Name: 259793-96-9|6-Fluoro-3-oxo-3,4-dihydropyrazine-2-carboxamide|97%
Brand: Ambeed
SKU: A827022
Price: 5.0 USD
Availability: InStock
Rating: 96 (30 reviews)

1
[ 10416-59-8 ]
[ 259793-96-9 ]
6-fluoro-3-((trimethylsilyl)oxy)pyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 0 - 20℃; for 1.5h;	5.3 g of <strong>[259793-96-9]6-fluoro-3-hydroxy-2-pyrazinecarboxamide</strong> was suspended in 53 mL of acetonitrile under nitrogen current, and 8.4 mL of N,O-bis(trimethylsilyl) acetamide was added thereto under ice cooling, followed by stirring at room temperature for 1.5 hours. 53 mL of an acetonitrile solution containing 9.4 g of (2R, 3R, 4R)-4,5-bis(acetyloxy)-2-(hydroxymethyl)tetrahydro-3-furanyl acetate that had been separately prepared by the method described in Carbohydrate Research (Carbohydr. Res.), Vol. 203, No. 9, pp. 324 to 329 (1990), and 7.2 mL of tin(IV) chloride were successively added to the reaction mixture under ice cooling, and the thus obtained mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into a mixed solution of 100 mL of ethyl acetate and 300 mL of a saturated sodium bicarbonate aqueous solution. The organic layers were separated, and the aqueous layer was then extracted with 700 mL of ethyl acetate. Such organic layers were combined, and the organic layers were then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The obtained residue was dissolved in 200 mL of methanol, and 100 mL of an 80% acetic acid aqueous solution was added thereto, followed by stirring at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluant; chloroform: methanol = 40 : 1]. Thereafter, chloroform and diisopropyl ether were added thereto, and the mixture was collected by filtration, so as to obtain 9.3 g of a light yellow solid, (2R, 3R, 4R, 5R)-4-(acetyloxy)-2-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-5-(hydroxymethyl)tetrahydro-3-furanyl acetate. IR(KBr)cm-1: 1752,16861H-NMR(DMSO-d6)delta: 2.04(3H,s), 2.10(3H,s), 3.64(1H,ddd,J=2.5,5.0,13Hz), 3.86(1H,ddd,J=2.5,5.0,13Hz), 4.29(1H,d,J=6.0Hz), 5.35(1H,t,J=6.0Hz), 5.49(1H,dd,J=3.0,5.0Hz), 5.65(1H,t,J=5.0Hz), 6.11(1H,d,J=3.0Hz), 7.96(1H,brs), 8.42(1H,d,J=5.0Hz), 8.49(1H,brs)

Reference： [1]Patent: EP1417967,2004,A1 .Location in patent: Page/Page column 53

Yield	Reaction Conditions	Operation in experiment
		PRODUCTION EXAMPLE 2 In a mixture of 3.44 ml of water and 0.5 mL of dioxane was suspended 0.17 g of3,6-difluoro-2-pyrazinecarboxamide. After adding 0.45 g of sodium hydrogen carbonate, the mixture thus obtained was stirred at 50 C. for 8.5 hours. Then, 0.95 mL of 6 mol/L hydrochloric acid was added to the reaction mixture, pH was adjusted to 1.0, and the deposited solid product was collected by filtration to obtain 89 mg of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a solid product.

3
[ 55321-99-8 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With fluorine; In water;	EXAMPLE II-12 In 200 mL of water was suspended 1.0 g of <strong>[55321-99-8]3-hydroxy-2-pyrazinecarboxamide</strong>. At room temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced at a rate of 45 mL per minute for a period of 25 minutes. Then, nitrogen gas was introduced for 45 minutes, and the liquid reaction mixture was neutralized with calcium carbonate, the deposited precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the solid product thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 0.008 g of 6-fluoro-<strong>[55321-99-8]3-hydroxy-2-pyrazinecarboxamide</strong> as a white-colored solid product.

Reference： [1]Patent: US2003/130213,2003,A1
[2]Patent: US2011/275817,2011,A1
[3]Patent: CN107641106,2018,A

4
6-fluoro-3-methoxy-2-pyrazinecarboxamide [ No CAS ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; sodium chloride; sodium thiosulfate; In chloroform; water; acetonitrile;	REFERENTIAL EXAMPLE I-5 In an atmosphere of nitrogen gas, 1.51 g of sodium iodide was dissolved in 22 mL of acetonitrile. After adding 1.10 g of trimethylsilyl chloride, the mixture thus obtained was stirred at room temperature for 20 minutes. Then, 0.43 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was added, and the mixture thus obtained was stirred at the same temperature as above for 18 hours. The reaction mixture was added to a mixture of 10 mL of water and 200 mL of chloroform, and the mixture thus formed was separated into layers. The organic layer was washed successively with 5% aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: hexane:ethyl acetate=2:1] to obtain 0.06 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white-colored solid product. IR (KBr) cm-1: 1685, 1658 1H-NMR (CDCl3) delta: 5.40-7.80(2H,m), 8.31 (1H,d,J=7.8 Hz), 12.33(1H,s)
	With chloro-trimethyl-silane; sodium iodide; sodium chloride; sodium thiosulfate; In chloroform; water; acetonitrile;	EXAMPLE 8 In a nitrogen atmosphere, 1.51 g of sodium iodide is dissolved in 22 mL of acetonitrile. Then, 1.10 g of trimethylsilyl chloride is added thereto. The resulting solution is stirred at ambient temperature for 20 minutes. Then, 0.43 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide is added thereto. The resulting solution is stirred at the same temperature as above for 18 hours. Then, a mixture of 10 mL of water and 200 mL of chloroform is added to the reaction mixture, and separated into layers. The organic layer thus obtained is washed successively with 5% aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent:hexane:ethyl acetate=2:1) to obtain 0.06 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide. IR(KBr) cm-1: 1685, 1670, 1656 NMR(CDCl3): 5.40-7.80(2H,m), 8.31(1H,d,J=7.82 Hz), 12.33(1H,s)

Reference： [1]Patent: US2003/130213,2003,A1
[2]Patent: US2002/13316,2002,A1

5
[ 356783-27-2 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; sodium chloride; ammonia; In methanol; water; ethyl acetate;	PRODUCTION EXAMPLE 1 In 3.0 mL of methanol was dissolved 0.12 g of methyl 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, gaseous ammonia was introduced into the solution at an ice-cooled temperature for a period of 10 minutes, after which the mixture thus obtained was allowed to stand at room temperature for 2 days. The solvent was removed under reduced pressure, the residue thus obtained was added to a mixture of 30 mL of ethyl acetate and 30 ml of water, pH was adjusted to 7.5 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. After adding 30 mL of ethyl acetate to the remaining aqueous layer, pH was adjusted to 1.0 with 1 mol/L hydrochloric acid, and the whole mixture was extracted with two 15 mL portions of ethyl acetate. The organic layers thus obtained were united, washed successively with 15 mL of water and 15 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The solid product thus obtained was washed with diisopropyl ether to obtain 0.015 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a yellow-colored solid product. IR (KBr) cm-1: 1685, 1671, 1655 1H-NMR (DMSO-d6) delta: 8.46(1H,brs), 8.50(1H,d,J=7.8 Hz), 8.70(1H,brs), 13.39(1H,s)

Reference： [1]Patent: US2003/130213,2003,A1

6
[ 356783-31-8 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sulfuric acid; dihydrogen peroxide; In water;	PRODUCTION EXAMPLE 4 At a water-cooled temperature, 2.2 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was dissolved in an aqueous solution of sodium hydroxide prepared from 1.27 g of sodium hydroxide and 24.2 ml of water. After adding 2.75 ml of 30% hydrogen peroxide at the same temperature as above, the mixture thus formed was stirred at 40 C. for 1.5 hours. After dropwise adding 2.77 mL of concentrated sulfuric acid to the reaction mixture obtained above while cooling it with ice, the mixture thus formed was cooled to 10 C. The deposited crystalline product was collected by filtration and washed with 2 mL of cold water to obtain 2.2 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a light yellow-colored solid product.

Reference： [1]Patent: US2003/130213,2003,A1

7
[ 356783-42-1 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; sodium chloride; sulfuric acid; sodium nitrite; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; di-isopropyl ether; water; ethyl acetate;	PRODUCTION EXAMPLE 3 While keeping 285 ml of 97% sulfuric acid at 5-12 C. by cooling it with ice, 28.5 g of 3-amino-6-fluoro-2-pyrazinecarboxamide was added thereto to form a uniform solution. After adding 18.9 g of sodium nitrite to the solution at 5-12 C., the mixture thus obtained was stirred for 1.5 hours while cooling it with ice. While keeping the reaction mixture at a temperature not exceeding 10 C., the reaction mixture was dropwise added to 1.4 L of ice water, and the mixture thus formed was extracted first with one 850 mL portion and then two 200 mL portions of ethyl acetate. The organic layers thus obtained were united, 400 mL of water was added, then 160 mL of saturated aqueous solution of sodium hydrogen carbonate was added, pH was adjusted to 3.0, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was washed with a mixture of diisopropyl ether and ethyl acetate to obtain 22.4 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a solid product.

Reference： [1]Patent: US2003/130213,2003,A1

8
[ 1137606-74-6 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
84%		10.0 mL of toluene and a sodium hydroxide aqueous solution (prepared by dissolving 0.656 g of sodium hydroxide in 20.0 mL of water) were added to 5.00 g (15.6 mmol) of dicyclohexylamine salt of T-705A, and the obtained mixture was then stirred at room temperature for 30 minutes. The reaction solution was left at rest for 10 minutes, and an upper layer was then removed. 10.0 mL of toluene was added to a lower layer, and it was then stirred and left at rest for 10 minutes. Thereafter, an upper layer was removed. A sodium hydroxide aqueous solution (prepared by dissolving 0.593 g of sodium hydroxide in 5.00 mL of water) was added to a lower layer. Subsequently, while keeping the internal temperature at 15 to 20 C., 2.68 mL (31.5 mmol) of 40.0% v/w hydrogen peroxide was added dropwise to the mixture. The obtained mixture was stirred at 25 C. for 30 minutes, and the pH of the solution was adjusted to pH 6.5 to 8.0 by hydrochloric acid. Thereafter, the mixture was heated to 40 C., so that the solid was completely dissolved in the solution. Thereafter, 0.250 g of activated carbon (SHIRASAGI A) was added to the reaction solution, and the obtained mixture was then stirred at 40 C. for 30 minutes, followed by filtration. A solid on a Nutsche was washed with 5.00 mL of water, and hydrochloric acid was then added to a mixed solution of a filtrate and a washing solution at an internal temperature of 35 to 45 C., so that the pH thereof was adjusted to pH 3 to 4. The mixed solution was cooled to 0 to 5 C., and it was then stirred for 1 hour. Thereafter, the precipitated solid was filtrated, and it was then washed with 5.00 mL of water and 5.00 mL of isopropyl alcohol, so as to obtain 2.06 g of a white solid (T-705). Yield: 84.0%
		300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25C and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30C and one-hour stirring at 20 to 30C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50C, and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10C the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid. 1H-NMR (DMSO-d6) delta values: 8.50 (1H, s), 8.51 (1H, d, J=7.8 Hz), 8.75 (1H, s), 13.41 (1H, s)

Reference： [1]Patent: US2013/245264,2013,A1 .Location in patent: Paragraph 0213
[2]Patent: EP2192117,2010,A1 .Location in patent: Page/Page column 6

9
[ 356783-31-8 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
92.3%		14.39 g of concentrated sulfuric acid was added to 3.45 g of the oily 6-fluoro-3-hydroxypyrazine-2-carbonitrile, and the resulting mixture was stirred at 50 C. for 4 hours. The reaction mixture was then added dropwise over a period of 20 minutes to 44.5 ml of water that had been cooled to 3 C. Following completion of the dropwise addition, the resulting mixture was stirred for 20 minutes at a temperature of not more than 10 C. Subsequently, 10.17 g of a 28% aqueous solution of sodium hydroxide was added dropwise to the reaction mixture over a period of 15 minutes. Following completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes. The solid product was then filtered off, and washed with 18 ml of water, yielding 2.22 g (yield: 92.3%) of 6-fluoro-3-hydroxypyrazine-2-carboxamide.
68.43%	With sulfuric acid; at 50℃; for 4h;	Combine the 3.26 g of the yellow oil (5) obtained in the previous step with 5 mL of concentrated sulfuric acid and control the temperature at 50C for 4 hours.Slowly added dropwise to 20 mL of ice water, followed by stirring for 1 h and extraction with ethyl acetate (20 mL*3) 3 times.The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure.The residue was purified by column chromatography to give a pale yellow solid6-fluoro-3-hydroxy-2-carboxamide (6) 2.69 g, yield 68.43%.

Reference： [1]Patent: US2011/275817,2011,A1 .Location in patent: Page/Page column 5-6
[2]Patent: CN106478528,2017,A .Location in patent: Paragraph 0048

10
6-bromo-3-hydroxypyrazine-2-carboxamide [ No CAS ]
[ 259793-96-9 ]

Reference： [1]Patent: US2011/275817,2011,A1
[2]Patent: CN106866553,2017,A
[3]Chemical Papers,2017,vol. 71,p. 2153 - 2158

11
[ 356783-16-9 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2011/275817,2011,A1
[2]Patent: CN107226794,2017,A
[3]Patent: CN106866553,2017,A
[4]Chemical Papers,2017,vol. 71,p. 2153 - 2158
[5]Patent: CN106478528,2017,A
[6]Chemical Papers,2019,vol. 73,p. 1043 - 1051

12
[ 356783-28-3 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
89.6%		39.9 g of 3,6-difluoro-2-cyanopyrazine and 72 g of anhydrous sodium acetate were mixed in 0.35 liters of water and 0.35 liters of tetrahydrofuran.Heat to reflux for 20 hours.After the reaction is complete,Concentrate the reaction solution,The pH of the system was then adjusted to 2.0 to 2.5 with 20% dilute sulfuric acid.Then it was extracted with 0.2 l of ethyl acetate.The resulting organic phase was concentrated under reduced pressure to give an oil.Add 0.2 liters of acetone and 50 grams of dicyclohexylamine,The resulting suspension was stirred at 0C-5C for 2 hours.Filtered6-fluoro-3-hydroxy-2-cyanopyrazineDicyclohexylamine saltWet products.It was then dried under vacuum at 50 degrees for 3 hours to give 62.4 g of light brown solids.Yield 70.3%,The purity by HPLC was 99.2%.44.5 g of 6-fluoro-3-hydroxy-2-cyanopyrazine dicyclohexylamine salt and 0.17 liters of 6.5% aqueous sodium hydroxide solutionMix and wash with 0.1 liters of toluene. Collect the aqueous phase after liquid separation and cool the water phase to 0C-5C, then add 28g30% hydrogen peroxide was stirred at 10C to 20C for 4 hours. After the reaction is completed, adjust the pH of the system with 20% dilute sulfuric acidIt is 2.0 to 2.5. A lot of solids precipitated. Filtered6-fluoro-3-hydroxy-2-pyrazineamide wet product,Vacuum drying at 50C 4Hours, 19.3 g of white solid was obtained. The yield was 89.6% and the purity by HPLC was 99.9%.

Reference： [1]Patent: CN107641106,2018,A .Location in patent: Paragraph 0071; 0072; 0074
[2]Patent: US2011/275817,2011,A1
[3]Chemical Papers,2019,vol. 73,p. 1043 - 1051

13
[ 259793-96-9 ]
[ 1366418-99-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water;pH 7.0;	Example 9 To a suspension of Compound A (75.0 g) in Water for Injection (420 mL) was added 1 mol/L aqueous sodium hydroxide solution, and the mixture was stirred to dissolve Compound A. Thereafter, 1 mol/L aqueous sodium hydroxide solution was further added to adjust the pH to 7.0. To the solution was added Water for Injection to give a total volume of 1000 mL. Thereafter, the mixture was filtered through a 0.22-mum membrane filter to obtain a liquid preparation (pH 7.0). Each vial was filled with the liquid preparation (8 mL), lyophilized, and then closed airtight to obtain a lyophilized preparation of a crystal. Water content: 0.08% The powder X-ray diffraction pattern of the lyophilized preparation was identical with that of example 5. Lyophilization method 1. Vials were cooled at a shelf temperature of -60C to freeze the content.2. The temperature of the vials was increased to a shelf temperature of -10C and the vials were maintained at the same temperature for 24 hours.3. The temperature of the vials was cooled to a shelf temperature of -55C and the vials were maintained at the same temperature for 2 hours.4. The temperature of the vials was increased to a shelf temperature of 40C under vacuum (50 Pa or below) and the vials were maintained at the same pressure and temperature for 70 hours.

Reference： [1]Patent: EP2623498,2013,A1 .Location in patent: Paragraph 0043

14
[ 6284-40-8 ]
[ 259793-96-9 ]
[ 1370365-08-4 ]

Yield	Reaction Conditions	Operation in experiment
	In water;	Example 7 To a suspension of Compound A (132 g) in Water for Injection (1900 mL) was added meglumine (166 g), and the mixture was stirred to dissolve Compound A. To the obtained solution was added Water for Injection to give a total volume of 2200 mL. Thereafter, the mixture was filtered through a 0.22-mum membrane filter to obtain a liquid preparation (pH 8.0). Each vial was filled with the liquid preparation (10 mL), lyophilized and then closed airtight to obtain a lyophilized preparation of a crystal. Water content: 0.01 % In the powder X-ray diffraction pattern of the lyophilized preparation, the same peaks as those of the crystal of Salt A anhydrate observed in Example 3 were observed. Lyophilization method 1. Vials were cooled at the shelf temperature of -60C to freeze the content. 2. The temperature of the vials was increased to the shelf temperature of -10C and the vials were maintained at the same temperature for 24 hours. 3. The temperature of the vials was cooled to the shelf temperature of -55C or below and the vials were maintained at the same temperature for 2 hours. 4. The temperature of the vials was increased to the shelf temperature of 40C under vacuum (50 Pa or below) and the vials were maintained at the same pressure and the same temperature for 48 hours.

Reference： [1]Patent: EP2623497,2013,A1 .Location in patent: Paragraph 0040

15
[ 1374986-08-9 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

16
[ 1374986-19-2 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

17
[ 1374986-28-3 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

18
[ 1374986-36-3 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

19
[ 1374986-38-5 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

20
C₁₁H₁₅N₂O₆^(1-)*K⁽¹⁺⁾ [ No CAS ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

21
[ 1374986-03-4 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

22
[ 1374986-04-5 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

23
[ 1374986-05-6 ]
[ 259793-96-9 ]

Reference： [1]Patent: US2013/245264,2013,A1

24
[ 929911-63-7 ]
[ 259793-96-9 ]
C₁₇H₁₆FN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		Sodium hydride (60%, 157.7 mg, 3.94 mmol, 1 eq.) Was suspended in dry DMF (10 mL)Then <strong>[259793-96-9]6-fluoro-3-hydroxypyrazine-2-carboxamide</strong> (650 mg, 4.14 mmol, 1.05 eq.)In DMF (2 mL)The mixture was stirred at room temperature for 1 h,Then 3 - ((methylsulfonyl) oxy) cyclobutyl) methylbenzoate (1.12 g, 3.94 mmol, 1 eq.) Was added.The reaction mixture was heated to 130 & lt; 0 & gt; CStirring 25h,Then diluted with 50 mL of water,And extracted with EtOAc (30 mL x 2)The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2)And then dried over anhydrous sodium sulfate,And then concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:PE / EtOAc (v / v) = 2.5 / 1) gave a white solidThe title compound (125 mg, 26%).

Reference： [1]Patent: CN104447583,2016,B .Location in patent: Paragraph 0204; 0205; 0206

25
[ 356783-29-4 ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium hydrogencarbonate; In 1,4-dioxane; water; at 60℃; for 8h;	10 (1.2 g, 7.5 mmol), sodium bicarbonate (3.8 g, 45.2 mmol) were added into a mixture of 1,4-dioxane (10 mL) and water (20 mL). The reaction mixture was heated at 60 Cfor 8 h. When the reaction was completed, hydrochloric acid (30 mL, 3 M) was added to adjust the pH to 3-4. The precipitate was collected, dried in vacuum to give a light yellow solid (0.83 g). The filtrate was extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (2 × 10 mL), dried over Na2SO4, and evaporated to give an other portion (0.14 g) of the product. The total yield was 82%. 6-Fluoro-3-hydroxypyrazine-2-carboxamide (favipiravir) Yield: 82%, light-yellow solid, M.p.: 176-178 C (175-177 C, Liu et al. 2017). 1H NMR (400 MHz,DMSO-d6): delta 13.40 (s, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.50(s, 1H). 1H NMR (400 MHz, CDCl3):delta 12.35 (br, 1H),8.31 (d, 1H, J = 8.0 Hz), 7.43 (br, 1H), 5.89 (br, 1H). 13CNMR (125 MHz, DMSO-d6): delta 169.20, 160.21, 152.87(d, J = 243.8 Hz), 136.58, 122.40. ESI-MS m/z: 156.1[M - H]-.
65%	With water; sodium hydrogencarbonate; at 50℃; for 8.5h;	Water (1 ml) and NaHCO3 (0.132 g, 1.57 mmol) were added, reacted at 50 C for 8.5 h, washed with 6N HCl,Adjusted to pH = 1.0, ethyl acetate (4 x 5 ml), and the organic layer was washed twice with saturated brine,Dried over anhydrous sodium sulfate, the organic solvent was distilled off,Recrystallization from 20 times ethanol (crude weight ratio of ethanol to 1: 5 to 30)The yield was 65% (calculated from the amount of reactants 6). mp: 175-177 C.
65%	With water; sodium hydrogencarbonate; at 50℃; for 8.5h;	KF (1 g, 6 eq) and TBAB (372.3 mg, 0.4 eq) were dissolved in a mixed solvent of toluene (10 ml) and dimethylsulfoxide (5 ml)After azeotropic removal of water,Compound 6 (500 mg, 1 eq) was added,55 conditions,Stir for 3 h.TLC shows the raw material reaction is complete,After falling to room temperature,30% H2O2 (0.35 ml) was added under ice bath,Reaction at 27 C for 2 h, add water (1 ml) andNaHCO3 (0.132 g, 1.57 mmol),50 reaction 8.5h,Ice bath with 6N HCl,Adjust pH = 1.0,Ethyl acetate (4 x 5 ml)The organic layer was washed twice with saturated brine,Dried over anhydrous sodium sulfate,The organic solvent was distilled off,Recrystallization from 20 times ethanol (crude weight ratio of ethanol to 1: 5 to 30)Obtained as white solid 7 (favipiravir),The yield was 65% (from the reactants6 is calculated).mp: 175-177 C.

0.25 g

With water; sodium hydrogencarbonate; In dimethyl sulfoxide; at 50℃; for 8h;

KF2H2O (1.3 g, 6 eq) and TBAB (tetrabutylammoniumbromide) (0.3 g, 0.4 eq) were added into the mixed solventcontaining 4 mL of DMSO and 8 mL of toluene. Thetoluene was subsequently removed by distillation underreduced pressure. A further 8 mL of toluene was thenadded and once again removed by distillation underreduced pressure with the purpose of removing the moisture of the reagent relating to the reaction. Then, 3,6-dichloropyrazine-2-carbonitrile (0.4 g, 1 eq) was addedand the mixture was stirred at 50 C for 3 h. Subsequently,anhydrous K2CO3 (0.04 g) and 30% H2O2(0.28 mL) were added into the solution at 0 C stirring for1.5 h at 25 C. Water (1 mL) and NaHCO3 (0.132 g)were added into the 3,6-difluoropyrazine-2-carboxamidewith magnetic stirring for 8 h at 50 C and TLC (MeOH:EA = 1:1, v/v, Rf = 0.72) was used to monitor thereaction. Then, 6 M HCl was added into the solution andthe pH of the solution was adjusted to 1.0. Then, thesolution was extracted with ethyl acetate (5 9 10 mL).The organic phase was washed with brine (3 9 10 mL),dried with anhydrous Na2SO4, and was filtered to removethe drying agent. The ethyl acetate was removed by distillationunder reduced pressure to obtain the crudecompound of 7. Then, the crude 7 was dissolved intoEtOH (6 mL, 95%). The suspension was heated to refluxfor 30 min and was filtered to crystallize. The filtrate wascooled to 25-30 C which was kept for 4 h. The crystal ofpure 6-fluoro-3-hyroxypyrazine-2-carboxamide (7)(0.25 g, 60%) was obtained in open system. 6-Fluoro-3-hydroxypyrazine-2-carboxamide (7)Yield: 60%, colorless crystals, needles, m.p.: 175-177 C,(Lit. 178.9-180.1 C) (Caldwell et al. 2012). 19F-NMR(376 MHz, CDCl3): d -92.79 (s, 1F). 1H-NMR (500 MHz,DMSO-d6): d 13.41 (s, OH), 8.75 (s, 1H), 8.51 (d, J = 7.7 Hz, 2H). 13C-NMR (126 MHz, DMSO-d6): d168.66, 159.66, 152.32 (d, J = 243.4 Hz), 135.87, 122.09.MS (ESI): m/z = 158.1 [M+H]+, 180.0 [M+Na]+.

Reference： [1]Chemical Papers,2019,vol. 73,p. 1043 - 1051
[2]Patent: CN107226794,2017,A .Location in patent: Paragraph 0043
[3]Patent: CN106866553,2017,A .Location in patent: Paragraph 0153; 0154; 0155; 0198; 0199; 0200; 0201-0212
[4]Chemical Papers,2017,vol. 71,p. 2153 - 2158

26
[ 19847-12-2 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN107226794,2017,A

27
[ 18960-19-5 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN107226794,2017,A
[2]Patent: CN106478528,2017,A

28
[ 5424-01-1 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN106866553,2017,A
[2]Chemical Papers,2017,vol. 71,p. 2153 - 2158

29
[ 16298-03-6 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN106866553,2017,A
[2]Chemical Papers,2017,vol. 71,p. 2153 - 2158

30
[ 6966-01-4 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN106866553,2017,A
[2]Chemical Papers,2017,vol. 71,p. 2153 - 2158
[3]Patent: CN104496917,2017,B

31
[ 21874-61-3 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN106866553,2017,A
[2]Chemical Papers,2017,vol. 71,p. 2153 - 2158
[3]Patent: CN104496917,2017,B

32
C₆H₅FN₂O₃ [ No CAS ]
[ 259793-96-9 ]

Yield	Reaction Conditions	Operation in experiment
92.3%	With ammonium carbonate;	Room temperature to 500 ml reaction flask add 22.5g VII, ammonium carbonate 62g, 50 C the left and the right insulation instead on invitation 10h to the raw basic reaction end. System for various 220 ml EA extraction 2 time, combined with the organic phase, sodium sulfate drying. Filtered, concentrated dry solvent to obtain 19g yellow solid I, yield 92.3%.

Reference： [1]Patent: CN104496917,2017,B .Location in patent: Paragraph 0071; 0072; 0073; 0074; 0075-0080

33
[ 486424-37-7 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN104496917,2017,B

34
C₁₃H₁₁BrN₂O₃ [ No CAS ]
[ 259793-96-9 ]

Reference： [1]Patent: CN104496917,2017,B

35
[ 990-91-0 ]
[ 259793-96-9 ]
dibenzyl (3-carbamoyl-5-fluoropyrazin-2-yl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		In a 10 mL two-necked flask, N, N-dimethylformamide (5 mL) and <strong>[259793-96-9]6-fluoro-3-hydroxypyrazine-2-carboxamide</strong> (200 mg,1.27 mmol) and NaH (60%, 203 mg, 5.08 mmol) was added portionwise under nitrogen atmosphere to the reaction system, followed by stirring for 1 hour. Tetrabenzyl diphosphate (820 mg, 1.52 mmol) was added in portions. Plus continue to room temperature for 3 hours. The solid was filtered off and the crude product purified by medium pressure preparation (mobile phase: CH3CN, H2O, 1% NH4HCO3). The fractions were collected and lyophilized to give 192 mg of product (36% yield) as a yellow solid.

Reference： [1]Patent: CN105884827,2016,A .Location in patent: Paragraph 0073-0076

36
[ 98-96-4 ]
[ 259793-96-9 ]

Reference： [1]Patent: CN106478528,2017,A

37
6-chloro-3-bromo-2-cyanopyrazine [ No CAS ]
[ 259793-96-9 ]

Reference： [1]Patent: CN107641106,2018,A

38
6-chloro-3-hydroxypyrazine-2-carboxamide [ No CAS ]
[ 259793-96-9 ]

Reference： [1]Patent: CN107641106,2018,A

39
[ 259793-96-9 ]
trans-4-(2'-hydroxymethyl-1',3'-oxathiolan-5'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazinecarboxamide [ No CAS ]

Reference： [1]Medicinal Chemistry,2018,vol. 14,p. 595 - 603

40
[ 139757-72-5 ]
[ 259793-96-9 ]
trans-4-(2'-(tert-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-5'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide [ No CAS ]
cis-4-(2'-(tert-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-5'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.8%; 11.8%		General procedure: 6-Fluoro-3-hydroxy-pyrazinecarboxamide (T-705) (3.77 g, 24mmol) was suspended in 45 mL acetonitrile under a stream of nitrogen and N,O-bis (trimethylsilyl) acetamide (6 mL, 24mmol) was added with cooling on ice, followed by stirring at room temperature for 1.5 h. An acetonitrile solution (45 mL)containing 2-(tert-butyl-diphenylsilyloxy)-methyl-5-acetoxy-1,3-oxathiolane (11.7 g, 28 mmol) and 5.2 mL tin (IV) chloride(43.7 mmol) were successively added to the reaction mixture on ice and the mixture was stirred at room temperature for 20 min. The reaction mixture was poured into a solution of 80 mL ethyl acetate and 200 mL of an aqueous saturated solution of sodium bicarbonate. The organic layers were separated and the aqueous layer was then extracted with 500 mL ethyl acetate. The organic layers were combined and dried with anhydrous magnesium sulfate. All solvents were then removed under reduced pressure. The residue was purified by silica gel column chromatography(eluant, EtOAc/CH2Cl2 2/3), to yield the desired compound.cis-4-(2-(tert-Butyl-diphenylsilyloxy) methyl-1,3-oxathiolan-5-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide(cis isomer, III-1a) (1.45 g, 2.81 mmol, yield 11.8%,pale yellow solid. Mp > 250C). 1H NMR (CDCl3, 400MHz) (ppm): 1.10 (s, 9H), 3.33 (d, J = 12.8 Hz, 1H), 3.70(dd, J = 12.8, 5.6 Hz, 1H), 3.96 (dd, J = 12.0 Hz, 3.6 Hz,1H), 4.26 (dd, J = 12.0, 2.4 Hz, 1H), 5.32 (dd, J = 3.6, 2.4Hz, 1H), 6.06 (brs, 1H), 6.42 (d, J = 5.6 Hz, 1H), 7.38-7.50(m, 6H), 7.67-7.69 (m, 4H) and 9.15 (brs, 1H). (A nuclearoverhauser effect (NOE) effect was observed between NCH( = 6.42 Hz) and O-CH-S ( = 5.32 Hz) of the 1,3-oxathiolan, which suggested a 2,4-cis configuration.) 13CNMR (DMSO-d6, 150 MHz), (ppm): 162.03, 154.15,147.12 (d, J = 217 Hz), 141.15, 135.06, 134.96, 130.31,127.97, 113.92 (d, J = 55.2 Hz), 105.22, 83.08, 71.17, 62.54,26.50, 18.71. ESI-MS: 514 [M + H]+. HRMS (ESI) m/z: [M+ Na]+, calcd for C20H24O3SSiNa+, 536.1446; found:536.1445. trans-4-(2-(tert-Butyl-diphenylsilyloxy)methyl-1,3-oxathiolan-5-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide(trans isomer, III-1b), [3.8 g (7.40 mmol), yield30.8%, pale yellow solid. Mp 174.7-175.9C]. 1H NMR(CDCl3, 400 MHz) (ppm): 1.09 (s, 9H), 3.24 (d, J = 12.8Hz, 1H), 3.60-3.78 (m, 2H), 3.85 (dd, J = 11.4 Hz, 4.0 Hz,1H), 5.75 (t, J = 4.3 Hz, 1H), 6.08 (brs, 1H), 7.40-7.50 (m,7H), 7.67-7.69 (m, 4H) and 9.15 (brs, 1H). (No NOE effectwas observed between N-CH ( = 6.08 Hz) and O-CH-S ( =5.75 Hz) of the 1,3-oxathiolan, which suggested a 2,4-transconfiguration.) ESI-MS: 514 [M + H]+. 13C NMR (DMSOd6, 150 MHz), (ppm): 162.00, 154.48, 147.40 (d, J = 217Hz), 140.39, 135.05, 132.48, 130.00, 127.94, 114.55 (d, J =57.5Hz), 105.63, 84.77, 70.34, 64.00, 26.51, 18.71. HRMS(ESI) m/z: [M + Na]+, calcd for C20H24O3SSiNa+, 536.1446;found: 536.1447.

Reference： [1]Medicinal Chemistry,2018,vol. 14,p. 595 - 603

41
2-tert-butyldiphenylsilyloxymethyl-4-acetyl-1,3-oxathiolane [ No CAS ]
[ 259793-96-9 ]
cis-4-(2'-(t-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-4'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide [ No CAS ]
trans-4-(2'-(t-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-4'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.7%; 27%		General procedure: 6-Fluoro-3-hydroxy-pyrazinecarboxamide (T-705) (3.77 g, 24mmol) was suspended in 45 mL acetonitrile under a stream of nitrogen and N,O-bis (trimethylsilyl) acetamide (6 mL, 24mmol) was added with cooling on ice, followed by stirring at room temperature for 1.5 h. An acetonitrile solution (45 mL)containing 2-(tert-butyl-diphenylsilyloxy)-methyl-5-acetoxy-1,3-oxathiolane (11.7 g, 28 mmol) and 5.2 mL tin (IV) chloride(43.7 mmol) were successively added to the reaction mixture on ice and the mixture was stirred at room temperature for 20 min. The reaction mixture was poured into a solution of 80 mL ethyl acetate and 200 mL of an aqueous saturated solution of sodium bicarbonate. The organic layers were separated and the aqueous layer was then extracted with 500 mL ethyl acetate. The organic layers were combined and dried with anhydrous magnesium sulfate. All solvents were then removed under reduced pressure. The residue was purified by silica gel column chromatography(eluant, EtOAc/CH2Cl2 2/3), to yield the desired compound.cis-4-(2-(tert-Butyl-diphenylsilyloxy) methyl-1,3-oxathiolan-5-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide(cis isomer, III-1a) (1.45 g, 2.81 mmol, yield 11.8%,pale yellow solid. Mp > 250C). 1H NMR (CDCl3, 400MHz) (ppm): 1.10 (s, 9H), 3.33 (d, J = 12.8 Hz, 1H), 3.70(dd, J = 12.8, 5.6 Hz, 1H), 3.96 (dd, J = 12.0 Hz, 3.6 Hz,1H), 4.26 (dd, J = 12.0, 2.4 Hz, 1H), 5.32 (dd, J = 3.6, 2.4Hz, 1H), 6.06 (brs, 1H), 6.42 (d, J = 5.6 Hz, 1H), 7.38-7.50(m, 6H), 7.67-7.69 (m, 4H) and 9.15 (brs, 1H). (A nuclearoverhauser effect (NOE) effect was observed between NCH( = 6.42 Hz) and O-CH-S ( = 5.32 Hz) of the 1,3-oxathiolan, which suggested a 2,4-cis configuration.) 13CNMR (DMSO-d6, 150 MHz), (ppm): 162.03, 154.15,147.12 (d, J = 217 Hz), 141.15, 135.06, 134.96, 130.31,127.97, 113.92 (d, J = 55.2 Hz), 105.22, 83.08, 71.17, 62.54,26.50, 18.71. ESI-MS: 514 [M + H]+. HRMS (ESI) m/z: [M+ Na]+, calcd for C20H24O3SSiNa+, 536.1446; found:536.1445. trans-4-(2-(tert-Butyl-diphenylsilyloxy)methyl-1,3-oxathiolan-5-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide(trans isomer, III-1b), [3.8 g (7.40 mmol), yield30.8%, pale yellow solid. Mp 174.7-175.9C]. 1H NMR(CDCl3, 400 MHz) (ppm): 1.09 (s, 9H), 3.24 (d, J = 12.8Hz, 1H), 3.60-3.78 (m, 2H), 3.85 (dd, J = 11.4 Hz, 4.0 Hz,1H), 5.75 (t, J = 4.3 Hz, 1H), 6.08 (brs, 1H), 7.40-7.50 (m,7H), 7.67-7.69 (m, 4H) and 9.15 (brs, 1H). (No NOE effectwas observed between N-CH ( = 6.08 Hz) and O-CH-S ( =5.75 Hz) of the 1,3-oxathiolan, which suggested a 2,4-transconfiguration.) ESI-MS: 514 [M + H]+. 13C NMR (DMSOd6, 150 MHz), (ppm): 162.00, 154.48, 147.40 (d, J = 217Hz), 140.39, 135.05, 132.48, 130.00, 127.94, 114.55 (d, J =57.5Hz), 105.63, 84.77, 70.34, 64.00, 26.51, 18.71. HRMS(ESI) m/z: [M + Na]+, calcd for C20H24O3SSiNa+, 536.1446;found: 536.1447.

Reference： [1]Medicinal Chemistry,2018,vol. 14,p. 595 - 603

42
[ 259793-96-9 ]
sodium 5-((3-carbamoyl-5-fluoropyrazin-2-yl)oxy)-3-oxapentanephosphonate [ No CAS ]