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With potassium fluoride In dimethyl sulfoxide at 20 - 130℃; for 0.916667 h;
2,6-Dichloro-5-fluoro-nicotinonitrile (25.67 g, 134 mmol) and spray-dried KF (23.6 g, 406 mmol) (Aldrich), both of which had been freshly powdered under air to remove clumps, were shaken together to ensure complete mixing before adding dry DMSO (30 mL). The mixture was efficiently stirred at rt under argon for 1-2 min, and then placed in a 100° C. oil bath and stirred for 5 min. The temperature was then raised to 130° C. over the course of 10 min, and the mixture was stirred at this temperature for 40 min. The NMR spectrum of reaction aliquots demonstrated 86percent conversion after 10 min at 130° C., and >95percent conversion after 40 min. The thick purple mixture was then allowed to cool to rt, shaken with DCM (30 mL) on an ice bath, and then loaded directly onto a flash silica column (1.0 kg silica gel; 120 mm.x.6) pre-equilibrated with DCM. DCM elution (140 mL fractions; fractions 10-19 combined) afforded 20.65 g of a clear light amber oil. A NMR spectrum demonstrated a 1:0.58 mol ratio of title compound:DMSO (16.0 g title compound; 76percent). 1H-NMR (300 MHz, CDCl3) δ 7.99 (m, 1H). LC/MS (ESI): calcd mass 158.0, found 159.5 (MH)+
With triethylamine; In acetonitrile; at 0℃; for 1h;
To a solution of <strong>[870065-73-9]2,5,6-trifluoronicotinonitrile</strong> (1.0 g, 6.3 mmol) and triethylamine (0.83 g, 8.2 mmol) in ACN (30 ml) at O0C was added 5 -methyl- lH-pyrazol-3 -amine (0.67 g, 6.9 mmol). The reaction was stirred at 00C for 1 hour, at which point the reaction was filtered. The resulting solid was washed with cold ACN, dried and collected to give the title compound (0.44 g, 29%). MS: Calcd.: 235; Found: [M+H]+ 236.
With triethylamine; In acetonitrile; at -5 - 5℃; for 1h;
A solution of <strong>[870065-73-9]2,5,6-trifluoronicotinonitrile</strong> (30.0 g, 189.8 mmol) in ACN (240 ml) was prepared in a 11 3 -neck flask at room temperature and then cooled to -5 0C using an ice-salt bath. An addition funnel containing triethylamine (29.1 ml, 208.8 mmol) and a second EPO <DP n="105"/>addition funnel containing a solution of S-cyclopropyl-lH-pyrazol-theta-amine (25.7 g, 208.8 mmol) in ACN (160 ml) were placed on top of the reaction flask. A total of 5 ml of triethylamine was added quickly dropwise to the reaction. The reaction was allowed to stir for 5 min, followed by the simultaneous dropwise addition of the remaining triethylamine and 5- cyclopropyl-lH-pyrazol-3-amine solution at a rate slow enough to keep the internal temperature at or below 5 0C. Upon completion of the addition, the reaction was allowed to stir for 1 hour at 0 0C, at which point no starting material remained, and the reaction was filtered through a fritted funnel. The remaining solids were washed with 0 0C ACN (3 x 100 ml). The solid product was then dried under vacuum for 30 minutes to give the title compound (25.2 g, 51 %) which was used without further purification. 1H NMR (400 MHz, CD3OD) delta 7.81-7.77 (m, IH), 6.33 (s, IH), 1.91 (septet, IH), 0.99-0.98 (m, 2H), 0.76-0.73 (m, 2H). MS: Calcd.: 261; Found: [M+H]+ 262.
With triethylamine; In acetonitrile; at 0℃; for 1h;Product distribution / selectivity;
To a solution of 2,5,6-trifluoronicotinonitrile (3.0 g, 19.0 mmol) and triethylamine (2.5 g, 24.7 mmol) in ACN (30 ml) at 0 0C was added 5-isopropoxy-l/f-pyrazol-3-amine (2.95 g, 20.9 mmol) in ACN (15 ml). The reaction was stirred at 0 0C for 1 hour, at which point the reaction was diluted with water (50 ml) and extracted with DCM (2 x 50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH = 100 :1) to give the title compound (0.48 g, 9%). MS: Calcd.: 279; Found: [M+H]+ 280.
A solution of tert-butyl 5-amino-3-isopropoxy-lH-pyrazole-l-carboxylate (Method 78, 4.Og, 16.4mmol) in THF (45ml) was cooled to -780C. A 1.0M THF solution of LiHMDS (2.6 Ig, 15.6mmol) was added dropwise and the reaction was stirred at -780C for 30 minutes. A -780C solution of <strong>[870065-73-9]2,5,6-trifluoronicotinonitrile</strong> (1.3g, 8.2mmol) in THF (20ml) was added dropwise via cannula to the above anion solution. Upon completion of the addition, the resulting reaction was allowed to stir for 10 minutes at -780C, and was then quenched with water (100ml). The reaction was allowed to warm to room temperature, extracted with DCM (3 x 100ml), dried (Na2SO4), filtered, and then concentrated to give the title compound (95% conversion by LCMS) which was used without further purification. MS: Calcd.: 379; Found: [M+H]+ 380.
2,6-di-tert-butoxy-5-fluoro-nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In tetrahydrofuran; tert-butyl alcohol; at 0 - 20℃; for 0.416667h;
A solution of 1.04 M KOtBu in t-BuOH (110 mL, 114 mmol) pre-mixed with THF (20 mL) was added dropwise over 15 min to a stirred 0 C. solution of <strong>[870065-73-9]2,5,6-trifluoro-nicotinonitrile</strong> (16.0 g, 101 mmol) contaminated with an additional 4.6 g DMSO, as prepared in the preceding step, in t-BuOH (80 mL) and THF (15 mL; to prevent freezing). The resulting homogeneous reddish-amber solution was stirred for an additional 5 min at 0 C., the ice bath was then removed, and the solution stirred for an addititional 20 min at rt. The reaction was then quenched with 5 M NH4Cl (100 mL) and extracted with ether (2×100 mL). The combined organic layers were washed with water (1×100 mL), 1 M NaCl (1×150 mL), and 4 M NaCl (1×100 mL), and the clear purple organic layer was dried (Na2SO4), concentrated under reduced pressure, taken up in ether (50 mL), and filtered through a pad of diatomaceous earth. The filter cake was washed with ether (3×50 mL), and the combined filtrates were concentrated under reduced pressure at 50-60 C. to afford 20.89 g of a clear purple oil. NMR indicated an 89:11 mol ratio of the title compound and 2,6-di-tert-butoxy-5-fluoro-nicotinonitrile (18.22 g title compound; 85%). 1H-NMR (300 MHz, CDCl3) delta 7.60 (dd, 1H), 1.67 (s, 9H)
With potassium fluoride; In dimethyl sulfoxide; at 20 - 130℃; for 0.916667h;
2,6-Dichloro-5-fluoro-nicotinonitrile (25.67 g, 134 mmol) and spray-dried KF (23.6 g, 406 mmol) (Aldrich), both of which had been freshly powdered under air to remove clumps, were shaken together to ensure complete mixing before adding dry DMSO (30 mL). The mixture was efficiently stirred at rt under argon for 1-2 min, and then placed in a 100 C. oil bath and stirred for 5 min. The temperature was then raised to 130 C. over the course of 10 min, and the mixture was stirred at this temperature for 40 min. The NMR spectrum of reaction aliquots demonstrated 86% conversion after 10 min at 130 C., and >95% conversion after 40 min. The thick purple mixture was then allowed to cool to rt, shaken with DCM (30 mL) on an ice bath, and then loaded directly onto a flash silica column (1.0 kg silica gel; 120 mm×6) pre-equilibrated with DCM. DCM elution (140 mL fractions; fractions 10-19 combined) afforded 20.65 g of a clear light amber oil. A NMR spectrum demonstrated a 1:0.58 mol ratio of title compound:DMSO (16.0 g title compound; 76%). 1H-NMR (300 MHz, CDCl3) delta 7.99 (m, 1H). LC/MS (ESI): calcd mass 158.0, found 159.5 (MH)+
,5-Difluoro-6-[(l-methyl-lH-imidazol-4-yl)aminolnicotinonitrile l-Methyl-4-nitro-lH-imidazole (Intermediate 5, 500 mg, 3.93 mmol) was dissolved in ethanol (7.868 mL) and Pd/C (10 wt%, Degussa, 105 mg, 0.10 mmol) was added. The reaction mixture was subjected to 1 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite and the filtrate was cooled to O0C. <strong>[870065-73-9]2,5,6-trifluoronicotinonitrile</strong> (497 mg, 3.15 mmol) and TEA (1.097 mL, 7.87 mmol) were added and the reaction mixture was allowed to warm to rt slowly overnight. The reaction mixture was filtered providing the title compound as a yellow solid (566 mg). LCMS: 236 [M+Eta]+.
6-((4,4-difluorocyclohexyl)oxy)-2,5-difluoronicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
To a solution/suspension of potassium 2-methylpropan-2-olate (2.90 g, 25.8 mmol) in 30 ml of tetrahydrofuran at 0C was added 4,4-difluorocyclohexanol (3.79 g, 27.8 mmol) under nitrogen. After stirring for 30 minutes the reaction mixture was cooled to -70C and <strong>[870065-73-9]2,5,6-trifluoronicotinonitrile</strong> (4.0 g, 25.3 mmol) in 15 ml of tetrahydrofuran was added slowly. The reaction mixture became orange and was stirred at -70C for 2 h and subsequently overnight at room temperature. After the addition of water, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulphate, filtered and the solvent was evaporated. The raw material (7.21 g of a red-brown oil) was purified by column chromatography on silica gel (80 g column; heptane 100%? ethylacetate/heptane 80:20, 15ml/min) to give 6-((4,4-difluorocyclohexyl)oxy)-2,5- difluoronicotinonitrile (6.94g, yield 37%) as a white solid.
2,5-difluoro-6-[4-methyl-5-oxo-3-(trifluoromethyl)-1,2,4-triazol-1-yl]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 16h;
To a solution of 2.5 g (16.0 mmol) of 4-methyl-3-(trifluoromethyl)-1 H-1 ,2,4-triazol-5-one (CAS 51856-10-1 ) in 40 ml. dimethyl sulfoxide was added 2.4 g (16.0 mmol) of 2,5,6-trifluoropyridine- 3-carbonitrile (CAS 870065-73-9) and 2.2 g (16.0 mmol) of potassium carbonate. The mixture was stirred for 16 hours at 20C. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MgS04, fil- tered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica (petrol ether/ethyl acetate) to give 3.1 g (9.6 mmol, 60%) of the desired compound 2 step 1.1 H-NMR (CDCIs, ppm): 7.96 - 8.08 (m, 1 H); 3.43 - 3.60 (m, 3 H).
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