g, 50 mmol) was heated to reflux for 45 minutes until a clear solution was obtained. Some gas evolved (ammonia). The reaction mixture was cooled to 50C, and concentrated in the vacuum to about half of the original volume. A turbid suspension was obtained. 13.2 g of dichloromethane, lithium trifluoromethane sulfonate (1.3 g, 8.3 mmol) and the "chloro sugar" C-137 (3.48 g, 8.1 mmol) were added. The beige mixture was stirred for 3 hours at ambient temperature (20-25C), while it became brownish, products (anomeric mixture [(beta-isomer) : (alpha-isomer) 55.6 : 44.4]) : starting material 99.0 : 1.0. Then the solvent was removed at 38C. A brownish sticky solid was obtained. The solid was dissolved in 3.0 g ethyl acetate. The solution was added drop wise to a mixture of 11 g of aqueous hydrogen carbonate (5 weight% solution in water), 11.0 g of water, 8.7 g of ethyl acetate, 1.8 g of cyclohexane and 3.5 g of acetonitrile at 32C. A three phase system was obtained. The reaction mixture was stirred over night at ambient temperature, and then filtered off, washed with 3.0 g of water, and finally with 3.6 g of a mixture of acetonitrile and ethyl acetate (1:1). Yield: 0.78 g, 19.7%.

Reference： [1]Patent: EP2048151,2009,A1 .Location in patent: Page/Page column 4

6
[ 2022-85-7 ]
[ 134877-42-2 ]
[ 155568-06-2 ]

Yield	Reaction Conditions	Operation in experiment
32%		Part C:According to a modification of a literature procedure (Kotra, L. P, et at. J. Med. Chem. 1997, 40, 3635) 5-fluorocytosine (1.42 g, 10.9 mmol) was treated with excess hexamethyldisilazane (35 mL, 167.8 mmol) in the presence of ammonium sulfate (50 mg) under argon and refluxed at 125C for 4 h. The reaction mixture was concentrated to remove excess solvent, and the resulting residue was dissolved in dry DCE (20 mL). A solution of compound 605C (2.50 g, 5.48 mmol) in DCE (20 mL) was added, and the reaction mixture was stirred for 10 min under argon. Then trimethylsilyl trifluoromethanesulfonate (1.98 mL, 10.9 mmol) was added to the mixture slowly, and the reaction was heated at 90-100 C under argon overnight. The reaction mixture was cooled to rt and washed with satd. NaHCO3 solution (2 X 40 mL) and brine (2 X 40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (chiralpak AD, 5 cm, 20 micron, 3/7 hexane/ethanol; 50 mLlambdanin) to afford 605D (0.82 g; 32%) as a white solid. HPLC-MS tfl = 1.90 min (UV254 nm); mass calculated for formula C2SH18F3N3O6489.11 , observed LCMS m/z 490.1 (M+H).

Reference： [1]Patent: WO2009/61781,2009,A1 .Location in patent: Page/Page column 102; 103

7
[ 2022-85-7 ]
(2R,5R)-5-hydroxy-[1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl ester [ No CAS ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
		Methylene chloride (450 ml) and methane sulfonic acid (0.80 g) was charged and the solution was cooled to 2O0C. (2R, 5R)-5-Hydroxy-[l,3]-oxathiolane-2- carboxylic acid, 2S-isopropyl-5R-methyl-lR-cyclohexyl ester (100 g,) was charged at 200C. To this solution dimethyl formamide (28 g) was added. The solution was further cooled to 8C. Thionyl chloride (44 g) was added drop wise at 8-1O0C. The temperature of the reaction mass was maintained at 10-150C for 4 hrs. The reaction mass was heated to reflux and maintained at reflux temperature for 4 hrs. Methylene chloride was distilled at atmospheric pressure up to residual volume of 300 ml-350 ml5-Fluorocytosine (45 g) was dissolved in toluene (120 ml) and subsequently hexamethyldisilazane (65.4 g) and methane sulfonic acid (0.4 g) were added. The entire reaction mass was heated to reflux and maintained for 5 hrs. 40 ml toluene was> distilled at atmospheric pressure. The reaction mass was cooled to 650C and triethylamine (35.5 g) was added at 65C. The reaction mass was cooled to 600C and the above residue was added drop wise at 55 - 65C. Temperature was maintained at mild reflux (53-560C) for 5 hrs. The reaction was monitored by HPLC and then reaction mass was cooled to 350C. The above reaction mass was added to a mixture of water (600 ml) and triethylamine (24.5 g) during at 25- 350C. The reaction mass was stirred for 1 hr at 25-35C. pH of the mass was adjusted to 7.8 with triethylamine. The organic layer was separated and solvent was distilled under vacuum completely <n="10"/>to give thick residue and a mixture of n-hexane (450 ml) and ethylacetate (50 ml) were added. The suspension was heated to reflux and maintained at reflux temperature for 2 hrs. The mass was slowly cooled to 25-35C. Stirring wais maintained for 10 hrs at 25-35C. Off white to light brown solid is filtered and washed with water.Wet cake was suspended in a mixture of water (200 ml), hexane (100 ml) and ethylacetate (100 ml). The suspension was stirred for 1 hr at 25-350C and filtered, washed with water (200 ml). Solid was dried at 60-650C to give 78 gm

Reference： [1]Patent: WO2009/84033,2009,A2 .Location in patent: Page/Page column 8-9

8
[ 2022-85-7 ]
[ 37076-71-4 ]
[ 161599-46-8 ]

Yield	Reaction Conditions	Operation in experiment
		5-fluorocytosine (2.32 g), HMDS (hexamethyldisilazane) (3.75 ml_), and TMS-CI (trimethylsilyl chloride) (0.4 ml_) are suspended in toluene (15 ml_) and heated to 1100C. The mixture is stirred for 30 minutes and cooled to 50-550C, then is distilled until no solvent distills at 50-60C under high vacuum. Dichloromethane (100 ml_) is charged to the residue at room temperature and the mixture is cooled to 0-50C. 5-deoxy-D-ribofuranose triacetate of Formula IV (5 g) and SnCI4 (2.4 ml_) are added and the temperature is raised to 25-30C. The mixture is stirred for 90 minutes. Sodium bicarbonate (8.1 g) and water (2.5 ml_) are added, followed by stirring for about 2 hours. The mixture is filtered and the filtrate is washed with 5% sodium bicarbonate solution (25 ml_). The obtained clear organic layer is concentrated completely under vacuum below 45C. The residue is stripped with isopropyl alcohol (5 ml_). lsopropyl alcohol (12.5 ml_) is charged to the obtained solid and heated to 40-500C. The mixture is cooled to room temperature and stirred for 15 minutes, then is further cooled to 0-5 C and stirred for 90 minutes. The obtained suspension is filtered and the solid is washed with isopropyl alcohol (2.5 ml_). The solid is dried at 47C under vacuum for 4-5 hours, to afford 3.7 g of the title compound.Purity: 98.28%; impurity at 1.56 RRT: 0.73%.2',3'-di-O-acetyl-5'-deoxy-5-fluoro-cytidine of Formula III (5 g) obtained above is dissolved in acetonitrile (9 ml_) at 500C with stirring for 15 minutes. The solution is cooled to room temperature and stirred for 2 hours, then is cooled to 0- 5C and stirred for 1 hour. The obtained suspension is filtered and the solid is dried for 3 hours at 40-45C under vacuum, to afford 2.9 g of the title compound. Purity: 99.56%; impurity at 1.56 RRT: 0.35%

Reference： [1]Patent: WO2010/65586,2010,A2 .Location in patent: Page/Page column 23

9
[ 2022-85-7 ]
[ 17985-72-7 ]
[ 1236199-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N,N,N,N,N,N-hexamethylphosphoric triamide; cesium fluoride; at 120℃;Inert atmosphere;Product distribution / selectivity;	Example 10:The hydroxamic acid derivatives with P represented by were synthesized according to the synthetic scheme below:To the aniline A (30 mmol) and silane (38 mmol) in dry HMPA (10 ml) solution was added anhydrous CsF (30 mmol) and the suspension stirred at 12O0C under Ar. After cooling, the mixture is dissolved in hexane/ether (1 : 1, 200 ml), washed with pH 7 phosphate buffer (0.4M, 2X40 ml), and dried. Evaporation of solvent followed by recrystalization gives the product B.

Reference： [1]Patent: WO2010/85377,2010,A2 .Location in patent: Page/Page column 47

10
[ 2022-85-7 ]
[ 129714-97-2 ]
[ 1265530-51-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 4-amino-5-fluoro-pyrimidin-2-ol With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 70℃; for 1h; Stage #2: 3,5-difluorobenzoyl chloride In acetonitrile at 20℃; for 12h;	4 To an 8 mL screw-cap vial containing 4-amino-5-fluoro-pyrimidin-2-ol* (100 mg, 0.775 mmol) and acetonitrile (CH3CN; 3 mL) was added bis-N,O-trimethylsilylacetamide (BSA; 378 microliters (μL), 1.55 mmol). The mixture was heated to 70° C. for 1 h resulting in a clear solution. After cooling to room temperature, 3,5-difluorobenzoyl chloride (182 μL, 1.55 mmol) was added, and the mixture was stirred at room temperature for 12 h. A white precipitate formed and was collected by vacuum filtration. The solid was washed with Et2O (1×10 mL) and air-dried overnight to yield the final product as a white solid (126 mg, 60%): mp 227-231° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (br s, 1H), 8.27 (br s, 1H), 8.14 (d, J=6.8 Hz, 1H), 7.80-7.35 (m, 3H); ESIMS m/z 270 (M+H), 268 (M-H). *4-Amino-5-fluoro-pyrimidin-2-ol can be purchased commercially.

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - US2011/34490, 2011, A1 Location in patent: Page/Page column 9

11
[ 628-21-7 ]
[ 2022-85-7 ]
[ 1265615-00-6 ]

Yield	Reaction Conditions	Operation in experiment
43%		To a suspension of 4-amino-5-fluoropyrimidin-2-ol (0.50 g, 3.87 mmol) in acetonitrile (CH3CN; 20 mL) was added BSA (1.58 g, 7.75 mmol), and the mixture was heated to 70 0C for 1 h resulting in a clear solution. After cooling to room temperature, 1,4-diiodobutane (1.2 g, 3.87 mmol) was added, and the mixture was stirred for 16 h at room temperature and then at 70 0C for 3 h. The solvent was evaporated and the residue was purified by normal phase chromatography (24 g SiO2; gradient, 0 to 15% MeOH/CH2Cl2) to give an orange oil. The oil was dissolved in EtOAc and the solution was slowly cooled. The resulting solid was collected by filtration, washed with additional EtOAc, and dried to give 4-amino-5-fluoro-l- (4-iodobutyl)-lH-pyrimidin-2-one (0.52 g, 43%) as a tan solid: mp 181-184 0C; 1H NMR (400 MHz, DMSO-J6) delta 8.56 (s, 2H), 8.25 (d, / = 6.7 Hz, IH), 3.70 (t, /= 6.7 Hz, 2H), 3.29 (t, / = 6.7 Hz, 2H), 1.73 (m, 4H); ESIMS m/z 312 ([M+H]+).

Reference： [1]Patent: WO2011/17540,2011,A1 .Location in patent: Page/Page column 28-29

12
[ 66-27-3 ]
[ 2022-85-7 ]
[ 155-15-7 ]

Yield	Reaction Conditions	Operation in experiment
37%	With 18-crown-6 ether; potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 21h;	A 25 mL screw-top vial was charged with 4-amino-5-fluoropyrimidin-2-ol (151.0 mg, 1.17 mmol), K2CO3 (289.2 mg, 2.09 mmol), 18C6 (278.6 mg, 0.901 mmol) and anhydrous DMF (10 mL). <strong>[66-27-3]Methyl methanesulfonate</strong> (0.0814 mL, 0.961 mmol) was added, and the resulting mixture was agitated on a rotary shaker at 85 0C for 21 h. After cooling to room temperature, the crude material was concentrated in vacuo and purified by reverse phase column chromatography to afford 4-amino-5-fluoro-l-methylpyrimidin-2(lH)-one (61.9 mg, 37%) as a beige solid: mp 195 0C (dec); 1H NMR (400 MHz, DMSO-J6) delta 7.94 (d, / = 6.8 Hz, IH), 7.52 (s, IH), 7.32 (s, IH), 3.18 (s, 3H); ESIMS m/z 144 ([M+H]+.

Reference： [1]Patent: WO2011/17540,2011,A1 .Location in patent: Page/Page column 29

13
[ 2022-85-7 ]
[ 638-41-5 ]
[ 862508-03-0 ]

Yield	Reaction Conditions	Operation in experiment
96.0%	With pyridine; tetrabutylammomium bromide; In dichloromethane; at 20℃; for 1.5h;	To a 500 ml three-necked flask, 30 g of 5-fluorocytosine, 23 g of pyridine, and 300 ml of dichloromethane were added.5 g of tetrabutylammonium bromide was stirred at room temperature, and then 39 g of n-amyl chloroformate was slowly added dropwise.After completion of the dropwise addition, the reaction was stirred at room temperature for 1.5 hours to obtain a viscous mixture.20 g of diatomaceous earth was added to a Buchner funnel, and the above viscous mixture was poured and suction-filtered to obtain a clear filtrate.The filtrate was washed with 150 ml of purified water, allowed to stand for separation, and the organic phase was collected, and the mixture was concentrated to dryness under reduced pressure at 50 C.200 ml of n-hexane was added to the residue, and the mixture was uniformly stirred and filtered to obtain a solid wet product. The mixture was dried at a temperature of 50 C to obtain 54.1 g of a white solid. The yield was 96.0%, and the purity was 99.21% (HPLC normalization method, chromatographic conditions: The column was an Inertsil ODS-2 column (4.6 mm × 250 mm 5 mum), and the mobile phase was methanol-0.1% acetic acid solution (45:55), the detection wavelength was 240 nm, and the flow rate was 1 ml/min.
94.3%	With pyridine; In dichloromethane; at -10 - 20℃; for 2h;Inert atmosphere;	The dichloromethane 80 ml is added to 1L is provided with a thermometer and constant pressure dropping funnel in the reaction bottle of the three-port, actuating magnetic stirring, added to the reaction bottle 5-fluoro cytosine 3.04g, then adding pyridine 7.1 g. Under the protection of nitrogen, added to the constant voltage dropping funnel the <strong>[638-41-5]chloroformic acid amyl ester</strong> 11.7g, then adding dichloromethane 10 ml. The reaction cooling to -10 C, and begin to drop Chlorization formic acid of amyl estermethylene chloride fluid, control is dripped under at -10 C-- 5 C, the gaseous mixture is removed after being added, the reaction to stir at room temperature 2 hours. After the reaction is ended, the hydrochloric acid 30ml0.2N, stirring 15 minutes, collecting the lower methylene chloride, dichloromethane phase reuse 0.2N hydrochloric acid washing three times (20 ml × 3). Methylene chloride is the final washing with water (50 ml × 1). Dichloromethane phase is dried with anhydrous sodium sulfate, filtered, the filtrate is 35 C decompression concentrated dry, product 12.1g, yield 94.3%.
300 g	With tetra(n-butyl)ammonium hydrogensulfate; triethylamine; In chloroform; water; at 5 - 10℃; for 1h;	(1) 100 g of 5-fluorocytosine, 800g chloroform, 117.6g triethylamine,Tetrabutylammonium hydrogen sulfate 2.1g, 200g water mixed,175 g of n-amyl chloroformate was added dropwise at 5 C to 10 C.After the addition, after 1.0 hours of heat preservation reaction,Wash with 300g of water, Layered, dry,A solution of pentyl (5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate in chloroform 1 was obtained.

Reference： [1]Patent: CN109336827,2019,A .Location in patent: Paragraph 0007; 0024-0030
[2]Patent: CN105566419,2016,A .Location in patent: Paragraph 0041; 0046; 0047
[3]Organic Letters,2012,vol. 14,p. 3348 - 3351
[4]Patent: CN104926901,2018,B .Location in patent: Paragraph 0033-0034; 0036-0037; 0039-0040

14
[ 2022-85-7 ]
[ 14660-52-7 ]
[ 1379471-11-0 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;	Ethyl ester of 4-N-carboxybutyl-5-fluorocytosine (I) 5-Fluorocytosine (1.29 g, 10 mmol) and K2CO3 (5.5 g, 48 mmol) were suspended in DMF (100 ml) at room temperature then ethyl-5-bromovalerate (6ml, 12 mmol) was added to the suspension. The mixture was stirred for 1 h. The precipitate was filtered off and the filtrate was concentrated in vacuo to dryness. The oily residue was solidified with ethyl acetate/diethyl ether and filtered off. 2.4 g (93.3%) white powder was obtained, Rf=0.79 (CH2Cl2/MeOH, 8:2), m.p.: 132-134°C.

Reference： [1]Somlai, Csaba; Correche, Estela; Olivella, Monica; Tolosa, Laia; Lechon, Maria José Gomez; Dombi, György; Tóth, Gábor K.; Penke, Botond; Enriz, Ricardo D. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4233 - 4237]

15
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[ 147027-09-6 ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		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 25-30C under Nitrogen atmosphere. The reaction mixture was heated up to 120- 130C to get clear solution and excess solvent was distilled out under vacuum at 90- 100C 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 25-30C 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 10-20C and precooled ( 10-20C) 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 40-45C. Yield: 48.5 g (80 %). Chiral Purity: 99.94 %; 0.06 % undesired isomer. ? NMR (DMSO-d6) delta (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 = 0.2%, MeOH).

Reference： [1]Organic Letters,2015,vol. 17,p. 2626 - 2629
[2]Patent: WO2013/21290,2013,A1 .Location in patent: Page/Page column 24; 25

16
[ 2022-85-7 ]
[ 98-68-0 ]
[ 1263302-66-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 4-amino-5-fluoro-pyrimidin-2-ol With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 70℃; for 1h; Stage #2: 4-methoxy-phenyl-sulphonyl chloride In acetonitrile at 20℃; for 24h;	1.1 4-Amino-5-fluoro-l-(4-methoxyphenylsulfonyl)pyrimidin-2(lH)-one To 4-amino-5- fluoro-pyrimidin-2-ol* (1.0 grams (g), 7.75 millimoles (mmol)) in acetonitrile (CH3CN; 50 milliliters (mL)) was added bis-N,O-trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated at 70 °C for 1 hour (h) resulting in a clear solution. After cooling to room temperature, 4-methoxybenzene-l-sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (EtOAc) and brine. The organic phase was dried over magnesium sulfate (MgSC^), filtered, and evaporated to yield the product as a pale yellow solid (1.48 g, 64%): mp 182 - 5 °C; 1H NMR (300 MHz, CDC13) δ 8.40 (br s, 1H), 8.11 (d, J = 5.9 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.02 - 6.96 (m, 2H), 5.77 (br s, 1H), 3.88 (s, 3H); ESIMS m/z 300 ([M+H]+).
64%	Stage #1: 4-amino-5-fluoro-pyrimidin-2-ol With N,O-Bis(trimethylsilyl)acetamide In acetonitrile at 70℃; for 1h; Stage #2: 4-methoxy-phenyl-sulphonyl chloride In acetonitrile for 24h;	1.1 Preparation of 4-Amino-5-fluoro-1-(4-methoxyphenylsulfonyl)pyrimidin-2(1H)-one (I-1) To commercially available 4-amino-5-fluoro-pyrimidin-2-ol (1.0 grams (g), 7.75 millimoles (mmol)) in acetonitrile (CH3CN; 50 milliliters (mL)) was added bis-N,Otrimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated at 70 °C for 1 hour (h), resulting in a clear solution. After cooling to room temperature, 4-methoxybenzene-1-sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (EtOAc) and brine. The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield the product as a pale yellow solid (1.48 g, 64%): mp 182-185 °C; 1H NMR (300 MHz, CDCl3) δ 8.40 (br s, 1H), 8.11 (d, J= 5.9 Hz, 1H), 8.04 -7.98 (m, 2H),7.02 - 6.96 (m, 2H), 5.77 (br s, 1H), 3.88 (s, 3H); ESIMS m/z 300 ([M+H]+)
64%	Stage #1: 4-amino-5-fluoro-pyrimidin-2-ol With N,O-Bis(trimethylsilyl)acetamide In acetonitrile at 70℃; for 1h; Stage #2: 4-methoxy-phenyl-sulphonyl chloride In acetonitrile at 20℃; for 24h;	1.1 Preparation of 4-Amino-5-fluoro-1-(4-methoxyphenylsulfonyl)pyrimidin-2(1H)-one (I-1) To commercially available 4-amino-5-fluoro-pyrimidin-2-ol (1.0 grams (g),7.75 millimoles (mmol)) in acetonitrile (CH3CN; 50 milliliters (mL)) was added bis-N, 0- trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated at 70 °C for 1 hour (h), resulting in a clear solution. After cooling to room temperature, 4-methoxybenzene- 1-sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. Thesolvent was evaporated and the residue was partitioned between ethyl acetate (EtOAc) and brine. The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield the product as a pale yellow solid (1.48 g, 64%): mp 182-1 85 °C; ‘H NMR (300 MHz, CDC13) ö 8.40 (br s, 1H), 8.11 (d, J= 5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.02 - 6.96 (m, 2H), 5.77 (br s, 1H), 3.88 (s, 3H); ESIMS m/z 300 ([M+H]+).

64%

Stage #1: 4-amino-5-fluoro-pyrimidin-2-ol With N,O-Bis(trimethylsilyl)acetamide In acetonitrile at 70℃; for 1h; Stage #2: 4-methoxy-phenyl-sulphonyl chloride In acetonitrile at 20℃; for 24h;

1.1 [0070] Step 1: Preparation of 4-Amino-5-fluoro-1-(4-methoxyphenylsulfonyl)pyrimidin-2(1H)-one (I-i) [0071] To commercially available 4-amino-5-fluoro-pyrimidin-2-ol (1.0 grams (g),7.75 millimoles (mmol)) in acetonitrile (CH3CN; 50 milliliters (mL)) was added bis-N, 0-trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated at 70 °C for 1hour (h), resulting in a clear solution. After cooling to room temperature, 4-methoxybenzene-1-sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (EtOAc) and brine. The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield the product as a pale yellow solid (1.48 g, 64%): mp 182-1 85 °C; 1H NMR (300 MHz, CDCl3) öδ 8.40 (br s, 1H), 8.11 (d, J= 5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.02 - 6.96 (m, 2H), 5.77 (br s, 1H), 3.88 (s, 3H); ESIMS m/z 300 ([M+H]).

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - WO2013/25795, 2013, A1 Location in patent: Paragraph 0059
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - WO2014/105821, 2014, A1 Location in patent: Paragraph 0069; 0070; 0071
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - WO2014/105844, 2014, A1 Location in patent: Paragraph 0068; 0069; 0070
[4]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - WO2014/105841, 2014, A1 Location in patent: Paragraph 0069; 0070; 0071

17
[ 2022-85-7 ]
[ 98-88-4 ]
[ 10357-07-0 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 2626 - 2629

18
[ 71-30-7 ]
[ 2022-85-7 ]

Yield	Reaction Conditions	Operation in experiment
95.7%		(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 15% 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: 95.7% yield, 97.7% pure.
87.4%	With 1,1,1,3',3',3'-hexafluoro-propanol; fluorine; at 20℃; under 1125.11 Torr;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 5mol% 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 7%) 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 mol% 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 98.6% and the product yield was 86.7%. 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 3% and the feed rate is 80 g / min. The raw material 1 is 20 mol% 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 99.3% and the product yield was 87.4%.
63%	With formic acid; for 1.5h;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 % 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 % 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 %, [M+H-F]+), 129 (8 %, [M]+), 130 (100 %, [M+H]+).

With formic acid; fluorine; at 9℃; for 0.0833333h;Inert atmosphere;

As shown in Fig. 1, using G1 SiC Reactor reaction equipment from Dow Corning,Use the metering pump<strong>[71-30-7]Cytosine</strong>Formic acid solution (10 wt%) and fluorine gas (mixed in nitrogen with a volume concentration of 10 vol%) were simultaneously pumped into a mixer of a microchannel reactor having a tubular structure of a DC type channel and having a T-shaped structure Mixed channel, controlling the flow rate of cytosolic solution (10wt% formic acid solution) 580g / h, fluorine gas (mixed in nitrogen, volume concentration 10vol%) flow 200g / h, controlled microchannel thermostatic reactor at 9 reaction , The reaction solution residence time of 300s. A product solution containing 5-fluorocytosine product was obtained. 500ml of n-butanol was added to precipitate a white product and the product was filtered and dried to obtain 5-fluorocytosine. The product was detected by liquid chromatography (HPLC). The results showed that the purity of 5-fluorocytosine was 99.7%The selectivity for 5-fluorocytosine was 95.2%.

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

19
[ 1993-63-1 ]
[ 2022-85-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; In methanol; water; at 40 - 60℃;	The 24.0g formula II compound are added 102g30wt % hydrogen chloride in methanol solution, heating to 40-60C, 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 % 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 95.0%, HPLC purity of 99.6%.

Reference： [1]Patent: CN105272922,2016,A .Location in patent: Paragraph 0041; 0042; 0043
[2]European Journal of Organic Chemistry,2019,vol. 2019,p. 5519 - 5526

20
[ 41864-22-6 ]
[ 2022-85-7 ]
[ 71-41-0 ]
[ 27821-07-4 ]
[ 154361-50-9 ]

Yield	Reaction Conditions	Operation in experiment
73.5%		Take 0.2m0l 5-fluorocytosine and 68g potassium carbonate, stirring to 300mL dichloromethane, stirring slowlyDropping O.Smol trimethylchlorosilane, heating reflux lh TLC detection reaction is complete, vacuum concentration, in a concentrate A, directly withIn the next step reaction,0.18 mol BF3 · OEt2 was dissolved in 300 mL dichloromethane and 0.2 mol was added with stirring1,2,3-triacetoxy-5-deoxy-D-ribose and concentrate A were stirred at 25 C under nitrogen,Should be 7h. TLC detection reaction is complete, concentrated under reduced pressure, obtained concentrate B, used directly in the next step should.The concentrate B was dissolved in 300 mL of methylene chloride, and 0.24 mL of N, N'-carbonyldi (1,2,4-triazoOxazole) and stir at 25 C. After completion of the reaction with TLC, the reaction solution C was obtained and used in the next stet. 0 .24 ml of n-pentanol was added to the reaction solution C and stirred at 25 C. The reaction was complete by TLC and concentrated under reduced pressure.The concentrate D was obtained and used directly in the next reaction.Concentrate D was dissolved in 200 mL of methanol and a 6.5 mol / L aqueous solution of sodium hydroxide was slowly added dropwise at 0 C with stirring,After the reaction was continued, the pH was adjusted to 6 with concentrated hydrochloric acid, the methanol was removed under reduced pressure, and the mixture was extracted with methyl tert-butyl etherThe organic layer was extracted twice with methyl tert-butyl ether, and the organic layers were combined, washed with saturated brine, washed with water, and dried over anhydrous sulfuric acidSodium dried, filtered, dropping n-heptane, precipitation products, filtration, vacuum drying at 40 C for 6 hours, that was capecitabine pure product (yield73.5 %.

Reference： [1]Patent: CN105646625,2016,A .Location in patent: Paragraph 0036; 0038; 0040; 0042; 0044

21
[ 945548-37-8 ]
[ 2022-85-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: N-acetyl-5-bromocytosine With acetamide; potassium fluoride In N,N-dimethyl-formamide at 130℃; for 5h; Inert atmosphere; Stage #2: With ammonia In methanol at 40℃; for 12h;	3; 9 Example-9 : Preparation of 5-fluorocytosine 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, 93%), the content of the HPLC 99.5%. 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]Current Patent Assignee: ZHEJIANG XIANFENG TECHNOLOGY CO LTD - CN103819412, 2016, B Location in patent: Paragraph 0028-0030;0041; 0042

22
[ 1612233-95-0 ]
[ 2022-85-7 ]

Yield	Reaction Conditions	Operation in experiment
91.1%	Stage #1: N-9-fluorenylmethoxycarbonyl-5-bromocytosine With potassium fluoride; tetrabutyl ammonium fluoride In N,N-dimethyl-formamide at 110℃; for 10h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,4-dioxane at 50℃; for 2h; Inert atmosphere;	6 Embodiment 6:preparation of 5-fluorocytosine The N-fluorenylmethyloxycarbonyl-5-bromine butcher pyrimidine (123.7g, 0 . 3mol) in the reaction bottle into the drying of, under the protection of nitrogen adding anhydrous potassium fluoride (23.2g, 0 . 4mol), tetrabutyl ammonium fluoride (7.8g, 0 . 03mol), DMF150mL, heating to 110 °C reaction 10h, distilling solvent by reduced pressure, cooling to room temperature, by adding 240 ml dioxane and 4mol/L sodium hydroxide solution of 80 ml, the temperature is increased to 50 °C reaction 2h, cooling to room temperature, add 1mol/L dilute hydrochloric acid adjusting pH is neutral, to continue cooling to 10 °C, filtering, with 320 ml water recrystallization to obtain white crystalline solid 5-fluoro cytosine (35.3g, 91.1%), HPLC content 99.2%.

Reference： [1]Current Patent Assignee: ZHEJIANG XIANFENG TECHNOLOGY CO LTD - CN103819412, 2016, B Location in patent: Paragraph 0036

23
[ 2022-85-7 ]
[ 98-59-9 ]
[ 1263302-64-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: Flucytosine With N,O-Bis(trimethylsilyl)acetamide In acetonitrile at 20 - 70℃; for 0.75h; Stage #2: p-toluenesulfonyl chloride In acetonitrile at 5℃; for 1h;	A Step A: Preparation of 5-fluoro-4-imino-1-[(4-methylphenyl)sulfonyl]-3,4-dihydropyrimidin-2(1H)-one (also named 5- fluoro-4-imino-1 -(p-tolylsulfonyl)pyrimidin-2-one) 1 .76 g (8.63 mmol) of N,O-Bis(trimethylsilyl)acetamide is added at room temperature to a stirred suspension of 1.01 g (7.85 mmol) of 5-fluorcytosine in 5 mL of acetonitrile and heated at 70 0 for 45 minutes. The clear yellow solution is cooled to 5 , 1 .65 g (8.63 mmo I) of 4-toluenesulfonyl chloride is added and the mixture iskept at 5 0 for 1 hour. The suspension is warmed t o room temperature overnight, poured into 75 mL of cold water and stirred for 1 hour. The white precipitate is collected, washed with plenty of water and dried by suction in air to yield 1 .74 g (73 % yield) of 5-fluoro-4-imino-1 -(p-tolylsulfonyl)pyrimidin-2-one as a fine white powder.logP 1.451H NMR (400 MHz, DMSO-d6): ö ppm 2.41 (s, 3H), 7.45 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 8.24 (bs,1 H), 8.28 (d, J=6.6 Hz, 1 H), 8.51 (bs, 1 H).
	With potassium carbonate In N,N-dimethyl acetamide; water at 0 - 5℃;	1-13 Example 1; reacting 5-fluorocytosine with compound having the formula (III) in DMA and water and K₂CO₃ as base. 5-fluorocytosine (99%, 80.1 gr) was added to 1L glass reactor that contains 200 gr of water and 200 gr of DMA. K2 O3 (solid, 114.9 gr, 1.35 mol equiv.) was added and the reactor was cooled to 0°C. Tosyl chloride (128 gr, 1.05 mol.equiv.) was added in one portion at 0°C and the solution was mixed at temperature of 0°C to 5°C. The reaction was monitored using HPLC and then 200 gr of water were added and the temperature was heated to 25°C and mixed for 2 hours. The obtained solid was filtered off using Buchner funnel. The cake was washed with water and dried in vacuum oven at 55 to 65°C. 178 gr Of desired product were obtained in purity of 90.9% and yield Of 93%. (0266) The product contains impurity A (2.4%) and impurity B (0.2%).
	With potassium carbonate In N,N-dimethyl acetamide; water at 0 - 5℃;	1 Example 1: reacting 5-fluorocytosine with compound having the formula (III) in DMA and water and K2CO3 as base. 5-fluorocytosine (99%, 80.1 gr) was added to IL glass reactor that contains 200 gr of water and 200 gr of DMA. K2CO3 (solid, 114.9 gr, 1.35 mol equiv. ) was added and the reactor was cooled to 0°C. Tosyl chloride (128 gr, 1.05 mol equiv.) was added in one portion at 0°C and the solution was mixed at temperature of 0°C to 5°C. The reaction was monitored using HPLC and then 200 gr of water were added and the temperature was heated to 25°C and mixed for 2 hours. The obtained solid was filtered off using Buchner funnel. The cake was washed with water and dried in vacuum oven at 55 to 65°C. 178 gr of desired product were obtained in purity of 90.9% and yield of 93% .The product contains impurity A (2.4%) and impurity B (0.2%) .

Reference： [1]Current Patent Assignee: BAYER AG - WO2017/72166, 2017, A1 Location in patent: Page/Page column 25
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - WO2021/181274, 2021, A1 Location in patent: Page/Page column 50-55
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - WO2023/42126, 2023, A1 Location in patent: Page/Page column 79-80

24
[ 2022-85-7 ]
5R-hydroxy-[1,3]oxathiolane-2R-carboxylic acid 2-(1'R,2'S,5'R)-isopropyl-5-methyl-cyclohexyl ester [ No CAS ]
[ 764659-72-5 ]

Yield	Reaction Conditions	Operation in experiment
50.5%		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 50.5% HPLC purity 98.17%.
50.5%		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 50.5%HPLC purity 98.17%.

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

25
[ 2022-85-7 ]
[ 1093856-79-1 ]
[ 2116468-24-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	4-amino-1-(4-ethynylbenzyl)pyrimidin-2(1H)-one (12a) General procedure: In a round-bottom flask, nucleoside bases (1a)(1 eq), compound 11 (1.2 eq), and anhydrous cesium carbonate (1.5 eq) was dissolved in anhydrous DMF and the mixture was stirred at room temperature for overnight; After the reaction was completed, extracted with DCM; the crude product was obtained, which was further purified by column chromatography to obtain pure product 12a (white solid; yield 79%)

Reference： [1]Sun, Qinsheng; Dai, Qiuzi; Zhang, Cunlong; Chen, Yan; Zhao, Lei; Yuan, Zigao; Jiang, Yuyang [Chinese Chemical Letters, 2021, vol. 32, # 8, p. 2479 - 2483]

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
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P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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

[ 2022-85-7 ] Synthesis Path-Downstream 1~25

Pharmaceutical Intermediates of [ 2022-85-7 ]

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