* 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.
2,5-Dibromopyridinc (2.5 g, 10.6 mmol) was treated with a 33percent MeNH2ZEtOH (13.2 ml, 106 mmol) at 800C for several days. The solvent was evaporated, the residue was dissolved in 1 M HCl and the aqueous solution was washed with DCM. The acidic layer was basified with 1 M NaOH to pH ~1 1 and the milky suspension was extracted with DCM. The organic layer was dried over MgSO.* and evaporated to give the target product as a brown solid in quantitative yield. (Calculated mass: 187.0, observed mass: 188.3).
1.20 g
at 80℃; for 72 h;
Synthesis of (5-bromo-pyridin-2-yl)-methyl-amine A 20 ml microwave reaction vessel is charged with 2,5-Dibromo-pyridine (2.00 g, 8.44 mmol) and treated with methylamine (10.45 ml of a 33percent solution in ethanol, 84.43 mmol) and warmed to 80° C. for 3 days. After this time the reaction is concentrated and the remaining solid is treated with 1M HCl (50 ml) and DCM. The layers are separated and the aqueous phase is basified using 1N NaOH (to pH˜11). The product was extracted into DCM (2*) and the combined organics were dried (MgSO4), filtered and concentrated to give the desired product I-96bis (1.20 g). 1H-NMR (400 MHz, DMSO-d6): 2.75 ppm (d, 3H), 6.44 ppm (d, 1H), 6.72 ppm (bs, 1H), 7.51 ppm (dd, 1H), 8.05 ppm (s, 1H)
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 0.666667 h; microwave
2-fluoro-5-bromopyridine (2.00 g, 11.37 mmol), methylamine-hydrochloride (1.92 g, 28.40 mmol) and JV-ethyldiisopropylamine (2.14 mL, 12.50 mmol) in NMP (10 mL) are stirred for 40 min in a microwave reactor at 1400C. The crude mixture is purified by normal phase chromatography. Yield: 1.33 g (63 percent).
A mixture of 5-bromo-2-chloropyridine (3g, 15.5 mmol), methylamine hydrochloride (3.16 g, 46.8 mmol), and DIPEA (8.17 mL, 46.8 mmol) was heated at 170°C under microwave for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layers was separated and washed with brine. Organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was applied to ISCO (24g silica gel, solid loading, 70-80percent ethyl acetate/hexane) to afford 5-bromo-N-methylpyridin-2- amine (800 mg, 4.28 mmol, 27.4 percent yield) as a brown solid.
A solution of 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) in THF (50 mL) was stirred with a solution of methylamine in THF (c=2 mol/L) (35 mL, 70 mmol) at 23° C. for 16 h. Water was added and the mixture was extracted with ether, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a residue which was purified by silica gel column chromatography with heptane/ether, followed by trituration with heptane to give the title compound as a white solid (630 mg, 24percent). MS (ISP) 187.1 [(M+H)+], 189.2 [(M+2+H)+].
a) 5-Bromo-2-(methylamino)pyridine and 5-bromo-2-(dimethylamino)pyridine To a suspension of NaH (60percent dispersion in mineral oil, 0.44 g, 11 mmole) in dry DMF (40 mL) was added solid 2-amino-5-bromopyridine (1.73 g, 10 mmole) in portions over 5-10 min. Gas evolution was allowed to subside between additions. The resulting amber mixture was stirred for 15 min, then' methyl iodide (0.61 mL, 10 mmole) was added all at once. The reaction mixture was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5percent NH4Cl (30 mL) and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography on silica gel (3percent MeOH/CH2Cl2) separated the products. 5-Bromo-2-(methylamino)pyridine (0.60 g, 32 percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.35; MS (ES) m/e 187 (M + H)+. 5-Bromo-2-(dimethylamino)pyridine (0.70 g, 34percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.77; MS (ES) m/e 201 (M + H)+.
Reference：
[1] Patent: EP1226138, 2004, B1,
8
[ 4597-87-9 ]
[ 84539-30-0 ]
[ 858839-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 707 - 718
9
[ 1072-97-5 ]
[ 67-56-1 ]
[ 84539-30-0 ]
Reference：
[1] Journal of Catalysis, 2017, vol. 347, p. 57 - 62
a) 5-Bromo-2-(methylamino)pyridine and 5-bromo-2-(dimethylamino)pyridine To a suspension of NaH (60percent dispersion in mineral oil, 0.44 g, 11 mmole) in dry DMF (40 mL) was added solid 2-amino-5-bromopyridine (1.73 g, 10 mmole) in portions over 5-10 min. Gas evolution was allowed to subside between additions. The resulting amber mixture was stirred for 15 min, then' methyl iodide (0.61 mL, 10 mmole) was added all at once. The reaction mixture was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5percent NH4Cl (30 mL) and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography on silica gel (3percent MeOH/CH2Cl2) separated the products. 5-Bromo-2-(methylamino)pyridine (0.60 g, 32 percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.35; MS (ES) m/e 187 (M + H)+. 5-Bromo-2-(dimethylamino)pyridine (0.70 g, 34percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.77; MS (ES) m/e 201 (M + H)+.
Reference：
[1] Patent: EP1226138, 2004, B1,
14
[ 84539-30-0 ]
[ 24424-99-5 ]
[ 227939-01-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 13 h; Inert atmosphere
NaHMDS (1 M, 12 mL) was added slowly to a mixture of 5-bromo-2-(N-methylamino)pyridine (2.0 g, 10.7 mmol) and (Boc)2O (2.8 g, 12.8 mmol, 3.0 mL) in THF (20 mL) at 0 °C under N2. The resulting mixture was allowed to warm to 20 °C and stirred for 13 hours. TLC (petroleum ether / ethyl acetate = 3/1) showed trace amount of compound 64 and a major new spot with lower polarity. The mixture was quenched with sat. NaHCO3 (30 mL) and extracted with EtOAc (50 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1 to 3/1) to give 5-bromo-2-(N-methyl-N-(t-butoxycarbonyl)amino)pyridine (2.8 g, 91percent yield) as a light yellow liquid. 1H NMR 400 MHz CDCl3 8.40 - 8.39 (m, 1H), 7.71 - 7.65 (m, 2H), 3.37 (s, 3H), 1.49 (s, 9H). ESI-MS (m/z): 287.0 (M+H)+.
A solution of 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) in THF (50 mL) was stirred with a solution of methylamine in THF (c=2 mol/L) (35 mL, 70 mmol) at 23 C. for 16 h. Water was added and the mixture was extracted with ether, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a residue which was purified by silica gel column chromatography with heptane/ether, followed by trituration with heptane to give the title compound as a white solid (630 mg, 24%). MS (ISP) 187.1 [(M+H)+], 189.2 [(M+2+H)+].
a) 5-Bromo-2-(methylamino)pyridine and 5-bromo-2-(dimethylamino)pyridine To a suspension of NaH (60% dispersion in mineral oil, 0.44 g, 11 mmole) in dry DMF (40 mL) was added solid 2-amino-5-bromopyridine (1.73 g, 10 mmole) in portions over 5-10 min. Gas evolution was allowed to subside between additions. The resulting amber mixture was stirred for 15 min, then' methyl iodide (0.61 mL, 10 mmole) was added all at once. The reaction mixture was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5% NH4Cl (30 mL) and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) separated the products. 5-Bromo-2-(methylamino)pyridine (0.60 g, 32 %) was obtained as a semisolid: TLC (3% MeOH/CH2Cl2) Rf 0.35; MS (ES) m/e 187 (M + H)+. 5-Bromo-2-(dimethylamino)pyridine (0.70 g, 34%) was obtained as a semisolid: TLC (3% MeOH/CH2Cl2) Rf 0.77; MS (ES) m/e 201 (M + H)+.
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 13h;Inert atmosphere;
NaHMDS (1 M, 12 mL) was added slowly to a mixture of <strong>[84539-30-0]5-bromo-2-(N-methylamino)pyridine</strong> (2.0 g, 10.7 mmol) and (Boc)2O (2.8 g, 12.8 mmol, 3.0 mL) in THF (20 mL) at 0 C under N2. The resulting mixture was allowed to warm to 20 C and stirred for 13 hours. TLC (petroleum ether / ethyl acetate = 3/1) showed trace amount of compound 64 and a major new spot with lower polarity. The mixture was quenched with sat. NaHCO3 (30 mL) and extracted with EtOAc (50 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1 to 3/1) to give 5-bromo-2-(N-methyl-N-(t-butoxycarbonyl)amino)pyridine (2.8 g, 91% yield) as a light yellow liquid. 1H NMR 400 MHz CDCl3 8.40 - 8.39 (m, 1H), 7.71 - 7.65 (m, 2H), 3.37 (s, 3H), 1.49 (s, 9H). ESI-MS (m/z): 287.0 (M+H)+.
With sodium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 3h;
NaHMDS (88 mL, 1 M in THF) was added dropwise to 5-bromo-iV-methylpyridin-2-amine (15.0 g, 80.2 mmol) and di-tert-butyl dicarbonate (21.0 g, 96.2 mmol) in THF (50 mL) at 0C. The reaction mixture was allowed to reach rt and was stirred for 3 h before it was concentrated under reduced pressure. The residue was partitioned between EtOAc and sat. aq. NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc.The combined organic layers were dried (Na2SO4) and concentrated. Filtration through silica, eluting with Heptane/EtOAc 9:1, gave tert-butyl (5-bromopyridin-2- yl)methylcarbamate (22.7 g) as a pale yellow oil. 1H NMR delta 8.48 (d, 1 H) 7.96 (dd, 1 H) 7.64 (d, 1 H) 3.27 (s, 3 H) 1.46 (s, 9 H).
With dmap; In tetrahydrofuran; at 65 - 72℃;Large scale;
Tert-Butyl dicarbonate (77.6 kg, 355.5 mol, 1.5 equiv) was added at room temperature with stirring,Add to(44.1 kg, 235.8 moles, 1.0 equiv.) And 4-dimethylaminopyridine (3.3 kg, 27.0 mol, 0.11 equiv.) In tetrahydrofuran (412.9 kg). The reaction solution was stirred at 65 to 72 C for 2 to 4 hours. The reaction solution was cooled to 0 to 10 degrees Celsius and the remaining dibutyl dicarbonate was quenched with 2M methylamine tetrahydrofuran solution and the reaction was stirred at 10 to 20 degrees Celsius for 1 hour. Then 25% sodium chloride solution (253.0 kg) was added, stirred at 20 to 30 degrees Celsius for 20 to 30 minutes, and then the layers were allowed to stand and the aqueous phase was separated. The separated aqueous phase was extracted again with ethyl acetate (250.0 kg). The extracted organic phase is combined with the preceding organic layer.And then with 10% citric acid solution (261.0 kg)× 3), 7% sodium bicarbonate solution (262.0 kg) and 25% sodium chloride solution (260.0 kg). The organic phase washed several times was concentrated under reduced pressure. Tetrahydrofuran (221.0 kg) and triisopropyl borate (38.4 kg, 356.8 mol, 1.5 equiv) were added to the concentrated product (compound 203) in the previous step. The reaction solution was then cooled to -70 to -80 C and then 2.5 M of n-butyllithium n-hexane solution (79.0 kg, 282.1 moles, 1.2 equivalents) was slowly added dropwise. After completion of the dropwise addition, the reaction solution was stirred at -70 to -80 C for 1 to 2 hours. The reaction solution was slowly warmed to -20 to -10 degrees Celsius, and water (175 kg) was slowly added to the reaction solution. The reaction solution after the dropwise addition is stirred at 20 to 30 degrees Celsius for 2 to 3 hours. Will be a(166.0 kg) was added to the reaction solution, and the mixture was stirred at 20 to 30 C for 30 minutes, and then the organic layer was allowed to stand for separation. The controlled temperature was below 35 C and 35% hydrochloric acid solution was slowly added to the separated aqueous phase. After completion of the dropwise addition, the mixture was stirred at 20 to 30 C for 2 to 3 hours. And then extend the reaction time of 2 to 3 hours. The reaction solution was cooled to 0 to 5 degrees Celsius and stirred at 0 to 5 degrees Celsius for 2 to 3 hours. The white solid 6-methylaminopyridine-3-borate hydrochloride (34.0 kg, yield: 63.4%) was isolated by centrifugation.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation;
A mixture of <strong>[84539-30-0]5-bromo-N-methylpyridin-2-amine</strong> (50 mg, 0.27 mmol), bis(pinacolato)diboron (75 mg, 0.30 mmol), Pd(dprhof)Cl2*DCM (6.5 mg, 0.008 mmol) and S KOAc (79 mg, 0.80 mmol) in DMF (2 mL) was heated at 150 C for 10 minutes in a microwave reactor. Then 2-bromo-6-fluoro-l,3-benzothiazole (93 mg, 0.40 mmol), another batch of Pd(dppf)Cl2*DCM (6.5 mg, 0.008 mmol) and 2 M aq. K2CO3 (0.5 mL) were added and the reaction mixture was heated at 100 C for 5 minutes in a microwave reactor. The mixture was allowed to cool and was partitioned between EtOAc and H2O. The 0 organic phase was washed with water and brine and was dried (Na2SO4). Concentration <n="94"/>under vacuum and purification by HPLC gave the title compound (8 mg). 1H NMR (CHLOROFORM-c/: CD3OD) delta 8.61 (d, 1 H) 8.02 (dd, 1 H) 7.87 (dd, 1 H) 7.57 (dd, 1 H) 7.22-7.15 (m, 1 H) 6.55 (d, 1 H) 2.94 (s, 3 H); MS m/z (M+H) 260, (M-H) 258.
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 80 - 90℃;
Example B-2: Preparation of (2S)-1-(4-(1-isopropyl-3-(6-(methylamino)pyridin-3-yl)-1H-pyrazol-4- yl)pyrimidin-2-ylamino)propan-2-ol (B-2)H2N N B-2-1 B-2-2 B-2-3B-2Preparation of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2 -amine B-2-3B-2-2 B-2-3 <n="64"/>To a solution of <strong>[84539-30-0]5-bromo-N-methylpyridin-2-amine</strong> B-2-2 (1 g, 5.37 mmol) in DMF (30 mL) were added KOAc (1.58 g, 16.1 mmol) and bis(pinacolato)diboron (2 g, 8.06 mmol). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3J2CI2 (0.5 g, 0.53 mmol) was added and the mixture was degassed again. The reaction was heated to 80-900C and stirred overnight. DMF was removed under reduced pressure. The residue was dissolved with EtOAc (40 mL), washed with saturated aqueous NaCI, dried over Na2SO4 and concentrated to give crude N-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-amine B-2-3 (2.3 g), which was used directly in next step.
To a solution of the compound obtained above (561 mg, 3 mmol) in heptane/THF (30 ml) cooled to -78C under N2 atmosphere, a solution of t-BuLi 1.7 M (3.4 ml, 6.6 mmol) was added. After 30 minutes ClSnBu3 (1.8 g, 6.6 mmol) in THF (3 ml) was added and the reaction mixture was stirred for 2 hr at -78 C. Then a solution of 5% AcOH/THF (20 ml) was added and the mixture was allowed to warm up to room temperature. The solvents were evaporated and the residue was dissolved in EtOAcZH2O. The compound was extracted into EtOAc and the organic layer was washed with aq. NaHCO3 and dried over Na2SO4. After filtration the solvent was evaporated and the residue was purified by silica gel chromatography, using a gradient of 0-100% 50%EtOAcZHex, to give the target compound in 380 mg yield. (Calculated mass = 397.2, observed mass = 399.0).
2,5-Dibromopyridinc (2.5 g, 10.6 mmol) was treated with a 33% MeNH2ZEtOH (13.2 ml, 106 mmol) at 800C for several days. The solvent was evaporated, the residue was dissolved in 1 M HCl and the aqueous solution was washed with DCM. The acidic layer was basified with 1 M NaOH to pH ~1 1 and the milky suspension was extracted with DCM. The organic layer was dried over MgSO.* and evaporated to give the target product as a brown solid in quantitative yield. (Calculated mass: 187.0, observed mass: 188.3).
1.20 g
In ethanol; at 80℃; for 72h;
Synthesis of (5-bromo-pyridin-2-yl)-methyl-amine A 20 ml microwave reaction vessel is charged with 2,5-Dibromo-pyridine (2.00 g, 8.44 mmol) and treated with methylamine (10.45 ml of a 33% solution in ethanol, 84.43 mmol) and warmed to 80 C. for 3 days. After this time the reaction is concentrated and the remaining solid is treated with 1M HCl (50 ml) and DCM. The layers are separated and the aqueous phase is basified using 1N NaOH (to pH?11). The product was extracted into DCM (2*) and the combined organics were dried (MgSO4), filtered and concentrated to give the desired product I-96bis (1.20 g). 1H-NMR (400 MHz, DMSO-d6): 2.75 ppm (d, 3H), 6.44 ppm (d, 1H), 6.72 ppm (bs, 1H), 7.51 ppm (dd, 1H), 8.05 ppm (s, 1H)
In methanol;Autoclave; Large scale;
A mixture of 2,5-dibromopyridine (60.0 kg, 253.3 mol, 1.0 equiv)Dissolved in 30% methylamineMethanol (389.0 thousand) G, 1728.8 moles, 6.8 equiv) in solution. The mixture was heated in an autoclave to 80 to 90 degrees Celsius and at a temperature range Stir for 40 hours. Then, 30% methylamine methanol (248.6 kg, 1104.5 mol, 4.3 equivalents) was added to the reaction solution, and then the reaction solution was heated to 80 to 90 degrees Celsius for 48 to 54 hours. The methanol in the solution after the reaction was completely replaced with ethyl acetate (810.0 kg). The filtered solution was filtered, washed with 330 kg of 7% sodium bicarbonate solution and 331 kg of 25% sodium chloride solution, and the ethyl acetate in the resulting solution was filtered with tetrahydrofuran (1068.0 kg) to give 5-bromo-2- Methylamine pyridineTetrahydrofuran solution (329.0 kg, yield: 93.0%).
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 120℃; for 0.25h;Microwave irradiation;
a) tert-butyl 5-methoxy-2-[6-(methylamino)pyridin-3-yl]-lH-indole-l-carboxylate <n="48"/>l-(tert-Butoxycarbonyl)-5-methoxyindole-2-boronic acid (2 mmol), 5-bromopyridine-2- methylamine (2 mmol), Pd(dppf)Cl2 (0.10 mmol) and 2M Na2CO3 (aq.) (3 mL) were mixed in THF/water 5:1 (10 mL) in a 20 mL microwave vial. The reaction mixture was stirred at 1200C in the microwave reactor for 15 min. Water was added and the solution was extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by flash chromatography (Heptane/EtOAc gradient) to afford the title intermediate (256 mg). 1H NMR delta ppm 8.04 (d, 1 H) 7.94 (d, 1 H) 7.43 (dd, 1 H) 7.08 (d, 1 H) 6.89 (dd, 1 H) 6.64 (d, 1 H) 6.53 (s, 1 H) 6.50 (d, 1 H) 3.78 (s, 3 H) 2.80 (d, 3 H) 1.36 (s, 9 H); MS m/z (M+H) 354.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 120℃; for 0.25h;Microwave irradiation;
a) tert-butyl 5-fluoro-2-[6-(methylamino)pyridin-3-yl]-lH-indole-l-carboxylate <n="46"/>l-(tert-butoxycarbonyl)-5-fluoroindole-2-boronic acid (1 mmol), 5-bromopyridine-2- methylamine (1 mmol), Pd(dppf)Cl2 (0.05 mmol) and 2M Na2CO3 (aq.) (1.5 mL) were mixed in THF/water 5:1 (10 mL) in a 20 mL microwave vial. The reaction mixture was stirred at 1200C in the microwave reactor for 15 min. Water was added and the solution was extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by flash chromatography (Heptane/EtOAc gradient) to give the title intermediate (114 mg); MS m/z (M+H) 342.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In ethanol; at 140℃; for 0.166667h;Microwave;
<strong>[551001-79-7]5-methoxybenzofuran boronic acid</strong> (1.2 mmol), 5-bromopyridine-2-methylamine (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 muL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140 C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (100 mg). 1H NMR delta ppm 8.53 (d, 1H) 7.84 (dd, 1H) 7.44 (d, 1H) 7.08 (d, 1H) 7.04 (s, 1H) 6.91 (d, 1H) 6.81 (dd, 1H) 6.55 (d, 1H) 3.78 (s, 3H) 2.83 (d, 3H); MS m/z 255 (M+H).
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 0.666667h;microwave;
2-fluoro-5-bromopyridine (2.00 g, 11.37 mmol), methylamine-hydrochloride (1.92 g, 28.40 mmol) and JV-ethyldiisopropylamine (2.14 mL, 12.50 mmol) in NMP (10 mL) are stirred for 40 min in a microwave reactor at 1400C. The crude mixture is purified by normal phase chromatography. Yield: 1.33 g (63 %).
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 150℃; for 0.25h;Inert atmosphere; microwave reactor;
To a microwave reaction vial was added N-(5-fert- butylisoxazol-3-yl)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)acetamide from Step 1 of Example 85 (350 mg, 0.91 mmol), 5-bromo-N- methylpyridin-2-amine (256 mg, 1.37 mmol), 2M aq sodium carbonate (1.37 mL, 2.73 mmol), acetonitrile (10 mL), and [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (74.3 mg, 0.091 mmol). The vial was purged with argon, sealed, and heated in a microwave reactor at 150 C for 15 min. The mixture was partitioned between EtOAc (50 mL) and water (50 mL), and the aqueous layer was separated and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (2 ^ 30 mL), dried over MgS04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0 - 70% EtOAc in hexanes to give N-(5-tert-butylisoxazol-3-yl)-2-(4-(6-(methylamino)pyridin-3- yl)phenyl)acetamide (165 mg, 50%) as an off-white solid. 1H NMR (300 MHz, DMSO-t/6) 6 11.20 (s, 1H), 8.30 (d, J= 2.3 Hz, 1H), 7.69 (dd, J= 2.4, 8.7 Hz, 1H), 7.52 (d, J= 8.1 Hz, 2H), 7.34 (d, J= 8.3 Hz, 2H), 6.61 (d, J= 4.7 Hz, 1H), 6.57 (s, 1H), 6.52 (d, J= 8.7 Hz, 1H), 3.66 (s, 2H), 2.80 (d, J= 4.9 Hz, 3H), 1.27 (s, 9H). LC- MS (ESI) m/z 365 (M +H)+.
Intermediate 16: N-methyl-5-(tributylstannyl)pyridin-2-amine 2,5-Dibromopyridine (6 g, 25 mmol) in 40 ml 33% CH3NH2 in ethanol (13 eq.) was heated at 80 C. for 60 hours. After evaporation the solid residue was suspended in CH2Cl2, extracted 3* with 1 N HCl. The combined aqueous phase was neutralized with 2 N NaOH (pH-10-11), and then back extracted 3* with CH2Cl2. The combined CH2Cl2 phase was washed with water and dried over sodium sulfate. Concentration gave 4.457 g of 5-bromo-N-methylpyridin-2-amine as off-white solid. (yield: 95.3%).
Intermediate 3 5-bromo-N-methyl-2-pyridinamine NaH (47.3 mg, 1.971 mmol) and 5-bromo-2-pyridinamine (310 mg, 1 .792 mmol, available from Aldrich) were added to ?,?-Dimethylformamide (DMF) (7 mL) and stirred in an ice bath for 30 mins. The reaction mixture was then allowed to warm to room temperature and methyl iodide (0.123 mL, 1 .971 mmol) was added and the reaction mixture stirred for 24hr. The reaction mixture was partitioned between DCM (20mL) and water (20mL) and the organic layer washed with more water (20mL) before being dried through an hydrophobic frit and concentrated. The residue was dissolved in DCM and and purified by SP4 on a 25+S silica cartridge using a gradient of 10% - 40% EtOAc in cyclohexane. Appropriate fractions were collected and concentrated to yield the desired product as a white solid (79.1 mg). LCMS (Method C): Rt 0.39 , MH+ = 187
NaH (47.3 mg, 1.971 mmol) and 5-bromo-2-pyridinamine (310 mg, 1.792 mmol, available from Aldrich) were added to N,N-Dimethylformamide (DMF) (7 mL) and stirred in an ice bath for 30 mins. The reaction mixture was then allowed to warm to room temperature and methyl iodide (0.123 mL, 1.971 mmol) was added and the reaction mixture stirred for 24 hr. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL) and the organic layer washed with more water (20 mL) before being dried through an hydrophobic frit and concentrated. The residue was dissolved in DCM and purified by SP4 on a 25+S silica cartridge using a gradient of 10%-40% EtOAc in cyclohexane. Appropriate fractions were collected and concentrated to yield the desired product as a white solid (79.1 mg). LCMS (Method C): Rt 0.39, MH+=187
1-methylethyl [(cis)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate[ No CAS ]
1-methylethyl {(cis)-1-acetyl-2-methyl-6-[6-(methylamino)-3-pyridinyl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 18h;Inert atmosphere;
Example 531 -methylethyl {(cis)-1 -acetyl-2-methyl-6-[6-(methylamino)-3-pyridinyl]-1 ,2,3,4- tetrahydro-4-quinolinyl}carbamate hydrochloride(+/-) CIH 1 -Methylethyl [(cis)-1 -acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 12)(80 mg, 0.192 mmol) , potassium carbonate (53.1 mg, 0.384 mmol), tetrakis(triphenylphosphine)palladium(0) (1 1 .10 mg, 9.61 muetaetaomicronIota) and 5-bromo-N-methyl-2- pyridinamine (43.1 mg, 0.231 mmol, Intermediate 3) were dissolved in Ethanol (0.5 mL) and toluene (0.5 mL). The reaction mixture was stirred heated under nitrogen for 18 hr at 90 C. The reaction mixture was filtered and the solvent evaporated before being taken up in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 0-10 % MeOH in DCM. Appropriate fractions were collected and concentrated but remained impure. The sample was dissolved in 1 :1 MeOH:DMSO 1 mL and purified by MDAP then repurified by loading onto a 10g SCX column, washed with MeOH (100ml_) and eluted with 10% 2M NH3 in MeOH (70ml_). The solvent was evaporated in vacuo. 2M HCI in ether (0.5ml_) was added to the residue to form the salt and the solvent was evaporated via nitrogen blow down to yield the desired product as a white / pale yellow solid (27.7 mg) LCMS (Method C): Rt = 0.65, MH+ = 397
1-methylethyl [(cis)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate[ No CAS ]
1-methylethyl {(cis)-1-acetyl-2-methyl-6-[6-(methylamino)-3-pyridinyl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1-Methylethyl [(cis)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 12) (80 mg, 0.192 mmol), potassium carbonate (53.1 mg, 0.384 mmol), tetrakis(triphenylphosphine)palladium(0) (11.10 mg, 9.61 mumol) and 5-bromo-N-methyl-2-pyridinamine (43.1 mg, 0.231 mmol, Intermediate 3) were dissolved in Ethanol (0.5 mL) and toluene (0.5 mL). The reaction mixture was stirred heated under nitrogen for 18 hr at 90 C. The reaction mixture was filtered and the solvent evaporated before being taken up in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 0-10% MeOH in DCM. Appropriate fractions were collected and concentrated but remained impure. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified by MDAP then repurified by loading onto a 10 g SCX column, washed with MeOH (100 mL) and eluted with 10% 2M NH3 in MeOH (70 mL). The solvent was evaporated in vacuo. 2M HCl in ether (0.5 mL) was added to the residue to form the salt and the solvent was evaporated via nitrogen blow down to yield the desired product as a white/pale yellow solid (27.7 mg) LCMS (Method C): Rt=0.65, MH+=397
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 80℃; for 48h;Microwave irradiation;
To a solution of I-69 (300 mg, 0.6 mmol) in DMF (10 mL) are added I-87 (140 mg, 0.7 mmol), tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol) and 2M Na2CO3 (1.5 mL, 3.0 mmol). The mixture is heated to 100 C. for 1 hour in a microwave reactor. The mixture is cooled down and is extracted with H2O (20 mL) and EtOAc (30 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (200 mg). Example 176-180, Table 1-the reaction is run at 120 C.Example 176-180, Table 1-the reaction is run at 120 C. [0509] Example 184-185, Table 1-the reaction is run at 120 C Example 280-281, Table 1-the reaction is run for 48 hours at 80 C.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 85℃;
To a solution of I-69 (300 mg, 0.6 mmol) in DMF (10 mL) are added I-87 (140 mg, 0.7 mmol), tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol) and 2M Na2CO3 (1.5 mL, 3.0 mmol). The mixture is heated to 100 C. for 1 hour in a microwave reactor. The mixture is cooled down and is extracted with H2O (20 mL) and EtOAc (30 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (200 mg). Example 176-180, Table 1-the reaction is run at 120 C.Example 176-180, Table 1-the reaction is run at 120 C. [0509] Example 184-185, Table 1-the reaction is run at 120 C Example 191, Table 1-the reaction is run at 120 C. Example 239-243, Table 1-the reaction is run for 6 hours at 100 C. in an oil bath
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 15h;
A mixture of <strong>[84539-30-0]5-bromo-N-methylpyridin-2-amine</strong> (1.0 g, 5.3 mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (1.76 g, 8.02 mmol) and Na2C03 (1.13 g, 10.6 mmol) in N,N-dimethylformamide (20 mL) containing water (5 mL) was degassed for 15 min. Pd(PPh3)4 (0.25 g, 0.2 mmol) was added to the reaction mixture and degassed for another 15 min. After heating at 100 C for 15 h, the reaction mixture was cooled, diluted with water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with brine (1 10 mL), dried (Na2S04), concentrated under vacuum and the residue purified by column chromatography (silica gel, 100-200 mesh) eluting with gradient of 1% methanol-dichloromethane to afford 450 mg of 4-(6- (methylamino)pyridin-3-yl)phenol. 1H NMR (DMSO-i: delta 9.40 (s, 1H), 8.21-8.20 (d, J = 2.1 Hz, 1H), 7.61-7.57 (m, 1H), 7.35 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 6.49-6.46 (d, 2H), 2.78 (d, J= 5.1 Hz, 3H); ESI MS, m/z 201.0 [M+H]+; HPLC retention time: 5.52 min.
With N-ethyl-N,N-diisopropylamine; at 170℃; for 4h;Microwave irradiation;
A mixture of 5-bromo-2-chloropyridine (3g, 15.5 mmol), methylamine hydrochloride (3.16 g, 46.8 mmol), and DIPEA (8.17 mL, 46.8 mmol) was heated at 170C under microwave for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layers was separated and washed with brine. Organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was applied to ISCO (24g silica gel, solid loading, 70-80% ethyl acetate/hexane) to afford 5-bromo-N-methylpyridin-2- amine (800 mg, 4.28 mmol, 27.4 % yield) as a brown solid.
benzyl(6’-(methylamino)-2-oxo-2H-[1,3‘-bipyridin]-3-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.2%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 115℃; for 12h;
A mixture of <strong>[84539-30-0]5-bromo-N-methylpyridin-2-amine</strong> (199 mg, 1.065 mmol), benzyl (2-oxo-1,2-dihydropyridin-3-yl)carbamate (200 mg, 0.819 mmol), K2C03 (226 mg, 1.638 mmol), N,N?-dimethyl-1,2-ethanediamine (0.035 mL, 0.328 mmol) and copper (I) iodide(31.2 mg, 0.164 mmol) in dioxane (8 mL) was heated at 115 C for 12 h. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (3 x 20 mL) and brine (20 mL), dried over anhydrous Na2504 and concentrated under vaccum. The residue was purified by ISCO (24g silica gel, solid loading, 50-60% ethyl acetate/hexane) to givebenzyl (6?-(methylamino)-2-oxo-2H- [1,3 ?-bipyridin] -3 -yl)carbamate (100 mg, 0.280 mmol, 34.2 % yield) as a beige solid.
5-bromo-2-(methylamino)pyridine-3-sulfonyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With chlorosulfonic acid; at 0 - 150℃; for 5h;
[00207] To chiorosulfonic acid (3.58 niL, 53.8 mmol) in a flask at 0C was added 5-bromo-N- methylpyridin-2-amine (1.00g, 5.35 mmol). The reaction mixture was allowed to stir at ii for 2 h, then heated at 150C for 3 h. The crude reaction mixture was added dropwise into a flask containing ice. The resulting precipitate was collected by filtration and dried under vacuum to afford a light yellow solid determined to be 5-bromo-2-(methylamino)pyridine-3-sulfonyl chloride (0.828 g, 54%). LCMS (FA):m/z= 287.l(M+H).
54%
With chlorosulfonic acid; at 20 - 150℃; for 5h;
Example 2 5-bromo-2-(methylamino)pyridine-3-sulfonyl chloride To chlorosulfonic acid (3.58 mL, 53.8 mmol) in a flask at 0 C. was added <strong>[84539-30-0]5-bromo-N-methylpyridin-2-amine</strong> (1.00 g, 5.35 mmol). The reaction mixture was allowed to stir at rt for 2 h, then heated at 150 C. for 3 h. The crude reaction mixture was added dropwise into a flask containing ice. The resulting precipitate was collected by filtration and dried under vacuum to afford a light yellow solid determined to be 5-bromo-2-(methylamino)pyridine-3-sulfonyl chloride (0.828 g, 54%). LCMS (FA): m/z=287.1 (M+H).
methyl (5-bromopyridin-2-yl)methylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In tetrahydrofuran; at 50℃; for 12h;
To a solution of <strong>[84539-30-0]5-bromo-N-methylpyridin-2-amine</strong> (Combi-Blocks, cat PY-1235: 138 mg, 0.738 mmol) in tetrahydrofuran (4 mL) was added cesium carbonate (288 mg, 0.885 mmol) and methyl chloroformate (285 muL, 3.69 mmol). The resulting mixture was heated for 12 h at 50 C., then diluted with ethyl acetate, filtered, and concentrated. The crude product was used without further purification. LC-MS calculated for C8H10BrN2O2 (M+H)+: m/z=245.0. found 245.0.
With caesium carbonate; In tetrahydrofuran; at 50℃; for 12h;
Step 1: methyl (5-bromopyridin-2-yl)methylcarbamate To a solution of <strong>[84539-30-0]5-bromo-N-methylpyridin-2-amine</strong> (Combi-Blocks, catNo.PY-1235: 138 mg, 0.738 mmol) in tetrahydrofuran (4 mL) was added cesium carbonate (288 mg, 0.885 mmol) and methyl chloroformate (285 muL, 3.69 mmol). The resulted mixture was heated for 12 h at 50 C., then diluted with ethyl acetate, filtered, and concentrated. The crude product was used without further purification. LC-MS calculated for C8H10BrN2O2(M+H)+: m/z=245.0. found 245.0.
N-hydroxy-2-[methyl({2-[6-(methylamino)pyridin-3-yl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-6-yl}methyl)amino]pyrimidine-5-carboxamide hydrochloride[ No CAS ]
N-hydroxy-2-[methyl({2-[6-(methylamino)pyridin-3-yl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-6-yl}methyl)amino]pyrimidine-5-carboxamide silfate[ No CAS ]
N-hydroxy-2-[methyl({2-[6-(methylamino)pyridin-3-yl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-6-yl}methyl)amino]pyrimidine-5-carboxamide methanesulfonate[ No CAS ]
N-hydroxy-2-[methyl({2-[6-(methylamino)pyridin-3-yl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-6-yl}methyl)amino]pyrimidine-5-carboxamide tartrate[ No CAS ]
N-hydroxy-2-[methyl({2-[6-(methylamino)pyridin-3-yl]-4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-6-yl}methyl)amino]pyrimidine-5-carboxamide sodium salt[ No CAS ]
Compound (M-47) (1.19 g, 6.36 mmol) was dissolved in DMF (21 mL), sodium hydride (229 mg, 9.54 mmol)was added and the mixture was stirred under ice-cooling for 20 min. Ethyl bromoacetate (1.4 mL, 13 mmol) was addedunder ice-cooling, and the mixture was warmed to room temperature and stirred for 1 hr. The mixture was heated to70C and stirred for 16 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer waswashed successively with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate) to give compound (M-48) (yield 644 mg, 37%)
37%
Compound (M-47) (1.19 g, 6.36 mmol) was dissolved in DMF (21 mL), Sodium hydride (229 mg, 9.54 mmol) was added thereto, and the mixture was stirred for 20 minutes under ice cooling.Ethyl bromoacetate (1.4 mL, 13 mmol)Was added under ice cooling, the temperature was raised to room temperature,And the mixture was stirred for 1 hour. Thereafter, the temperature was raised to 70 C.,And the mixture was stirred for 16 hours. Add water,And extracted with ethyl acetate. The organic layer was washed with water,And then washed successively with saturated brine,The organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate)Compound (M-48)(Yield 644 mg, Yield 37%)Was obtained.
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