* 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] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 5, p. 1428 - 1433
2
[ 394-31-0 ]
[ 57772-57-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h; Stage #2: With potassium iodide In water at 90℃; for 0.5 h;
The solution of 5-hydroxyanthoranic acid (1.99 g, 1.33 mmol) in water (20 ml) was added to HCl (10 ml) and NaNO2 (1.08 g, 45.6 mmol). The mixture was stirred at 0 °C for 30 min and then mixture was added KI (3.24 g, 19.5 mmol) and water (5 ml). The result mixture was stirred at 90 °C for 30 min. The mixture extracted with ethyl acetate, and organic layer was washed with H2O, dried (MgSO4) and evaporated. The product was isolated by silica gel column chromatography to give the title compound 2 (2.15 g, 88percent) as brown solid mp=180 °C; IR (KBr) νmax=3293, 1700, 1666, 1583, 1477, 1427, 1307, 1265, 1241, 1222, 1018, 933, 877, 827, 782 cm-1; 1H NMR (500 MHz, DMSO): δ=6.69 (1H, d, J=8.5 Hz), 7.13 (1H, s), 7.71 (1H, d, J=8.5 Hz), 9.9 (1H, s), 13C NMR (DMSO) δ=80.5, 117.8, 120.6, 137.9, 141.7, 157.8, 168.3. HRMS (APCI): m/z [M+H]+ calcd for C7H5IO3: 264.9361; found: 264.9377.
37%
Stage #1: With sulfuric acid In water at 4℃; Stage #2: With potassium iodide; sodium nitrite In water at 4 - 90℃;
Synthesis of 5-Hydroxy-2-iodo-benzoic acid (2).; Suspension of 2-amino-5- hydroxybenzoic acid (5.0 g, 32.7 mmol) in deionized water (100 mL) was mixed with 60 mL of concentrated sulfuric acid, which was added dropwise, resulting in a clear solution, which was held at 4 0C overnight, yielding suspension of white crystals. The suspension, while still cold, was mixed with 20 mL of an aqueous solution of sodium nitrite (2.4 g, 34.8 mmol). The resulting yellow-orange solution was mixed with 20 mL of an aqueous solution of potassium iodide (7.4 g, 44.6 mmol), which was added dropwise. The resulting mixture, dark-brown in color, was kept at 90 0C for 1 h and then was kept at 4 0C overnight affording dark red to brown crystals, which were filtered off and redissolved in 100 mL of deionized boiling water. Activated charcoal (7 g) was added to the hot solution, which was held at 90 0C for 1 h. The slurry, while hot, was filtered off using filter paper (retention, 10 μm) and the supernatant was kept at 40C resulting in faintly orange crystals, which were filtered off and dried in a desiccator at r.t. C7H5IO3, found (calc): C, 31.51 (31.84); H, 2.14 (1.91); I, 47.31 (48.07). 1H NMR (400 MHz, DMSO-d6): δ 5.1 (s, IH, OH), 6.81, 7.38, 7.71 (H3, H5, H2, IH each, in aromatic ring), 11 (s, 1 H, COOH). Yield, 3.2 g (37 molpercent).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 5, p. 1428 - 1433
[2] Angewandte Chemie - International Edition, 2001, vol. 40, # 23, p. 4393 - 4394
[3] Tetrahedron, 2016, vol. 72, # 47, p. 7633 - 7637
[4] Chemistry - An Asian Journal, 2016, vol. 11, # 22, p. 3267 - 3274
[5] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
[6] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 15, p. 2047 - 2049
[7] Patent: WO2009/55128, 2009, A2, . Location in patent: Page/Page column 40
[8] Journal of the American Chemical Society, 1984, vol. 106, # 9, p. 2651 - 2655
[9] Tetrahedron, 2000, vol. 56, # 27, p. 4777 - 4792
[10] Angewandte Chemie - International Edition, 2001, vol. 40, # 23, p. 4395 - 4397
[11] Journal of the American Chemical Society, [12] Journal of the American Chemical Society, 2009, vol. 131, p. 251 - 262
[13] Patent: WO2011/32277, 2011, A1, . Location in patent: Page/Page column 87
[14] Tetrahedron, 2012, vol. 68, # 39, p. 8358 - 8366
[15] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7360 - 7377
[16] Organic and Biomolecular Chemistry, 2017, vol. 15, # 11, p. 2403 - 2410
3
[ 99-06-9 ]
[ 57772-57-3 ]
Reference：
[1] Journal of the American Chemical Society, 1917, vol. 39, p. 452
[2] Tetrahedron, 2012, vol. 68, # 39, p. 8358 - 8366
4
[ 107946-58-7 ]
[ 57772-57-3 ]
Reference：
[1] Journal of the American Chemical Society, 1984, vol. 106, # 9, p. 2651 - 2655
Reference：
[1] Journal of the American Chemical Society, 1917, vol. 39, p. 452
10
[ 10034-85-2 ]
[ 57772-57-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1891, vol. 263, p. 234
11
[ 57772-57-3 ]
[ 74-88-4 ]
[ 857599-37-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 5, p. 1428 - 1433
[2] Chemistry - An Asian Journal, 2016, vol. 11, # 22, p. 3267 - 3274
12
[ 57772-57-3 ]
[ 77-78-1 ]
[ 857599-37-2 ]
Reference：
[1] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
[2] Journal of the American Chemical Society, [3] Journal of the American Chemical Society, 2009, vol. 131, p. 251 - 262
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7360 - 7377
13
[ 186581-53-3 ]
[ 57772-57-3 ]
[ 857599-37-2 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2314,2317
14
[ 57772-57-3 ]
[ 54413-93-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7360 - 7377
The solution of 5-hydroxyanthoranic acid (1.99 g, 1.33 mmol) in water (20 ml) was added to HCl (10 ml) and NaNO2 (1.08 g, 45.6 mmol). The mixture was stirred at 0 C for 30 min and then mixture was added KI (3.24 g, 19.5 mmol) and water (5 ml). The result mixture was stirred at 90 C for 30 min. The mixture extracted with ethyl acetate, and organic layer was washed with H2O, dried (MgSO4) and evaporated. The product was isolated by silica gel column chromatography to give the title compound 2 (2.15 g, 88%) as brown solid mp=180 C; IR (KBr) numax=3293, 1700, 1666, 1583, 1477, 1427, 1307, 1265, 1241, 1222, 1018, 933, 877, 827, 782 cm-1; 1H NMR (500 MHz, DMSO): delta=6.69 (1H, d, J=8.5 Hz), 7.13 (1H, s), 7.71 (1H, d, J=8.5 Hz), 9.9 (1H, s), 13C NMR (DMSO) delta=80.5, 117.8, 120.6, 137.9, 141.7, 157.8, 168.3. HRMS (APCI): m/z [M+H]+ calcd for C7H5IO3: 264.9361; found: 264.9377.
37%
Synthesis of 5-Hydroxy-2-iodo-benzoic acid (2).; Suspension of 2-amino-5- hydroxybenzoic acid (5.0 g, 32.7 mmol) in deionized water (100 mL) was mixed with 60 mL of concentrated sulfuric acid, which was added dropwise, resulting in a clear solution, which was held at 4 0C overnight, yielding suspension of white crystals. The suspension, while still cold, was mixed with 20 mL of an aqueous solution of sodium nitrite (2.4 g, 34.8 mmol). The resulting yellow-orange solution was mixed with 20 mL of an aqueous solution of potassium iodide (7.4 g, 44.6 mmol), which was added dropwise. The resulting mixture, dark-brown in color, was kept at 90 0C for 1 h and then was kept at 4 0C overnight affording dark red to brown crystals, which were filtered off and redissolved in 100 mL of deionized boiling water. Activated charcoal (7 g) was added to the hot solution, which was held at 90 0C for 1 h. The slurry, while hot, was filtered off using filter paper (retention, 10 mum) and the supernatant was kept at 40C resulting in faintly orange crystals, which were filtered off and dried in a desiccator at r.t. C7H5IO3, found (calc): C, 31.51 (31.84); H, 2.14 (1.91); I, 47.31 (48.07). 1H NMR (400 MHz, DMSO-d6): delta 5.1 (s, IH, OH), 6.81, 7.38, 7.71 (H3, H5, H2, IH each, in aromatic ring), 11 (s, 1 H, COOH). Yield, 3.2 g (37 mol%).
To a mixture of 2-amino-5-hydroxybenzoic acid (25.0 g, 163 mmol) in water (500 mL) and H2S04 16M (33 mL) at 0 C is added, over 30 min, a solution of NaN02 (20.9 g, 304 mmol) in 100 mL of water. The temperature is maintained at 0-5 C during the addition. After diazotization, a solution of Kl (67.6 g, 406 mmol) in 100 mL water is added and the resulting reaction mixture is heated to 80-90 C for 1 h. The reaction mixture is cooled to 0 C and the solid is collected by filtration and the filtrate is extracted with Et20. The combined organic layers are concentrated and combined with the filter solid. Treatment with charcoal in hot water and co-evaporation with MeOH (6x) provides iodide 84a1.
A solution of sodium nitrite (1.56 g, 22.5 mmol) in water (4.5 mL) was added dropwise to a solution of 2-amino-5-hydroxybenzoic acid (2.30 g, 15.0 mmol) in a mixture of water (20 mL) and concentrated sulfuric acid (2.8 mL) at 0 C. After stirring for 5 min, a solution of potassium iodide (3.74 g, 22.5 mmol) in water (4.5 mL) was added dropwise to the mixture. The resulting solution was heated at 100 C with stirring for 1 h and then allowed to cool to room temperature. After stirring for 14 h,the mixture was cooled to 0 C. The precipitate was collected by filtration, washed with cold water, and dried in vacuoto give crude 5-hydroxy-2-iodobenzoic acid (3.26 g) as a brown solid, which was dissolved in anhydrous DMF (65 mL). To this solution were added potassium carbonate (12.8 g, 92.7 mmol) and iodomethane (5.8 mL, 92.7 mmol) at room temperature under a nitrogen atmosphere. After stirring for 12 h, the mixture was filtered through a pad of celite and the pad was washed with Et2O. The filtrate was acidified with 10% HCl and then extracted with Et2O. The organic layer was washed with saturated aqueous NaHCO3, water, and brine, dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give methyl 2-iodo-5-methoxybenzoate [2] (3.44 g, 79% in 2 steps) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) delta 7.83(1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 2.9 Hz), 6.75 (1H, dd, J = 8.6, 2.9 Hz), 3.93 (3H, s), 3.82 (3H, s). To a solution of methyl 2-iodo-5-methoxybenzoate (1.21 g, 4.13 mmol) in a 3:1 mixture of MeOH and water (47 mL) was added lithium hydroxide hydrate (260 mg, 6.2 mmol) at room temperature. After stirring for 15 h, the resulting mixture was diluted with saturated aqueous NaHCO3 and washed with CH2Cl2. The aqueous layer was acidified with 10% HCl and then extraceted with CH2Cl2. The last organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in thionyl chloride (5.1 mL). After heating at reflux with stirring for 2 h, the resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH2Cl2 (13.5 mL). To the mixture were added isopropylamine (290 mg, 4.9 mmol) and triethylamine (1.24 g, 12.2 mmol) at 0 C under a nitrogen atmosphere. After stirring at room temperature for 6 h, the resulting solution was diluted with EtOAc. The mixture was washed with10% HCl, saturated aqueous NaHCO3, water, and brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl3 to give 17 (991 mg, 75% in 3 steps) as colorless needles.
With caesium carbonate; In acetonitrile; at 65℃; for 15h;
a) 2-Iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester To a stirred solution of <strong>[57772-57-3]2-iodo-5-hydroxybenzoic acid</strong> (prepared according to the method described in J. Am. Chem. Soc., 1984, 106, 2651) (27.15 g, 103 mmol) in anhydrous acetonitrile (400 mL) was added cesium carbonate (73.80 g, 227 mmol) and 4-methoxybenzyl chloride (33.5 mL, 247 mmol). The resulting solid mass was broken up and the mixture heated at 65 C. for 15 h. The reaction mixture was poured into sat. NaHCO3 (aq.) (400 mL) and the resultant mixture extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel with a gradient of ethyl acetate:hexanes (1:9, v/v) to ethyl acetate:hexanes (1:3, v/v) as eluent to afford 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester (15.39 g, 30.52 mmol, 30%). Data for 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester: 1H NMR (400 MHz, (CD3)2SO): delta 7.81 (d, 1H), 7.39 (d, 2H), 7.32 (d, 2H), 7.27 (d, 1H), 6.95-6.84 (m, 5H), 5.21 (s, 2H), 5.01 (s, 2H), 3.73 (s, 3H), 3.71 (s, 3H) ppm.
4-[5-(2-amino-ethyl)-2-(methyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride[ No CAS ]
[ 57772-57-3 ]
[ 80029-43-2 ]
[ 254451-29-1 ]
Yield
Reaction Conditions
Operation in experiment
With 1,2-dichloro-ethane; triethylamine; In methanol; N,N-dimethyl-formamide;
Step B: Preparation of N-{2-[3-(4-Cyano-3-fluoro-benzyl)-2-methyl-3H-imidazol-4-yl]-ethyl}-5-hydroxy-2-iodobenzamide A stirred mixture of 4-[5-(2-amino-ethyl)-2-(methyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride as prepared in Example 10, Step A (2.00 g, 6.038 mmol), <strong>[57772-57-3]5-hydroxy-2-iodobenzoic acid</strong> (1.594 g, 6.038 mmol), 1-Hydroxybenzotriazole hydrate (816 mg, 6.038 mmol), and triethylamine (2.52 mL, 18.114 mmol) in dry DMF (12.0 mL) was cooled to 0 C., and EDC (1.158 g, 6.038 mmol) was added. After stirring at 0 C. for 15 minutes, the reaction mixture was stirred at ambient temperature overnight, then poured into water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was preabsorbed onto silica gel and purified by flash chromatography eluding with a gradient of 6-9% MeOH/CH2Cl2 to give the titled product. 1H NMR: CD3OD (delta, 400 MHz) 7.73 (1H,dd, J=6.8 and 7.9 Hz), 7.59(1H, d, J=8.6 Hz), 7.01(1H, d, J=9.9 Hz), 6.95(1H, d, J=8.0 Hz), 6.85(1H, s), 6.71(1H, d, J=2.9 Hz), 6.61(1H, dd, J=2.9 and 8.6 Hz), 5.37(2H, s), 3.47(2H, t, J=7.2 Hz), 2.78(2H, d, J=7.2 Hz), and 2.28(3H, s) ppm.
With dibutyltin dilaurate; In tetrahydrofuran; at 70℃; for 8h;
Synthesis of 5- [3-(Triethoxysilanyl)-propylcarbamoyloxy] -2-iodo-benzoic acid (3).; Solution of 2 (264 mg, 1 mmol) and 5 mg of of dibutyltin dilaurate in 100 mL of dry THF was mixed with 247 mg (1 mmol) of 3-isocyanatopropyltriethoxysilane and the resulting solution was kept under reflux at 70 0C for 8 h. Following solvent evaporation under vacuum and washing by hexane and drying under vacuum, the ensuing faintly yellowish paste weighed 460 mg (yield 90 mol%). CnH26INO7Si, found (calc): C, 39.33 (39.93); H, 4.44 (5.12); I, 24.41 (24.82); N, 3.76 (2.74). 1H NMR (400 MHz, DMSO-d6): delta 1.0 (m, C- CH2-Si), 1.76 (m, CH3), 2.94 (m, C-CH2-N), 3.94 (m, C-CH2-O), 7.14 (IH, H3 benzene), 7.73 (d, H2, H5 benzene), 9.79 (IH, NH-C=O), 13 (IH, COOH).
With potassium carbonate; In acetone; for 5h;Reflux; Inert atmosphere;
To a solution of <strong>[57772-57-3]2-iodo-5-hydroxybenzoic acid</strong>1 (8.00 g, 30.3 mmol) in acetone (606 mL) were added benzyl bromide (14.0 mL, 121 mmol) and potassium carbonate (41.9 g, 303 mmol), and then the resulting mixture was heated to reflux for 5 h. After being cooled to room temperature, the reaction mixture was filtered through a pad of Super-Cel and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (hexane:AcOEt = 9:1) to afford iodo benzyl ester S1 (12.8 g, 95%)
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere;
A solution of sodium nitrite (1.56 g, 22.5 mmol) in water (4.5 mL) was added dropwise to a solution of 2-amino-5-hydroxybenzoic acid (2.30 g, 15.0 mmol) in a mixture of water (20 mL) and concentrated sulfuric acid (2.8 mL) at 0 C. After stirring for 5 min, a solution of potassium iodide (3.74 g, 22.5 mmol) in water (4.5 mL) was added dropwise to the mixture. The resulting solution was heated at 100 C with stirring for 1 h and then allowed to cool to room temperature. After stirring for 14 h,the mixture was cooled to 0 C. The precipitate was collected by filtration, washed with cold water, and dried in vacuo to give crude <strong>[57772-57-3]5-hydroxy-2-iodobenzoic acid</strong> (3.26 g) as a brown solid, which was dissolved in anhydrous DMF (65 mL). To this solution were added potassium carbonate (12.8 g, 92.7 mmol) and iodomethane (5.8 mL, 92.7 mmol) at room temperature under a nitrogen atmosphere. After stirring for 12 h, the mixture was filtered through a pad of celite and the pad was washed with Et2O. The filtrate was acidified with 10% HCl and then extracted with Et2O. The organic layer was washed with saturated aqueous NaHCO3, water, and brine, dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give methyl 2-iodo-5-methoxybenzoate [2] (3.44 g, 79% in 2 steps) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) delta 7.83(1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 2.9 Hz), 6.75 (1H, dd, J = 8.6, 2.9 Hz), 3.93 (3H, s), 3.82 (3H, s). To a solution of methyl 2-iodo-5-methoxybenzoate (1.21 g, 4.13 mmol) in a 3:1 mixture of MeOH and water (47 mL) was added lithium hydroxide hydrate (260 mg, 6.2 mmol) at room temperature. After stirring for 15 h, the resulting mixture was diluted with saturated aqueous NaHCO3 and washed with CH2Cl2. The aqueous layer was acidified with 10% HCl and then extraceted with CH2Cl2. The last organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in thionyl chloride (5.1 mL). After heating at reflux with stirring for2 h, the resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH2Cl2 (13.5 mL). To the mixture were added isopropylamine (290 mg, 4.9 mmol) and triethylamine (1.24 g, 12.2 mmol) at 0 C under a nitrogen atmosphere. After stirring at room temperature for 6 h, the resulting solution was diluted with EtOAc. The mixture was washed with10% HCl, saturated aqueous NaHCO3, water, and brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl3 to give 17 (991 mg, 75% in 3 steps) as colorless needles.
With sodium hydroxide; In methanol; water; for 0.25h;
The methyl benzoate 7 (11.6 mg, 42 muM, 1 equiv) was placed into a round-bottom flask followed by the addition of MeOH (100 muL) and 1 N NaOH solution (200 muL, 210 mumol, 5 equiv). The progress of the reaction was monitored with TLC, and the reaction was stopped 15 min after complete consumption of the methyl ester by adding 1 N HCl (500 muL). After extraction with EtOAc (3 × 5 mL) the solvent was dried over Na2SO4 and evaporated under reduced pressure to give a pale yellow crystalline solid. The solid was dried in fine vacuum overnight yielding the title compound 5-hydroxy-2-iodobenzoic acid (3) (10.0 mg, 38 mumol, 91%). The 1H NMR data are identical to the reported values from ref. 22a. 1H NMR (400 MHz, DMSO-d6): delta = 13.11 (br s, 1 H, COOH), 9.97 (s, 1 H, ArOH), 7.71(d, 1 H, 3JH-H = 8.6 Hz, ArCH-3), 7.13 (d, 1 H, 4JH-H = 3.0 Hz, ArCH-6),6.68 (dd, 1 H, 3JH-H = 8.6 Hz, 4JH-H = 3.0 Hz, ArCH-4) ppm.13C NMR (100 MHz, DMSO-d6): delta = 167.8 (ArCOOH), 157.4(ArCOH), 141.2 (ArCH-3), 137.5 (ArCCOOH), 120.2 (ArCH-4),117.3 (ArCH-6), 80.0 (ArCI) ppm. HRMS (ESI-): m/z calcd forC7H4IO3 [M - H]- = 262.9211; found: 262.9208.
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