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Product Details of [ 100-70-9 ]

CAS No. :100-70-9 MDL No. :MFCD00006218
Formula : C6H4N2 Boiling Point : -
Linear Structure Formula :- InChI Key :FFNVQNRYTPFDDP-UHFFFAOYSA-N
M.W :104.11 Pubchem ID :7522
Synonyms :

Calculated chemistry of [ 100-70-9 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 28.95
TPSA : 36.68 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.62 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.23
Log Po/w (XLOGP3) : 0.45
Log Po/w (WLOGP) : 0.95
Log Po/w (MLOGP) : -0.23
Log Po/w (SILICOS-IT) : 1.37
Consensus Log Po/w : 0.76

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.32
Solubility : 4.94 mg/ml ; 0.0474 mol/l
Class : Very soluble
Log S (Ali) : -0.79
Solubility : 16.9 mg/ml ; 0.163 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.04
Solubility : 0.954 mg/ml ; 0.00916 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.44

Safety of [ 100-70-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 100-70-9 ]

* 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 [ 100-70-9 ]
  • Downstream synthetic route of [ 100-70-9 ]

[ 100-70-9 ] Synthesis Path-Upstream   1~46

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Reference: [1] Patent: US2008/188665, 2008, A1, . Location in patent: Page/Page column 1
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YieldReaction ConditionsOperation in experiment
89% With tetraphosphorus decasulfide; ammonia In methanol at 20℃; for 12 h; General procedure: a. Ground phosphoruspentasulfide (115 g, 0.5 mol) was added to asolution of 4-cyanopyridine (52 g, 0.5 mol) in 250 mLof 20percent ammonium in methanol under vigorous stirringmaintaining the reaction mixture temperature below35–40°C. The reaction mixture was kept at roomtemperature for 12 h, After the reactionended, 150 mL of water was added and the mixturewas heated up to 70–75°C by water bath till the gasevolution stopped. After cooling the precipitate wasfiltered off, washed with water, and dried. Yield 89percent(61.8 g), Rf 0.45, mp 137° (136–137° [21]). Found,percent: 52.09; H 4.31; N 20.30; S 23.30. C6H6N2S.Calculated, percent: 52.15; H 4.38; N 20.27; S 23.20.
85% With hydrogen sulfide In dimethyl sulfoxide at 20℃; General procedure: The corresponding nitrile (100 mmol) prepared as described previously18 was dissolved in DMSO (25 mL) and H2S was slowly bubbled through the solution until no more gas was consumed. The solution was stirred at r.t. and the reaction progress was monitored by TLC (acetone). H2O was added to precipitate the product, the solid formed was collected by filtration, and recrystallized from DMF.
67% With sodiumsulfide nonahydrate In N,N-dimethyl-formamide at 130℃; for 2.5 h; General procedure: Benzonitrile 1a (1 mmol), Na2S*9H2O (1.2 mmol) and DMF (1 mL) were added into a 10 mL bottle. The reactor was placed in a heating magnetic stirrer at 130 °C. After 2.5 h, by adding about 3 mL H2O after the reaction to disperse the solid product, the reaction mixture was extracted with EtOAc (3 x 3 mL), and the mixture was purified by column chromatography.
Reference: [1] Synlett, 2004, # 14, p. 2615 - 2617
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 1994, vol. 96, # 1-4, p. 325 - 326
[3] Synthesis, 2002, # 12, p. 1649 - 1651
[4] Journal of the Iranian Chemical Society, 2010, vol. 7, # 3, p. 752 - 758
[5] Russian Journal of General Chemistry, 2015, vol. 85, # 10, p. 2295 - 2298[6] Zh. Obshch. Khim., 2015, vol. 85, # 10, p. 1663 - 1666,4
[7] Synlett, 2009, # 14, p. 2338 - 2340
[8] European Journal of Organic Chemistry, 2004, # 16, p. 3422 - 3434
[9] Synthesis (Germany), 2014, vol. 46, # 1, p. 126 - 134
[10] RSC Advances, 2018, vol. 8, # 1, p. 170 - 175
[11] Russian Chemical Bulletin, 2009, vol. 58, # 4, p. 844 - 850
[12] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 2, p. 363 - 371
[13] Heterocycles, 2018, vol. 96, # 3, p. 509 - 517
[14] Journal of Medicinal Chemistry, 2001, vol. 44, # 11, p. 1741 - 1748
[15] Journal of the Chemical Society. Dalton Transactions, 2001, # 5, p. 550 - 559
[16] Synthesis, 1992, # 12, p. 1219 - 1220
[17] Helvetica Chimica Acta, 1945, vol. 28, p. 820,823
[18] Journal of the Chemical Society, 1952, p. 742
[19] Synthesis, 2010, # 10, p. 1603 - 1608
[20] Zeitschrift fur Anorganische und Allgemeine Chemie, 2010, vol. 636, # 7, p. 1380 - 1385
[21] European Journal of Organic Chemistry, 2012, # 27, p. 5231 - 5247
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1778 - 1783
[2] European Journal of Inorganic Chemistry, 2009, # 14, p. 2162 - 2169
[3] Patent: US2451779, 1947, ,
[4] Bulletin de la Societe Chimique de France, 1957, p. 714,716
[5] Journal of the Chemical Society, 1949, p. 449,453
[6] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1269 - 1273
[7] Patent: WO2005/40133, 2005, A1, . Location in patent: Page/Page column 126
[8] Patent: US2012/202806, 2012, A1,
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  • [ 4039-32-1 ]
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YieldReaction ConditionsOperation in experiment
49% With hydrogenchloride In tetrahydrofuran; diethyl ether; water Pyridine-2-carboxamidine
Lithium hexamethyl disilazide (1M solution in THF, 60.5 ml, 60.5 mmol) was added to a solution of pyridine-2-carbonitrile (3.0 g, 28.8 mmol) in Et2O (30 ml) at 0° C.
The reaction was allowed to warm to room temperature overnight.
The reaction was cooled to 0° C. and 3 M HCl (54 ml) was added and the reaction was stirred for 30 min.
Water (135 ml) was added and the organic phase was separated and discarded.
The aqueous layer was basified to pH 14 with saturated aqueous NaOH and extracted with DCM (*3).
The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (1.70 g, 49percent).
Reference: [1] Patent: US2012/202806, 2012, A1,
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  • [ 19402-64-3 ]
  • [ 52313-50-5 ]
Reference: [1] Journal of the Chemical Society, 1948, p. 303,308
[2] Bulletin de la Societe Chimique de France, 1957, p. 714,716
[3] Journal of the Chemical Society, 1946, p. 147,149
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  • [ 52313-50-5 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1957, p. 714,716
[2] Journal of the Chemical Society, 1947, p. 390,391
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  • [ 1620-76-4 ]
Reference: [1] Chemistry Letters, 1984, p. 769 - 772
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  • [ 107-15-3 ]
  • [ 7471-05-8 ]
YieldReaction ConditionsOperation in experiment
92% at 80℃; for 0.0833333 h; Neat (no solvent); Microwave irradiation The typical reaction procedure under MW irradiation. A mixture of nitrile (10 mmol), EDA (40 mmol) and Cu(II)-(IAA)2 (2.0 mmol) was irradiated with microwave (1000 W) for 5-20 min by pulsed irradiation. At the end of the reaction (monitored by TLC, eluent: EtOAc/MeOH, 3:1), the mixture was cooled to room temperature, CH2Cl2 was then added and the catalyst was filtered. Evaporation of the solvent gave the almost pure product. Further purification was performed as for the procedure used in the synthesis of imidazolines under reflux condition. The identities of products were confirmed by mp, 1H NMR, MS and IR data.
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[2] Canadian Journal of Chemistry, 2010, vol. 88, # 2, p. 135 - 141
[3] Monatshefte fur Chemie, 2007, vol. 138, # 6, p. 579 - 583
[4] Tetrahedron Letters, 2011, vol. 52, # 14, p. 1578 - 1582
[5] Tetrahedron Letters, 2006, vol. 47, # 13, p. 2129 - 2132
[6] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 2, p. 249 - 254
[7] Arkivoc, 2010, vol. 2010, # 2, p. 97 - 109
[8] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 3, p. 585 - 592
[9] Chemistry - A European Journal, 2015, vol. 21, # 12, p. 4703 - 4711
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Reference: [1] Patent: US4680304, 1987, A,
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  • [ 14034-59-4 ]
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Reference: [1] Journal of the Chemical Society, 1947, p. 497,500
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  • [ 100367-55-3 ]
Reference: [1] Heterocycles, 2002, vol. 58, p. 301 - 310
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  • [ 100-58-3 ]
  • [ 39930-11-5 ]
Reference: [1] Patent: WO2005/21545, 2005, A1, . Location in patent: Page/Page column 18
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  • [ 100-59-4 ]
  • [ 39930-11-5 ]
Reference: [1] European Journal of Inorganic Chemistry, 2008, # 17, p. 2739 - 2745
[2] Organometallics, 2011, vol. 30, # 15, p. 4074 - 4086
  • 14
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  • [ 39930-11-5 ]
Reference: [1] Patent: US2002/45747, 2002, A1,
[2] Patent: US6506782, 2003, B1,
  • 15
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  • [ 105-36-2 ]
  • [ 26510-52-1 ]
Reference: [1] Green Chemistry, 2017, vol. 19, # 6, p. 1420 - 1424
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  • [ 27652-89-7 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 17, p. 4144 - 4147
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  • [ 37943-90-1 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 35, p. 9566 - 9570
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  • [ 829-85-6 ]
  • [ 37943-90-1 ]
Reference: [1] Chemical Communications, 2015, vol. 51, # 35, p. 7540 - 7542
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  • [ 3939-15-9 ]
Reference: [1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731
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  • [ 58481-14-4 ]
  • [ 97483-79-9 ]
Reference: [1] Heterocycles, 1987, vol. 26, # 3, p. 731 - 744
[2] Heterocycles, 1987, vol. 26, # 3, p. 731 - 744
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  • [ 1671-87-0 ]
Reference: [1] European Journal of Organic Chemistry, 2008, # 12, p. 2156 - 2166
[2] Journal of Organic Chemistry, 2005, vol. 70, # 21, p. 8468 - 8471
[3] Chemical Communications, 2012, vol. 48, # 12, p. 1736 - 1738
[4] Angewandte Chemie - International Edition, 2013, vol. 52, # 52, p. 14112 - 14116[5] Angew. Chem., 2013, vol. 125, # 52, p. 14362 - 14366,5
[6] Organic and Biomolecular Chemistry, 2014, vol. 12, # 23, p. 3950 - 3955
[7] Patent: US2016/106859, 2016, A1,
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  • [ 75-05-8 ]
  • [ 57537-63-0 ]
  • [ 1671-87-0 ]
Reference: [1] Chemistry - A European Journal, 2016, vol. 22, # 39, p. 13985 - 13998
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  • [ 33252-29-8 ]
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  • [ 139485-42-0 ]
Reference: [1] J. Appl. Chem. USSR (Engl. Transl.), 1991, vol. 64, # 6.2, p. 1155 - 1159[2] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1991, vol. 64, # 6, p. 1297 - 1301
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  • [ 67-56-1 ]
  • [ 586-98-1 ]
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Reference: [1] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 9, p. 2906 - 2910
[2] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 9, p. 2906 - 2910
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  • [ 64-17-5 ]
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Reference: [1] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 9, p. 2906 - 2910
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  • [ 38180-46-0 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 1, p. 135 - 137
[2] Tetrahedron, 2006, vol. 62, # 25, p. 5862 - 5867
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 22, p. 6442 - 6446[4] Angew. Chem., 2015, vol. 127, # 22, p. 6542 - 6546,5
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YieldReaction ConditionsOperation in experiment
79% With hydrazine hydrate In ethanol at 20 - 50℃; for 9 h; Inert atmosphere 2-Pyridinecarboximidic Acid, Hydrazide
Pyridine 2-Amidrazone Intermediate
To a 1 L four neck round-bottomed flask equipped with a mechanical stirrer, a reflux condenser, and a nitrogen inlet/outlet was charged 2-pyridinecarbonitrile (50 g, 480 mmol), hydrazine hydrate (26.4 g, 528 mmol) and ethanol (25 mL).
The resulting mixture was stirred at room temperature for six hours, after which time TLC showed some remaining starting material.
Another 7.2 g (144 mol) portion of hydrazine hydrate was added and the mixture heated at 50° C. for three hours.
The mixture was cooled in an ice bath and filtered then dried to give 40.2 g of product as a solid.
The mother liquor was concentrated, triturated with hexanes and dried to give 11.6 g of additional product as a solid (51.8 g total, 381 mmol, 79percent).
1H NMR (400 MHz, CDCl3) 8.50 (m, 1H, Ar-H), 8.01 (d, 1H, Ar-H), 7.68 (t, 1H, Ar-H), 7.28 (m, 1H, Ar-H) 5.38 (br s, 2H, -NH2), 4.62 (br s, 1H, -N-H), 2.40 (br s, 1H, -N-H).
71% With hydrazine hydrate In ethanol at 0℃; for 36 h; A round botton flask, protected from light with aluminumfoil, was filled with an ethanolic solution (20 ml) of 2-cyanopyridine (10.5g, 0.101 mol) and kept at 0°C with an ice bath. Hydrazine hydrate 98percent (34.7 g, 0.69 mol), dissolvedin a minimum volume of EtOH, was added and the mixture was allowed to stir for36 h at 0°C. The white-pinky precipitate was filtered and crystallized fromtoluene in order to obtain 9.76 g (0.072 mol, yield: 71percent) of white crystals.Only the required quantity for the next step was used at the time, while theremaining crystals were kept in refrigerator (in a flask protected from light)in a toluene solution.
63% With hydrazine hydrate In ethanol at 20℃; for 2 h; 2-cyanopyridine (1.06 g, 10 mmol), ethanol (9 mL) and 80percent hydrazine hydrate (24 mL) were mixed and stirred at room temperature for two hours.Diluted with an equal volume of water, extracted with dichloromethane, dried over anhydrous sodium sulfate for 16 h, and removed the solvent on a rotary evaporator.Crystallization from benzene gave pale yellow crystals with a yield of 63percent (0.86 g).
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[2] Molecular Crystals and Liquid Crystals, 2010, vol. 520, p. 68 - 74
[3] Molecular Crystals and Liquid Crystals, 2012, vol. 567, # 1, p. 156 - 162,7
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3287 - 3290
[5] Inorganic Chemistry, 2017, vol. 56, # 24, p. 15259 - 15270
[6] Patent: CN107759639, 2018, A, . Location in patent: Paragraph 0014
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[8] Farmaco, 1999, vol. 54, # 11-12, p. 761 - 767
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Reference: [1] Patent: US2012/202806, 2012, A1,
[2] Patent: US2012/202806, 2012, A1,
[3] Patent: CN106608869, 2017, A,
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YieldReaction ConditionsOperation in experiment
62%
Stage #1: With sodium methylate In methanol at 40℃; for 1 h; Inert atmosphere
Stage #2: With acetic acid In methanol for 1 h; Inert atmosphere; Reflux
2-Pyridinecarbonitrile (10.4 g, 100 mmol) was added to a solutionof NaOMe (0.54 g, 10.0 mmol) in abs. MeOH (40 ml). The mixture was stirred for 1 h at 40 °C before it was allowed to cool down. 2,2-Dimethoxyethylamine (10.5 g, 100 mmol) and glacial acetic acid (11 ml) was added drop wise and the resulting mixture was refluxed for 1 h and was afterwards allowed to cool down before MeOH (50 ml) and 6 M HCl (50 ml) was added. The mixture was then refluxed for further 4 h before the solvent was removed under reduced pressure. The residue was digested in a solution of K2CO3(50 g) in H2O (50 ml) before DCM (50 ml) was added to the resulting suspension. The mixture was filtered and the organic phase separated .The aqueous phase was extracted several times with DCM and the combined organic layers were dried over Na2SO4 before removal of the solvent under reduced pressure and recrystallisation of the residue from ethyl acetate (50 ml) gave a tan amorphous powder of I. Yield: 62percent. 1H NMR (200.13 MHz, DMSO-d6): δ = 12.77 (bs, 1 H, 1-imH), 8.58 (d, 1 H, 6-pyH), 8.04 (d, 1 H, 3-pyH), 7.87 (ddd, 1 H, 4-pyH), 7.34 (ddd, 1 H, 5-pyH), 7.22 (s, 1 H,5-imH or 4-imH), 7.08 (s, 1 H, 5-imH or 4-imH) ppm. 13C NMR (50.33 MHz, DMSO-d6): δ = 149.2 (2-pyC), 148.9 (6-pyC), 145.5 (2-imC), 137.1 (4-pyC), 129.5 (4-imC or 5-imC), 123.0 (5-pyC), 119.4 (3-pyC), 118.7 (4-imC or 5-imC) ppm. EI-MS (MeOH) m/z (rel. abundance, fragment) = 145.0 (100percent, I+). IR (diamond, ATR): ~v = 3046, 2983, 2887, 2821, 2743, 1594 (s), 1568, 1479 (vs), 1458 (vs), 1415, 1382, 1308, 1139, 1109 (s), 992, 954 (s), 909, 786 (vs), 758,736 (vs), 706 (vs), 630 (s), 621, 504, 464, 403 cm-1. Elemental analysis(percent) Anal. Calc. for C8H7N3 (145.16 g mol1): C, 66.19; H, 4.86 N,28.95. Found: C, 65.89, H, 4.97; N, 29.09percent.
Reference: [1] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 3, p. 609 - 615
[2] Polyhedron, 2015, vol. 93, p. 28 - 36
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Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 43, p. 5593 - 5595
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YieldReaction ConditionsOperation in experiment
82%
Stage #1: With sodium methylate In methanol at 20℃; for 1 h;
Stage #2: for 10 h; Reflux
General procedure: 5 ml of sodium methoxide methanolic solution (35 wtpercent) was added to a solution of 2-cyanopyridine (0.05 mol) in20 ml of methanol and stirred at room temperature for 1 h. Then the respective hydrazide was added to the generate dimino ester solution and refluxed for 10 h. The obtained mixture was cooled to room temperature and the solvent removed in vacuo. The resulting residue was diluted with water and acidified with 2 ml of acetic acid to produce a white solid. The crystals were separated via filtration, dried and recrystallized from toluene (HL1–3). The physical properties and analytical data of compounds HL1-3 are listed in Table 1, and the spectral data of compounds HL1-3are listed in Table 2.
Reference: [1] Chemical Papers, 2017, vol. 71, # 10, p. 2003 - 2009
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Reference: [1] Chemistry - A European Journal, 2013, vol. 19, # 24, p. 7825 - 7834
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YieldReaction ConditionsOperation in experiment
83%
Stage #1: at 20℃; for 22 h;
Stage #2: for 6 h;
Compound 1 (26.01) was stirred with sodium methoxide solution at room temperature for 22 hours, then ammonium chloride (28-01) was added for 6 hours, and unreacted ammonium chloride was removed by filtration, The filtrate was spin-dried to remove the methanol solvent to give a pale yellow solid powder which was then washed three times with diethyl ether to remove unreacted compound 1 and recrystallized from a mixed solvent of ethanol-ether to give compound 2 as a white product. Yield: 83percent.
83%
Stage #1: With sodium methylate In methanol at 20℃; for 22 h;
Stage #2: With ammonium chloride In methanol at 20℃; for 6 h;
Prepare fresh sodium methoxide solution in a single mouth bottle, anhydrous methanol 20 mL asolution of 50 mg of sodium wire was added with stirring and the mixture was allowed to react completely with sodium, followed by 2-cyanopyridine (2.67 g, 26 mmol) and stirred at room temperature for 22 hours to form a homogeneous solution. After addition of ammonium chloride (1.1 g, 28 mmol), stirring was continued at room temperature for 6 hours. The unreacted ammonium chloride was removed by filtration and the filtrate was spin dried to remove the methanol solvent to give a pale yellow solid which was washed three times with ether to remove unreacted 2-cyanopyridine and recrystallized from ethanol-diethyl ether to give the product Py-NH2 as a white product. Yield: 83percent. 1H NMR (400MHz, DMSO) δ=9.69(s,4H), 8.85–8.73(m,1H), 8.45(d,J=8.0Hz,1H), 8.14(td,J=7.8,1.7Hz,1H), 7.85–7.71(m,1H). 13C NMR(101MHz,DMSO)δ=162.67 ,150.33, 144.37, 138.76, 129.01, 124.00
66%
Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere
Stage #2: With ammonium chloride In methanol at 20℃; for 4 h;
Synthesis of 10-1Step A: Picolinamidine hydrochloride (10-b)To a solution of 2-cyanopyridine (10-a) (Sigma-Aldrich) (lOOg, 0.95mol) in methanol (1.5L) under nitrogen was added sodium methoxide (2.5g, 44mmol). The reaction mixture was stirred at room temperature for 24 hours. Ammonium chloride (53.5g, lmol) was added to the reaction mixture. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide compound 10-b (lOOg, 66percent).
66%
Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere
Stage #2: With ammonium chloride In methanol at 20℃; for 4 h;
SSSBLAI Pfco)in3/4mjd-ne hydrochloride flo-b)To a solution of 2-cyanopyridine (10-a) (Sigma-Aldrich) (lOOg, 0.95mol) in methanol (1.5L) under nitrogen was added sodium methoxide (2.5g, 44mmoJ). The reaction mixture was stirred at room temperature for 24 hours. Ammonium chloride (53.5g, lmol) was added to the reaction mixture. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide compound 10-b (lOOg, 66percent).
66%
Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere
Stage #2: With ammonium chloride In methanol at 20℃; for 4 h;
Sodium methoxide (2.5g, 44mmol) was added to a solution of 2-cyanopyridine (lOOg, 0.95mol) in methanol (1.5L) under nitrogen. The reaction mixture was stirred at room temperature for 24 hours. Then ammonium chloride (53.5g, lmol) was added. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide the product, 1-1-g, (100g, 66percent).
66%
Stage #1: With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere
Stage #2: With ammonium chloride In methanol at 20℃; for 4 h; Inert atmosphere
Step D: Picolinamidine hydrochloride (1-1-g) Sodium methoxide (2.5g, 44mmol) was added to a solution of 2-cyanopyridine (1 OOg, 0.95mol) in methanol (1.5L) under nitrogen. The reaction mixture was stirred at room temperature for 24 hours. Then ammonium chloride (53.5g, lmol) was added. The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=l/10 and dried in vacuo to provide the product, 1-1-g, (lOOg, 66percent).
87% With ammonium chloride; sodium methylate In methanol EXAMPLE 27
2-Pyridinecarboxamidine hydrochloride
To a solution of 2-cyanopyridine (20.0 g, 0.19 mol) in methanol (300 ml) under argon was added sodium methoxide (0.5 g).
The reaction mixture was stirred at room temperature for 24 hours, then ammonium chloride (10.7 g, 0.2 mol) was added.
The mixture was stirred at room temperature for 3.5 hours and the solvent was removed in vacuo.
The residue was diluted with isopropanol (20 ml) and ether (400 ml) and a solid was collected by filtration to afford 28.2 g (87percent) of 2-pyridinecarboxamidine hydrochloride as a white solid, m.p. 141°-142° C. when dried at 40° C. in high vacuum.
3.99 g
Stage #1: With sodium methylate In ethanol at 20℃; for 4 h; Inert atmosphere
Stage #2: With ammonium chloride In ethanol for 6 h; Reflux; Inert atmosphere
A mixture of 2-cyanopyridine (3.15 g, 30.3 mmol) and NaOCH3 (0.16 g, 3 mmol) is prepared in 10 mL ethanol and stirred at RT for 4 h under inert atmosphere. After 4 h, NH 4CI (1.81 g,33.8 mmol) is added to the solution. The mixture is refluxed for 6 hours, cooled down and filtered to remove excess salt. Ethanol is removed and a white solid of 2-pyridinecarboximidamide hydrochloride (3.99 g, 25.2 mmol) is obtained.

Reference: [1] Patent: CN105399775, 2016, A, . Location in patent: Paragraph 0026-0028
[2] Patent: CN103936795, 2016, B, . Location in patent: Paragraph 0032-0035
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[4] Patent: WO2011/130908, 2011, A1, . Location in patent: Page/Page column 53
[5] Patent: WO2011/133444, 2011, A1, . Location in patent: Page/Page column 52
[6] Patent: WO2013/40790, 2013, A1, . Location in patent: Page/Page column 33; 102; 103
[7] Patent: WO2013/43624, 2013, A1, . Location in patent: Page/Page column 32; 33; 102; 103
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[9] Patent: US5294612, 1994, A,
[10] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1719 - 1729
[11] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 299 - 301
[12] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 111 - 118
[13] Dyes and Pigments, 2013, vol. 99, # 1, p. 67 - 73
[14] Patent: KR2015/13888, 2015, A, . Location in patent: Paragraph 0237; 0238; 0239; 0240
[15] Angewandte Chemie - International Edition, 2016, vol. 55, # 34, p. 9947 - 9951[16] Angew. Chem., 2016, vol. 128, p. 10101 - 10105,5
[17] Tetrahedron, 2016, vol. 72, # 50, p. 8335 - 8341
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  • 41
  • [ 100-70-9 ]
  • [ 917-54-4 ]
  • [ 52568-28-2 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With cerium(III) chloride In tetrahydrofuran; diethyl ether at -76 - -60℃;
Stage #2: at -76 - 15℃;
Add THF (240 mL) to anhydrous cerium (III) chloride (35 g, 144 mmol) and stir the slurry under nitrogen for 30 minutes. Cool the mixture to -760C in a dry-ice acetone bath. Add a 1.6 M solution of methyl lithium in Et2O (90 mL, 144 mmol) dropwise maintaining the internal reaction temperature below -600C. Stir for 30 minutes after the addition is complete, cool the reaction to -760C, then add 2-cyanopyridine (5 g, 48 mmol) as a solution in THF (20 mL) controlling the addition to keep the reaction below -600C. Stir the mixture in the dry-ice bath for 15 minutes, then remove the bath and allow the reaction to warm to 15 0C. Cool the reaction in the dry-ice bath then add ammonium hydroxide (90 mL) with stirring. Allow the reaction to warm to room temperature with stirring overnight. Decant the solution from the mixture and wash the solids well with THF. Combine the filtrate and washes, then evaporate to give 1 -methyl- l-pyridin-2-yl- ethylamine in quantitative mass balance. 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J= 4.0 Hz, IH), 7.60 (td, J= 7.7, 1.6 Hz, IH), 7.42 (d, J= 7.9 Hz, IH), 7.15-7.08 (m, IH), 1.47 (s, 6H).
73%
Stage #1: With cerium(III) chloride In tetrahydrofuran; diethyl ether at -70℃; for 0.5 h;
Stage #2: at -60 - 23℃; for 2.5 h;
Example 121 5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-(at))thiophene-2-sulfonic acid (1 -methyl-1 - pyridin-2-yl) ethylamide hydrochloride Step 1: 1-methyl-1-pyridm-2-yl) ethylamine: Anhydrous cerium chloride (5.10g, 20.69 mmol) is placed in a flask and vacuum dried for 15 min while being heated with a heat gun, then it is cooled to 0°C and tetrahydrofuran (45 mL) is added. After stirring at room temperature for 2 hr, the mixture is cooled to -70°C and treated with 2.0 M methyl lithium in diethyl ether (10.5 mL, 21 mmol). After stirring for an additional period of 0.5 hrs, 2-cyanopyridine (720 mg, 6.91 mmol) in tetrahydrofuran (1 mL) is added. The reaction temperature is kept below-60°C for 0.5 hr, then the temperature is raised to 23°C while stirring for 2 hr. The reaction is quenched with isopropanol (3 mL), filtered through a pad of Celite that is washed thoroughly with dichloromethane. The combined filtrate and wash is concentrated and the residue is purified by flash chromatography on an ISCO Redisep 35 g cartridge eluting with dichloromethane-10percent methanol to afford 1-methyl-1-pyridin-2-yl)ethylamine (688 mg, 73percent yield) as an oil that solidified on standing to yellow solid. 1H NMR (No., ppm) : 1.6 (6H, s), 7.42 (1H), 7.64 (1H), 7.90 (1H), 8.2 (2H, br s), 8.65 (1H).
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  • [ 75-16-1 ]
  • [ 52568-28-2 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: at 0 - 100℃;
Stage #2: With hydrogenchloride; water In toluene at 0℃;
Stage #3: With sodium hydroxide In water
Synthesis of 1-methyl-1-pyridin-2-yl-ethylamine (217), Scheme 8; To a solution of 2-cyanopyridine (33.0 g, 0.32 mol) in 800 mL of toluene was added MeMgBr (566 mL, 2.5 equiv) slowly at 0° C. The mixture was heated at 100° C. overnight, and then quenched with 2 N HCl in an ice bath. The aqueous layer was collected and basified with 4 N NaOH, and then extracted with ether (500 mL.x.3). The combined organic layer was dried and concentrated to give the title compound (35.0 g, 81percent).
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[12] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2241 - 2246
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[2] Patent: US2012/202806, 2012, A1,
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