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Product Details of [ 20826-04-4 ]

CAS No. :20826-04-4 MDL No. :MFCD00009783
Formula : C6H4BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :FQIUCPGDKPXSLL-UHFFFAOYSA-N
M.W :202.01 Pubchem ID :88707
Synonyms :

Calculated chemistry of [ 20826-04-4 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.9
TPSA : 50.19 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.16
Log Po/w (XLOGP3) : 1.07
Log Po/w (WLOGP) : 1.54
Log Po/w (MLOGP) : -0.34
Log Po/w (SILICOS-IT) : 1.43
Consensus Log Po/w : 0.97

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.14
Solubility : 1.45 mg/ml ; 0.00717 mol/l
Class : Soluble
Log S (Ali) : -1.72
Solubility : 3.89 mg/ml ; 0.0193 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.26
Solubility : 1.12 mg/ml ; 0.00555 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.33

Safety of [ 20826-04-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 20826-04-4 ]

* 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.

  • Upstream synthesis route of [ 20826-04-4 ]
  • Downstream synthetic route of [ 20826-04-4 ]

[ 20826-04-4 ] Synthesis Path-Upstream   1~43

  • 1
  • [ 20826-04-4 ]
  • [ 13535-01-8 ]
Reference: [1] ChemMedChem, 2014, vol. 9, # 1, p. 217 - 232
  • 2
  • [ 20826-04-4 ]
  • [ 113118-81-3 ]
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 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Patent: WO2006/103120, 2006, A2, . Location in patent: Page/Page column 115
  • 6
  • [ 20826-04-4 ]
  • [ 24242-19-1 ]
YieldReaction ConditionsOperation in experiment
74% 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 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Tetrahedron: Asymmetry, 1992, vol. 3, # 7, p. 871 - 901
[2] Patent: WO2016/73847, 2016, A2, . Location in patent: Paragraph 00198
  • 8
  • [ 10400-19-8 ]
  • [ 20826-04-4 ]
YieldReaction ConditionsOperation in experiment
94% at 0 - 155℃; for 10 h; 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).
Reference: [1] Patent: WO2004/35545, 2004, A2, . Location in patent: Page 45-46
  • 9
  • [ 28733-43-9 ]
  • [ 20826-04-4 ]
YieldReaction ConditionsOperation in experiment
98% at 80℃; for 24 h; 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): 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] Tetrahedron Letters, 2015, vol. 56, # 37, p. 5153 - 5156
  • 10
  • [ 27848-84-6 ]
  • [ 20826-04-4 ]
  • [ 35155-28-3 ]
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 ]
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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 ]
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  • [ 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. &lt;2&gt; 138, p. 244,257
[4] Chemische Berichte, 1886, vol. 19, p. 2766
[5] Monatshefte fuer Chemie, 1889, vol. 10, p. 705
  • 17
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  • [ 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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] Patent: EP2163554, 2010, A1, . Location in patent: Page/Page column 64
  • 22
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  • [ 29681-44-5 ]
Reference: [1] Patent: US2002/19531, 2002, A1,
[2] Journal fuer Praktische Chemie (Leipzig), 1933, vol. &lt;2&gt; 138, p. 244,257
  • 23
  • [ 186581-53-3 ]
  • [ 20826-04-4 ]
  • [ 29681-44-5 ]
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 ]
YieldReaction ConditionsOperation 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
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[3] Patent: US2016/375131, 2016, A1, . Location in patent: Paragraph 0080
[4] ACS Combinatorial Science, 2017, vol. 19, # 5, p. 286 - 298
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[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
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  • [ 75-04-7 ]
  • [ 20986-40-7 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 16, p. 4407 - 4410
  • 26
  • [ 20826-04-4 ]
  • [ 20986-40-7 ]
YieldReaction ConditionsOperation in experiment
101% With thionyl chloride In 1,2-dichloro-ethane 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).
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[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,
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  • [ 7664-93-9 ]
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  • [ 17965-71-8 ]
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  • [ 71719-06-7 ]
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[2] Patent: US2016/375131, 2016, A1,
[3] ACS Combinatorial Science, 2017, vol. 19, # 5, p. 286 - 298
[4] Patent: WO2008/151073, 2008, A1,
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  • [ 20826-04-4 ]
  • [ 51035-70-2 ]
Reference: [1] Chemistry - A European Journal, 2002, vol. 8, # 5, p. 1218 - 1226
  • 31
  • [ 20826-04-4 ]
  • [ 37669-64-0 ]
YieldReaction ConditionsOperation 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
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[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 ]
YieldReaction ConditionsOperation 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,
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  • [ 20826-04-4 ]
  • [ 59105-50-9 ]
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  • [ 39741-46-3 ]
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  • [ 20826-04-4 ]
  • [ 106726-82-3 ]
Reference: [1] Patent: EP2533783, 2015, B1,
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  • [ 20826-04-4 ]
  • [ 135124-71-9 ]
Reference: [1] Patent: US2011/294788, 2011, A1,
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  • [ 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 ]
YieldReaction ConditionsOperation 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

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[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 14, p. 4535 - 4546
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[4] Patent: WO2006/82373, 2006, A1, . Location in patent: Page/Page column 107
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