* 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 lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 12h;
Example 1:; 5-FIuoro-3-(2-fluoro-4-iodo-phenylamino)-pyridine-2-carbonitrile; To solution of 2-fluoro-4-iodoaniline (930.5 mg, 3.93 mmol) and 3,5-difluoropyridine- 2-carbonitrile (500 mg, 3.57 mmol) in THF (8 mL) at -78°C, was added LiHMDS (6.1 ml, 7.50 mmol). The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture as diluted with ethyl acetate and washed with H2O and brine. The <n="35"/>organic layer was dried with solid Na2SO4 and was concentrated. The resulting residue was purified by flash chromatography in silica (25percent ethyl acetate-hexane) to give pure product. LC/MS [7.72 min; 358 (M+l)].
7-Fluoro-pyrido[3,2-d]pyrimidin-4-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 100℃; for 16h;
Example 31 7-Fluoro-pyrido[3,2-d]pyrimidin-4-ylamine; <strong>[298709-29-2]3,5-Difluoro-pyridine-2-carbonitrile</strong> (2.54 mmol, 356 mg) is dissolved in DMA (5 mL) and then formamidine acetate is added (2.54 mmol, 264.6 mg) followed by DIEA (7.62 mmol, 983 mg). The reaction mixture is stirred for 16 h at 100° C., then poured into saturated NH4Cl aq. and extracted 3 times with CH2Cl2. The organics are dried with Na2SO4, concentrated, and purified on Biotage with 0-20percent MeOH in CH2Cl2. This gives the desired product 7-Fluoro-pyrido[3,2-d]pyrimidin-4-ylamine (27 mg, LC/MS m/z=165 [M+H]+) as a white powder.
With polyethylene glycol 8000; potassium fluoride; In dimethyl sulfoxide; at 160℃; for 0.5h;
[0172] 50 g (0.29 mol) of 2-cyano-3,5-dichloropyridine from Example IV, 33.6 g (0.58 mol) of potassium fluoride and 10 g of polyethylene glycol 8000 are mixed with 125 ml of DMSO and heated at 160° C. for 30 minutes. After cooling, the product is distilled out together with the DMSO under high vacuum, the distillate is added to water and, after extraction with toluene, dried over sodium sulfate. The product is reacted further as solution in toluene. [0173] Rf: 0.43 (cyclohexane/ethyl acetate=7:3)
With diisobutylaluminium hydride; In tetrahydrofuran; at -20℃; for 4h;Inert atmosphere;
2-Cyano-3,5-difluoropyridine (350 mg, 2.5 mmol) was dissolved in tetrahydrofuran (THF) (30 mL) under N2 atmosphere, and diisobutyl hydrogenation was added dropwise at -20°C. A solution of aluminum (DIBAL-H) (1.0 M) in toluene (2.5 mL 2.5 mmol). The mixture was stirred at -20 °C for 4 h. Methanol was added to quench the reaction and 1N HCl was added to adjust the pH to 4-5. The reaction mixture was diluted with ethyl acetate, washed twice with water, and the organic layer was dried over anhydrous sodium sulfate. Concentration by filtration and column chromatography of the residue gave 3,5-difluoro-2-pyridinecarboxaldehyde as a white solid (153 mg, yield 44percent).
20%
EXAMPLE 83 COMPOUND 83: N1-(3,5-difluoro-pyridin-2-ylmethyl)-N1-(3-isoiropyl-pyridin-2-ylmethyl)-butane-1,4-diamine (HBr salt) To a solution of 3,5-difluoro-pyridine-2-carbonitrile (0.440 g, 3.14 mmol) (Niewoehner, U. et al. PCT Int. Appl. (2001), WO 2001068647) in dry CH2Cl2 (20 mL) cooled at -78° C., was added DIBAL-H (1.0 M in CH2Cl2, 3.2 mL, 3.2 mmol). After the mixture was stirred a t-78° C. for 1 h, aqueous HCl (3 N, 10 mL) was added, and the mixture was warmed to room temperature. Saturated aqueous NaHCO3 (20 mL) was added, and the mixture was extracted with CH2Cl2 (3*20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording afford 3,5-difluoro-pyridine-2-carbaldehyde as a colorless crystalline solid (0.0880 g, 20percent). 1H NMR (CDCl3) delta 7.32-7.39 (m, 1H), 8.53 (d, 1H, J=2.4 Hz), 10.16 (s, 1H).
[A] 3 5-Difluoropicolinaldehyde[0250][0251]To a stirred solution of 3 5-difluoropicolinonitrile (30 g 214 mmol) in THF (300 mL) was added DIBAL (235.7 mL 235.7 mmol) and stirred at-20 for 2 h. After TLC (petroleum etherEtOAc 51 Rf 0.4) showed the starting material was consumed the reaction was quenched with 1 N HCl to pH 5. The reaction mixture was extracted with EtOAc (500 mL x 3) and the combined organic layers were washed with brine dried over anhy. Na2SO4 filtered and concentrated in vacuo to give a crude title compound difluoropicolinaldehyde (25 g 81.7yield) as a yellow solid. It was used directly in the next step without further purification.
Example 8: Synthesis of 6-(2,4-Difluoro-phenoxy)-3-(2-methoxy-phenyl)-lH- pyrazolo [4,3-b] pyridine; Step 1. Preparation of(3,5-Difluoro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone; 2-Methoxyphenyl magnesium bromide (53.3 mL of 1.75 M solution in THF was cooled to 00C. 3,5-Difluoronicotinonitrile (5.0 g, 35.6 mmol) was added over 20 min to the reaction mixture at 00C. The reaction was quenched by addition of of 60 mL of 2M H2SO4, and the mixture was allowed to warm to RT. The reaction mixture was extracted with 40 mL 50 mL EtOAc, and the aqueous phase was basified by addition 12 mL of 5M NaOH. The aqueous phase was then extracted twice with 70 mL of EtOAc, and the combined organic layers were washed with water, and dried (MgSO4). The MgSO4 was removed by filtration and solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 mm x 15 cm) with hexanes/EtOAc (0:1 to 4:1) to yield 7.9 g of (3,5- difluoro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone. Mass Spec. M+H = 250.
2-Methoxyphenyl magnesium bromide (53.3 mL of 1.75 M solution in THF was cooled to 0° C. 3,5-Difluoronicotinonitrile (5.0 g, 35.6 mmol) was added over 20 minutes to the reaction mixture at 0° C. The reaction was quenched by addition of of 60 mL of 2M H2SO4, and the mixture was allowed to warm to room temperature. The reaction mixture was extracted with 40 mL 50 mL EtOAc, and the aqueous phase was basified by addition 12 mL of 5M NaOH. Tee aqueous phase was then extracted twice with 70 mL of EtOAc, and the combined organic layers were washed with water, and dried (MgSO4). The MgSO4 was removed by filtration and solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 mm*15 cm) with hexanes/EtOAc (0:1 to 4:1) to yield 7.9 g of (3,5-difluoro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone. Mass Spec. M+H=250.
A solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50ml) was stirred under N2 and cooled to -780C. 3,5-difiuoropicolinonitrile (15.0 g, 107.07 mmol) in THF (50 ml) was added drop wise with an addition funnel at such a rate that the internal temperature was kept below -40C. After the addition was complete, the reaction mixture was poured into a IM HCl (100 ml, chilled in an ice bath). The reaction mixture was stirred at O0C for 30 minutes and at room temperature for 30 minutes. To this solution 150 ml of EtOAc was added to extract product. The aqueous phase was neutralized to pH9 with NaHCO3 and extracted with EtOAc (2 X 20 ml). The organic layers were combined and the volatiles were removed under reduced pressure. Purification utilizing ISCO (0-10percent EtOAc- hexanes) gave the title compound as light yellow oil. LC-MS: 158 [M+H]+.
Intermediate 33 ; l-(3,5-Difluoropyridin-2-yl)ethanoneA solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50ml) was stirred under N2 and cooled to -780C. <strong>[298709-29-2]3,5-difluoropicolinonitrile</strong> (15.0 g, 107.07 mmol) in THF (50 ml) was added drop wise with an addition funnel at such a rate that the internal temperature was kept below -40C. After the addition was complete, the reaction mixture was poured into a IM HCl (100 ml, chilled in an ice bath). The reaction mixture was stirred at O0C for 30 minutes and at room temperature for 30 minutes. To this solution 150 ml of EtOAc was added to extract product. The aquous phase was neutralized to pH9 with NaHCO3 and extracted with EtOAc (2 x 20 ml). The organic layers were combined and the volatiles were removed under reduced pressure. Purification utilizing ISCO (0-10percent EtOAc- hexanes) gave the title product as light yellow oil. LC-MS: 158 [M+H]+.
Intermediate 45 l-(3,5-Difluoropyridin-2-yr)ethanoneA solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50ml) was stirred under N2 and cooled to -78°C. <strong>[298709-29-2]3,5-difluoropicolinonitrile</strong> (15.0 g, 107.07 mmol) in THF (50 ml) was added drop wise with an addition funnel at such a rate that the internal temp, was kept below -4°C. After the addition was complete, the reaction was poured into a IM HCl (100 ml, chilled in an ice bath). The reaction was stirred at 00C for 30 minutes and r.t. for 30 minutes. To this solution 150 ml of EtOAc was added to extract product. The aqueous phase was neutralized to pH9 with NaHCO3 and extracted with EtOAc (2 X 20 ml). The organic phase were combined and the volatiles were removed under reduced pressure. Purification by ISCO (0-10percent EtOAc- hexanes) gave the title compound as light yellow oil. LC-MS: 158 [M+H].
A solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50ml) was stirred under N2 and cooled to -78°C. 3,5-Difluoropicolinonitrile (15.0 g, 107.07 mmol) in THF (50 ml) was added drop wise with an addition funnel at such a rate that the internal temperature was kept below -4°C. After the addition was complete, the reaction mixture was poured into a IM HCl (100 ml, chilled in an ice bath). The reaction mixture was stirred at 00C for 30 minutes and room temperature for 30 minutes. To this solution 150 ml of EtOAc was added to extract product. The aqueous phase was neutralized to pH 9 with NaHCO3 and extracted with EtOAc (2 X 20 ml). The organic layers were combined and the volatiles were removed under reduced pressure. Purification by ISCO (0-10percent EtOAc- hexanes) gave the title product as light yellow oil. <n="82"/>LCMS: 158 [M+H]
To a solution of <strong>[298709-29-2]3,5-difluoropicolinonitrile</strong> (10.0 g, 71.4 mmol) in THF (200 ml) was added methylmagnesium bromide (61.2 ml, 85.7 mmol) in THF solution at 0 0C. The reaction was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate solution (50 ml) was added, extracted with ether (100 ml), and dried over sodium sulfate. The solvent was removed. The residue (11.2 g, 71.28 mmol), hydroxylamine hydrochloride (9.907 g, 142.6 mmol) and sodium acetate (11.70 g, 142.6 mmol) in EtOH (100 ml) and water (50 ml) was heated at reflux for 3 hours. The solvent was removed and diluted with 50 ml of saturated sodium bicarbonate and extracted with EtOAc (2 x 200 ml). After dried over sodium sulfate, the solvent was removed and the title compound was used directly in next step without purification.
1-(3,5-difluoropyridin-2-yl)methanamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; ethanol; water; under 2585.81 Torr; for 5h;
A mixture of <strong>[298709-29-2]3,5-difluoropicolinonitrile</strong> (1.4 g, 10 mmol), conc. HCl (12 ml) and 10percent Pd-C (200 mg) in 1:1 ethanol/tetrahydrofuran was shaken under a hydrogen atmosphere (50 psi) for 5 h. The reaction mixture was filtered and the ethanol removed in vacuo. The remaining solution was lyophilized to afford an off-white solid (2.16 g, 100percent yield). LCMS (M+H) calcd for C6H7F2N2: 145.06; found: 145.12.
To a solution of <strong>[298709-29-2]3,5-difluoropicolinonitrile</strong> (10.0 g, 71.4 mmol) in THF (200 ml) was added methylmagnesium bromide (61.2 ml, 85.7 mmol) in THF solution at 0 0C. The reaction was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate solution (50 ml) was added, extracted with ether (100 ml), and dried over sodium sulfate. The solvent was removed. The residue (11.2 g, 71.28 mmol), hydroxylamine hydrochloride (9.907 g, 142.6 mmol) and sodium acetate (11.70 g, 142.6 mmol) in EtOH (100 ml) and water (50 ml) was heated at reflux for 3 hours. The solvent was removed and diluted with 50 ml of saturated sodium bicarbonate and extracted with EtOAc (2 x 200 ml). After dried over sodium sulfate, the solvent was removed and the title compound was used directly in next step without purification.
(3,5-difluoropyridin-2-yl)methanamine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; ethanol; water; under 2585.81 Torr; for 5h;
A mixture of <strong>[298709-29-2]3,5-difluoropicolinonitrile</strong> (1.4 g, 10 mmol), conc. HCl (12 ml) and 10percent Pd-C (200 mg) in 1:1 ethanol/tetrahydrofuran was shaken under a hydrogen atmosphere (50 psi) for 5 h. The reaction mixture was filtered and the ethanol removed in vacuo. The remaining solution was lyophilized to afford an off-white solid (2.16 g, 100percent yield). LCMS (M+H) calcd for C6H7F2N2: 145.06; found: 145.12.
3,5-Difluoropyridine-2-carbonitrile (3.5g, 25mmol) was dissolved in EtOH (5OmL) and 4N HCl/l,4-dioxane (5OmL) was added. This reaction mixture was refiuxed for 24 hours under a nitrogen atmosphere. The reaction mixture was concentrated, dissolved in ethyl acetate (10OmL), and washed with saturated NaHCO3. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (EtOAc : Hexanes = 1 :9) gave the title compound (3.1g, 69percent) as a semi solid. LCMS: [M+H]+188
With urea hydrogen peroxide adduct; trifluoroacetic anhydride; In dichloromethane; at 0 - 20℃; for 13.5h;
A mixture of <strong>[298709-29-2]3,5-difluoro-2-cyano pyridine</strong> (40 g, 0.28 mol) and urea-hydrogen peroxide complex (52.64 g, 0.56 mol) in dichloromethane (250 mL) was cooled to 0° C. Trifluoroacetic anhydride (88.2 g, 0.42 mol) was slowly added over 1.5 h at 0° C., and the reaction mixture was slowly warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc in hexanes (35percent to 50percent) to give <strong>[298709-29-2]3,5-difluoro-2-cyano pyridine</strong> N-oxide as a white powder (25 g, 58percent).
5-fluoro-3-(4-hydroxy-cyclohexylamino)-pyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 150℃; for 0.5h;Sealed; microwave irradiation;
<strong>[298709-29-2]3,5-Difluoro-pyridine-2-carbonitrile</strong> (2 g, 14.27 mmol) and trans-1,4-aminocyclohexanol (1.644 g, 14.27 mmol) were dissolved in DMSO (12 mL). Diisopropyl-ethylamine (1.845 g, 14.27 mmol) was added and the reaction was sealed and heated to 150° C. for 30 minutes in the microwave. The reaction mixture was poured into saturated NH4Cl aq. solution (200 mL) and extracted 3 times with EtOAc (100 mL). The organics were dried with Na2SO4 and concentrated to a brown oil and purified on a 40-M (100 g) Biotage silica gel column using a 0 to 75percent EtOAc in Hexane gradient. 5-Fluoro-3-(4-hydroxy-cyclohexylamino)-pyridine-2-carbonitrile was isolated (1.214 g) as a white powder. LC/MS m/z=236 [M+H]+.
With potassium carbonate; In dimethyl sulfoxide; at 115℃; for 1h;Inert atmosphere; Microwave irradiation;
500 mg of <strong>[298709-29-2]2-cyano-3,5-difluoropyridine</strong>, 493 mg of trans-4-aminocyclohexanol and 987 mg of potassium carbonate in 7.5 ml of dimethyl sulphoxide are charged to a 20 ml microwave tube-reactor.The mixture is then microwave-heated for 1 hour at 115° C.The reaction medium is run into 100 ml of water and 100 ml of ethyl acetate.The aqueous phase is re-extracted twice with 50 ml of ethyl acetate.The combined organic phases are washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure.After flash chromatography on silica gel (40-63 mum), elution being carried out with a mixture of ethyl acetate and cyclohexane (50:50 v/v), with the first eluted product being collected, 309 mg of 2-cyano-5-fluoro-3-(trans-4-hydroxycyclohexylamino)pyridine are obtained in the form of a white powder, the characteristics of which are the following:TLC on silica gel: Rf=0.20 (50/50 ethyl acetate/cyclohexane).1H NMR spectrum (400 MHz, delta in ppm, DMSO-d6): 1.20 to 1.47 (m, 4H); 1.75 to 1.89 (m, 4H); 3.32 to 3.45 (m, 2H); 4.54 (d, J=4.4 Hz, 1H); 6.23 (d, J=8.1 Hz, 1H); 7.30 (dd, J=12.1 and 2.3 Hz, 1H); 7.85 (d, J=2.4 Hz, 1H)
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