* 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] Tetrahedron Asymmetry, 2001, vol. 12, # 8, p. 1121 - 1124
[2] Tetrahedron, 2002, vol. 58, # 37, p. 7381 - 7389
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6299 - 6310
[4] Journal of Medicinal Chemistry, 2001, vol. 44, # 26, p. 4509 - 4523
[5] Heterocycles, 2000, vol. 53, # 10, p. 2183 - 2189
[6] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1608 - 1628
[7] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[8] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2> 138, p. 244,257
3
[ 20826-04-4 ]
[ 38940-62-4 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
[2] Patent: WO2013/37779, 2013, A1,
[3] Patent: US2013/72679, 2013, A1,
4
[ 20826-04-4 ]
[ 35590-37-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
[2] Patent: CN104557357, 2018, B,
5
[ 20826-04-4 ]
[ 27828-71-3 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With sodium hydroxide In water for 30 h; Heating / reflux Stage #2: With sodium sulfide In water at 20℃;
Stage A: 5-hydroxynicotinic acidTo 10.1 g (0.05 mol) of 5-bromonicotinic acid was added 1O g of NaOh dissolved in 63 mL of water, 3.1 g of coppersulfate pentahydrate and 0.42 g of copper (0). The reaction mixture was vigorously stirred and heated under reflux for 30 hours. After cooling the mixture to room temperature, 4.8 g of Na2S-H2O was added and stirring was pursued overnight. The reaction mixture was heated to 7O0C and treated with H2S gas until disappearance of the white precipitate (3h). After cooling to room temperature, the mixture was filtered and the pH of the filtrate was adjusted to 5.2 with concentrated hydrochloric acid. The precipitate was filtered and the pH of the filtrate was adjusted to 4.6 with concentrated hydrochloric acid. The white precipitate was then filtered, washed with water and dried under reduced pressure giving 4.3 g(yield: 62percent) of product of molecular formula C7H5NO3. Aspect: white powder.Melting point: > 2600C. NMR spectrum of the protonIn DMSO-<4 at 300MHz, chemical shifts (ppm) and multiplicity: 8.48 (d, J = 1.5 Hz, IH),8.26 (d, J = 2.6 Hz, IH), 7.51 (d, J = 1.9 Hz, IH).Infrared spectrumIR spectrum was obtained as potassium bromide pellets. Absorption bands are given in cm 1: 3273, 1538, 1393, 1294.
With copper(I) sulfate; ammonia In water at 120℃; for 16 h; Acidic aqueous solution
To a mixture of 5-bromo-3-pyridinecarboxylic acid (i. e. the product of Step A) (25 g, 0.124 mol) in aqueous ammonia (67.32 mL) was added copper sulphate pentahydrate (8.41 g), and the reaction mixture heated in an autoclave at [120 C] for 16 h. Progress of the reaction was monitored by thin layer chromatography, using ninhydrin to visualize the product. The reaction mixture was washed with saturated solution of sodium sulfide to remove copper ions and was then acidified to a pH of about 4-5 using concentrated hydrochloric acid, causing a solid to separate as the acidified mixture cooled. The solid was collected using filtration and dried to provide the title compound (12.9 g, 74percent yield).
64%
With ammonia In water at 180℃; for 15 h;
Copper [(II)] sulfate (12.5g, [50MMOL)] was added to 5-bromo-nicotinic acid (50g, [248MMOL)] in aqueous ammonium hydroxide solution (d = 0.88). The reaction was sealed in an autoclave reactor and heated at [180°C] for 15 hours. The mixture was cooled, diluted with water [(300MUT),] sodium sulfite [(13.] 5g, [173MMOL)] was added and the mixture stirred for 20 minutes. The black precipitate was filtered away through celite, and the filtrate was adjusted to pH 3-4 upon treatment with 2M HCI. The mixture was filtered through celite and the filtrate concentrated to [200ML] volume upon which a white precipitate formed. The solution was cooled, filtered and the solid dried under vacuum at [40°C] overnight to give the title compound (22g, 159mmol, 64percent). 'NMR [(400MHZ,] d6-DMSO) 5.60 (2H, broad s), 7.41 (1H, d, J=3Hz), 8.10 [(1H,] d, J=3Hz), 8.24 (1H, d, J=3Hz), 13.05 (1 H, broad s). GC/MS [MH+] 139.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 17, p. 6340 - 6350
[2] Patent: WO2004/35545, 2004, A2, . Location in patent: Page 46
[3] Patent: WO2003/101959, 2003, A1, . Location in patent: Page 50-51
[4] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1981, vol. 35, # 4, p. 289 - 294
[5] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
[6] Chemistry - A European Journal, 2002, vol. 8, # 5, p. 1218 - 1226
7
[ 29681-44-5 ]
[ 20826-04-4 ]
Yield
Reaction Conditions
Operation in experiment
33%
With water; sodium hydroxide In tetrahydrofuran at 20℃; for 0.166667 h;
[00198] To a solution of methyl 5-bromonicotinate (500 mg, 2.3 mmol) in THF (5 ml) was added sodium hydroxide (iN aqueous solution) (5 ml, 2.3 mmol). The reaction stined at room temperature for 10 mm. The reaction was acidified to pH 6 with acetic acid, then extracted 3x with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid (153 mg, 33percent).
Thionyl chloride (96.74 g, 58.9 [ML,] 0. [813] mol) was added to 3-pyridinecarboxylic acid (also named nicotinic acid) (20 [G,] 0.163 mol) and heated at reflux [(-80 C)] for 3 h. The thionyl chloride was then distilled off under reduced pressure. The resulting acid chloride was cooled to 0 [TO-5 C,] and bromine (13 mL, 0.163 mol) was added. The reaction mixture was heated at [155 C] for 8-10 h, then cooled to room temperature and quenched with ice- cold water (200 mL) added dropwise, causing a white solid to form. The solid was collected using filtration and dried to provide the title compound (31.5 g, 94percent yield).
5-Bromo-3-pyridinecarboxamide (0.2010 g, 1 mmol) wasdissolved in acetic acid (2 mL), and to the stirring solution was added amyl nitrite (0.40 mL, 3 mmol).The reaction was placed under N2 atmosphere and heated to 80 °C for 24 hours, whereupon thereaction was complete by consumption of starting material by TLC. The solution was condensed andco-evaporated with toluene (2 x 5 mL), then purified via trituration from EtOAc and Hexane. Theresulting suspension was filtered to afford off-white powder (0.1993 g, 0.98 mmol). 1H-NMR (400MHz; MeOD): δ 9.12 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.62 (dd, J = 2.3, 1.7 Hz, 1H); MSm/z 200 (M-, 100percent); melting point: 180-183 °C; IR (neat) νmax 3033 (w br, O-H stretch), 1673 (s,C=O stretch), 1287 (acyl C-O), 688 (s, aromatic C-H) cm-1
Reference：
[1] Journal of Pharmaceutical Sciences, 1995, vol. 84, # 9, p. 1120 - 1125
11
[ 5332-24-1 ]
[ 20826-04-4 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 393
12
[ 59-67-6 ]
[ 20826-04-4 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
13
[ 625-92-3 ]
[ 20826-04-4 ]
Reference：
[1] Journal of Organic Chemistry, 1951, vol. 16, p. 1485,1491
14
[ 3430-16-8 ]
[ 20826-04-4 ]
Reference：
[1] Synthesis, 2003, # 4, p. 551 - 554
15
[ 99-73-0 ]
[ 20826-04-4 ]
[ 109440-03-1 ]
Reference：
[1] Journal of the American Chemical Society, 1987, vol. 109, # 6, p. 1885 - 1886
16
[ 98555-51-2 ]
[ 20826-04-4 ]
Reference：
[1] Yakugaku Zasshi, 1931, vol. 51, p. 542,571; dtsch. Ref. S. 73, 76[2] Chem.Abstr., 1931, p. 5427
[3] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2> 138, p. 244,257
[4] Chemische Berichte, 1886, vol. 19, p. 2766
[5] Monatshefte fuer Chemie, 1889, vol. 10, p. 705
17
[ 20826-04-4 ]
[ 15366-65-1 ]
Reference：
[1] European Journal of Organic Chemistry, 1999, # 2, p. 373 - 378
18
[ 20826-04-4 ]
[ 28733-43-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
[2] Yakugaku Zasshi, 1931, vol. 51, p. 542,571; dtsch. Ref. S. 73, 76[3] Chem.Abstr., 1931, p. 5427
[4] Patent: EP1348706, 2003, A1, . Location in patent: Page/Page column 61
[5] ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232
[6] Patent: CN104557357, 2018, B, . Location in patent: Paragraph 0135; 0136; 0137; 0146
19
[ 20826-04-4 ]
[ 36052-25-2 ]
Reference：
[1] Chemistry - A European Journal, 2002, vol. 8, # 5, p. 1218 - 1226
20
[ 67-56-1 ]
[ 20826-04-4 ]
[ 29681-44-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
for 3 h; Heating / reflux
Preparation 2; SYNTHESIS OF 5-[4-(5-FLUORO-2-TRIFLUOROMETHYLBENZOYL)PIPERAZIN-1-YL]-NICOTINIC ACID METHYL ESTER; A. A mixture of 5-bromonicotinic acid (1.000 g, 4.95 mmol) and 5 drops of concentrated sulfuric acid in anhydrous methanol (30 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with 20 mL of water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue obtained was used for next step reaction without further purification. Yield 0.965 g, 90percent.
87.5%
at 0 - 5℃; Heating / reflux
To the solution of 24a (500mg, 2.48mmol) in methanol (2OmL) was added thionyl chloride (590mg, 4.95mmol) at 0-50C. The mixture was heated under reflux overnight, neutralized with sat.NaHCO3 and evaporated. The residue was dissolved in ethyl acetate and washed with water and brine subsequently. The resulting organic layer was dried over anhydrous Na2SO4 and evaporated to provide 24b (468mg, 87.5percent).
85.1%
at 0℃; for 15 h; Inert atmosphere; Reflux
Example-1 Preparation of methyl 5-bromonicotinate A solution of 5-bromonicotine acid (10 g, 49.76 mmol) in 200 ml of methanol was cooled to 0° C. under nitrogen atmosphere and was added conc. H2SO4 (2.4 ml, 49.76 mmol) slowly drop wise. And slowly heated to reflux and continued for 15 h, after completion of the reaction volatiles were removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (200 ml) and washed with saturated sodium bicarbonate solution (2*50 ml), the combined organic layer was dried over with sodium sulfate, filtered and evaporated under reduced pressure to obtain methyl 5-bromonicotinate 2 as an off white solid (9.1 g, 85.1percent yield). 1HNMR (500 MHz, CDCl3): δ ppm: 9.12 (s, 1H), 8.84 (s, 1H), 8.43 (s, 1H), 3.96 (s, 3H); Mass (m/z): 216 (M+H)+, 218 (M+2H)+.
81%
Heating / reflux
5-Bromo-nicotinic acid methyl ester (Example 1); 5-Bromo-nicotinic acid (300mg, 1. 5mmol) was added methanol (6ml) and concentrated H2SO4 (1. lml). This reaction mixture was then heated at reflux for overnight. After cooling down, about 5ml of concentrated NaHCO3 solution was added to adjust the PH to 7-8. The product was then extracted with DCM (20ml). Removal of the solvent gave the product as white solid in 81 percent yield. IR: 3450,3047, 1722,1577, 1419,1311, 1107,1016, 955,764, 688; IH NMR (270 MHz, CDC13): 9.12 (s, 1H, H-2), 8. 85 (m, 1H, H-6), 8.44 (m, 1H, H-4), 3.99 (s, 3H, Cl3) ; 13C NMR (100.4 MHz, CDC13) : 164.4 (CO), 154.4 (C2), 148.7 (C6), 139. 6 (C4), 127.4 (C3), 120.7 (C5), 52.9 (CH3) ; MS: m/z (FAB+) 216.2 (M+).
80%
for 15 h; Reflux
The solution of 5-bromonicotinic acid (3.0g, 15mmol) was dissolved in anhydrous methanol (20ml), 98percent concentrated sulfuric acid (4ml) was added dropwise at room temperature, and the mixture was stirred for 10min, then heated to reflux for 15h, Adding water to dilute, adding saturated sodium bicarbonate aqueous solution, adjusting pH to neutral, extracting with ethyl acetate, washing with water, drying with anhydrous sodium sulfate, filtering, distilling off the solvent and subjecting the residue to silica gel column chromatography to obtain white flaky crystals (2.6g, 80percent).
71%
at 0℃; for 3 h; Reflux
To cooled methanol (20 mL, 0°C) was added dropwise concentrated H2S04 (2 mL). To the resulting clear solution was added 5-bromonicotinic acid (2 g, 10 mmol) and the mixture was refluxed for 3 h. After being cooled to room temperature, the solvent was evaporated and theresidue was partitioned between EtOAc and water. The organic layer was washed with saturatedNaHCO3 (a.q.), dried over Na2SO4 and concentrated to give methyl 5-bromonicotinate (1.5 g, yield:71percent). ‘H-NMR (CDC13, 400 MHz) 9.10 (d, J= 1.6 Hz, 1H), 8.81 (d, J= 2.4 Hz, 1H), 8.41 (t, J=2.4 Hz, 1H), 3.94 (s, 3H). MS (M+H): 216 / 218.
71%
for 3 h; Reflux
To cooled methanol (20 mL, 0°C) was added dropwise concentrated H2S04 (2 mL). To the resulting clear solution was added 5-bromonicotinic acid (2 g, 10 mmol) and the mixture was refluxed for 3 h. After being cooled to room temperature, the solvent was evaporated and the residue was partitioned between EtOAc and water. The organic layer waswashed with saturated NaHCO3 (a.q.), dried over Na2SO4 and concentrated to give methyl 5- bromonicotinate (1.5 g, yield: 71percent). ‘H-NMR (CDC13, 400 MHz) 9.10 (d, J= 1.6 Hz, 1H), 8.81 (d, J= 2.4 Hz, 1H), 8.41 (t, J= 2.4 Hz, 1H), 3.94 (s, 3H). MS (M+H): 216 / 218.
66%
at 0℃; for 12 h; Reflux
A solution of 5-bromonicotinic acid (10 g, 49.5 mmol) in MeOH (200mL) was cooled to 0 °C and conc. H2SO4 (5 mL) was added dropwise. The reaction mixture was heated to reflux for 12 h. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water and the aqueous layer was washed with EtOAc. The resulting mixture was poured over an aqueous saturated NaHCO3 solution to adjust the pH 7-8, it was then extracted with EtOAc and the organic layer was dried over anhydrous Na2SO4.
Reference：
[1] Tetrahedron Letters, 2001, vol. 42, # 24, p. 3959 - 3961
[2] Patent: US2008/167321, 2008, A1, . Location in patent: Page/Page column 15
[3] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 18, p. 3533 - 3537
[4] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 49
[5] Patent: US2013/123106, 2013, A1, . Location in patent: Paragraph 0089; 0090
[6] Patent: WO2005/54198, 2005, A2, . Location in patent: Page/Page column 52-53
[7] Patent: CN103626693, 2016, B, . Location in patent: Paragraph 0089-0091
[8] Patent: WO2014/205592, 2014, A1, . Location in patent: Page/Page column 30
[9] Patent: WO2014/209729, 2014, A1, . Location in patent: Page/Page column 28
[10] Patent: EP2533783, 2015, B1, . Location in patent: Paragraph 0147-0148
[11] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2137 - 2140
[12] Patent: WO2012/148808, 2012, A1, . Location in patent: Page/Page column 48
[13] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1637 - 1647
[14] Patent: WO2009/134668, 2009, A2, . Location in patent: Page/Page column 28; 29
21
[ 20826-04-4 ]
[ 74-88-4 ]
[ 29681-44-5 ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
5-Bromonicotinic acid (15.0 g, 74.3 mmol) was dissolved in DMF (200 mL), and the mixture was stirred at room temperature for 3 hours after adding potassium carbonate (15.4 g, 0.111 mol) and methyl iodide (9.25 mL, 0.149 mol). The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 5-bromonicotinate (10.0 g, 63percent). ESI-MS: m/z 215, 217 [M + H]+.
Reference：
[1] Nucleosides and Nucleotides, 1994, vol. 13, # 10, p. 2345 - 2366
[2] Monatshefte fuer Chemie, 1995, vol. 126, # 6/7, p. 805 - 810
24
[ 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] Chemistry - A European Journal, 2002, vol. 8, # 5, p. 1218 - 1226
31
[ 20826-04-4 ]
[ 37669-64-0 ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: With 4-methyl-morpholine; chloroformic acid ethyl ester In tetrahydrofuran at -10℃; for 0.333333 h; Inert atmosphere Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at -70 - 20℃; for 13.5 h;
19.1 (5-bromopyridin-3-yl)methanol To a solution of 12 g (59.4 mmol) of 5-bromopyridine-3-carboxylic acid in 300 mL of anhydrous THF, under argon, are added, at -10° C., 6.6 mL of NMM and then 5.7 mL (59.4 mmol) of ethyl chloroformate. After stirring for 20 minutes at -10° C., 6.8 g (179.8 mmol) of sodium borohydride are added portionwise. The medium is then cooled to -70° C. and 400 mL of MeOH are added over 1 hour 30 minutes. The temperature is then allowed to rise to room temperature and stirring is continued for 12 hours. The medium is then concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 8.4 g of (5-bromopyridin-3-yl)methanol are obtained in the form of a yellow oil. Yield=75percent 1H NMR, CDCl3, 400 MHz, δ (ppm): 8.5 (s, 1H); 8.4 (s, 1H); 7.9 (s, 1H); 4.6 (s, 2H); 2.8 (bs, 1H)
46%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0 - 20℃; for 1 h; Inert atmosphere Stage #2: at 20℃;
Step l : Synthesis of (5-bromopyridin-3-yl)methanol5-Bromonicotinic acid (1.00 g; 4.95 mmol) is dissolved in 30 mL anhydrous THF and triethylamine (0.76 mL; 5.44 mmol ) is added by syringe, the flask is flushed with argon and cooled to 0 °C. Ethylchloroformate (0.52 mL; 5.44 mmol ) is then added dropwise by syringe and the mixture is stirred at RT for 60 min. The crude mixture is filtered and the residue is washed twice with 5 mL THF, the filtrate is transferred to a 100 mL RBF and cooled to 0 °C. Sodium borohydride (468 nig: 12.4 mmol) is added in portions, followed by 5 ml , 1 LO which is added dropwise via a syringe. The mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is extracted 6 times with EtOAc, the organic layers are combined and dried over anhydrous sodium sulfate, concentrated in vacuo and deposited on silica. Purification by column chromatography on silica gel (pre washed with 1percent NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc and then to 50percent MeOH in EtOAc, led to the isolation of the product as a clear, colorless oil (426 mg, 46percent yield). NMR (300 MHz, CDC13) δ 8.60 (d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 7.89 (s, 1 H), 4.74 (d, ./ = 5.8 Hz, 2H), 1.96 (t, J = 5.7 Hz, 1H).
22%
Stage #1: With borane In tetrahydrofuran at 20℃; for 7 h; Heating / reflux Stage #2: With hydrogenchloride In tetrahydrofuran; water at 20℃; for 1 h; Stage #3: With sodium hydroxide In tetrahydrofuran; water
To a solution of 5-bromonicotinic acid (20.00 g, 97.00 mmol) in anhydrous THF (250 mL) was added a solution of BH3 (1 M in THF, 197 mL) slowly at rt over a period of 1 h. The reaction mixture was stirred for 1 h at rt and then was heated at reflux temperature for 5 h. The reaction mixture was cooled to rt and treated with 1 M HCl (100 mL) drop-wise. The resulting mixture was stirred for 1 h and treated with 10percent aq. NaOH until pH 10. The solution was then extracted with ethyl acetate (4*200 mL). The combined organic extracts were washed with H2O, dried over anhydrous Na2SO4, filtered and concentrated to yield the crude alcohol (10.71 g). Purification of the crude compound (SiO2: 0-5percent 2 M NH3 in MeOH/DCM) gave (5-bromo-pyridin-3-yl)-methanol (4.14 g, 22percent).
Reference：
[1] Patent: US2011/294788, 2011, A1, . Location in patent: Page/Page column 24
[2] Patent: WO2011/147038, 2011, A1, . Location in patent: Page/Page column 36
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1067 - 1088
[4] Journal of Medicinal Chemistry, 2001, vol. 44, # 26, p. 4509 - 4523
[5] Patent: US2005/222151, 2005, A1, . Location in patent: Page/Page column 17-18
[6] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[7] Tetrahedron, 2003, vol. 59, # 24, p. 4303 - 4308
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 13, p. 2832 - 2840
[9] Organic Preparations and Procedures International, 1992, vol. 24, # 2, p. 143 - 146
[10] Journal of medicinal chemistry, 1998, vol. 41, # 26, p. 5265 - 5271
[11] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1608 - 1628
[12] Nucleosides and Nucleotides, 1994, vol. 13, # 10, p. 2345 - 2366
[13] Patent: US6642237, 2003, B1, . Location in patent: Page/Page column 182
[14] Patent: WO2010/34838, 2010, A2, . Location in patent: Page/Page column 62
[15] Patent: US2007/60618, 2007, A1, . Location in patent: Page/Page column 14
[16] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3201 - 3215
[17] Patent: CN103626693, 2016, B,
32
[ 20826-04-4 ]
[ 37669-64-0 ]
Yield
Reaction Conditions
Operation in experiment
8.1%
With thionyl chloride; sodium borohydrid In tetrahydrofuran
Under a nitrogen atmosphere, a solution of 5-bromonicotinic acid (5.05 g, 25.0 mmol) and thionyl chloride (10 mL) was stirred and heated. The excess thionyl chloride was removed by distillation, and the residue was dried briefly under high vacuum. To the resulting light-yellow solid in dry tetrahydrofuran (40 mL) was added sodium borohydride (1.90 g, 50.0 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred 1 h at 0° C. and allowed to warm to ambient temperature. The mixture was added to a cold, saturated aqueous NH4 Cl solution (100 mL) and extracted with diethyl ether (3*50 mL). The combined ether extracts were dried (Na2 SO4), filtered, and concentrated by rotary evaporation to a semisolid (2.77 g). Thin layer chromatography analysis on silica gel indicated mostly 5-bromonicotinic acid; therefore the semisolid was partitioned between ether and saturated aqueous NaHCO3 solution. The ether layer was separated and concentrated by rotary evaporation to a residue (0.75 g). Purification by column chromatography on silica gel, eluding with ethyl acetate-hexane (1:1, v/v) afforded 379 mg (8.1percent) of 3-bromo-5-hydroxymethylpyridine.
8.1%
With thionyl chloride; sodium borohydrid In tetrahydrofuran
Under a nitrogen atmosphere, a solution of 5-bromonicotinic acid (5.05 g, 25.0 mmol) and thionyl chloride (10 mL) was stirred and heated. The excess thionyl chloride was removed by distillation, and the residue was dried briefly under high vacuum. To the resulting light-yellow solid in dry tetrahydrofuran (40 mL) was added sodium borohydride (1.90 g, 50.0 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred 1 h at 0° C. and allowed to warm to ambient temperature. The mixture was added to a cold, saturated aqueous NH4 Cl solution (100 mL) and extracted with diethyl ether (3*50 mL). The combined ether extracts were dried (Na2 SO4), filtered, and concentrated by rotary evaporation to a semisolid (2.77 g). Thin layer chromatography analysis on silica gel indicated mostly 5-bromonicotinic acid; therefore the semisolid was partitioned between ether and saturated aqueous NaHCO3 solution. The ether layer was separated and concentrated by rotary evaporation to a residue (0.75 g). Purification by column chromatography on silica gel, eluding with ethyl acetate-hexane (1:1, v/v) afforded 379 mg (8.1percent) of 3-bromo-5-hydroxymethylpyridine.
Reference：
[1] Patent: US5861423, 1999, A,
[2] Patent: US5811442, 1998, A,
33
[ 20826-04-4 ]
[ 59105-50-9 ]
Reference：
[1] Patent: CN103626693, 2016, B,
34
[ 20826-04-4 ]
[ 39741-46-3 ]
Reference：
[1] Nucleosides and Nucleotides, 1994, vol. 13, # 10, p. 2345 - 2366
35
[ 20826-04-4 ]
[ 106726-82-3 ]
Reference：
[1] Patent: EP2533783, 2015, B1,
36
[ 20826-04-4 ]
[ 135124-71-9 ]
Reference：
[1] Patent: US2011/294788, 2011, A1,
37
[ 20826-04-4 ]
[ 443649-18-1 ]
Reference：
[1] Chemistry - A European Journal, 2002, vol. 8, # 5, p. 1218 - 1226
38
[ 20826-04-4 ]
[ 75-65-0 ]
[ 361550-43-8 ]
Yield
Reaction Conditions
Operation in experiment
78%
With diphenyl phosphoryl azide; triethylamine In toluene at 65 - 100℃; for 22.7 h;
3-Chloroaniline (29.4 g, 229 mmol) was dissolved in THF (250 mL) at [20 °C.] A THF solution (80 mL) of Boc2O (50 g, 229 mmol) was added slowly to the mixture of 3-chloroaniline and THF. The resulting mixture was stirred for 3 days and then concentrated. The crude product was purified by recrystallization from EtOAc/Hexane three times to give Compound 1A (40.4 g, 78percent) as a white [SOLID. IH] NMR (300 MHz, [CDCL3)] [5] 7.52 (s, 1H), 7.17 [(M,] 2H), 7.00 (dt, J= 7.4, 1.8 Hz, 1H), 6.49 (s, 1H), 1.52 (s, 9H); MS (ES) [M/Z] : 250 (M+Na). Anal. Calcd. For [CLLHL4NO2CL] : C, 58.03 ; H, 6. 20 ; N, 6.15. Found: C, 58. 14; H, 6.22 ; N, 6.10. THF (150 mL) was added to a mixture of Compound [1A] (5.5 g, 24.2 mmol) and NaH (60percent in mineral oil, 2.4 g, 60.6 mmol) at 0 [°C] under N2. The mixture was stirred at [20 °C] for 1 h and then cooled to [0 °C] and Compound 1B (6.2 g, 41.2 mmol; prepared as described in Harris, R. L. N. Synthesis 1981,907) was added. After the mixture was stirred at [20 °C] overnight, the solvent was evaporated and the residue was purified by flash chromatography (10percent EtOAc in hexanes) to give Compound 1C (4.3 g, 52percent) as a white solids NMR (300 MHz, [CDC13)] 8 8.72 (s, 1H), 7.40 (m, 2H), 7.22 (brs, 1H), 7.11 [(M,] [1H),] 1.48 (s, 9H); MS (ES) m/z: 363 (M+Na). Anal. Calcd. For [C14HL4N402CL2] : C, 49.28 ; H, 4.14 ; N, 16.42. Found: C, 49. 52 ; H, 4.13 ; N, 16.41. A mixture of 5-bromonicotinic acid Compound 1D (10 g, 49.5 mmol), [T-BUOH] (100 [ML),] triethylamine (15.2 g, [150] mmol) and DPPA (20.4 g, 74 mmol) in toluene (100 mL) was stirred at [65 °C] for 40 min and then warmed to [100 °C FOR] 22 h under nitrogen. The mixture was cooled and concentrated under vacuum. The crude product was purified by column chromatography on [SI02] eluting with ethyl acetate/hexane to give Compound [1E] (10.52 g, 78percent) as a white [SOLID. LH NMR (300 MHZ, CDCL3) 6 8.] 32 (m, 3H), 6.97 (brs, 1H), 1.53 (s, 9H); MS (ES) [M/Z] : 273,275 [(M+H+).] Anal. Calcd. For [CLOHI3N202BR] : C, 43.98 ; H, 4.80 ; N, 10.26. Found: C, 43. 88 ; H, 4.52 ; N, 10.20. A mixture of Compound [1E] (2.85 g, 10.44 mmol), (3-bromopropoxy)-t- butyldimethylsilane (3.96 g, 15.66 mmol) and [CS2CO3] (10.21 g, 31.3 mmol) in anhydrous DMF (55 mL) was stirred at 70 [°C] for 23 h under nitrogen. The mixture was cooled, diluted with water and extracted with ether (3x). The organic phase was dried [(NA2S04)] and concentrated. The product was purified by column chromatography (eluting with EtOAc/hexane) to give Compound IF (4.2 g, 90percent) as a yellow [OIL. 1H] NMR (300 MHz, [CDCL3)] [8] 8.45 (brs, 2H), 7.77 (brs, 1H), 3.73 (brt, J= 7.3 Hz, 2H), 3.62 (t, J= 5.9 Hz, 2H), 1.81 [(M,] 2H), 1.45 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H); MS (ES) m/z: 445,447 [(M+H+).] Anal. Calcd. For [CLGH33N203BRSI] : C, 51.23 ; H, 7.47 ; N, 6.29. Found: C, 51.45 ; H, 7.47 ; N, 6.53. [N-BULI] (2.3 [ML,] 2.5 M, 5.65 mmol) was added dropwise to a solution of Compound IF (1.26 g, 2.82 mmol) in anhydrous THF (10 mL) at-78 °C and the mixture was stirred for 20 min. Anhydrous zinc chloride (8.47 mL, 1 M in ether, 8.47 mmol) was added dropwise to the THF solution containing Compound IF at-78 [°C] and stirred for 10 min before it was warmed to [20 °C] by removing the dry-ice bath. A mixture of Compound 1C (640 mg, 1.88 mmol) and [PD (PPH3)] 4 (109 [MG,] 0.094 mmol) in dry THF (8 mL) was added. The resulting mixture was stirred at 20 [°C] for 10 min, then at 70 [°C] for 22 h and the solvent was removed under vacuum. The residue was partitioned between water and ether and then separated. The aqueous layer was extracted with ether (3x). The combined organic layers were dried [(NA2SO4)] and concentrated. The product (a mixture of bis-Boc-and mono-Boc-protected coupling products) was purified by column chromatography to give 458 mg of yellow foam. The yellow foam was mixed with TFA (5 mL) and the mixture was stirred at [20 °C] for 2 h and then concentrated. NH40H was added, followed by water addition until the pH of the aqueous layer reached about 10-11. A yellow solid was formed, collected through filtration and then dried under vacuum. The product was purified by column chromatography to give Compound 1 (208 mg, 73percent) as a yellow [SOLID. 1H] NMR (300 MHz, DMSO-d6) 6 10.55 (s, [1H),] 8.89 (s, [1H),] 8.18 (brs, [1H),] 8.06 (s, [1H),] 7.76 (s, 1H), 7.71 (d, [J=] 8.0 Hz, 1H), 7.41 (t, [J= 8. 0 HZ, 1H),] 7.15 (d, [V= 7. 9 HZ, 1H),] 6.19 (brs, 1H), 4.54 (t, [J= 5. 0 HZ,] 1H), 3.55 [(M,] 2H), 3.18 [(M,] 2H), 1.80 [(M,] 2H); MS (ES) [M/Z] : 357 [(M+H+).] Anal. Calcd. For C17H17N6OCl30. 35 [H20] : C, 56.23 ; H, 4.91 ; N, 23.14. Found: C, 56.63 ; H, 4.78 ; N, 22.76.
72%
With diphenyl phosphoryl azide; triethylamine In toluene for 1.5 h; Heating / reflux
Intermediate 17; tert-butyl (5-bromopyridin-3-yl)carbamateTriethylamine (7 mL) followed by DPPA (10.9 niL) was added to a solution of 5- bromonicotinic acid (10.1 g) and t-BuOH (7.1 mL) in toluene (100 mL) and the reaction heated at reflux under an inert atmosphere for 1.5 hours. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated, washed with NaHCO3 (3 x 50 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using 0-4percent EtOAc in DCM as the eluent to give the title compound as a beige solid (9.82 g, 72percent); 1H NMR (DMSO-d6) 1.50 (s, 9H)5 8.19 (t, IH), 8.30 (d, IH), 8.57 (d, IH), 9.80 (s, IH);MS m/e MH+ 273/275.
72%
With diphenyl phosphoryl azide; triethylamine In toluene for 1.5 h; Heating / reflux
tert-butyl (5-bromopyridin-3-yl)carbamate Triethylamine (7 mL) followed by DPPA (10.9 mL) was added to a solution of 5-bromonicotinic acid (10.1 g) and t-BuOH (7.1 mL) in toluene (100 mL) and the reaction heated at reflux under an inert atmosphere for 1.5 hours. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated, washed with NaHCO3 (3*50 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using 0-4percent EtOAc in DCM as the eluent to give the title compound as a beige solid (9.82 g, 72percent); 1H NMR (DMSO-d6) 1.50 (s, 9H), 8.19 (t, 1H), 8.30 (d, 1H), 8.57 (d, 1H), 9.80 (s, 1H); MS m/e MH+273/275.
72%
With diphenylphosphoryl azide; triethylamine In toluene for 1.5 h; Heating / reflux
Triethylamine (7 mL) followed by DPPA (10.9 mL) was added to a solution of 5- bromonicotinic acid (10.1 g) and t-BuOH (7.1 mL) in toluene (100 mL) and the reaction heated at reflux under an inert atmosphere for 1.5 hours. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated, washed with NaHCO3 (3 x 50 mL), dried (MgS04), filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using 0-4percent EtOAc in DCM as the eluent to give the title compound as a beige solid (9.82 g, 72percent); 'H NMR (DMSO-d6) 1.50 (s, 9H), 8.19 (t, 1H), 8.30 (d, 1H), 8.57 (d, 1H), 9.80 (s, 1H) ; MS m/e MH+ 273/275
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 695 - 709
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 14, p. 4535 - 4546
[3] Patent: WO2004/9562, 2004, A1, . Location in patent: Page 31-33
[4] Patent: WO2006/82373, 2006, A1, . Location in patent: Page/Page column 107
[5] Patent: US2008/194552, 2008, A1, . Location in patent: Page/Page column 31
[6] Patent: WO2005/60970, 2005, A1, . Location in patent: Page/Page column 150
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1886 - 1900
[8] Patent: WO2010/100144, 2010, A1, . Location in patent: Page/Page column 138
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).
A solution of 5-bromonicotinic acid (10 g, 49.5 mmol) in SOCI2 (80 mL) was stirred at reflux temperature for 12 hours. SOCI2 was evaporated in vacuum to give 5-bromonicotinoyl chloride <n="130"/>(10.5 g, 95 %). A solution of 5-bromonicotinoyl chloride (2.06 g, 9.4 mmol) and Et3N (15 mL) was stirred in DCM (80 mL), then Benzylamine(l g, 9.4 mmol) was added into the above solution at 0 0C, which was stirred at room temperature for 12 h. The solution was diluted with H2O, and extracted with DCM. The organic layer was washed with brine, dried over NaOSO4, and filtered. The filtrate was evaporated to give N-benzyl-5-bromonicotinamide (2.98 g, 86.5%). MS (m/z) (M*+H): 291 and 293.
64%
With thionyl chloride; In dichloromethane; for 2h;Reflux;
5-bromonicotinic acid (2.0 g, 10 mmol) was dissolved in DCM (5 mL), then SOCl2 (1 mL) was added dropwise to this mixture. The reaction mixture was heated to reflux and allowed to stir at this temperature for 2 hours. The reaction mixture was concentrated in vacuo, then DCM (2 mL) was added and the resulting solution was concentrated in vacuo again. The resulting residue was diluted with DCM (30 mL) and the resulting solution was added to a solution of 2,6-difluoro aniline (1.05 g, 9.48 mmol) and TEA (1.05 g, 10.34 mmol) in DCM (20 mL) at 0 C dropwise. The mixture was allowed to stir at room temperature for 2 hours, and then diluted with DCM. The diluted mixture was washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using columnchromatography (eluted with PE : EtOAc = 10 : 1) to provide 2-bromo-N-2,6- difiuorophenyl)isonicotinamide (1.4 g, yield: 64.0%) as a white solid. 1H-NMR (CDC13, 400 MHz) delta 9.07 (s, 1H), 8.89 (s, 1H), 8.80-8.84 (m, 1H), 8.40-8.42 (m, 1H), 7.62-7.64 (m, 2H), 7.02-7.06 (m, 1H). MS (M+H)+: 313 / 315.
With thionyl chloride; for 6h;Heating / reflux;
Step 1 5-bromonicotinoyl chloride To 5.00 g of 5-bromonicotinic acid, 74 ml of thionyl chloride was added and the mixture was heated at reflux for 6 hours. After the solvent was distilled off under reduced pressure, the crystal was washed with diisopropyl ether and collected by filtration to obtain 4.09 g of the objective compound as a colorless crystal. Melting point: 72-74C 1H-NMR(CDCl3)delta: 8.51(1H, t), 8.96(1H, d), 9.21(1H, d)
With thionyl chloride;
Compound VI is readily synthesized from commercially- available 5-bromonicotinic acid by lithium aluminum hydride reduction of the corresponding primary amide (Figure 4).
Intermediate G9:; l-[5-(4.4.5.5-Tetramethyl-[1.3.2]dioxaborolan-2-yl)-pyridin-3-yl]-ethanone; Step 1: 5-Bromo-nicotinoyl chloride; 5-Bromonicotinic acid (1 g, 4.950 mmol) is placed in a 100ml round bottomed flask and purged with Argon. Dry THF (20 ml)is added and the resulting solution is treated with NaH (60% dispersed in mineral oil) (0.202 g, 5.049 mmol) over a period of 5 minutes. The reaction mixture is stirred at room temperature for 10 minutes and then oxalyl chloride ( 0.453 ml, 5.198 mmol) is added slowly over 5 minutes followed by dry DMF (10 ul). The reaction mixture is stirred for a further 5 minutes, filtered through filter paper, concentrated in vacuo and dried under vacuum to afford the title compound.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;
Step A: (5-Bromo-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone. To a solution of 5-bromonicotinic acid (73.3 mmol) in CH2Cl2 (0.5 M) was added DMF (catalytic, ~100 muL) followed by oxalyl chloride (29.7 mmol). The reaction mixture was allowed to stir at rt for 1 h. The mixture was concentrated, diluted with CH2Cl2, and concentrated again. The resulting residue was diluted with CH2Cl2 (0.5 M), cooled to 0 C., and treated with Et3N (74.2 mmol) followed by 1-cyclobutyl-[1,4]diazepane dihydrochloride (17.8 mmol). The reaction mixture was allowed to warm to rt and was stirred for 18 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2*). The organic layer was dried and concentrated to provide the title compound (4.74 g, 94%). MS (ESI): mass calcd. for C15H20BrN3O, 337.08; m/z found, 388.0 [M+H]+. 1H NMR (500 MHz, CDCl3): delta 8.75-8.69 (m, 1H), 8.60-8.56 (m, 1H), 7.96-7.86 (m, 1H), 3.84-3.70 (m, 2H), 3.52-3.44 (m, 2H), 3.02-2.76 (m, 1H), 2.67-2.61 (m, 1H), 2.55-2.49 (m, 1H), 2.49-2.43 (m, 2H), 2.13-1.91 (m, 3H), 1.92-1.52 (m, 7H).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.2h;
Example 53; N-(3,5-difluorophenyl)-5-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)nicotinamide; Example 53A; 5-bromo-N-(3,5-difluorophenyl)nicotinamide; Oxalyl chloride (1.2 mL) and DMF (25 muL) were added to 5-bromonicotinic acid (1.0 g, 4.95 mmol) suspended in CH2Cl2 (30 mL). The resulting mixture was stirred at room temperature for 12 min. It was then concentrated to dryness and azeotroped with toluene. The residual was then dissolved in toluene (30 mL). 3,5-Difluoroaniline (1.0 g, 7.8 mmol) was added followed by triethylamine (1.1 mL, 7.5 mmol). The resulting suspension was stirred at room temperature for 10 min. The reaction mixture was taken in 5% acetic acid(aq) (300 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extract was washed with 1.0 M Na2CO3(aq) (2×100 mL) and brine. The organic layers were combined, dried (Na2SO4) and concentrated to dryness to provide the title compound (1.4 g, 93%). MS (APCI) m/z 313, 315 (M+H)+.
With thionyl chloride; for 6h;Heating / reflux;
Step 1 5-bromonicotinoyl chloride To 5.00 g of 5-bromonicotinic acid, 74 ml of thionyl chloride was added and the mixture was heated at reflux for 6 hours. After the solvent was distilled off under reduced pressure, the crystal was washed with diisopropyl ether and collected by filtration to obtain 4.09 g of the objective compound as colorless crystals. Melting point: 72-74C
With thionyl chloride;N,N-dimethyl-formamide; for 16h;Heating / reflux;
Thionyl chloride (6OmL) was added to 5-bromonicotinic acid (12g, 59.4mmoi) followed by N,N-dimethylformamide (3 drops, cat.) and the mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool and then the excess thionyl chloride was removed by distillation. To the residue was added toluene (3OmL) and the toluene removed under reduced pressure on a rotary evaporator. This step was repeated to produce 5-bromonicotinoyl chloride (13.Og). The crude acid chloride was dissolved in anhydrous 1,4-dioxane (10OmL) to which was added 2,6-dimethylaniline (7.15g, 58.97mmol). After stirring at room temperature for 15 min. diisopropylethylamine (11.92mL, 68.41mmol) was added and the resultant solution was stirred at room temperature for 5 hours. The volatiles were then removed under reduced pressure on a rotary evaporator. The crude residue was dissolved in ethyl acetate (10OmL) and washed with IN HCl solution <n="38"/>(2xl00mL), waiter (10OmL), saturated sodium bicarbonate solution (10OmL) and brine (10OmL), dried (Na2SO4) and re-concentrated in vacuo. The residue was recrystallized from ethyl acetate/ether to afford the product.
With thionyl chloride; for 4h;Reflux;
A solution of 5-bromonicotinic acid (4 g, 0.02 mol) in thionyl chloride (25 rnL) was heated under reflux for 4 h. The excess thionyl chloride was removed under reduced pressure to provide 5-bromonicotinyl chloride which was used without further purification. To 5-bromonicotinyl chloride (3.5 g, 13.6 mmol) was added glycine ethylester (2.1 g, 20.3 mmol) and diisopropyl ethyl amine (2.6 g, 20.1 mmol) in THF (70 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with brine solution. The combined organic layers were dried over a2S04, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography using 25 % EtOAc in hexane to provide ethyl 2-(5-bromonicotinamido)acetate 1.2 g (33 %) as a brown solid. LCMS Method T: retention time 1.28 min; [M+l] = 288.2
With thionyl chloride;N,N-dimethyl-formamide;Reflux;
To a mixture of 5-bromonicotinic acid (10 g) in thionyl chloride (25 mL) was added anhydrous DMF (0.5 mL). The mixture was refluxed overnight, cooled to room temperature, and excess thionyl chloride was removed under reduced pressure. A white solid 1 (11 g) was obtained, which was used for the next step without further purification.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;
Reference Example 24b; N,N-Dimethylformamide (8.6 muL) and oxalyl chloride (0.14 mL) were added to a methylene chloride (5 mL) suspension of 5-bromopyridine-3-carboxylic acid (0.23 g) at room temperature, followed by stirring at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and methylene chloride (2.5 mL) was added to the residue. The reaction mixture was added to a solution mixture of tert-butyl 2-amino-4-phenylbenzoate (0.25 g) in methylene chloride (5 mL) and pyridine (0.19 mL) at room temperature, followed by stirring at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.39 g of tert-butyl 2-(5-bromopyridine-3-carboxamido)-4-phenylbenzoate as a white solid.1H-NMR (CDCl3) delta: 1.65 (9H, s), 7.37-7.45 (2H, m), 7.45-7.53 (2H, m), 7.68-7.74 (2H, m), 8.10 (1H, d, J=8.6 Hz), 8.52 (1H, dd, J=2.1, 2.1 Hz), 8.86 (1H, d, J=2.2 Hz), 9.17 (1H, d, J=2.0 Hz), 9.22 (1H, d, J=1.9 Hz), 12.52 (1H, s).
With thionyl chloride;N,N-dimethyl-formamide;Reflux;
To a mixture of 5-bromonicotinic acid (10 g) in thionyl chloride (25 ml) was added anhydrous DMF (0.5 ml). The whole was heated to reflux for overnight. After cooled to RT, the excess thionyl chloride was removed under reduced pressure. A white solid 5 (11 g) was obtained, which was used for the next step without further purification.
With thionyl chloride; In dichloromethane; for 2h;Reflux;
5-bromonicotinic acid (2.0 g, 10 mmol) was dissolved in DCM (5 mL), then SOCl2 (1 mL) was added dropwise to this mixture. The reaction mixture was heated to reflux and allowed to stir at this temperature for 2 hours. The reaction mixture was concentrated in vacuo, then DCM (2 mL) was added and the resulting solution was concentrated in vacuo again. The resulting residue was diluted with DCM (30 mL) and the resulting solution was added to a solution of 2,6-difluoro aniline (1.05 g, 9.48 mmol) and TEA (1.05 g, 10.34 mmol) in DCM (20 mL) at 0 C dropwise. The mixture was allowed to stir at room temperature for 2 hours, and then diluted with DCM. The diluted mixture was washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using columnchromatography (eluted with PE : EtOAc = 10 : 1) to provide 2-bromo-N-2,6- difiuorophenyl)isonicotinamide (1.4 g, yield: 64.0%) as a white solid. 1H-NMR (CDC13, 400 MHz) delta 9.07 (s, 1H), 8.89 (s, 1H), 8.80-8.84 (m, 1H), 8.40-8.42 (m, 1H), 7.62-7.64 (m, 2H), 7.02-7.06 (m, 1H). MS (M+H)+: 313 / 315.
With thionyl chloride; In dichloromethane; at 20℃;
SOCl2 (10.84 mL, 148.5 mmol) was added to a suspension of 5-bromonicotinic acid (5 g, 24.75 mmol) in DCM (60 mL) and the RM was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (40 mL), the mixture was cooled to 0C under a nitrogen atmosphere, DIPEA (8.65 mL, 49.5 mmol) was added dropwise, followed with a solution of 4-trifluoromethoxyaniline (3.65 mL, 27.2 mmol) in DCM (20 mL). The RM was stirred for 2 h, treated with sat. aq. Na2CC>3 (100 mL), and extracted EtOAc. The combined extracts were washed with sat. solution of KH2P04 (pH = 4), brine, dried over MgS04 and the solvent was evaporated off under reduced pressure to give a residue which was recrystallized from n-heptane / EtOAc to afford the title compound as beige needles. UPLC- MS (Condition 1) tR = 2.71 min, m/z = 360.9-362.9 [M+H]+, m/z = 358.9-361.0 [M-H]"; XH-NMR (400 MHz, DMSO-d6) delta ppm 7.40 (d, J=8.3 Hz, 2 H) 7.87 (d, 2 H) 8.55 (t, J=2.1 Hz, 1 H) 8.93 (d, J=2.2 Hz, 1 H) 9.07 (d, J=1.7 Hz, 1 H) 10.67 (s, 1 H).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;
General procedure: To a solution of 3-iodo-4-methylbenzoic acid 5-1 (262mg, 1.0mmol) in dry DCM (10mL) at 0C was added oxalyl chloride (0.13mL, 1.5mmol) and 3 drops of dry DMF. The resulting reaction mixture was stirred at room temperature for 3h, and then the solvent was removed under reduced pressure. The crude product was used directly for the next step without further purification.
With thionyl chloride; at 80℃;Inert atmosphere;
General procedure: Using a typical scale of 2.0 mmol, the appropriate aryl carboxylicacid (2.0 mmol) was added to a small round-bottomed flask, which was flushed with N2(g). SOCl2 (3 mL, 41.4 mmol) was added afterwhich the reaction mixture was refluxed, with stirring, at 80 C andleft overnight to ensure complete conversion. The reaction mixturewas cooled and excess SOCl2 was completely removed underreduced pressure. The crude acid chloride was then used as a reagentfor subsequent reactions.
With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 18h;
5-Bromonicotinic acid (1 g, 4.9 mmol) was added to thionyl chloride (5 mL), followed by dimethylformamide (100 muL, 1.36 mmol). The reaction mixture is allowed to react at 80 DEG C for 18 hours. After the reaction, the thiotylchloride was removed by concentration under reduced pressure, and the concentrated product was used without purification in the next reaction.
With thionyl chloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 3h;Heating / reflux;
3A. 5-Bromonicotinoylchloride: A suspension of 5-bromonicotinic acid (5.0 g, 24.8 mmol), thionyl chloride (5.4 mL, 74.2 mmol), and DMF (a few- drops) in DCE (83 mL) was warmed to reflux. After 3h, the reaction was cooled to rt and concentrated to give an off-white solid. The solid was dissolved in CH2CI2 and concentrated. The process was repeated twice to give the acid chloride as an off- white solid.
With thionyl chloride; In toluene; for 2h;Reflux;
To asolution of 5-bromonicotinic acid (6.0mmol, 1.2g) in toluene(10mL), we added thionyl chloride (10mL) at roomtemperature. The mixture was refluxed for 2h and concentratedunder vacuum to give crude acyl chloride (1.3g),which, without further purification, was used in the nextreaction. To a solution of tryptamine (6.0mmol, 1.0g) andN,N-dimethyl-4-aminopyridine (DMAP, 1.2mmol, 146mg)in pyridine (10mL), we added the acyl chloride at 0C.After stirring at room temperature for 4h, the reaction mixturewas diluted with CHCl3and successively washed withwater and brine, dried (Na2SO4), concentrated, and purifiedby column chromatography on NH-SiO2. Elution withCHCl3/MeOH (20:1, v/v) gave 3 (1.26g, 62%) as a yellowcrystal; IR (Zn-Se) max 3272, 1644cm-1; 1H-NMR (CDCl3) 8.72 (d, 1H, J = 2.0Hz), 8.66 (d, 1H, J = 2.0Hz), 8.18(brs, 1H), 8.15 (t, 1H, J = 2.0Hz), 7.62 (d, 1H, J = 8.0Hz),7.39 (d, 1H, J = 8.0Hz), 7.23 (dd, 1H, J = 7.2, 7.2Hz), 7.14(dd, 1H, J = 7.2, 7.2Hz), 7.07 (d, 1H, J = 1.6Hz), 6.29 (brs,1H), 3.80 (q, 2H, J = 6.4Hz), 3.11 (t, 2H, J = 6.4Hz); 13CNMR(CDCl3) 164.3, 152.9, 145.8, 137.8, 136.5, 131.7,127.3, 122.3, 122.2, 120.9, 119.5, 118.5, 112.5, 111.5, 40.7,25.1; HRESIMS m/z 368.0179 [calcd. for C16H14BrN3NaO(M + Na)+, 368.0198].
With thionyl chloride; for 3h;Reflux;
5-bromonicotinic acid (1.5 g, 5.36 mmol) was dissolved in thionylchloride (15 mL) and refuxed for 3 h. Then, the excess thionyl chloridewas removed under vacuum to give 5-bromopicolinoyl chloride yellow crystalline solid. Next, 5-bromonicotinoyl chloride (0.99 g, 5.36 mmol) were dissolved in dry dichloromethane(30 ml), and then aluminum trichloride (0.85 g,6.4 mmol) was added slowly at 0 C followed by stirring at room temperaturefor 6 h and refluxed for 3 h. Then, the reaction mixture wasquenched through pouring into 200 mL ice-HCl solution and extractedwith dichloromethane for three times. The combined organic phase waswashed three times with water and dried over anhydrous MgSO4. Thesolvent was removed under reduced pressure and the residue waspurified on a silica gel column using petroleum ether/dichloromethanemixture (4:1, v/v) as eluent to afford the product as yellow powder in57% yield. 1H NMR (600 MHz, DMSO-d6) delta [ppm]: 8.97-8.91 (m, 2H),8.96-8.92 (m, 2H), 8.48 (d, J=7.1 Hz, 1H), 8.48 (d, J=7.1 Hz, 1H),8.39 (dd, J=8.3, 2.3 Hz, 1H), 8.39 (dd, J=8.3, 2.3 Hz, 1H), 8.22 (d,J=8.4 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.13-8.07 (m, 2H), 8.12-8.08(m, 2H), 8.03 (dd, J=8.4, 0.5 Hz, 1H), 7.57 (dtd, J=21.4, 7.2, 1.2 Hz,2H). 13C NMR (151 MHz, DMSO) delta [ppm]: 192.73, 153.70, 150.00,144.29, 140.86, 139.38, 135.17, 135.14, 132.89, 129.04, 128.21,126.55, 125.68, 125.19, 124.41, 123.73, 123.38, 123.00. MS (LC-MS)[m/z]: calcd for C18H10BrNO5, 366.97; found, 367.96.
With thionyl chloride; In toluene; at 110℃; for 2h;
General procedure: Compound 9b (2.16 g, 10 mmol) and thionyl chloride (10 mL) were placed in 30 mL of toluene, and reacted at 110 C for 2 h, then The reaction mixture was concentrated under reduced pressure, and then the remaining solid compound was dissolved in THF (40 mL), 2-chloro-6-methylaniline (3.186 g, 22.6 mmol) was slowly added in an ice bath, and the reaction was held at 90 C for 6 h. After cooling to room temperature, 20 mL of a saturated aqueous solution of potassium carbonate was added, and then the mixture was extracted with EtOAc. Then, it was extracted with EA three times, and the EA layer was combined, washed with brine, dried over anhydrous sodium sulfate and filtered. The crude material was separated and purified by silica gel column chromatography (PE/EA = 8:1) and then recrystallized to afford the compound 10b.
With thionyl chloride;Inert atmosphere; Reflux;
Under the protection of N2, thionyl chloride (36 ml, 494 mmol) was added dropwise to 5-bromonicotinic acid (5.00 g, 24.7 mmol). After the addition was completed, the mixture was heated to reflux for 2-3 h until the solution was clarified.The thionyl chloride was removed under reduced pressure to give a pale yellow solid.The solid was dissolved in 30 ml of anhydrous dichloromethane.The active intermediate solution was slowly added dropwise to the cyclopropylamine (3.77 ml) under ice bath.In a solution of dichloromethane (30 ml). After the completion of the dropwise addition, the mixture was allowed to react to room temperature overnight.After the completion of the reaction, 20 ml of a 2 mol/L K2CO3 solution was added to the reaction system.The dichloromethane phase was separated and the aqueous phase was extracted with dichloromethane (15 ml×3).The organic phases were combined and dried over anhydrous Na 2 SO 4 . Separated and purified by column chromatography.(petroleum ether: ethyl acetate = 1:1),A white solid was obtained in 5.27 g, yield 89%.
With thionyl chloride;Inert atmosphere; Reflux;
1) Under the protection of N2, thionyl chloride (36 ml, 494 mmol) was added dropwise to 5-bromonicotinic acid (5.00 g, 24.7 mmol). After the addition was completed, the mixture was heated to reflux for 2-3 h until the solution was clarified and decompressed. The thionyl chloride was spun off to give a pale yellow solid.The solid was dissolved in 30 ml of anhydrous dichloromethane.The active intermediate solution was slowly added dropwise to a solution of cyclopropylamine (3.77 ml) dichloromethane (30 ml). After the completion of the dropwise addition, the mixture was allowed to react to room temperature overnight.After the completion of the reaction, 20 ml of a 2 mol/L K2CO3 solution was added to the reaction system. The methylene chloride phase was separated, and the aqueous phase was extracted with dichloromethane (15 ml×3), and the organic phase was combined and dried over anhydrous Na2SO4.Separated and purified by column chromatography. (Petroleum ether: ethyl acetate = 1:1) gave a white solid, 5.27 g, yield 89%.
With copper(I) sulfate; ammonia; In water; at 120℃; for 16h;Acidic aqueous solution;
To a mixture of 5-bromo-3-pyridinecarboxylic acid (i. e. the product of Step A) (25 g, 0.124 mol) in aqueous ammonia (67.32 mL) was added copper sulphate pentahydrate (8.41 g), and the reaction mixture heated in an autoclave at [120 C] for 16 h. Progress of the reaction was monitored by thin layer chromatography, using ninhydrin to visualize the product. The reaction mixture was washed with saturated solution of sodium sulfide to remove copper ions and was then acidified to a pH of about 4-5 using concentrated hydrochloric acid, causing a solid to separate as the acidified mixture cooled. The solid was collected using filtration and dried to provide the title compound (12.9 g, 74% yield).
64%
With ammonia;copper(II) sulfate; In water; at 180℃; for 15h;
Copper [(II)] sulfate (12.5g, [50MMOL)] was added to 5-bromo-nicotinic acid (50g, [248MMOL)] in aqueous ammonium hydroxide solution (d = 0.88). The reaction was sealed in an autoclave reactor and heated at [180C] for 15 hours. The mixture was cooled, diluted with water [(300MUT),] sodium sulfite [(13.] 5g, [173MMOL)] was added and the mixture stirred for 20 minutes. The black precipitate was filtered away through celite, and the filtrate was adjusted to pH 3-4 upon treatment with 2M HCI. The mixture was filtered through celite and the filtrate concentrated to [200ML] volume upon which a white precipitate formed. The solution was cooled, filtered and the solid dried under vacuum at [40C] overnight to give the title compound (22g, 159mmol, 64%). 'NMR [(400MHZ,] d6-DMSO) 5.60 (2H, broad s), 7.41 (1H, d, J=3Hz), 8.10 [(1H,] d, J=3Hz), 8.24 (1H, d, J=3Hz), 13.05 (1 H, broad s). GC/MS [MH+] 139.
Stage #1: 5-bromo-3-pyridinecarboxylic acid With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: methylamine In N,N-dimethyl-formamide
2 Preparation of 5-bromo-N-methyl-pyridine-3-carboxamide
A mixture of 5-bromopyridine-3-carboxylic acid (200 mg, 990.07 μmol), HATU (0.564 g, 1.48 mmol) and DIPEA (0.51 g, 3.95 mmol) in DMF (4 mL) was stirred at r.t. for 30 min. Methylamine (2 M, 0.99 mL, 1.98 mmol) was added. The resulting mixture was stirred at r.t. for 18h and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated NaHCO3and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 20-100% EtOAc/Hexane to afford the title compound (0.12 g, Yield 57%).
57%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: methylamine In N,N-dimethyl-formamide
2 Preparation of 5-bromo-N-methyl-pyridine-3-carboxamide
A mixture of 5-bromopyridine-3-carboxylic acid (200 mg, 990.07 μmol), HATU (0.564 g, 1.48 mmol) and DIPEA (0.51 g, 3.95 mmol) in DMF (4 mL) was stirred at r.t. for 30 min. Methylamine (2 M, 0.99 mL, 1.98 mmol) was added. The resulting mixture was stirred at r.t. for 18h and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated NaHCO3and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 20-100% EtOAc/Hexane to afford the title compound (0.12 g, Yield 57%).
Stage #1: 5-bromo-3-pyridinecarboxylic acid With thionyl chloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane at 0℃; for 5h; Reflux;
Stage #2: methylamine In tetrahydrofuran
171.1 Step 1
Alternate route to prepare N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-7-(3,5-dimethyl-isoxazol-4-yl)-6-methoxy-9H-pyrido[3,4-b]indol-4-amine (Cpd. No. 323) Step 1: 5-Bromonicotinic acid (25 g, 124 mmol) was dissolved in 1,2-dichloroethane (200 mL). SOCl2 (27 mL, 371 mmol) was added at 0° C. followed by anhydrous DMF (0.2 mL) to initiate the reaction. The reaction mixture was heated at reflux for 5 h then concentrated on a rotatory evaporator. CH2Cl2 (100 mL) was added and removed on a rotatory evaporator and this process was repeated once. The remaining residues were dissolved in THF (100 mL) and methyl amine (124 mL, 2 M in THF) was added. Volatile components were removed on a rotatory evaporator and the remaining residues were dissolved in ethyl acetate followed by addition of water. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, then dried over anhydrous Na2SO4. The ethyl acetate was removed on a rotary evaporator affording ZYJ22 as a solid in 25.3 g. 1H NMR (300 MHz, DMSO-d6): 8.94 (d, J=1.73 Hz, 1H), 8.83 (d, J=2.17 Hz, 1H), 8.72 (br, 1H), 8.37 (t, J=1.93 Hz, 1H), 2.79 (s, 1.5H), 2.78 (s, 1.5H). ESI-MS calculated for C7H879BrN2O [M+H]+=214.98; Observed: 215.0.
Stage #1: 5-bromo-3-pyridinecarboxylic acid With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -50℃; for 0.5h;
Stage #2: carbon dioxide In tetrahydrofuran; hexane
Stage #3: With hydrogenchloride In water
12.5g
Stage #1: 5-bromo-3-pyridinecarboxylic acid With n-butyllithium; 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran at -60℃; for 0.5h;
Stage #2: carbon dioxide In tetrahydrofuran at 25℃; for 3h;
46 Synthesis of compound 502-A2
At -60 °C, a solution of 2,2,6,6-Tetramethyl-piperidine (16.8 g, 118.8 mmol) in 200 mL of THF was added n-BuLi(2.5 M, 44 mL, 108.9 mmol) by dropwise slowly and stirred for 15 minutes. Then 502-A1 (5-bromonicotinic acid, 10 g,49.5 mmol) was added and stirred at -60 °C for 0.5 hour. Then, dry CO2 was bubbled into the reaction mixture at 25 °Cfor 3 hours. Water (150 mL) was added to quench the reaction. The THF was removed. The water phase was adjustedto pH=3 with IN HCl, concentrated and the resulting precipitate solid was collected by filtration and dried to give compound502-A2 (5-bromopyridine-3,4-dicarboxylic acid, 12.5 g) as brown solid.1H NMR (300 MHz, DMSO-d6) δ 9.02-9.03 (m, 2H), 8.73 (br s, 2H).
Stage #1: 5-bromo-3-pyridinecarboxylic acid With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -50℃; for 0.5h;
Stage #2: With iodine In tetrahydrofuran; hexane at -50℃; for 2h;
Stage #3: With hydrogenchloride In water
Stage #1: 5-bromo-3-pyridinecarboxylic acid With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran at -50℃; for 0.5h; Inert atmosphere;
Stage #2: With iodine In tetrahydrofuran at -50℃; for 2h; Inert atmosphere;
86.1 Step 1:
Step 1: Under nitrogen gas atmosphere, n-butyl lithium (1.8 mL, 4.4 mmol) was added dropwise into a solutionof 2,2,6,6-tetramethyl piperidine (0.81 mL, 4.8 mmol) in THF(10 mL) at -50°C. After 5 min, 5-bromonicotinic acid (0.40g, 2.0 mmol) was added. After 30 min, a solution of I2 (0.61 g, 2.4 mmol) in THF (5 mL) was added dropwise at -50 °C.The obtained reaction mixture was stirred at -50 °C for 2 h. The reaction mixture was quenched with H2O (10 mL), theaqueous phase was separated and extracted with Et2O (10 mL), then the aqueous phase was acidfied with 1 M hydrochloric acid to pH = 3. The precipitate was filtrated and the filtrate cake was dried to deliver compound 86-2 as beigepowder. MS ESI calcd for C6H3BrINO2 [M+H]+ 328, found 328.
5-bromo-N-(2-piperidin-1-yl-ethyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane; acetonitrile; at 20℃;
General procedure: A mixture of 1 mmol (1 equiv.) of carboxylic acids, 1.4 mmol (1.4 equiv.) of amine, 552 mg (1.8 equiv.) of PyBOP and 2 mL of triethylamine was stirred overnight at room temperature in 40 ml of a 1:1 mixture of CH2Cl2 and CH3CN. After solvent evaporation, the crude product was purified by column chromatography on silica (CHCl3:CH3CH2OH = 9:1) resulting in yellow thick oil that slowly crystallized.
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
i) Production of 5-bromonicotinamide 5-Bromonicotinic acid (5.05 g), ammonium chloride (2.10 g), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (7.30 g), 1-hydroxy-1H-benzotriazole monohydrate (3.90 g) and triethylamine (5.5 ml) were suspended in DMF (40 ml) and the mixture was stirred at room temperature for 16 hrs. Ethyl acetate and water were added to the reaction mixture and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was concentrated by drying and recrystallized from ethyl acetate to give the title compound (2.33 g) as colorless needle crystals. 1H-NMR (CDCl3+CD3OD)delta: 8.41 (1H, t, J= 2.2 Hz), 8.77 (1H, d, J=2.2 Hz), 8.94 (1H, d, J=2.2 Hz). IR (KBr): 3389, 3194, 3032, 1657, 1620 cm-1.
With ammonia; at 195℃; for 0.5h;
General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1percent by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99percent).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wtpercent of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min).
With 4-pyrrolidin-1-ylpyridine; triethylamine In tetrahydrofuran at 20℃; for 48h;
1 Example 1; Tert-Butyl 5-bromonicotinate
To a mixture of 5-bromonicotinic acid (0. 30g, 1. 49mmol) and di-tert-butyldicarbonate (0. 45g, 2. 06mmol) in THF (15mL) was added triethylamine (0. 25mL, L79mmol) followed by 4- (PYRROLIDINO) PYRIDINC (3OMG, O. 20MMOL). T'HE RESULTANT SOLUTION was stirred at ambient temperature FOR 48 HE. THE VOLATILCS WERE THEN removed under vacuum and the residue was purified by column chromatography on silica (gradient, CH2Cl2 to 3% MEOH/CH2Cl2) TO PROVIDE the product as a white solid (0. 35g, 91%) 1H-n.m. r. (CDCL3) #1. 60 (s, 9H, t-butyl), 8.35 (m, 1H, Ar), 8.79 (d, J2.5 Hz, 1H, Ar), 9. 06 (D, 1.4 Hz, 1H, Ar).
91.07%
With dmap In tetrahydrofuran at 25℃; for 12h;
5-(cyclobutylamino)nicotinic acid
tert-butyl 5-bromonicotinate. Di-tert-butyl dicarbonate (7.72 g, 35.40 mmol, 8.12 mL) was added to a stirred mixture of 5-bromopyridine-3-carboxylic acid (5.5 g, 27.23 mmol) and N,N-dimethylpyridin-4-amine (1.66 g, 13.61 mmol) in THF (100 mL) at 25° C. The reaction mixture was stirred at 25° C. for 12 hr, and evaporated in vacuo. The residue was dissolved in dichloromethane (100 ml) and washed successively with aqueous sodium hydrogen sulphate (1.80 g, 14.97 mmol) solution (40 ml), and water (50 ml). The organic layer was separated, dried over sodium sulphate and evaporated in vacuo to afford tert-butyl-5-bromopyridine-3-carboxylate (6.4 g, 24.80 mmol, 91.07% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 1.61 (s, 9H), 8.36 (t, 1H), 8.81 (d, 1H), 9.07 (d, 1H). LCMS(ESI): [M+H]+ m/z: 258.1 calcd; found 259.0; Rt=1.508 min.
82%
With dmap In tetrahydrofuran at 20℃; for 1.5h; Cooling with ice;
Tert-butyl 5-bromopyridine-3-carboxylate
Boc20 (4.28 g, 19.6 mmol) in THF (40 ml) was added to an ice-cold solution of 5-bromonicotinic acid (3.6 g, 17.82 mmol) and DMAP (1.09 g, 8.91 mmol) in THF (70 ml). The reaction mixture was stirred and allowed to warm to room temperature over 1.5 h then concentrated in vacuo. The residue was dissolved in saturated NaHC03 (aq) and extracted with DCM (3 x 100 ml). The combined organic extracts were dried (Na2S04), filtered and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-10% EtOAc / heptane) afforded the title compound (3.79 g, 82%) as a coloirless oil which solidified over time. 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 9.09 (m, 1 H), 8.83 (d, J = 2.2 Hz, 1 H), 8.38 (t, J = 2.2 Hz, 1 H), 1.63 (s, 9H) HPLCMS (Method M): [m/z]: 259.85 / 261.85 [M+H]+
63.A A.
A. 5-(3-chlorophenyl)-nicotinic acid A three neck flask was charged with 5-bromonicotinic acid (2 g, 9.90 mmol), 3-chlorophenylboronic acid (1.55 g, 9.90 mmol), a 0.4 M solution of sodiumcarbonate in water (37 mL, 14.8 mmol) and Acetonitrile (37 mL). The solution was degassed under vacuum and tetrakistriphenylphoshine Pd(0) (0.57 g, 0.495 mmol) was added and the reaction refluxed overnight under nitrogen. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was partially evaporated under reduced pressure and the remaining solution acidified to pH=2 with 1N HCl. The resulting solid was collected by filtration and dried under vacuum. 1H NMR [(CD3)2SO]: δ9.15-9.05 (m, 2H), 8.45 (s, 1H), 7.85 (s, 1H), 7.80-7.65 (m, 1H), 7.60-7.42 (m, 2H).
With triethylamine; In N-methyl-acetamide; dichloromethane; water;
3-(2-Pyridyl)-5-(5-bromopyrid-3-yl)-1,2,4-oxadiazole In a similar fashion, 5-bromonicotinoyl chloride was prepared from 5-bromonicotinic acid (2.02 g, 10 mmol). Treatment of the acid chloride with pyrid-2-ylamidoxime (1.37 g, 10 mmol) and triethylamine (4.04 g, 40 mmol) in dichloromethane (20 mL), followed by heating in dimethylformamide (20 mL) at 120 C. for 16 hours. After this time water was added and the precipitate collected and dried. Filtration through silica gel using dichloromethane followed by trituration with hexane afforded 2.58 g (85%) of 3-(2-pyridyl)-5-(5-bromopyrid-3-yl)-1,2,4-oxadiazole.
Stage A: 5-hydroxynicotinic acidTo 10.1 g (0.05 mol) of 5-bromonicotinic acid was added 1O g of NaOh dissolved in 63 mL of water, 3.1 g of coppersulfate pentahydrate and 0.42 g of copper (0). The reaction mixture was vigorously stirred and heated under reflux for 30 hours. After cooling the mixture to room temperature, 4.8 g of Na2S-H2O was added and stirring was pursued overnight. The reaction mixture was heated to 7O0C and treated with H2S gas until disappearance of the white precipitate (3h). After cooling to room temperature, the mixture was filtered and the pH of the filtrate was adjusted to 5.2 with concentrated hydrochloric acid. The precipitate was filtered and the pH of the filtrate was adjusted to 4.6 with concentrated hydrochloric acid. The white precipitate was then filtered, washed with water and dried under reduced pressure giving 4.3 g(yield: 62%) of product of molecular formula C7H5NO3. Aspect: white powder.Melting point: > 2600C. NMR spectrum of the protonIn DMSO-<4 at 300MHz, chemical shifts (ppm) and multiplicity: 8.48 (d, J = 1.5 Hz, IH),8.26 (d, J = 2.6 Hz, IH), 7.51 (d, J = 1.9 Hz, IH).Infrared spectrumIR spectrum was obtained as potassium bromide pellets. Absorption bands are given in cm 1: 3273, 1538, 1393, 1294.
methyl 5-(methylamino)pyridine-3-carboxylate[ No CAS ]
[ 91702-88-4 ]
Yield
Reaction Conditions
Operation in experiment
With methylamine In water
16 EXAMPLE 16
The intermediate methyl 5-methylamino-nicotinate has been obtained as follows: reaction of methylamine (40% in water) with 5-bromo-nicotinic acid in autoclave at 140° C. for seven hours gives 5-methylamino-nicotinic acid, m.p. 239°-242° C. from ethanol/water; this acid reacts with SOCl in methanol under reflux for seven hours to afford the ester (methyl 5-methylaminonicotinate; m.p. 113°-115° C., from petroleum ether.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃;
14
Reference Example 14: 5-Bromo-nicotinic acid tert-butyl ester. 5-Bromo-nicotinic acid (20.2g, lOOmmol) was dissolved in CHCI3 (200 mL) and tert-BuOR (40 mL); and WSC (21. Ig, 1 lOmmol) andDMAP (21. Ig, 1 lOmmol) was added thereto in order, and stirred at room temperature over night. The reaction mixture was diluted with chloroform, washed with 0.5N HCl aq. (220 mL), 0.5N NaOH aq. (100 mL), brine and dried over MgSO4 and silica gel. After filtration, the solvents were removed in vacuo to afford 5-Bromo-nicotinic acid fer^-butyl ester as a colorless solid. This solid was used for the next step without further purification.
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In chloroform at 20℃;
19
REFERENCE EXAMPLE 19 5-Bromo-nicotinic acid tert-butyl ester 5-Bromo-nicotinic acid (20.2 g, 100 mmol) was dissolved in CHCl3 (200 mL) and tert-BuOH (40 mL); and WSC (21.1 g, 110 mmol) and DMAP (21.1 g, 10 mmol) was added thereto in order, and stirred at room temperature over night. The reaction mixture was diluted with chloroform, washed with 0.5N HCl aq. (220 mL), 0.5N NaOH aq. (100 mL), brine and dried over MgSO4 and silica gel. After filtration, the solvents were removed in vacuo to afford 5-Bromo-nicotinic acid tert-butyl ester as a colorless solid.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃;
5
5-Bromo-nicotinic acid (20.2g, lOOmmol) was dissolved in CHCI3 (200 mL) and tert-BuOH (40 mL); and WSC-HCl (21. Ig, 1 lOmmol) and DMAP (21. Ig, 1 lOmmol) was added thereto in order, and stirred at room temperature over night. The reaction mixture was diluted with chloroform, washed with 0.5N HCl aq. (220 mL), 0.5N NaOH aq. (100 mL), brine and dried over MgSO4 and silica gel. After filtration, the solvents were removed in vacuo to afford 5-Bromonicotinic acid tert-butyl ester as a colorless solid. This solid was used for the next step without further purification.
Stage #1: 5-bromo-3-pyridinecarboxylic acid; methylamine hydrochloride With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h;
Stage #2: With sodium hydrogencarbonate In water; N,N-dimethyl-formamide
79
To a solution of 5.00 g of 5-bromonicotinic acid in 30 ml of DMF are added 1.99 g of methylamine hydrochloride, 3.31 g of 1-hydroxybenzotriazole, 9.54 g of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and 8.04 ml of N-methylmorpholine. After stirring for 24 hours at ambient temperature, the mixture obtained is quenched with saturated aq. sodium hydrogen carbonate solution. After exhaustive extraction with EtOAc, the combined organic extracts obtained are dried and concentrated. 5-Bromo-N-methyl-nicotinamide is obtained.
With dmap; benzotriazol-1-ol; caesium carbonate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 17h;
N-(5-Bromonicotinoyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline (8) 6,7-Dimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (200 mg, 0.870 mmol), 5-bromonicotinic acid (193 mg, 0.958 mmol), N-(3-dimethylaminopropyl)~N'- ethyl-carbodiimide hydrochloride (250 mg, 1.31 mmol), 1-hydroxybenzotriazole hydrate (133 mg, 0.870 mmol), 4-dimethylaminopyridine (213 mg, 1.74 mmol) and caesium carbonate (567 mg, 1.74 mmol) were suspended in 10 mL DMF and stirred at room temperature for 17 hours. The reaction mixture was then diluted with 40 mL ethyl acetate, washed with 2*40 mL NaHCO3 (sat aq), dried over MgSO4 and evaporated into a pale mass. Purification with flash chromatography (pet.ether/EtOAc 1/1 → 1/2) yielded 214 mg (65%) of N-(5-bromonicotinoyl)-6,7-dimethoxy-l,2,3,4- tetrahydroisoquinoline as white solids. 1H-NMR (CDCl3) rotameric mixture δ 8.73 (s, IH), 8.60 (s, IH), 7.94 (s, IH), 6.67-6.60 (ma)(br, 2H), 6.55 (mi)(s, IH), 6.40 (mi)(br s, IH), 4.79 (ma)(br s, 2H), 4.50 (mi)(br s, IH), 4.39, (mi)(br s, IH), 3.96 (mi)(br s, IH), 3.85 (br d, 6H), 3.77 (ma)(br s, 2H), 3.62 (mi)(br s, IH) 2.92-2.77 (ma+mi)(br m, 2H). TLC (pet.ether/EtOAc 1/1) Rf 0.28.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 24h; Inert atmosphere;
4.1.2. General synthesis of target compounds 14-55, 60-61 and 70-73
General procedure: To a solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride7 (100 mmol) in dry CH2Cl2 (250 mL) were added variousbromo-thiophene(pyridine)carboxylic acid 8-10, 56-57 and 62-65(100 mmol), EDCI (120 mmol), HOBt (120 mmol) and triethylamine(130 mmol) under argon. The mixture was stirred for 24 h at roomtemperature, diluted with CH2Cl2 (250 mL), washed with 1 mol L 1 HCl(150 mL × 2), saturated aqueous NaHCO3 (150 mL × 2), and brine (150mL × 2), dried over Na2SO4, and concentrated to dryness. The residuewas purified by silica gel column chromatography (50:1, V:V, chloroform:methanol) to give intermediate 11-13, 58-59 and 66-69 as ayellow solid (85-95%). Target compounds 14-55, 60-61 and 70-73were prepared according to the same operation of Suzuki-Miyauracoupling reaction. Intermediate 11-13, 58-59 and 66-69 (1 mmol),Pd(PPh3)4 (0.023 mmol), Na2CO3 (4 mmol) and different substitutedbenzeneboronic acid (1 mmol) were added in mixed solvent of DMSO (5mL) and H2O (2.5 mL) under argon. The reaction mixture was stirred for8 h at 100 , and then the mixture was filtered and concentrated. Thedried residue was dissolved in 50 mL of CHCl3 and then washed withsaturated aqueous NaHCO3 (50 mL × 2), H2O (50 mL × 2) and brine (50mL × 2), dried over Na2SO4, and concentrated to dryness. The residuewas purified by silica gel column chromatography (20:1, V:V,chloroform:methanol) to give target compounds (79-93%).
Stage #1: 5-bromo-3-pyridinecarboxylic acid With thionyl chloride Inert atmosphere; Reflux;
Stage #2: Cyclopropylamine In dichloromethane at 20℃;
2.1
Under the protection of N 2 , Thionyl chloride (36 ml, 494 mmol) was added dropwise to 5-bromonicotinic acid (5.00 g, 24.7 mmol). After the addition, Heat to reflux for 2-3 h until the solution is clear. The thionyl chloride was removed under reduced pressure to give a pale yellow solid. The solid was dissolved in 30 ml of anhydrous dichloromethane. The active intermediate solution was slowly added dropwise to a solution of cyclopropylamine (3.77 ml) dichloromethane (30 ml). After the completion of the dropwise addition, the mixture was allowed to react to room temperature overnight. After the reaction, 20 ml of a 2 mol/L K 2 CO 3 solution was added to the reaction system. Divide the dichloromethane phase, The aqueous phase was extracted with dichloromethane (15 ml x 3). Combine the organic phase, Dry with anhydrous Na 2 SO 4 . Separated and purified by column chromatography. (Petroleum ether: ethyl acetate = 1:1) gave a white solid, 5.27 g, yield 89%.
89%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With thionyl chloride Inert atmosphere; Reflux;
Stage #2: Cyclopropylamine In dichloromethane at 20℃;
2.1 1) Synthesis of 5-bromo-N-cyclopropylnicotinamide:
Thionyl chloride (36 ml, 494 mmol) was added dropwise to 5-bromonicotinic acid (5.00 g, 24.7 mmol) under N2.After the completion of the dropwise addition, the mixture was heated to reflux for 2-3 h until the solution was clarified, and the thionyl chloride was evaporated under reduced pressure to give a pale yellow solid.The solid was dissolved in 30 ml of dry dichloromethane and the active intermediate solution was slowly added dropwise to a solution of cyclopropylamine (3.77 ml) dichloromethane (30 ml). After the completion of the dropwise addition, the mixture was allowed to react to room temperature overnight.After the completion of the reaction, 20 ml of a 2 mol/L K2CO3 solution was added to the reaction system. Divide the dichloromethane phase,The aqueous phase was extracted with dichloromethane (15 mL x 3). Separated and purified by column chromatography.(Petroleum ether: ethyl acetate = 1:1) gave a white solid, 5.27 g, yield 89%.
89%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With thionyl chloride for 12h; Inert atmosphere; Reflux;
Stage #2: Cyclopropylamine In dichloromethane at 20℃;
2.1
1) Under the protection of N2, thionyl chloride (36 ml, 494 mmol) was added dropwise to 5-bromonicotinic acid (5.00 g, 24.7 mmol). After the addition was completed, the mixture was heated to reflux for 2-3 h until the solution was clarified and decompressed. The thionyl chloride was spun off to give a pale yellow solid. The solid was dissolved in 30 ml of dry dichloromethane and the active intermediate solution was slowly added dropwise to a solution of cyclopropylamine (3.77 ml) dichloromethane (30 ml). After the completion of the dropwise addition, the mixture was allowed to react to room temperature overnight.After the completion of the reaction, 20 ml of a 2 mol/L K2CO3 solution was added to the reaction system.The dichloromethane phase was separated and the aqueous phase was extracted with dichloromethane (15 ml×3).The organic phases were combined and dried over anhydrous Na 2 SO 4 . Separated and purified by column chromatography.(petroleum ether: ethyl acetate = 1:1) gave 5.27 g of a white solid.The yield was 89%.
89%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With thionyl chloride Inert atmosphere; Reflux;
Stage #2: Cyclopropylamine In dichloromethane at 20℃; Inert atmosphere;
2.1 1) Synthesis of 5-bromo-N-cyclopropylnicotinamide
Thionyl chloride (36 ml, 494 mmol) was added dropwise to 5-bromonicotinic acid (5.00 g, 24.7 mmol) under N2.After the completion of the dropwise addition, the mixture was heated to reflux for 2-3 h until the solution was clarified, and the thionyl chloride was evaporated under reduced pressure to give a pale yellow solid.The solid was dissolved in 30 ml of dry dichloromethane and the active intermediate solution was slowly added dropwise to a solution of cyclopropylamine (3.77 ml) dichloromethane (30 ml).After the completion of the dropwise addition, the mixture was allowed to react to room temperature overnight.After the completion of the reaction, 20 ml of a 2 mol/L K2CO3 solution was added to the reaction system.The methylene chloride phase was separated, and the aqueous phase was extracted with dichloromethane (15 ml×3), and the organic phase was combined and dried over anhydrous Na2SO4.Separated and purified by column chromatography.(Petroleum ether: ethyl acetate = 1:1) gave a white solid, 5.27 g, yield 89 %
Stage #1: 5-bromo-3-pyridinecarboxylic acid With diphenylphosphoranyl azide; triethylamine In toluene at 20℃; for 0.5h;
Stage #2: benzyl alcohol In toluene at 20℃; Heating / reflux;
BENZYL 5-BROMO-3-PYRIDINYL CARBAMATE: To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at room temperature for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at room temperature for 1 h then refluxed overnight. After cooling to room temperature, the reaction mixture was washed with H2O, NaHCO3 and brine, dried over MgSO4 and concentrated. Purification by flash chromatography (15-50% EtOAc/Hexane) provided 22.2 g (72.5 mmol, 73 %) of benzyl 5-bromo-3-pyridinylcarbamate: 1H NMR (400 MHz, CDCl3) δ 8.39-8.32 (m, 2 H), 8.29 (s, 1 H), 7.45-7.32 (m, 5 H), 6.94 (s, 1 H), 5.22 (s, 2 H); ESMS m/e: 307.0 (M+H)+.
73%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 0.5h;
Stage #2: benzyl alcohol In toluene at 20℃; Heating / reflux;
Benzyl 5-bromo-3-pyridinyl carbamate: To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at room temperature for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at room temperature for 1 h then refluxed overnight. After cooling to room temperature, the reaction mixture was washed with H2O, NaHCO3 and brine, dried over MgSO4 and concentrated. Purification by flash chromatography (15-50% EtOAc in Hexane) provided 22.2 g (72.5 mmol, 73%) of benzyl 5-bromo-3-pyridinylcarbamate: 1H NMR (CDCl3) δ 8.39-8.32 (m, 2H), 8.29 (s, 1H), 7.45-7.32 (m, 5H), 6.94 (s, 1H), 5.22 (s, 2H); ESMS m/e: 307.0 (M+H)+.
73%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 0.5h;
Stage #2: benzyl alcohol In toluene at 20℃; Heating / reflux;
To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at room temperature for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at room temperature for 1 h then refluxed overnight. After cooling to room temperature, the reaction mixture was washed with H2O, saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated. Purification by flash column chromatography (eluent: 15-50% EtOAc in Hexane) provided benzyl 5-bromo-3-pyridinylcarbamate (22.2 g, 72.5 mmol, 73% yield): 1H NMR (CDCl3) δ 8.39-8.32 (m, 2H), 8.29 (s, 1H), 7.45-7.32 (m, 5H), 6.94 (s, 1H), 5.22 (s, 2H); ESMS m/e: 307.0 (M+H)+.
73%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 0.5h;
Stage #2: benzyl alcohol In toluene at 20℃; Heating / reflux;
Benzyl 5-bromo-3-pyridinyl carbamate: To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at room temperature for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at room temperature for 1 h then refluxed overnight. After cooling to room temperature, the reaction mixture was washed with H2O, saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated. Purification by flash chromatography (15-50% EtOAc in Hexane) provided 22.2 g (72.5 mmol, 73% yield) of benzyl 5-bromo-3-pyridinylcarbamate: 1H NMR (CDCl3) δ 8.39-8.32 (m, 2 H), 8.29 (s, 1 H), 7.45-7.32 (m, 5 H), 6.94 (s, 1 H), 5.22 (s, 2 H); ESMS m/e: 307.0 (M+H)+.
Stage #1: 5-bromo-3-pyridinecarboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 25℃; for 0.5h;
Stage #2: benzyl alcohol In toluene at 20℃; Heating / reflux;
To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at room temperature for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at room temperature for 1 h then refluxed overnight. After cooling to room temperature, the reaction mixture was washed with H2O, NaHCO3 and brine, dried over MgSO4 and concentrated. Purification by flash chromatography (15-50% EtOAc in Hexane) provided 22.2 g (72.5 mmol, 73%) of benzyl 5-bromo-3-pyridinylcarbamate: 1H NMR (CDCl3) 6 8.39-8.32 (m, 2H), 8.29 (s, 1H), 7.45-7.32 (m, 5H), 6.94 (s, 1H), 5.22 (s, 2H); ESMS m/e: 307.0 (M+H)+.
Stage #1: 5-bromo-3-pyridinecarboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 0 - 20℃; for 2.5h;
Stage #2: ethylamine In tetrahydrofuran at -10 - 15℃;
3a
Step 3a: Synthesis of 5-bromo-N-ethyl-nicotinamide; 2 Q5-bromo-nicotinic acid Q (2 kg, 9.9 M) was dissolved in THF (19 L) and cooled to 0 0C. 1,1'- Carbonyldiimidazole (1.76 kg, 10.9 M) was then added over 30 minutes and the reaction mixture was allowed to warm to ambient temperature with additional stirring for 2 hours.The reaction solution was cooled to -10 0C and ethylamine solution (6.5 L, 13 M) in THF was then added over 20 minutes. The temperature was allowed to rise to 15 0C, after which the reaction was stirred at ambient temperature overnight.The reaction solution was concentrated until solid precipitated out (~ 4 L). Distilled water (4 L) was added and the mixture was stirred for 2 h. Solid was collected by filtration, washed with water and dried in vacuo at 45 0C to afford product 2 as white crystals (1.85 kg, 8.08 M, 82%). 1H NMR (CDCI3) δ 1.27(t, 3H), 3.52(m, 2H), 8.25(S1 1H), 8.77(s, 1H), 8.86(s, 1 H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 70 - 80℃;
4.1. Chemistry
General procedure: The synthesis route of compounds 1-24 followed the general pathway outlined in Scheme 1. The substituted nicotinic acid (1 mmol) mixed with benzenesulfonamide (1 mmol) through by using 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (1.2 mmol) and 4-dimethylaminopyridine (DMAP) (1.2 mmol) in anhydrous CH2Cl2 for 6-8 h at 70-80 °C. The reaction was monitored by TLC. The products are extracted with ethyl acetate. The extract is washed successively with 1 N HCl, water, 1 M NaHCO3, and water, dried over MgSO4, filtered and evaporated. The residue is purified by column chromatography using petroleum ether and ethyl acetate (1:1).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 70 - 80℃;
General procedure: The synthesis route of compounds 1-24 followed the general pathway outlined in Scheme 1. The substituted nicotinic acid (1 mmol) mixed with benzenesulfonamide (1 mmol) through by using 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (1.2 mmol) and 4-dimethylaminopyridine (DMAP) (1.2 mmol) in anhydrous CH2Cl2 for 6-8 h at 70-80 C. The reaction was monitored by TLC. The products are extracted with ethyl acetate. The extract is washed successively with 1 N HCl, water, 1 M NaHCO3, and water, dried over MgSO4, filtered and evaporated. The residue is purified by column chromatography using petroleum ether and ethyl acetate (1:1).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In dichloromethane; acetonitrile at 20℃;
1 General synthesis of 1a-o, 1r-t and 4a-d using Method A [11-13]
General procedure: A mixture of 1 mmol (1 equiv.) of carboxylic acids, 1.4 mmol (1.4 equiv.) of amine, 552 mg (1.8 equiv.) of PyBOP and 2 mL of triethylamine was stirred overnight at room temperature in 40 ml of a 1:1 mixture of CH2Cl2 and CH3CN. After solvent evaporation, the crude product was purified by column chromatography on silica (CHCl3:CH3CH2OH = 9:1) resulting in yellow thick oil that slowly crystallized.
With triethylamine; diisopropyl-carbodiimide In dichloromethane at 50℃; Inert atmosphere;
1 5-bromo-N-(2-(phenylamino)phenyl)nicotinamide (1E)
A mixture of 5-bromonicotinic acid (20.0 g, 99 mmol), N-phenyl-o-phenylenediamine (19.32 g, 105 mmol), diisopropylcarbodiimide (DIC) (26.5 g, 210 mmol), and triethylamine (Et3N)(2.65 g, 27 mmol) in DCM (anhydrous, 350 mL) was heated to about 50° C. and degassed overnight under argon. After cooling to RT, the solids were then filtered off. The filtrate was washed with water (2×200 mL), dried over sodium sulfate and loaded onto silica gel. A flash column (gradient of 3% to 10% ethyl acetate in DCM) gave 30.32 g of 1E; 83% yield, pure by HNMR.
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 4h;
9.1 Step 1
To a solution of 5-bromonicotinic acid (XLII) (500 mg, 2.49 mmol) in DMF (8 mL) was added cyclohexanamine (XLIII) (247 mg, 2.49 mmol) and DIPEA (643 mg, 4.98 mmol). The reaction was cooled at 0°C before adding HATU (947 mg, 2.49 mmol). The reaction was warmed to room temperature and stirred for 4 hrs. The reaction was diluted with EtOAc, washed with 2x water, brine, dried over MgS04 and concentrated under vacuum to yield crude 5-bromo-N-cyclohexylnicotinamide (XLIV). The product was used without further purification. ESIMS found for C12H15BrN20 mlz 283 (M+H).
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 4h;
1
To a solution of 5-bromonicotinic acid (XLII) (500 mg, 2.49 mmol) in DMF (8 mL) was added cyclohexanamine (XLIII) (247 mg, 2.49 mmol) and DIPEA (643 mg, 4.98 mmol). The reaction was cooled at 0°C before adding HATU (947 mg, 2.49 mmol). The reaction was warmed to room temperature and stirred for 4 hrs. The reaction was diluted with EtOAc, washed with 2x water, brine, dried over MgS04 and concentrated under vacuum to yield crude 5-bromo-N-cyclohexylnicotinamide (XLIV). The product was used without further purification. ESIMS found for Ci2Hi5BrN20 mlz 283 (M+H).
General procedure: To 6-chloronicotinic acid 19a (10 g) in methylene chloride(100 ml) solution, N,N’-diisopropyl-O-tert-butylisourea (50 g) wasadded and the mixture was stirred under heating and reflux for16 h. The insoluble compound was filtered out, and the filtratewas concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 6/1) to obtain the compound 20a (11.66 g). To the compound 20a (6.0 g) in dimethylacetoamide (30 ml) solution, tris(dibenzylideneacetone)dipalladium (0.51 g), zinc cyanide (0.22 g), diphenylphosphinoferrocene (0.62 g), and zinc powder (1.98 g) were added and the mixture was stirred under argon atmosphere at 120 °C for 3 h. The reaction solution was filtered by sellite, which was then washed with ethyl acetate. Then, the filtrate was washed with distilled water and saturated saline, then the organic layer was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate= 5/1) to obtain the compound 21a (3.59 g). To copper(I) iodide(0.93 g) in tetrahydrofuran (50 ml) suspension, ethylmagnesium bromide (0.86 M tetrahydrofuran solution)(12.5 ml) was added dropwise under cooling at 0 °C, the mixture was stirred at 0 °C for 30 min, then the compound 21a (1.0 g) obtained above in tetrahydrofuran (10 ml) solution was added atthe 20 °C. After stirring for 30 min at that temperature, 28% ammonia solution in water and ethyl acetate were added to the mixture and the solution separated. The aqueous layer was extracted with ethyl acetate, while the combined organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate= 8/1) to obtained the compound 22a (0.47 g). To the compound 22a (200 mg) in tetrahydrofuran (1 ml) solution, (-)-B-chlorodiisopinocampheylborane (65% hexane solution) (0.92 ml) was added dropwise under cooling at 20 °C, then the mixture was stirred at that temperature for 18 h. Then, ether and distilled water were added to the reaction mixture, and the solution was separated. The organic layer was extracted with distilled water and 1 M hydrogen chloride. Then, the combined aqueous layer was neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated to obtained the title compound (150 mg, 84% ee). The optical purity was determined using CHIRALCEL AD-H(Daicel Chemical Industries) (movement phase: hexane/ethanol= 98/2, 1.0 ml/min).
Stage #1: 5-bromo-3-pyridinecarboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0 - 20℃; for 0.25h; Inert atmosphere;
Stage #2: O-pivaloylhydroxylamine trifluoromethanesulfonate salt In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
tert-butyl 4-((5-bromonicotinamido)methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 80℃; for 2h; Microwave irradiation;
1 Preparation of tert-bulyl 4-((5-bromonicotinamido)methyl)piperidine-] -carboxylate (104)
Preparation of tert-bulyl 4-((5-bromonicotinamido)methyl)piperidine-] -carboxylate (104)5-Bromo-3-pyridinecarboxylic acid (98) (2.25g, lOmmol), 4-aminomethyl- 1 -Bocpiperidine (103) (2.13g, lOmmol), HATU (4.5g, lOmmol) and DIPEA (5m1, 3Ommol) were dissolved in DMF (lOml). The reaction mixture was heated at 80 °C for two hours in the microwave reactor. The reaction mixture was diluted with ethyl acetate (50m1) and washed withwater (50 ml) and brine (50 ml). The ethyl acetate solution was dried over sodium sulfate and concentrated. The crude material was purified by automated column chromatography using petroleum ether and ethyl acetate as eluents to give tert-butyl 4-((5- bromonicotinamido)methyl)piperidine- 1 -carboxylate (104) (3. 98g) as an off white solid. Yield:100%. Synthesis confimed by LCMS and MS (positive ion mode).
Stage #1: 3-(trifluoromethyl)phenylmagnesium bromide With titanium(IV) tetraethanolate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 5-bromo-3-pyridinecarboxylic acid With tributylphosphine; cobalt(II) chloride In tetrahydrofuran at 20℃; Inert atmosphere; chemoselective reaction;
[Zn(5-bromonicotinate)2(2,2'-biimidazole)][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium hydroxide; In water; at 160℃; for 72h;Autoclave;
A mixture of Zn(NO3)2 6H2O (44.6mg,0.15mmol),5-Brnic(60.6 mg,0.3mmol),H2biim (20.1mg,0.15mmol),NaOH(12.0mg,0.3 mmol),and H2O (10mL)was stirred at room temperature for 15min,and then sealed in a25mL Teflon-lined stainless steel vessel,and heated at 160 1C for 3days,followed by cooling to room temperature at a rate of 10 1C/h. Colorless block-shaped crystals were isolated manually,and washed with distilled water.Yield: 55%(basedon5-BrnicH).CalcdforC24H14Br2ZnN4O4:C 44.51%,H2.18%,N8.65%.Found:C44.17%,H1.84%,N8.24%.IR (KBr,cm1): 1609vs,1552m,1441m,1394w,1370vs,1342w,1281m,1237w,1181w,1125s,1088w,1028m,991w,925w,887w,862w,771m,754m,732m,687m,553w,and434w.
Stage #1: 5-bromo-3-pyridinecarboxylic acid; 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol With potassium fluoride In 1,4-dioxane Inert atmosphere;
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 90℃; for 12h; Inert atmosphere;
5-(6-hydroxynaphthalen-2-yl)nicotinic Acid (14)
General procedure: Compounds I or II (1 eq.),potassium fluoride (3 eq.), and appropriate bromo derivatives(1.1 eq.) were dissolved in dioxane, respectively, thenmixed and deoxygenated for 10 min with a stream of N2.After deoxygenation, PdCl2(dppf) (0.05 eq.) was added, andwas brought to reflux, allowed to be stirred under N2 for10~22 h until the reaction was complete as indicated by TLCanalysis (step b in Schemes 1, 2 and 3).
5-bromo-N-[dimethyl(oxido)-λ4-sulfanylidene]nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere;
3 5-Bromo-N-[dimethyl(oxido)-λ4-sulfanylidene]nicotinamide
To the mixture of dimethylsulfoximine (4.0 g, 43 mmol, 1 eq) and 5-bromonicotinic acid (9.31 g, 1.05 eq) in anhydrous DMF (85 mL) under nitrogen atmosphere was added diisopropylamine (15 mL, 2.0 eq) and BOP (21.6 g, 1.1 eq). After the reaction was stirred at RT for 15 minutes, it was poured into saturated aq NaHCO3 and extracted with EtOAc. The organic phase was separated, washed sequentially with saturated NaHCO3 (1×), brine (1×), aq NH4Cl (1×), and brine (1×), and finally dried with anhydrous Na2SO4. The upper brown solution was decanted, concentrated, and the brown oily residue was subject to a gradient column chromatography (EtOAc-Hexane 1:4 to 1:1). The corresponding product fractions were collected and concentrated. The solid residue was treated with EtOAc-Hexane (1:7) and the resulting mixture was stirred at RT for 2 hours. The white solid was collected by filtration and dried to give the title compound (8.89 g, 75%).
With acetic acid; isopentyl nitrite; at 80℃; for 24h;Inert atmosphere;
5-Bromo-3-pyridinecarboxamide (0.2010 g, 1 mmol) wasdissolved in acetic acid (2 mL), and to the stirring solution was added amyl nitrite (0.40 mL, 3 mmol).The reaction was placed under N2 atmosphere and heated to 80 °C for 24 hours, whereupon thereaction was complete by consumption of starting material by TLC. The solution was condensed andco-evaporated with toluene (2 x 5 mL), then purified via trituration from EtOAc and Hexane. Theresulting suspension was filtered to afford off-white powder (0.1993 g, 0.98 mmol). 1H-NMR (400MHz; MeOD): delta 9.12 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.62 (dd, J = 2.3, 1.7 Hz, 1H); MSm/z 200 (M-, 100percent); melting point: 180-183 °C; IR (neat) numax 3033 (w br, O-H stretch), 1673 (s,C=O stretch), 1287 (acyl C-O), 688 (s, aromatic C-H) cm-1
In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere;
To a solution of 5-bromonicotinic acid (XVI) (1.01 g, 5 mmol) in dry DCM (10 mL) under nitrogen was addedoxalyl chloride (0.654 mL, 7.5 mmol) followed by dry DMF (0.1 mL). The solution was stirred at r.t. for 30 min. The solventwas evaporated under vacuum before adding dry pyridine (10 mL) followed by cyclopropylmethanamine (0.39 mL, 4.5mmol). The solution was stirred at r.t. under nitrogen for 2 h. The solution was poured into ice water, basified with sat.aq. NaHCO3 and extracted with DCM. The combined organic phases were dried over MgSO4, concentrated and driedunder vacuum to yield 5-bromo-N-(cyclopropylmethyl) nicotinamide (XVII) as an off-white solid (0.82 g, 3.2 mmol, 71%yield). 1H NMR (DMSO-d6) delta ppm -0.07-0.07 (m, 2H), 0.15-0.29 (m, 2H), 0.68-0.88 (m, 1H), 2.93 (t, J=6.22 Hz, 2H),8.20 (t, J=1.88 Hz, 1H), 8.62 (d, J=1.70 Hz, 2H), 8.75 (s, 1H); ESIMS found C10H11BrN2O m/z 254,256 (M+, M+2).
HATU (116 mg, 0.305 mmol) was added to 5-bromonicotinic acid (61.6 mg, 0.305 mmol) and DIPEA (66 mu, 0.381 mmol) in DMF (2 ml). The mixture was stirred at rt for 15 min before <strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (43 mg, 0.254 mmol) in DMF (1 ml) was added. The mixture was stirred at ambient temperature for 10 d before solvent was evaporated and residue purified by flash chromatography using 10-20percent EtOAc in hexanes as eluent. Yield: 28.7 mg (32percent).
With pyridine; methanesulfonyl chloride In acetonitrile at 0℃; for 3.16667h;
General Procedure for the Preparation of the Intermediate 3
General procedure: A mixture of 10.0 mmol 5-bromonicotinic acid and 10.0 mmol anthranilic acid were dissolved with 250 mL of acetonitrile in 100 mL of reaction flask. Then, 5 mL of pyridine was added dropwise to completely dissolve the reaction raw material under stirring at 0 °C. Finally, 3 mL of methanesulfonyl chloride was dropwise added to the reaction system within 10 min. Upon completion of addition, the ice bath was removed and the reaction solution continued stirring at room temperature. After reacting for 3.0 h, a certain amount of water was added to end the reaction, and the resulting mixture was adjusted to pH = 7-8 with saturated sodium carbonate. A large amount of solid was precipitated, followed by filtration and drying to give the intermediate 3
With diphenylphosphoranyl azide; triethylamine In toluene; <i>tert</i>-butyl alcohol at 100℃; for 2.5h;
122.1 1st step
1st step Triethylamine (8.3 ml), DPPA (12.8 ml), and tert-butanol (7.6 ml) were added to a toluene (100 ml) solution containing 5-bromo-nicotinic acid (10 g), followed by stirring at 100°C for 2.5 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, n-hexane : ethyl acetate (= 10:1) was added, and an insoluble precipitate was collected by filtration, and a white solid of benzyl(5-bromopyridin-3-yl)carbamate (10.8 g) was thus obtained. 1H-NMR (DMSO-d6, 400MHz) δ:10.25 (s, 1H), 8.59 (d, 1H, J = 2.2Hz), 8.34 (d, 1H, J = 2.2Hz), 8.20-8.15 (m, 1H), 7.46-7.33 (m, 5H), 5.19 (s, 2H)
5-bromo-nicotinic acid (3.2 g, 2.5 mmol) was dispersed in 20 mL of thionyl chloride.The reaction system was heated to 82 C, kept under reflux for 2 hours, and cooled to room temperature.The reaction solution was added to 20 mL of toluene while maintaining a slow stirring.Concentrate under reduced pressure to a pale yellow oil. After the concentrate was dissolved in 100 mL of dichloromethane, <strong>[35944-64-0]3-iodo-4-methylaniline</strong> was added to the solution.(874 mg, 3.8 mmol) and triethylamine (0.5 mL),The reaction was stirred at room temperature overnight until the starting material disappeared.The reaction solution was concentrated under reduced pressure and then evaporated.Wash with 2N HCl solution and saturated brine,The organic phase was dried over anhydrous magnesium sulfate and concentrated.Compound 18 (1.0 g, 96%) was obtained as a pale yellow solid.
5-bromo-N-(4-isopropyl-3-methylphenyl)pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.2%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
HATU (4.2 g, 11.14 mmol) was added to a solution of 5-bromopyridine-3-carboxylic acid (1.5 g, 7.43 mmol), 4-isopropyl-3-methyl-aniline hydrochloride (1.38 g, 7.43 mmol) and DIPEA (3.07 mL, 18.56 mmol) in DMF (30 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and the solids were filtered off, washed with water (100 mL) and dried in vacuo at 60C to give 5-bromo-N-(4-isopropyl-3-methyl- phenyl)pyridine-3-carboxamide (2.43 g, 7.29 mmol, 98.2% yield) as a brown solid. Data: LC- MS (Method A) Rt: 6.90 min; m/z 333.1 + 335.1 (1:1) (M+H)+.
5-Bromonicotinic acid (23.2g, 0.15mol) was suspended and dissolved in dichloromethane (1000mL), and oxalyl chloride (0.12mol) was added dropwise. The solids gradually dissolved. After stirring at room temperature for about 3h, no more gas was released. Add 1-methyl-10alpha-methoxy light ergosterol (30.2g, 0.1mol) in batches, and then add triethylamine (0.25mol) dropwise. After the addition, stir the reaction at room temperature for 2-3 hours, TLC detection (UV254 , Methanol/chloroform/ammonia=1:8:0.1) The reaction is completed. Cool to room temperature, add saturated sodium bicarbonate aqueous solution to the reaction solution, stir for 1h, separate the liquid, wash the organic phase with water, and then decolorize with activated carbon (10-15%) for 1h, filter, dry over anhydrous sodium sulfate, filter, and reduce pressure Concentrate to dryness, then heat and dissolve with acetone-water (10:1), cool to 0-5C to crystallize, filter, and dry to obtain 44.2 g of nicergoline and HPLC purity 99.0%.
5-bromo-N-(2-(trifluoromethyl)benzyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; Inert atmosphere;
Stage #2: o-trifluoromethylbenzylamine With 4-methylmorpholine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere;
64%
With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 72h; Inert atmosphere;
5-Bromo-V-(2-(trifluoromethyl)benzyl)nicotinamide 19:
General procedure: Under an argon atmosphere 0.24 g (1.17 mmol, 1 eq) 18, 0.67 (1.76 mmol, 1.5 eq) HBTU were dissolved in 15 mL dry DMF and cooled to o °C. To the solution 0.23 g (1.29 mmol, 1.1 eq) 10a, 0.7 mL (7.02 mmol, 6.0 eq) 4-methylmorphline and 0.34 g (1.76 mmol, 1.5 eq) EDC-HC1 were added. The approach stirred for 3 d at room temperature. The solvent was evaporated, and the residue was suspended in water. The aqueous phase was extracted with ethyl acetate (4x) and the combined organic phase was washed with brine. After drying over MgS04 and filtration the solvent was removed, and the crude product was purified via flash chromatography (hexane:ethyl acetate 2:1). A white solid was obtained (0.27 g, 0.75 mmol, 64%); -NMR (300 MHz, DMS0-d6) d = 9.39 (t, J=5-6 Hz, lH), 9.04 (d, J=i.8 Hz, lH), 8.89 (d, J= 2.2 Hz, lH), 8.50 (t, J= 2.1 Hz, lH), 7.77 - 7.46 (m, 4H), 4.67 (d, J=5-5 Hz, 2H) ppm; MS (ESI) m/z: 358.90 [M + H+].
5-bromo-N-(sec-butyl)-N-methylnicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.2%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: N-methyl-sec-butylamine In N,N-dimethyl-formamide at 0 - 20℃;
Step 1: Synthesis of 5-bromo-N-(sec-butyl)-N-methylnicotinamide
To a solution of 5-bromonicotinic acid (2.0 g, 9.901 mmol) and HATU (5.65 g, 14.851 mmol) in DMF (40 mL) at 0° C. was added DIPEA (5.2 mL 9.9 mmol). The resulting mixture was stirred for 30 min at 0° C. and then N-methylbutan-2-amine (0.91 g, 10.396 mmol) was added. The resulting mixture was warmed to room temperature and stirred overnight, then diluted with H2O (40 mL). The mixture was extracted with EtOAc (3*30 mL) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/pet. ether) to afford the desired product (1.96 g, 73.2% yield). LCMS (ESI) m/z: [M+H] calcd for C11H15BrN2O: 271.04; found 271.1.
73.2%
Stage #1: 5-bromo-3-pyridinecarboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: N-methyl-sec-butylamine In N,N-dimethyl-formamide at 20℃;
1 Step 1: Synthesis of 5-bromo-N-(sec-butyl)-N-methylnicotinamide
To a solution of 5-bromonicotinic acid (2.0 g, 9.901 mmol) and HATU (5.65 g, 14.851 mmol) in DMF (40 mL) at 0 °C was added DIPEA (5.2 mL 9.9 mmol). The resulting mixture was stirred for 30 min at 0 °C and then N-methylbutan-2-amine (0.91 g, 10.396 mmol) was added. The resulting mixture was warmed to room temperature and stirred overnight, then diluted with H2O (40 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/pet. ether) to afford the desired product (1.96 g, 73.2% yield). LCMS (ESI) m/z. [M + H] calcd for CnHisBrNaO: 271.04; found 271.1.
5-bromo-N-(methyl-d<SUB>3</SUB>)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
To a solution of 5-bromonicotinic acid (100 mg, 0.49 mmol) and HATU (226 mg, 0.59 mmol) in DMF (4 ml) was added DIPEA (259 µl, 1.49 mmol), and the reaction mixture was stirred at room temperature for 5 min. Methylamine-d3 hydrochloride (41.9 mg, 0.59 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was partitioned between water and EtOAc, and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (0-100% EtOAc/hexanes) to afford the title compound (94 mg, 87%) as a white solid. LCMS calculated for C7H5D3BrN2O (M+H)+: m/z = 218.0; found: 218.0.
With copper(l) iodide In tetrahydrofuran at -70 - 20℃; Inert atmosphere;
Intermediate 7A 5-tert-Butylnicotinic acid
To a solution of 5-bromonicotinic acid (4.0 g, 19.99 mmol) and copper(I) iodide (380 mg, 2.00 mmol) in tetrahydrofuran (100 mL) was added a solution of tert-butylmagnesium chloride in tetrahydrofuran (1.7 M, 29.4 mL, 50.0 mmol) dropwise at -70 °C under N2 atmosphere. Then the mixture was stirred overnight at room temperature. The reaction was quenched by careful addition of ammonium chloride solution. The resulting mixture was concentrated and poured into water, then extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to give 80 mg of desired product as a white solid. LC-MS (method 4, gradient 0.01-2.50 min 5-100% B): Rt = 0.718 min; MS (ESIpos): m/z = 180 [M+H]+.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere;
1 Example 1 Synthesis of methyl 2-((5-bromopyridin-3-ylformamido)methyl)benzoate (3)
Add compound 1 (404.02 mg, 2.0 mmol), compound 2 (443.63 mg, 2.2 mmol), HBTU (834.33 mg, 2.2 mmol), N2 protection in a 50 ml two-necked flask, dissolve with anhydrous DMF (8 mL), and add N , N-diisopropylethylamine (568.66mg, 4.4mmol), after the addition, the reaction was stirred at room temperature for 1.5h, and then the reaction system was added water and ethyl acetate extraction, combined ethyl acetate layer, respectively, water, saturated salt Washed with water, dried with anhydrous sodium sulfate, dried, filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 3 (434.4 mg), white Solid, yield: 62.2%
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