* 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.
With hydrazine In ethanol for 2 h; Heating / reflux
Pyrazine-2-carboxylic acid hydrazide. To a stirred solution of pyrazine-2-carboxylic acid methyl ester (11.1 g, 80 mmol) in 140 mL OF ETOH was added hydrazine hydrate (15.6 ML, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100percent) as a white solid. The product was used in subsequent steps without purification.
100%
With hydrazine In ethanol for 2 h; Heating / reflux
Example 261; 5-Phenyl-2-(3-pyrazin-2-yl-ureido)-thiophene-3-carboxylic acid (S)-azepan-3-ylamide pyrazine-2-carbohydrazide. ; To a stirred solution of methyl pyrazine-2-carboxylate (11.1 g, 80 mmol) in 140 mL of EtOH was added hydrazine hydrate (15.6 mL, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100percent) as a white solid. The product was used in subsequent steps without purification.'H NMR (d6-DMSO 8 10.1, br s, 1H; 8 9.12, d, 1H ; 8 8. 83, d, 1H ; 8 8.70, dd, 1H; 8 4.64, br s, 2H), LC/MS (APCI, ES, M+H=139).
75%
With hydrazine hydrate In methanol for 5 h; Reflux
General procedure: To a solution of an appropriate methyl esters17(a–j) (1.0 mmol) in 50 mL of methanol was added 99 percenthydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
68%
at 78℃;
Example 21.1Pyrazine-2-carbohydrazide To the title compound of Example 19.1 (1.28 mg, 9.3 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.54 mL, 11.1 mmol) and then heated at 78° C. overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with ethyl acetate, filtered and dried to give the title product as a yellow solid (870 mg, 68percent).1H NMR (300 MHz, (CD3)2SO): δ (ppm) 10.16 (broad s, 1H), 9.13 (s, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 4.65 (broad s, 2H).
56%
With hydrazine In tetrahydrofuran for 3 h; Reflux
Methyl pyrazine-2-carboxylate (0.5g; 3.6mmol) was dissolved in THF (5mL), and 98percent hydrazine (0.53mL; 11mmol) was added. The mixture was refluxed for 3h and cooled to rt. The resulting solid was filtered off, washed with THF and dried over P2O5 to give 0.28g (56percent) of a white solid. Rf=0.53 (CHCl3/MeOH 10:1). mp 166–169°C (lit. 167–169°C) [64]. 1H NMR (300MHz, DMSO): δ 10.11 (s, 1H, NH), 9.12 (s, 1H, Ar), 8.82 (d, J=2.4Hz, 1H, Ar), 8.68 (d, J=2.4Hz, 1H, Ar), 4.65 (s, 2H, NH2). 13C NMR (75MHz, DMSO): δ 161.7, 147.4, 145.1, 143.7, 143.4.
Reference：
[1] Patent: WO2005/16909, 2005, A1, . Location in patent: Page/Page column 73
[2] Patent: WO2005/66163, 2005, A2, . Location in patent: Page/Page column 128
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 14, p. 5007 - 5015
[4] European Journal of Inorganic Chemistry, 2011, # 32, p. 5036 - 5042
[5] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 4954 - 4959
[6] Letters in Drug Design and Discovery, 2010, vol. 7, # 4, p. 275 - 280
[7] Medicinal Chemistry, 2011, vol. 7, # 3, p. 245 - 249
[8] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[9] Patent: US2007/259862, 2007, A1, . Location in patent: Page/Page column 26
[10] Chemistry - A European Journal, 2018, vol. 24, # 39, p. 9928 - 9939
[11] Chemical Communications, 2012, vol. 48, # 5, p. 708 - 710
[12] Chemistry - A European Journal, 2012, vol. 18, # 2, p. 442 - 445
[13] European Journal of Medicinal Chemistry, 2016, vol. 120, p. 97 - 110
[14] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 22, p. 622
[15] Patent: US2149279, 1935, ,
[16] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[17] Patent: US6297235, 2001, B1,
[18] European Journal of Medicinal Chemistry, 2010, vol. 45, # 8, p. 3384 - 3388
[19] Patent: WO2010/125102, 2010, A1, . Location in patent: Page/Page column 125-126
[20] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6356 - 6365
[21] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 90 - 95
[22] Dalton Transactions, 2017, vol. 46, # 30, p. 9875 - 9885
[23] Pharmaceutical Chemistry Journal, 2018, vol. 51, # 10, p. 907 - 917
[24] Chemical Research in Toxicology, 2018, vol. 31, # 6, p. 435 - 446
[25] Patent: US2149279, 1935, ,
2
[ 6924-68-1 ]
[ 768-05-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrazine hydrate In ethanol for 6 h; Reflux
General procedure: A mixture of the ester derivative 8a or 8b (5.5 mmol) and hydrazine hydrate (11 mmol) in 50 mL of ethanol was heated under reflux for 6 h. The reaction mixture was left overnight at room temperature, and the solid which separated was collected by filtration. The solid was then washed with ethanol, dried, and recrystallized from ethanol (Yoshino et al., 2006; Vlaovic et al., 1990).
Reference：
[1] Medicinal Chemistry Research, 2015, vol. 24, # 6, p. 2529 - 2550
[2] European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 452 - 461
[3] Journal of the Chemical Society, Dalton Transactions, 2002, # 21, p. 4048 - 4054
[4] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
3
[ 98-96-4 ]
[ 768-05-8 ]
Yield
Reaction Conditions
Operation in experiment
80%
With hydrazine hydrate In ethanol for 12 h; Reflux
A mixture of pyrazine-2-carboxamide (1) 50 g (0.406 mol) in ethanol (500 mL) and hydrazine hydrate (98percent) 34.76 g (0.695 mol) was refluxed for 12 h. The completion of reaction was monitored by TLC (Hexane 6: Ethyl acetate 4). The reaction mass cooled to 10-15°C and filtered off under vacuum. Pyrazin-2-carboxamide is highly soluble in iso-octane at 25-30°C. Iso-octane (50 mL) washing given and suck dried to give pure white to off white solid compound (2) 41.50 g (80.00percent) mp-168-170°C. IR (KBr, cm-1): 3352.4 (-NH2 stretch), 3230.3 (>NH stretch), 2845 (-OCH3), 1640.65 (>C=O stretch), 764 (>C-Br); 1HNMR (400 MHz, DMSO-d6 ppm): δ 4.50 (s, 2H, amine), 8.59 (s, 1H, amide), 8.74 (d, 1H, CH-pyrazine), 9.16 (d, 1H, CH-pyrazine), 9.90 (s, 1H, C=NH); 13C NMR (400MHz, DMSO-d6 ppm): 143.36 (pyrazine C-N), 143.71 (pyrazine C=N), 144.74 (pyrazine C=N), 147.38 (pyrazine C=N), 162.10 (-C=O). MS: 137; m/z: 138 (M+H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3845 - 3850
4
[ 98-97-5 ]
[ 768-05-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 817 - 821
[2] Journal of the Chemical Society, Dalton Transactions, 2002, # 21, p. 4048 - 4054
[3] Letters in Drug Design and Discovery, 2010, vol. 7, # 4, p. 275 - 280
[4] European Journal of Inorganic Chemistry, 2011, # 32, p. 5036 - 5042
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6356 - 6365
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 90 - 95
[7] Medicinal Chemistry Research, 2015, vol. 24, # 6, p. 2529 - 2550
[8] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[9] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2224 - 2228
[10] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
[11] Pharmaceutical Chemistry Journal, 2018, vol. 51, # 10, p. 907 - 917
[12] Journal of Molecular Structure, 2018, vol. 1164, p. 459 - 469
5
[ 19847-10-0 ]
[ 768-05-8 ]
Reference：
[1] Pakistan Journal of Scientific and Industrial Research, 1993, vol. 36, # 11, p. 466 - 467
6
[ 103435-88-7 ]
[ 768-05-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 817 - 821
With hydrazine; In ethanol; for 2h;Heating / reflux;
Pyrazine-2-carboxylic acid hydrazide. To a stirred solution of pyrazine-2-carboxylic acid methyl ester (11.1 g, 80 mmol) in 140 mL OF ETOH was added hydrazine hydrate (15.6 ML, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100%) as a white solid. The product was used in subsequent steps without purification.
100%
With hydrazine; In ethanol; for 2h;Heating / reflux;
Example 261; 5-Phenyl-2-(3-pyrazin-2-yl-ureido)-thiophene-3-carboxylic acid (S)-azepan-3-ylamide pyrazine-2-carbohydrazide. ; To a stirred solution of methyl pyrazine-2-carboxylate (11.1 g, 80 mmol) in 140 mL of EtOH was added hydrazine hydrate (15.6 mL, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100%) as a white solid. The product was used in subsequent steps without purification.'H NMR (d6-DMSO 8 10.1, br s, 1H; 8 9.12, d, 1H ; 8 8. 83, d, 1H ; 8 8.70, dd, 1H; 8 4.64, br s, 2H), LC/MS (APCI, ES, M+H=139).
75%
With hydrazine hydrate; In methanol; for 5h;Reflux;
General procedure: To a solution of an appropriate methyl esters17(a-j) (1.0 mmol) in 50 mL of methanol was added 99 %hydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
68%
With ethanol; hydrazine; at 78℃;
Example 21.1Pyrazine-2-carbohydrazide To the title compound of Example 19.1 (1.28 mg, 9.3 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.54 mL, 11.1 mmol) and then heated at 78 C. overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with ethyl acetate, filtered and dried to give the title product as a yellow solid (870 mg, 68%).1H NMR (300 MHz, (CD3)2SO): delta (ppm) 10.16 (broad s, 1H), 9.13 (s, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 4.65 (broad s, 2H).
56%
With hydrazine; In tetrahydrofuran; for 3h;Reflux;
Methyl pyrazine-2-carboxylate (0.5g; 3.6mmol) was dissolved in THF (5mL), and 98% hydrazine (0.53mL; 11mmol) was added. The mixture was refluxed for 3h and cooled to rt. The resulting solid was filtered off, washed with THF and dried over P2O5 to give 0.28g (56%) of a white solid. Rf=0.53 (CHCl3/MeOH 10:1). mp 166-169C (lit. 167-169C) [64]. 1H NMR (300MHz, DMSO): delta 10.11 (s, 1H, NH), 9.12 (s, 1H, Ar), 8.82 (d, J=2.4Hz, 1H, Ar), 8.68 (d, J=2.4Hz, 1H, Ar), 4.65 (s, 2H, NH2). 13C NMR (75MHz, DMSO): delta 161.7, 147.4, 145.1, 143.7, 143.4.
With hydrazine; In methanol;
d Pyrazine-2-hydrazide To a solution of the product from Example 1 step c) (22 g, 159 mmol) in methanol (250 ml) was slowly added hydrazine monhydrate (36.6 ml, 710 mmol). The reaction mixture was stirred for 1.5 h. The precipitate produced was filtered, washed with diethyl ether and dried in the oven at 80 C. to give the required product (30 g). 1H NMR (250 MHz, DMSO) delta 4.66 (2H, broad peak), 8.66 (1H, m), 8.84 (1H, d, J=2.5 Hz), 9.13 (1H, d, J=2.5 Hz), 10.15 (1H, broad peak); MS (ES+) m/e 139 [MH+].
With hydrazine hydrate; In ethanol; at 20 - 80℃; for 5.0833h;
Methyl 2-pyrazinecarboxylate (1132) (42 g, 304 mmol) was dissolved in ethanol (750 mL) and treated with hydrazine hydrate (22.17 mL, 456 mmol). The solution was stirred at room temperature for 5 minutes whereupon a precipitate started to form. The mixture was cautiously heated to 80 0C for 5 h and cooled to room temperature. Approximately 50% of the solvent was then removed in vacuo, the slurry was heated to reflux and the solution cooled to room temperature overnight. The resulting solid was filtered, washed with a little ethanol, diethyl ether and dried in a vacuum oven to afford product in 39.77 g as beige needles. LC/MS = 139 (M+H)+, retention time = 0.32 minutes (2 minute method (high pH)).
With hydrazine hydrate; In ethanol; at 80℃;
Equimolar quantities (15 mmol) of (2) and the 85% hydrazine monohydrate were dissolved in anhydrous ethanol (25 mL) and vigorously stirred at 80 under oil bath for 4-5 h . The crude was precipitated from the solvent, collected using suction filtration and dried, and followed by recrystallization in ethanol.
With hydrazine hydrate; In methanol; for 21h;Reflux;
(1) Pyrazine-2-carboxylic acid is fully dissolved in anhydrous methanol,Then add an appropriate amount of concentrated sulfuric acid and heat to reflux for 5 h.After the reaction is cooled, adjust the pH to neutral with saturated NaHCO3,Extract with dichloromethane and keep the dichloromethane layer,The solvent was removed by rotary evaporation to obtain an oily pyrazine-2-carboxylic acid methyl ester;After dissolving it in anhydrous methanol, hydrazine hydrate was added dropwise, and after heating under reflux for 21 h,Cool to room temperature, remove methanol by rotary evaporation to obtain pyrazine-2-hydrazide as a red solid product;The ratio of the amount of pyrazine-2-carboxylic acid methyl ester to the amount of hydrazine hydrate is 1: 2.
Pyrazine-2-carbonyl azide. Pyrazine-2-carboxylic acid hydrazide (11.1 g, 80 mmol) was dissolved in 140 mL of water and charged with 6N HC1 (13.3 mL, 80 mmol) and cooled to 0 C. To the stirred reaction mixture was added a solution of sodium nitrite (8. 3 g, 120 mmol) in 80 mL of water was added slowly over a period of 15-30 minutes using an addition funnel. After the addition was complete the reaction was warmed to room temperature and stirred for an additional 5h. The solution was the neutralized by the careful addition of solid NAHCO3 and then extracted with CHC13 (3x). The pooled organic fractions were dried over NA2S04, filtered, concentrated and dried under high vacuum overnight to yield 2.5 g (21%) the title acyl azide. The product was used in subsequent steps without PURIFICATION.
21%
With hydrogenchloride; sodium nitrite; In water; at 0 - 25℃; for 5.25 - 5.5h;
pyrazine-2-carbonvl azide.; <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (11.1 g, 80 mmol) was dissolved in 140 mL of water and charged with 6N HC1 (13.3 mL, 80 mmol) and cooled to 0C. To the stirred reaction mixture was added a solution of sodium nitrite (8.3 g, 120 mmol) in 80 mL of water was added slowly over a period of 15-30 minutes using an addition funnel. After the addition was complete the reaction was warmed to room temperature and stirred for an additional 5h. The solution was the neutralized by the careful addition of solid NaHC03 and then extracted with CHC13 (3x). The pooled organic fractions were dried over Na2SO4, filtered, concentrated and dried under high vacuum overnight to yield 2.5 g (21%) the title acyl azide. The product was used in subsequent steps without purification. IH NMR (d6-DMSO 8 9.30, d, 1H; 8 9.03, d, 1H; 8 8.90, dd, 1H).
With hydrazine hydrate; In ethanol; for 24h;Reflux;
Pyrazine-2-carboxylic acid (100.0 mg, 0.80 mmol) was dissolved indry DCM (50.0 mL) in a round bottom flask under the inert atmosphere.Then, oxalyl chloride (0.10 mL) and one drop dry DMF were added tothe reaction mixture. The stirring was prolonged for 4 hr at roomtemperature (?25 C). After completion of reaction, the solvent wasremoved by vacuum to get solid compound. The solid compound wasdissolved in 20 mL ethanol and excess amount (0.5 mL) of hydrazinehydrate was added. After refluxing for 24 hr, it was cooled down toroom temperature and the solvent was removed. The combined residuewas workup with ethyl acetate and water, the organic part was concentratedunder reduced pressure to get compound 5. Following sameprocedure, Compound 6 and Compound 7 were synthesized followingthe same procedure taking pyridine-2carboxylic acid and benzoylchloride as a starting material.1H NMR (400 MHz, d6-DMSO) of compound 5: delta 9.09 (d,J=1.5 Hz, 1H), 8.91 (s, 1H), 8.79 (d, J=2.5 Hz, 1H), 8.66 (m, 1H),4.61 (s, 2H). 13C NMR (100 MHz, d6-DMSO) of compound 5: delta169.29, 162.01, 147.70, 143.92, 143.65.
With potassium hydroxide; In ethanol; at 20℃; for 8h;
To a stirred solution of hydrazide (3) (12 mmol) and KOH (10.8 mmol) in ethanol (25 mL), carbon disulde (CS2) (13.2 mmol) was slowly added. Then, the resulting mixture was stirred at room temperature for 8 h until the (4) precipitated from the solvent, collected using suction filtration and dried, and followed by recrystallization in ethanol.
With hydrazine hydrate; In ethanol; for 6.0h;Reflux;
General procedure: A mixture of the ester derivative 8a or 8b (5.5 mmol) and hydrazine hydrate (11 mmol) in 50 mL of ethanol was heated under reflux for 6 h. The reaction mixture was left overnight at room temperature, and the solid which separated was collected by filtration. The solid was then washed with ethanol, dried, and recrystallized from ethanol (Yoshino et al., 2006; Vlaovic et al., 1990).
340 mg
With hydrazine hydrate; In ethanol; for 3.0h;Reflux;
To as stirred solution of Ethyl pyrazine-2-carboxylate (450 mg, leq, 0.986 mmoles) in ethanol (20 ml) was added hydrazine Hydrate (65.13 mg, l.2eq, and 1.184 m moles). Reaction mixture was refluxed for 3 hour. Reaction was monitored by NMR. Reaction Mixture was concentrated under reduced pressure to obtained ppt. was triturated with hexane to obtained pyrazine-2-carbohydrazide (340 mg, Brown Solid). XH NMR (400 MHz, DMSO-ri6) d 10.13 (br. s., 1H), 9.13 (d, J = 1.32 Hz, 1H), 8.83 (d, J= 2.19 Hz, 1H), 8.59 - 8.78 (m, 1H), 4.65 (br. s., 2H).
To a suspension of 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (I3)(O.78 g, 3.04 mmol) in Dichloromethane (DCM) (7.60 ml) was added triethyloxonium tetrafluoroborate (0.606 g, 3.19 mmol) and the mixture was stirred at room temperature under argon. After 5-10 minutes it turned to a yellow solution. TLC showed the formation of the imidate (some unreacted starting material always present due to instability of imidate on TLC). After 1 hour 2-pyrazinecarbohydrazide (0.504 g, 3.65 mmol, commercially available) was added but it was insoluble. After 15 minutes the solvent was evaporated in vacuo and the residue taken in n-butanol (7.60 ml) and heated at reflux (120 0C). After 2 hours LCMS showed a main peak which is consistent with the desired product. It was concentrated in vacuo and the residue was purified by flash chromatography (Biotage SP4, 40 + M cartridge) with a gradient of 2M ammonia in MeOH 0 to 10% in DCM. The crude product was then dissolved in EtOAc (50 mL), the precipitate filtered off (50 mg of impurity by LCMS) and the solution washed with sat. NH4CI (3OmL), water (30 mL) and brine (30 mL) and finally dried over MgSO4 to afford an off-white solid that was fruther purified by MDAP to isolate the desired product in 310 mg as a white solid.LC/MS: (M+H)+= 359, retention time = 0.74 minutes (2 minutes run). 1H NMR (500 MHz; d6-DMSO) delta 9.37 (1 H, d), 8.74 (2H, m), 7.65 (1 H, m), 7.63 (1 H, dd), 7.37 (1 H, td), 5.28 (1 H, d), 4.94 (1 H, d), 4.43 (2H, m), 3.67 (2H, m).
A solution of 4-[(2,4-dichlorophenyl)carbonyl]-2-piperazinone (I6) (0.273 g, 1 mmol) in dry Dichloromethane (DCM) (3 ml) was stirred at room temperature under argon. Triethyloxonium tetrafluoroborate (0.199 g, 1.050 mmol) was added and the reaction solution was stirred for 10 minutes. 2-pyrazinecarbohydrazide (0.166 g, 1.200 mmol, commercially available) was then added and the solution was stirred for a further 1 hour. The solvent was then concentrated before n-butanol (3.00 ml) was added and the solution was stirred, under reflux and argon, for 4 hours. LCMS confirmed product location, thus the solution was cooled to room temperature before the solvent was evaporated in vacuo. The remaining residue was then purified by flash chromatograpghy (Biotage SP4, 25M cartridge) with a gradient of 0 to 10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining residue was then further purified by mass-directed automated HPLC. The solvent was then evaporated in vacuo, and the remaining solid was triturated with ether, and dried in a vacuum oven to yield the product in 0.137 g.LCMS: m/z = 375 (M+ H)+, retention time = 0.83 minutes (2 minutes). 1H NMR (500 MHz; d6-DMSO) delta 9.37 (1 H, d), 8.75 (1 H, m), 8.74 (1 H, m), 7.79 (1 H, d), 7.61 (1 H, d), 7.57 (1 H, dd), 5.27 (1 H, d), 4.94 (1 H, d), 4.47 (1 H, m), 4.38 (1 H, m), 3.69 (2H, m).
With potassium hydroxide; In ethanol; for 12h;Reflux;
In a dried RB flask, KOH (1.42 g, 25.33 mmol) was suspended in ethanol (50 mL) atambient temperature. Then <strong>[768-05-8]pyrazine-2-carbohydrazide</strong>6a (5 g, 36.19 mmol) was added and reaction mass was cooled.Carbon disulfide (2.4 mL, 39.81 mmol)was added dropwise and the resulting mixture was refluxed for 12 h. Thereaction progress was monitored by TLC and after completion of the reactionsolvent was distilled under vacuum. The reaction pH was adjusted to 6.0-7.0 by adding4N HCl. The precipitated solid was collected by filtration, washed with water(50 mL) and dried to give white solid compound 7a. Yield: 5.71 g, 87 %; 1HNMR (CDCl3, 400 MHz, delta inppm): 14.817 (s, 1H, -SH), 9.193 (bs, 1H, Ar-H), 8.793 (s, 1H, Ar-H), 8.764 (s,1H, Ar-H); 13C NMR (100 MHz, CDCl3) delta (ppm): 168.7, 164.2, 152.6, 147.7, 145.4, 143.5; ESI-MS (m/z)= 181.1 (M+H)+; calculated for C6H4N4OS;C, 39.99; H, 2.24; N, 31.09; S, 17.80. Found: C, 39.97; H, 2.25; N, 31.05; S,17.84.
With potassium phosphate; In water; at 20℃;Reflux;
General procedure: A mixture of the corresponding acylhydrazine (3 mmol), potassium phosphate (1.02 g, 3 mmol), and carbon disulfide (0.23 g, 3 mmol) in water (15 mL) was stirred at rt for 10 min. After refluxing for an additional 2-3 h, propylene oxide (0.18 g, 3 mmol) was added. Stirring was continued at rt until the intermediate convert completely (monitored by TLC, about 0.5-1 h), the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization or silica gel column to afford the corresponding product 10a-l.
With potassium hydroxide; In ethanol; at 20℃; for 12h;Reflux;
Potassium hydroxide 11.5 g (0.20 mol) was dissolved in absolute ethanol (400 mL) at ambient temperature. Then <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (2) 40g (0.299 mole) added and reaction mass was cooled. Carbon disulfide 25.08 g (0.33 mol) added in small portions and the mixture was stirred at reflux temperature for 12 h. The reaction mixture changed to green colour with the evolution of hydrogen sulfide. The completion of reaction was monitored by TLC (Chloroform 9.5: Methanol 0.5). Ethanol completely distilled under vacuum below 50C. The reaction mass cooled to 25-30C. Water (100 mL) added to dissolve salts and pH 6.0-7.0 adjusted by conc. HCl (20 mL). Solid precipitated out. Stir at 25-30C for 1h, solid filtered, water (50 mL) washing given and dried to give white to off white solid compound (3) 36.32 g (70.00%). Thus yield obtained was used in the next step without further purification. mp- 208-210C. IR (KBr, cm-1): 3352.4 (-NH2 stretch), 3230.3 (>NH stretch), 2845 (-OCH3), 1640.65 (>C=O stretch), 764 (>C-Br); 1H NMR (400 MHz, DMSO-d6 ppm): delta 8.76 (s, 1H), 8.80 (s, 1H), 9.19 (s, 1H), 14.82 (s, 1H). 13C NMR (400MHz, DMSO-d6 ppm): 138.58 (pyrazine C-N), 143.45 (pyrazine C=N), 145.28 (pyrazine C=N), 147.29 (pyrazine C=N), 158.32 (-C=O), 178.48 (-C-SH). MS: 178.9; m/z: 179.9 (M+H).
General procedure: To a solution of 5.5 mmol of substituted acid hydrazides 9a or 9b in 30 mL of ethanol, 5.5 mmol of the appropriate aryl or alkylisothiocyanate 10 (isothiocyanatomethane, isothiocyanatobenzene,1-isothiocyanato-4-methoxybenzene, 1-isothiocyanatonaphthalene,1-isothiocyanato-4-nitrobenzene) was added. The mixture was refluxed for 3 h. The solid product, obtained on cooling, was washed with distilled water and recrystallized from ethanol to obtain compounds 11a-h (Ilyinet al., 2007).
General procedure: To the solution of pyrazine carboxylic acid hydrazide (0.55 g, 4 mmol) in methanol (30 mL) was added dropwise with continuous stirring, a solution of 2-benzoyl pyridine (0.73 g, 4 mmol) in the same solvent. The reaction mixture was then refluxed for 5 h. The solid product so obtained was filtered and recrystallised in hot methanol.
General procedure: To the solution of pyrazine carboxylic acid hydrazide (0.55 g, 4 mmol) in methanol (30 mL) was added dropwise with continuous stirring, a solution of 2-benzoyl pyridine (0.73 g, 4 mmol) in the same solvent. The reaction mixture was then refluxed for 5 h. The solid product so obtained was filtered and recrystallised in hot methanol.
(Z)-N'-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-acryloyl)pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19.4%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at -60℃; for 1h;
Example 8. Synthesis of ( )-iV-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol- l-yl)acryloyl)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (Compound 8). [00278] In a 25 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in dichloromethane (5 mL) and cooled to -60 C where pyrazine-2- carbohydrazide (0.216 g, 1.1 eq.) was introduced. T3P (50% in EtOAc) (3.39 mL, 4 eq.) was added dropwise followed by DIPEA (0.5 mL, 2 eq.) and the reaction mixture was stirred for 1 h at -60 C. The reaction mixture was concentrated under reduced pressure (25 C, 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3 % methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-/V-(3 -(3 -(3 ,5-bis(trifluoromethyl)phenyl)- 1 H- 1 ,2,4-triazol- 1 - yl)acryloyl)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (0.13 g, yield: 19.4%).
4-((4-hydroxy-3-(2-(pyrazine-2-carbonyl)hydrazono)methyl)phenyl)diazen-yl-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In ethanol; at 60℃; for 3h;
The Schiff base H2L was prepared by mixing hot solution 60 C of 4-((3-formyl-4-hydroxyphenyl)diazenyl)benzenesulfonamide (100.75, 0.33 mol) with hot solution 60 C of <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (45.54 g, 0.33 mol) in 50 ml ethanol. The mixture was refluxed for 3 h. The formed solid product was separated by filtration, purified by crystallization from ethanol, washed several times with diethyl ether and dried in vacuum over anhydrous calcium chloride to give orange crystals, yield 85%.
General procedure: Acid hydrazides 18(a-j) (1.0 mmol)were dissolved in ethanol (50 mL),and to this potassiumhydroxide was added (1.49 mmol) which is dissolved inwater (2 mL), and then carbondisulfide was added(4.0 mmol). Then, the reaction mixture was heated at reflux for 10-12 h. Solvent was evaporated, and the residue wasacidified with 10 % HCl. The precipitate was collected byfiltration, washed with water and dried. The products 19(a-j) were used without further purification.
2-bromoethyl-5-(2-pyrazinyl)-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; In toluene; at 100℃; for 2h;
General procedure: A mixture of benzoylhydrazine 23 (0.68 g, 5 mmol), 3-<strong>[590-92-1]bromopropionic acid</strong> (1.2 g, 7.5 mmol), POCl3 (4 mL) in toluene (20 mL) was stirred at 100 C for 2 h. After cooling to room temperature, the mixture was poured into ice water slowly, and extracted with ethyl acetate (20 mL* 3). The organic layer was combined, dried over Na2SO4, and concentrated to afford crude 2-(2-bromoethyl)-5-phenyl-1,3,4- oxadiazole 19o as a yellow solid in 41% of yield. This crude product was used without purification. Following the same procedure for the synthesis of 17a, targetcompound 17o was obtained using crude 2-(2-bromoethyl)-5-phenyl-1,3,4-oxadiazole 19o as halide.
(E)-N'-[1-(2-hydroxyphenyl)ethylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With acetic acid; In methanol; at 110℃; for 24h;Autoclave;
2-Hydroxyacetophenone (0.1g; 0.73mmol), hydrazide 3c (0.1g; 0.73mmol) and acetic acid (0.20mL) were dissolved in methanol (5mL) and heated at 110C in an autoclave for 24h. After cooling to rt, the solid was filtered off, washed with methanol and dried over P2O5. The filtrate was diluted with water and left to crystallize at 4C for 24h. A second load of solid was filtered off, washed with water and methanol and dried over P2O5. The overall yield of yellow solid was 0.14g (74%; lit [37]. 63%). Rf=0.88 (CHCl3/MeOH 20:1). mp 237-239C. IR (KBr): numax, 3347; 1690; 1508; 1489; 1250; 1157; 1043; 1021cm-1. 1H NMR (300MHz, DMSO) delta 13.03 (s, 1H, OH), 11.53 (s, 1H, NH), 9.25 (s, 1H, Ar), 8.96-8.87 (m, 1H, Ar), 8.84-8.68 (m, 1H, Ar), 7.64 (dd, J=8.1, 1.5Hz, 1H, Ar), 7.43-7,16 (m, 1H, Ar), 7.02-6.73 (m, 2H, Ar), 2.46 (s, 3H, CH3). 13C NMR (75MHz, DMSO): delta 160.9, 160.4, 159.2, 148.5, 144.7, 144.6, 144.0, 132.2, 129.3, 119.6, 119.2, 117.8, 14.4. Anal. Calcd. for C13H12N4O2: C, 60.93; H, 4.72; N, 21.86; Found: C, 61.27; H, 4.83; N, 21.76.
General procedure: Compound 4a or compound 4b (1.0 eq) was dissolved in ethanol (2mL) and then the corresponding amine derivative (1.0 eq) was added. The reaction mixture was stirred at room temperature until the reaction was done (monitored by TLC). The resultant mixture was concentrated under reduced pressure and purified by column chromatography to give the corresponding product.
General procedure: Compound 4a or compound 4b (1.0 eq) was dissolved in ethanol (2mL) and then the corresponding amine derivative (1.0 eq) was added. The reaction mixture was stirred at room temperature until the reaction was done (monitored by TLC). The resultant mixture was concentrated under reduced pressure and purified by column chromatography to give the corresponding product.
N'-[2r,4c-bis(m-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-ylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With acetic acid; In methanol; chloroform;Reflux;
General procedure: 2.3. General procedure for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong>(8-14)The quest for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (8-14) wasaccomplished in two steps as outlined in Scheme 1. A mixture of2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one (1-7) (1 mmol),commercially available <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (PZH)(1.5 mmol) in methanol and chloroform mixture (1:1 v/v), andcatalytic amount of acetic acid (0.1 mL) was added and refluxed for2-3 h. On the completion of reaction, a solid mass was formed.After cooling to room temperature, the precipitate was filtered offand washed with cold mixture of ethanol and water. The crude product was recrystallized from ethanol [16].
N'-[2r,4c-bis(p-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-ylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With acetic acid; In methanol; chloroform;Reflux;
General procedure: 2.3. General procedure for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong>(8-14)The quest for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (8-14) wasaccomplished in two steps as outlined in Scheme 1. A mixture of2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one (1-7) (1 mmol),commercially available <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (PZH)(1.5 mmol) in methanol and chloroform mixture (1:1 v/v), andcatalytic amount of acetic acid (0.1 mL) was added and refluxed for2-3 h. On the completion of reaction, a solid mass was formed.After cooling to room temperature, the precipitate was filtered offand washed with cold mixture of ethanol and water. The crude product was recrystallized from ethanol [16].
N'-[2r,4c-bis(p-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-ylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With acetic acid; In methanol; chloroform;Reflux;
General procedure: 2.3. General procedure for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong>(8-14)The quest for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (8-14) wasaccomplished in two steps as outlined in Scheme 1. A mixture of2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one (1-7) (1 mmol),commercially available <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (PZH)(1.5 mmol) in methanol and chloroform mixture (1:1 v/v), andcatalytic amount of acetic acid (0.1 mL) was added and refluxed for2-3 h. On the completion of reaction, a solid mass was formed.After cooling to room temperature, the precipitate was filtered offand washed with cold mixture of ethanol and water. The crude product was recrystallized from ethanol [16].
N'-[2r,4c-bis(p-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-ylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With acetic acid; In methanol; chloroform;Reflux;
General procedure: 2.3. General procedure for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong>(8-14)The quest for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (8-14) wasaccomplished in two steps as outlined in Scheme 1. A mixture of2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one (1-7) (1 mmol),commercially available <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (PZH)(1.5 mmol) in methanol and chloroform mixture (1:1 v/v), andcatalytic amount of acetic acid (0.1 mL) was added and refluxed for2-3 h. On the completion of reaction, a solid mass was formed.After cooling to room temperature, the precipitate was filtered offand washed with cold mixture of ethanol and water. The crude product was recrystallized from ethanol [16].
N'-[2r,4c-bis(p-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-ylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With acetic acid; In methanol; chloroform;Reflux;
General procedure: 2.3. General procedure for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong>(8-14)The quest for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (8-14) wasaccomplished in two steps as outlined in Scheme 1. A mixture of2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one (1-7) (1 mmol),commercially available <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (PZH)(1.5 mmol) in methanol and chloroform mixture (1:1 v/v), andcatalytic amount of acetic acid (0.1 mL) was added and refluxed for2-3 h. On the completion of reaction, a solid mass was formed.After cooling to room temperature, the precipitate was filtered offand washed with cold mixture of ethanol and water. The crude product was recrystallized from ethanol [16].
N'-[2r,4c-bis(m-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-ylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With acetic acid; In methanol; chloroform;Reflux;
General procedure: 2.3. General procedure for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong>(8-14)The quest for the synthesis of N'-(2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)<strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (8-14) wasaccomplished in two steps as outlined in Scheme 1. A mixture of2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one (1-7) (1 mmol),commercially available <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> (PZH)(1.5 mmol) in methanol and chloroform mixture (1:1 v/v), andcatalytic amount of acetic acid (0.1 mL) was added and refluxed for2-3 h. On the completion of reaction, a solid mass was formed.After cooling to room temperature, the precipitate was filtered offand washed with cold mixture of ethanol and water. The crude product was recrystallized from ethanol [16].
pyrazine-2-carboxylic acid [1-(1,3-dioxo-indan-2-yl)-3-methyl-butylidene]hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In methanol; at 20℃;Reflux; Inert atmosphere;
General procedure: The 2-(3-methylbutanoyl)-1H-indene-1,3(2H)-dione neededfor the synthesis was prepared by the Claisen condensation of diethylphthlate and appropriate ketone under the inuence ofsodium methoxide according to the procedure as described inthe literature.32,33 Schi bases were synthesized by dissolving 1:1molar ratio methanolic solution of 2-(3-methylbutanoyl)-1Hindene-1,3(2H)-dione with benzoic acid, pyrazine acid, nicotinic acid, and isonicotinic acid hydrazides. The solution wasstirred and reuxed for 5-6 h. The solution was kept overnightat room temperature. The white and red color solids so obtainedwere fltered and recrystallized in methanol and chloroformsolution (1:1, v/v).
Compound 5a (150 mg, 515.87 [mu] mol)And pyrazinohydrazide (75.06 mg, 515.87 [mu] mol) were added to the reaction flask,Add 2 mL of ethanol,Room temperature reaction,TLC monitoring reaction was carried out.After the reaction,There is a lot of solid precipitation.Direct suction filter,Get cake.The cake was dried in an oven at 60 C for 6 h to obtain pure compound 6j.Yellow solid.Yield 90%.
The compound 5b (150 mg, 453.45 [mu] mol)And pyrazinohydrazide (62.64 mg, 453.45 [mu] mol) were added to the reaction flask,Add 2 mL of ethanol,Room temperature reaction,TLC monitoring reaction was carried out.After the reaction,There is a lot of solid precipitation.Direct suction filter,Get cake.The cake was dried in an oven at 60 C for 6 h to obtain pure compound 6z.Green solid.Yield 94%.
With hydrazine hydrate; In ethanol; for 12h;Reflux;
A mixture of pyrazine-2-carboxamide (1) 50 g (0.406 mol) in ethanol (500 mL) and hydrazine hydrate (98%) 34.76 g (0.695 mol) was refluxed for 12 h. The completion of reaction was monitored by TLC (Hexane 6: Ethyl acetate 4). The reaction mass cooled to 10-15C and filtered off under vacuum. Pyrazin-2-carboxamide is highly soluble in iso-octane at 25-30C. Iso-octane (50 mL) washing given and suck dried to give pure white to off white solid compound (2) 41.50 g (80.00%) mp-168-170C. IR (KBr, cm-1): 3352.4 (-NH2 stretch), 3230.3 (>NH stretch), 2845 (-OCH3), 1640.65 (>C=O stretch), 764 (>C-Br); 1HNMR (400 MHz, DMSO-d6 ppm): delta 4.50 (s, 2H, amine), 8.59 (s, 1H, amide), 8.74 (d, 1H, CH-pyrazine), 9.16 (d, 1H, CH-pyrazine), 9.90 (s, 1H, C=NH); 13C NMR (400MHz, DMSO-d6 ppm): 143.36 (pyrazine C-N), 143.71 (pyrazine C=N), 144.74 (pyrazine C=N), 147.38 (pyrazine C=N), 162.10 (-C=O). MS: 137; m/z: 138 (M+H).
4-((4-((3-formyl-10H-phenothiazin-10-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl) benzonitrile[ No CAS ]
(E)-N'-((10-((1-(4-cyanobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-10H-phenothiazin-3-yl)methylene)pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With sulfuric acid; In ethanol; at 20℃; for 1h;
General procedure: A mixture of compound 12/13 (1mmol) and hydrazine derivative (1mmol) was taken in ethanol (10mL) in a dry 50mL RB flask. A catalytic amount of conc. H2SO4 was added and the mixture was stirred for 10-15min at RT. After the complete consumption of both starting materials (monitored by TLC), the reaction mixture was poured into ice cold water (10mL). The solid separated was filtered off under suction and washed with ethanol and water.
4-((4-((7-formyl-2-(trifluoromethyl)-10H-phenothiazin-10-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile[ No CAS ]
(E)-N'-((10-((1-(4-cyanobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-8-(trifluoromethyl)-10H-phenothiazin-3-yl)methylene)pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sulfuric acid; In ethanol; at 20℃; for 1h;
General procedure: A mixture of compound 12/13 (1mmol) and hydrazine derivative (1mmol) was taken in ethanol (10mL) in a dry 50mL RB flask. A catalytic amount of conc. H2SO4 was added and the mixture was stirred for 10-15min at RT. After the complete consumption of both starting materials (monitored by TLC), the reaction mixture was poured into ice cold water (10mL). The solid separated was filtered off under suction and washed with ethanol and water.
(5-hydroxy-6-methyl-4-{(E)-[2-oxo-2-(pyrazin-2-yl)ethyl]hydrazinylidenemethyl}pyridin-3-yl)methylphosphate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.6%
In water; at 20 - 80℃; for 1h;
A mixture of a solution of 0.618 g (2.5 mmol) of pyridoxal-5-phosphate 1 in 15 mL of water and a solution of 0.345 g (2.5 mmol) of <strong>[768-05-8]pyrazine-2-carbohydrazide</strong> 2 in 15 mL of water (both solutions heated to 70-80 C) was cooled during 1 h at room temperature. The formed crystalline precipitate was filtered off, washed with small amount of cold distilled water and acetone, and dried in air. Yield 0.815 g (84.6%), light yellow crystals, Rf 0.86 (mobile phase 25% aqueous ammonia, Polygram Sil G/UV254). UV spectrum (pH = 7.4, H2O), lambdamax, nm (log epsilon): 302 (4.29); green luminescence in solid phase at lambdaex = 365 nm. 1H NMR spectrum (D2O, pD ~12), delta, ppm: 8.90 d (1H, H3, 4J = 0.9 Hz), 8.65 s (1H, CH=), 8.47 d. d (1H, H5', 3J = 2.4, 4J = 0.9 Hz), 8.41 d (1H, H6', 3J = 2.4 Hz), 7.51 s (1H, H6), 4.75 d (2H, CH2, 3J = 4.3 Hz), 2.22 s (3H, CH3). 13C NMR spectrum, deltaC, ppm: 166.1 (C=O),158.5 (C3), 151.2 (C2), 149.4 (C2'), 147.7 (CH=), 145.6 (C3'), 144.0 (C5'), 143.5 (C6'), 134 (C6), 130.4 (C5), 120.3 (C4), 61.7 (CH2), 18.2 (CH3). 31P NMR spectrum: deltaP 3.79 ppm. Mass spectrum, m/z: 368.07 [ M + H]+. Found, %: C 42.22; H 4.00; N 18.61. C13H14N5O6P. Calculated, %: C 42.52; H 3.84; N 19.07. M 367.25.
(E)-N'-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methylene)pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In ethanol; at 20℃;
General procedure: The desired compounds 1a-g and 2a-f were prepared by reaction between pyridoxal hydrochloride (0.15 g, 0.74mmol) and the appropriate aromatic or heteroaromatic hydrazine or N-acylhydrazine (1.1 eq., 0.81mmol) in ethanol (10.0 mL). The reaction mixture was stirred for 1-48 hours at room temperature. After that, product was purified by wash-ing with cold ethanol (3.0 mL) and cold diethyl ether (3.0 mL), leading to the pure derivatives 1a-g and 2a-f as solid in 42-86% yields.
(E)-N'-[1-(2-pyrazinyl)ethylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With acetic acid; In ethanol; for 12h;Reflux;
General procedure: To a stirred solution of the acid hydrazide 5 (2mmol, 0.27g) in absolute ethanol (10ml), the appropriate heteroaromatic ketone or substituted pyrazolaldehyde (2mmol) was added in the presence of catalytic amount of glacial acetic acid (5 drops), the mixture was refluxed for 12-16h. The product obtained was filtered, washed with diethyl ether, dried and recrystallized from ethanol.
(E)-N'-[1-(3-pyridinyl)ethylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With acetic acid; In ethanol; for 12h;Reflux;
General procedure: To a stirred solution of the acid hydrazide 5 (2mmol, 0.27g) in absolute ethanol (10ml), the appropriate heteroaromatic ketone or substituted pyrazolaldehyde (2mmol) was added in the presence of catalytic amount of glacial acetic acid (5 drops), the mixture was refluxed for 12-16h. The product obtained was filtered, washed with diethyl ether, dried and recrystallized from ethanol.
(E)-N'-[1-(4-pyridinyl)ethylidene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With acetic acid; In ethanol; for 12h;Reflux;
General procedure: To a stirred solution of the acid hydrazide 5 (2mmol, 0.27g) in absolute ethanol (10ml), the appropriate heteroaromatic ketone or substituted pyrazolaldehyde (2mmol) was added in the presence of catalytic amount of glacial acetic acid (5 drops), the mixture was refluxed for 12-16h. The product obtained was filtered, washed with diethyl ether, dried and recrystallized from ethanol.
(E)-N'-[(1,3-diphenyl-1H-pyrazol-4-yl)methylene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With acetic acid; In ethanol; for 16h;Reflux;
General procedure: To a stirred solution of the acid hydrazide 5 (2mmol, 0.27g) in absolute ethanol (10ml), the appropriate heteroaromatic ketone or substituted pyrazolaldehyde (2mmol) was added in the presence of catalytic amount of glacial acetic acid (5 drops), the mixture was refluxed for 12-16h. The product obtained was filtered, washed with diethyl ether, dried and recrystallized from ethanol.
(E)-N'-[(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With acetic acid; In ethanol; for 16h;Reflux;
General procedure: To a stirred solution of the acid hydrazide 5 (2mmol, 0.27g) in absolute ethanol (10ml), the appropriate heteroaromatic ketone or substituted pyrazolaldehyde (2mmol) was added in the presence of catalytic amount of glacial acetic acid (5 drops), the mixture was refluxed for 12-16h. The product obtained was filtered, washed with diethyl ether, dried and recrystallized from ethanol.
(E)-N'-[(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)methylene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With acetic acid; In ethanol; for 16h;Reflux;
General procedure: To a stirred solution of the acid hydrazide 5 (2mmol, 0.27g) in absolute ethanol (10ml), the appropriate heteroaromatic ketone or substituted pyrazolaldehyde (2mmol) was added in the presence of catalytic amount of glacial acetic acid (5 drops), the mixture was refluxed for 12-16h. The product obtained was filtered, washed with diethyl ether, dried and recrystallized from ethanol.
(E)-N'-[(3-(4-chlorophenyl)-1-(4-nitrophenyl)-1H-pyrazol-4-yl)methylene]pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With acetic acid; In ethanol; for 16h;Reflux;
General procedure: To a stirred solution of the acid hydrazide 5 (2mmol, 0.27g) in absolute ethanol (10ml), the appropriate heteroaromatic ketone or substituted pyrazolaldehyde (2mmol) was added in the presence of catalytic amount of glacial acetic acid (5 drops), the mixture was refluxed for 12-16h. The product obtained was filtered, washed with diethyl ether, dried and recrystallized from ethanol.
(E)-N’-(3–methoxy-4-(prop–2-yn-1-yloxy)benzylidene)pyrazine-2-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In ethanol at 60℃; for 12h;
2.3.1. General procedure for the synthesis of pyrazine-2-carbohydrazide substituted alkynes (5a,5b)
General procedure: Pyrazine-2-carbohydrazide and alkynes were synthesized by the known procedure in literatures [28,29]. For the synthesis of pyrazine-2-carbohydrazide substituted alkynes, compound (2) was added in a 100 mL round bottom flask (RBF) with 50 mL ethanol as solvent. The mixture was stirred for 10 min. to get a clear solution. After that, already synthesized alkyne (1 Equiv.) was added and the reaction mixture was refluxed for 12 h. at 60 °C.After completion of the reaction, the solid product was filtered and recrystallized with MeOH/CH3CN.
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