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Chemical Structure| 19847-12-2
Chemical Structure| 19847-12-2
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Product Details of [ 19847-12-2 ]

CAS No. :19847-12-2 MDL No. :MFCD00049361
Formula : C5H3N3 Boiling Point : -
Linear Structure Formula :- InChI Key :PMSVVUSIPKHUMT-UHFFFAOYSA-N
M.W : 105.10 Pubchem ID :73172
Synonyms :
Pyrazinecarbonitrile

Calculated chemistry of [ 19847-12-2 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 26.75
TPSA : 49.57 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.95 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.79
Log Po/w (XLOGP3) : -0.01
Log Po/w (WLOGP) : 0.35
Log Po/w (MLOGP) : -1.48
Log Po/w (SILICOS-IT) : 0.92
Consensus Log Po/w : 0.11

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.04
Solubility : 9.58 mg/ml ; 0.0911 mol/l
Class : Very soluble
Log S (Ali) : -0.58
Solubility : 27.5 mg/ml ; 0.262 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.67
Solubility : 2.26 mg/ml ; 0.0215 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.78

Safety of [ 19847-12-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 19847-12-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 19847-12-2 ]
  • Downstream synthetic route of [ 19847-12-2 ]

[ 19847-12-2 ] Synthesis Path-Upstream   1~36

  • 1
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YieldReaction ConditionsOperation in experiment
82.6% at 20 - 60℃; for 5 h; A 500ml three-neck flask, was added at a concentration of 20percent sodium hydroxide (30g) solution, and sodium hypochlorite solution (100ml), was added 2-cyano-pyrazine (21g, 0.2mol) at room temperature, the reaction was stirred for 1h. Then for 4h at 50 ~ 60 , with dichloromethane (4 × 200ml) was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid 15.7g, yield 82.6percent.
Reference: [1] Patent: CN105622526, 2016, A, . Location in patent: Paragraph 0020; 0021; 0022
[2] Patent: CN108570011, 2018, A, . Location in patent: Paragraph 0012; 0013; 0014
  • 2
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  • [ 22047-25-2 ]
Reference: [1] Journal of the American Chemical Society, 1992, vol. 114, # 5, p. 1838 - 1843
  • 3
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  • [ 917-64-6 ]
  • [ 22047-25-2 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1999, vol. 64, # 7, p. 1159 - 1179
[2] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 7, p. 1093 - 1101
[3] Molecules, 2009, vol. 14, # 10, p. 4197 - 4212
  • 4
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  • [ 75-16-1 ]
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Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 3617,3618,3620
[2] Patent: US2677686, 1952, ,
  • 5
  • [ 98-96-4 ]
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YieldReaction ConditionsOperation 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,
  • 6
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  • [ 557-21-1 ]
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Reference: [1] Organic Letters, 2007, vol. 9, # 9, p. 1711 - 1714
  • 7
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  • [ 557-21-1 ]
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Reference: [1] Organic Letters, 2017, vol. 19, # 8, p. 2118 - 2121
  • 8
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Reference: [1] Patent: US4496729, 1985, A,
[2] Applied Catalysis A: General, 2012, vol. 443-444, p. 111 - 118
[3] Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases, 1988, vol. 84, # 7, p. 2397 - 2408
[4] Chemical Communications, 2001, # 20, p. 2088 - 2089
[5] Patent: US4778890, 1988, A,
[6] Patent: US4778890, 1988, A,
[7] Journal of Chemical Sciences, 2014, vol. 126, # 2, p. 487 - 498
[8] Catalysis Science and Technology, 2014, vol. 4, # 9, p. 3306 - 3316
[9] Catalysis Communications, 2018, vol. 108, p. 17 - 22
  • 9
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Reference: [1] Arkivoc, 2010, vol. 2010, # 6, p. 47 - 52
  • 10
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  • [ 143-33-9 ]
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Reference: [1] Synthetic Communications, 2001, vol. 31, # 14, p. 2203 - 2207
  • 11
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  • [ 7677-24-9 ]
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 11, p. 2877 - 2882
  • 12
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
  • 13
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Reference: [1] Patent: CN104557357, 2018, B,
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
  • 15
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Reference: [1] Chemical Communications, 2011, vol. 47, # 29, p. 8394 - 8396
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
  • 18
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  • [ 98-96-4 ]
YieldReaction ConditionsOperation in experiment
98% at 100℃; for 0.333333 h; 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)].

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[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
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[24] Tetrahedron, 2018, vol. 74, # 13, p. 1527 - 1532
  • 19
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  • [ 1339045-85-0 ]
  • [ 6924-68-1 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Patent: WO2011/123890, 2011, A1, . Location in patent: Page/Page column 63-64
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Reference: [1] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 169 - 171
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Reference: [1] Chemical Communications, 2011, vol. 47, # 29, p. 8394 - 8396
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  • [ 1339045-85-0 ]
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YieldReaction ConditionsOperation 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.
Reference: [1] Patent: WO2011/123890, 2011, A1, . Location in patent: Page/Page column 63-64
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
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YieldReaction ConditionsOperation in experiment
51% With sulfuryl dichloride In N,N-dimethyl-formamide; toluene at 20℃; for 5.6 h; Cooling with ice To a solution of pyrazine-2-carbonitrile 13 (6.90 g, 65.65 mmol) in toluene (48 mL) and DMF (5 mL) was added sulfuryl chloride (21.2 mL, 260.8 mmol) over 10 min. The reaction mixture was stirred for 30 min in an ice bath, then allowed to warm up to room temperature gradually, after which it was stirred for 5 h. The toluene layer was decanted, and the reddish oil residue was extracted three times with diethyl ether. The combined toluene and ether layers were quenched with ice water and cooled in an ice bath. The combined layers were then neutralized with solid NaHCO3, then separated, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to afford the title compound. The crude product was purified by silica gel chromatography (eluent: 100percent dichloromethane) to give 3-chloropyrazine-2-carbonitrile 14 as a white powder (4.7 g, 51percent). Rf = 0.76 (dichloromethane); mp 44-46 °C (lit. [14] : 47-48 °C); IR (KBr) νmax (cm-1): 3088 (νCHar), 2242 (νCN), 1377 (νC=C), 1087 (νC-N); 1H NMR (400 MHz, DMSO-d6): δ 8.91 (d, 1H, J = 2.4 Hz, H-6), 8.88 (d, 1H, J = 2.4 Hz, H-5); 13C NMR (100 MHz, DMSO-d6): δ 150.67 (C-3), 147.97 (C-5), 144.26 (C-6), 129.87 (C-2), 114.66 (CN); MS (ESI) m/z (percent): 140.3 (100) [M + H]+, 142.3 (40) [M + H + 2]+. Anal. calcd for C5H2ClN3: C, 43.04; H, 1.44; N, 30.11. Found: C, 43.18; H, 1.45; N, 30.16.
Reference: [1] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 171 - 183
[2] Patent: EP1582521, 2005, A1, . Location in patent: Page/Page column 133-134
[3] Magnetic Resonance in Chemistry, 2009, vol. 47, # 7, p. 617 - 624
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Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
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  • [ 20010-99-5 ]
YieldReaction ConditionsOperation in experiment
100% With Ni-doped silica; hydrogen In toluene at 140℃; for 4 h; Autoclave; Inert atmosphere The synthesis of 2-aminomethyl pyradine(2-AMPZ) was carried out by a method shown below, byreference to the method described in literature (JP A 2001-894594). 2-cyanopyradine used was from Sigma-Aldrich Co.LLC.1.05 g of 2-cyanopyradine (10 mmol) and 100mg of60 wt percent-Ni/5i02 were placed in an autoclave (5U53 16) with20 mL of toluene and replaced with argon gas. This waspressurized with hydrogen gas to 50 atm, stirred at 140°C. for4 hours. The reaction solution was filtered and concentratedto give 2-aminomethyl pyradine (2-AMPZ) quantitatively.10152] ‘H-NMR spectrum (399.78 MHz, CDC13):ö8.60-8.45 (m, 3H), 4.07 (s, 2H), 1.79 (br, 2H)
98% With hydrogen In 1,4-dioxane at 60℃; for 8 h; Autoclave Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 °C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98percent) as a brown oil. MS m/z (ESI): 110 [M+1]
98% With hydrogen In 1,4-dioxane at 60℃; for 8 h; Autoclave Step 6
C-Pyrazin-2-yl-methylamine
Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave.
The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60 °C and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98percent) as a brown oil. MS m/z (ESI): 110 [M+1].
98% With hydrogen In 1,4-dioxane at 60℃; for 8 h; Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave.
The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60° C. and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98percent) as a brown oil. MS m/z (ESI): 110 [M+1].
98% With pyridine; hydrogen In 1,4-dioxane at 60℃; for 8 h; Autoclave 2-cyano-pyrazol 1g (10.5 g, 100 mmol) was dissolved in 150 mL 1,4- dioxane was added 1.0 g Raney nickel in 250 mL autoclave at 60 , 40 atm of hydrogen the reaction was stirred for 8 hours. Filtered, and the filtrate was concentrated under reduced pressure, to give C- pyridin-2-yl - methylamine 1h (10.7 g, brown oil). Yield: 98percent.
98.9% With hydrogen In 1,4-dioxane at 60℃; for 48 h; Pyrazine-2-carbonitrile (19 g, 180 mmol) was dissolved in 1,4-dioxane (280 mL), and then Raney nickel (1.9 g) was added. The reaction mixture was reacted in hydrogen atmosphere at 60°C for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (1) (19 g, 98.9percent) as a brown oil. 1H MR (400 MHz, DMSO-d6): δ 871 (s, 1H), 8.54-8.53 (m, 2H), 8.48 (d, J = 2.4Hz, 1H), 3.86 (s, 2H), 1.97 (br, 2H).

Reference: [1] Patent: US2015/31920, 2015, A1, . Location in patent: Paragraph 0150; 0151; 0152
[2] Patent: EP2230241, 2010, A1, . Location in patent: Page/Page column 18
[3] Patent: EP2404921, 2012, A1, . Location in patent: Page/Page column 9
[4] Patent: US2012/65209, 2012, A1, . Location in patent: Page/Page column 9
[5] Patent: TWI522358, 2016, B, . Location in patent: Page/Page column 15; 18
[6] Patent: WO2018/175512, 2018, A1, . Location in patent: Page/Page column 21
[7] Synlett, 2001, # 10, p. 1623 - 1625
[8] Patent: WO2005/66126, 2005, A1, . Location in patent: Page/Page column 61-62
[9] Patent: WO2006/108103, 2006, A1, . Location in patent: Page/Page column 30
[10] Patent: US2008/119496, 2008, A1, . Location in patent: Page/Page column 10
[11] Patent: WO2008/60301, 2008, A1, . Location in patent: Page/Page column 29
  • 32
  • [ 19847-12-2 ]
  • [ 138588-41-7 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With sodium methylate In methanol at 20 - 30℃; for 6 h;
Stage #2: at 25℃; for 22 h;
To a solution of sodium methoxide (NaOCH3) (51.4 g, 0.952 mol) in methanol (3800 ml) there is added cyanopyrazine (1.00 KG, 9.53 mol) slowly at room temperature. The mixture is heated to 30° C. and stirred for 6 h. The mixture is cooled to 25° C. followed by the addition of ammonium chloride (NH4Cl) (572 g, 10.5 mol). The reaction mixture is stirred for 22 h and methyl t-butyl ether (4000 mL) is added and the mixture is stirred for 15 min forming a solid. The solid is filtered and washed with methyl t-butyl ether (2.x.1000 mL) then dried at 40° C./0-10 mmHg for 17 h to give white solid product (1435 g) in 95percent yield with 95percent HPLC purity. 1H NMR (DMSO-D6): δ 9.7 (bs, 3H), 9.49 (d, 1H, J=1.5 Hz), 9.04 (m, 1H), 8.93 (t, 1H, J=1.5 Hz)
1.2 g
Stage #1: With sodium methylate In methanol at 20℃; for 12 h;
Stage #2: With ammonium chloride In methanol for 3 h; Reflux
To a solution of pyrazine-2-carbonitrile (1.0 g, 9.52 mmol) in methanol (20 mL) was addedNaOCH3 (0.10 g, 1.90 mmol). The resulting mixture was heated with stirring at rt for 12 hrs. Tothe reaction mixture was added NH4C1 (0.51 g, 9.52 mmol). After being heated under reflux for 3 hrs, the resulting reaction mixture was concentrated in vacuo. The residue was suspended in ethanol (30 mL). The suspension was heated under reflux for 1 hr, then cooled to rt and filtered. The filtrate was concentrated in vacuo to give pyrazine-2-carboxamidine hydrochloride (1.2 g),which was used in the next step without further purification.
Reference: [1] Patent: US2006/281760, 2006, A1, . Location in patent: Page/Page column 5; 8
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 111 - 118
[3] Patent: US2005/75357, 2005, A1, . Location in patent: Page/Page column 35
[4] Patent: WO2005/79798, 2005, A1, . Location in patent: Page/Page column 150
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 299 - 301
[6] Synthesis, 2010, # 7, p. 1091 - 1096
[7] Patent: WO2016/107832, 2016, A1, . Location in patent: Page/Page column 67
  • 33
  • [ 67-56-1 ]
  • [ 19847-12-2 ]
  • [ 138588-41-7 ]
Reference: [1] Patent: US2005/75357, 2005, A1, . Location in patent: Page/Page column 35
  • 34
  • [ 19847-12-2 ]
  • [ 645-36-3 ]
  • [ 119165-68-3 ]
YieldReaction ConditionsOperation in experiment
1.49 g
Stage #1: With sodium methylate In methanol at 10 - 35℃; for 0.416667 h;
Stage #2: With acetic acid In methanol at 50℃; for 1 h;
Stage #3: With hydrogenchloride In methanolReflux
Step 1:
2-(1H-Imidazol-2-yl)pyrazine
2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL).
To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25percent solution in methanol).
After stirring for 25 minutes at room temperature, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50° C. for 1 hour. MeOH (40 mL) and 6N HCl (12 mL) were added and the reaction was stirred at reflux overnight.
The reaction mixture was cooled to room temperature and partitioned between 1:1 Et2O and water (60 mL) and the layers were separated.
The aqueous layer was basified to pH 9/10 and extracted with 10percent MeOH in DCM.
The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired compound (1.49 g yellow solid).
1H NMR (400 MHz, MeOH-d4) δ ppm: 7.67 (s, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 5.72 (s, 2H)
Reference: [1] Patent: WO2012/93148, 2012, A1, . Location in patent: Page/Page column 36-37
[2] Patent: US2014/11802, 2014, A1, . Location in patent: Paragraph 0196; 0197
  • 35
  • [ 19847-12-2 ]
  • [ 22483-09-6 ]
  • [ 119165-68-3 ]
Reference: [1] Chemical Communications, 2015, vol. 51, # 12, p. 2425 - 2428
  • 36
  • [ 19847-12-2 ]
  • [ 356783-16-9 ]
Reference: [1] Patent: CN107226794, 2017, A,
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