* 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.
With 8-quinolinol; sodium hydroxide; copper dichloride In water at 20℃; for 0.333333 h; Sealed tube; Microwave irradiation
General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.
Add 5-bromo-2-iodobenzoic acid (1998 g, 6.11 mol) portion wise to a 20 °C solution of sulfuric acid (100 mL) in methanol (13 L). Heat the suspension to reflux for 24 hours, then cool to 20 °C and remove the solvent under reduced pressure. Pour the residue into a 1 : 1 mixture of methyl-ieri-butyl ether and ice water (20 L) and separate the phases. Extract the aqueous phase with methyl-tert-butyl ether (1.5 L), combine the organic phases and wash with aqueous 0.2 M NaOH (5 L), wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve the crude product in 40-45 °C petroleum ether (10 L), filter through a pad of diatomaceous earth and evaporate under reduced pressure. Dissolve the residue in petroleum ether (5 L) and cool to -50 °C, filter the first crop solids, wash the solid with ice cold petroleum ether. Evaporate the mother liquor, redissolve the solid in petroleum ether (1 L), cool to -50 °C, and filter a second crop. Combine first and second crops and dry in open air to provide the title compound as a yellow solid (1880 g, 90percent).
Reference：
[1] Organic Letters, 2008, vol. 10, # 14, p. 3001 - 3004
[2] Tetrahedron, 2011, vol. 67, # 1, p. 125 - 143
[3] Patent: WO2014/143601, 2014, A1, . Location in patent: Page/Page column 10
[4] Journal of the Chemical Society, 1937, p. 1096,1101
6
[ 21740-00-1 ]
[ 181765-86-6 ]
Reference：
[1] Journal of the Chemical Society, 1956, vol. 78, p. 6130,6134
[2] RSC Advances, 2013, vol. 3, # 38, p. 17271 - 17280
7
[ 21740-00-1 ]
[ 77-78-1 ]
[ 181765-86-6 ]
Reference：
[1] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
8
[ 5794-88-7 ]
[ 21740-00-1 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With hydrogenchloride; sodium hydroxide; sodium nitrite In water at 0℃; for 2 h; Inert atmosphere Stage #2: With sulfuric acid; potassium iodide In water at 35 - 90℃; for 0.833333 h; Inert atmosphere
A solution of 8 (3.9 g, 0.018 mol), NaNO2 (1.5 g, 0.022 mol) and NaOH (0.90 g, 0.023 mmol) in H2O (55 mL) was added dropwise to a stirred solution of conc. HCl (6.4 mL) in H2O (9 mL) cooled at 0 °C over a period of 1.5 h. After addition the stirring was continued for another 30 min at 0 °C. The formed suspension of diazonium salt was added to a stirred solution of KI (4.5 g, 0.027 mol) and conc. H2SO4 (1.1 mL) in H2O (7.4 mL) at 35 to 40 °C over 20 min. The mixture was then heated to 90 °C and stirred for 30 min. Unreacted iodine was removed by steam distillation. The mixture was stirred and cooled. The crude product was filtered and washed with H2O, and then dissolved in NaOH solution (aq. 40percent). The polymeric components were separated by decantation and the clear solution was acidified with conc. HCl. The product was extracted by Et2O. The extract was dried over MgSO4 and concentrated under vacuum. The residue was crystallized from MeOH/H2O (1:1, v/v) to give compound 9 (3.56 g, 0.0109 mol, 60percent) as a pale yellow solid.
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 46, p. 10851 - 10854
[2] Organic Letters, 2008, vol. 10, # 14, p. 3001 - 3004
[3] Tetrahedron, 2011, vol. 67, # 1, p. 125 - 143
[4] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
[5] Collection of Czechoslovak Chemical Communications, 1984, vol. 49, # 1, p. 86 - 109
[6] Synthesis, 1997, # 11, p. 1301 - 1304
[7] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
[8] RSC Advances, 2013, vol. 3, # 38, p. 17271 - 17280
[9] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 5031 - 5037
[10] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
[11] Patent: WO2014/189370, 2014, A1, . Location in patent: Page/Page column 28
9
[ 88-67-5 ]
[ 21740-00-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 5, p. 640 - 647
[2] Chemische Berichte, 1896, vol. 29, p. 1410
[3] Tetrahedron Letters, 2011, vol. 52, # 29, p. 3726 - 3728
10
[ 121554-10-7 ]
[ 21740-00-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 1036 - 1040
11
[ 118-92-3 ]
[ 21740-00-1 ]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
12
[ 21740-00-1 ]
[ 199786-58-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 65℃; for 8.33333 h; Stage #2: With water In tetrahydrofuran
To a stirred mixture of acid 2-iodo-5-bromobenzoic acid (15.0 g, 45.9 mmol) in dry THF (100 mL) under argon was added neat BH3.DMS (16.0 mL, 169 mmol) dropwise over 20 minutes. The resulting mixture was heated at 65° C. for 8 hours, cooled to room temperature and quenched by the dropwise addition of water (40 mL). The reaction mixture was concentrated in vacuo. The crude alcohol was diluted with of EtOAc (300 mL), washed with 1N NaOH (2.x.30 mL), 1N HCl (1.x.30 mL), saturated aqueous NaHCO3 solution (1.x.30 mL) and brine (1.x.30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 2-iodo-5-bromobenzyl alcohol (13.8 g, 96percent). 1H NMR (CDCl3): δ 7.56 (d, 1H, J=8.25 Hz), 7.54 (s, 1H), 7.04 (d, 1H, J=8.25 Hz), 4.47 (s, 2H). HPLC: Rt=3.12 min. m/z=312 M+H+).
54%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 1 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water for 1.5 h;
5-Bromo-2-iodobenzoic acid (7c) (750 mg, 2.3 mmol) was dissolved in dry THF (25 mL) and the reaction mixture was cooled to 0 °C. NEt3 (0.48 mL, 3.4 mmol) and ethyl chloroformate (0.33 mL, 3.4 mmol) were added and the reaction mixture was stirred for 1 hour. Next a solution of NaBH (130 mg, 3.4 mmol) in H20 (2 mL) was added and the mixture was stirred for 1.5 hour. The reaction was quenched with H20 (15 mL), whereupon CH2C12 (20 mL) was added and the layers were separated. Hereupon, the H20-layer was extracted with CH2C12 (20 mL). Subsequently, the combined organic layers were washed with H20 (25 mL) and brine (25 mL), dried over MgS04 and concentrated in vacuo. The crude product was purified by gradient column chromatography (-heptane/EtOAc, 19: 1 to 9: 1) to obtain compound 7c as a white solid (410 mg, 54percent over 2 steps). RF = 0.40 (EtOAc/-heptane, 1 :4). 1H- NMR (400 MHz, CDC13) δ: 7.65 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.3, 2.5 Hz, 1H), 4.64 (d, J = 6.1 Hz, 2H), 1.96 (t, J = 6.2 Hz, 1H).
Reference：
[1] Synthesis, 1997, # 11, p. 1301 - 1304
[2] Patent: US2005/250753, 2005, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2014/189370, 2014, A1, . Location in patent: Page/Page column 30
[4] Journal of Organic Chemistry, 2002, vol. 67, # 26, p. 9428 - 9438
[5] Patent: WO2004/48314, 2004, A1, . Location in patent: Page 49-50
[6] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6181 - 6189
[7] Tetrahedron, 2011, vol. 67, # 1, p. 125 - 143
[8] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
[9] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 5031 - 5037
[10] Patent: WO2014/146490, 2014, A1, . Location in patent: Page/Page column 142
[11] Angewandte Chemie - International Edition, 2015, vol. 54, # 43, p. 12777 - 12781[12] Angew. Chem., 2015, vol. 127, # 43, p. 12968 - 12972,5
[13] Journal of Organic Chemistry, 2016, vol. 81, # 5, p. 1733 - 1745
[14] Organic Letters, 2016, vol. 18, # 9, p. 2126 - 2129
[15] Organic and Biomolecular Chemistry, 2017, vol. 15, # 11, p. 2403 - 2410
[16] Journal of the American Chemical Society, 2018, vol. 140, # 30, p. 9400 - 9403
13
[ 21740-00-1 ]
[ 689291-89-2 ]
Reference：
[1] Tetrahedron, 2011, vol. 67, # 1, p. 125 - 143
[2] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
[3] Organic Letters, 2016, vol. 18, # 9, p. 2126 - 2129
[4] Journal of the American Chemical Society, 2018, vol. 140, # 30, p. 9400 - 9403
With N-Bromosuccinimide; sulfuric acid at 60℃; for 2h;
86%
With N-Bromosuccinimide; sulfuric acid at 60℃; for 2h;
86%
With N-Bromosuccinimide; sulfuric acid at 60℃; for 2h;
9 Preparation of Compound 6
Add compound 5 (8.44 g, 34.03 mmol) to a 250 ml round bottom flaskAnd 60ml concentrated sulfuric acid, stir to 60 ° C and add N-bromosuccinimide(4.82 g, 38.06 mmol), reacted for 2 h, and after cooling to room temperature, the solution was dropped into ice water.Extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.Column chromatography gave 9.54 g of white solidCompound 6, yield 86%.
80%
With N-Bromosuccinimide; sulfuric acid for 2h;
With bromine at 160 - 180℃;
With N-Bromosuccinimide; sulfuric acid at 60℃; regioselective reaction;
Procedure for the preparation of 5-bromo-2-iodobenzoic acid (2) from 2-iodobenzoic acid (1).
Preparation of compound 2 was carried out according to the reported method.3 Thus, 2-iodobenzoic acid 1 (1.240 g, 5.0 mmol) was taken up in concentrated H2SO4 (10.0 mL) and heated to 60 C. To this was added solid NBS (1.068 g, 6.0 mmol) in three portions, each during 15 min. When the reaction was considered complete as determined by TLC analysis, the mixture was poured into crushed ice (40 g) to precipitate the solids. The precipitated solids were filtered and washed with cold water (20 mL). The solid residue was dissolved in ethyl acetate and washed with water and brine, the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in acetone, then, petroleum ether was added. The solid obtained was triturated and washed with a mixture of acetone and petroleum ether to afford 5-bromo-2-iodobenzoic acid (2) 0.809 g, 49% yield as an off white solid, mp 155-157 C. From liquor mothers was crystallized 5-bromo-2-iodobenzoic acid (2) 0.399 g, 24% yield as an off white solid, mp 153-154 C. For purposes of characterization the product was recrystallized either from boiling aqueous ethanol or from acetone/petroleum ether and 5-bromo-2-iodobenzoic acid (2) was obtained as a white solid; mp 160-161°C. (lit.4 160-161 °C)
Stage #1: 2-Iodobenzoic acid With sulfuric acid at 60℃; for 0.333333h;
Stage #2: With N-Bromosuccinimide for 2.75h;
5-bromo-2-iodobenzoic acid (1f).
Prepared according to literature procedure. A solution of 2-iodobenzoic acid (1,240 mg, 5.0 mmol) in Conc. H2SO4 ( 10.00 mL) was heated at 60 °C for 20 minutes. The solution was yellow orange. Then N-bromosuccinimide (1,668 mg, 6.0 mmol) was added in three portions each during 15 minutes. The mixture was brown and allowed to stir for 2 hours. After the reaction was completed, filtered and wash with cold water. A white solid was obtain. The aqueous eluted was extracted with EtOAc, the organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated that to obtain white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4, 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.7, 143.2, 136.6, 134.9, 134.7, 122.4, 92.7. Other data was identical to the literature values.
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride In water at 0℃; for 0.25h;
Stage #2: With sodium nitrite In water at 0℃; for 1.58333h;
Stage #3: With potassium iodide In water at 0 - 25℃; for 21.1667h;
87%
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium nitrite In water at 0 - 40℃; for 3h;
Stage #2: With sulfuric acid; potassium iodide In water at 90℃; for 1.33333h;
1 Example 1. Synthesis of 2-iodo-5-bromobenzoic acid (2)
2-Amino-5-bromobenzoic acid (2.14 g, 10 mmol), NaNO2 (0.828 g, 12 mmol) and NaOH (0.55 g,11 mmol) was dissolved in 40 ml of water, stirred, cooled to 0 ° C in an ice bath, and 12 ml of a 6 mol/L hydrochloric acid solution was added dropwise thereto, and the mixture was dropped over 2 hours. After the completion of the dropwise addition of hydrochloric acid, the reaction system was continued at 0 ° C for 1 h, then the reaction system was heated to 35-40 ° C, and a solution of KI [(KI 2.5 g, 15 mmol), H 2 SO 4 (0.6 ml) and water (5 ml) was slowly added. ], 20min added. The reaction system was then heated to 90 ° C for 1 h. After the reaction,The reaction system was slowly cooled to room temperature to precipitate a large amount of solids.Filtered, washed with water to give a crude yellow product. The crude product was recrystallized from 50% ethanol to give a pale yellow solid, 2.87g.The yield was 87%.
77%
Stage #1: 5-Bromo-2-aminobenzoic acid With nitrosonium tetrafluoroborate In dichloromethane; acetonitrile at -30 - 20℃; Inert atmosphere;
Stage #2: With potassium iodide In dichloromethane; acetonitrile at 20℃; Inert atmosphere;
60%
Stage #1: 5-Bromo-2-aminobenzoic acid With sodium hydroxide; sodium nitrite In water at 0℃; Inert atmosphere;
Stage #2: With hydrogenchloride In water at 0℃; for 2h; Inert atmosphere;
Stage #3: With sulfuric acid; potassium iodide In water at 35 - 90℃; Inert atmosphere;
60%
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium hydroxide; sodium nitrite In water at 0℃; for 2h; Inert atmosphere;
Stage #2: With sulfuric acid; potassium iodide In water at 35 - 90℃; for 0.833333h; Inert atmosphere; Further stages;
1.2. Synthesis of 5-bromo-2-iodobenzoic acid (9).
A solution of 8 (3.9 g, 0.018 mol), NaNO2 (1.5 g, 0.022 mol) and NaOH (0.90 g, 0.023 mmol) in H2O (55 mL) was added dropwise to a stirred solution of conc. HCl (6.4 mL) in H2O (9 mL) cooled at 0 °C over a period of 1.5 h. After addition the stirring was continued for another 30 min at 0 °C. The formed suspension of diazonium salt was added to a stirred solution of KI (4.5 g, 0.027 mol) and conc. H2SO4 (1.1 mL) in H2O (7.4 mL) at 35 to 40 °C over 20 min. The mixture was then heated to 90 °C and stirred for 30 min. Unreacted iodine was removed by steam distillation. The mixture was stirred and cooled. The crude product was filtered and washed with H2O, and then dissolved in NaOH solution (aq. 40%). The polymeric components were separated by decantation and the clear solution was acidified with conc. HCl. The product was extracted by Et2O. The extract was dried over MgSO4 and concentrated under vacuum. The residue was crystallized from MeOH/H2O (1:1, v/v) to give compound 9 (3.56 g, 0.0109 mol, 60%) as a pale yellow solid.
58%
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium hydroxide; sodium nitrite In water at 0℃; for 1.5h; Inert atmosphere;
Stage #2: With sulfuric acid; potassium iodide In water at 40 - 90℃; for 1.75h; Inert atmosphere;
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium nitrite In water at 0℃; for 1h;
Stage #2: With potassium iodide In water at 0 - 90℃;
Stage #1: 5-Bromo-2-aminobenzoic acid With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.5h; Inert atmosphere;
Stage #2: With sulfuric acid; potassium iodide In water at 10 - 90℃; for 1h; Inert atmosphere;
Stage #1: 5-Bromo-2-aminobenzoic acid With sulfuric acid; sodium nitrite In dimethyl sulfoxide at 20℃; for 1h;
Stage #2: With potassium iodide In water; dimethyl sulfoxide for 2h;
7.1 g
Stage #1: 5-Bromo-2-aminobenzoic acid With sulfuric acid; sodium nitrite In water at 5℃; for 0.5h; Inert atmosphere;
Stage #2: With sulfuric acid; potassium iodide In water at 100℃; for 1h; Inert atmosphere;
Stage #1: 5-Bromo-2-aminobenzoic acid With sulfuric acid; sodium nitrite In dimethyl sulfoxide at 0 - 20℃; for 1h;
Stage #2: With potassium iodide In water; dimethyl sulfoxide at 20℃; for 2h;
4 Example 4: 5-Bromo-2-iodobenzoic acid (7c)
2-Amino-5-bromobenzoic acid (6c, 2.0 g, 9.2 mmol) was dissolved in DMSO (50 mL) and 30% H2S04 (50 mL) and NaN02 (0.89 g, 13 mmol) were added. The reaction mixture was stirred for 1 hour at room temperature, whereupon a solution of KI (3.1 g, 19 mmol) in H20 (20 mL) was added and the reaction mixture was stirred for another hour. Next, another portion of KI (3.1 g, 19 mmol) in H20 (10 mL) was added and the reaction mixture was stirred for an additional hour. The reaction mixture was quenched with a saturated aqueous Na2SC"3-solution (75 mL), EtOAc (100 mL) was added and the layers were separated. Hereupon, the H20-layer was extracted with EtOAc (100 mL). The combined organic layers were washed with H20 (2 x 100 mL) and brine (100 mL). The organic layer was dried over MgS04 and concentrated in vacuo to afford compound 7c as a yellow solid. 7c was not further purified further and used as a crude in the following reaction. i? = 0.05 (EtOAc/-heptane, 1 :4). 1H-NMR (400 MHz, CDC13) δ: 8.13 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4, 2.4 Hz, 1H).
To a stirred mixture of acid 2-iodo-5-bromobenzoic acid (15.0 g, 45.9 mmol) in dry THF (100 mL) under argon was added neat BH3.DMS (16.0 mL, 169 mmol) dropwise over 20 minutes. The resulting mixture was heated at 65 C. for 8 hours, cooled to room temperature and quenched by the dropwise addition of water (40 mL). The reaction mixture was concentrated in vacuo. The crude alcohol was diluted with of EtOAc (300 mL), washed with 1N NaOH (2×30 mL), 1N HCl (1×30 mL), saturated aqueous NaHCO3 solution (1×30 mL) and brine (1×30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 2-iodo-5-bromobenzyl alcohol (13.8 g, 96%). 1H NMR (CDCl3): delta 7.56 (d, 1H, J=8.25 Hz), 7.54 (s, 1H), 7.04 (d, 1H, J=8.25 Hz), 4.47 (s, 2H). HPLC: Rt=3.12 min. m/z=312 M+H+).
54%
5-Bromo-2-iodobenzoic acid (7c) (750 mg, 2.3 mmol) was dissolved in dry THF (25 mL) and the reaction mixture was cooled to 0 C. NEt3 (0.48 mL, 3.4 mmol) and ethyl chloroformate (0.33 mL, 3.4 mmol) were added and the reaction mixture was stirred for 1 hour. Next a solution of NaBH (130 mg, 3.4 mmol) in H20 (2 mL) was added and the mixture was stirred for 1.5 hour. The reaction was quenched with H20 (15 mL), whereupon CH2C12 (20 mL) was added and the layers were separated. Hereupon, the H20-layer was extracted with CH2C12 (20 mL). Subsequently, the combined organic layers were washed with H20 (25 mL) and brine (25 mL), dried over MgS04 and concentrated in vacuo. The crude product was purified by gradient column chromatography (-heptane/EtOAc, 19: 1 to 9: 1) to obtain compound 7c as a white solid (410 mg, 54% over 2 steps). RF = 0.40 (EtOAc/-heptane, 1 :4). 1H- NMR (400 MHz, CDC13) delta: 7.65 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.3, 2.5 Hz, 1H), 4.64 (d, J = 6.1 Hz, 2H), 1.96 (t, J = 6.2 Hz, 1H).
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 14h;
C. N, N-DIMETHYL-5-BROMO-2-IODOPHENYLACETAMIDE 5-Bromo-2-iodobenzoic acid (100 g, 0.306 mol) is dissolved in THF (350 mL) and cooled in an ice bath. Borane-THF complex (460 mL of 1 M in THF, 0.460 mol) is added dropwise. After addition is complete, the reaction is warmed to room temp and stirred for 14 hours. The mixture is transferred a large ERLENMEYER FLASK (4 L), cooled in an ice bath and carefully quenched with water (250 mL). Evaporation of the THF by rotary evaporator gives a white suspension which is treated with additional water (1 L) and then filtered and dried in a vacuum dessicator over P205 to give 5-bromo-2-iodobenzyl alcohol. The above benzyl alcohol is dissolved in 48% HBr (500 mIL and heated at reflux temperature for 4 hours. The resulting benzyl bromide is isolated as a yellow solid by pouring the cooled mixture into a large volume (1.5 L) of water followed by filtration. The benzyl bromide is dissolved in EtOH (400 mL) and stirred at room temperature. Sodium cyanide (56 g, 1.14 mol) is dissolved in a minimum amount (-100 mL) of water and then added to the ethanolic solution of the benzyl bromide. The reaction is heated to reflux temperature for 3 hours and then cooled to room temperature. Ethanol is removed by rotary evaporator and the residue washed with a large volume (1 L) of water. The resulting 5-bromo-2-iodophenylcetonitrile is isolated by filtration. The above phenylacetonitrile is dissolved in ETOH (350 mL) and treated with NAOH (32 g, 0.8 mol) which had been dissolved in water (200 mL). The reaction is heated at reflux temperature for 14 hours. After cooling to room temperature, ethanol is removed by rotary evaporator and 6 N HCI added until the pH = 1. The solid 5-bromo-2-iodophenylacetic acid that formed is filtered and washed with water (2 x 500 mL). After drying over P205 in a vacuum dessicator, 5-BROMO-2-IODOPHENYLACETIC acid (m. p. 165-169C) (102 g, 0.3 mol) is dissolved in CH2CI2 (450 mL) that contains several drops of DMF. Thionyl chloride (32 mL, 0.450 mol) is added and the reaction heated to reflux temperature overnight. After cooling to room temperature, the reaction mixture is diluted with additional CH2CI2 (500 mL) and washed with water (2 x 250 mL), saturated NAHCO3 (250 mL) and brine (250 mL). The solution is dried (MGS04) and concentrated by rotary evaporator to give 5-bromo-2- iodophenylactetyl chloride as a yellowish oil. Dimethylamine (200 mL of 2 M in THF) is added dropwise to a solution of the above 5-bromo-2-iodophenylacetyl chloride in ET20 (500 mL), cooled in an ice bath. After the addition is complete, EtOAc (350 mL) is added and the solution washed with water (350 mL), brine (250 mL) and dried (MGS04). Evaporation by rotary evaporator and trituration with 1: 1 ET2O/HEXANES GIVES N, N-DIMETHYL-5-BROMO-2-IODOPHENYLACETAMIDE (m. p. 127-129C).
With borane-THF; In tetrahydrofuran; at 15 - 25℃; for 16h;Inert atmosphere;
A I L round-bottom flask was charged with a solution of 5-bromo-2-iodobenzoic acid (15.0 g, 45.9 mmol) in tetrahydrofuran (150 mL) then borane-tetrahydrofuran (459 mL, 0.460 mol, 1.0 M) was added dropwise. The reaction was stirred at ambient temperature for 16 hours then quenched by addition of water (200 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, CD3OD) 57.72 (d, / = 8.4 Hz, 1H), 7.66 (d, / = 2.4 Hz, 1H), 7.20-7.17 (m, 1H), 4.54 (s, 2H).
STEP 1. Preparation of 5-Bromo-2-iodobenzamide HATU (25 g, 65.8 mmol) was added to 5-bromo-2-iodobenzoic acid (20 g, 61.2 mmol) in 1:1 mixture of CH2Cl2 and dimethylformamide (200 mL) and the solution stirred 2 min. Ammonium chloride (20 g) was added, and the heterogeneous mixture was stirred 1 h. Ammonium hydroxide (20 mL) was added. The solution was filtered, diluted with ethyl acetate, washed with water, 1 N HCl, saturated sodium bicarbonate, and saturated NaCl, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to yield a white precipitate. The solid was filtered to provide 5-bromo-2-iodobenzamide (14.4 g). ESI MS m/z 327.0 [M+H]+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃;
A solution of 5-bromo-2-iodobenzoic acid (5. 00g, 15. [3MMOL)] in dimethylformamide [(60ML)] was treated with EDAC. [HC1] (3.. [51G, 18. 4MMOL), 1-] [HYDROXYBENZOTRIAZOLE] hydrate (2. [48G,] 18. 4mmol), and <strong>[107045-28-3]4-aminomethylbenzoic acid tert-butyl ester</strong> (3.74g, 18. [4MMOL),] then stirred overnight at room temperature. The solution was treated with water [(40ML),] saturated aqueous sodium bicarbonate solution (15mL), followed by water [(40ML)] and the mixture stirred at room temperature for 1 hour. The solid was collected by filtration, washed with water and allowed to air dry overnight. The solid was heated in hexanes/ethyl acetate 2: 1, cooled to room temperature, and the crystals collected by filtration. Drying afforded the product as 6.30g of white solid (79.8% yield). [1H-NMR] [(CDC13)] ; d 7.98-7. 96 (d, [2H),] 7.70-7. 68 (d, 1H), 7.53-7. 52 (d, [1H),] 7.44-7. 43 (d, [2H),] 7.24-7. 21 (dd, 1H), 6.13 (bs, 1H), 4.67 (d, 2H), 1.60 (s, [9H).] MS: M+ +1 = 515.9/517. 9 Da.
With oxalyl dichloride In dichloromethane at 40℃; for 0.5h;
17.1
Step 1 5-Bromo-2-iodo-benzoic acid ethyl ester; 5-Bromo-2-iodo-benzoic acid (25.Og, 76.47 mol) was dissolved in CH2Cl2 (75 ml) at room temperature. Oxalyl chloride (14.5 ml, 152.94 mmol) was added and the mixture was stirred at 4O0C for 30 minutes. The mixture was allowed to cool to room temperature and EtOH (6.69 ml, 114.71 mmol) was added. The mixture was concentrated under reduced pressure to give 27.2 g (quantitative) of 5-bromo-2-iodo-benzoic acid ethyl ester as a yellow crystalline solid.
With trimethylene hydrogen phosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 12 - 46.7℃; for 60.5h;
2-(2-r(T2i?.5i?V5-([('5-Fluoropyridin-2-v?oxylmethvU-2-methylpiperidin-l-yl)carbonyll-4- methylphenvUpyrimidine (E-5)The solution of D-9 (1 kg, 4.46 mol) was charged in a visually clean and dry 50 L flask equipped with a thermocouple and mechanical stirrer and was solvent switched to DCM (11.00 L). DIPEA (2 L, 1 1.45 mol) is added and then EA (1.22 kg, 5.67 mol) was added to this stirring solution. This solution was cooled with an ice bath (12 C). To this stirring solution was added T3P (7.87 L, 13.38 mol) through an addition funnel keeping the reaction temperature <21 0C over Ih. Once addition was completed, the reaction became yellow and heterogenous. To facilitate stirring 2L of DCM were added. The reaction was heated to 44 0C (small exotherm at 42C, which causes the temperature to rise to 46.7 C and maintain that temperature for 30 min). The reaction was aged at this temperature overnight. After 17 h the reaction was not complete and T3P (1.1 L, 1.870 mol) was added to accelerate conversion. The next day (42 h) the reaction was deemed complete by HPLC and was cooled in an ice bath to 4 C. 20 L of water was added (slowly for the first 1.5 L then pretty fast.) keeping the reaction temperature under 17 0C. This <n="48"/>mixture was stirred at room temperature for 30 minutes. Then the mixture was transferred into a 50 L extractor charged with 20 L of MTBE. The flask was rinsed with an additional 2 L of water and 4 L of MTBE. The layers were cut and the organics are washed with 20 L IN NaOH and then 10 L of IN NaOH. Finally, the organics were washed twice with 10 L of brine 15%. The organic fractions (quantitative HPLC assay at 1.65 kg) are then treated with ~50w% of Darco KB (75Og) for 1.75 h, filtered on Solka floe and rinsed with 10 mL/g of MTBE (1.559 kg, 94.5% recovery). To a visually clean and dry 50 L RBF equipped with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was charged the crude material from above (E-5 solution and all solvents used were filtered using a 1 mum in-line filter). The reaction mixture was solvent switched to IPAc and the final volume was adjusted to 7.5 L (about 4 mL/g of IPAc). The reaction mixture was warmed to 75 0C (all soluble), cooled to room temperature slowly and seeded at 45 0C with 18 g OfE1S (front run material, obtained from rex in IP Ac/heptane) stirred overnight (16 hr) at room temperature then heptane was added (6 ml/g) over 60 min. The reaction mixture was aged for 1 hr before to be cooled to 5 0C and stirred for 30 min. The suspension was then transferred onto a filter pot and rinsed with IPAC/heptane (2 x 3mL/g of cold 15% IPAc) and heptane (5 mL/g). The residual beige solid was dried under a flow of nitrogen for 18 hr (the product was found to be dry with < 0.3 wt% of solvents). 1.2 kg of E-5 was isolated as a light beige solid (99.4 LCAP, > 99.5 % ee, > 99.5 % dr, Pd level of 8 ppm and KF of 0.1). Data for E^: HRMS m/z (M+H): 421.2067, found. 421.2035, required.
With thionyl chloride; for 1h;Reflux; Inert atmosphere;
A mixture of 5-bromo-2-iodobenzoic acid (2) (800 mg, 2.447 mmol) and 3.5 mL of thionyl chloride was refluxed with stirring for 1 h under a N2 atmosphere, then excess of thionyl chloride was removed in vacuo. Under N2 atmosphere, sodium azide (191 mg, 2.9 mmol) and dry acetone (7 mL) were poured into the flask containing the crude acyl chloride and the mixture was stirred at room temperature for 10 min, after that, acetone was removed in vacuo. CAUTION, the acyl azide is potentially explosive, the solution should not be evaporated to complete dryness. The residue was dissolved in dry toluene (7 mL) and the mixture was stirred at 80-85 C for 3.5 h under a N2 atmosphere. To the reaction flask was added benzyl alcohol (258.0 µL, 2.5 mmol) and 4-dimethylaminopyridine (DMAP, 7.5 mg, 0.06 mmol), the resulting mixture was again stirred at 80-85 C for 1 h under N2 atmosphere. The reaction mixture was diluted with ethyl acetate and after the usual aqueous work up, the organic layer was concentrated to yield a solid residue. This solid was dissolved in dichloromethane and then petroleum ether was added to precipitate the product which was triturated and washed with dichloromethane/petroleum ether mixture to afford (3) 861 mg, 81% yield.
With 8-quinolinol; sodium hydroxide; copper dichloride; In water; at 20℃; for 0.333333h;Sealed tube; Microwave irradiation;
General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
