* 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.
[Referential Example 21]; 6-Methoxypyridine-2-carbonitrile; Copper(I) cyanide (2.68 g) was added to 2-bromo-6-methoxypyridine (5.62 g) in N,N-dimethylformamide (112 mL) at room temperature, followed by stirring at 165°C for 15 hours. The resultant mixture was cooled in air. Water and ethyl acetate was added to the mixture. The insoluble matter that was formed in the mixture was filtered by Celite. The filtrate was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound as a solid substance (1.78 g, 44percent) .1H-NMR(400MHz,CDCl3)δ: 3.96(3H,s), 6.95-6.98(1H,m), 7.29-7.31(1H,m), 7.64-7.67(1H,m). MS (EI)m/z: 134 (M+) .
Reference：
[1] Synlett, 2001, # 6, p. 765 - 768
[2] Journal of the Chemical Society. Perkin Transactions 1, 2002, vol. 2, # 1, p. 58 - 68
[3] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 33
Synthesis of 6-methoxypicolinonitrile:To a stirred solution of 2-bromo-6-methoxypyridine (5.0 g, 26.59 mmol) in DMF (50 mL) was added Cu(I)cyanide (7.14 g, 79.77 mmol) at room temperature. The resulting reaction mixture was heated at 100 °C and stirred for 16 h. The reaction mixture was diluted with water, filtered through a pad of celite and the filtrate was extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 6-methoxypicolinonitrile (1.4 g, 39percent) as white solid. 1H-NMR (DMSO d6, 400 MHz): δ 7.94 (t, 1H), 7.64 (d, 1H), 7.18 (d, 1H), 3.92 (s, 3H); LC-MS: 99.14percent; 135.8 (M++l); (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 3.31 min. 0.1percent Aq TFA: ACN; 0.8 ml/min); TLC: 10percent EtOAc/Hexane (Rf:
39%
at 100℃; for 16 h;
Synthesis of 6-methoxypicolinonitrile [0524] To a stirred solution of 2-bromo-6-methoxypyridine (5.0 g, 26.59 mmol) in DMF (50 mL) was added Cu(I)cyanide (7.14 g, 79.77 mmol) at room temperature. The resulting reaction mixture was heated at 100 °C and stirred for 16 h. The reaction mixture was diluted with water, filtered through a pad of celite and the filtrate was extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 6-methoxypicolinonitrile (1.4 g, 39percent) as white solid. 1H-NMR (DMSO d6, 400 MHz): δ 7.94 (t, IH), 7.64 (d, IH), 7.18 (d, IH), 3.92 (s, 3H); LC-MS: 99.14percent; 135.8 (M++l); (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 3.31 min. 0.1percent Aq TFA: ACN; 0.8 ml/min); TLC: 10percent EtOAc/Hexane (Rf: 0.3).
Reference：
[1] Chemical Communications, 2012, vol. 48, # 76, p. 9468 - 9470
9
[ 40473-07-2 ]
[ 68-12-2 ]
[ 54221-96-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 13, p. 2126 - 2135
[2] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 3130 - 3141
[4] Tetrahedron, 2005, vol. 61, # 26, p. 6207 - 6217
[5] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
[6] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[7] Patent: US2008/103130, 2008, A1, . Location in patent: Page/Page column 50
[8] Patent: US2007/173508, 2007, A1, . Location in patent: Page/Page column 90
10
[ 626-05-1 ]
[ 124-41-4 ]
[ 40473-07-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 120℃; for 19 h;
[Referential Example 20] ;2-Bromo-6-methoxypyridine; In an argon atmosphere, sodium methoxide (1.82 g) was added to 2,6-dibromopyridine (8.0 g) in toluene (120 mL), followed by stirring at 120°C for 13 hours. Subsequently, sodium methoxide (0.728 g) was added to the mixture, followed by stirring at 120°C for 6 hours. The mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound in an oily substance (5.64 g, 89percent).1H-NMR(400MHz,CDCl3)δ: 3.93(3H,s), 6.68(1H,d,J=8.0Hz), 7.05(1H,d,J=7.2Hz), 7.39-7.42(1H,m).
Reference：
[1] Bulletin des Societes Chimiques Belges, 1986, vol. 95, # 11, p. 1009 - 1020
[2] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 33
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 3130 - 3141
[4] Journal of the American Chemical Society, 2002, vol. 124, # 35, p. 10443 - 10450
[5] Tetrahedron, 2010, vol. 66, # 4, p. 862 - 870
[6] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[7] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
[8] Patent: EP1375496, 2004, A1, . Location in patent: Page 36; 28
[9] Patent: US2008/207902, 2008, A1, . Location in patent: Page/Page column 63-64
11
[ 626-05-1 ]
[ 67-56-1 ]
[ 40473-07-2 ]
Yield
Reaction Conditions
Operation in experiment
7 g
at 15 - 25℃; for 3 h;
Step A 2-bromo-6-methoxypyridine (3a) To a solution of sodium metal (1.5 g, 62 mmol) in methanol (200 mL) stirred at room temperature for 10 min was added 2,6-dibromopyridine (10 g, 46 mmol). The resulting solution was stirred at room temperature for 3 h. The reaction mixture was quenched with dilute HCl and then extracted with dichloromethane. The combined organic layer was washed with water, brine successively, dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The resulting crude product was purified by column by eluting with 5percent ethyl acetate in petroleum ether (v/v) to afford 2-bromo-6-methoxypyridine (7 g). MM-ESI+APCI [M+H]+m/z 187.8.
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 23, p. 7816 - 7821
[2] Synlett, 2001, # 6, p. 765 - 768
[3] Journal of the Chemical Society. Perkin Transactions 1, 2002, vol. 2, # 1, p. 58 - 68
[4] Tetrahedron, 2005, vol. 61, # 26, p. 6207 - 6217
[5] Journal of the American Chemical Society, 1994, vol. 116, # 8, p. 3657 - 3658
[6] Patent: WO2015/50798, 2015, A1, . Location in patent: Page/Page column 50
Reference：
[1] Synthetic Communications, 1990, vol. 20, # 19, p. 2971 - 2977
[2] Journal of Chemical Research - Part S, 1996, # 4, p. 194 - 195
19
[ 40473-07-2 ]
[ 103505-54-0 ]
Reference：
[1] Liebigs Annalen der Chemie, 1992, # 9, p. 953 - 960
[2] Liebigs Annalen der Chemie, 1992, # 9, p. 953 - 960
[3] Journal of the American Chemical Society, 2016, vol. 138, # 16, p. 5433 - 5440
20
[ 40473-07-2 ]
[ 182275-70-3 ]
Reference：
[1] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[2] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
[3] Tetrahedron, 1996, vol. 52, # 35, p. 11385 - 11404
[4] Chemistry - A European Journal, 1998, vol. 4, # 1, p. 67 - 83
[5] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2840 - 2846
21
[ 40473-07-2 ]
[ 623942-84-7 ]
Reference：
[1] Patent: WO2011/28395, 2011, A1,
22
[ 40473-07-2 ]
[ 73183-34-3 ]
[ 1034297-69-2 ]
Reference：
[1] Patent: WO2008/74997, 2008, A1, . Location in patent: Page/Page column 88
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 12, p. 2496 - 2500
23
[ 40473-07-2 ]
[ 909720-21-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3307 - 3312
[2] Patent: US2008/207902, 2008, A1, . Location in patent: Page/Page column 64
24
[ 40473-07-2 ]
[ 124-38-9 ]
[ 1060806-62-3 ]
Yield
Reaction Conditions
Operation in experiment
42.9%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexanes at -78℃; Inert atmosphere Stage #2: at -78 - 20℃; for 3 h; Stage #3: With water In tetrahydrofuran; hexanes; ethyl acetateAcidic aqueous solution
Preparation 21 : 2-methoxy-6-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- nicotinamide; Step 1 : ψ-bromo^-methoxy-nicotinic acid; A solution of 2,2,6,6-tetramethylpiperidine (0.766 g, 5.32 mmol) in tetrahydrofuran (5 mL) was cooled to -78°C under nitrogen. 2.5M n-butyllithium in hexanes (2.34 ml_, 0.375 g, 5.85 mmol) and the mixture was stirred at -780C for 30 min. To the reaction mixture was added a solution of 2-bromo-6-methoxypridine (1.00 g, 5.32mmol) in tetrahydrofuran (5 mL) dropwise. The reaction was stirred at -78°C for 1 h. After this time, an excess of dry ice was added to the reaction mixture and the reaction was allowed to warm to room temperature for 3 h. To the mixture was added water and ethyl acetate, the layers were separated. The aqueous layer was acidified to pH 4. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to an off-white solid (0.530 g, 42.9 percent) 1 H NMR (500 MHz, DMSO-d6) δ ppm 2.52 (2 H, br. s.), 3.32 (1 H, br. s.), 3.92 (1 H, m), 3.90 (1 H, d, J=2.9 Hz), 8.03 (1 H, d, J=7.8 Hz).
[Referential Example 20] ;2-Bromo-6-methoxypyridine; In an argon atmosphere, sodium methoxide (1.82 g) was added to 2,6-dibromopyridine (8.0 g) in toluene (120 mL), followed by stirring at 120C for 13 hours. Subsequently, sodium methoxide (0.728 g) was added to the mixture, followed by stirring at 120C for 6 hours. The mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound in an oily substance (5.64 g, 89%).1H-NMR(400MHz,CDCl3)delta: 3.93(3H,s), 6.68(1H,d,J=8.0Hz), 7.05(1H,d,J=7.2Hz), 7.39-7.42(1H,m).
In methanol; at 80℃; for 2h;
While heating under stirring a mixture of 200 g of 2,6-dibromopyridine and 150 ml of methanol on an oil bath at 80C, 250 ml of a 28% sodium methoxide/methanol solution was added dropwise slowly. The mixture was heated under stirring as it was for 2 hours, and after standing to cool, it was extracted with diethyl ether-water. The organic layer was washed with water andbrine, and then dried over anhydrous magnesium sulfate. The solvent was removed, to give 150 g of the title compound.1H-NMR(CDCl3) delta ppm=3.94(3H, s), 6.68(1H, d, J=7Hz), 7.06(1H, d, J=8Hz), 7.40(1H, t, J=8Hz)
In methanol; at 0℃; for 5h;Heating / reflux;
Example 259 2-bromo-6-methoxypyridine In a nitrogen atmosphere, sodium methoxide (36.6 g) was added to 2,6-dibromopyridine (93.0 g) in methanol (200 mL) in an ice bath. The mixture was refluxed for 5 hours and was allowed to cool. The resulting crystals were collected by filtration and the filtrate was concentrated. Water was then added to the residue and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title compound as a yellow oil (69.5 g, substantially pure product). 1H NMR (200 MHz, CDCl3) delta 7.37 (1H, t, J=7.8 Hz), 7.00 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=8.3 Hz), 3.89 (3H, s). 13C NMR (50 MHz, CDCl3) delta 163.59, 140.22, 138.48, 120.04, 109.29, 53.91
With manganese; zirconocene dichloride; [(2,9-dimethyl-1,10-phenanthroline)dichloro nickel(II)]; lithium chloride; In 1,2-dimethoxyethane; at 20℃; for 12h;Inert atmosphere;
General procedure: To a suspension of a NiCl2-complex (0.01 mmol, 0.02 equiv), Zr(cp)2Cl2 (Strem, 99%; 7.3 mg, 0.025 mmol, 0.05 equiv), Mn powder (Aldrich, 99.99%; 54.9 mg, 1.0 mmol, 2.0 equiv) and LiCl (Aldrich, anhydrous, ground powder; 42.4 mg, 1.0 mmol, 2.0 equiv) in DME (Aldrich, anhydrous, 99.5%; 1.0 mL) was added an iodide (0.5 mmol) under nitrogen. The mixture was stirred at rt under nitrogen until the reaction completed (TLC). Except for the dipyridyls, the mixture was loaded on silica gel directly, and the flash chromatography on silica gel gave the homo-coupling product. For dipyridyls, the reaction was quenched with aq. NH4OH (27% w/w, 0.6 mL), stirred for 10 min, extracted with CH2Cl2 (10 mL × 3), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the homocoupling product. For alkenyl halide substrates (Fig. 3 and Table 3), the reaction was done in 0.2 mmol scale (C: 0.5 M) with added toluene (42 mul, 0.4 mmol, 2.0 equiv) as an internal standard. After the reaction was completed, a small portion (50 muL) of the mixture was passed through a small silica pad, and eluted with CDCl3 (1 mL). The yield was estimated from 1H NMR (600 MHz, CDCl3).
2-bromo-6- methoxypyridine (10 mL, 81.374 mmol, 1.0 eq) was added to cold concentrated H2S04 (40.0 mL followed by dropwise addition of HN03 (10.0 mL). The resulting mxture was stirred at rt for overnight. The progress of reaction was monitored by LCMS. The reaction mixture was poured into ice cold water (500.0 mL), and filtered to afford the desired compound (13.02 g, 68.67%) as light yellow solid. LCMS (M+l)+ 233.0; NMR (400 MHz, CDCb): 8.19 (d, 7=9.21 Hz, 1 H) 6.79 (d, 7=8.77 Hz, 1 H) 4.05 (s, 3 H).
To a solution of the compound of Preparation 113 (5.6 g, 29.8 mmol) in anhydrous tetrahydrofuran (100 ml), at -78° C. and under nitrogen, was added n-butyllithium (1.6M in hexane, 19.5 ml), via syringe. The mixture was stirred at -78° C. for 30 min, before addition of N,N-dimethylformamide (2.5 ml, 32.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 h, before being acidified with sulphuric acid (2M) and then neutralised by addition of sodium hydrogen carbonate. The mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (4*150 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (3.0 g). 1H-NMR (CDCl3): 4.01-4.05 (3H), 6.95-7.00 (1H), 7.54-7.58 (1H), 7.70-7.76 (1H), 9.95-9.98 (1H)
In DMF (N,N-dimethyl-formamide); at 20 - 165℃; for 15h;
[Referential Example 21]; 6-Methoxypyridine-2-carbonitrile; Copper(I) cyanide (2.68 g) was added to 2-bromo-6-methoxypyridine (5.62 g) in N,N-dimethylformamide (112 mL) at room temperature, followed by stirring at 165C for 15 hours. The resultant mixture was cooled in air. Water and ethyl acetate was added to the mixture. The insoluble matter that was formed in the mixture was filtered by Celite. The filtrate was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound as a solid substance (1.78 g, 44%) .1H-NMR(400MHz,CDCl3)delta: 3.96(3H,s), 6.95-6.98(1H,m), 7.29-7.31(1H,m), 7.64-7.67(1H,m). MS (EI)m/z: 134 (M+) .
With potassium phosphate; In ethanol; water; at 100℃; for 8h;
General procedure: A dried round bottomed flask equipped with a magnetic stirring bar was charged with 10mg Polymer anchored-Pd(II) D catalyst (PS-NPPZ-Pd) (0.0045mmol/Pd), 2-halopyridine (0.5mmol), phenylboronic acid (0.6mmol) and K3PO4 (1.0mmol) were added to a reaction vessel. The mixture was stirred in 4mL of H2O: EtOH (1:1) at 100C for 8h and then cooled to room temperature. The catalyst was filtered and the filtrate was extracted with ethyl acetate (3×10mL). The combined organic layers were extracted with water, and dried over anhydrous Na2SO4. The organic layers were evaporated under reduced pressure and the resulting crude product was purified by column chromatography by using ethyl acetate/hexane (10:90) as eluent to give the corresponding coupled products. The products were characterized by 1H NMR, 13C NMR and HRMS analysis.
With triethylamine;palladium diacetate; johnphos; In acetonitrile; at 100℃; for 18h;
A. 5-{2-Benzyloxy-4-[(E)-2-(6-methoxypyridin-2-yl)-vinyl]-phenyl}-1 ,1 -dioxo-2-(2- trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-oneTo a solution of 5-(2-benzyloxy-4-vinylphenyl)-1 ,1-dioxo-2-(2-trimethylsilanylethyl)- 1 ,2,5-thiadiazolidin-3-one (Example 81, step A) (75 mg, 0.17 mmol) in acetonitrile (2 ml_), in a pressure vessel, is added <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (32 mg, 0.17 mmol), NEt3 (0.05 ml_, 0.34 mmol), Pd(OAc)2 (8 mg, 0.034 mmol), and 2-(di-/-butyiphosphino)biphenyl (20 mg, 0.068 mmol). The vessel is sealed and stirred at 100 C for 18 h. The reaction is cooled to RT and filtered through Celite. The solvent is removed under reduced pressure and the <n="82"/>crude material purified by column chromatography using a gradient of 0-35% EtOAc/hexanes as eluent to afford the title compound as a yellow oil: (M + H)+ = 552.
bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In triethylamine; for 2.5h;Heating / reflux;
To a 300 mL three-necked round-bottom flask equipped with a condenser and nitrogen inlet was added 5g (26.6 mmol) of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong>, 4.2g (42.9 mmol) of (trimethylsilyl)acetylene, and 120 mL of triethylamine. The above solution was treated with 479 mg (0.685 mmol) PdCI2(Ph3P)2, followed by the addition of 235 mg (1.26 mmol) CuI. The reaction mixture was then heated under reflux for 2.5 hours, then allowed to cool to room temperature. The reaction mixture was filtered through diatomaceous earth and the solvent evaporated. Flash 40 chromatography (40-L) eluting with 20% methylene chloride/hexanes afforded 4.42 g of the product as a yellow oil, 81%. Mass spectrum (APCI) m/e 206 p+1. 1H NMR (CDCI3, 400 MHz)_7.47(dd, J = 7.1 Hz1 7.5 Hz, J = 18.5 Hz, 1 H), 7.05 (d, J = 7.1 Hz, 1 H), 6.65 (d, J = 7.5 Hz, 1 H), 3.91 (s, 3H), 0.235 (s, 9H) ppm.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 20℃;Inert atmosphere;
mmol), Pd(PPh3)2Cl2 (280 mg, 0.40 mmol) and Cul (152 mg, 0.80 mmol) in TEA (20 mL) was added ethynyltrimethylsilane (862 mg, 8.79 mmol) at room temperature under nitrogen atmosphere, and the solution was stirred at room temperature overnight. After completion of the reaction indicated by LCMS, the mixture was filtered and the filtrate was concentrated in vacuum, and the residue was purified by column chromatography to give Int-32 (1.0 g, 61%) as colorless liquid. LCMS (Agilent LCMS 1200-6120, Column: Halo C18 (30 mm *4.6 mm*2.7 pm); Column Temperature: 40 C; Flow Rate: 3.0 ml/min; Mobile Phase: from 95% [water + 0.05% TFA] and 5% [CCN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CCN + 0.05% TFA] in 0.8 min, then under this condition for 0.4 min, finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.01 min and under this condition for 0.2 min) . Purity: 90.62%; Rt = 0.94 min; MS Calcd.: 205.1; MS Found: 206.3 [M+H]+.
Compound 38 was dissolved in Toluene (5.0 mL) and a solution of isopropyl chloroformate (0.36 mL, 0.364 mmol) was added. The mixture was allowed to stir at room temperature until TLC indicated the completion of the reaction (solution A). In a separate flask, <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (169 mg, 0.91 mmol) was dissolved in THF and cooled to -78 C. To this mixture was added n-BuLi (0.58 mL, 0.93 mmol) and the mixture was allowed to stir for 1.0 hour at -78 C. To this solution at -78 C. was added a solution of CuCN-2LiCl (0.62 mL, 0.364 mmol, 0.59 M in THF). The mixture was stirred for an additional hour at -78 C. (solution B). Keeping the cuprate mixture (solution B) at -78 C., the chloride mixture (solution A) was added. The mixture was allowed to slowly warm to room temperature and stirred overnight. The mixture was poured into a solution of ammonium chloride and ammonium hydroxide (4:1) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by silica gel chromatography (5% EtOAc/Hexanes) to give compound 39 as a solid (25% yield. MS: M+1=478).
3-{3-tert-butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester[ No CAS ]
[ 40473-07-2 ]
3-{3-tert-butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 85℃; for 4.16667h;
Step 3: 3-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester F-2 (0.25 g, 0.35 mmol), <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (0.09 g, 0.48 mmol), and K2CO3 (0.15 g, 1.05 mmol) were dissolved in DME (3.5 mL) and water (1.8 ml) and degassed with N2 for 10 minutes. Pd(PPh3)4 (0.06 g, 0.05 mmol) was added, and the reaction mixture was degassed with N2 for an additional 10 minutes. The solution was heated to 85 C. for 4 hours, and then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc, the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (F-3).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 4h;Inert atmosphere;
F-2 (0.25g, 0.35mmol), <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (0.09g, 0.48mmol), and K2CO3 (0.15g, 1.05mmol) were dissolved in DME (3.5mL) and water (1.8mL) and degassed with N2 for 10 minutes. Pd(PPh3)4 (0.06g, 0.05mmol) was added, and the reaction mixture was degassed with N2 for an additional 10 minutes. The solution was heated to 85C for 4 hours, and then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc, the combined organic layers were washed with water, brine, dried over MgS04, filtered, and concentrated. The crude material was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (F-3).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80.0℃; for 2.0h;
To a mixture of 2-methoxy-6-bromopyridine (374 mg; 2.0 mmol) and bis(pinacolato) diboron (1.1 g; 4.0 mmol) in dimethylsulfoxide (degassed, 10 ml_) was added [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (82mg; 0.1 mmol) and potassium acetate (0.60 g; 6.0 mmol). The mixture was heated at 800C under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water (150 ml_) with stirring to give a dark precipitate, which was collected by filtration, washed with water, and dried under reduced pressure. The crude product was used without further purification. 1H (400MHz, CDCI3) 7.57 (1 H, dd), 7.44 (1 H, d), 6.78 (1 H, d), 4.02 (3H, s), 1.36 (12H, s).
With N-Bromosuccinimide; In acetonitrile; at 80 - 90℃; for 24.0h;
Example 260 2,3-dibromo-6-methoxypyridine NBS (302 g) was added to the compound of Example 259 (295 g) in acetonitrile (575 mL) and the mixture was stirred at 80 to 90 C. for 1 day in a nitrogen atmosphere. After cooling, the crystallized imide was removed by filtration and the filtrate was concentrated. Purification of the resulting residue by silica gel column chromatography (ether:petroleum ether=1:1) gave a 6:1 mixture of the title compound and 2,5-dibromo form. This product was crystallized from cold petroleum ether to afford the title compound as a colorless powder (223 g). 1H NMR (200 MHz, CDCl3) delta 6.68 (1H, d, J=8.7 Hz), 6.60 (1H, d, J=8.7 Hz), 3.91 (3H, s). 13C NMR (50 MHz, CDCl3) delta 162.01, 143.29, 139.68, 113.69, 111.10, 54.40 LRMS (EI+): 264[M+]
Example 80 4-[1-(6-Methoxy-pyridin-2-yl)-ethoxy]-2-trifluoromethyl-benzonitrile Step 1-Nucleophilic Addition to Aldehyde A colorless solution of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (3.06 g, 16.3 mmol) in THF was cooled to -78 C. BuLi (20 mmol, 1.2 equiv) was added over approximately 15 min and the reaction stirred at -78 C. for 1 h: Acetaldehyde (1.1 equiv) was added. The reaction was stirred for 1 h, then it was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0 C., quenched with water and diluted with EtOAc. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by CombiFlash flash chromatography with 50% ether/hexane and yielded 1-(6-methoxy-pyridin-2-yl)-ethanol as an orange oil, 1.97 g (79%).
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 90℃;
To a 500 mL flask was added <strong>[4347-31-3]2-formylthiophene-3-boronic acid</strong> (3OA, 5.00 g, 32.1 mmol, 1.0 eq.), 2-bromo-6-methoxypyridine (3OB, 6.03 g, 32.1 mmol, 1.0 eq.), toluene (100 mL), EtOH (100 mL), aqueous sodium carbonate (2N, 32 ml, 64 mmol, 2.0 eq.), and Pd(dppf)Cl2 (1.17 g, 1.6 mmol, 0.05 eq.). The reaction was stirred overnight at 90 0C. The reaction was cooled and saturated aqueous NaCl (100 mL) was added and the mixture was stirred for 20 min. The reaction mixture was extracted with EtOAc (2 x 100 mL) and the resulting organic layers were combined and passed through a Celite pad to remove residual Pd. The organic phases were washed with a succession Of H2O (100 mL) and saturated aqueous NaCl (100 mL) and then dried over anhydrous Na2SO4, filtered, and concentrated to give a bubbly brown solid that was used in the next step without further purification (6.2 g, 88percent). ESI-MS: m/z 220.2 (M+H)+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; for 12h;Inert atmosphere; Reflux;
A mixture of compound 34 (200mg, 0.44mmol, leq), <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (90mg, 0.48mmol, l.leq), Pd (PPh3)4 (lOmg, O.OOdeltammol, 0.02eq), Na2CO3 (137mg, 1.3mmol, 3eq), toluene (1OmL) and H2O (2mL) was degassed and protected with N2. The mixture was refluxed for 12 h. After cooling to room temperature, the mixture was diluted with water and extracted with EA. The organic phase was dried over MgSO4, filtered. The filtrate was concentrated and purified by column chromatography (silica gel) to give 35f, 2-(4-((6-(6-methoxypyridin-2-yl)-3- nitroquinolin-4-yl)methyl) phenyl) -2-methyl propanenitrile (120 mg,: 63%).
To a solution of ethyl 1-(2-chlorophenyl)-5-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}thio)-1H-pyrazole-3-carboxylate (1.06 g) in ethanol (10 mL) was added sodium ethoxide (314 mg) at 0C. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. A mixture of the residue, <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (462 mg), tris(dibenzylideneacetone)dipalladium (0) (83 mg) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (106 mg) was stirred at 80C for 4 hr in toluene (10 mL). The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a yellow oil (yield 599 mg, yield 68%). 1H-NMR(CDCl3)delta:1.42(3H,t,J=7.2Hz), 3.75(3H,s), 4.45(2H,q,J=7.2Hz), 6.44-6.50(2H,m), 7.22-7.41(5H,m), 7.46-7.49(1H,m).
Preparation 21 : 2-methoxy-6-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- nicotinamide; Step 1 : theta-bromo^-methoxy-nicotinic acid; A solution of 2,2,6,6-tetramethylpiperidine (0.766 g, 5.32 mmol) in tetrahydrofuran (5 mL) was cooled to -78C under nitrogen. 2.5M n-butyllithium in hexanes (2.34 ml_, 0.375 g, 5.85 mmol) and the mixture was stirred at -780C for 30 min. To the reaction mixture was added a solution of 2-bromo-6-methoxypridine (1.00 g, 5.32mmol) in tetrahydrofuran (5 mL) dropwise. The reaction was stirred at -78C for 1 h. After this time, an excess of dry ice was added to the reaction mixture and the reaction was allowed to warm to room temperature for 3 h. To the mixture was added water and ethyl acetate, the layers were separated. The aqueous layer was acidified to pH 4. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to an off-white solid (0.530 g, 42.9 %) 1 H NMR (500 MHz, DMSO-d6) delta ppm 2.52 (2 H, br. s.), 3.32 (1 H, br. s.), 3.92 (1 H, m), 3.90 (1 H, d, J=2.9 Hz), 8.03 (1 H, d, J=7.8 Hz).
To an oven-dried round bottomed flask was added nBuLi (2.5 M in hexanes, 3.6 mL, 9.0 mmol, 1.1 eq) at -45 to -40 C. under N2. An Et2O solution (12 mL) of 2-bromo-6-methoxypyridine (1 mL, 8.14 mmol) was added dropwise at the above temperature. The resulting light brownish yellow solution was stirred at -40 to -35 C. for 20 min. The mixture was cooled to -78 C., an Et2O solution (3 ml) of <strong>[149793-69-1]3-fluoro-5-trifluoromethyl-benzonitrile</strong> (1.50 g, 7.94 mmol) was added dropwise at -78 to -70 C. The resulting solution was stirred at this temperature for 1 h. Pretreated TMSCl (1.08 mL, 8.55 mmol, 1.05 eq) was added dropwise at -78 C. The mixture was allowed to warm to room temperature for 30 min, and then stirred at room temperature for 30 min. The reaction mixture was cooled back to -78 C., and benzyl magnesium chloride (4.1 ml, 8.2 mmol) was added dropwise. The resulting mixture was stirred at -78 C. for 0.8 h, and then warmed up to room temperature for 1 h. The reaction mixture was quenched by adding sat'd NH4Cl and 1N HCl, and stirred for 10 min. The resulting solution was extracted with EtOAc, washed with 1N NaOH, saturated NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(6-methoxypyridin-2-yl)-2-phenylethanamine as light brownish gum (1.42 g, yield: 44.7%). LC-MS ESI (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=3.20 min, 391.12 (M+H); 1H NMR (400 MHz, CDCl3) delta ppm 7.73 (s, 1H), 7.47-7.57 (m, 2H), 7.11-7.21 (m, 4H), 6.99 (d, J=7.6 Hz, 1H), 6.80 (dd, J=7.6, 2.0 Hz, 2H), 6.61 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 3.92 (d, J=13 Hz, 1H) 3.40 (d, J=13 Hz, 1H).
With benz<b>oxazole; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 50℃; for 6h;Inert atmosphere; Sealed tube;
General procedure: Under Ar atmosphere, DMSO (2 mL), ArBr 1 (1.0 mmol), diethyl malonate 2 (1.5 mmol), CuI (0.1mmol), benzoxazole (0.2 mmol) and K3PO4 (3 mmol) were successively added into a sealed tube.The mixture was stirred at 50C for about 3-9 h. When the reaction completed indicated by TLC,the reaction mixture was poured into saturated ammonium chloride aqueous solution (20 mL)and extracted with ethyl acetate (3×20 mL).The combined organic phase was washed with saturated ammonium chloride aqueous solution(2×20 mL) and water (2×20 mL). Then the separated organic layer was dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel using hexane/ethyl acetate to afford the desired product.
43%
With 2-Picolinic acid; caesium carbonate;copper(l) iodide; In 1,4-dioxane; at 95℃; for 96h;
A slurry of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (1.8 g, 9.57 mmol), copper(I) iodide (0.16 g, 0.86 mmol), 2-picolinic acid (0.21 g, 1.72 mmol), cesium carbonate (4.7 g, 14.4 mmol) and diethyl malonate (4.4 mL, 28.7 mmol) in dioxane (15 mL) was heated at 95 C. for 4 days. After cooling to room temperature, ethyl acetate and saturated aqueous NH4Cl were added. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The product was purified twice by flash chromatography (SiO2; heptane/ethyl acetate, gradient 0-80% and second chromatography using heptane/ethyl acetate gradient 0-20%) giving the product.Yield: 1.1 g (43%).1H NMR (400 MHz, chloroform-d) delta ppm 7.60 (dd, 1H), 7.01 (d, 1H), 6.68-6.73 (m, 1H), 4.86 (s, 1H), 4.22-4.31 (m, 4H), 3.91 (s, 3H), 1.29 (t, 6H). MS (ES+) m/z 268 (M+H)+.
Bromopyridine 4 (5.7 g, 30.3 mmol) was dissolved in 28.5 mL of THF in a 250 mL flask. The solution was cooled to -65C. n-Hexyllithium (14.50 mL of 2.3M solution, 33.3 mmol) was added while maintaining the temperature below -60C. After addition, the solution was aged for 5 minutes at -65C. LC analysis showed complete reaction. DMF (2.82 ml, 36.4 mmol) was added dropwise while maintaining the temperature below -60C. After 5 minutes age, LC showed presence of the aldehyde product. The mixture was warmed to -30C. Methanol (22.80 mL) was added. The low temperature bath was replaced with an ice bath. NaBl¾ (0.688 g, 18.19 mmol) was added. The temperature increased to 12C, then dropped again. LC analysis showed that no aldehyde remained. The solution was concentrated to a final volume of -25 mL and was then diluted with MTBE and water. 3N HC1 was added to quench the excess NaBH4 and bring the pH to 8. The layers were separated. The organic layer was dried with MgS04- The solvent was removed by evaporation. The product 5 was left under vacuum for the weekend. The product (4.4 g) was used directly in the next step without purification.
With N,N,N,N,-tetramethylethylenediamine; di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium; zinc; In water; at 20℃; for 48h;Inert atmosphere;
General procedure: In a 5 mL round-bottom flask under argon containing zinc powder (197 mg, 3 mmol) and PdCl2(Amphos)2 (7 mg, 0.01 mmol) was added 2% PTS solution in water (1.5 mL). N,N,N',N'-Tetramethylethylenediamine (TMEDA, 232 mg, 2 mmol) was added at rt followed by the addition of the alkyl halide (2 mmol) and the heteroaromatic halide (0.5 mmol). The flask was stirred vigorously at rt for the indicated time. The product was extracted with EtOAc.11 Silica gel (1 g) was added to the combined organic phase and solvents were removed under vacuum. The resulting dry, crude silica was introduced on top of a silica gel chromatography column to purify the product.
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 16h;Inert atmosphere;
To a solution of 2-bromo-6-methoxypy?dine (122) (150 mg, 0.8 mmol) and 1 -methyl piperazine (240 mg, 2.4 mmol) in 2 ml DMF was added of K2CO3 (220 mg, 1.6 mmol) and the resulting mixture was heated to 13O0C for 16 h. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography with (5-10% MeOH in CH2Cl2) to afford 145 mg (88%) of 123. 1H NMR (500MHz, CDCl3): delta 7.41 (t, J = 8.0 Hz, IH), 6.16 (d, J= 8.0 Hz, IH), 6.08 (d, J= 8.0 Hz, IH), 3,87 (s, 3H), 3.54 (m, 4H), 2.51 (m, 4H), 2.54 (s, 3H); 13C NMR (125 MHz, CDCl3): delta 163.1, 158.3, 140.1, 98.2, 98.1, 54 8, 52.9, 46.2, 45.1; MS (m/z): [M+H]+ 208.4.
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; for 16h;Reflux; Inert atmosphere;
General procedure: To a mixture of aryl bromide or aryl iodide (1 eq), boronic acid (1.1 eq) in dimethoxyethane (0.1 M) was added 1M aqueous NaHCO3 solution (3 eq) followed by Pd(Ph3)4 (0.075 eq). The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution and brine. The combined organic layers were dried over anhydrous Mg504 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO2, ethyl acetate/hexanes) to give the desired product.
With potassium fluoride; copper(l) iodide; palladium diacetate; catacxium A; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;
General procedure: 2-Trimethylsilylpyridine (1.2mmol), the aryl halide (1mmol), palladium acetate (0.10mmol), CataXCium A (0.2mmol), CuI (76mg, 0.4mmol) and KF (2.20mmol) were combined in reaction tubes in a Radleys green-house parallel synthesiser under a flow of nitrogen and degassed DMF (1ml) was added. The resulting suspensions were stirred at 90 oC under nitrogen for 12 hours. Reactions were analysed by LC-MS at 1mg/1ml in methanol to determine the yield.
2-(2,6-difluorophenyl)-5-methoxypyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With water; sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 110℃; for 48h;
A solution of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (1.0 equiv.), 2,6 difluorophenylboronic acid (2 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in 3:1 DME/2M Na2CO3 was heated at 110 C. for 48 hours. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (10-20% EtOAc/hexanes eluant) to yield the Suzuki product. The material was treated with dioxane/H2O/HCl(conc.) in a 3:1:0.25 ratio at 100 C. for 72 hours. Upon removal of the volatiles in vacuo, a solution of the crude hydroxylpyridine (1.0 equiv.), diisopropylethylamine (2.0 equiv.), and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.5 equiv.) in CH2Cl2 was stirred for 16 hours. The solution was partitioned between EtOAc and Na2CO3(sat.). Upon separation, the organic layer was washed further with Na2CO3(sat.) and NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography to yield 6-(2,6-difluorophenyl)pyridin-2-yl trifluoromethanesulfonate.
dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 100℃; for 0.333333h;Microwave irradiation;
A solution of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (1.0 equiv.), 0.5M 2-thiazole-zincbromide in THF (2 equiv.) and Pd(dppf)Cl2-DCM (0.2 equiv.) in a THF (0.1 M) was heated at 100 C. for 20 min in a microwave. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (20% EtOAc/hexanes eluant) to yield 2-(6-methoxypyridin-2-yl)thiazole (73%). The material was treated with dioxane/H2O/HCl(conc.) in a 3:1:0.25 ratio at 100 C. for 72 hours. Upon removal of the volatiles in vacuo, a solution of the crude hydroxylpyridine (1.0 equiv.), diisopropylethylamine (2.0 equiv.), and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.5 equiv.) in CH2Cl2 was stirred for 16 hours. The solution was partitioned between EtOAc and Na2CO3(sat.). Upon separation, the organic layer was washed further with Na2CO3(sat.) and NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography to yield 6-(thiazol-2-yl)pyridin-2-yl trifluoromethanesulfonate.
potassium (RS)-(4-(ethoxycarbonyl)cyclohex-1-enyl)trifluoroborate[ No CAS ]
[ 40473-07-2 ]
[ 1342801-87-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate;(1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride;Reflux;
General Procedure (III)To a mixture of potassium (RS)-(4-(ethoxycarbonyl)cyclohex-1-enyl)trifluoroborate (1 eq), a heteroaryl halide (1.2 eq) and potassium carbonate (3 eq) in an alcohol such as ethanol or methanol (0.2 M) is added (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) chloride (0.02 eq). The mixture is stirred at reflux for 1-20 h. After cooling to room temperature the solvent is evaporated. The residue is triturated in an organic solvent such as tert-butyl methyl ether or ethyl acetate. The precipitates are removed by filtration. The filtrate is concentrated to dryness. Purification by flash-chromatography gives a 4-heteroaryl-cyclohex-3-enecarboxylic acid ester intermediate of formula (V).; 4-Heteroaryl-cyclohex-3-enecarboxylic acid ester 5(RS)-4-(6-Methoxy-pyridin-2-yl)-cyclohex-3-enecarboxylic acid ethyl esterThe title compound was obtained as light yellow liquid in 86% yield from <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> according to general procedure (III). MS m/e: 262 ([M+H]+)
86%
With potassium carbonate; In ethanol;Reflux;
To a mixture of potassium (RS)-(4-(ethoxycarbonyl)cyclohex-l-enyl)trifluoroborate (1 eq), a heteroaryl halide (1.2 eq) and potassium carbonate (3 eq) in an alcohol such as ethanol or methanol (0.2 M) is added (l,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) chloride (0.02 eq). The mixture is stirred at reflux for 1-20 h. After cooling to room temperature the solvent is evaporated. The residue is triturated in an organic solvent such as iert-butyl methyl ether or ethyl acetate. The precipitates are removed by filtration. The filtrate is concentrated to dryness. Purification by flash-chromatography gives a 4-heteroaryl-cyclohex-3-enecarboxylic acid ester intermediate of formula (V). 4-Heteroaryl-cyclohex-3-enecarboxylic acid ester 5(RS)-4-(6-Methoxy-pyridin-2-yl)-cyclohex-3-enecarboxylic acid ethyl esterThe title compound was obtained as light yellow liquid in 86% yield from 2-bromo-6- methoxypyridine according to general procedure (III). MS m/e: 262 ([M+H]+)
potassium 6-fluoropyridine-2-trifluoroborate[ No CAS ]
[ 1245646-08-5 ]
Yield
Reaction Conditions
Operation in experiment
82%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate; In ethanol; at 85℃; for 16h;Inert atmosphere;
General procedure: A 10-mL Schlenk tube was charged with Pd(OAc)2 (1.7 mg, 0.0075 mmol, 3.0 mol %), SPhos (6.2 mg, 0.015 mmol, 6.0 mol %), Na2CO3 (53.0 mg, 0.50 mmol, 2.0 equiv), potassium 6-fluoropyridine-2-trifluoroborate (101.5 mg, 0.50 mmol, 2.0 equiv) and heteroaryl halides (0.25 mmol, 1.0 equiv), followed by the addition of ethanol (2.0 ml). The reaction was carried out at 85 C for 16 h under the protection of nitrogen gas. Then, the reaction mixture was allowed to cool down to room temperature and the reaction solution was filtered through a thin pad of silica gel (eluting with ethyl acetate) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate/hexane=1:2-1:80).
potassium 6-methoxypyridine-2-trifluoroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
General procedure: A 100 mL single-neck flask was evacuated under vacuum, flame-dried and then charged with nitrogen gas three times. Anhydrous THF was added to the flask via syringe and a solution of a variety of functional groups 2-bromopyridine (1.0 equiv) in THF was added following by triisopropyl borate (1.1 equiv) via syringe at -78 C. A solution of 2.5 M n-BuLi in hexane (1.1 equiv) was added dropwise via constant pressure funnel over 2.0 h at -78 C. After the addition of n-BuLi was complete, the mixture was kept at -78 C with stirring for an additional 3.0 h, then allowed to warm up room temperature overnight. The mixture was then cooled to 0 C and an aqueous solution of KHF2 (3.0 equiv) was added dropwise with vigorous stirring. After stirring for an additional 4.0 h, the solvents were completely removed under vacuum. The crude product was then taken up in methanol and filtered, elimination of the solvent of methanol gave the white solid, and then the white solid was washed with acetone and filtered, collected, and dried in vacuo to afford the desired pure product as a light white solid (A-E).
Synthesis of 6-methoxypicolinonitrile:To a stirred solution of 2-bromo-6-methoxypyridine (5.0 g, 26.59 mmol) in DMF (50 mL) was added Cu(I)cyanide (7.14 g, 79.77 mmol) at room temperature. The resulting reaction mixture was heated at 100 C and stirred for 16 h. The reaction mixture was diluted with water, filtered through a pad of celite and the filtrate was extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 6-methoxypicolinonitrile (1.4 g, 39%) as white solid. 1H-NMR (DMSO d6, 400 MHz): delta 7.94 (t, 1H), 7.64 (d, 1H), 7.18 (d, 1H), 3.92 (s, 3H); LC-MS: 99.14%; 135.8 (M++l); (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 3.31 min. 0.1% Aq TFA: ACN; 0.8 ml/min); TLC: 10% EtOAc/Hexane (Rf:
39%
In N,N-dimethyl-formamide; at 100℃; for 16h;
Synthesis of 6-methoxypicolinonitrile [0524] To a stirred solution of 2-bromo-6-methoxypyridine (5.0 g, 26.59 mmol) in DMF (50 mL) was added Cu(I)cyanide (7.14 g, 79.77 mmol) at room temperature. The resulting reaction mixture was heated at 100 C and stirred for 16 h. The reaction mixture was diluted with water, filtered through a pad of celite and the filtrate was extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 6-methoxypicolinonitrile (1.4 g, 39%) as white solid. 1H-NMR (DMSO d6, 400 MHz): delta 7.94 (t, IH), 7.64 (d, IH), 7.18 (d, IH), 3.92 (s, 3H); LC-MS: 99.14%; 135.8 (M++l); (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 3.31 min. 0.1% Aq TFA: ACN; 0.8 ml/min); TLC: 10% EtOAc/Hexane (Rf: 0.3).
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 1.5h;Inert atmosphere; Sealed tube;
-(5 -fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3 -amineTo 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine ( 1 1 .4 mg. 0.6001 mmol ) and<strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> ( 1 10.0 uL, 0.8951 mmol) was added 1,4-dioxane (4.0 mL, 51 mmol). Nitrogen gas was bubbled through this mixture while stirring for 10 minutes, and then palladium ( I . ) acetate (14.5 mg, 0.0646 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.1 mg, 0.0987 mmol), and cesium carbonate (397.6 mg. 1.220 mmol ) were added. The reaction mixture was stirred in a sealed vial at 100 C for 90 minutes. The reaction mixture was diluted with dichloromethane, filtered through cclite, and evaporated in vacuo. The crude residue was purified via flash chromatography on sil ica gel ( 12 g silica. solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 227.4 mg of the title compound as 80% pure material . 52.4 mg of this material was purified via reverse phase HPLC and lyophilized to yield 1 7.9 mg of 7-(5-fluoro-2-methyiphenyi)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine. LCMS (ESI) : RT (min ) = 5.057. M+H = 360. 1 , method = E; ' H M R (400 MHZ, DMSO-d6) delta 9.80 (S, I H). 9. 1 1 (s, I H ). 8.58 (s, 1H), 7.97 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.38 (q, J = 6.3 Hz, 1H), 7.15 (t, J = 8.5 Hz, 2H), 6.82 (d, J = 7.8 Hz, 1H), 6.28 (d, J = 7.8 Hz, 1H), 4.01 (s, 3H), 2.26 (s, 3H).
General procedure: In a Schlenk tube, flushed under argon, rac-BINOL (0.3 g, 1.05 mmol, 1 equiv) was dissolved in anhydrous THF (7.5 mL). n-BuLi (1.6 M in hexanes, 1.3 mL, 2.1 mmol, 2 equiv) was slowly added at -5 C. After stirring at this temperature for 1 h, n-BuMgCl (2 M in THF, 0.52 mL, 1.05 mmol, 1 equiv) was added at -5 C and the resulting solution was stirred for additional 1 h at the same temperature. The 2-bromopyridine derivative (1 equiv) was then added at -5 C. The mixture was warmed to room temperature and stirred for 1 h. The reaction was monitored by TLC (eluent: cyclohexane/ethyl acetate 8:2.5). The medium was then cooled to -60 C and the electrophile (1.5 equiv) was added. The mixture was warmed to room temperature and stirred for a time t. The reaction was quenched with a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with ethyl acetate and acidified (pH=3-4) using a 0.4 M hydrochloric acid aqueous solution. The aqueous solution was then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography, leading to products 2a-l and 5-7.
lithium triisopropyl 2-(6-methoxypyridyl) borate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
General procedure: Pyridines substituted at the 2-position with halides shown in Tables 2 and 3 are stirred in a mixture of toluene (900 mL) and anhydrous ether (600 mL). The resulting solutions were cooled to < -100 C for 20 min at which point n-BuLi/hexane was added slowly over 22 min. After maintaining the temperature below -100 C for 20 min, triisopropylborate was added dropwise, and then the reaction mixture was stirred below -70 C. After stirring for 4 h, ether (500 mL) was added and the solution was allowed to stand overnight at room temp. Isopropanol was added (30mL), then the reaction mixture was stirred for 30 min, the allowed to stand without stirring for an additional 2 h. The resulting precipitate was collected by filtration then washed with ethyl ether and dried under nitrogen atmosphere for 1.5 h. The resulting triisopropoxy analog was treated with a mixture of acetone and water (450 mL/50 mL) to remove any contaminating n-butylborate lithium salt. The solids were collected by filtration, washed with acetone/water (9:1, 300 mL), and dried in air for 2h, then lyophilized overnight to afford product.
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 96h;Inert atmosphere;
To a solution of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (3 g, 16 mmol) in DMF(20mL) was added NCS (2.3 g, 17.6 mmol). The mixture was stirred at r.t. for 4 days. The reaction mixture was poured into 150ml water, followed by extraction with ethyl ether. The organic layer was washed with water, NaHC03 aqueous solution, NaCl saturated solution, dried over MgS04 and the solvent was distilled off under reduced pressure to give crude product 2-bromo-3-chloro-6- methoxypyridine (2 g, 57%), which was used to next step without further purification.. 1HNMR (400MHz, CDC13) ? 7.56~7.54(d, 1H, J=8), 6.67-6.65 (d, 1H, J=8), 3.92(s, 3H) .
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere;
In a 100 mL three-necked flask, <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (2.0 g, 10 mmol) was added successively, DMF (30 mL) And N-chlorosuccinimide (1.42 g, 10 mmol). Under nitrogen, stir at room temperature for 2 days. Saturated brine was added and extracted with ethyl acetate And the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give the title compound.
With N-chloro-succinimide; In N,N-dimethyl-formamide;
10297] Compound WXO2O-1 (500.00 mg, 2.66 mmol,326.80 pL, 1.00 eq) was added to a round-bottom flask containing anhydrous N,N-dimethylformamide (10.00 mE), and N-chlorosuccinimide (800.00 mg, 6.00 mmol, 2.26 eq) was added. After reaction, 25 mE of water was added. The mixture solution was extracted with 30 mE of ethyl acetate. The organic phase was washed with 20 mE of water, 25 mE of saturated sodium bicarbonate solution and 25 mE of saturated sodium chloride solution in ordet The organic phase was dried with anhydrous sodium sulfate, and filtered. The filtrate was dried by rotary evaporation under vacuum to obtain WXO2O-2. ?H NMR (400 MHz, CDC13) oe ppm: 3.93 (s, 3H), 6.68 (d, J=8.78 Hz, 1H), 7.57 (d, J=8.53 Hz, 1H).
With [Pd(N,N'-bis(2,6-bis(di-p-tolylmethyl)-4-methylphenyl)-imidazol-2-ylidene)(acetylacetonate)Cl]; lithium hexamethyldisilazane; In 1,4-dioxane; at 110℃; for 3h;Inert atmosphere; Sealed tube;
General procedure: A glassvial was charged with [Pd(IPr*me)(acac)Cl],neat amine (1.1 mmol), and the arylhalide (1 mmol) in dry 1,4-dioxane (1 mL) under an atmosphere of argonand sealed with a screw cap fitted with aseptum. LiHMDS (1.1 mmol) was subsequently injected at roomtemperature under argon, the reaction mixture was then refluxed at 110 for 3 h, After this time, dioxane was evaporated, the crude product wasdissolved in CH2Cl2. The solution was filtered on a padof silica covered with Celite, and thepad was eluted with CH2Cl2. After chromatography onsilica gel, the pure complex was obtained.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 1.5h;Microwave irradiation;
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (290 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130C for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate = 0:100 to 20:80, gradient) to obtain the title compound (426 mg, 79%) as a light yellow oily substance. 1H-NMR (500 MHz, CDCl3) delta: 0.06 (3H, s), 0.08 (3H, s), 0.92 (9H, s), 1.20 (3H, s), 1.45-1.53 (2H, m), 1.58-1.62 (1H, m), 1.65-1.69 (1H, m), 2.51-2.57 (1H, m), 2.64-2.71 (1H, m), 3.40 (2H, s), 3.50-3.57 (2H, m), 4.03 (3H, s), 4.06-4.12 (1H, m), 4.29-4.36 (1H, m), 6.67-6.70 (1H, m), 7.14-7.18 (2H, m), 7.30-7.32 (1H, m), 7.60-7.64 (1H, m), 7.96-7.99 (2H, m)
2-[5-(6-methoxypyridin-2-yl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 20℃; for 2h;Reflux; Inert atmosphere;
General procedure: Pd(PPh3)4 (3 mol%) was added to a suspension of the appropriate benzoxazole 7 and (het)aryl bromide (1 equiv) in 1 M aq K2CO3 (3equiv) and 1,4-dioxane (0.15 M) at r.t. The mixture was stirred at reflux for 2 h then cooled to r.t. H2O was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel,hexane-EtOAc or CHCl3-MeOH).
rac-tert-butyl 4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
rac-tert-butyl 4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64.6%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;
To a dried flask under nitrogen was added tert-butyl 4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-I ,2 ,3,4-tetrahydroq uinolin-6-yl)-5,6-dihydropyridine- I (2H)-carboxylate (for a preparation see Intermediate 81, 250 mg, 0.587 mmol), <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (0.087 mL, 0.705 mmol), DavePhos (88 mg, 0.223 mmol), Pd2(dba)3 (102 mg, 0.112 mmol) and sodium tert-butoxide (169 mg, 1 .762 mmol). To this was added I ,4-dioxane (5 mL) and the solution was degassed with nitrogen for-5 mm. The mixture was then heated for 2 h at 90 C under nitrogen. The mixture was allowed to cool to rt, filtered through a 2.5 g celite cartridge, washed through with ethyl acetate and concentrated in vacuo to afford a dark orange oil. The crude product was taken up in DCM and purified on a 25 g silica cartridge by flash chromatography eluting with 0-50% EtOAc/cyclohexane. The appropriate fractions were collected and concentrated in vacuo to afford the desired product asan off-white foam (202 mg, 0.379 mmol, 64.6%). LCMS (2 mm Formic): Rt = 1.33 mi [MH] = 533.
rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
rac-1-((2S,3R,4R)-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 90℃; for 8h;Inert atmosphere;
A solution of rac- I -((2S,3R,4R)-4-am ino-2-cyclopropyl-3-methyl-6-morpholino-3,4-dihydroqu inolin1(2H)-yl)ethanone (for a preparation see Intermediate 83, 70 mg, 0.212 mmol), DavePhos (8.36 mg,0.021 mmol), Pd2(dba)3 (9.73 mg, 10.62 iJmol), sodium tert-butoxide (0.027 mL, 0.425 mmol) and 2-bromo-6-methoxy-pyridine (47.9 mg, 0.255 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen at 90 C for 8 h. The reaction mixture was allowed to cool to rt, filtered through celite and rinsed with ethyl acetate. The solvent was evaporated in vacuo to give the title compound (120 mg, 0.275 mmol, 92% pure) as a brown gum. LCMS (2 mm Formic): Rt = 1.03 mi [MH] = 437.
rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 100℃; for 16h;
The rac- I -((2S,3R,4R)-4-am ino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihyd roquinolin- I (2H)-yl)ethanone (for a preparation see Intermediate 146, 100 mg, 0.381 mmol) 2-bromo-6- methoxypyridine (108 mg, 0.572 mmol), Pd2(dba)3 (52.4 mg, 0.057 mmol), sodium tert-butoxide (110 mg, 1.144 mmol) and DavePhos (15.00 mg, 0.038 mmol) were suspended in 1,4-dioxane (10 mL) and allowed to stir at 100C for 16 h. The reaction was allowed to cool to rt and was filtered throughcelite and concentrated to a gum. This gum was purified using a MDAP (Formic) to give a solid which was eluted through a NH2 SPE (5 g) with MeOH, the eluent was concentrated and dried to give the product (69 mg, 0.187 mmol, 49.0%). LCMS (2 mm Formic): Rt = 1.14 mi [MH] = 370.
(S)-tert-butyl 4-((2S,3R,4R)-1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(S)-tert-butyl 4-((2S,3R,4R)-1-acetyl-2-cyclopropyl-4-((6-methoxypyridin-2-yl)amino)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-methylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.4%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 90℃; for 1.5h;Inert atmosphere;
To a dried flask flask under nitrogen was added DavePhos (40.0 mg, 0.102 mmol), (S)-tert-butyl 4-((2S,3R,4R)- I -acetyl-4-am ino-2-cyclopropyl-3-methyl- I ,2,3,4-tetrahydroq uinolin-6-yl)-2-methylpiperazine-1-carboxylate (for a preparation see Intermediate 220, 75 mg, 0.169 mmol), <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (0.025 mL, 0.203 mmol), Pd2(dba)3 (31.0 mg, 0.034 mmol) and sodiumtert-butoxide (48.9 mg, 0.508 mmol). The reactants were dissolved in 1,4-dioxane (3 mL), and the solution was heated under nitrogen at 90 C for 90 mm. The reaction mixture was allowed to cool, filtered over a 2.5 g celite cartridge, and washed through with ethyl acetate. The solution was concentrated in vacuo to afford a dark brown oil. This crude residue was dissolveddichloromethane, loaded onto a 10 g silica flash cartridge and eluted by silica gel chromatography in0-30% ethyl acetate in cyclohexane. The appropriate fractions were collected and concentrated invacuo to afford a yellow oil (62.8 mg, 0.114 mmol, 67.4%).LCMS (2 mm Formic): Rt = 1.32 mi [MH] = 550.
rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
rac-1-((2S,3R,4R)-2-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-4-((6-methoxypyridin-2-yl)amino)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.1%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
The 2-bromo-6-methoxypyrid me (0.200 mL, 1 .593 mmol), rac- I -((2S,3R,4R)-4-amino-2-cyclopropyl-6-(3,6-dihyd ro-2H-pyran-4-yl)-3-methyl-3,4-dihyd roquinolin- I (2H)-yl)ethanone (for a preparation see Intermediate 78, 260 mg, 0.796 mmol), Pd2(dba)3 (109 mg, 0.119 mmol), sodium tert-butoxide (230 mg, 2.389 mmol) and DavePhos (31 .3 mg, 0.080 mmol) were suspended in I ,4-dioxane (10 mL) and allowed to stir at 100 C for 16 h. The reaction was concentrated and partitioned between water andEtOAc, the organic layer was washed with brine, dried using a hydrophobic frit and concentrated to a gum. This gum was purified using a 25 g silica column, elute: 0-50% EtOAc:cyclohexane one major peak was eluted, the appropriate fractions were summed and concentrated to give the product (242 mg, 0.558 mmol, 70.1%) as a yellow solid.LCMS (2 mm Formic): Rt = 1.12 mi [MH] = 434.
4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one[ No CAS ]
4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one[ No CAS ]
4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%; 37%
With palladium diacetate; caesium carbonate; XPhos; In toluene; tert-butyl alcohol; at 160℃; for 1h;Microwave irradiation;
Example 207a (0.243 g, 0.5 mmol), 2-b iDmo-6-methoxypyridine (0.188 g, 1 mmol), diacetoxypalladium(0028 g, 0.125 mmol), dicy lohexyliS^'^'-triisopropyl-tl^ 2-yl)phjosphme (0.12 g, 0.25 mmol), and cesium caob onate (0.326 g, 1 mmol) were co b ined in a 5-mL microwave vial. ArLhydrous toluene (4 mL) and tert-butanol (1 mL)were added. The vial was capped and the mixture was heated at 160 * C for 1 hour in a B iotage microwave reactor. The reaction rraxture was filtered through a f tted funnel to remove the palladium solids . The filtrate was partitioned between ethyl acetate and water. The organic layerwas washed with saturated aqueous sodium chloride, treated with 3-mercaptopropyl- functionalized silica gel for 20 minutes , dned over anhydrous magnes ium sulfate, filtered through a plug of Celite, and concentrated. The residue was purified by flash chromatography (silica geL 0-100 % ethyl acetate in dichloromethane, then 5-10 % methanol in ethyl acetate) to give 0.15 g (51%) of the title compound and 0.08 g (37%) of Example 256b
1-(6-methoxypyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: In a typical procedure, for mono-hpp substitution reactions, a100 mL oven-dried round-bottomed flask was charged with(±)-BINAP (3 mol% with respect to N-haloheterocycle) and dissolvedin dry toluene (5 mL) under an inert N2 atmosphere at ca.60 C to give a clear colorless solution. To this solution wasadded Pd(OAc)2 (2 mol% with respect to the halogenated N-heterocycle),and the reaction mixture was stirred at ambient temperatureunder N2 atmosphere to give a clear dark red solution.To this solution was added the halogenated N-heterocycle (1mmol), and the reaction was heated to 60 C under N2 atmospherefor 15-20 min, with a concomitant color change fromdark-red to yellow. To the resulting clear yellow solution wasadded H-hpp (1.1 equiv with respect to starting halogenated Nheterocycle),followed by the addition of KOt-Bu (2.5 equiv withrespect to halogenated N-heterocycle), and the resulting brownish-red solution was heated at elevated temperature and for thetime indicated in Table 1. After this time, the reaction mixturewas cooled to r.t., and the solvent was evaporated to dryness. Tothe resulting brownish-green solid was added an aliquot of amixture of toluene and Et2O (10:60, v/v), and the mixture wasfiltered. The pale-yellow filtrate was evaporated to dryness. Thedesired product was isolated as colorless or yellow solid by triturationwith acetone (1-2 mL). Subsequent drying undervacuum afforded the compound in the yield as indicated inTable 1.
ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate[ No CAS ]
ethyl 5-(2-chloro-5-(6-methoxypyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; at 60℃; for 18h;Reflux;
The reaction was cooled to 60C and to the reaction was added water (0.1 mL), 2- bromo-6-methoxypyridine (210 mg, 1.1 mmol) and Na2003 (570 mg, 3.3 mmol). The reaction was degassed for 5 minutes before the addition of Pd(dppf)Cl2 (40 mg, 0.05 mmol) and heating at reflux for 18 hours. The reaction was cooled, filtered throughCelite and concentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 5-80% DCM in TBME to afford the title compound (340 mg,65%).1H NMR (400MHz, CDCI3): O ppm 1.39-1.43 (m, 3H), 4.00 (5, 3H), 4.41-4.47 (m, 2H),6.74 (d, 1H), 7.34-7.56 (m, 6H), 7.70 (t, 1H), 7.80 (dd, 1H), 8.11 (dd, 1H), 8.23 (5, 1H),8.53 (d, 1H).LCMS Rt = 3.63 minutes MS mlz 477 [M+H]
(1,6-dimethyl-1H-benzo[d]imidazol-2-yl)(phenyl)methanone[ No CAS ]
(1,6-dimethyl-1H-benzo[d]imidazol-2-yl)(6-methoxypyridin-2-yl)(phenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
[0385j Step A: Preparation of (1 ,6-dimethyl- 1H-benzo [dlimidazol-2-yl)(6- methoxypyridin-2-yl)(phenyl)methanol: To a solution of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> (0.11 g, 0.6 mmol) in THF (10 mL)was added n-BuLi (2.4 M, 0.5 mL, 1.2 mmol) in hexane at -78 C. The reaction mixture was stirred at -78 C for 1 hour. (1,6-Dimethyl-1H-benzo[d]imidazol-2- yl)(phenyl)methanone (0.10 g, 0.4 mmol) was added at -78C. The reaction mixture was stirred at -78 C for 1 hour. Saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give (1,6-dimethyl-1H-benzo[d]imidazol-2-yl)(6- methoxypyridin-2-yl)(phenyl)methanol (0.1 g, 69%) as solid.
With C37H45ClN2O3PPd; potassium carbonate; In ethanol; water; at 80℃; for 6h;Inert atmosphere; Schlenk technique;
A 10-mL round-bottom flask was charged with the prescribe damount of catalyst, 1,4-benzenediboronic acid (0.5 mmol), N-heteroaryl halides (1.5 mmol), the selected base (1.5 mmol) and solvent (4 mL). The flask was placed in an oil bath and heated at 80 °C for 6 h, then cooled to room temperature and extracted with CH2Cl2. The crude products obtained from evaporation were purified by flash chromatography on silica gel. The products 5b?c, 5f, 5m [21], 5d [22], 5e [23], 5l [24] were known compounds and characterized by the comparison of data with those in the literature. The products 5a, 5g?k, 5n?o were new compounds and characterized by elemental analysis, IR, MS,1H and 13C NMR.
Under nitrogen protection, n-butyl lithium (2.5M, 8.0mL, 20.0mmol) at -78 C,It was added dropwise to a solution of acetonitrile (1.1 mL, 21.2 mmol, dried molecular sieve) in anhydrous tetrahydrofuran (20 mL), and reacted at this temperature for 30 min.A solution of the compound <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> 33a (1 g, 5.32 mmol) in anhydrous tetrahydrofuran (5 mL).After the completion of the dropwise addition, the temperature was gradually raised to room temperature and stirred for 4 hours.The mixture was poured into ice water and extracted with EtOAc EtOAc.Purified by column chromatography to give the title compound 33b (474mg, 3.2mmol), 60% yield.
58%
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃; for 4.75h;
(Step 14)l.6M n-Butyllithium/hexane solution (300 mL, 479.43 rnmol) was added to a solution of acetonitrile (21.87 g, 532.70 rnmol) in THF (630 mL) at -78C under argon atmosphere, and themixture was stirred at -78C for 30 mi 2-Bromo-6- methoxypyridine (25.04 g, 133.18 rnmol) was added dropwise thereto over 15 mm at -78C, and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture waspoured into ice water (900 mL), and the mixture was extracted with ethyl acetate (x 3) . The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solvent gradient; 2-20% ethyl acetate/hexane) to give 2-(6- methoxypyridin-2-yl)acetonitrile (11.37 g, 77 rrunol, 58%) as a colorless oil.?HNMR(300MHz,CDCl3):oe3.81(2H,s),3.93(3H,s),6.69(lH,d,J=8.3Hz),6.93-6.98(1H,m),7.58(1H,dd,J=8.3,7.6Hz).
58%
1.6 M n-Butyllithium/hexane solution (300 mL, 479.43 mmol) was added to a solution of acetonitrile (21.87 g, 532.70 mmol) in THF (630 mL) under argon gas atmosphere at -78C, and the mixture was stirred at -78C for 30 min. 2-Bromo-6-methoxypyridine (25.04 g, 133.18 mmol) was added dropwise thereto at -78C over 15 min, and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water (900 mL), and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2?20% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)acetonitrile (11.37 g, 77 mmol, 58%) as a colorless oil.
With 5%-palladium/activated carbon; oxygen; potassium carbonate; In ethanol; water; at 80℃; for 3h;
General procedure: A mixture of aryl halide (0.5 mmol), potassium aryltrifluoroborate (0.6 mmol), K2CO3 (1.0 mmol), Pd/C (5%; 0.5 mol%), ethanol (3 mL), and distilled water (1 mL) was stirred at 80 C in air for the time indicated. The reaction mixture was added to brine (15 mL) and extracted with ethyl acetate (4×15 mL). The organic solvent was removed under vacuum, and the product was isolated by short-column chromatography.
2-allyl-1-(6-methoxypyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 12h;Inert atmosphere;
I1 (1.0 g, 4.5 mmol) was added into 1,4- dioxane (10 mL), and 2-bromo-6-methoxylpyridine (1.02 g, 5.4 mmol, 664 muL), potassium carbonate (622 mg, 4.5 mmol), cuprous iodide (857 mg, 4.5 mmol) and N,N'-dimethylethylenediamine (397 mg, 4.5 mmol, 490 muL) were added while stirring, heated to 95C under nitrogen atmosphere, then reacted for 12 h. 100 mL ammonia was added into the reacted mixture, then extracted by 100 mL EA, the organic phase was washed by 100 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was crystalized by EtOAc, then purified by silica gel chromatography (PE/EA = 10/1 to 2/1), to give the compound 47-1. 1H NMR (400MHz, CDCl3) delta = 8.92 (s, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 5.83 - 5.69 (m, 1H), 5.07 (d, J=10.4 Hz, 1H), 4.96 (br d, J=17.2 Hz, 1H), 4.84 (d, J=6.0 Hz, 2H), 3.93 (s, 3H), 2.56 (s, 3H)
4,6-diphenyl-2-[3-(6-methoxypyridine-2-yl)-5-(9-phenanthryl)phenyl]-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 2h;Inert atmosphere; Reflux;
A stream of argon, 4,6-diphenyl-2- [5- (9-phenanthryl) -3- (4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) phenyl] - 1,3,5-triazine (0.300g, 0.49mmol), 2- bromo-6-methoxy-pyrimidine (0.111g, 0.59mmol), tetrakis (triphenylphosphine) palladium (17.3mg, 0.015mmol ), and weighed potassium carbonate (0.207 g, 1.5 mmol), was suspended in tetrahydrofuran (7.5 mL) and water (1.5 mL). The mixture was heated to reflux for 2 hours. After cooling, water was added, and the precipitated solid was filtered off and washed with water, methanol, a solid with hexane. By further purified by recrystallization (toluene)4,6-diphenyl-2- [3- (6-methoxy-2-yl) -5- (9-phenanthryl) phenyl] -1,3,5-triazineIt was obtained (Compound the A-35) as a white solid (Yield 0.261 g, 90% yield).
2-methoxy-6-(2,3,4,5-tetrafluorophenyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
2-(3,5-dichloro-2-fluorophenyl)-6-methoxypyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
2-(2,5-difluorophenyl)-6-methoxypyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
2-(2-fluoro-5-(trifluoromethyl)phenyl)-6-methoxypyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
cyclopropyl(4-fluoro-3-(6-methoxypyridin-2-yl)phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 90℃; for 3h;
The reaction vessel was charged with 2-phenylpyridine-5-boronic acid (3.36 g, 16.9 mmol), <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong>(3.18, 16.9 mmol), tetrakistriphenylphosphine palladium (0.7 g, 1.08 mmol), potassium carbonate (5.3 g, 38.3 mmol)500 mL of toluene, 40 mL of ethanol and 40 mL of distilled water were stirred at 90 C for 3 hours. Distilled water was stopped after the reaction was completedExtract with ethyl acetate. The organic layer is dried over MgSO4. The solvent was distilled off under reduced pressure and then purified on a silica gel column to give the compound3-4-A (2.22 g, 50%).
2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine[ No CAS ]
2',6'-bis(benzyloxy)-6-methoxy-2,3'-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.4%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;
A stirred solution of <strong>[40473-07-2]2-bromo-6-methoxypyridine</strong> 26-1 (150 mg, 797 mumol) , 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 25-1 (496 mg, 1.19 mmol) and Potassium phosphate (366 mg, 1.59 mmol) in water: dioxane (10 mL ) was degassed with argon for 10 minutes. PdCl2dppf.DCM (65.0 mg, 79.7 mumol) was added to above reaction mixture and the solution was again purged with argon and refluxed for 16 hours at 100C. Upon completion of reaction as monitored by TLC ( Rf = 0.5 in 20 % EtOH/Hexane), the reaction mixture was filtered through celite and the filtrate was evaporated to dryness. The residue was again dissolved in EtOAc (50 mL), washed with water and brine and evaporated. The product was purified by combi flash chromatography (4 g Isco gold, hexane/EtOAc 80-20%) to give 2',6'- bis(benzyloxy)-6-methoxy-2,3'-bipyridine (26-2) (125 mg, 313 mumol, 39.4 %) as a white gummy solid. LC MS: ES+ 393.3.
General procedure: The aryl halide was dissolved in 5mL of methanol per mmol of (hetero)arylhalide, magnesium (5 equiv.) added and the mixture was stirred at room temperature. After completion of the reaction (between 6-12h), the reaction mixture was poured into water, acidified with dilute HCl, and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The product was purified if necessary by column chromatography on silica gel.
With palladium(II) trimethylacetate; 4,7-bis-(4-fluorophenyl)-1,10-phenanthroline; caesium carbonate; In toluene; at 120℃; for 24h;Inert atmosphere;
General procedure: A mixture of Pd(OPiv)2 (6 mg, 0.02 mmol), ligand 7 (7 mg,0.02 mmol), Cs2CO3 (65 mg, 0.20 mmol), imidazole 1b (14 mg,0.100 mmol), and 2-iodopyridine (41 mg, 0.200 mmol) in toluene(0.5 mL) was stirred at 120C for 24 h. After completion ofthe reaction, the reaction mixture was filtered through a celitepad. After concentration of the filtrate, the crude product was purified by column chromatography on silica gel (EtOAc/MeOH = 20 : 1) to give desired product 3b as brown oil (16 mg,74% yield).
With N-Bromosuccinimide; In acetonitrile; at 20 - 90℃; for 16.0h;
To a stirred solution of 2-bromo-6-methoxypyridine (10 g, 0.053 mol) in dry ACN (100 ml_), was added A/-bromosuccinimide (18.82 g, 0.106 mol) at RT. The reaction mixture was stirred at 90? for 16 h. The completion of reaction was monitored by TLC. After completion, the reaction was filtered through a celite bed, diluted with water (30 mL) and exacted with 10% EtOAc in petroleum ether (2 x 100 mL). The combined organic layer washed with water (10 mL), brine (10mL) dried over Na2SC>4 and concentrated. The resulting crude material was purified by crystallization (5 mL DCM in 50 mL n- pentane). The solid was filtered, washed with n-pentane and then dried unber vacuum to get afford the tittle compound. Yield: 35% (4.92 g, off white solid). 1H NMR (400 MHz, CDCI3): d 7.70 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 3.93 (s, 3H), LCMS: (Method A) 367.9 (M+H), Rt. 2.4 min, 96.7% (Max).
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