* 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.
Reference:
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 664
2
[ 98-96-4 ]
[ 22047-25-2 ]
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 7, p. 1093 - 1101
3
[ 98-96-4 ]
[ 19847-12-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 325℃; for 1 h;
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99percent).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
34%
With trichlorophosphate In acetonitrile for 6 h; Inert atmosphere; Reflux
In a dried 500 ml, three necked, jacketed flask fitted with a mechanical stirrer, temperature probe, a reflux condenser, a circulation bath, and a positive nitrogen atmosphere set-up was charged with 2-pyrazinecarboxamide 20.0 gm (0.162 mol), acetonitrile 240 ml, and POCl3 59.6 gm (0.389 mol). The white slurry was agitated and heated to reflux. The reaction mixture was maintained at reflux for at least 6 hours. Then the excess POCl3 was distilled off under reduced pressure. After aqueous work up, the reaction mixture was extracted with 4.x.70 ml ethyl acetate. The combine ethyl acetate extracts were washed with 3.x.70 ml water, distilled under reduced pressure to remove ethyl acetate and to afford cyanopyrazine as a brown oil: 5.76 gm (34percent yield); HPLC purity, >98 area percent; 1H NMR (300 MHz, CDCl3) δ 8.67 (pair d, J=1.7 and 2.5 1H), 8.75 (d, J=2.5, 1H), 8.87 (d, J=1.3 1H); 13C NMR (300 MHz, CDCl3) δ 115.1, 130.7, 145.3, 147.3, 148.1.
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 7, p. 1093 - 1101
[2] Patent: CN104557357, 2018, B, . Location in patent: Paragraph 0150; 0151; 0152; 0160
[3] Chemical Communications, 2007, # 3, p. 301 - 303
[4] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 10, p. 731 - 742
[5] Patent: US2009/292122, 2009, A1, . Location in patent: Page/Page column 12-13
[6] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 247, p. 822
[7] Patent: US4442095, 1984, A,
[8] Patent: US4442097, 1984, A,
[9] Patent: US4442096, 1984, A,
4
[ 109-08-0 ]
[ 290-37-9 ]
[ 19847-12-2 ]
[ 98-96-4 ]
Reference:
[1] Chemical Communications, 2011, vol. 47, # 29, p. 8394 - 8396
5
[ 98-96-4 ]
[ 98-97-5 ]
Reference:
[1] Angewandte Chemie - International Edition, 2009, vol. 48, # 48, p. 9176 - 9179
[2] Journal of the Indian Chemical Society, 2013, vol. 90, # 2, p. 181 - 185
[3] Biocatalysis and Biotransformation, 2017, vol. 35, # 1, p. 74 - 85
[4] Journal of Molecular Structure, 2018, vol. 1173, p. 469 - 480
6
[ 290-37-9 ]
[ 77287-34-4 ]
[ 98-96-4 ]
Yield
Reaction Conditions
Operation in experiment
86%
at 70℃; for 12 h;
General procedure: In an oven dried glass tube containing a mixture of pyridine 1a (100 mg, 1.26 mmol), and potassium persulphate (683 mg, 2.53 mmol), formamide 2a (2 ml) was added and the reaction mixture was heated at 70 °C. Upon the completion of the reaction (monitored by TLC), saturated sodium bicarbonate solution (5 mL) was added and the crude product was extracted in ethyl acetate (3 X 5 mL). The crude product was purified by column chromatography to furnish compound 3aa as a white crystalline solid (122 mg, 79percent yield)
Reference:
[1] Tetrahedron Letters, 2017, vol. 58, # 50, p. 4709 - 4712
[2] Tetrahedron, 1985, vol. 41, # 19, p. 4157 - 4170
[3] Chemical Communications, 2002, # 21, p. 2496 - 2497
7
[ 56423-63-3 ]
[ 15226-74-1 ]
[ 98-96-4 ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1H-imidazole; 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; ammonium chloride; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 90℃; for 3 h; Sealed tube
General procedure: To a stirred solution of aryl halide (Br/I) (1 mmol) in dry dioxane in a 25 mL sealed tube, was added Pd(OAc)2 (5 molpercent), dppf (6 mol percent), DIPEA (2 mmol), imidazole (0.25 mmol), ammonium chloride (2 mmol) and then Co2(CO)8 (0.3 mmol). The seal tube was closed immediately and stirred at 90 °C for 3h. After the reaction time the reaction mixture was cooled to room temperature. The reaction mixture was filtered through celite pad and washed with dioxane, the filtrate was concentrated under reduced pressure and the residue obtained was purified by column chromatography.
A solution of nitrile 3 in ethanol/H2O (0.6 M, 8:1 v/v) was passed through the column reactor R2 (100 mm × 10 mm, 5 g hydrous zirconia) heated at 100 °C, with a residence time of 20 minutes, to obtain a quantitative recovery of the primary amide 2 after concentration of the reactor output (>98percent yield). White solid; m.p. 191–194 °C; δ H (400 MHz, d6-DMSO, 25 °C) 7.84 (1H, br. s), 8.24 (1H, br. s), 8.70 (1H, dd, J = 2.5 Hz, J 1.5 Hz), 8.85 (1H, d, J = 2.5 Hz), 9.17 (1H, d, J = 1.5 Hz); δ C (100 MHz, CDCl3, 25 °C) 143.46 (CH), 143.69 (CH), 145.18 (C), 147.46 (CH), 165.13 (C); FTIR (neat, ν): 3422, 3132, 1669, 1583, 1525, 1481, 1432, 1373, 1171, 1089, 1046, 1021, 870, 791 cm−1; LC-MS: retention time 0.28 min, m/z [M + H]+ = 124.19; HRMS (ESI): m/z calcd for C5H6ON3+: 124.0505; found 124.0504. Elemental analysis: calcd C = 48.78percent, H = 4.09percent, N = 34.13percent; found C = 48.60percent, H = 4.19percent, N = 33.70percent.
96%
at 110℃; for 6 h;
General procedure: Two milli liter water at room temperature was added to astirred mixture of nitrile (1mmol) and catalyst (40mg) thenheated with an oil bath maintained at 110°C, and stirred. After completion of the reaction (monitored by TLC), thecatalyst was removed from the reaction mixture by externalmagnet. Then the mixture was extracted with ethyl acetate,subsequently purified by column chromatography on silicagel to provide the corresponding amide products.
65%
With copper(l) iodide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene In nitromethane; water at 20 - 80℃; for 0.25 h;
To a nitromethane (0.10 mL) solution of pyrazine-2-carbonitrile (4e) (30 mg, 0.285 mmol) were addedH2O (1.0 mL), DBU (87 mg, 0.571 mmol), copper (I) iodide (11 mg, 0.0571 mmol), cesium (I)carbonate (47 mg, 0.143 mmol), 4-dimethylaminopyridine (35 mg, 0.285 mmmol) at roomtemperature. The reaction mixture was heated at 80 °C for 15 min and then poured into water (50mL). The organic layer was separated and the aqueous layer was extracted with AcOEt. Thecombined organic layer was dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (2:1) to givepyrazine-2-carboxamide (5e) S11 (23 mg, 65percent) as pale yellow powders.5e: mp 187-188 °C,
92 %Chromat.
Stage #1: With dimethyl sulfoxide; sodium hydroxide In ethanol; water at 25℃; for 0.0416667 h; Flow reactor Stage #2: With dihydrogen peroxide In ethanol; water at 25℃; for 0.0694444 h; Flow reactor
General procedure: 0.6 mmol benzonitrile and 0.6 mmol DMSO were solved in 3 mL EtOH and pumped into inlet A, 50 μL 1 M NaOH (aq) solved in 1 mL EtOH and pumped into inlet B, 30percent H2O2 (aq) was solved in 7 mL ethanol and pumped into inlet C (flow rate A: B: C = 1.54 μl/min:0.46 μl/min:0.3 μl/min for a 400s residence time). The whole system was maintained on 25 °C. The flow system was equilibrated for 30 min, then the product stream was quenched and collected in a glass vessel with saturated aqueous NaHSO3 in it for 2 h. After being filtered, 5.0 ml of this solution was injected to the HPLC instrument for analysis. The conversion of the reaction was determined by relative area percentage of nitriles and corresponding amides. Conversion = Area (benzamide)/[Area (benzamide) + Area (benzonitrile)].
Reference:
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 11, p. 2814 - 2819
[2] Organic Letters, 2014, vol. 16, # 4, p. 1060 - 1063
[3] Chemistry - A European Journal, 2017, vol. 23, # 32, p. 7761 - 7771
[4] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 641 - 652
[5] ACS Catalysis, 2015, vol. 5, # 1, p. 20 - 26
[6] Chemical Communications, 2009, # 22, p. 3258 - 3260
[7] Organic Syntheses, 2017, vol. 94, p. 34 - 45
[8] New Journal of Chemistry, 2018, vol. 42, # 18, p. 15221 - 15230
[9] Catalysis Letters, 2018, vol. 148, # 11, p. 3378 - 3388
[10] Journal of Organic Chemistry, 2015, vol. 80, # 8, p. 4148 - 4151
[11] ChemSusChem, 2012, vol. 5, # 8, p. 1392 - 1396
[12] Applied Catalysis A: General, 2012, vol. 421-422, p. 114 - 120
[13] ChemSusChem, 2013, vol. 6, # 8, p. 1341 - 1344
[14] New Journal of Chemistry, 2016, vol. 40, # 1, p. 358 - 364
[15] Synthetic Communications, 2002, vol. 32, # 11, p. 1731 - 1734
[16] ACS Catalysis, 2014, vol. 4, # 6, p. 1901 - 1910
[17] Green Chemistry, 2014, vol. 16, # 4, p. 2136 - 2141
[18] Dalton Transactions, 2016, vol. 45, # 34, p. 13590 - 13603
[19] Green Chemistry, 2016, vol. 18, # 18, p. 4865 - 4870
[20] Synlett, 2018, vol. 29, # 15, p. 2061 - 2065
[21] Synthetic Communications, 2000, vol. 30, # 10, p. 1713 - 1718
[22] Chemistry - A European Journal, 2011, vol. 17, # 41, p. 11428 - 11431
[23] Inorganica Chimica Acta, 2016, vol. 442, p. 134 - 144
[24] Tetrahedron, 2018, vol. 74, # 13, p. 1527 - 1532
9
[ 98-97-5 ]
[ 98-96-4 ]
Reference:
[1] Dalton Transactions, 2015, vol. 44, # 6, p. 2880 - 2892
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 2, p. 315 - 318
[3] Journal of Chemical Thermodynamics, 2005, vol. 37, # 1, p. 49 - 53
[4] Journal of the American Chemical Society, 1940, vol. 62, p. 664
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1424 - 1427
[6] Patent: CN104557357, 2018, B, . Location in patent: Paragraph 0135; 0136; 0137; 0145
10
[ 19847-10-0 ]
[ 98-96-4 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1424 - 1427
11
[ 306990-94-3 ]
[ 98-96-4 ]
Reference:
[1] Journal of Organic Chemistry, 2000, vol. 65, # 24, p. 8210 - 8213
To a solution of pyrazinecarbonitrile (1.00 g, 9.5 mmol) in dry ethanol (30 ml) was introduced a stream of dry HCl gas bubbled through the solution with stirring. Shortly after the HCl was introduced the temperature quickly rose requiring cooling with an ice/water bath. At this time a heavy white precipitate had fonned and after 2 h the gas inlet was replaced with a calcium' chloride drying tube and the reaction mixture stirred overnight. The HC1 gas stream was re-introduced into the reaction mixture for 2 h before again replacing the gas inlet with a drying tube and stirring for 1 h. Dry diethyl ether (45 ml) was then added to the mixture and stirring continued for 10 min before the solid was filtered under nitrogen using a Schlenk apparatus. The collected material was washed with dry diethyl ether (3 x 20 ml) and dried under vacuum to give 1.59 g of a highly moisture- sensitive white powder. nmr revealed the solid to be a mixture of the desired ethyl pyrazine-2-carbimidate hydrochloride (65percent) and the two hydrolysis products pyrazine-2- carboxamide (30percent) and ethyl pyrazine-2-carboxylate (5percent).*H nmr (400 MHz, de-dmso) δ 1.49, t (J = 7.0 Hz), 3H, OEt; 4.73, q (J = 6.9 Hz), 2H, OEt; 7.85, br, lH, C=NH2+; 8.24, br, 1H, C=NH2+; 8.93, dd (J = 1.6, 2.4 Hz), 1H, H6; 9.06, d (J = 2.4 Hz), 1H, H5; 9.33, d (J = 1.2 Hz), 1H, H3.
Reference:
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 664
[2] Yakugaku Zasshi, 1956, vol. 76, p. 470[3] Chem.Abstr., 1956, p. 14777
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 22, p. 622
[5] Journal of Chemical Thermodynamics, 2005, vol. 37, # 1, p. 49 - 53
Reference:
[1] Journal of Chemical Thermodynamics, 2005, vol. 37, # 1, p. 49 - 53
21
[ 4744-50-7 ]
[ 98-96-4 ]
Reference:
[1] Yakugaku Zasshi, 1956, vol. 76, p. 470[2] Chem.Abstr., 1956, p. 14777
22
[ 73763-86-7 ]
[ 98-96-4 ]
Reference:
[1] Yakugaku Zasshi, 1956, vol. 76, p. 470[2] Chem.Abstr., 1956, p. 14777
23
[ 109-08-0 ]
[ 290-37-9 ]
[ 19847-12-2 ]
[ 98-96-4 ]
Reference:
[1] Chemical Communications, 2011, vol. 47, # 29, p. 8394 - 8396
24
[ 67367-37-7 ]
[ 98-96-4 ]
Reference:
[1] Yakugaku Zasshi, 1956, vol. 76, p. 470[2] Chem.Abstr., 1956, p. 14777
[3] Patent: US2780624, 1953, ,
25
[ 2423-84-9 ]
[ 77287-34-4 ]
[ 98-96-4 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 949 - 953
[2] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 949 - 953
26
[ 89-01-0 ]
[ 57-13-6 ]
[ 98-96-4 ]
Reference:
[1] Patent: US2705714, 1952, ,
27
[ 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
28
[ 19847-12-2 ]
[ 64-17-5 ]
[ 98-96-4 ]
[ 1339045-85-0 ]
[ 6924-68-1 ]
Yield
Reaction Conditions
Operation in experiment
65%
Cooling with ice
To a solution of pyrazinecarbonitrile (1.00 g, 9.5 mmol) in dry ethanol (30 ml) was introduced a stream of dry HCl gas bubbled through the solution with stirring. Shortly after the HCl was introduced the temperature quickly rose requiring cooling with an ice/water bath. At this time a heavy white precipitate had fonned and after 2 h the gas inlet was replaced with a calcium' chloride drying tube and the reaction mixture stirred overnight. The HC1 gas stream was re-introduced into the reaction mixture for 2 h before again replacing the gas inlet with a drying tube and stirring for 1 h. Dry diethyl ether (45 ml) was then added to the mixture and stirring continued for 10 min before the solid was filtered under nitrogen using a Schlenk apparatus. The collected material was washed with dry diethyl ether (3 x 20 ml) and dried under vacuum to give 1.59 g of a highly moisture- sensitive white powder. nmr revealed the solid to be a mixture of the desired ethyl pyrazine-2-carbimidate hydrochloride (65percent) and the two hydrolysis products pyrazine-2- carboxamide (30percent) and ethyl pyrazine-2-carboxylate (5percent).*H nmr (400 MHz, de-dmso) δ 1.49, t (J = 7.0 Hz), 3H, OEt; 4.73, q (J = 6.9 Hz), 2H, OEt; 7.85, br, lH, C=NH2+; 8.24, br, 1H, C=NH2+; 8.93, dd (J = 1.6, 2.4 Hz), 1H, H6; 9.06, d (J = 2.4 Hz), 1H, H5; 9.33, d (J = 1.2 Hz), 1H, H3.
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99%).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
34%
With trichlorophosphate; In acetonitrile; for 6h;Inert atmosphere; Reflux;
In a dried 500 ml, three necked, jacketed flask fitted with a mechanical stirrer, temperature probe, a reflux condenser, a circulation bath, and a positive nitrogen atmosphere set-up was charged with 2-pyrazinecarboxamide 20.0 gm (0.162 mol), acetonitrile 240 ml, and POCl3 59.6 gm (0.389 mol). The white slurry was agitated and heated to reflux. The reaction mixture was maintained at reflux for at least 6 hours. Then the excess POCl3 was distilled off under reduced pressure. After aqueous work up, the reaction mixture was extracted with 4×70 ml ethyl acetate. The combine ethyl acetate extracts were washed with 3×70 ml water, distilled under reduced pressure to remove ethyl acetate and to afford cyanopyrazine as a brown oil: 5.76 gm (34% yield); HPLC purity, >98 area %; 1H NMR (300 MHz, CDCl3) delta 8.67 (pair d, J=1.7 and 2.5 1H), 8.75 (d, J=2.5, 1H), 8.87 (d, J=1.3 1H); 13C NMR (300 MHz, CDCl3) delta 115.1, 130.7, 145.3, 147.3, 148.1.
With sodium carbonate; In trichlorophosphate;
A. Cyanopyrazine In 10 ml of phosphoryl chloride at reflux temperature there was stirred pyrazineamide (20 g; 0.162 M) for 1 hour. Excess phosphoryl chloride was then removed and water aspirated. Ice was added to the residue, followed by sodium carbonate until basic, then extraction with 150 ml of ether five times. The combined extracts were dried over sodium sulfate, and the solvent then removed in vacuo to give the title compound (12.9 g).
With sodium carbonate; In trichlorophosphate;
A. Cyanopyrazine In 100 ml of phosphoryl chloride at reflux temperature there was stirred pyrazineamide (20 g; 0.162 M) for 1 hour. Excess phosphoryl chloride was then removed and water aspirated. Ice was added to the residue, followed by sodium carbonate until basic, the extraction with 150 ml of ether five times. The combined extracts were dried over sodium sulfate, and the solvent then removed in vacuo to give title compound (12.9 g).
With formic acid; dihydrogen peroxide; at 40 - 45℃;
a) Preparation of 4-oxy-<strong>[98-96-4]pyrazine-2-carboxylic acid amide</strong>To a solution of pyrazine 2-carboxamide (100.0 g, 812 mmol) and hydrogen perox- ide (144 g, 4.2 mol) in formic acid (200 ml.) and the mixture was gently heated and became higly exothermic at 45C heating (precipitation of a white solid starts) was continued while maintaining the temperature at 400C for an additional 2 h. The heterogeneous mixture was then allowed to cool to room temperature and placed at 4C overnight. The white precipitate was collected by filtration and washed with ice cold water (2 x 100 ml_), ice cold methanol (100 ml.) and diethyl ether (2 x 100 m L). After drying overnight the desired product (42.5 g, 306 mmol, 38 %) was immediately used in the next step.
With dipotassium peroxodisulfate; at 70℃; for 12h;
General procedure: In an oven dried glass tube containing a mixture of pyridine 1a (100 mg, 1.26 mmol), and potassium persulphate (683 mg, 2.53 mmol), formamide 2a (2 ml) was added and the reaction mixture was heated at 70 C. Upon the completion of the reaction (monitored by TLC), saturated sodium bicarbonate solution (5 mL) was added and the crude product was extracted in ethyl acetate (3 X 5 mL). The crude product was purified by column chromatography to furnish compound 3aa as a white crystalline solid (122 mg, 79% yield)
In a 500 mL reactor, 94.1 g (1 mol) of 2-methylpyrazine was added.0.2 g (0.0016 mol) of ferrous chloride, and 225 g (1.99 mol) of hydrogen peroxide having a mass concentration of 30% was added dropwise at 30 C.After the completion of the dropwise addition for 4 hours, the temperature was raised to 50 C, and 40 g (2.35 mol) of ammonia gas was introduced. After the completion of the ammonia gas, the temperature was maintained for 7 hours.After cooling to 10 C, the crude product was filtered.The crude product was recrystallized from 3 times by weight of water to give 117 g of the desired pyrazinamide in a yield of 95%.
A solution of nitrile 3 in ethanol/H2O (0.6 M, 8:1 v/v) was passed through the column reactor R2 (100 mm × 10 mm, 5 g hydrous zirconia) heated at 100 C, with a residence time of 20 minutes, to obtain a quantitative recovery of the primary amide 2 after concentration of the reactor output (>98% yield). White solid; m.p. 191-194 C; delta H (400 MHz, d6-DMSO, 25 C) 7.84 (1H, br. s), 8.24 (1H, br. s), 8.70 (1H, dd, J = 2.5 Hz, J 1.5 Hz), 8.85 (1H, d, J = 2.5 Hz), 9.17 (1H, d, J = 1.5 Hz); delta C (100 MHz, CDCl3, 25 C) 143.46 (CH), 143.69 (CH), 145.18 (C), 147.46 (CH), 165.13 (C); FTIR (neat, nu): 3422, 3132, 1669, 1583, 1525, 1481, 1432, 1373, 1171, 1089, 1046, 1021, 870, 791 cm-1; LC-MS: retention time 0.28 min, m/z [M + H]+ = 124.19; HRMS (ESI): m/z calcd for C5H6ON3+: 124.0505; found 124.0504. Elemental analysis: calcd C = 48.78%, H = 4.09%, N = 34.13%; found C = 48.60%, H = 4.19%, N = 33.70%.
96%
With water; at 110℃; for 6h;
General procedure: Two milli liter water at room temperature was added to astirred mixture of nitrile (1mmol) and catalyst (40mg) thenheated with an oil bath maintained at 110C, and stirred. After completion of the reaction (monitored by TLC), thecatalyst was removed from the reaction mixture by externalmagnet. Then the mixture was extracted with ethyl acetate,subsequently purified by column chromatography on silicagel to provide the corresponding amide products.
65%
With copper(l) iodide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In nitromethane; water; at 20 - 80℃; for 0.25h;
To a nitromethane (0.10 mL) solution of pyrazine-2-carbonitrile (4e) (30 mg, 0.285 mmol) were addedH2O (1.0 mL), DBU (87 mg, 0.571 mmol), copper (I) iodide (11 mg, 0.0571 mmol), cesium (I)carbonate (47 mg, 0.143 mmol), 4-dimethylaminopyridine (35 mg, 0.285 mmmol) at roomtemperature. The reaction mixture was heated at 80 C for 15 min and then poured into water (50mL). The organic layer was separated and the aqueous layer was extracted with AcOEt. Thecombined organic layer was dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (2:1) to givepyrazine-2-carboxamide (5e) S11 (23 mg, 65%) as pale yellow powders.5e: mp 187-188 C,
With C40H45ClN3O2PRu; In methanol; water; at 20℃; for 4h;Inert atmosphere; Schlenk technique; Green chemistry;Catalytic behavior;
General procedure: Organic nitrile (1 mmol) and distilled water (1 mL) were sequentially added to 3 mL methanol solution of the [Ru-NHC] catalyst (0.5 mol%) and the reaction mixture was stirred at room temperature. The progress of the reaction in each case was monitored by TLC analysis. After completion of reaction the catalyst was extracted from the reaction mixture by the addition of CH2Cl2/petroleum ether followed by filtration. The filtrate was subjected to GC analysis and the product was identified with authentic samples.
92%Chromat.
General procedure: 0.6 mmol benzonitrile and 0.6 mmol DMSO were solved in 3 mL EtOH and pumped into inlet A, 50 muL 1 M NaOH (aq) solved in 1 mL EtOH and pumped into inlet B, 30% H2O2 (aq) was solved in 7 mL ethanol and pumped into inlet C (flow rate A: B: C = 1.54 mul/min:0.46 mul/min:0.3 mul/min for a 400s residence time). The whole system was maintained on 25 C. The flow system was equilibrated for 30 min, then the product stream was quenched and collected in a glass vessel with saturated aqueous NaHSO3 in it for 2 h. After being filtered, 5.0 ml of this solution was injected to the HPLC instrument for analysis. The conversion of the reaction was determined by relative area percentage of nitriles and corresponding amides. Conversion = Area (benzamide)/[Area (benzamide) + Area (benzonitrile)].
General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1% by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min).
With dihydrogen peroxide; trichlorophosphate; In N-methyl-acetamide; water; acetic acid; butan-1-ol;
Preparation 28 2-Amino-6-cyanopyrazine This intermediate was prepared via a stepwise procedure. A mixture of 21 g. of pyrazine-2-carboxamide, 85 ml. of glacial acetic acid, and 75 ml. of 30 percent hydrogen peroxide was heated at about 55° C. for about 35 hours. The reaction product mixture was cooled and filtered. The solid which was collected was extracted with n-butanol and the extracts discarded. The solid which was insoluble in n-butanol was recrystallized from hot water to yield a white solid having a melting point of about 302°-305° C. The solid was identified by elemental analyses as pyrazine-2-carboxamide 4-oxide. To a mixture of 4 g. of the pyrazine oxide (prepared above) in 40 ml. of dimethylformamide cooled in an ice bath, there was quickly added 12 ml. of phosphorus oxychloride. The reaction mixture was poured into water and the aqueous mixture extracted with ethyl acetate, and the extracts saved. Additional water was added to the aqueous layer and the aqueous mixture extracted with hexane-ether. The ethyl acetate and hexane-ether extracts were combined and concentrated in vacuo to leave a residue. The residue was identified by elemental analyses and IR spectrum as 2-chloro-6-cyanopyrazine, and was used without further purification in the next step. A mixture of 1 g. of the above chlorocyanopyrazine and 25 ml. of dimethyl sulfoxide was prepared and anhydrous ammonia was bubbled thereinto. The reaction mixture was stirred overnight and then poured into water. The aqueous mixture was extracted with ethyl acetate, and the extracts dried. The drying agent was filtered off and the solvent removed in vacuo to leave a solid which was identified by its IR spectrum as 2-amino-6-cyanopyrazine. It was used as is without further purification in the preparation of final products of the invention.
Ag2(saccharinate)2(pyrazine-2-carboxamide)2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In water; acetonitrile solid Na(sac)*2H2O mixed with 1 equiv. of AgNO3 in H2O, pptd., dissolvedin CH3CN, treated with 1 equiv. of pyrazine-2-carboxamide, stirred at 5 0°C for 45 min; crystd. at room temp., elem. anal.;
With triethylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere; Schlenk tube;
Example 13; Synthesis of Cp*IrCl(<strong>[98-96-4]Pyrazinamide</strong>) complex (Ir-8); 200 mg (0.251 mmol) of [Cp*IrCl2]2 (MW: 796.67) and 61.8 mg (0.502 mmol) of <strong>[98-96-4]Pyrazinamide</strong> (MW: 123.11) were introduced in a 20-mL Schlenk tube and subjected to argon-gas replacement. 6 mL of dehydrated methylene chloride (Kanto Chemical Co., Inc.) and 70 muL (0.502 mmol) of triethylamine (MW: 101.19) were added and the mixture was stirred at room temperature for 16 hr. After 12 ml of methylene chloride was added to the solution and this solution was washed twice with 2 ml of water, the methylene chloride was distilled away. Then, 18 ml of dehydrated diisopropyl ether (Kanto Chemical Co., Inc.) and 2 ml of dehydrated methylene chloride were added and the mixture was stirred at room temperature for 1 hr, and a crystal was collected by filtration, washed with a small amount of dehydrated diisopropyl ether, dried under reduced pressure to give 176 mg of brown powder crystal (72% isolated yield).1H-NMR (400 MHz, CDCl3, delta/ppm): 1.75 (s, 15H), 5.87 (brs, 1H), 8.51 (dd, J=3.2, 0.9, 1H), 8.75 (brs, 1H), 9.27 (s, 1H)13C-NMR (100 MHz, CDCl3, delta/ppm): 9.0, 87.0, 143.3, 148.4, 148.4, 148.4, 171.1
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 150℃; for 1h;Sealed tube; Inert atmosphere; Mirowave irradiation;
To a mixture of Xantphos (30.8 mg, 0.05 mmol), cesium carbonate (154 mg, 0.47 mmol), palladium(II) acetate (7.98 mg, 0.04 mmol) and <strong>[98-96-4]pyrazinamide</strong> (72.9 mg, 0.59 mmol) in a microwave vial under argon was added a solution of 2-(3-bromophenyl)-2-(4- (difluoromethoxy)-3,5-dimethylphenyl)-5-methyl-2H-imidazol-4-amine (100 mg, 0.24 mmol) in dry tetrahydrofuran (1.0 mL). The reaction mixture was heated with microwaves at 150 0C for 1 hour. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with Na2SO4, filtered and evaporated.The mixture was diluted with MeOH (5 mL), filtered and purified by preparative HPLC. The product was partitioned between Saturated aqueous NaHCO3 and DCM . The organic layer was separated, dried with Na2SO4 and concentrated to give the title compound, 7 mg (6% yield): 1H NMR (500 MHz, DMSO-J6) delta ppm 10.66 (s, 1 H), 9.28 (d, 1 H), 8.92 (d, 1 H), 8.79 (dd, 1 H), 8.05 - 8.18 (m, 1 H), 7.60 - 7.74 (m, 1 H), 7.28 - 7.36 (m, 3 H), 7.20 - 7.27 (m, 1 H), 6.87 (t, 1 H), 6.62 (br. s., 2 H), 2.23 (s, 3 H), 2.18 (s, 6 H);MS(ES+) m/z 465 [M+H]+.
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 150℃; for 1h;Microwave irradiation;
Example 27 N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)phenyl)pyrazine-2-carboxamide Pyrazine-2-carboxamide (63.2 mg, 0.51 mmol), 2-(3-bromophenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine (50 mg, 0.17 mmol), palladium(II) acetate (3.84 mg, 0.02 mmol), cesium carbonate (112 mg, 0.34 mmol) and Xantphos (14.85 mg, 0.03 mmol) were dissolved in THF (2 mL) and heated to 150 0C for 1 h using MW. After filtration and removal of solvents in vacuo, were the title compound isolated using preparative HPLC to give 33mg (58% yield): 1H NMR (500 MHz, DMSO-J6) delta ppm 10.65 (s, 1 H), 9.29 (d, 1 H), 8.92 (d, 1 H), 8.81 (m, 1 H), 8.13 (t, 1 H), 7.69 (m, 1 H), 7.35 (m, 1 H), 7.26 (t, 1 H), 6.45 (br. s., 2 H), 2.16 (s, 3 H), 1.50 (m, 1 H), 0.33 (m, 2 H), 0.22 (m, 1 H), 0.02 (m, 1 H); MS (ES) m/z 335 [M+l]+.
To a solution of pyrazinecarbonitrile (1.00 g, 9.5 mmol) in dry ethanol (30 ml) was introduced a stream of dry HCl gas bubbled through the solution with stirring. Shortly after the HCl was introduced the temperature quickly rose requiring cooling with an ice/water bath. At this time a heavy white precipitate had fonned and after 2 h the gas inlet was replaced with a calcium' chloride drying tube and the reaction mixture stirred overnight. The HC1 gas stream was re-introduced into the reaction mixture for 2 h before again replacing the gas inlet with a drying tube and stirring for 1 h. Dry diethyl ether (45 ml) was then added to the mixture and stirring continued for 10 min before the solid was filtered under nitrogen using a Schlenk apparatus. The collected material was washed with dry diethyl ether (3 x 20 ml) and dried under vacuum to give 1.59 g of a highly moisture- sensitive white powder. nmr revealed the solid to be a mixture of the desired ethyl pyrazine-2-carbimidate hydrochloride (65%) and the two hydrolysis products pyrazine-2- carboxamide (30%) and ethyl pyrazine-2-carboxylate (5%).*H nmr (400 MHz, de-dmso) delta 1.49, t (J = 7.0 Hz), 3H, OEt; 4.73, q (J = 6.9 Hz), 2H, OEt; 7.85, br, lH, C=NH2+; 8.24, br, 1H, C=NH2+; 8.93, dd (J = 1.6, 2.4 Hz), 1H, H6; 9.06, d (J = 2.4 Hz), 1H, H5; 9.33, d (J = 1.2 Hz), 1H, H3.
With Fe3+ exchanged montmorillonite K-10; In neat (no solvent); at 140℃; for 30h;Inert atmosphere;
General procedure: A typical procedure for transamidation of benzamide with n-octylamineis as follows. Fe-mont (121.4mg, 1.0 mol% Fe-mont with respect to benzamide) was added to the mixture of benzamide (1.0 mmol), n-octylamine (1.1 mmol) in a reaction vessel equipped with a condenser under N2. The resulting mixture was vigorously stirred at 140 C. The reaction mixture was analyzed by GC.Conversion and yield of the products were determined based on benzamide and n-octyl benzamide using dodecane as an internal standard. After completion of the reaction, acetone (2 g) was added to the mixture, and then the Fe-mont catalyst was separated by centrifugation. The crude product was isolated by column chromatography and the resulting product was identified by GCMS, 1H-NMR and 13C-NMR analyses.
With Lawessons reagent; In tetrahydrofuran;Reflux;
General procedure: The mixture of the corresponding amide (0.2 mmol) and Lawesson?s reagent (0.3 mmol) in tetrahydrofuran 4 mL was refluxed and the reaction was monitored by thin layer chromatography (TLC). After the reaction was complete, the crude product was puried by silica-gel column chromatography using ethyl acetate/hexane as eluent solvent system. The pure product was obtained and identified.
With ammonium hydroxide; In tetrahydrofuran; at 20℃; for 2h;
General procedure: To a solution of an appropriate substituted carboxylic acid (10 mmol) in CHCl3 (50 mL) was added thionyl chloride (3.6 mL, 50 mmol), dropwise over 10 min. The resulting solution was refluxed for 8 h and then concentrated in vacuo. The residual light brown oil was dissolved in THF (50 mL), diluted with a solution of 30% NH4OH (6 mL), and stirred at room temperature for an additional 2 h. At that point, saturated aqueous NaHCO3 (10 mL) was added and the reaction mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude amide was carried directly to the next step without further purification.
[Zn(pyrazinamide)(1,10-phenanthroline)2]ClO4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
General procedure: Complex 3 was prepared in a similar way to 2 with the use ofphen (3 mmol, 0.6 g) instead of bipy. The yield of the synthesiswas 74%.hot aqueous solution (50 mL) of PZAH2 (0.36 g, 3 mmol) wasadded slowly with stirring to 80 mL aqueous solution of CoCl22H2O(0.72 g, 3 mmol) and KClO4 (1.68 g, 6 mmol). The solution was stirredand refluxed for 2 h. The color of the mixing solution turnedbrown immediately from Rose-colored. The methanol solution(50 mL) of bipy (0.912 g, 6 mmol) was added to reaction mixtureand the solution was stirred for 1 h at room temperature Anal. Calc. C29H20ClZnN7O5 (%): C, 53.81; H, 3.11; N,15.15; and Found (%): C, 53.76; H, 3.02; N, 15.07. Selected FT-IR data(Fig. S3), m (cm1): m (NH): 3264 (w); m (aromatic CAH): 3182 (w); m(CO): 1715 (vs); m (CN):1569 (s); m (CC):1427 (s); m (Ringbreath):1045; m (ClO): 1123 (s). 1H NMR (DMSO-d6, d/ppm)(Fig. S6): 7.86 (s, H, NH), 8.11-8.14 (dd, 4H, Ar), 8.27 (s, 4H, Ar),8.85-8.86 (d, 4H, Ar), 8.91-8.92(d, 2H, Ar), 9.11-9.10 (d, 4H, Ar),9.19 (s, H, Ar).
[Zn(pyrazinamide)(2,2'-bipyridine)2](ClO4)2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
General procedure: Complex 2 was prepared in a similar way to 1 with the use ofZn(OAc)22H2O (3 mmol, 0.648 g) instead of CoCl22H2O and KClO4(0.84 g, 3 mmol). hot aqueous solution (50 mL) of PZAH2 (0.36 g, 3 mmol) wasadded slowly with stirring to 80 mL aqueous solution of CoCl22H2O(0.72 g, 3 mmol) and KClO4 (1.68 g, 6 mmol). The solution was stirredand refluxed for 2 h. The color of the mixing solution turnedbrown immediately from Rose-colored. The methanol solution(50 mL) of bipy (0.912 g, 6 mmol) was added to reaction mixtureand the solution was stirred for 1 h at room temperatureThe yield of the synthesis was 70%. Anal. Calc.C25H20ClZnN7O5 (%): C, 50.10; H, 3.36; N, 16.36; and Found (%):C, 50.02; H, 3.29; N, 16.32. Selected FT-IR data (Fig. S2), m(cm1): m (NH): 3257 (s); m (aromatic CAH): 3180 (w); m (CO):1712 (vs); m (CN):1567(s); m (CC):1474 (s); m (Ringbreath):1042; m (ClO): 1120 (s). 1H NMR (DMSO-d6, d/ppm)(Fig. S5): 7.67 (s, H, NH), 8.17-8.26 (dd, 2H, Ar), 8.56 (s, H, Ar),8.72-8.74 (m, 8H, Ar), 8.86-8.88 (d, 4H, Ar), 9.19 (d, 4H, Ar, both).
[Co(pyrazinamide)(2,2'-bipyridine)2](ClO4)2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
General procedure: hot aqueous solution (50 mL) of PZAH2 (0.36 g, 3 mmol) wasadded slowly with stirring to 80 mL aqueous solution of CoCl22H2O(0.72 g, 3 mmol) and KClO4 (1.68 g, 6 mmol). The solution was stirredand refluxed for 2 h. The color of the mixing solution turnedbrown immediately from Rose-colored. The methanol solution(50 mL) of bipy (0.912 g, 6 mmol) was added to reaction mixtureand the solution was stirred for 1 h at room temperature. Browncoloredcrystals [Co(PZAH)(bipy)2](ClO4)2, 1 (65%) suitable for Xraystructure determination, was deposited after two month. Anal.Calc. C25 H20 Cl2 Co N7 O9 (%): C, 43.37; H, 2.91; N, 14.16; and Found(%): C, 43.21; H, 3.04; N, 14.07. Selected FT-IR data (Fig. S1), m(cm1): m (NH): 3214 (s); m (aromatic CAH): 3069 (w); m (CO):1710 (vs); m (CN):1575 (s), (CC): 1441 (s); m (Ring breath):1040;m (ClO): 1125 (s). UV-Vis/MeOH (k/nm): 467, 492, 596 (Fig. S4).
[Pt(2-pyrazinecarboxamide)(μ-Cl)2Pt(bipyridine)]Cl2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
In ethanol; water;
General procedure: Equimolar amounts of the selected ligand, either PCA or PC with either pyridine or bipyridine (0.5 mmol from each), are mixed and dissolved in the minimum amount of ethanol. The ethanolic solution is added dropwise with constant stirring to an aqueous solution of [MCl4]2, M=Pd or Pt (0.5 mmol). Some ternary complexes were precipitated on heating to70C for 0.5 h, while the others were obtained on cold. The solvent was evaporated and the solid residue was washed with hot petroleum ether and then recrystallized from hot ethanol. The isolated fine crystals were left to dry under vacuum for several hours.
The synthesis of the co-crystals was carried out in solution crystallization experiments. Co-crystal 1 was obtained by the following procedure: stoichiometric amounts of PZA (0.5 mmol, 61.5 mg) and MHBA (0.5 mmol, 69.1 mg) were dissolved separately in a beaker with 10 ml of methanol solution, then combined and slowly evaporated at room temperature. A week later, we got club-shaped colorless crystals (yield 91 % based on MHBA).
General procedure: The synthesis of the co-crystals was carried out in solution crystallization experiments. Co-crystal 1 was obtained by the following procedure: stoichiometric amounts of PZA (0.5 mmol, 61.5 mg) and MHBA (0.5 mmol, 69.1 mg) were dissolved separately in a beaker with 10 ml of methanol solution, then combined and slowly evaporated at room temperature. A week later, we got club-shaped colorless crystals (yield 91 % based on MHBA).
General procedure: The synthesis of the co-crystals was carried out in solution crystallization experiments. Co-crystal 1 was obtained by the following procedure: stoichiometric amounts of PZA (0.5 mmol, 61.5 mg) and MHBA (0.5 mmol, 69.1 mg) were dissolved separately in a beaker with 10 ml of methanol solution, then combined and slowly evaporated at room temperature. A week later, we got club-shaped colorless crystals (yield 91 % based on MHBA).
General procedure: A solution of the selected ligand, either PCA or PC (0.5 mmol) in a minimum amount of ethanol is added dropwise with constant stirring to a 0.5 mmol solution of [MCl4]2, M=Pd or Pt. The complexes were precipitated either on cold or after heating for half an hour at 70C. The residue was filtered off, washed with hot petroleum ether, and then recrystallized from hot ethanol. The isolated fine crystals were left to dry under vacuum for several hours.
With 1H-imidazole; 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; ammonium chloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90℃; for 3h;Sealed tube;
General procedure: To a stirred solution of aryl halide (Br/I) (1 mmol) in dry dioxane in a 25 mL sealed tube, was added Pd(OAc)2 (5 mol%), dppf (6 mol %), DIPEA (2 mmol), imidazole (0.25 mmol), ammonium chloride (2 mmol) and then Co2(CO)8 (0.3 mmol). The seal tube was closed immediately and stirred at 90 C for 3h. After the reaction time the reaction mixture was cooled to room temperature. The reaction mixture was filtered through celite pad and washed with dioxane, the filtrate was concentrated under reduced pressure and the residue obtained was purified by column chromatography.
With thionyl chloride; In toluene; at 120℃; for 96h;
A solution of 2-quinoxaline carboxylic acid (97 mg, 0.57 mmol) in thionyl chloride (3 mL) was refluxed for 1.5 hours at 120 C, then removed from the heat, allowed to cool to 60 C and evaporated to total dryness under a flow of dry N2(g). A suspension of 2-pyrazinecarboxamide (70 mg, 0.57 mmol) in dry toluene (20 mL) was promptly added, and the resulting suspension was refluxed at 120 C for 4 days. The solvent was removed at reduced pressure, and the resulting purple solid was suspended in 2:1 MeOH/EtOAc (30 mL), sonicated and filtered through celite. The celite pad was washed with MeOH and EtOAc (30mL each) and the combined orange filtrate set aside. The celite pad was then washed with CHCl3 (3 x 50 mL), and the combined bright orange chloroform solution was taken to dryness at reduced pressure to give Hquinoxpz (63 mg) as a pink solid. The MeOH/EtOAc solution was taken to dryness to give a brown oil that was purified by column chromatography on silica gel, eluting with 9:1 CHCl3/acetone to give a further crop of Hquinoxpz (12 mg, Rf 0.5). Combined yield: 75 mg (0.27mmol, 48%). Elemental analysis calcd (%) for C14H9N5O2 (279.26): Calc. C 60.21 H 3.25 N 25.08; found: C 60.10 H 3.22 N 24.85. 1H NMR (400 MHz, d6-DMSO): delta (ppm) 12.60 (s, 1H, H4), 9.61 (s, 1H, H5), 9.40 (d, J3-2 = 1.4 Hz, 1H, H3), 9.06 (d, J1-2 = 2.5 Hz, 1H, H1), 8.95 (dd, J2-1 = 2.5 Hz, J2-3 = 1.4 Hz, 1H, H2), 8.30 (m, 2H, H6/9), 8.07 (m, 2H, H8/7) 1H NMR (400 MHz, CDCl3): delta (ppm)12.76 (s, 1H, H4), 9.78 (s, 1H, H5), 9.58 (d, J3-2 = 1.4 Hz, 1H, H3), 8.93 (d, J1-2 = 2.5 Hz, 1H, H1), 8.77 (dd, J2-1 = 2.5 Hz, J2-3 = 1.4 Hz, 1H, H2), 8.29 (m, 2H, H6/9), 7.95 (m, 2H, H8/7).
General procedure: A 15 mL round-bottom flask was charged with a stirring bar, 2.0 mL ethyl acetate, N,N-dimethylaniline derivative (0.9 mmol), amide (0.5 mmol) and complex 2 (27.9 mg, 0.05 mmol) were added. After stirring 15 min, TBHP (0.75 mmol, 108 mL) was added without extrusion of the air. The mixture was stirred for 8 h at 40 oC. After cooling to room temperature, 10 mL ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using ethyl acetate/pet ether (60-90 oC) as eluent to give the desired product.
[Zn(l1,5-dicyanamide)2(pyrazinamide)2](pyrazinamide)2}n[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
<strong>[98-96-4]Pyrazinamide</strong> (0.2 mmol, 0.025 g) was added with stirring to an aqueous solution of Zn(NO3).6H2O (0.1 mmol, 0.030 g). The mixture was stirred for 10 min, after which sodium dicyanamide (0.2 mmol, 0.018 g) was added. The colourless solution was stirred for 30 additional minutes. The colourless single crystals of 1 were grown from the solution by slow evaporation at room temperature within 3 weeks. The yield is 84 %, based on Zn. Elemental analysis. C24H20N18O4Zn (689.97), Calcd (%): C, 41.78; N, 36.54; H, 2.92. Found (%): C, 41.72; N, 36.58; H, 2.95. IR (KBr pellet, cm-1): nu(NH2): 3417(s); nus(C?N): 2183(s); nu(C=O): 1706(s); nu(C=N): 1576(s); nu(C-N): 1371(s).
With ammonium hydroxide; In N,N-dimethyl-formamide; at 20℃;Darkness;
The synthesis of 4 was similar to that of 1, but with H2pna (53.2 mg, 0.2 mmol) in place of H2pca. The resultant solution was allowed to evaporate slowly in darkness at room temperature for several days to afford the product as irregular-shaped colourless crystals of 4. (Yield: 73%, based on silver). Anal. Calc. (found) for Ag2C22H22N6O9: C, 36.19 (36.23); H, 3.04 (3.12); N, 11.51 (11.58)%. IR (KBr): nu (cm-1) = 3415 (m), 3281 (m), 3148 (m), 1677 (s), 1556 (m), 1450 (m), 1410 (m), 1377 (s), 1258 (m), 1167 (m), 1046 (m), 1021 (m), 861 (w), 789 (m), 651 (w), 575 (w), 556 (w), 524 (w), 435 (w).
With ammonium hydroxide; In N,N-dimethyl-formamide; at 20℃;Darkness;
The synthesis of 2 was similar to that of 1, but with H2pda(33.4 mg, 0.2 mmol) in place of H2pca. The resultant solution wasallowed to evaporate slowly in darkness at room temperature forseveral days to afford the product as block-shaped pink crystalsof 2. (Yield: 69%, based on silver). Anal. Calc. (found) for Ag2C12H10N4O6: C, 27.72 (27.69); H, 1.55 (1.61); N, 10.78 (10.96)%. IR (KBr): m(cm1) = 3395 (m), 3326 (m), 3211 (m), 3058 (m), 1664 (s), 1613(s), 1562 (s), 1428 (m), 1371 (s), 1268 (m), 1167 (w), 1046 (w),1021 (m), 900 (w), 816 (m), 753 (m), 715 (s), 651 (m), 619 (m),575 (w), 511 (w), 448 (w).
With ammonium hydroxide; In N,N-dimethyl-formamide; at 20℃;Darkness;
A mixture of Ag2O (23.2 mg, 0.1 mmol), pza (24.6 mg,0.2 mmol) and H2pca (33.3 mg, 0.2 mmol) was stirred in water-DMF (DMF = N,N0-dimethylformamide) mixed solvent (6 mL, v/v:1/1). Then aqueous NH3 solution (25%, 0.5 mL) was dropped intothe mixture to give a clear solution under ultrasonic treatment.The resultant solution was allowed to evaporate slowly in darknessat room temperature for several days to afford the product aslamellar clear yellow crystals of 1. (Yield: 75%, based on silver).Anal. Calc. (found) for Ag6C29H17N3O14: C, 27.24 (27.95); H, 1.34(1.42); N, 3.29 (3.52)%. IR (KBr): m (cm1) = 3409 (m), 3313 (m),1689 (m), 1562 (s), 1441 (m), 1403 (s), 1378 (s), 1257 (w), 1154(m), 1084 (m), 1027 (m), 849 (m), 823 (m), 766 (m), 696 (m),645 (m), 575 (w), 416 (w).
With ammonium hydroxide; In N,N-dimethyl-formamide; at 20℃;Darkness;
The synthesis of 3 was similar to that of 1, but with H2pma (50.8 mg, 0.2 mmol) in place of H2pca. The resultant solution was allowed to evaporate slowly in darkness at room temperature for several days to afford the product as needle-shaped clear white crystals of 3. (Yield: 79%, based on silver). Anal. Calc. (found) for AgC15H15N6O8: C, 34.97 (34.89); H, 2.94 (2.97); N, 16.31 (16.52)%. IR (KBr): nu (cm-1) = 3415 (s), 3345 (s), 3179 (s), 2217 (w), 1982 (w), 1931 (w), 1829 (w), 1721 (s), 1670 (s), 1562 (s), 1479 (s), 1415 (s), 1377 (s), 1238 (s), 1161 (m), 1091 (m), 1053 (m), 1027 (m), 918 (w), 855 (m), 810 (m), 607 (m), 518 (m), 441 (m).
tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
tert-butyl 4-{2-oxo-10-[(pyrazin-2-ylcarbonyl)amino]-1,2-dihydropyrimido[1,2-b]indazol-4-yl}piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With potassium phosphate; t-BuBrettPhos; [(2-di-tert-butylphosphino-3,6-dimethoxy-2?,4?,6?-triisopropyl-1,1?-biphenyl)-2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; at 110℃; for 16h;Inert atmosphere;
Under argon, tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate (200 mg, 447 muiotaetaomicron), pyrazine-2-carboxamide (138 mg, 1.12 mmol), Tripotassium phosphate (133 mg, 626 muiotaetaomicron), tBuBrettPhos (13.0 mg, 26.8 muiotaetaomicron), and tBuBrettPhos Pd G3 (22.9 mg, 26.8 muiotaetaomicron) were dissolved in l-Methoxy-2-propanol (5.0 ml, 52 mmol). The mixture was stirred at 110 C for 16 h and then purified via reverse phase chromatography (Method: Reprosil CI 8; 10 muiotaeta; 125x30 mm / flow: 50 ml/min / solvents: A = water (0,01% formic acid), B = Acetonitrile / gradient : 0.00-4.25 min = 20%B, 4.50min = 30%B, 19.00-22.50min = 100%B, 22.75-25.00min = 20%B) which afforded the product after drying in vacuo. The obtained amout was 105 mg (48 % of theory). LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 490 [M+H]+
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).
With acetic acid; 3-chloro-benzenecarboperoxoic acid; In ethyl acetate; at 0 - 20℃; for 24h;
At a controlled temperature of 0 to 5C, <strong>[98-96-4]pyrazinamide</strong> (1) 4.92 g was dispersed in 5 ml of ethyl acetate, and 17.92 g of m-chloroperbenzoic acid (85%) was dissolved in 35 ml of ethyl acetate and washed once with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was added dropwise to the <strong>[98-96-4]pyrazinamide</strong> ethyl acetate solution. After completion of the addition, the reaction was performed at room temperature for 24 hours.After TLC showed the reaction was complete, it was filtered, and the filter cake was washed with ethyl acetate (10ml*3). The filter cake was recrystallized from 90% methanol and vacuum dried to give 1,4-diamino<strong>[98-96-4]pyrazinamide</strong> (2) 5.23 as a white powder. g, Yield 84.37%
[Cu(pyrazinecarboxamide)(dipicolinate)(H2O)].H2O}[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
The synthesis of the compound [Cu(pca)(dipic)(H2O)]H2O}was proceeded in the following manner: to a water solution of copper(II) acetate monohydrate (0.15 g, 0.75 mmol) was added a stoichiometric amount of N-donor ligand pyrazinecarboxamide (0.09g, 0.75 mmol). The mixture was stirred for half an hour at laboratory temperature to obtain a homogeneous solution, then further reacted with stoichiometric ratio 1:1 of dipicolinic acid (0.125 g,0.75 mmol) and heated. The resulting blue solution was cooled down to the ambient temperature, filtered and left to slowly evaporate at laboratory temperature, what after a few days resulted in the single-crystals formation of targeted compound. Single-crystals for X-ray diffraction analysis were used directly from mother liquid.IR (ATR, cm-1): 3483(m), 3450(m), 3350(m), 3208(m), 3080(w),3043(w), 1688(s), 1673(s), 1634(s), 1606(s), 1593(s), 1527(w),1429(w), 1383(m), 1360(s), 1347(s), 1269(w), 1172(m), 1163(m),1088(m), 1080(m), 1022(m), 912(m), 883(w), 866(w), 781(s), 739(m), 705(w), 685(m), 633(m), 569(m), 515(w), 461(s), 440(s)UV-Vis (nm): 206, 274, 691.Elemental analysis for complex 1 (C12H12CuN4O7, Mw = 387.79g mol1) found % (expected %): C 36.99 (37.17); N 14.77 (14.45); H3.12 (3.12). Yield: 85%.
1 g of beta-cyclodextrin was weighed and dissolved in hot water at 70-100 C, and <strong>[98-96-4]pyrazinamide</strong> (about 0.108 g) equivalent to the number of moles of beta-cyclodextrin was added thereto and stirred for 0.5-1 h.The mixed solution was freeze-dried overnight in a refrigerator at -5 to 0 C.Wash the unencapsulated <strong>[98-96-4]pyrazinamide</strong> with dichloromethane,Finally, the residual solvent was removed to obtain a white clathrate powder.The resulting clathrate is stored at a low temperature in a closed and dry place.The inclusion ratio and yield of the clathrate were determined according to the above method.The results were 81.33% and 85.37%, respectively.
a. Dissolve 10 mg of beta-cyclodextrin in 5 mL of a 0.25% acetic acid solution and swell for 24 hours.Until the beta-cyclodextrin is completely dissolved, a beta-cyclodextrin solution is obtained;b. Take 1.7mg of <strong>[98-96-4]pyrazinamide</strong> dissolved in 0.1mL of 0.1mol / L NaOH solution,After fully dissolving, a <strong>[98-96-4]pyrazinamide</strong> solution is obtained;c. Take 3 mg of isoniazid rifamycin oxime dissolved in 1 mL of 0.1 mol/L NaOH solution, and take 0.3 mL therefrom to add to the <strong>[98-96-4]pyrazinamide</strong> solution prepared in step b,Add 1 mL of a 2 g/L sodium tripolyphosphate (TPP) aqueous solution and mix well to obtain a mixed solution;d. The <strong>[98-96-4]pyrazinamide</strong>, isoniazid rifamycin oxime prepared in step c,The mixed solution of TPP was slowly added dropwise to the swollen beta-cyclodextrin solution obtained in the step a, and stirred at room temperature for 30 min.Add a small amount of lactose as a protective agent, then freeze-dry at -5 to 0 C for 36-48h.A <strong>[98-96-4]pyrazinamide</strong>-isoindole rifamycin -beta-cyclodextrin inclusion complex was obtained.The resulting clathrate is stored at a low temperature in a closed and dry place. The inclusion ratio and yield of the clathrate were measured by the above method, and the results were 79.85 and 82.235%, respectively.
1) Weigh 1.0g of acetylsalicylic acid,Add it together with 10 mL of dichloromethaneInto a 100mL single-mouth bottle,Stir at room temperature for 30 min.After the acetylsalicylic acid is fully dissolved,Add 5 ml of thionyl chloride and stir at room temperature for 30 min.Then add 1 drop of DMF,After stirring, it is found that gas is slowly generated.The temperature was raised to 40 C and refluxed for 3 hours.Finally, distillation under reduced pressure gave crude acetylsalicylic acid chloride.2) 0.6g <strong>[98-96-4]pyrazinamide</strong> and 40mLChloroform is placed in a three-neck bottle.Warm up to 40 C to fully dissolve it,Add 1 mL of triethylamine,A <strong>[98-96-4]pyrazinamide</strong> reaction solution was obtained.3) Add the crude acetyl salicyl chloride obtained in step 1Dilute in 2 ml of dichloromethane,A reaction solution of acetylsalicylic acid chloride was obtained.Then slowly add the acetylsalicylic acid chloride reaction solution to step 2In the <strong>[98-96-4]pyrazinamide</strong> reaction solution,The dropping process is completed within 10 minutes.The temperature was then raised to 35-45 C to reflux the reaction.acetylsalicylic acid 4) After 1 hour, the sampling board is monitored.Found that new substances are produced,After the reaction for 12 hours, some of the starting <strong>[98-96-4]pyrazinamide</strong> remained unreacted.Stop the reaction.5) Take out the reaction solution for post-treatment,Purification by column chromatography gave 0.4832 g of the acetylsalicylic acid-pyrazine amide hybrid product.The purity of the product was determined by HPLC to be 95.4%.The calculated yield was 35%.
With terephthalic acid; In water; for 0.166667h;Heating;
To a hot solution of Cu(CH3COO)2*H2O (0.02 g, 0.1 mmol) in 5 ml H2O, pyrazinecarboxamide (0.024 g, 0.2 mmol) and 1,4-benzenedicarboxilyc acid (0.016 g, 0.1 mmol) was added. The reaction mixturewas heated for 10 min, filtered off and then slowly cooled toroom temperature giving green crystals. Yield: 58%. Anal. Calc. for C13H17Cu2N3O9 (%): C, 32.07; H, 3.49; N, 8.63. Found: C, 31.99; H,3.42; N, 8.57. IR (cm-1): 3387(w), 3237(w), 1609(s), 1167(m),1686(s), 1584(w), 1423(s), 1382(m), 1349(w), 1061(w), 1022(s),870(s), 784(s), 681(w).
2.1. Chemicals and sample preparation
Anhydrous solid-state DIF (purity 99%) was acquired by J&K ChemicalCompany (Shanghai, China). The sample PZA (purity 99%) was purchasedfromSigma-Aldrich Company (Shanghai, China). All compoundswere used as received without additional purification. The DIF-PZA drug-drug co-crystal was obtained by liquid assistedgrinding method, which is one of commonly used methods in the fieldof co-crystal preparation and analysis. At room temperature, the mixtureof molar ratio 1:1 stoichiometry of DIF (0.01 mol, ~250 mg) and PZA (0.01 mol, ~122 mg) was added in 25 ml stainless steel millingjars. Co-grinding the physical mixture was performed in an oscillatoryball mill (Mixer Mill MM400, with grinding-time lasting around60 min and frequency at 15 Hz), and several drops of water (around0.05 ml)was added to themixture compounds before starting mechanicalgrinding in the planetarymill. In order to design a set of control experiment,another physicalmixture was obtained by gently mixing twocompounds above with a 1:1 equal-molar ratio in a glass vial by using avortex mixer. Approximately 0.25 g DIF, PZA, physical mixture and thecorresponding co-crystal were weighed and they were ground gentlyto achieve particles with the mean size of several micrometers inorder to minimize the scattering effects from sample particles duringTHz spectralmeasurements. These samples were respectively preparedby using a hydraulic compression machine (HANDTAB-100, IchihashiSeiki, Kyoto, Japan) with a diameter of about 13.00mmand a thicknessof around 1.60 mm. The pressure is continuously applied for 30 s at aconstant pressure of around 4.0 MPa to obtain final pellets, and theyare sealed in plastic bags in order to avoid probable deliquescence atroom temperature before further THz spectral measurements. As forRaman spectral measurements, there is no need for further samplepreparation.
With ammonium hydroxide In water at 120℃; for 24h; Sealed tube; Autoclave;
S8. Procedure for the synthesis of amides
General procedure: A magnetic stir bar and the alcohol substrate were transferred to 8 mL glass vial and then 2 mL of H2O wasadded. Then, 3 mg catalyst was added followed by the addition of aq. NH3. Then, the vial was f itted with aseptum, cap, and needle. The reaction vials were placed into a 300 mL autoclave (8 vials containing differentsubstrates were placed at a time in the autoclave) and then the autoclave was pressurized with 10 bar air. Theautoclave was placed into an aluminium block and the temperature of the aluminum block was set in orderobtain 120 °C inside the autoclave. Temperature of the aluminum block was set to 130 oC to attain 120 oCinside the autoclave, which was considered as the reaction temperature. The reactions were allowed toprogress under continuous stirring for the required time at 120 °C. Af ter completion of the reaction, theautoclave was cooled down to room temperature and the remaining air was gradually discharged. Afterwards,the catalyst was f iltered-off and washed with methanol. The solvent f rom the f iltrate containing the reactionproducts was removed in vacuum and the corresponding amide was purified by column chromatography. Allproducts were analyzed by GC-MS and NMR spectroscopy analysis.