* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 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
3
[ 100-70-9 ]
[ 52313-50-5 ]
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,
4
[ 100-70-9 ]
[ 4039-32-1 ]
[ 52313-50-5 ]
Yield
Reaction Conditions
Operation 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,
5
[ 100-70-9 ]
[ 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
6
[ 100-70-9 ]
[ 1147550-11-5 ]
[ 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
7
[ 100-70-9 ]
[ 67-56-1 ]
[ 1620-76-4 ]
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
8
[ 100-70-9 ]
[ 107-15-3 ]
[ 7471-05-8 ]
Yield
Reaction Conditions
Operation 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.
Reference：
[1] Journal of the Serbian Chemical Society, 2012, vol. 77, # 9, p. 1181 - 1189,9
[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
9
[ 100-70-9 ]
[ 7471-05-8 ]
Reference：
[1] Patent: US4680304, 1987, A,
10
[ 100-70-9 ]
[ 14034-59-4 ]
[ 7471-05-8 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 497,500
11
[ 100-70-9 ]
[ 100367-55-3 ]
Reference：
[1] Heterocycles, 2002, vol. 58, p. 301 - 310
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,
22
[ 100-70-9 ]
[ 75-05-8 ]
[ 57537-63-0 ]
[ 1671-87-0 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 39, p. 13985 - 13998
23
[ 100-70-9 ]
[ 2176-62-7 ]
[ 33252-29-8 ]
[ 17824-83-8 ]
[ 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
24
[ 100-70-9 ]
[ 67-56-1 ]
[ 586-98-1 ]
[ 83621-01-6 ]
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
25
[ 100-70-9 ]
[ 64-17-5 ]
[ 586-98-1 ]
[ 83621-01-6 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 9, p. 2906 - 2910
26
[ 100-70-9 ]
[ 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
27
[ 100-70-9 ]
[ 1005-02-3 ]
Yield
Reaction Conditions
Operation 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).
Reference：
[1] Patent: US2016/244860, 2016, A1, . Location in patent: Paragraph 0168-0169
[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
[7] Journal of Medicinal Chemistry, 2004, vol. 47, # 19, p. 4645 - 4648
[8] Farmaco, 1999, vol. 54, # 11-12, p. 761 - 767
[9] Chemistry Letters, 2005, vol. 34, # 6, p. 836 - 837
[10] Journal of Materials Chemistry, 2007, vol. 17, # 27, p. 2824 - 2831
[11] Molecular Crystals and Liquid Crystals, 2011, vol. 538, p. 67 - 74
[12] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 76 - 81
[13] Journal of Nanoscience and Nanotechnology, 2011, vol. 11, # 5, p. 4414 - 4418
[14] Molecular Crystals and Liquid Crystals, 2009, vol. 504, # 1, p. 59 - 66
[15] Dyes and Pigments, 2013, vol. 99, # 1, p. 67 - 73
[16] Dalton Transactions, 2015, vol. 44, # 18, p. 8467 - 8477
[17] Chemistry - A European Journal, 2015, vol. 21, # 13, p. 5161 - 5172
[18] New Journal of Chemistry, 2015, vol. 39, # 11, p. 8908 - 8914
[19] Dyes and Pigments, 2016, vol. 130, p. 191 - 201
[20] Organometallics, 2016, vol. 35, # 22, p. 3870 - 3877
[21] Patent: CN106045977, 2016, A, . Location in patent: Paragraph 0030
[22] Chinese Journal of Chemistry, 2016, vol. 34, # 9, p. 873 - 877
[23] Patent: CN106905295, 2017, A, . Location in patent: Paragraph 0049; 0050
[24] Dalton Transactions, 2017, vol. 46, # 39, p. 13456 - 13462
[25] Patent: CN106939000, 2017, A, . Location in patent: Paragraph 0043; 0044
[26] Journal of Materials Chemistry C, 2017, vol. 5, # 18, p. 4455 - 4462
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
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
32
[ 100-70-9 ]
[ 25433-36-7 ]
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 24, p. 7825 - 7834
33
[ 100-70-9 ]
[ 51285-26-8 ]
Yield
Reaction Conditions
Operation 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
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 9, p. 2600 - 2617
[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
[8] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1230 - 1241
[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
Reference：
[1] Green Chemistry, 2011, vol. 13, # 4, p. 983 - 990
40
[ 100-70-9 ]
[ 117408-98-7 ]
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 1, p. 74 - 77
[2] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1637 - 1642
41
[ 100-70-9 ]
[ 917-54-4 ]
[ 52568-28-2 ]
Yield
Reaction Conditions
Operation 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).
Reference：
[1] Patent: WO2009/131814, 2009, A2, . Location in patent: Page/Page column 43
[2] Journal of the American Chemical Society, 2014, vol. 136, # 33, p. 11574 - 11577
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 51, p. 13588 - 13592[4] Angew. Chem., 2013, vol. 125, # 51, p. 13833 - 13837,5
[5] Patent: WO2005/97750, 2005, A1, . Location in patent: Page/Page column 147-148
[6] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3730 - 3742
[7] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 4, p. 373 - 377
42
[ 100-70-9 ]
[ 75-16-1 ]
[ 52568-28-2 ]
Yield
Reaction Conditions
Operation 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).
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 1, p. 139 - 149
[2] Patent: US2008/207573, 2008, A1, . Location in patent: Page/Page column 80; 87
[3] Chemical Communications, 2014, vol. 50, # 61, p. 8353 - 8355
[4] Chemistry--A European Journal, 2015, vol. 21, # 1, p. 205 - 209
[5] Chemical Communications, 2015, vol. 51, # 19, p. 4069 - 4072
[6] Chemical Communications, 2016, vol. 52, # 27, p. 4934 - 4937
[7] Organic Letters, 2014, vol. 16, # 15, p. 3904 - 3907
[8] Chemical Communications, 2015, vol. 51, # 24, p. 5093 - 5096
[9] Journal of the American Chemical Society, 2015, vol. 137, # 25, p. 8219 - 8226
[10] Organic Letters, 2014, vol. 16, # 21, p. 5644 - 5647
[11] Advanced Synthesis and Catalysis, 2017, vol. 359, # 23, p. 4117 - 4121
[12] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2241 - 2246
1. Synthesis of 1-(pyridin-2-yl)butan-1-one A solution of 2-cyanopyridine (2.20 g, 21.13 mmol) in Et2O (35 mL) added over 10 min to a rapidly stirring solution of freshly prepared n-PrMgBr (from n-PrBr (2.71 g, 22.03 mmol) and Mg (0.62 g) in Et2O (35 mL). Once addition was completed, the reaction was heated to reflux in a warm water bath for 2.5 hours. The reaction was cooled to RT then placed in ice, quenched with 5 mL H2O followed by 60 mL 5N H2SO4. The ether phase was separated. The aqueous phase was heated in warm water for 15 minutes, then cooled in ice, basified with sat. K2CO3. The mixture was extracted with CHCl3 and dried over K2CO3. The solution was filtered, concentrated and purified on Biotage Horizon (10-100% A=Hex, B=2:1 Hex:EtOAc) to afford 1.16 g of 1-(pyridin-2-yl)butan-1-one as an oil: 1H NMR (400 MHz, CDCl3) delta ppm 8.67 (ddd, J=4.74, 1.71, 0.88 Hz, 1H), 8.03 (dt, J=7.83, 1.01 Hz, 1H), 7.82 (td, J=7.71, 1.77 Hz, 1H), 7.45 (ddd, J=7.52, 4.74, 1.14 Hz, 1H), 3.15-3.21 (m, 2H), 1.71-1.80 (m, J=7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2H), 1.00 (t, J=7.33 Hz, 3H).
Example 15: pyridine-2-carboximidamide [00305] To a slurry of NH, C . (4.62 g, 86.4 mmol) in toluene (34 mL) at 0C was added dropwise a solution of AI (CH3) 3 (7.6 mL, 79.7 mmol) in toluene (32 mL). The reaction mixture was warmed to room temperature and stirred for 2 h prior to the addition of a solution of 2-cyanopyridine (5.0 g, 48.0 mmol) in toluene (15.0 mL). The resulting solution was heated to 80C for 20 h. The cooled reaction mixture was poured into a slurry of silica gel (24.0 g) in CHCI3 (80 mL), followed by vigorous stirring for 10 min. The silica gel was filtered off and the cake was rinsed in turn with methanol and an aqueous solution of 2N NaOH (100 mL). The combined filtrates were extracted with CHCI3 (3 x 300 mL), then concentrated to dryness under reduced pressure, diluted with a small amount of methanol, and treated with a 2N HCI solution in methanol. The precipitate that formed was isolated by filtration and dried in a vacuum oven to afford the title compound as an off-white HCI salt.'H NMR (500 MHz, DMSO- d6) 5 9.66 (s, 2H), 9.52 (s, 2H), 8.85-8. 81 (m, 1 H), 8.37 (d, J = 7.9 Hz, 1 H), 8.17 (td, J= 1.8, 1.6 Hz, 1H), 7.80 (ddd, J= 7.7, 4.7, 0.9 Hz, 1H).
With ammonium chloride; In methanol;
Pyridine-2-carboxamidine A solution of sodium metal (74 mg, 3.2 mmol) in MeOH (5 ml) was added to a solution of 2-cyanopyridine (3 g, 28 mmol) in MeOH (25 ml) and the mixture was stirred for 16 h at room temperature. Ammonium chloride (4.5 g, 84 mmol) was added and the mixture was stirred at 70 C. for 3 h. After cooling, the mixture was concentrated in vacuo. The residue was diluted with EtOH (40 ml) and the mixture was heated under reflux for 0.5 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was washed with Et2O/iso-propanol (4:1) and dried under high vacuum to obtain the title compound as the HCl salt (4.5 g, 99%).
With cupric indole-3-acetate; at 80℃; for 0.0833333h;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.
With sodium methylate; In methanol; 2-ethoxy-ethanol; at 130℃; for 16h;
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of l-(tert- butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, ~26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaEtaCObeta. The organic layer was dried over anhydrous Na2SO_i, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-l-carboxylate as an off-white solid. NMR(CDCl3): 56.77 (1Eta, br s), 4.15 (2Eta, br s), 3.90 (2H, v br s),2.75 (2H, b s), 2.22 (IH, m), 1.78 (2H, br d, J=I 1.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s).This material (2.43g, 10 rnmol) was dissolved in anhydrous 2-ethoxyethanol (20 mL) and 2-cyanopyridine (1.14 g, 11 mmol) was added to the solution. After 25 wt. % sodium methoxide/methanol (1.1 mL, ~5 mmol) was added the mixture was heated to 1300C for 16 hours. The EPO <DP n="53"/>cooled reaction was neutralized with acetic acid and partitioned between ethyl acetate and aq. NaHCO3.The organic layer was dried over Na2SO4, the salts removed by filtration and the solvent evaporated under vaccum. This residue was triturated with diethyl ether to give tert-butyl 4-(5-pyridin-2- yl-lH-l,2,4-triazol-3-yl)piperidine-l-carboxylate as a white solid. NMR(CDCl3): 58.70 (1Eta, d, J=3.9Etaz), 8.19 (IH, d, J=7.9Hz), 7.87 (IH, d t, J=1.7Hz, J=8Hz), 7.40 (IH, m), 4.20 (2H, br s), 3.03 (IH, m), 2.95 (2H, br s), 2.09 (2H, br d, J= 12 Hz), 1.86 (2H, br q, J= 4.2Hz), 1.49 (9H, s); m/e (m+1): 330.2This material (2.68 g, 8.14 mmol) was suspended in 4 N HCl/dioxane. The stoppered reaction mixture was stirred at room temoerature for 16 hours and then diluted with diethyl ether. The solids were isolated by filtration and the hydroscopic solid was digested in acetonitrile. This solid was isolated by filtration and partially dissolved in hot methanol. Upon cooling and addition of some ethyl ether to the mixture 2-(3-piperidin-4-yl-lH-l,2,4-triazol-5-yl)pyridine (A) was obtained as the dihydrochloride salt. NMR(DMSO-d): 89.10 (1Eta, br s), 8.92 (1Eta, br s), 8.73 (1Eta, d, J=4.9Etaz), 8.10- 8.20 (2H, m), 7.64 (IH, t, J=5.7 Hz), 3.33 (2H, br d, J=12.7 Hz), 3.16 (IH, m), 3.05 (2H, br q, J=I 1.9 Hz, J=21.8 Hz),2.18 (2H, br d, J=11.5 Hz), 1.99 (2H, br q, j=11.0 Hz, J=22.2 Hz): m/e(m+l): 230.3.
With sodium methylate; In methanol; 2-ethoxy-ethanol; at 130℃; for 16h;
This material (2.43g, 10 mmol) was dissolved in anhydrous 2-ethoxyethanol (20 mL) and 2-cyanopyridine (1.14 g, 11 mmol) was added to the solution. After 25 wt. % sodium methoxide/methanol (1.1 mL, -5 mmol) was added the mixture was heated to 130 C for 16 hours. The cooled reaction was neutralized with acetic acid and partitioned between ethyl acetate and aq.NaHC03.The organic layer was dried over Na2S04, the salts removed by filtration and the solvent evaporated under vaccum. This residue was triturated with diethyl ether to give tert-butyl 4-(5-pyridin-2- yl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate as a white solid. NMR(CDC13): 88.70 (1H, d, J= 3.9Hz), 8.19 (1H, d, J=7.9Hz), 7.87 (1H, d t, J=1.7Hz, J=8Hz), 7.40 (1H, m), 4.20 (2H, br s), 3.03 (1H, m), 2.95 (2H, br s), 2.09 (2H, br d, J=12 Hz), 1.86 (2H, br q, J= 4.2Hz), 1.49 (9H, s); m/e (m+1): 330.2
With sodium methylate; In methanol; 2-ethoxy-ethanol; at 130℃; for 16h;
2-(3-Piperidin-4-yl-lH-l ,2,4-triazol-5-yl)pyridine Dihvdrochloride (1-5)Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of l-(tert- butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, -26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaHCtheta3. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded <strong>[187834-88-4]tert-butyl 4-(hydrazinocarbonyl)-piperidine-1-carboxylate</strong> as an off-white solid. IH NMR(500 MHz, CDC13): 56.77 (IH, br s), 4.15 (2H, br s), 3.90 (2H, v br s),2.75 (2H, b s), 2.22 (IH, m), 1.78 (2H, br d, J=I 1.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s). This material (2.43g, 10 mmol) was dissolved in anhydrous 2-ethoxyethanol (20 mL) and 2-cyanopyridine (1.14 g, 11 mmol) was added to the solution. After 25 wt. % sodium methoxide/methanol (1.1 mL, ~5 mmol) was added the mixture was heated to 13O0C for 16 hours. The cooled reaction was neutralized with acetic acid and partitioned between ethyl acetate and aq. NaHCtheta3.The organic layer was dried over Na2SO4, the salts removed by filtration and the solvent evaporated under vaccum. This residue was triturated with diethyl ether to give tert-butyl 4-(5-pyridin-2- yl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate as a white solid. IH NMR(500 MHz, CDCI3): 58.70(IH, d, J= 3.9Hz), 8.19 (IH, d, J=7.9Hz), 7.87 (IH, d t, J=1.7Hz, J=8Hz), 7.40 (IH, m), 4.20 (2H, br s), EPO <DP n="46"/>3.03 (IH, m), 2.95 (2H, br s), 2.09 (2H, br d, J=12 Hz), 1.86 (2H, br q, J= 4.2Hz), 1.49 (9H, s); m/e (m+1): 330.2This material (2.68 g, 8.14 mmol) was suspended in 4 N HCl/dioxane. The stoppered reaction mixture was stirred at room temperature for 16 hours and then diluted with diethyl ether. The solids were isolated by filtration and the hygroscopic solid was digested in acetonitrile. This solid was isolated by filtration and partially dissolved in hot methanol. Upon cooling and addition of some ethyl ether to the solution 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine slowly precipitated as the dihydrochloride salt. IH NMR (500 MHz, DMSO-d6): 59.10 (IH, br s), 8.92 (IH, br s), 8.73 (IH, d, J=4.9Hz), 8.10-8.20 (2H, m), 7.64 (IH, t, J=5.7 Hz), 3.33 (2H, br d, J=12.7 Hz), 3.16 (IH, m), 3.05 (2H, br q, J=11.9 Hz, J=21.8 Hz),2.18 (2H, br d, J=11.5 Hz), 1.99 (2H, br q, j=11.0 Hz, J=22.2 Hz): m/e(m+l): 230.3.
With sodium methylate; In methanol; 2-ethoxy-ethanol; at 130℃; for 16h;
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of l-(tert- butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, -26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaHCtheta3. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-l-carboxylate as an off-white solid. IH NMR(500 MHz, CDCI3): beta 6.77 (IH, br s), 4.15 (2H, br s), 3.90 (2H, v br s),2.75 (2H, b s),2.22 (IH, m), 1.78 (2H, br d, J=I 1.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s).This material (2.43g, 10 mmol) was dissolved in anhydrous 2-ethoxyethanol (20 mL) and 2-cyanopyridine (1.14 g, 11 mmol) was added to the solution. After 25 wt. % sodium methoxide/methanol (1.1 mL, ~5 mmol) was added the mixture was heated to 1300C for 16 hours. The cooled reaction was neutralized with acetic acid and partitioned between ethyl acetate and aq. NaHCtheta3. The organic layer was dried over Na2SO4, the salts removed by filtration and the solvent evaporated under vacuum. This residue was triturated with diethyl ether to give tert-butyl 4-(5-pyridin-2-yl-lH- l,2,4-triazol-3-yl)piperidine-l-carboxylate as a white solid. IH NMR(500 MHz, CDCI3): delta 8.70 (IH, d, J= 3.9Hz), 8.19 (IH, d, J=7.9Hz), 7.87 (IH, d t, J=1.7Hz, J=8Hz), 7.40 (IH, m), 4.20 (2H, br s), 3.03 (IH, m), 2.95 (2H, br s), 2.09 (2H, br d, J=12 Hz), 1.86 (2H, br q, J= 4.2Hz), 1.49 (9H, s); m/e (m+1): 330.2This material (2.68 g, 8.14 mmol) was suspended in 4 N HCl/dioxane. The stoppered reaction mixture was stirred at room temperature for 16 hours and then diluted with diethyl ether. The solids were isolated by filtration and the hygroscopic solid was digested in acetonitrile. This solid was isolated by filtration and partially dissolved in hot methanol. Upon cooling and addition of some ethyl ether to the solution 2-(3-piperidin-4-yl-lH-l,2,4-triazol-5-yl)pyridine slowly precipitated as the EPO <DP n="92"/>dihydrochloride salt. IH NMR (500 MHz, DMSO-d6): delta 9.10 (IH, br s), 8.92 (IH, br s), 8.73 (IH, d, J=4.9Hz), 8.10-8.20 (2H, m), 7.64 (IH, t, J=5.7 Hz), 3.33 (2H, br d, J=12.7 Hz), 3.16 (IH, m), 3.05 (2H, br q, J=I 1.9 Hz, J=21.8 Hz),2.18 (2H, br d, J=I 1.5 Hz), 1.99 (2H, br q, j=11.0 Hz, J=22.2 Hz): m/e(m+l): 230.3.
EXAMPLE 5 5-Fluoro-6-chlorooxindole (III) From (IV) In a polypropylene flask was placed 20 ml of HF-pyridine. Then 4 ml of 2-cyanopyridine was added followed by 2.0 g (10.9 mmol) of (IV). The flask was sealed and heated to 45 C. for 18 hours. The reaction mixture was poured into 160 ml of water and extracted with ethyl acetate (3*200 ml). The combined ethyl acetate extracts were washed with 5% HCl (3*100 ml) and dried with MgSO4. Filtration and evaporation of the solvents left 3.39 g of a waxy brown solid that still contained 2-cyanopyridine. Trituration of this solid with isopropyl ether removed the 2-cyanopyridine leaving 1.80 g of a tan solid. The NMR of this material was identical to that obtained in Example 4.
With hydrazine hydrate; In ethanol; water; ethylenediamine; acetone;
(A) 2-(2-Pyridyl)-imidazoline 5 Grams of 2-thiocarboxamidopyridine and 10 ml of ethylene diamine were mixed and heated to 130 for 3 hours. The solution was then cooled and poured into 300 ml of water. It was extracted into ether and dried. Evaporation provided an oil which solidified on trituration with ether. It was filtered and dried, to provide 1.85 g (20%) of a solid, m.p. 97.5-98.5 C. (lit. 98.5-99 C.). This solid was sublimed to repurify; m.p. 96.5-98.5 C. 8.3 Grams (80 mM) of 2-cyanopyridine was dissolved in 80 ml absolute ethanol and placed in a 250 ml round-bottom flask. 20 Ml of hydrazine hydrate (90%) in 30 ml of ethanol was added to it in one portion and stirred at room temperature for 5 hours. TLC (15:35 chloroform/n-pentane on silica gel) showed no starting material. The reaction mixture was then treated with 25 ml acetone and stirred for 1 hour. It was concentrated to about 100 ml, when a yellow precipitate formed. The latter was washed with water and filtered, to give 9.5 g (65%) yellow crystals. They were dried in vacuo overnight, after which the melting point was 95-97 C. IR: 3300-3400 cm-1 (N-H stretch). NMR: 7.0-8.6 (complex multiplet, aromatic, 4H); 6.2 (broad, exchangeable with D2 O, amine, 2H); 2.05, 2.1 (sharp singlets, methyls, 6H).
With hydrogenchloride; In tetrahydrofuran; diethyl ether; ammonia; water;
EXAMPLE VII A solution of 15.15 g (0.1 mol) of <strong>[50712-68-0]4-chloro-2-methylbenzonitrile</strong> in 40 ml of anhydrous tetrahydrofuran was added under a nitrogen atmosphere to a suspension of 0.2 mol of potassium amide in liquid ammonia at -33 C. After 10 minutes a solution of 15.7 g (0.15 mol) of 2-cyanopyridine in 60 ml of anhydrous tetrahydrofuran was added. The mixture was kept overnight (ca. 16 hours), during which time the ammonia evaporated, and it was then hydrolyzed with 200 ml of water. The tetrahydrofuran was subsequently distilled off and the aqueous residue was extracted with chloroform. After evaporation of the chloroform the crude product was sublimed at 220-250 C. The sublimate was crystallized from chloroform, dissolved in diethyl ether and converted into the hydrochloride by addition of an ethereal solution of hydrogen chloride. The precipitate obtained was filtered off and twice crystallized from ethanol, to yield 1-amino-6-chloro-3-(2-pyridyl)isoquinoline hydrochloride, melting point 243 C.
EXAMPLE 9 A mixture of 2-cyanopyridine (5.21 g), sodium methoxide (270 mg) and anhydrous methanol (35 g) was stirred at room temperature for 3.3 hours to give methanolic solution of methyl imino picolinate. To this solution were added acetic acid (3.6 ml), <strong>[62009-47-6]aminomalonamide</strong> (3.51 g) and anhydrous methanol (40 ml) and the mixture was stirred for 3 hours under reflux. After cooling to 0-5 C., the precipitated product was separated from the solution by filtration, washed with ethanol and isopropylether, and dried under vacuum to give pale yellow crystalline (6.01 g) of 2-(2-pyridyl)-5-hydroxy-1H-imidazole-4-carboxamide. Recrystallization from aqueous methanol gave slightly yellowish fine needles.
With potassium amide; ammonia; In tetrahydrofuran; diethyl ether; at -78℃;
A suitable synthesis scheme for the synthesis of substituted l-amino-3 (2-pyridyl) isoquinolines is presented in Figure l(la-c). Potassium amide, freshly prepared in 500 ml ammonia, was stirred continuously into a three-neck flask, equipped with a mechanical stirrer. The mixture was cooled at -78 0C. Then, 0.5 mole of substituted 2- methylbenzonitril in 200 ml anhydrous diethylether was slowly added while maintaining the temperature at -780C.After addition of the 2-methylbenzonitril, a solution of 0.5 mole of 2-cyanopyridine in 250 ml THF was added in 20 minutes. The cooling was then stopped and the mixture was stirred continuously overnight to allowevaporation of the ammonia. Subsequently, the mixture was hydrolysed by adding a small volume of water. The compound was then extracted with diethylether and recrystallised from methanol. This procedure was used to synthesize thefollowing compounds:6-fluoro-3- (pyridine-2-yl) isoquinoline-1-amine :Yield 65percent; 1H NMR: 5,34 (br s, 2H, NH2), 7, 12 (m,IH, ArH), 7,21 (dd, J = 7,8 Hz, 1 Hz, IH, ArH), 7,35 (d, J = 1 Hz, IH, ArH), 7,65 (m, IH, ArH), 7,85 (d, J = 7,8 Hz, IH, ArH), 8,11 (s, IH), 8,50 (dd, IH), 8,58 (dd, IH).
2-8. Preparation of 3-Trifluoromethyl-5-(2-pyridyl)-1,2,4-triazole (23) 2-Cyanopyridine (0.93 ml, 9.6 mmol), purchased from Aldrich, in ethanol (30.0 ml) was added to 20 (2.5 g, 19.5 mmol) and stirred at room temperature. After 30 min, 28% NaOCH3 solution in methanol (1.4 g) was added to reaction mixture and refluxed. After 2 h, ethanol was removed in vacuo and the remaining yellow gummy liquid was heated at 130 C. overnight. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and the filtrate was evaporated in vacuo. The crude product was subjected to column chromatography on silica (solvent: ethyl acetate/chloroform=1/5) and yellow solid, 23 (1.06 g, 5.0 mmol, 52%), was obtained. 1H-NMR (CDCl3) delta 8.84 (d, J=5.1 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.01-7.95 (m, 1H), 7.57-7.52 (m, 1H)
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, 49%).
General procedure: The respective heteroarylcarbonitrile (5 mmol) wasrefluxed with 0.6 cm3 DBU (4 mmol) in 10 cm3 of methanolfor 0.5 h. Then 0.77 g <strong>[33263-43-3]4-chloropyridine-3-sulfonamide</strong>(4 mmol) were added and the mixture was refluxed foranother 3 h. Methanol was removed under vacuum and30 cm3 of water were added to the residue. The clearsolution was acidified with glacial acetic acid. The precipitatewas filtered off and recrystallized from a suitablesolvent.
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