* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
5
[ 20986-40-7 ]
[ 28733-43-9 ]
Reference：
[1] Yakugaku Zasshi, 1931, vol. 51, p. 542,571; dtsch. Ref. S. 73, 76[2] Chem.Abstr., 1931, p. 5427
6
[ 20826-04-4 ]
[ 64-17-5 ]
[ 20986-40-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: Reflux Stage #2: for 2 h; Reflux Stage #3: With sodium hydrogencarbonate In dichloromethane; water
5-Bromonicotinic acid (2.66 g, 13.1 rnmol) in excess thionyl chloride (6 mL, 82.3 mmol) was brought to reflux conditions and left to stir overnight. The reaction mixture was cooled to room temperature, placed in an ice bath, and excess ethanol (7 tnL) was added to the mixture portion-wise, with stirring. The reaction mixture was returned to reflux conditions and stirred for 2 h. The solution was then cooled to room temperature and solvent removed en vacuo and redissolved in dichloromethane to produce a suspension. 10? NaHCO3 was added with stirring to obtain a pH = 8. The dichloromethane layer was removed and the aqueous layer was extracted 2 more times with dichloromethane. The organic fractions were combined, back extracted with water, extracted with brine, and dried over Na2SO4. After filtration, the solvent was removed in vacuo and used without further purification (2.99 g, 99percent yield) . 1H NMR (300 MHz, CDC13) ? ppm 9.04 {d, IH), 8.75 (d, IH), 8.34 (dd, IH), 4.35 {d, 3H) , 1.34 Ct, 2H) .
89%
for 18 h; Inert atmosphere; Reflux; Cooling with ice
To an ice-cool solution of 5-bromonicotinic acid (iS g, 75 mmol) in ethanol (2S0 mL) was added concentrated sulthric acid (4 mL) slowly drop wise and refluxed under argon for 18 h. Ethanol was removed under reduced pressure and resulting white residue was dissolved in water. The aqueous solution was made basic to pH 8 with sat. sodium bicarbonate and extracted with ethet The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under diminished pressure afforded 1 as a pale yellow solid: yield1S.20 g (89percent); ‘H NMR (400 MHz, CDC13) ö 1.39 (t, 3H, J=7.2 Hz), 4.40 (q, 2H, J=7.6, 14.8 Hz), 8.40 (t, 1H, J=2.0 Hz), 8.81 (d, 1H, J=2.4 Hz) and 9.10 (d, 1H, J=1.6 Hz); ‘3C NMR (100 MHz, CDC13) ö 14.3, 62.0, 120.7, 127.6, 139.S, 149.0, 1S4.S and 164.1.
82%
for 22.08 h; Heating / reflux
EXAMPLE 1; 2-Amino-4-(5-cyano-pyridin-3-yl)-3-cyano-7-methyl-4H-pyrrolo[2,3-h]chromene; a) Ethyl 5-bromonicotinate:; To a white stirring suspension of 5-bromonicotinic acid (3.00 g, 14.9 mmol) in ethyl alcohol (30.0 mL) was added concentrated H2SO4 (9.0 mL) dropwise over 5 min to form a clear solution. The clear solution was then heated for 22 h, cooled to room temperature, quenched with water (30 mL) and then extracted with dichloromethane (75 mL). The organic layer was washed with 10percent Na2CO3 (20 mL), water (20 mL), dried over MgSO4, filtered through sintered glass and concentrated to yield 2.8 g (82percent) of the title compound as a white solid. 1H NMR (CDCl3): 9.13 (d, J=1.7 Hz, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.42 (m, J=2.2, 1.7 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
82%
at 20℃; for 96 h;
20 ml (27 mmol) of thionyl chloride are added dropwise, at room temperature, to a solution of 10 g (49 mmol) of 5-bromonicotinic acid in 250 ml of ethanol. The reaction medium is stirred at room temperature for 4 days and then evaporated under vacuum. The residue is taken up in dichloromethane and washed with aqueous sodium carbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 9 g (82percent) of ethyl 5-bromonicotinate are obtained.
Reference：
[1] Patent: WO2008/151073, 2008, A1, . Location in patent: Page/Page column 39-40; 44
[2] Journal of Organic Chemistry, 2001, vol. 66, # 12, p. 4115 - 4121
[3] Patent: US2016/375131, 2016, A1, . Location in patent: Paragraph 0080
[4] ACS Combinatorial Science, 2017, vol. 19, # 5, p. 286 - 298
[5] Organic Preparations and Procedures International, 1992, vol. 24, # 2, p. 143 - 146
[6] Patent: US2006/104998, 2006, A1, . Location in patent: Page/Page column 16
[7] Patent: WO2004/113331, 2004, A1, . Location in patent: Page 43
[8] Yakugaku Zasshi, 1931, vol. 51, p. 542,571; dtsch. Ref. S. 73, 76[9] Chem.Abstr., 1931, p. 5427
[10] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1608 - 1628
[11] Patent: US2006/287522, 2006, A1, . Location in patent: Page/Page column 26
[12] Medicinal Chemistry Research, 2014, vol. 23, # 4, p. 2080 - 2092
[13] Patent: US2015/17201, 2015, A1, . Location in patent: Paragraph 0165
EXAMPLE 1 Ethyl 5-bromo-3-pyridinecarboxylate To a slurry of 5-bromo-3-pyridinecarboxylic acid (100.0 g, 0.495 mol) in 1,2-dichloroethane (200 mL), thionyl chloride (108 mL, 1.485 mmol) was slowly added over a period of 30 min with intermittent cooling in an ice bath to maintain a temperature below 20° C. The reaction mixture was allowed to warm to room temperature, and heated to reflux for 18 h. The reaction mixture was cooled to 10° C., and additional thionyl chloride (14.7 g, 0.12 mmol) was added dropwise. The reaction was warmed to reflux for 6 h, then allowed to cool to room temperature. Residual thionyl chloride and solvent were removed by rotary evaporation followed by high vaccum to provide 5-bromo-3-pyridinecarbacyl chloride hydrochloride as a colorless solid (128 g, 101percent).
Reference：
[1] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4308 - 4312
[4] Patent: US5723477, 1998, A,
[5] Patent: US5594011, 1997, A,
[6] Patent: US5703100, 1997, A,
[7] Patent: US5705512, 1998, A,
[8] Patent: US5677459, 1997, A,
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 8, p. 3593 - 3610
12
[ 59-67-6 ]
[ 20986-40-7 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
13
[ 39620-02-5 ]
[ 64-17-5 ]
[ 20986-40-7 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
[2] Justus Liebigs Annalen der Chemie, 1959, vol. 621, p. 106,119
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4308 - 4312
[4] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 12, p. 4115 - 4121
[2] Journal of Organic Chemistry, 1998, vol. 63, # 4, p. 1109 - 1118
[3] Journal of Medicinal Chemistry, 1996, vol. 39, # 17, p. 3235 - 3237
[4] Journal of Organic Chemistry, 1982, vol. 47, # 21, p. 4165 - 4167
[5] Patent: US2016/375131, 2016, A1,
[6] ACS Combinatorial Science, 2017, vol. 19, # 5, p. 286 - 298
[7] Patent: WO2008/151073, 2008, A1,
19
[ 20986-40-7 ]
[ 37669-64-0 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With sodium tetrahydroborate In methanol at 0℃; for 0.5 h; Stage #2: With water In methanol
(5-bromopyridin-3-yl)methanol. To a cold (0° C.) solution of ethyl-5-bromonicotinate (1.0g, 4.3 mmoL) in MeOH (15mL) was added sodium borohydride (650 mg, 17 mmol) portion wise. After 30 min. the reaction was quenched by the addition of water (10 mL). The reaction was then extracted with methylene chloride (3x). The extracts were combined, dried (MgSO4) the filtrate was concentrated and purified by column chromatography on silica gel (0 to 80percent ethyl acetate/hexanes)to produce 475 mg (60percent) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ8.57 (s, 1H), 8.49 (s, 1H), 7.91 (s, 1H), 4.73 (s, 2H), 2.51 (s,br,1H). Mass spec.:188.12 (MH)+.
60%
With sodium tetrahydroborate In methanol at 0℃; for 0.5 h;
To a cold (00C) solution of ethyl-5- bromonicotinate ( 1.Og, 4.3 mmoL) in MeOH ( 15mL) was added sodium borohydride (650 mg, 17 mmol) portion wise. After 30 min. the reaction was quenched by the addition of water (10 mL). The reaction was then extracted with methylene chloride (3x). The extracts were combined, dried (MgSO4) the filtrate was concentrated and purified by column chromatography on silica gel (0 to 80percent ethyl acetate / hexanes)to produce 475 mg (60percent) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, IH), 8.49 (s, IH), 7.91 (s, IH), 4.73 (s, 2H), 2.51 (s,br,lH). Mass spec: 188.12 (MH)+.
58%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at -78 - 20℃; for 3.16 h; Stage #2: With water In tetrahydrofuran
b) (5-Bromo-pyridin-3-yl)-methanol
A clear solution of ethyl-5-bromonicotinate (2.80 g, 12.2 mmol) in THF (35 mL) was cooled to -78° C. and lithium aluminum hydride (LAH, 0.470 g, 12.2 mmol) was added in small portions over the next 10 min. After stirring for 1 h at -78° C., the cold bath was removed. The reaction mixture was stirred at room temperature for 2 h, quenched by the slow addition of water (5 mL), filtered through a layer of celite and washed with ethyl acetate (100 mL). The organic layer was then dried over MgSO4, filtered through sintered glass and concentrated to yield 1.5 g (66percent) of a yellow oil residue. The residue was purified by column chromatography (elution with EtOAC:hexanes, 1:1) and yielded 1.32 g (58percent) of the title compound as a yellow oil. 1H NMR (CDCl3): 8.48 (d, J=1.9 Hz, 1H), 8.39 (s, 1H), 7.88 (t, J=1.9 Hz, 1H), 4.69 (s, 2H).
54%
at 0℃; for 0.666667 h;
To a cold solution of ethyl 5-bromonicotinate (1.003 g, 4.36 mmol) in methanol (15 ml, 371 mmol) was added sodium borohydride (0.652 g, 17.23 mmol) portion wise on 10 min. The reaction was stirred for 30 min. at 0 °C. The reaction was quenched with water and extracted three times with CH2Cl2. The combined organic layers were dried on anh. Na2SO4 and concentrated. The residue was purified on ISCO using a 80g SILICYCLE® column (Hex/EtOAc) and afforded the title material (0.477 g, 54percent) as a clear oil. LC (Method B): 0.756 min. MS(ESI) calcd. for C6H7BrNO [M+H]+ m/z: 187.97; found: 190.0, 191.0. 1H NMR (400 MHz, acetone) δ ppm 8.50 - 8.58 (m, 2H) 7.93 - 7.98 (m, 1H) 4.67 - 4.74 (m, 2H) 4.48 - 4.56 (m, 1H)
50%
Stage #1: With sodium tetrahydroborate In methanol at 20℃; for 2 h; Heating / reflux Stage #2: With sodium hydroxide In water
A solution of 9 g (40 mmol) of ethyl 5-bromo- nicotinate in 25 ml of methanol is added dropwise, at room temperature, to a suspension of 14.8 g (400 mmol) of sodium borohydride in 75 ml of methanol. After addition, the reaction medium is refluxed for 2 hours. The reaction medium is evaporated to dryness, taken up in aqueous sodium hydroxide solution to pH 9, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. 3.7 g (50percent) of (5-bromopyrid-3-yl)- methanol are obtained.
Reference：
[1] Patent: US2008/27056, 2008, A1, . Location in patent: Page/Page column 27
[2] Patent: WO2009/96941, 2009, A1, . Location in patent: Page/Page column 29
[3] Patent: US2006/104998, 2006, A1, . Location in patent: Page/Page column 16
[4] Patent: WO2013/163241, 2013, A1, . Location in patent: Paragraph 00148
[5] Journal of Organic Chemistry, 2008, vol. 73, # 9, p. 3497 - 3507
[6] Patent: WO2004/113331, 2004, A1, . Location in patent: Page 43-44
[7] Organic Preparations and Procedures International, 1992, vol. 24, # 2, p. 143 - 146
[8] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1608 - 1628
[9] Patent: US6090812, 2000, A,
[10] Patent: US2006/287522, 2006, A1, . Location in patent: Page/Page column 26
5-Bromonicotinic acid (2.66 g, 13.1 rnmol) in excess thionyl chloride (6 mL, 82.3 mmol) was brought to reflux conditions and left to stir overnight. The reaction mixture was cooled to room temperature, placed in an ice bath, and excess ethanol (7 tnL) was added to the mixture portion-wise, with stirring. The reaction mixture was returned to reflux conditions and stirred for 2 h. The solution was then cooled to room temperature and solvent removed en vacuo and redissolved in dichloromethane to produce a suspension. 10? NaHCO3 was added with stirring to obtain a pH = 8. The dichloromethane layer was removed and the aqueous layer was extracted 2 more times with dichloromethane. The organic fractions were combined, back extracted with water, extracted with brine, and dried over Na2SO4. After filtration, the solvent was removed in vacuo and used without further purification (2.99 g, 99% yield) . 1H NMR (300 MHz, CDC13) ? ppm 9.04 {d, IH), 8.75 (d, IH), 8.34 (dd, IH), 4.35 {d, 3H) , 1.34 Ct, 2H) .
89%
With sulfuric acid; for 18h;Inert atmosphere; Reflux; Cooling with ice;
To an ice-cool solution of 5-bromonicotinic acid (iS g, 75 mmol) in ethanol (2S0 mL) was added concentrated sulthric acid (4 mL) slowly drop wise and refluxed under argon for 18 h. Ethanol was removed under reduced pressure and resulting white residue was dissolved in water. The aqueous solution was made basic to pH 8 with sat. sodium bicarbonate and extracted with ethet The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under diminished pressure afforded 1 as a pale yellow solid: yield1S.20 g (89%); ?H NMR (400 MHz, CDC13) oe 1.39 (t, 3H, J=7.2 Hz), 4.40 (q, 2H, J=7.6, 14.8 Hz), 8.40 (t, 1H, J=2.0 Hz), 8.81 (d, 1H, J=2.4 Hz) and 9.10 (d, 1H, J=1.6 Hz); ?3C NMR (100 MHz, CDC13) oe 14.3, 62.0, 120.7, 127.6, 139.S, 149.0, 1S4.S and 164.1.
82%
With sulfuric acid; for 22.08h;Heating / reflux;
EXAMPLE 1; 2-Amino-4-(5-cyano-pyridin-3-yl)-3-cyano-7-methyl-4H-pyrrolo[2,3-h]chromene; a) Ethyl 5-bromonicotinate:; To a white stirring suspension of 5-bromonicotinic acid (3.00 g, 14.9 mmol) in ethyl alcohol (30.0 mL) was added concentrated H2SO4 (9.0 mL) dropwise over 5 min to form a clear solution. The clear solution was then heated for 22 h, cooled to room temperature, quenched with water (30 mL) and then extracted with dichloromethane (75 mL). The organic layer was washed with 10% Na2CO3 (20 mL), water (20 mL), dried over MgSO4, filtered through sintered glass and concentrated to yield 2.8 g (82%) of the title compound as a white solid. 1H NMR (CDCl3): 9.13 (d, J=1.7 Hz, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.42 (m, J=2.2, 1.7 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
82%
With thionyl chloride; at 20℃; for 96h;
20 ml (27 mmol) of thionyl chloride are added dropwise, at room temperature, to a solution of 10 g (49 mmol) of 5-bromonicotinic acid in 250 ml of ethanol. The reaction medium is stirred at room temperature for 4 days and then evaporated under vacuum. The residue is taken up in dichloromethane and washed with aqueous sodium carbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 9 g (82%) of ethyl 5-bromonicotinate are obtained.
With sulfuric acid; for 18h;Heating / reflux;
Example 6 N-[(5-BROMOPYRIDIN-3-YL)METHYLL]-10-[(2'-METHOXY-1,1'-BIPHENYL-4-YL)CARBONYL]-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE Step A. 5-Bromonicotinic acid ethyl ester; A solution of 5-bromonicotinic acid (5.15 g, 25.5 mmol) in ethanol (100 mL) containing 1 mL of concentrated sulfuric acid was refluxed for 18 hours. The solvent was removed under reduced pressure and the residue basified with saturated aqueous sodium bicarbonate. The solution was then extracted three times with ether. The organics were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the tittle compound (5.29 g) as an off white solid. Anal. Calcd for C8H8BrNO2: C, 41.77; H, 3.5; N, 6.09. Found: C, 41.74; H, 3.2; N, 5.75.
With sulfuric acid;
As exemplified for the nicotine hapten shown at the upper left of the FIG. 18, (S)-nornicotine (6) was synthesized, as shown in FIG. 19, starting from 5-bromonicotinic acid (1) (Scheme 1), which upon esterification gave compound 2. Bromo ester 2 was condensed with N-vinyl pyrrolidinone, followed by in situ acid catalyzed hydrolysis, decarboxylation and base-promoted cyclization to afford compound 3. Imine 3 upon reduction with sodium borohydride provided racemic 5-bromonornicotine (4). This racemic mixture was resolved with alpha-methoxy-alpha-trifluoromethyl phenyl acetic acid (MTPA) as the corresponding MTPA salts ((R)-5-bromonornicotine MTPA salt (5a) and (S)-5-bromonornicotine MTPA salt (5b)). The (S)-bromonornicotine MTPA salt (5b) upon reductive debromination with hydrogen and palladium catalyst afforded (S)-nornicotine (6, Scheme 1).
Sodium hydride (3.44 g, 86 mmol, 60% dispersion in oil) in a three-neck flask was washed with three 20 mE portions of hexane. The flask was fitted with a reflux condenser, flushed with argon, and charged with THF (70 mE). A solution of 1 (10 g, 66.1 mmol) and 1-vinyl-2- pyrrolidinone (7.89 g, 71 mmol) in THF (15 mE) was added in one portion. The mixture was stirred and refluxed for 1 h and then cooled to room temperature. A solution of concentrated HC1 (12 mE) in water (18 mE) was added, and the THF was removed on a rotary evaporator. Additional concentrated HC1 (18 mE) and water (36 mE) were added, and the mixture was heated at reflux overnight. In an ice-cooled bath, the solution was made basic with concentrated aqueous NaOH, which resulted in precipitation of the crude product, and then it was extracted with CH2C12 (2x75 mE). The combined CH2C12 layer was washed with water, brine, dried over anhydrous Mg504 and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel colunm (15x5 cm) eluting with 19:1 CH2C12- acetone afforded 2 as a pale yellow solid: yield 6.87 g (70%); ?H NMR (400 MHz, CDC13) oe 2.00-2.08 (m, 2H), 2.86-2.92 (m, 2H), 4.02-4.08 (m, 2H), 8.31 (t, 1H, J=1.6 Hz), 8.67 (d, 1H, J=2.0 Hz) and 8.83 (d, 1H, J=1.6 Hz); ?3C NMR (100 MHz, CDC13) oe 22.6, 34.9, 61.8, 121.0, 131.7, 137.2, 147.1, 152.2 and 169.9.
53%
To a stirred solution containing ethyl 5-bromonicotinate (3.49 g, 15.2 mmol) , N-vinylpyrrolidinone (2.03 g, 18.2 mmol, 1.2 equiv) and dry THF (5.1 mL) under N2, NaH (0.511 g, 21.3 mmol, 1.4 equiv) in 14.2 mL dry THF was added. The reaction was left to stir for 10 - 15 min until the exothermic reaction was complete and then brought to reflux conditions. After 1 h, the reaction mixture was allowed to cool to room temperature and 4.47 mL of 4.7 M HCl (2 equiv) was added with stirring. The solvent was removed en vacuo and 10.7 mL of 4.7 M HCl (3.33 equiv) was added to the residue. The solution was brought to reflux conditions and left to stir for 18 h. After cooling the reaction mixture to room temperature, 50% NaOH was added portion-wise, with vigorous stirring, to make the solution basic and a thick precipitate formed. The basic solution was extracted twice with dichloromethane. The organic fractions were combined and solvent removed in vacuo. Crude material (1.8O g, 8.0 mmol, 53% crude yield) was used for further reactions. A fraction of the material was purified for characterization (flash chromatography on Si gel, 2% MeOH/CH2C12, Rf = 0.21) . 1H NMR (300 MHz,CDC13) 6 ppm, 8.82 (d, IH), 8.65 Cd, 1H), 8.29 (t, IH), 4.04 (tt, 2H), 2.88 (m, IH), 2.03 {m, 2H). LCMS (ESI+) , m/z [M+H] + = 225.14.
As exemplified for the nicotine hapten shown at the upper left of the FIG. 18, (S)-nornicotine (6) was synthesized, as shown in FIG. 19, starting from 5-bromonicotinic acid (1) (Scheme 1), which upon esterification gave compound 2. Bromo ester 2 was condensed with N-vinyl pyrrolidinone, followed by in situ acid catalyzed hydrolysis, decarboxylation and base-promoted cyclization to afford compound 3. Imine 3 upon reduction with sodium borohydride provided racemic 5-bromonornicotine (4). This racemic mixture was resolved with alpha-methoxy-alpha-trifluoromethyl phenyl acetic acid (MTPA) as the corresponding MTPA salts ((R)-5-bromonornicotine MTPA salt (5a) and (S)-5-bromonornicotine MTPA salt (5b)). The (S)-bromonornicotine MTPA salt (5b) upon reductive debromination with hydrogen and palladium catalyst afforded (S)-nornicotine (6, Scheme 1).
(5-bromopyridin-3-yl)methanol. To a cold (0 C.) solution of ethyl-5-bromonicotinate (1.0g, 4.3 mmoL) in MeOH (15mL) was added sodium borohydride (650 mg, 17 mmol) portion wise. After 30 min. the reaction was quenched by the addition of water (10 mL). The reaction was then extracted with methylene chloride (3x). The extracts were combined, dried (MgSO4) the filtrate was concentrated and purified by column chromatography on silica gel (0 to 80% ethyl acetate/hexanes)to produce 475 mg (60%) as a clear oil. 1H-NMR (CDCl3, 400 MHz) delta8.57 (s, 1H), 8.49 (s, 1H), 7.91 (s, 1H), 4.73 (s, 2H), 2.51 (s,br,1H). Mass spec.:188.12 (MH)+.
60%
With sodium tetrahydroborate; In methanol; at 0℃; for 0.5h;
To a cold (00C) solution of ethyl-5- bromonicotinate ( 1.Og, 4.3 mmoL) in MeOH ( 15mL) was added sodium borohydride (650 mg, 17 mmol) portion wise. After 30 min. the reaction was quenched by the addition of water (10 mL). The reaction was then extracted with methylene chloride (3x). The extracts were combined, dried (MgSO4) the filtrate was concentrated and purified by column chromatography on silica gel (0 to 80% ethyl acetate / hexanes)to produce 475 mg (60%) as a clear oil. 1H-NMR (CDCl3, 400 MHz) delta 8.57 (s, IH), 8.49 (s, IH), 7.91 (s, IH), 4.73 (s, 2H), 2.51 (s,br,lH). Mass spec: 188.12 (MH)+.
58%
b) (5-Bromo-pyridin-3-yl)-methanol A clear solution of ethyl-5-bromonicotinate (2.80 g, 12.2 mmol) in THF (35 mL) was cooled to -78 C. and lithium aluminum hydride (LAH, 0.470 g, 12.2 mmol) was added in small portions over the next 10 min. After stirring for 1 h at -78 C., the cold bath was removed. The reaction mixture was stirred at room temperature for 2 h, quenched by the slow addition of water (5 mL), filtered through a layer of celite and washed with ethyl acetate (100 mL). The organic layer was then dried over MgSO4, filtered through sintered glass and concentrated to yield 1.5 g (66%) of a yellow oil residue. The residue was purified by column chromatography (elution with EtOAC:hexanes, 1:1) and yielded 1.32 g (58%) of the title compound as a yellow oil. 1H NMR (CDCl3): 8.48 (d, J=1.9 Hz, 1H), 8.39 (s, 1H), 7.88 (t, J=1.9 Hz, 1H), 4.69 (s, 2H).
54%
With methanol; sodium tetrahydroborate; at 0℃; for 0.666667h;
To a cold solution of ethyl 5-bromonicotinate (1.003 g, 4.36 mmol) in methanol (15 ml, 371 mmol) was added sodium borohydride (0.652 g, 17.23 mmol) portion wise on 10 min. The reaction was stirred for 30 min. at 0 C. The reaction was quenched with water and extracted three times with CH2Cl2. The combined organic layers were dried on anh. Na2SO4 and concentrated. The residue was purified on ISCO using a 80g SILICYCLE column (Hex/EtOAc) and afforded the title material (0.477 g, 54%) as a clear oil. LC (Method B): 0.756 min. MS(ESI) calcd. for C6H7BrNO [M+H]+ m/z: 187.97; found: 190.0, 191.0. 1H NMR (400 MHz, acetone) delta ppm 8.50 - 8.58 (m, 2H) 7.93 - 7.98 (m, 1H) 4.67 - 4.74 (m, 2H) 4.48 - 4.56 (m, 1H)
50%
A solution of 9 g (40 mmol) of ethyl 5-bromo- nicotinate in 25 ml of methanol is added dropwise, at room temperature, to a suspension of 14.8 g (400 mmol) of sodium borohydride in 75 ml of methanol. After addition, the reaction medium is refluxed for 2 hours. The reaction medium is evaporated to dryness, taken up in aqueous sodium hydroxide solution to pH 9, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. 3.7 g (50%) of (5-bromopyrid-3-yl)- methanol are obtained.
With sodium tetrahydroborate; In ethanol;
Step ii (scheme A3): To a stirred solution of 3-bromo-5-pyridine-carboxylic acid ethyl ester (9.5 g, 41.3 mmol) in EtOH (96%, 220 ml), NaBH4 (14.4 g, 380 mmol) was added slowly at 25 C. The reaction was mildly endothermic. The mixture was stirred under an nitrogen atmosphere at room temperature for 6 hrs. The resulting milky mixture was diluted with H2 O (150 ml), the EtOH was evaporated in vacuo and the residue was extracted with CH2 Cl2 (3*). The combined organic layers were dried on Na2 SO4. After filtration the filtrate was concentrated in vacuo to give 9 g of a crude oil which was purified by flash chromatography on silica gel (eluent: Et2 O) to give 3-bromo-5-hydroxymethyl-pyridine (3.5 g, 45%).
Step B. (5-Bromo-pyridin-3-yl)-methanol; Crushed pellets of sodium borohydride were added over 30 minutes to a solution of 5-bromonicotinic acid ethyl ester of Step A (5.0 g, 21.7 mmol) in ethanol (150 mL). The reaction was stirred at room temperature for five days and then quenched with water. The ethanol was removed under reduced pressure and the aqueous residue was extracted three times with methylene chloride. The combined organics were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a yellow oil. The material was purified by flash chromatography over silica gel Marck-60 using 2:1 hexane/ethyl acetate as an eluant to give the title compound (1.41 g) as a light yellow liquid which was used in the next step without further purification.
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In ethyl acetate; at 50℃; for 20h;
Step 4 - Representative procedure for the Sonagashira reaction of ethyl 5-bromonicotinate with acetylenes5-Phenylethynyl-nicotinic acid ethyl esterTo a solution of ethyl 5-bromonicotinate (1.15 g, 5 mmol) in ethyl acetate (20 mL) under an N2 atmosphere, was added triethylamine (1.1 mL, 7.5 mmol, 1.5 eq.), phenyl acetylene (0.766 g, 7.5 mmol, 1.5 eq.), dichloro-fe(triphenylphosphine)-palladium(II) (176 mg, 0.25 mmol, 0.05 eq.), and copper iodide (10 mg, 0.05 mmol, 0.01 eq). The reaction mixture was heated at 50 0C for 20 h before being cooled to room temperature, filtered through a pad of celite, and solvent evaporated to provide a dark brown oil. Silica gel column chromatography (9/1 - 4/1 hexanes/EtOAc elution) provided the title compound as a pale yellow oil (1.26 g, yield 100%). 1H NMR (300 MHz, CDCl3) delta 9.11 (d, J= 1.8 Hz, IH), 8.87 (d, J= 2.1 Hz, IH), 8.39 (dd, J=1.8, 2.1 Hz, IH), 7.56- 7.53 (m, 2H), 7.40-7.30 (m, 3H), 4.42 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2Hz, 3H); ESI-MS m/z 251.9 (M+H)+.
3-bromo-5-(ethoxycarbonyl)pyridine-1-oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With dihydrogen peroxide; acetic acid; at 80℃; for 18h;
Step-l :3-Bromo-5-(ethoxycarbonyl)pyridine-l-oxide: To a stirred solution of ethyl 5- bromonicotinate (2.0 g, 8.69 mmol) in acetic acid (50 mL) was added urea hydrogen peroxide (4.09 g, 43.5 mmol) at 0 C.After that the reaction mixture was heated to 80C and further maintained for 18 h. The reaction was cooled to 0C and basified with solid sodium carbonate (till whole acetic acid layer was covered) and diluted with DCM (50 mL). The resulting suspension was then filtered and the filtrate was evaporated. The crude product was triturated with hexane (10 mL) to afford 2.0 g (93%) of the desired product as a white solid. GC- MS (m/z) 245, 247[M+, Br 79'81].
To a solution of 5-bromo-nicotinic acid ethyl ester (1 eq) in THF was added diethyl (3-pyridyl) borane (2 eq), tetrakis (triphenylphosphine) palladium (10%), potassium carbonate (3 eq) and H20. The solution was left stirring in a 80C oil bath for 60 hours. Upon cooling, the reaction was filtered and concentrated. The crude solid was treated with 3 N HCl and ethyl acetate. Once the aqueous layer was seperated, it was added to ethyl acetate and the whole was treated with sodium bicarbonate under vigorous stirring to obtain an approximate basic pH 7. The organic phase was seperated and washed with NACI (sat. ), dried over sodium sulfate, filtered, and concentrated to give [3, 3'] bipyridinyl-5-COOH ethyl ester (82%). MH+ (229)
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 80℃; for 16h;
[0852] A mixture of 3-bromo-5-carboxyethylpyridine (0.108 g, 0.469 mmol), hexamethylditin (0.088 mL, 0.422 mmol) and tetrakis(triphenylphosphine)palladium (0.010 g, 0.008 mmol) in dry THF (2 mL) was degassed with a stream of Ar bubbles for 10 min. The reaction vessel was then sealed and the mixture was heated at 80 C. (oil bath temperature) for 16 h. The cooled mixture was then evaporated to dryness and the residue chromatographed (SiO2/hexane-EtOAc, 1:1) to give the title compound (0.113 g, 77%) as a clear yellow oil: [0853] LCMS: m/e 316 (M+H)+.
Add a solution of ethyl 5-bromopyridine-3-carboxylate (22.5 g, 98 mmol) in tetrahydrofuran (350 m L) to a solution of 3M methylmagnesium bromide in diethyl ether (98 mL, 293 mmol, 3 eq.) with internal temperature below 30'C. Upon completion of reaction, cool the mixture in an ice bath and quench with saturated aqueous ammonium chloride and keep stirring until most solids dissolve. Add water (500 mL) and extract with ethyl acetate (3×500 mL). Dry the organic layer over sodium sulfate, filter and concentrate the organic layer to a residue. Purify the residue by silica gel column chromatography eluting with solvent of ethyl acetate:hexane (1:1), to afford the titled product as an oil (19.4 g, 92%). MS (ESI) m/z (M+H)+214.9, 216.9.
To a solution of 5-bromo-nicotinic acid ethyl ester [(L.] Oeq. ) in Et20 (0.3M) at-30C was added MeMgBr (2.7eq. ; 3M in Et20). The mixture was refluxed for 2h, poured in [0.] 5M aqueous [NAH2P04] and extracted with Et20 (2x). The combined organic extracts were washed with brine, dried over [NA2SO4,] filtered and concentrated. Flash chromatography (Hex: Et20: [CH2CL2] ; 2: 1: 2) afforded the title compound as a yellow oil.
In diethyl ether; at -30℃; for 2h;Heating / reflux;
To a solution of ethyl 5-bromonicotinate (1.02 g, 4.4 mmol) in diethyl ether (15 ml) at -30 C. was added a 3M solution of methyl magnesium bromide (4 ml, 12 mmol) in ether. The resulting slurry was then refluxed for 2 hours then cooled and quenched with an excess of 0.5M aqueous monobasic sodium phosphate and partitioned between ether and water. The product from the organic phase was chromatographed on silica gel eluting with a 2:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-Bromo-5-(1-hydroxy-1-methylethyl)pyridine compound as a yellow oil.
To a solution of ethyl 5-bromonicotinate (3.9 g, 16.9 mmol) in ether (50 ml) at 0 C. was added a 3M solution of methylmagnesium bromide (16.9 ml, 50.8 mmol). The resulting thick slurry was warmed slowly to room temperature and after 1.5 hours it was poured slowly into an excess of 1M aqueous monobasic sodium phosphate. The mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel, eluting with a 1:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-acetyl-5-bromopyridine compound. This preparation also afforded 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine described in Example 25.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In ethyl acetate; at 50℃; for 16h;
A solution of ethyl-5-bromonicotinate (30 g, 130. 40 mmol), triethylamine (78 mL) and ethyl acetate (130 mL) is degassed for 15 min. Add trimethylsilylacetylene (88. 46 mL, 625. 92 mmol), bis (triphenylphosphine) palladium (II) dichloride (4. 57 g, 6. 52 mmol) and copper (I) iodide (0. 25 g, 1. 30 mmol) and stir at 50 C under nitrogen for 16 h. Cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 10 : 1 hexanes : ethyl acetate, to give the title compound (27. 7 g, 86%). 1HNMR (300MHz, CDCl3) 80. 20 (s, 9H), 1. 34 (t, J = 7. 1 Hz, 3 H), 4. 34 (q, J = 7. 1 (ES) : m/z = 248 [M+H] +.
With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 90℃; for 0.25h;
Step 1: Synthesis of 5-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester Into a 20 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.995 g, 2.18 mmol), 5-Bromo-nicotinic acid ethyl ester (0.645 g, 2.33 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (95.5 mg, 0.117 mmol), acetonitrile (10 mL) and saturated aqueous NaHCO3 (10 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90 C. for 15 min. The layers were separated, and the aqueous phase was extracted 3* with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 5-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester as a white powder (0.794 g, 69%). MS: m/z 528.1 [MH+].
With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 90℃; for 0.25h;Microwave irradiation;
Into a 20 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)- 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.995 g, 2.18 mmol), 5 -Bromo -nicotinic acid ethyl ester (0.645 g, 2.33 mmol), 1,1'- bis(diphenylphosphino)ferrocenepalladium(ii)-dichloride dichloromethane adduct (95.5 mg, 0.117 mmol), acetonitrile (10 mL) and saturated aqueous NaHCO3 (10 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90 C for 15 rnin. The layers were separated, and the aqueous phase was extracted 3X with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 5-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-nicotinic acid ethyl ester as a white powder (0.794 g, 69%). MS: m/z 528.1 [MH+].
Step 1 3-Acetyl-5-Bromopyridine To a solution of ethyl 5-bromonicotinate (3.9 g, 16.9 mmol) in ether (50 ml) at 0 C. was added a 3M solution of methylmagnesium bromide (16.9 ml, 50.8 mmol). The resulting thick slurry was warmed slowly to room temperature and after 1.5 hours it was poured slowly into an excess of 1M aqueous monobasic sodium phosphate. The mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel, eluding with a 1:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-acetyl-5-bromopyridine compound. This preparation also afforded 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine described in Example 25.
With caesium fluoride;copper(I) chloride; In 2,4-dichlorophenoxyacetic acid dimethylamine; ethyl acetate;
EXAMPLE 202 (R)-N-{2-Chloro-4-([5-ethoxycarbonyl-3-pyridyl]sulphanyl)phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide Caesium fluoride (0.26 g) was added to a solution of (R)-N-(2-chloro-4-(triisopropylsilylsulphanyl)phenyl]-2-hydroxy-2-methyl-3,3,3 trifluoropropanamide (0.74 g) (Method 28) in anhydrous DMA (5 ml) under argon and the mixture was stirred for 17 hours. Copper(I) chloride (0.17 g) followed by 3-bromo-5-carboethoxypyridine (0.37 g) were added and the mixture was heated to 155 C. for 4 hours and allowed to cool to ambient temperature. Ethyl acetate (20 ml) and brine (20 ml) were added and the mixture was filtered through a pad of diatomaceous earth which was washed with ethyl acetate (3*50 ml). The filtrates were combined, washed with brine (3*50 ml) and then dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column eluding with 10-40% ethyl acetate/iso-hexane to give the title compound (in 53% yield) as a foam. NMR (CDCl3): 1.39 (t, 3H), 1,57 (s, 3H), 4.00 (s, 1H), 4.40 (q, 2H), 7.34-7.37 (m, 1H), 7.46 (d, 1H), 8.18 (s, 1H), 8.42 (d, 1H), 8.62 (s, 1H), 9.03 (s, 1H), 9.04 (s, 1H); MS (ESP-): 447.
With potassium carbonate;1,4-diaza-bicyclo[2.2.2]octane; palladium diacetate; In acetone; at 110℃; for 2h;Microwave reactor;
A solution of 4-nitrophenylboronic acid (0.5g, 3 mmol), ethyl 5-bromonicotinate (0.49 g, 2.1 mmol), K2CO3 (1.25 g, 9 mmol), Pd(OAc)2 (67 mg, 0.3 mmol) and diazabicyclooctane (67 mg, 0.6 mmol) in acetone (5 ml) was purged with Ar in a microwave reaction vessel. The mixture was heated at 110C for 2 h via a microwave reactor, cooled to room temperature and diluted with EtOAc and water. Insoluble material was removed by filtration and washed well with additional EtOAc. The EtOAc was separated and washed with brine. Drying and removal of solvent gave a residue that was purified by chromatography, 100% DCM with gradient elution to 5% MeOH in DCM. A solid was obtained and was recrystallized from ethanol to give 320 mg of product as a solid. M/z = 273; NMR: 1.37 (t, J=7.06 Hz, 3H), 4.34 - 4.45 (q, EPO <DP n="64"/>2H), 8.13 (d, J-8.85 Hz, 2H), 8.36 (d, J=8.67 Hz, 2H), 8.60 (t, J=2.07 Hz, IH), 9.17 (d, J=I.70 Hz, IH), 9.26 (d, J=2.26 Hz, IH).
With hydrogenchloride; acetic acid; lithium hexamethyldisilazane; In tetrahydrofuran; methanol; dichloromethane; tert-butyl methyl ether; water;
EXAMPLE 2 5-Bromo-3-(2-pyrrol in-1-yl) pyridine A mixture of lithium bis(trimethylsilyl)amide (300 mL of a 1 M solution in THF, 300 mmol) and t-butyl methyl ether (250 mL) under inert atmosphere was cooled to -50 C. (internal temperature) and N-vinylpyrrolidinone (32 mL, 300 mmol) was added. Stirring was continued for 30 minutes at -50 C. and <strong>[20986-40-7]ethyl 5-bromo-3-pyridinecarboxylate</strong> (44.5 g, 193 mmol) in t-butyl methyl ether (100 mL) was added. The reaction mixture was allowed to warm to 25 C. and stirred for 18 h before quenching the reaction with a mixture acetic acid (20 mL) and methanol (20 mL). The solvents were removed in vacuo, water (100 mL) and concentrated HCl (100 mL) were added and the mixture heated under reflux for 18 h. The reaction flask was cooled to 0 C. and basified with sodium hydroxide solution (60 g in 250 mL water) and extracted with dichloromethane (3*200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum amount of dichloromethane and filtered through a pad of silica gel with ethyl acetate as the eluant. The filtrate was concentrated in vacuo and the solid which crystallized out during this process was collected, washed with ethyl acetate and dried to afford 5-bromo-3-(2-pyrrolin-1-yl)pyridine (26 g, 60%) as a solid. M.p. 98-99 C. (EtOAc); 1 H NMR (CDCl3, 300 MHz) delta 8.88 (s, 1 H), 8.71 (s, 1 H), 8.35 (d, J=2 Hz, 1 H), 4.10 (td, J=8, 2 Hz, 2 H), 2.94 (td, J=8, 2 Hz, 1 H), 2.09 (quintet, J=8 Hz, 2 H).
60%
With hydrogenchloride; acetic acid; lithium hexamethyldisilazane; In tetrahydrofuran; methanol; dichloromethane; tert-butyl methyl ether; water;
EXAMPLE 2 5-Bromo-3-(2-pyrrolin-1-yl)pyridine A mixture of lithium bis(trimethylsilyl)amide (300 mL of a 1M solution in THF, 300 mmol) and t-butyl methyl ether (250 mL) under inert atmosphere was cooled to -50 C. (internal temperature) and N-vinylpyrrolidinone (32 mL, 300 mmol) was added. Stirring was continued for 30 minutes at -50 C. and <strong>[20986-40-7]ethyl 5-bromo-3-pyridinecarboxylate</strong> (44.5 g, 193 mmol) in t-butyl methyl ether (100 mL) was added. The reaction mixture was allowed to warm to 25 C. and stirred for 18 h before quenching the reaction with a mixture acetic acid (20 mL) and methanol (20 mL). The solvents were removed in vacuo, water (100 mL) and concentrated HCl (100 mL) were added and the mixture heated under reflux for 18 h. The reaction flask was cooled to 0 C. and basified with sodium hydroxide solution (60 g in 250 mL water) and extracted with dichloromethane (3*200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum amount of dichloromethane and filtered through a pad of silica gel with ethyl acetate as the eluant. The filtrate was concentrated in vacuo and the solid which crystallized out during this process was collected, washed with ethyl acetate and dried to afford 5-bromo-3-(2-pyrrolin-1-yl)pyridine (26 g, 60%) as a solid. M.p. 98-99 C. (EtOAc); 1 H NMR (CDCl3, 300 MHz) delta 8.88 (s, 1 H), 8.71 (s, 1 H), 8.35 (d, J=2 Hz, 1 H), 4.10 (td, J=8, 2 Hz, 2 H), 2.94 (td, J=8, 2 Hz, 1 H), 2.09 (quintet, J=8 Hz, 2 H).
60%
With hydrogenchloride; acetic acid; lithium hexamethyldisilazane; In tetrahydrofuran; methanol; dichloromethane; tert-butyl methyl ether; water;
EXAMPLE 2 5-Bromo-3-(2-pyrrolin-1-yl)pyridine A mixture of lithium bis(trimethylsilyl)amide (300 mL of a 1M solution in THF, 300 mmol) and t-butyl methyl ether (250 mL) under inert atmosphere was cooled to -50 C. (internal temperature) and N-vinylpyrrolidinone (32 mL, 300 mmol) was added. Stirring was continued for 30 minutes at -50 C. and <strong>[20986-40-7]ethyl 5-bromo-3-pyridinecarboxylate</strong> (44.5 g, 193 mmol) in t-butyl methyl ether (100 mL) was added. The reaction mixture was allowed to warm to 25 C. and stirred for 18 h before quenching the reaction with a mixture acetic acid (20 mL) and methanol (20 mL). The solvents were removed in vacuo, water (100 mL) and concentrated HCl (100 mL) were added and the mixture heated under reflux for 18 h. The reaction flask was cooled to 0 C. and basified with sodium hydroxide solution (60 g in 250 mL water) and extracted with dichloromethane (3*200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum amount of dichloromethane and filtered through a pad of silica gel with ethyl acetate as the eluant. The filtrate was concentrated in vacuo and the solid which crystallized out during this process was collected, washed with ethyl acetate and dried to afford 5-bromo-3-(2-pyrrolin-1-yl)pyridine (26 g, 60%) as a solid. M.p. 98-99 C. (EtOAc); 1 H NMR (CDCl3, 300 MHz) delta8.88 (s, 1H), 8.71 (s, 1H), 8.35 (d, J=2 Hz, 1H), 4.10 (td, J=8, 2 Hz, 2H), 2.94 (td, J=8, 2 Hz, 1H), 2.09 (quintet, J=8 Hz, 2H).
60%
With hydrogenchloride; acetic acid; lithium hexamethyldisilazane; In tetrahydrofuran; methanol; dichloromethane; tert-butyl methyl ether; water;
EXAMPLE 2 5-Bromo-3-(2-pyrrolin-1-yl)pyridine A mixture of lithium bis(trimethylsilyl)amide (300 mL of a 1M solution in THF, 300 mmol) and t-butyl methyl ether (250 mL) under inert atmosphere was cooled to -50 C. (internal temperature) and N-vinylpyrrolidinone (32 mL, 300 mmol) was added. Stirring was continued for 30 minutes at -50 C. and <strong>[20986-40-7]ethyl 5-bromo-3-pyridinecarboxylate</strong> (44.5 g, 193 mmol) in t-butyl methyl ether (100 mL) was added. The reaction mixture was allowed to warm to 25 C. and stirred for 18 h before quenching the reaction with a mixture acetic acid (20 mL) and methanol (20 mL). The solvents were removed in vacuo, water (100 mL) and concentrated HCl (100 mL) were added and the mixture heated under reflux for 18 h. The reaction flask was cooled to 0 C. and basified with sodium hydroxide solution (60 g in 250 mL water) and extracted with dichloromethane (3*200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum amount of dichloromethane and filtered through a pad of silica gel with ethyl acetate as the eluant. The filtrate was concentrated in vacuo and the solid which crystallized out during this process was collected, washed with ethyl acetate and dried to afford 5-bromo-3-(2-pyrrolin-1-yl)pyridine (26 g, 60%) as a solid. M.p. 98-99 C. (EtOAc); 1 H NMR (CDCl3, 300 MHz) delta 8.88 (s, 1H), 8.71 (s, 1H), 8.35 (d, J=2 Hz, 1H), 4.10 (td, J=8, 2 Hz, 2H), 2.94 (td, J=8, 2 Hz, 1H), 2.09 (quintet, J=8 Hz, 2H).
ethyl 5-(2-methoxyphenyl)pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 50℃; for 12h;
Stage A: ethyl 5-(2-methoxyphenyl)pyridine-3-carboxylateA solution of ethyl 5-bromonicotinate (2.29 g, 10 mmol), prepared as reported in the Journal of Medicinal Chemistry 1995, 38, 1608-28, 2-methoxy phenyl boronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5%mol), K2CO3 (5g) in DMF/water (3/1) is stirred at 500C for 12 hours.The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3x10OmL). the combined organic layers are washed with water (3x200mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 72h;
Example 55A|00413] /erf-Butyl 5-(5-ethoxycarbonylpyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate <n="66"/>|00414] A suspension of tert-buty hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (2.00 g, 9.42 mmol; see Schrimpf, Michael R.; Tietje, Karin R.; Toupence, Richard B.; Ji, Jianguo; Basha, Anwer; Bunnelle, William eta.; Daanen, Jerome F.; Pace, Jennifer M.; Sippy, Kevin B. WO 2001081347), ethyl 5-bromonicotinate (2.80 g, 12.0 mmol; Aldrich), ttauis(dibenzylideneacetone)dipalladium(0) (259 mg, 0.283 mmol; Strem), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (491 mg, 0.848 mmol; Aldrich) and cesium carbonate (4.91 g, 15.1 mmol; Aldrich) in anhydrous dioxane (50 mL) was heated at 90 0C for 72 hours. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated and the residue was purified by silica gel chromatography (50% ethyl acetate in hexane, Rf = 0.15) to afford the title compound. MS (APCI) m/z= 362 (M+eta)+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 4h;
A mixture 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-{4-[2- (trifluoromethyl)phenoxy]piperidin-l-yl}pyridine, ethyl 5-bromonicotmate (2.5 equiv.), Pd(Ph3P)4 (0.1 equiv.), 2M Na2CO3 (3.0 equiv.) in DMF (0.08 M) was heated at 100 0C. After a period of 4 h, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, dried over Na2SO4 and evaporated. The title compound was purified by flash chromatography eluting with 40% ethyl acetate to 50% ethyl acetate in hexane; The title compound was prepared as described in example 1, step 4. MS: m/z 472.2 (ESI+)
ethyl 5-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]nicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
Example 3 ethyl 5-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]nicotinic acid (140) A solution of compound (41) (0.25 g, 0.91 mmol) in tetrahydrofuran (5 ml) was cooled to -78§C under an argon atmosphere and 1.6 M n-butyllithium-hexane solution (0.57 ml, 0.91 mmol) was added. After stirring at -78§C for 30 min., a solution of zinc chloride (0.12 g, 0.91 mmol) in tetrahydrofuran (2 ml) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 30 min. and ethyl 5-bromonicotinate (0.21 g, 0.91 mmol) and tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol) were added. The mixture was heated to 75§C and stirred for 2 hrs. After cooling, the reaction mixture was poured into ice water and partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate and the extracts were combined and dried (MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and crystallized from ethyl acetate-n-hexane to give white crystals (0.16 g, 51%). melting point: 132-135§C 1H-NMR (200Hz, CDCI3) delta: 1.50 (3H, t, J = 7.1 Hz), 4.49 (2H, q, J = 7.1 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.59 (1H, s), 7.96 (2H, d, J = 8.6 Hz), 8.86 (1H, s), 9.27 (1H, s), 9.41 (1H, s).
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In N,N-dimethyl-formamide; at 80 - 85℃;Inert atmosphere;
Add tris(dibenzylideneacetone)dipalladium(0) (3.98 g, 4.35 mmol), tricyclohexylphosphine (2.44 g, 8.7 mmol) and potassium acetate (42.65 g, 435 mmol) to a solution of bis(pinacolato) diboron (35.88 g, 141.3 mmol) in dimethylformamide (175 mL). Bubbling N2 into the mixture for 15 minutes, then heat it to 80~85 C. Then add ethyl 5-bromonicotinate (25.0 g, 108.8 mmol) in dimethylformamide (75 mL) slowly to the mixture at 80~85 C., and stir the formed mixture at 80~85 C. for 4-5 hours. Cool the reaction mixture to 15-35 C., and then add methyl tertiary butyl ether (250 mL) and water (250 mL). Filter the mixture with diatomite and separate the organic and aqueous layers. Back extract the aqueous layer with methyl tertiary butyl ether (250 mL). Wash the combined organic layer with brine (150 mL) and water (150 mL). Concentrate the organic under vacuum, re-crystallize the crude product with methyl tertiary butyl ether/heptane (1:6), and then dry it below 55 C. to give the title compound as a grey solid (18.67 g, 62%). 1H NMR (acetone-d6, 400 MHz) delta40-1.43 (m, 15H), 4.44 (q, J=7.1 Hz, 2H), 8.57 (t, J=1.9 Hz, 1H), 9.02 (d, J=1.5 Hz, 1H), 9.225 (d, J=2.3 Hz, 1H)
1.5 g
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine tetrafluoroborate; In 1,4-dioxane; at 80 - 100℃; for 16h;Inert atmosphere;
To a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2- yl))-1,3,2-dioxaborolane (1.54 g, 6.09 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.1 12 g, 0.304) in 1,4-dioxane (20 mL) at ambient temperature was added KOAc (1.71 g, 17.4 mmol) and the reaction mixture was purged with nitrogen gas for 10 min. The reaction mixture was heated to 80 C. Pd2(dba)3 (0.199 g, 0.217 mmol) was added to the reaction mixture and the resulting reaction mixture purged with nitrogen for 10 min at 80 C. The reaction mixture was heated to 90 C and a solution of ethyl 5- bromonicotinate (1.00 g, 4.35 mmol) in 1,4-dioxane (5 mL) was added. The resulting mixture was stirred at 100 C for 16 h. The reaction mixture was allowed to cool to ambient temperature, filtered through CELITE and the filtrate was concentrated under reduced pressure to obtain ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (1.50 g). The residue was taken to the next step without further purification. LCMS (Condition 11): retention time 0.52 min, [M+1] = 196.1. 1H NMR (400 MHz, DMSO-d6) delta 1.16 (s, 12 H), 1.35 (t, J= 7.2 Hz, 3 H), 4.36 (q, J= 7.2 Hz, 2 H), 8.43 (dd, J= 1.6 Hz, J = 2.0 Hz, 1 H), 8.95 (d, J= 1.6 Hz, 1 H), 9.16 (br s, 1 H).
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine tetrafluoroborate; In 1,4-dioxane; at 80 - 100℃; for 16h;Inert atmosphere;
To the solution of 4,4,5, 5-tetramethyl-2-(4,4,5, 5-tetramethyl(l, 3,2-dioxaborolan- 2-yl))-l,3,2-dioxaborolane (1.54 g, 6.09 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.1 12 g, 0.304) in 1,4-dioxane (20 mL) at ambient temperature was added potassium acetate (1.71 g, 17.4 mmol) and the reaction mixture was purged with nitrogen gas for 10 min. The reaction mixture was heated to 80 C. Pd2(dba)3 (0.199 g, 0.217 mmol) was added to the reaction mixture and again nitrogen was passed through for the next 10 min at 80 C. The reaction mixture was heated to 90 C and a solution of ethyl 5-bromonicotinate (1.00 g, 4.35 mmol) in 1,4-dioxane (5 mL) was added. The resulting mixture was stirred at 100 C for 16 h. The reaction mixture was allowed to cool to ambient temperature, filtered through CELITE and the filtrate was concentrated under reduced pressure to obtain ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)nicotinate (1.5 g). The residue was taken to the next step without further purification. LCMS (Condition 5): retention time 0.52 min, [M+l] = 196.1. XH NMR (400 MHz, DMSO-d6) delta 1.16 (s, 12 H), 1.35 (t, J= 7.2 Hz, 3 H), 4.36 (q, J= 7.2 Hz, 2 H), 8.43 (dd, J = 1.6 Hz, J= 2.0 Hz, 1 H), 8.95 (d, J= 1.6 Hz, 1 H), 9.16 (br s, 1 H).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 72h;
Example 33; 5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-(trifluoromethyl)benzyl)nicotinamide; Example 33A; (3aR,6aS)-tert-butyl 5-(5-(ethoxycarbonyl)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; A suspension of the product from Example 1C (2.00 g, 9.42 mmol), ethyl 5-bromonicotinate (2.80 g, 12.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (259 mg, 0.283 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (491 mg, 0.848 mmol) and cesium carbonate (4.91 g, 15.1 mmol) in anhydrous dioxane (50 mL) were heated at 90 C. for 72 hours. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluted with 50% EtOAc in hexane) to afford the title compound (3.2 g, 94%). MS (APCI) m/z 362 (M+H)+.
With potassium fluoride;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene;Inert atmosphere; Reflux;
According to General Method 1A, 29 g (126 mmol) of ethyl 5-bromonicotinate and 23 g (152 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted. Yield: 32 g (82% of theory).LC-MS (Method 6B): Rt=3.80 min; MS (ESIpos): m/z=256 [M+H]+. A mixture of the appropriate bromopyridine in toluene (1.8 ml/mmol) is admixed under argon at RT with tetrakis(triphenylphosphine)palladium (0.02 eq.), with a solution of the appropriate arylboronic acid (1.2 eq.) in ethanol (0.5 ml/mmol) and with a solution of potassium fluoride (2.0 eq.) in water (0.2 ml/mmol). The reaction mixture is stirred under reflux for several hours until the conversion is substantially complete. After addition of ethyl acetate and phase separation, the organic phase is washed once with water and once with saturated aqueous sodium chloride solution, dried (magnesium sulphate), filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel 60, eluent: dichloromethane/methanol mixtures).
tert-Buty 6-bromopyridin-3-ylcarbamate (Intermediate 1; 1.67 g, 6.11 mmol), and trans-dichlorobis (triphenylphosphine) palladium (II) (214 mg, 0.30 mmol) were weighed into a flask. The flask was degassed and placed under argon, and 1,4-dioxane (30 ml) was added. Hexamethylditin (2.00 g, 6.10 mmol) was dissolved in 5 ml of 1,4-dioxane, and the solution was added to the mixture. The suspension was heated at 90 0C for ca. 3 h, then a solution of ethyl 5-bromonicotinate (1.41 g, 6.11 mmol) in 1,4-dioxane (5 ml) was added. The mixture was heated for an additional 16h, then diluted with water, and extracted with DCM. The phases were separated, and the organic phase was adsorbed onto silica gel and concentrated under vacuum. The material was purified by flash chromatography on silica gel using 50% EtOAc/hexanes to give 756 mg of the desired product. M/z 344; NMR: 1.37 (t, 3H), 1.50 (s, 9H), 4.37 (q, 2H), 8.04-8.13 (m, 2H), 8.76 (m, IH), 8.83 (m, IH), 9.07 (m, IH), 9.47 (m, IH), 9.82 (br s, IH).
Step 1: Ethyl-5-benzylnicotinate. A suspension of Zn (1.0 g, 15 mmol) and t (130 mg, 0.5 mmol) in DMA (15 mL) was stirred vigorously until the red color dissipated (3-5 min). Benzyl bromide (1.7 g, 10 mmol) was introduced and the resulting slurry was heated at 80 0C for 2.5 h at which point Cl2Pd(PPh3)2 (250 mg, 0.35 mmol) and a solution of ethyl-5-bromonicotinate (1.1 g, 5.0 mmol) in benzene (10 mL) were introduced and the reaction was heated at 80 0C for 1 h. The reaction was allowed to cool to room temperature and was diluted with EtOAc (100 mL). The mixture was poured into NaHCtheta3 (5% aqueous, 100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially washed with H2O (3 x 100 mL) and brine before being dried over Na2SO4. Concentration and purification by silica gel chromatography (hexane -> 50% EtOAc/hexane) provided the title compound as a brown oil. MS m/z: 242.1 (M+l).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; water; toluene; at 75℃; for 2h;Inert atmosphere;
General procedure: Pd(PPh3)4 (17.3 mg, 0.015 mmol) was added to a solution of 5-bromonicotinic acid ethylester(115.1 mg, 0.5 mmol) and aryl boronic acid (0.6 mmol) in MeOH (0.2 mL), toluene (0.8mL), and 2 M Na2CO3 (0.2mL) under N2. The mixture was heated to 75 C for 2 h, then cooledto room temperature and concentrated under reduced pressure. Water was added to theresidue and the aq. phase was extracted with DCM (3 × 5 mL). The combined organic layerswere washed with brine, dried over Na2SO4, and evaporated to obtain the crude product.Purification by column chromatography on silica gel afforded the desired product.
With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; caesium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; Sealed tube;
[00432] Intermediate 51 A. Ethyl 5-(3-chloro-2-fluorophenyl)nicotinate: To a solution of (3-chloro-2-fluorophenyl)boronic acid (148 mg, 0.848 mmol), ethyl 5-bromonicotinate (150 mg, 0.652 mmol), tetrabutylammonium bromide (315 mg, 0.978 mmol) and CS2CO3 (637 mg, 1.956 mmol) in dimethoxyethane (9 mL) and water (1 mL) was added Pd(Ph3P)4 (113 mg, 0.098 mmol) and the resulting heterogeneous solution was purged with N2. It was then sealed and heated at 120 C for 0.5 h in a microwave reactor. The reaction mixture was diluted with DCM and washed with brine (2x). The organic solution was dried over Na2S04, filtered and concentrated in vacuo, yielding oily residue which was purified by silica gel column chromatography to provide the desired product (100 mg, 55%). MS(ESI) m/z:280.1 (M+H)+.
[A] Lithium 4-bromo-6-(methoxycarbonyl)-5H-cyclopenta[c]pyridin-7-olate[0356]<strong>[20986-40-7]Ethyl 5-bromonicotinate</strong> (5 g, 21.7 mmol) in THF (22 mL) was added over a period of 20 min to a solution of LDA (23.9 mmol) [generated from N,N-diisopropylamine (3.41 mL, 23.9 mmol) and n-butyllithium (14.9 mL, 23.9 mmol, 1.6M in hexane) in THF (95 mL)] at -78 C. The resulting dark red solution was stirred for 30 min, then methyl acrylate (4.9 mL, 54.3 mmol) in THF (22 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH (43.5 mL, 76.1 mmol) was added (giving a pH of 4-5) and the reaction was allowed to warm to room temperature. Evaporation under reduced pressure afforded the title compound (in 50% purity, determined by 1H-NMR) as dark green amorphous solid. MS: 270.0 (M+H+, 1Br).
[A] Lithium 4-bromo-6-(methoxycarbonyl)-5H-cyclopenta[c]pyridin-7-olate<strong>[20986-40-7]Ethyl 5-bromonicotinate</strong> (5 g, 21.7 mmol) in THF (22 mL) was added over a period of 20 min to a solution of LDA (23.9 mmol) [generated from N,N-diisopropylamine (3.41 mL, 23.9 mmol) and n-butyllithium (14.9 mL, 23.9 mmol, 1.6M in hexane) in THF (95 mL)] at -78 C. The resulting dark red solution was stirred for 30 min, then methyl acrylate (4.9 mL, 54.3 mmol) in THF (22 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH (43.5 mL, 76.1 mmol) was added (giving a pH of 4- 5) and the reaction was allowed to warm to room temperature. Evaporation under reduced pressure afforded the title compound (in 50%> purity, determined by 'H-NMR) as dark green amorphous solid. MS: 270.0 (M+H+, IBr).
<strong>[20986-40-7]Ethyl 5-bromonicotinate</strong> (5 g, 21.7 mmol) in THF (22 mL) was added over a period of 20 min to a solution of LDA (23.9 mmol) [generated from N,N-diisopropylamine (3.41 mL, 23.9 mmol) and n-butyllithium (14.9 mL, 23.9 mmol, 1.6M in hexane) in THF (95 mL)] at -78 C. The resulting dark red solution was stirred for 30 min, then methyl acrylate (4.9 mL, 54.3 mmol) in THF (22 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH (43.5 mL, 76.1 mmol) was added (giving a pH of 4-5) and the reaction was allowed to warm to room temperature. Evaporation under reduced pressure afforded the title compound (in 50%) purity, determined by 'H-NMR) as dark green amorphous solid. MS: 270.0 (M+H+, IBr).
[A] Lithium 4-bromo-6-(methoxycarbonyl)-5H-cyclopenta[c]pyridin-7-olate <strong>[20986-40-7]Ethyl 5-bromonicotinate</strong> (5 g, 21.7 mmol) in THF (22 mL) was added over a period of 20 min to a solution of LDA (23.9 mmol) [generated from N,N-diisopropylamine (3.41 mL, 23.9 mmol) and n-butyllithium (14.9 mL, 23.9 mmol, 1.6M in hexane) in THF (95 mL)] at -78 C. The resulting dark red solution was stirred for 30 min, then methyl acrylate (4.9 mL, 54.3 mmol) in THF (22 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH (43.5 mL, 76.1 mmol) was added (giving a pH of 4-5) and the reaction was allowed to warm to room temperature. Evaporation under reduced pressure afforded the title compound (in 50% purity, determined by 1H-NMR) as dark green amorphous solid. MS: 270.0 (M+H+, 1 Br).
With bis(tri-t-butylphosphine)palladium(0); dicyclohexylmethylamine; lithium chloride; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;
General procedure: A flask containing LiCl (980 mg,23.1 mmol), 2-bromo-4-fluoroanisole (1.0 mL, 7.7 mmol), DCMA (1.8 mL,8.4 mmol) and <strong>[1001-26-9]ethyl 3-ethoxyacrylate</strong> (3.3 mL, 23 mmol) in 1,4-dioxane(20 mL) was degassed by passing a stream of nitrogen through the mixturefor 10 min. Bis(tri-t-butylphosphine) palladium(0) (166 mg, 0.32 mmol) wasadded, and reaction mixture was heated at reflux under nitrogen for 16 h. Thebrown mixture was then cooled and partitioned between ethyl acetate andwater. The layers were separated, and the organic layer was washedsequentially with aqueous NH4Cl and brine, followed by drying over Na2SO4.The mixture was filtered, and the filtrate was concentrated under reducedpressure to give an oil which was purified by flash chromatography on silica(40 g, 10?50percent ethyl acetate in heptane) to afford 22c as an orange oil (1.93 g,92percent) as an inseparable mixture of E- and Z-isomers: 1H NMR (CDCl3, 500 MHz)alkene protons d: 5.21, 5.33 ppm (1:1 ratio); LCMS (ES): 269.2 (MH). HRMSCalcd for C14H17FO: 269.1184. Found: 269.1196.
1-(4-(bromomethyl)benzyl)pyridin-2(1H)-one[ No CAS ]
ethyl 5-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.1%
A mixture of methyl ethyl 5-bromonicotinate (5.0 g, 21.73 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (5.5 g, 21.73 mmol, 1.0 eq), Pd(dppf)Cl2 (790 mg, 1.08 mmol, 5%) and KOAc (6.4 g, 65.21 mmol, 3.0 eq) in dioxane (180 mL) was degassed with N2 and stirred at 85 C for 3 h, cooled, l-(4- (bromomethyl)benzyl)pyridin-2(lH)-one (6.0 g, 21.73 mmol, 1.0 eq), Pd(dppf)Cl2 (790 mg, 1.08 mmol, 5%) and an aqueous solution of Na2C03 (6.9 g, 65.21 mmol, 3.0 eq) in 30 mL of water were added. The mixture was degassed and stirred at 95 C under N2 overnight. Cooled and filtered through celite, concentrated, the residue was dissolved in DCM (150 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via silica gel column chromatography (5% MeOH in DCM) then purified by flash chromatography to afford ethyl 5-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)nicotinate as a yellow solid (4.17 g, 55.1%).
1-(4-(bromomethyl)-2-fluorobenzyl)pyridin-2(1H)-one[ No CAS ]
ethyl 5-(3-fluoro-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
To a solution of ethyl 5-bromonicotinate (336 mg, 1.46 mmol, 1.0 eq) in 1,4-dioxane (10 mL) were added AcOK (420 mg, 4.38 mmol, 3.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (371 mg, 1.46 mmol, 1.0 eq) and Pd(dppf)Cl2 (54 mg, 0.07 mmol, 0.05 eq). The mixture was heated at 85 C overnight under N2, and then the mixture was cooled to rt, to the mixture were added l-(4-(bromomethyl)-2- fluorobenzyl)pyridin-2(lH)-one (432 mg, 1.46 mmol, 1.0 eq), Pd(dppf)Cl2 (54 mg, 0.07 mmol, 0.05 eq) and Na2C03 (464 mg, 4.38 mmol, 3.0 eq) in water (5 mL). The mixture was heated to 95 C for 2 h. The mixture was concentrated to dryness under reduced pressure. The residue was mixed with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04 and concentrated. The residue was purified via flash chromatography to afford ethyl 5-(3-fluoro-4- ((2-oxopyridin-l(2H)-yl)methyl)benzyl)nicotinate as a white solid (100 mg, 48%).
5-(chloromethyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzonitrile[ No CAS ]
ethyl 5-(3-cyano-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
The mixture of ethyl 5-bromonicotinate (374 mg, 1.6 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (406 mg, 1.6 mmol, 1.0 eq), Pd(dppf)Ck (58 mg, 0.05 eq) and KOAc (470 mg, 4.8 mmol, 3.0 eq) in dioxane (15 mL) was degassed with N2 and stirred at 85 C overnight. Then the mixture was cooled, 5-(chloromethyl)-2-((2-oxopyridin-l(2H)-yl)methyl)benzonitrile (420 mg, 1.6 mmol, 1.0 eq), Pd(dppf)Ci2 (58 mg, 0.05 eq) and an aqueous solution of Na2CC>3 (509 mg, 4.8 mmol, 3.0 eq) in 8 mL of water were added. The mixture was degassed with N2 and stirred at 95 C overnight. Then the mixture was cooled and concentrated, the residue was dissolved in EtOAc (150 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via silica gel column (DCM/EtOAc = 1/1) to afford ethyl 5-(3-cyano-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)nicotinate as a yellow solid (410 mg, 69%).
ethyl 5-((4-((2-oxopyridin-1(2H)-yl)methyl)phenyl)amino)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 120℃;Inert atmosphere;
To a solution of l-(4-aminobenzyl)pyridin-2(lH)-one (500 mg, 2.5 mmol, 1.0 eq) in toluene (15 mL) were added ethyl 5-bromonicotinate (633 mg, 2.7 mmol, 1.1 eq), K3PO4 (1.06 g, 5 mmol, 2.0 eq), Pd2(DBA)3 (36 mg, 0.0375 mmol, 0.015 eq) and X-phos (58 mg, 0.1 mmol, 0.04 eq) at rt. The mixture was heated at 120 C overnight under N2. After cooled to 25 C, the mixture was mixed with water (10 mL) and extracted with EA (10 mL X 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04 and concentrated. The resulting residue was purified via silica gel column (DCM/MeOH = 200/1, v/v) to afford ethyl 5-((4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)amino)nicotinate as a yellow solid (350 mg, 40%).
1-((5-(chloromethyl)pyridin-2-yl)methyl)pyridin-2(1H)-one[ No CAS ]
methyl 5-((6-((2-oxopyridin-1(2H)-yl)methyl)pyridin-3-yl)methyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
The mixture of ethyl 5-bromonicotinate (1 g, 4.3 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (1.1 g, 4.3 mmol, 1.0 eq), Pd(dppf)Cl2 (157 mg, 0.05 eq) and KOAc (1.26 g, 12.9 mmol, 3.0 eq) in dioxane (30 mL) was degassed with N2 and stirred at 85 C overnight. Then the mixture was cooled, 1- ((5-(chloromethyl)pyridin-2-yl)methyl)pyridin-2(lH)-one (1.02 g, 4.3 mmol, 1.0 eq), Pd(dppf)Cl2 (157 mg, 0.05 eq) and an aqueous solution of Na2CC>3 (1.37 g, 12.9 mmol, 3.0 eq) in 10 mL of water were added. The mixture was degassed with N2 and stirred at 95 C for 2 h. Then the mixture was cooled and concentrated, the residue was dissolved in EtOAc (150 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via silica gel column (PE/EtOAc = 1/1 -quant EtOAc) to afford methyl 5-((6-((2- oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)nicotinate as a brown solid (620 mg, 41%).
ethyl 5-((2-cyanopyridin-3-yl)methyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
The mixture of ethyl 5-bromonicotinate (1 g, 4.34 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l ,3,2- dioxaborolane) (l . lg, 4.34 mmol, 1.0 eq), Pd(dppf)Cl2 (157 mg, 5%) and KOAc (1.27 g, 13 mmol, 3.0 eq) in dioxane (36 mL) was degassed with N2 and stirred at 85 C overnight. After cooling to rt, 3- (bromomethyl)picolinonitrile (0.85 g, 4.34 mmol, 1.0 eq), Pd(dppf)Ci2 (157 mg, 5%) and an aqueous solution of Na2CC>3 (1.38 g, 13 mmol, 3.0 eq) in 10 mL of water were added. The mixture was degassed with N2 and stirred at 95 C for 2 h. Then the mixture was concentrated. The residue was diluted with EtOAc (100 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via silica flash chromatography (PE/EtOAc = 1/1) to afford ethyl 5-((2-cyanopyridin-3-yl)methyl)nicotinate as a yellow solid (340 mg, 29%).
The mixture of ethyl 5-bromonicotinate (1 g, 4.34 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (l . lg, 4.34 mmol, 1.0 eq), Pd(dppf)Cl2 (157 mg, 5%) and KOAc (1.27 g, 13 mmol, 3.0 eq) in dioxane (36 mL) was degassed with N2 and stirred at 85 C overnight. After cooling to rt, 2- (bromomethyl)benzonitrile (0.85 g, 4.34 mmol, 1.0 eq), Pd(dppf)Ci2 (157 mg, 5%>) and an aqueous solution of Na2CC>3 ( 1.38 g, 13 mmol, 3.0 eq) in 10 mL of water were added. The mixture was degassed with N2 and stirred at 95 C for 2 h. Then the mixture was concentrated. The residue was diluted with EtOAc (100 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via silica flash chromatography (PE/EtOAc = 5/1) to afford ethyl 5-(2-cyanobenzyl)nicotinate as a yellow oil (750 mg, 65%).
ethyl 5-(4-(2-oxopyrrolidin-1-yl)benzyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
The mixture of ethyl 5-bromonicotinate (345 mg, 1.5 mmol, 1.5 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (381 mg, 1.5 mmol, 1.5 eq), [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 5%>) and potassium acetate (441 mg, 4.5 mmol, 4.5 eq) in dioxane (10 mL) was degassed with N2 and stirred at 80 C for 3.5 h, then cooled, l-(4- (chloromethyl)phenyl)pyrrolidin-2-one (210 mg, 1.0 mmol, 1.0 eq), [1,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 5%>) and an aqueous solution of sodium carbonate (447 mg, 4.5 mmol, 4.5 eq) in 5 mL of water were added. The mixture was degassed and stirred at 95 C under N2 overnight. The reaction mixture was cooled and filtered through celite, concentrated, and the residue was dissolved in DCM (150 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via flash chromatography (5%> MeOH in DCM) to afford ethyl 5-(4-(2-oxopyrrolidin-l - yl)benzyl)nicotinate as a yellow solid (170 mg, 52%>).
1-(4-(chloromethyl)phenyl)pyridin-2(1H)-one[ No CAS ]
ethyl 5-(4-(2-oxopyridin-1(2H)-yl)benzyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
The mixture of ethyl 5-bromonicotinate (345 mg, 1.5 mmol, 1.5 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (381 mg, 1.5 mmol, 1.5 eq), Pd(dppf)Cl2 (55 mg, 5%) and KOAc (441 mg, 4.5 mmol, 4.5 eq) in dioxane (10 mL) was degassed with N2 and stirred at 80 C for 3.5 h. after cooling, l-(4- (chloromethyl)phenyl)pyridin-2(lH)-one (210 mg, 1.0 mmol, 1.0 eq), Pd(dppf)Cl2 (55 mg, 5%) and an aqueous solution of Na2C03 (447 mg, 4.5 mmol, 4.5 eq) in 5 mL of water were added to this mixture. The mixture was degassed and stirred at 95 C under N2 overnight. It was cooled and filtered through celite, concentrated. And the residue was dissolved in DCM (150 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via silica flash chromatography (DCM/MeOH = 20/1) to afford ethyl 5-(4-(2-oxopyridin-l(2H)-yl)benzyl)nicotinate as a yellow solid (170 mg, 52%).
To a solution of ethyl 5-bromonicotinate (5 g, 21.73 mmol, 1 eq) in 1,4-dioxane was added B2(Pin)2 (6.1 g, 23.91 mmol, 1.1 eq), KOAc (4.3 g, 43.46 mmol, 2 eq), and Pd(dppf)Cl2 (1.59 g, 2.17 mmol, 0.1 eq) under N2. The mixture was stirred at 90 C for 3 h. Then to the mixture was added 4-(bromomethyl)benzonitrile (4.3 g, 21.73 mmol, 1 eq), water, and Na2CC>3 (4.6 g, 43.46 mmol, 2 eq). The mixture was stirred at 90 C for 3 h, and then poured into water, extracted with EA. The organics was concentrated and purified via flash chromatography (PE/EtOAc = 5/1) to afford ethyl 5-(4-cyanobenzyl)nicotinate as a yellow solid (3.5 g, 60 %).
1-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)pyridin-2(1H)-one[ No CAS ]
ethyl 5-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;
A mixture of l-(4-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl)benzyl)pyridin-2(lH)-one (200 mg, 0.615 mmol, 1.0 eq), ethyl 5-bromonicotinate (170 mg, 0.738 mmol, 1.2 eq), Pd(PPh3) i (71 mg, 0.061 mmol, 0.1 eq), Na2C03 (196 mg, 1.84 mmol, 3.0 eq) in dioxane/H20 (20 mL/2 mL) under N2 was stirred at 95 C overnight and concentrated. The residue was extracted with EA (50 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified via flash chromatography (MeCN/H20 = 30%-95%, v/v) to afford ethyl 5-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)nicotinate
ethyl 5-((2-cyanoquinolin-6-yl)methyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
The mixture of ethyl 5-bromonictic acid (1.86 g, 8.1 mmol, 1.0 eq), BPDB (2.06 g, 8.1 mmool, 1.0 eq), potassium acetate (2.38 g, 24.3 mmol, 3.0 eq) and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (296 mg, 5 mol%) were mixed in 1,4-dioxane (100 mL). The mixture was degassed with nitrogen, heated to 85 C and stirred for 16 h, then cooled to rt, and 6- (bromomethyl)quinoline-2-carbonitrile (2.0 g, 8.1 mmol, 1.0 eq), [Iota, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (296 mg, 5 mol%) and sodium carbonate (2.57 g, 24.3 mmol, 3.0 eq, dissolved in 30 mL of water) were added. The mixture was degassed, heated to 95 C and stirred overnight. Cooled and the mixture was filtered through celite, water (100 mL) and DCM (100 mL) were added to the filtrate. The DCM layer was separated and washed with brine, dried over anhydrous sodium sulfate, and purified on silica gel column to afford ethyl 5-((2-cyanoquinolin-6-yl)methyl)nicotinate as a red solid (670 mg, 26%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 3h;Inert atmosphere;
10 mmol of 5-bromonicotinic acid ethyl ester, 12 mmol of phenylboronic acid,20 mmol of potassium carbonate, 0.5 mmol of tetrakis (triphenylphosphine) palladium was suspended in DME / H2O (40/10 mL)The reaction was carried out at 85 C for 3 hours after purging with nitrogen.After cooling, the filtrate was extracted with ethyl acetate and the ethyl acetate layer was washed three times with brine,Dried over anhydrous magnesium sulfate. Filtration, filtrate concentrated silica gel sample flash column chromatography (0-10% ethyl acetate / petroleum ether) to give 2.1 g of colorless oil.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; water; toluene; at 75℃; for 2h;Inert atmosphere;
General procedure: Pd(PPh3)4 (17.3 mg, 0.015 mmol) was added to a solution of 5-bromonicotinic acid ethylester(115.1 mg, 0.5 mmol) and aryl boronic acid (0.6 mmol) in MeOH (0.2 mL), toluene (0.8mL), and 2 M Na2CO3 (0.2mL) under N2. The mixture was heated to 75 C for 2 h, then cooledto room temperature and concentrated under reduced pressure. Water was added to theresidue and the aq. phase was extracted with DCM (3 × 5 mL). The combined organic layerswere washed with brine, dried over Na2SO4, and evaporated to obtain the crude product.Purification by column chromatography on silica gel afforded the desired product.
ethyl 5-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
1.3M /PrMgCI.LiCI in THF (6.69 ml, 8.69 mmol) was added dropwise to tertbutyl 3-iodoazetidine-1- carboxylate (1.85 g, 6.52 mmol) in THF (20 ml) at 0C. The reaction mixture was stirred at 0C for 20 min and the resultant solution was added dropwise to a solution of ethyl 5-bromopyridine-3-carboxylate (0.5 g, 2.17 mmol) and FeCb (anhydrous) (0.22 g, 1 .74 mmol) at 0C. The mixture was stirred at 0C for 25 min. The reaction mixture was quenched with saturated NH CI (aq), further diluted with water and DCM and stirred vigourously for 10 min. The mixture was extracted with DCM (3 x 80 ml) aid the combined organic extracts were dried (Na2S04), filtered and evaporated under vacuum. Purification by flash column chromatography (eluting with a gradient of 0-80% EtOAc / heptane) afforded the title compound (0.652 g, 94%) as a yellow oil. 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 9.15 (d, J = 1 .9 Hz, 1 H), 8.72 (d, J = 2.2 Hz, 1 H), 8.35 (t, J = 2.1 Hz, 1 H), 4.52 - 4.37 (m, 4H), 4.02 (dd, J = 8.6, 5.8 Hz, 2H), 3.91 - 3.78 (m, 1 H), 1 .50 (s, 9H), 1.45 (t, J = 7.1 Hz, 3H) HPLCMS (Method M): [m/z]: 307.40 [M+H]+
tetraethyl 5,5',5'',5'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetranicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.1%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In 5,5-dimethyl-1,3-cyclohexadiene; at 50℃; for 0.5h;
Cyclen, 58.7 g of ethyl 5-bromonicotinate, 27.9 g of t-BuONa, and 400 ml of xylene are added and stirred. 2.4 g of 50% (t-Bu) 3P toluene solution was added to the mixture, and the mixture was stirred for 30 minutes. After heating to 50 C, 1.7 g of Pd (dba) 2 was added and the mixture was heated to reflux. After cooling to room temperature, 1000 ml of purified water is added, and the mixture is left to stand for 30 minutes to separate the layers, and the aqueous layer is discarded. The organic layer was treated with MgSO4, concentrated in vacuo and purified by MC-MeOH column to obtain tetraethyl 5,5 ', 5' ', 5' '' - (1,4,7,10-tetraazacyclododecane-1,4,7,10- 17.9 g of tetranicotinate was obtained. (Yield: 40.1%).
diethyl 5,5'-((2-((5-(ethoxycarbonyl)pyridin-3-yl)(2-((5-(ethoxycarbonyl)pyridin-3-yl)(2-((5-(ethoxycarbonyl)pyridin-3-yl)(2-(ethoxycarbonyl)pyridin-4-yl)amino)ethyl)amino)ethyl)amino)ethyl)azanediyl)dinicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27.8%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In 5,5-dimethyl-1,3-cyclohexadiene; at 50℃; for 0.5h;
10.0 g of triethylenetetramine, 108.5 g of ethyl 5-bromonicotinate, 46.0 g of t-BuONa and 600 ml of xylene are added and stirred. The temperature was raised to 35 C and 2.8 g of 50% (t-Bu) 3P toluene solution was added. After stirring for 30 minutes, the temperature was raised to 50 C. and 2.0 g of Pd (dba) 2 was added. After cooling to room temperature, 1000 ml of purified water is added, and the mixture is left to stand for 30 minutes to separate the layers, and the aqueous layer is discarded. The organic layer was MgSO4-treated, concentrated in vacuo and purified by MC-MeOH column to obtain diethyl 5,5 '- ((2- ((5- (ethoxycarbonyl) pyridin- amino) ethyl) amino) ethyl) azanediyl) dinicotinate (19.8 g) was obtained in the same manner as in Synthesis Example 1, . (Yield: 27.8%)
ethyl 5-oct-1-ynylpyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In diethylamine; N,N-dimethyl-formamide; at 50℃; for 0.25h;Inert atmosphere;
Ethyl 5-bromopyridine-3-carboxylate (1 mmol, 0.23 g), bis(triphenylphosphine) palladium(II) dichloride (0.1 mmol, 0.070 g), copper(I) iodide (0.2 mmol, 0.038 g) and 1-octyne (1 mmol, 0.154 mL) were mixed in dry dimethylformamide (5 mL) and diethylamine (2 mmol, 0.183 mL) was added. The vial was filled with nitrogenand stirred for several minutes to give a clear orange solution and then heated at 50 C for 15 min. Solvent was evaporated in vacuo and the product was isolated by SiO2 column chromatography (ethyl acetate/isohexane 5:95) giving 0.222 g of compound 11 (87% yield).
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃; for 15h;Inert atmosphere;
<strong>[20986-40-7]Ethyl 5-bromonicotinate</strong> (Compound A-1, 4.60 g, 20.0 mmol), zinc cyanide (9.94 g, 84.6 mmol), tetrad (triphenylphosphine) (4.69 g, 4.06 mmol), and DMF (100 mL) were added to a 300 mL round bottom flask. The mixture was heated at 90 C. under argon for 15 hours. After cooling, the reaction was quenched with 10% ammonium acetate solution and extracted with ethyl acetate. The combined organic extracts were washed with water, brine and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 2/98 (v/v, volume to volume ratio) ethyl acetate/hexane to 10/90 (v/v) ethyl acetate/hexane to give product A-2: 3.36 g (92%). ESI-MS M/Z 177 (MH)+.
N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3 (4H)-yl]phenyl}-1-(4-methylpiperazin-1-yl)cyclopropane-1-carboxamide[ No CAS ]
ethyl 5-{3-[4-(methoxymethyl)-3-[1-(4-methylpiperazin-1-yl)cyclopropane-1-carbonyl]amino}phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide; at 80℃; for 1.5h;Inert atmosphere;
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(4-methylpiperazin-l-yl)cyclopropane-l -carboxamide (65.4 mg, 114 muiotaetaomicron), ethyl 5-bromopyridine-3-carboxylate (35.4 mg, 154 muiotaetaomicron), [l,l -bis-(diphenylphosphino)- ferrocen]-dichloropalladium-dichloromethane-complex (4.65 mg, 5.70 muiotaetaomicron) and potassium carbonate (31.5 mg, 228 muiotaetaomicron) in N,N-dimethylformamide (100 mu), water (400 mu) and 1 ,2-dimethoxyethane (550 mu) was degassed by passing argon through it for 5 min and then the mixture was heated at 80C for 1.5 h and then stored at -18C overnight. The reaction mixture was then filtered thorugh a silica gel column eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water to deliver 18.3 mg (27 % yield) of the title compound.LC-MS (Method 6): Rt= 1.26 min; MS (ESIneg): m/z = 595 [M-H] - MR (400 MHz, DMSO-d6) delta [ppm]: -0.008 (0.46), 1.070 (0.80), 1.083 (2.02), 1.090 (2.45), 1.100 (1.20), 1.177 (1.17), 1.186 (2.46), 1.193 (1.86), 1.206 (0.82), 1.234 (0.42), 1.367 (3.72), 1.385 (7.91), 1.403 (3.79), 2.209 (9.69), 3.386 (16.00), 4.392 (1.15), 4.409 (3.64), 4.427 (3.60), 4.445 (1.13), 4.634 (5.31), 7.271 (1.17), 7.276 (1.15), 7.291 (1.27), 7.296 (1.30), 7.538 (2.00), 7.558 (1.76), 8.030 (1.15), 8.034 (1.16), 8.050 (1.29), 8.055 (1.36), 8.180 (2.35), 8.184 (2.23), 8.308 (2.19), 8.329 (1.93), 8.365 (2.17), 8.370 (2.15), 8.413 (4.72), 8.631 (1.40), 8.637 (2.46), 8.642 (1.44), 9.162 (2.06), 9.167 (2.01), 9.314 (2.35), 9.320 (2.32), 10.637 (2.05).
(2- acetamidoimidazo[1,2-b]pyridazin-6-yl)boronic acid[ No CAS ]
ethyl 5-(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44.6%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 0.166667h;Inert atmosphere; Sealed tube;
21 J: Ethyl 5-(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)nicotinate: In a sealed 40 mL tube, to the crude reaction mixture containing (2-acetamidoimidazo[1,2-b]pyridazin-6-yl)boronic acid (598 mg, 2.718mmol) was added ethyl 5-bromonicotinate (414 mg, 1.800 mmol) and l,l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (35.2 mg, 0.054 mmol). The mixture was degassed by bubbling N2 through for 5 min. 2M K3P04 (2.70 mL, 5.40 mmol) was added and the reaction mixture stirred 10 min at 100 C. Upon cooling to rt, the reaction mixture was diluted with ethyl acetate (150 mL). The organics were washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was loaded onto a 40 g silica column and purified by flash chomatography, eluting with 0-10% MeOH in DCM to afford ethyl 5-(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)nicotinate (275 mg, 0.803 mmol, 44.6 % yield). MSESI m/z 325.8 (M+H)
4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide[ No CAS ]
ethyl 5-[[5-[4-(dimethylcarbamoyl)phenyl]-2-pyridyl] amino]pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃;Microwave irradiation;
Step 1 : Intermediate 33 -- Ethyl 5-[[5-[4-(dimethylcarbamoyl)phenyl]-2- pyridyl] amino] pyridine-3-carboxylate [0510] The title compound was prepared as described in Example 25, starting from 4-(6- amino-3-pyridyl)-N,N-dimethyl-benzamide and ethyl 5-bromopyridine-3-carboxylate, replacing NaO/Bu with CS2CO3 and heating at 160 C, to give the product as a solid (472 mg, 41%). MS ES+ m/z 391 [M+H]+.
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