* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bulletin de la Societe de Pharmacie de Lille, 1956, p. 39,42
[2] Polish Journal of Chemistry, 2001, vol. 75, # 9, p. 1237 - 1245
[3] Patent: WO2008/71404, 2008, A1, . Location in patent: Page/Page column 36
2
[ 100-48-1 ]
[ 584-08-7 ]
[ 41050-96-8 ]
Reference：
[1] Patent: US4406897, 1983, A,
3
[ 100-48-1 ]
[ 802294-64-0 ]
[ 1531-18-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
4
[ 100-48-1 ]
[ 64-17-5 ]
[ 1531-18-6 ]
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
[2] Chemistry Letters, 1984, p. 769 - 772
[3] Chemistry Letters, 1984, p. 769 - 772
With potassium <i>tert</i>-butylate; copper(ll) bromide In <i>tert</i>-butyl alcohol at 20℃; for 37 h;
General procedure: A 10 mL round-bottomed flask was charged with the appropriate nitrile 2 (0.50 mmol), arylboronic acid 1(0.60 mmol), CuBr2 (6 mg, 5molpercent), t-BuOK (168 mg, 1.50 mmol), and t-BuOH (3.0 mL), and the mixture was stirred at r.t. until the reaction was complete (TLC). H2O (4.0 mL) was added, and the mixture was extracted with EtOAc (3 ×10 mL). The combined organic layers were washed twice with H2O,dried (Na2SO4), and concentrated to give a residue that was purified by column chromatography (silica gel, PE–EtOAc).
With ammonium peroxydisulfate; sulfuric acid; silver nitrate In dichloromethane; waterReflux
Step 1 : 2-Acetylisonicotinonitrile To a solution of isonicotinonitrile (52 g, 0.5 mol) in dichloromethane (1300 mL) and water (1 100 mL) were added ammonium persulfate ((NH4)2S208) (170 g, 0.75 mol), silver nitrate (6.8 g, 0.04 mol) and aqueous sulfuric acid (40 mL, 98percent sulfuric acid in 400 mL). A solution of 3-oxo-butyric acid (1 10 g, 1.25 mol) in dichloromethane (100 mL) was added dropwise while keeping the mixture refluxing. The reaction mixture was refluxed for 2 h. The resulting mixture was basified to pH -8-9 using sodium carbonate powder. The mixture was filtered and the filtrate was extracted with dichloromethane (500 mL x 3). The combined organics were dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to afford 2-acetylisonicotinonitrile (52.0 g, 71.9percent).
Reference：
[1] Journal of Chemical Research, Miniprint, 1982, # 10, p. 2801 - 2815
[2] Journal of Chemical Research, Miniprint, 1982, # 10, p. 2801 - 2815
Stage #1: for 0.5 h; Heating / reflux Stage #2: With ammonium peroxydisulfate In water for 1.5 h; Heating / reflux Stage #3: With potassium carbonate In water
Sulfuric acid (1.5 ml) was added to the solution of 4-cyanopyridine (15.7 g, 151 mmol) in methanol (225 ml) at room temperature and refluxed for 30 minutes. A solution of ammonium peroxodisulfate (54.9 g, 241 mmol) in H2O (100 ml) was slowly added over 30 minutes under reflux and the mixture was refluxed with stirring for 1 hour. After cooling, precipitated materials were filtered off and methanol was removed from the filtrate under reduced pressure. The residue was neutralized (pH = 9) by adding saturated aqueous K2CO3 solution and precipitated materials were filtered off again. The filtrate was extracted with chloroform (100 ml x 4), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (chloroform/methanol) to give 2- (hydroxymethyl)isonicotinonitrile (7.95 g, 39 percent, off-white solid).
28%
Stage #1: With ammonium persulfate; sulfuric acid In water for 24 h; Heating / reflux Stage #2: at 0℃;
Add ammonium persulfate (70.1 g, 307 mmol) to a solution of isonicotinonitrile (16.00 g, 154 mmol) in methanol: water: sulfuric acid (275 mL:135 mL:l 1 mL). Heat solution to reflux. After 24 hours, pour reaction onto ice and neutralize with ammonium hydroxide (70 ml). Extract solution with chloroform (3x600 ml). Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with acetone :dichloromethane (1:6) to yield the title compound as a white solid (5.86 g, 28percent): 1H NMR (CDCl3) δ 3.17 (t, IH), 4.84 (d, IH), 7.45 (m, IH), 7.58 (s, IH), 8.74 (d, IH)
5.08 g
With sulfuric acid; ammonium peroxodisulfate In water for 14 h; Reflux
A) 2-(hydroxymethyl)isonicotinonitrile To a solution of 4-cyanopyridine (10.4 g) in methanol (180 mL), a solution of conc. sulfuric acid (6.98 mL) in water (90 mL) and ammonium peroxodisulfate (45.6 g) were successively added at room temperature, and the mixture was heated under reflux for 14 hr. The solvent was evaporated under reduced pressure, and 28percent aqueous ammonia (40 mL) was added. The reaction mixture was extracted with a mixed solvent of ethyl acetate and THF, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.08 g) as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4. 62 (2H, d, J = 5.8 Hz), 5.63 (1H, t, J = 5.8 Hz), 7.73 (1H, d, J = 4.9 Hz), 7.80 (1H, s), 8.75 (1H, d, J = 5.0 Hz).
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 41, p. 6239 - 6245
[2] Patent: WO2008/8398, 2008, A2, . Location in patent: Page/Page column 356
[3] Patent: WO2006/57860, 2006, A1, . Location in patent: Page/Page column 136
[4] Tetrahedron, 1985, vol. 41, # 3, p. 617 - 620
[5] Patent: EP2816023, 2014, A1, . Location in patent: Paragraph 0406
23
[ 100-48-1 ]
[ 7285-11-2 ]
[ 7664-93-9 ]
[ 51454-63-8 ]
Reference：
[1] Patent: US4385058, 1983, A,
24
[ 100-48-1 ]
[ 7664-93-9 ]
[ 51454-63-8 ]
Reference：
[1] Patent: US6043248, 2000, A,
25
[ 100-48-1 ]
[ 68325-15-5 ]
Yield
Reaction Conditions
Operation in experiment
53%
Stage #1: With 2,2,6,6-tetramethyl-piperidine In tetrahydrofuran at -78 - 25℃; for 0.5 h; Stage #2: With hexachloroethane In tetrahydrofuran at -78℃; for 0.5 h;
To a stirred solution of 2,2,6,6-tetramethyl piperidine (17.16 mL, 100.854 mmol) in THF (100 mL) was added n-BuLi (2.17 M, 44.26 mL, 96.052 mmol) at -30°C. After stirring the mixture for 15 mm at 25°C, it was cooled to -78°C and 4-cyanopyridine (5 g, 48.026 mmol) in THF (40 mL) was added dropwise. After stirring the reaction mixture for 30 mm at -78°C, hexachioroethane (23.87 g, 100.854 mmol) in THF (50 mL) was added at -78°C. The resulting mixture was stirred for 30 mm at -78°C and was quenched with saturated NH4C1 solution. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (4 x 300 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude material which was purified by column chromatography using silica (100-200 mesh) and 5percent EtOAc-hexane as eluent to afford 3-chloropyridine-4-carbonitrile (3.5 g, 25.26 1 mmol, 53percent) as pale white solid. GCMS: 138 (mlz).
Reference：
[1] Tetrahedron, 2006, vol. 62, # 25, p. 5862 - 5867
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10118 - 10129
[3] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 182; 183
[4] Tetrahedron Letters, 2005, vol. 46, # 1, p. 135 - 137
[5] Journal of the American Chemical Society, 2013, vol. 135, # 24, p. 9213 - 9219
Stage #1: at 25℃; for 1 h; Stage #2: for 0.166667 h; Stage #3: at 80℃; for 7 h; Reflux
100 ml of anhydrous ethanol was put into a 500 ml reaction flask, and sliced sodium was added.Stir the reaction to prepare sodium ethoxide. After the reaction is complete, continue stirring for 1 hour. Add 10.8 g of 4-cyanopyridine, control the temperature at 25°C and stir for 1 hour. Add acetic acid to adjust the pH to 5.0.Stir for 10 minutes,Added 14 g of the intermediate 2-cyanoisonicotinic acid hydrazide prepared in Example 1,Start oil bath heating and circulation, reflux temperature 80 °C, reflux 7h, HPLC monitoring,When the raw material 2-cyanoisonicotinic acid hydrazide obtained by the peak area normalization method is ≤ 0.5percent,Stop the heating and circulation, release the heat transfer oil in the jacket, wait until the temperature drops below 30°C, feed and centrifuge, and filter cake is rinsed twice with 50 ml of ethanol. The filter cake was transferred to an enamel baking dish and dried under reduced pressure (80°C/<-0.9 MPa/8h) to obtain 18 g of solid with a yield of 87.1percent.
85.6%
With sodium methylate In methanol for 8 h; Reflux
The 4-cyano pyridine 11.5g (110mmol) dissolved in 500 ml methanol, then adding sodium methoxide 3.5g, stir to dissolve. Then add 2-cyano [...] 16.2g (100mmol), heating reflux for 8 hours. After the reaction, the separated solid filter, vacuum drying after washing with methanol, to obtain he holds a department 21.4g, yield 85.6percent, purity 99.5percent (HPLC).
78%
With sodium methylate In methanol for 10 h; Reflux
A solution of 1.04 g (10 mmol) of the compound of the formula (2) in 50 ml of methanol was added with sodium methoxide 50mg, stirring to dissolve. Then, 1.62 g (10 mmol) of the compound of the formula (3) 2-cyanoisoniazide was added and the mixture was refluxed for 10 hours Time. After the completion of the reaction, the precipitated solid was filtered off, washed with methanol and dried with vacuum chestnut to give a yellow powdery product Pisitatum (1.93 g, yield 78percent, HPLC purity (normalized method): 98.5percent.
Reference：
[1] Patent: CN107573330, 2018, A, . Location in patent: Paragraph 0039; 0040-0042; 0065; 0067; 0069; 0071; 0073-0076
[2] Patent: CN105566301, 2016, A, . Location in patent: Paragraph 0064; 0065
[3] Patent: CN104151297, 2016, B, . Location in patent: Paragraph 0049; 0050
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux;
General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). N'-Hydroxyisonicotinimidamide (AM-1). Compound was synthesized by following GP1 starting from isonicotinonitrile (10 g, 0.1 mol) in 85% (11.6 g) yield
83%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; water; for 3h;Reflux;
General procedure: 4-Methylbenzonitrile 42b (940 mg, 8.0 mmol) in EtOH (30 mL) wasadded to NH2OH.HCl (3.34 g, 48 mmol) and NaHCO3 (2.54 g,24 mmol) in water (30 mL) and the mixture was boiled under reflux for 3 h. TheEtOH was evaporated and the residue was poured into water. The precipitatewas collected, washed (water) and dried to give 44b (940 mg, 78%) as awhite powder.
76.7%
With hydroxylamine; In ethanol; water; for 18h;Heating / reflux;
Reaction of 4-pyridinecarbonitrile to give the product N'-hydroxyisonicotinimidamide: Pyridinecarbonitrile (1 g, 9.6 mmol) and hydroxylamine (50% in water, 0.88 cm3, 14.4 mmol, 1.5 eq) in EtOH (10 cm3) were stirred under reflux for 18 hours, after which the volatiles were removed under reduced pressure and the residue was recrystallised from EtOH to give the product N'-hydroxyisonicotinimidamide (1.01 g, 76.7%) as a solid, mp 203-205 C.
With hydroxylamine hydrochloride; sodium carbonate; In water;
Reference Example 2: Synthesis of 4-(5-amino-1,2,4-oxadiazol-3-yl)pyridine. 17.1 g of 4-cyanopyridine, 70 ml of water, 11.4 g of hydroxylamine hydrochloride and 8.7 g of Na2CO3 were stirred in an autoclave for 8 hours with heating at 70C and, after cooling, the resulting reaction mixture was mixed with 60 ml of water, heated again and then spontaneously cooled to obtain 20.8 g of isonicotinamidoxime.
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; water; for 6h;Reflux;
General procedure: Sodium bicarbonate (5.88 g, 70 mmol) was added in portionsto a solution of 4.79 g hydroxylamine hydrochloride(70 mmol) in 20 cm3 of water. A solution of aryl nitriles(35 mmol) in 50 cm3 of ethanol was then added, and themixture stirred under reflux for 6 h. The precipitate formedwas filtered off and purified by crystallization from ethanol.Melting points of compounds 1b-1f were in agreementwith the literature values [23, 25-28].
With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; for 8h;Reflux;
General procedure: All solvents and reagents were obtained from commercialsources. All synthesized compounds were purified by chromatography and analyzed by IR, HRMS, and NMR. Purity of synthesizedcompounds was verified prior to biological tests by chromatographic analyses and NMR (see supplementary material) and in allthe cases purity was higher than 95%. IR spectra have been registered (in Nujol) with a Shimadzu FTIR-8300 spectrophotometer;melting points have been determined on a Reichart-Thermovarhotstage Kofler and are uncorrected. NMR spectra have beenregistered on a Bruker AVANCE DMX 300 using CDCl3 and DMSO assolvent. HRMS spectra were recorded by analyzing a 50 ppm solution of the compound in a 6540 UHD Accurate-Mass Q-TOF LC/MS(Agilent Technologies) equipped with a Dual AJS ESI source. GC-MSspectra have been registered by using either an Agilent 7890B/7000C GC-MS-TQ or a GC-MS Shimadzu QP-2010 Instrument. Flashchromatography was performed by using silica gel (Merck,0.040e0.063 mm) and mixtures of ethyl acetate and petroleumether (fraction boiling in the range of 40e60 C) in various ratios. 3-Methyl-benzamidoxime [31], 2-picolin-amidoxime [32],isonicotin-amidoxime [33], nicotin-amidoxime [33], and benzamidoxime [34] were synthesized as reported. Generally, an acqueous solution of hydroxylamine was prepared by mixingNH2OH*HCl (36 mmol) and NaOH (36 mmol) in water (20 mL). Thehydroxylamine solution was then added to an alcoholic solution ofthe corresponding nitrile (30 mmol) dissolved in ethanol (100 mL)in a 250 mL round bottomed flask. The mixture was refluxed for 8 h.The solvent was then removed under vacuum and 100 mL waterwere added to the residue. The amidoxime was filtered as a whitesolid and re-crystallized from ethanol.
With hydroxylamine monohydrate; In ethanol; at 90℃; for 1h;Sealed tube;
General procedure: In a pressurized sealed vial, aqueous hydroxylamine 50% w/w (4equiv) was added to a stirred solution of the appropriate carbonitrile(1 equiv) in absolute ethanol. The resulting mixture washeated at 90 C for 1 h. The solvent was then evaporated to drynessproviding the desired amidoxime quantitatively, which was usedwithout further purification.
With hydroxylamine hydrochloride; sodium carbonate; In ethanol; water; at 20℃; for 17.1667h;
The compounds 4-pyridyl carbonitrile (commercially available) (25g, 240.13mmoles), hydroxylamine hydrochloride (61.24g, 881.28mmoles) and sodium carbonate (43.77g, 413.02mmoles) were dissolved in a solution of water (125ml) and ethanol (375ml). The reaction mixture was then stirred for 10 minutes at room temperature followed by refluxing for 17 hrs. The resulting reaction mixture was cooled to room temperature and diluted with ice-cold water. The precipitate thus obtained were collected by filtration, washed with water and dried under vacuum to furnish the title compound.Yield = 30g.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 50 - 60℃; for 8h;
General procedure: 0.01mol nitrile dissolved in 10 ml ethanol. After that, 0.011 mol hydroxylamine hydrochloride, 10 ml water and 1.23g sodium acetate was added as followed, stirred in room temperature for 0.5 h then refluxed in 50-60 for 8 h. The ethanol was mostly evaporated in vacuum and then the aqueous residue was extracted with CH2Cl2 three times. The combined organic layer was dried over MgSO4 and evaporated to dryness to afford the desired product.
Sulfuric acid (1.5 ml) was added to the solution of 4-cyanopyridine (15.7 g, 151 mmol) in methanol (225 ml) at room temperature and refluxed for 30 minutes. A solution of ammonium peroxodisulfate (54.9 g, 241 mmol) in H2O (100 ml) was slowly added over 30 minutes under reflux and the mixture was refluxed with stirring for 1 hour. After cooling, precipitated materials were filtered off and methanol was removed from the filtrate under reduced pressure. The residue was neutralized (pH = 9) by adding saturated aqueous K2CO3 solution and precipitated materials were filtered off again. The filtrate was extracted with chloroform (100 ml x 4), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (chloroform/methanol) to give 2- (hydroxymethyl)isonicotinonitrile (7.95 g, 39 %, off-white solid).
28%
Add ammonium persulfate (70.1 g, 307 mmol) to a solution of isonicotinonitrile (16.00 g, 154 mmol) in methanol: water: sulfuric acid (275 mL:135 mL:l 1 mL). Heat solution to reflux. After 24 hours, pour reaction onto ice and neutralize with ammonium hydroxide (70 ml). Extract solution with chloroform (3x600 ml). Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with acetone :dichloromethane (1:6) to yield the title compound as a white solid (5.86 g, 28%): 1H NMR (CDCl3) delta 3.17 (t, IH), 4.84 (d, IH), 7.45 (m, IH), 7.58 (s, IH), 8.74 (d, IH)
5.08 g
With sulfuric acid; ammonium peroxodisulfate; In water; for 14h;Reflux;
A) 2-(hydroxymethyl)isonicotinonitrile To a solution of 4-cyanopyridine (10.4 g) in methanol (180 mL), a solution of conc. sulfuric acid (6.98 mL) in water (90 mL) and ammonium peroxodisulfate (45.6 g) were successively added at room temperature, and the mixture was heated under reflux for 14 hr. The solvent was evaporated under reduced pressure, and 28% aqueous ammonia (40 mL) was added. The reaction mixture was extracted with a mixed solvent of ethyl acetate and THF, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.08 g) as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 4. 62 (2H, d, J = 5.8 Hz), 5.63 (1H, t, J = 5.8 Hz), 7.73 (1H, d, J = 4.9 Hz), 7.80 (1H, s), 8.75 (1H, d, J = 5.0 Hz).
With sodium methylate; sodium; In methanol; water; N,N-dimethyl-formamide;
(a) 2-(4'-Pyridyl)-s-triazine 1.0 g of sodium and then 104 g of 4-cyanopyridine (1 mole) are dissolved at room temperature in 500 ml of absolute methanol and the solution is subsequently stirred for 6 hours at 25-30 C. Then 162 g of sodium methylate (3 moles) and a solution of 240 g of <strong>[6313-33-3]formamidine hydrochloride</strong> (3 moles) in 500 ml of absolute dimethyl formamide are added at 25-30 C. After the reaction mixture has been stirred for 16 hours at 25-30 C., it is refluxed for 6 hours at 100 C. bath temperature. After it has cooled, the mixture is concentrated by rotary evaporation and the residue is diluted with 4 liters of water. The precipitate is collected with suction and the filter residue is washed with water and dried in vacuo at 80 C., giving 121.4 g of 2-(4'-pyridyl)-s-triazine (77% of theory) with a melting point of 189-191 C.
To a stirred solution of 2,2,6,6-tetramethyl piperidine (17.16 mL, 100.854 mmol) in THF (100 mL) was added n-BuLi (2.17 M, 44.26 mL, 96.052 mmol) at -30C. After stirring the mixture for 15 mm at 25C, it was cooled to -78C and 4-cyanopyridine (5 g, 48.026 mmol) in THF (40 mL) was added dropwise. After stirring the reaction mixture for 30 mm at -78C, hexachioroethane (23.87 g, 100.854 mmol) in THF (50 mL) was added at -78C. The resulting mixture was stirred for 30 mm at -78C and was quenched with saturated NH4C1 solution. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (4 x 300 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude material which was purified by column chromatography using silica (100-200 mesh) and 5% EtOAc-hexane as eluent to afford 3-chloropyridine-4-carbonitrile (3.5 g, 25.26 1 mmol, 53%) as pale white solid. GCMS: 138 (mlz).
/7-cyanopyridine (8.00 g, 76.8 mmol) was added to a 1:1 mixture of chlorobenzene/water (1.5 L) in a 2 L round-bottom flask. Isovaleric acid (21.74 g, 212.8 mmol), (NH4^S2O8 (34.40 g, 150.7 mmol), trifluoroacetic acid (8.78 g, 77.0 mmol) and AgNO3 (1.040 g, 6.1 mmol) were added and the heterogeneous mixture was vigorously stirred and refluxed for 2 h. The reaction was cooled down to 0 0C and 8 M NaOH was added slowly until pH 9-10. The mixture was filtered through Celite and extracted with EtOAc (x3). The combined organic extracts were dried with MgStheta4 and the solvent removed in vacuo. The dark-brown oil was purified via flash chromatography (1:4 EtOAc/Hexane) to give a brown oil (6.538 g, 54 %); 1H NMR (400 MHz, CDCl3): delta 0.95 (d, J= 6.8 Hz, 6H), 2.13 (m, IH), 2.73 (d, J= 6.8 Hz, 2H), 2.37 (m, 2H), 8.73 (m, IH); 13C NMR (100 MHz, CDCl3): D 22.3, 29.1, 47.3, 116.8, <n="33"/>120.4, 122.4, 125.0, 150.2, 163.3; HRMS-EI (tn/z): [MH-H+] calcd for [C I0H13N2f, 161.1079; found, 161.1073.
32.5%
With ammonium persulfate; sulfuric acid; silver nitrate; In water; at 100℃; for 3h;
Step 1: Synthesis of2-isobutylpyridine-4-carbonitrile (2) [0185] To a suspension of 4-cyano pyridine (1) (30 g, 0.288 mol, 1 equiv.) in water (210 mL), concentrated sulfuric acid (15.3 mL, 0.288 mol, 1 equiv.) was added dropwise maintaining the temperature at 20-25 C. After formation of a clear solution, AgN03 (4.9 g, 0.028 mmol, 0.0001 equiv.) followed by <strong>[503-74-2]isovaleric acid</strong> (160 mL, 1.47 mol, 5 equiv.) were added in to the reaction mixture. A white hazy solution formed. Ammonium peroxydisulfate (66 g, 0.288 mol, 1 equiv.) dissolved in water (90 mL) was then added. A black clear solution formed. The reaction mixture was then heated to reflux at 100 C for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was basified (pH = 7-8) using a saturated solution of sodium bicarbonate, and extracted with EtOAc (3x750 mL). The extracts were combined and were washed with brine (3x300 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel: 100-200) using 0-6 % EtOAc in hexane as eluant to afford 2- isobutylpyridine-4-carbonitrile (2) (15 g (32.5 % yield)) as a pale yellow liquid. 1H NMR (400 MHz, Chloroform-;/): delta (ppm): 8.78 - 8.63 (m, 1H), 7.41 - 7.27 (m, 2H), 2.72 (d, J= 7.2 Hz, 2H), 1.35 - 1.23 (m, 1H), 0.94 (d, J= 6.6 Hz, 6H).
32.5%
With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In water; at 20 - 100℃; for 3h;
To a suspension of 4-cyano pyridine (1) (30 g, 0.288 mol, 1 equiv.) in water (210 mL), concentrated sulfuric acid (15.3 mL, 0.288 mol, 1 equiv.) was added dropwise maintaining the temperature at 20-25 C. After formation of a clear solution, AgNO3 (4.9 g, 0.028 mmol, 0.0001 equiv.) followed by <strong>[503-74-2]isovaleric acid</strong> (160 mL, 1.47 mol, 5 equiv.) were added in to the reaction mixture. A white hazy solution formed. Ammonium peroxydisulfate (66 g, 0.288 mol, 1 equiv.) dissolved in water (90 mL) was then added. A black clear solution formed. The reaction mixture was then heated to reflux at 100 C. for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was basified (pH=7-8) using a saturated solution of sodium bicarbonate, and extracted with EtOAc (3*750 mL). The extracts were combined and were washed with brine (3*300 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel: No.100-200) using 0-6% EtOAc in hexane as eluant to afford 2-isobutylpyridine-4-carbonitrile (2) (15 g (32.5% yield)) as a pale yellow liquid. 1H NMR (400 MHz, Chloroform-d): delta (ppm): 8.78-8.63 (m, 1H), 7.41-7.27 (m, 2H), 2.72 (d, J=7.2 Hz, 2H), 1.35-1.23 (m, 1H), 0.94 (d, J=6.6 Hz, 6H).
32.5%
With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In water; at 20 - 100℃; for 3h;
To a suspension of 4-cyano pyridine (1) (30 g, 0.288 mol, 1 equiv.) in water (210 mL), concentrated sulfuric acid (15.3 mL, 0.288 mol, 1 equiv.) was added dropwise maintaining the temperature at 20-25 C. After formation of a clear solution, AgNO3 (4.9 g, 0.028 mmol, 0.0001 equiv.) followed by <strong>[503-74-2]isovaleric acid</strong> (160 mL, 1.47 mol, 5 equiv.) were added in to the reaction mixture. A white hazy solution formed. Ammonium peroxydisulfate (66 g, 0.288 mol, 1 equiv.) dissolved in water (90 mL) was then added. A black clear solution formed. The reaction mixture was then heated to reflux at 100 C. for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was basified (pH=7-8) using a saturated solution of sodium bicarbonate, and extracted with EtOAc (3*750 mL). The extracts were combined and were washed with brine (3*300 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel: No.100-200) using 0-6% EtOAc in hexane as eluant to afford 2-isobutylpyridine-4-carbonitrile (2) (15 g (32.5% yield)) as a pale yellow liquid. 1H NMR (400 MHz, Chloroform-d): delta (ppm): 8.78-8.63 (m, 1H), 7.41-7.27 (m, 2H), 2.72 (d, J=7.2 Hz, 2H), 1.35-1.23 (m, 1H), 0.94 (d, J=6.6 Hz, 6H).
General procedure: Trifluoroacetic acid (4 mL) was added to a mixture of nitrile(1.0 mmol) and thiosemicarbazide (1.1 mmol). The reaction mixturewas stirred and refluxed for 6 h. Then, it was cooled to roomtemperature and aqueous ammonia was added. The precipitatedsolidwas filtered,washed with hot water and air-dried. It should benoted that the compounds f1-f35 were directly used for the nextreaction without further purification.
51%
A mixture of 4-cyanopyridine (5.2 g, 50 mmol) and thiosemicarbazide (6.37 g, 70 mmol) was heated in polyphosphoric acid at 100C overnight. The reaction mixture was poured onto 200 g ice and the pH was adjusted to approximately 7.5 by addition of 6N NaOH. The product precipitated and was filtered and dried to afford 5-pyridin-4-yl- [1, 3,4] thiadiazol-2-ylamine (4.59 g, 51%).'H NMR CD30D: 7.8 (d, 2H), 8.62 (d, 2H).
With trifluoroacetic acid; at 60 - 70℃;
General procedure: To a stirred mixture of nitrile (1.0 mmol) and thiosemicarbazide(1.1 mmol) was added trifluoroacetic acid (4 mL) and then themixture was refluxed for 6 h under stirring. After completion ofreaction cooled to room temperature and diluted with aqueousammonia. The precipitated solid was filtered off, washed with hotwater and dried in air. The product 14a-f were used in the next stepwithout further purification. Spectral data of compounds such as 5-phenyl-1,3,4-thiadiazol-2-amine (14a) [63], 5-(p-tolyl)-1,3,4-thiadiazol-2-amine (14b) [63], 5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazol-2-amine (14c) [64], 5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (14d) [63], 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine(14e) [63] and 5-(thiophen-2-yl)-1,3,4-thiadiazol-2-amine (14f)[63] were agreement with literature report.
5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30 % sulfuric acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0C. After 15 mins, this solution was added slowly to dilute sulfuric acid (50 %, 250 ml) at 110 C. Stirring was continued for 15 min. The reaction mixture was cooled to RT, ice water was added, extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The phenol product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24.0 %. [00153] K2CO3 (23.84 g, 0.172 mol) was added to 2-chloro-5- nitrophenol (10.0 g, 0.058 mol) in acetonitrile (100 ml) at RT. After cooling to 0 C, methyl iodide (19.6 g, 0.138 mol) was added slowly and the reaction mixture stirred at RT overnight. Water (100 ml) was added and the aqueous layer extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography to yield the ANISOLE (6.0 g, 55.55%). [00154] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 C and the temperature was slowly raised to 50 C. Stirring was continued for 2 h. After cooling to RT, the reaction mixture was basified with 50 % NAOH solution, extracted by ethyl acetate, washed with water, then brine and dried over NA2SO4. 3-METHOXY-4-CHLOROANILINE was obtained upon concentration and was purified further by column chromatography. Yield : 4.0 g, 79.36 %. [00155] To 3-METHOXY-4-CHLOROANILINE (2.0 g, 0.0126 mol) in trichloroethylene (30 ml) was added BC13 (2.18 g, 1 M solution in DCM, 0.0188 mol) AT 0 C. After stirring for 10 min, 4-CYANOPYRIDINE (1.6 g, 0.0153 mol) and AIC13 (2.35 g, 0.018 mol) were added and the temperature was raised to RT, with further stirring for 30 min. The temperature was raised further to 85 C and maintained at the same temperature for 1 h. DCM was distilled off and the solution was stirred at 115 C for 4 h and then at RT over night. 3N HCI was added at RT and the reaction mixture REFLUXED for 1.5 h. The reaction mixture was allowed to cool and made basic using NAOH (6 N), diluted with water and extracted with DCM, washed with water, brine and dried over NA2SO4. The crude title compound was obtained upon concentration and was purified by column chromatography. Yield : 0.50 g, 15 %.
With potassium tert-butylate; In DMF (N,N-dimethyl-formamide); tert-butyl alcohol; at 20℃; for 1h;
To a 500 mL round bottom flask (RBF), was added ethyl (3-bromo- phenyl) acetate (10.3 g, 42.2 mmol), 4-cyanopyridine (4.4 g, 42.2 mmol) and 56 mL DMF. The mixture was stirred at room temperature under nitrogen. 42 [ML] 1 M KOtBu in tBuOH was added drop wise, and stirred for 1 h at rt. Methyl isothiocyanate (3.08 g, 42.2 mmol) was added in one portion, and stirred for another one hour at rt. The mixture was cooled down to [0 C,] iodomethane (2.7 mL, 42.2 mmol) was added drop wise and stirred for 1 h at [0 C.] To quench the reaction, 100 mL H20 was added. Yellow solid was precipitated. After filtration and washed with [H20,] the [5- (3-BROMO-PHENYL)-3-METHYL-2-METHYLSULFANYL-6-] pyridin-4-yl-3H-pyrimidin-4-one was obtained in 9.2 g as pale yellow powder. MS (ES+): 388 (M+H) [+] ; (ES-): 386 (M-H).
In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water;
Part A A solution of 4-cyanopyridine (5.20 g, 50.0 mmol) in 90 ml of methanol is treated with a mixture of H2 SO4 (6.42 g, 65.5 mmol, 1.31 equiv.) and water (45 ml) at once followed by the addition of (NH4)2 S2 O8 (22.8 g, 100 mmol, 2.0 equiv.). The contents were heated to reflux at which point vigorous refluxing ensued for several minutes. After refluxing for 24 h, the reaction mixture is partially concentrated to remove most of the methanol, treated with ice-water mixture and basified with ammonium hydroxide (20 ml, 29% aq). The residue is extracted four times with chloroform, the combined extracts are dried with anhyrous Na2 SO4 and concentrated at reduced pressure. Chromatography is accomplished using 300 g of silica gel packed and eluted with acetone-methylene chloride (1:6) to provide 2.65 g (39.5%) of 4-Cyano-2-hydroxymethylpyridine. TLC (silica gel GF): Rf =0.30 acetone-methylene chloride (1:4). 1 H NMR (CDCl3,TMS):delta 8.78 (d, 1H,J=5.07 Hz), 7.66 (s, 1H), 7.49 (d, 1H, J=5.12 Hz), 4.88 (d, 2H, J=4.96 Hz), 3.64 (t, 1H, J=5.21 Hz). UV (lambda max, ethanol): 216 sh (7,710), 220 sh (6,590), 280 (3,510), 287 sh (3,020). Analysis: Calculated for C7 H6 N2 O: C, 62.69; H, 4.48; N, 20.89. Found: C, 62.66; H, 4.46; N, 21.00. Mass Spectrum: M/Z (relative intensity %): 134 (73), 133 (100), 105 (79), 104 (39), 77 (38), 50 (30).
With sodium methylate; In methanol; 2-ethoxy-ethanol; at 130℃; for 12h;
To a stirring solution of tert-butyl 4-(hydrazinocarbonyl)piperidine-l-carboxylate (2.0 g,8.22 mmoles) in 2-ethoxyethanol (41 mL) was added isonicotinonitrile (1.02 g, 9.86 mmoles) followed by sodium methoxide (25 wt % in methanol, 1.07 mL). After heating the reaction to 130 0C for 12 hrs, the solution was cooled, neutralized with acetic acid, and partitioned between EtOAc and aq. NaHCO3. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced vacuum. The residue was purified by silica gel chromatography (CH2Cl2 to 85 %CH2C12/ 15% MeOH). LRMS m/z (M+H)Calcd.: 330.2, found 330.2 tert-Butyl 4-(5-pyridin-4-yl-4H-l,2,4-triazol-3-yl)piperidine-l-carboxylate (1.67 g, 5.07 mmoles) was treated with N,N diisopropylethyl amine (2.65 mL, 15.2 mmoles) followed by di-fert-butyl dicarbonate (1.66 g, 7.61 mmoles) in CH2Cl2 (10 mL). After stirring for 12 hrs, the reaction mixture was diluted with CH2Cl2 and partitioned with brine. The organic layer was separated, dried with Na2SO4, filtered, and concentrated under reduced vacuum. The residue was purified by silica gel chromatography(Hexane to 100% EtOAc). LRMS m/z (M+H) Calcd.: 430.5, found 430.This material (1.80 g, 4.19 mmoles) was dissolved in CH2Cl2 (20 mL) and treated with meta- chloroperoxybenzoic acid (75% max., 2.41 g, 13.9 mmoles) and stirred overnight. The reaction mixture was diluted with CH2Cl2 and washed with 10% sodium thiosulfate and (sat.) sodium bicarbonate.The organic layers were collected and dried with Na2SO4, filtered, and concentrated under reduced vacuum.A portion of this material (240 mg, 0.698 mmoles) was dissolved in CH2Cl2 (5 mL) and stirred with trifluoroacetic acid (2.5 mL) for 30 min. The reaction mixture was concentrated to dryness under reduced pressure to afford the title compound. LRMS m/z (M+H) Calcd.: 246.1, found 246.1
With sodium methylate; In methanol; isopropyl alcohol;
70 g (1 mol) of hydroxyammonium chloride in 500 ml of methanol are introduced into the vessel, and a solution of 54 g (1 mol) of sodium methylate in 500 ml of methanol is added. After about 30 minutes, the sodium chloride is filtered off, 41.6 g (0.4 mol) of pyridine-4-carboxylic acid nitrile are added to the filtrate, and the batch is refluxed for 24 hours. Subsequently, the methanol is distilled off, and the residue is recrystallized from 2000 ml of isopropanol with simultaneously clarification with bleaching earth. 49.1 g (89.5% of th., relative to the nitrile used) of pyridine-4-amidoxime having a melting point of 207-208 C. are obtained which are reacted without further purification.
(a) A mixture of 4-cyanopyridine (31.2 g), ammonium persulphate (136.8 g), methanol (450 ml), concentrated sulphuric acid (16.2 ml) and water (210 ml) was heated under reflux for 24 hours, and the methanol was removed by distillation. Crushed ice (450 g) was added and the mixture was adjusted to pH 12 with 10 M sodium hydroxide and extracted with chloroform. The chloroform extracts were combined and evaporated and the residue was purified by elution from a silica gel column with methanol-chloroform (7.5% v/v) to give 4-cyano-2-hydroxymethylpyridine (18.5 g, 46%) m.p. 92-94.
EXAMPLE 10 A mixture of 4-cyanopyridine (5.21 g), sodium methoxide (2.70 mg) and anhydrous methanol (35 g) was stirred at room temperature for 2.7 hours to give methanolic solution of methyl imino isonicotinate. 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. In the course of the reaction, methanol (50 ml) was added again. After cooling to 0-5 C., the precipitate was separated from the solution by filtration, washed with ethanol and isopropylether, and dried under vacuum to give yellow crystalline (5.76 g) of 2-(4-pyridyl)-5-hydroxy-1H-imidazole-4-carboxamide. Recrystallization from aqueous methanol gave dark yellow fine plates.
With sodium hydroxide; In water; at 27℃; for 44h;pH 7.0;Medium; fermentation;Product distribution / selectivity;
Example 3: Accumulating reaction of the 2-hydroxy-4-substituted pyridine using a resting bacterial cell of Delftia species YGK-A649 As in Example 1, the Delftia species YGK-A649 (FERM BP-10389) was cultured, and thus, the bacterial cells in 200 mL of the culture were collected by centrifugation to obtain the resting bacterial cell. The resting bacterial cells were added to 100 mL of a 0.1 M potassium phosphate buffer (adjusted to pH 7.0) containing 4-substituted pyridine described in Table 2 (0.5 w/v%) respectively, and were suspended. The suspension was charged to a reaction vessel (100 mL volume) capable of shaking, aerating, controlling temperature, and controlling pH, and a reaction was carried out at 27C, and pH 7.0, while shaking and aerating. After the reaction for 44 hours, the 2-hydroxy-4-substituted pyridine was measured. The reaction products were identified by HPLC analysis and HPLC--MS. The results are shown in Table 2.One hundred mL of isopropanol was added to the resulting broth containing 0.27 g of 2-hydroxy-4-pyridinaldoxime obtained from the reaction with 4-pyridinaldoxime as a substance. After shaking for 30 minutes, the solid contents were removed by filtration. After an addition of 100 mL of water to the filtrate, the whole was concentrated under a reduced pressure, whereby isopropanol was removed to precipitate the crystals. The precipitated crystals were separated by filtration to obtain 0.20 g of crude crystals. The resulting crystals were washed by water, and then were separated by filtration to obtain 0.15 g of white crystals of 2-hydroxy-4-pyridinaldoxime (rate of isolated yield = 53%). The structure of the crystals was identified by IR analysis, proton NMR analysis and MS analysis. IR (KBr, cm-1); 3180, 3070, 2920, 1660, 1520, 1430, 1330, 1300, 1250, 1000, 900, 870, 800, 770 1H-NMR(Dimethylsulfoxide, ppm) ; 11.78 (1H, s), 11.48(1H, s), 7.95(1H, s), 7.29(1H, d), 6.40 (1.H, s), 6.40(1H, d) MS (MH+) ; 139; Example 4: Accumulating reaction of the 2-hydroxy-4-substituted pyridine using a resting bacterial cell of each bacteria As in Example 1, the Delftia species YGK-A649 (FERM BP-10389), Delftia species YGK-C217 (FERM BP-10388), or Acidovorax species YGK-A854 (FERM BP-10387) was cultured, and then each bacteria in 10 mL of the culture was collected by centrifugation to obtain the resting bacterial cells. Then each resting bacterial cells were added to 2 mL of a 0.1 M boric acid-sodium hydrate buffer (adjusted to pH7.0) containing 4-substituted pyridine described in Table 3 (0.5 w/v%) respectively, and were suspended. Then each suspension was charged to a reaction vessel (15 mL volume) and a reaction was carried out at 27C, pH7.0, while shaking. After the reaction for 44 hours, each 2-hydroxy-4-substituted pyridine was measured. The results are shown in Table 3.
With sodium hydroxide; In water; at 27℃; for 44h;pH 7.0;Medium; fermentation;Product distribution / selectivity;
Example 4: Accumulating reaction of the 2-hydroxy-4-substituted pyridine using a resting bacterial cell of each bacteria As in Example 1, the Delftia species YGK-A649 (FERM BP-10389), Delftia species YGK-C217 (FERM BP-10388), or Acidovorax species YGK-A854 (FERM BP-10387) was cultured, and then each bacteria in 10 mL of the culture was collected by centrifugation to obtain the resting bacterial cells. Then each resting bacterial cells were added to 2 mL of a 0.1 M boric acid-sodium hydrate buffer (adjusted to pH7.0) containing 4-substituted pyridine described in Table 3 (0.5 w/v%) respectively, and were suspended. Then each suspension was charged to a reaction vessel (15 mL volume) and a reaction was carried out at 27C, pH7.0, while shaking. After the reaction for 44 hours, each 2-hydroxy-4-substituted pyridine was measured. The results are shown in Table 3.
With sodium hydroxide; In water; at 27℃; for 44h;pH 7.0;Medium; fermentation;Product distribution / selectivity;
Example 4: Accumulating reaction of the 2-hydroxy-4-substituted pyridine using a resting bacterial cell of each bacteria As in Example 1, the Delftia species YGK-A649 (FERM BP-10389), Delftia species YGK-C217 (FERM BP-10388), or Acidovorax species YGK-A854 (FERM BP-10387) was cultured, and then each bacteria in 10 mL of the culture was collected by centrifugation to obtain the resting bacterial cells. Then each resting bacterial cells were added to 2 mL of a 0.1 M boric acid-sodium hydrate buffer (adjusted to pH7.0) containing 4-substituted pyridine described in Table 3 (0.5 w/v%) respectively, and were suspended. Then each suspension was charged to a reaction vessel (15 mL volume) and a reaction was carried out at 27C, pH7.0, while shaking. After the reaction for 44 hours, each 2-hydroxy-4-substituted pyridine was measured. The results are shown in Table 3.
Intermediate 1: Z/E 1-(4-Bromo-2, 5-difluorophenvl}-1-(4-pvridinvl) methanimine; A stirred solution of 1,4-dibromo-2, 5-difluorobenzene (2.72g) in anhydrous diethylether (50ml) u nder n itrogen w as c ooled t o-78C i n a d ry-ice/acetone b ath t hen treated with n-butyllithium (1.6M in hexanes, 7. 2mi). The reaction mixture was stirred for 20min and a solution of 4-cyanopyridine (1. 4g) in diethylether (60moi) was added dropwise. The resulting mixture was stirred for a further 20min then treated with saturated aqueous ammonium chloride. The ether layer was separated, washed with brine, dried (sodium sulfate) and concentrated under vacuum. The crude product was purified on an SPE cartridge (silica) using a cyclohexane/ethyl acetate gradient as eluant to give the title compound as a colourless gum (1.50g). NMR: [8H CDCI3] 10.35 (1 H, s, minor), 10.35 (1 H, s, major) 8.74 (2H, d, J=6Hz, major and minor), 7.58 (2H, d, J=6Hz, major), 7.48-7. 42 (1H, m, ), 7.40-7. 03 (4H, m, major and minor)
With 1-methyl-3-(4-sulfonylbutyl)-1H-imidazol-3-ium trifluoromethanesulfonate; acetic acid; at 80℃; for 13h;Inert atmosphere; Ionic liquid;
<strong>[1462-03-9]1-methylcyclopentanol</strong> (2 mmol), catalytic amounts of the ionic liquid, and 1-2 mL of acetic acid were charged into an oven-dried Schlenk tube under nitrogen. The reaction mass was stirred for 15-20 minutes at r.t. before adding the selected nitrile (1 mmol). The reaction mass was stirred at the indicated temperature for the specified time (see Table 3). The progress of the reaction was monitored by TLC and GC-MS. After completion of reaction, the reaction mass was quenched with distilled water followed by neutralization with dilute NaHCO3 solution. The product was extracted with diethyl ether, dried over anhydrous MgSO4, and the ether layer was evaporated in vacuum. The resulting crude products were chromatographed with hexane-ethyl acetate mixture (80:20) to afford pure colorless solids.
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 potassium 2,2-dimethyl-1-propanolate; In 1,4-dioxane; toluene; at 20℃;
Synthesis of 6-methyl-2-pyridin-4-yl-thieno [3,2-d]pyrimidin-4-ol [BB-01] To a solution of 4-cyanopyridine (552 mg, 5.3 mmol) in dry dioxane (10 ml) was added <strong>[76575-71-8]3-amino-5-methyl-thiophene-2-carboxylic acid methyl ester</strong> (1 g, 5.84 mmol) followed by potassium-tert-pentylate 1.7M in toluene (6.9 ml, 11.7 mmol). The reaction mixture was stirred at room temperature overnight. After completion the precipitate formed was filtered and washed with diethyl ether. The residue was used without any further purification in the next step. LCMS method: 3, RT: 2.44 min, MI: 244 [M+l]. 1H NMR (300MHz, DMSO): 2.60 (s,3H), 7.23 (d,lH), 8.05 (m,2H), 8.76 (m,2H).
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.
With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In dichloromethane; water;Reflux;
Step 1 : 2-Acetylisonicotinonitrile To a solution of isonicotinonitrile (52 g, 0.5 mol) in dichloromethane (1300 mL) and water (1 100 mL) were added ammonium persulfate ((NH4)2S208) (170 g, 0.75 mol), silver nitrate (6.8 g, 0.04 mol) and aqueous sulfuric acid (40 mL, 98% sulfuric acid in 400 mL). A solution of 3-oxo-butyric acid (1 10 g, 1.25 mol) in dichloromethane (100 mL) was added dropwise while keeping the mixture refluxing. The reaction mixture was refluxed for 2 h. The resulting mixture was basified to pH -8-9 using sodium carbonate powder. The mixture was filtered and the filtrate was extracted with dichloromethane (500 mL x 3). The combined organics were dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to afford 2-acetylisonicotinonitrile (52.0 g, 71.9%).
Synthesis of 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [A001] A mixture of 4-Cyanopyridine (8.25 g, 79.2 mmol), sodium methoxide (891 mg, 16.5 mmol) and methanol (400 mL) was stirred at room temperature for 60 minutes. 3-Amino- isonicotinic acid (9.12g, 66.0 mmol) was added and the mixture heated to reflux for 3 days. After cooling to room temperature the solid precipitate was collected by filtration then dried in the vacuum oven to yield the title compound as an off-white solid (6.02 g): (IH, 300MHz, d6-dmso) 13.10 (IH, br s), 9.16 (IH, s), 8.80 (2H, dd), 8.70 (IH, d), 8.10 (2H, dd), 8.00 (IH, dd)
6.02 g
Synthesis of 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [A001] (0137) A mixture of 4-Cyanopyridine (8.25 g, 79.2 mmol), sodium methoxide (891 mg, 16.5 mmol) and methanol (400 mL) was stirred at room temperature for 60 minutes. 3-Amino-isonicotinic acid (9.12 g, 66.0 mmol) was added and the mixture heated to reflux for 3 days. After cooling to room temperature the solid precipitate was collected by filtration then dried in the vacuum oven to yield the title compound as an off-white solid (6.02 g): (1H, 300 MHz, d6-dmso) 13.10 (1H, br s), 9.16 (1H, s), 8.80 (2H, dd), 8.70 (1H, d), 8.10 (2H, dd), 8.00 (1H, dd)
With sodium tetrahydroborate; La0.5Ca0.5CoO3; In methanol; at 40℃; under 760.051 Torr; for 0.333333h;
General procedure: To a stirring mixture of the appropriate nitrile (1 mmol) and nanosized La0.5Ca0.5CoO3 perovskite (1 mol%, 1.9 mg) in MeOH (5 ml) at 40C, NaBH4 (2 mmol, 0.08 g) was added portion wise. After the completion of the reaction which was monitored by TLC using CHCl3: MeOH (30:1) as eluent, the catalyst was centrifuged off and the solvent was evaporatedunder reduced pressure. To the resulting oily liquid, water (20 ml) was added and the mixture was extracted with CH2Cl2 (2 × 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to afford the pure products.
With C22H27ClN3Ru(1+)*F6P(1-); hydrogen; In isopropyl alcohol; at 80℃; under 45004.5 Torr; for 12.0h;
General procedure: All of the hydrogenation reactions were performed at constant pressures using a stainless steel 50mL Parr hydrogenation reactor. The reactor was flushed three times with hydrogen gas at 2-4bar prior to the addition of catalyst and substrate. Catalyst 1 (0.02mmol), nitrile (1mmol), and dodecane (1mmol) in case of symmetrical amine synthesis or, catalyst 1 (0.02mmol), nitrile (1mmol), amine (3mmol) and dodecane (1mmol) in case of asymmetrical amine synthesis were dissolved in iPrOH (5mL) under a nitrogen atmosphere. The solution was then injected into the reactor against a flow of hydrogen gas. The hydrogen gas was adjusted to 60bar. The temperature of the system was maintained at 80C using a thermostat. Small aliquots of the reaction mixture were withdrawn after 12h with a syringe and diluted with 2mL of EtOAc and passed through a very short column of silica and subjected to GC-MS analysis. A few selected secondary amines were purified by flash chromatography and characterized by 1H and 13C NMR spectra.
The 2 - cyano-isonicotinic acid methyl ester by adding (487.1g, 3 muM) soluble in 1L in the ethanol in the reactor, stirring at the room temperature, dropping hydrazine hydrate (187.9g, 3 muM), then heating to 40 C stirring 4h, TLC detection reaction (ethyl acetate: petroleum ether=1:2), the reaction is finished. Then adding sodium methoxide (28g, 0.5 muM), stirring 20min to dissolve, then the compound is added 4 - cyanopyridine (312.33g, 3 muM), 80 C reaction 10h, TLC detection (ethyl acetate: petroleum ether=1:4), after the reaction, cooling the room-temperature crystallization, the separated solid filtering, for 500 ml ethanol after cleaning, vacuum drying to obtain a pale yellow powdery product holds a department he 405.5g, yield 63%.
With potassium tert-butylate; copper(ll) bromide; In tert-butyl alcohol; at 20℃; for 37h;
General procedure: A 10 mL round-bottomed flask was charged with the appropriate nitrile 2 (0.50 mmol), arylboronic acid 1(0.60 mmol), CuBr2 (6 mg, 5mol%), t-BuOK (168 mg, 1.50 mmol), and t-BuOH (3.0 mL), and the mixture was stirred at r.t. until the reaction was complete (TLC). H2O (4.0 mL) was added, and the mixture was extracted with EtOAc (3 ×10 mL). The combined organic layers were washed twice with H2O,dried (Na2SO4), and concentrated to give a residue that was purified by column chromatography (silica gel, PE-EtOAc).
(1-(pyridin-4-yl)-N-(pyridin-4-ylmethylene)methanamine)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dodecacarbonyl-triangulo-triruthenium; hydrogen; triphenylphosphine; In tetrahydrofuran; at 200℃; under 3102.97 Torr; for 72.0h;
4-cyanopyridine (0.5g, 4.8mmol), [Ru3(CO)12] (1) (3mg, 0.0048mmol), TPP (4mg, 0.0144mmol) and THF (25mL) were charged in a 100-mL Parr reactor; the reactor was closed and pressurized out of the dry box with H2 (60psi). Afterward, the reaction vessel was heated up to 200C for 72h. Following this, the reactor was cooled down to room temperature and vented into a hood; 1muL of the reaction mixture was directly analyzed by GC-MS. All samples produced at the end of the hydrogenation experiments were centrifuged (10-15min at 5000 cycles/min) in order to recover the corresponding ruthenium nanoparticles and further analyzed by TEM.
4-cyanopyridine (3.38 g, 32.48 mmol), <strong>[55-98-1]busulfan</strong> (4 g, 16.24 mmol) and 3 ml of toluene were placed in a 100 ml round bottom flask (RBF) (reflux) overnight. The reaction product was dissolved in methanol (MeOH) and precipitated in acetone (Acetone) to obtain Compound 1-4.
Sodium salt of p-nitrobenzoic acid (0.189 g, 1.0 mmol) was dissolved in 15 ml distilled water in a round-bottom flask. An aqueous solution of MnCl2*4H2O (0.198 g, 1 mmol) was added to the above solution. The solution was then stirred at room temperature for about an hour. To the resulting colorless solution, 4-CNpy (0.208 g, 2 mmol) was added slowly and the mixture was stirred mechanically for about two hours (Scheme 2). The solution obtained was then filtered and left unperturbed for crystallization. Colorless crystals with irregular shape were obtained from the mixture after few weeks with a yield of 74% based on Mn. The large crystals were filtered off, washed with water and dried in air. Anal. Calcd. for C26H16Cl0MnN6O8: C, 49.50; H, 2.56;N, 13.32. Found: C, 49.30; H, 2.61; N, 13.20. IR (KBr pellet, cm-1): 3414 (m), 3092 (sh), 2235 (m), 1942 (m), 1612 (vs), 1547 (m), 1496(s), 1416 (vs), 1218 (s), 1115 (w), 1064 (m), 1005 (m), 831 (vs), 786 (m), 552 (m).
In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water;
Part A A solution of 4-cyanopyridine (5.20 g, 50.0 mmol) in 90 ml of methanol is treated with a mixture of H2 SO4 (6.42 g, 65.5 mmol, 1.31 equiv.) and water (45 ml) at once followed by the addition of (NH4)2 S2 O8 (22.8 g, 100 mmol, 2.0 equiv.). The contents were heated to reflux at which point vigorous refluxing ensued for several minutes. After refluxing for 24 h, the reaction mixture is partially concentrated to remove most of the methanol, treated with ice-water mixture and basified with ammonium hydroxide (20 ml, 29% aq). The residue is extracted four times with chloroform, the combined extracts are dried with anhyrous Na2 SO4 and concentrated at reduced pressure. Chromatography is accomplished using 300 g of silica gel packed and eluted with acetone-methylene chloride (1:6) to provide 2.65 g (39.5%) of 4-Cyano-2-hydroxymethylpyridine. TLC (silica gel GF): Rf =0.30 acetone-methylene chloride (1:4). 1 H NMR (CDCl3,TMS):delta 8.78 (d, 1H,J=5.07 Hz), 7.66 (s, 1H), 7.49 (d, 1H, J=5.12 Hz), 4.88 (d, 2H, J=4.96 Hz), 3.64 (t, 1H, J=5.21 Hz). UV (lambda max, ethanol): 216 sh (7,710), 220 sh (6,590), 280 (3,510), 287 sh (3,020). Analysis: Calculated for C7 H6 N2 O: C, 62.69; H, 4.48; N, 20.89. Found: C, 62.66; H, 4.46; N, 21.00. Mass Spectrum: M/Z (relative intensity %): 134 (73), 133 (100), 105 (79), 104 (39), 77 (38), 50 (30).
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