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With sodium tetrahydroborate; sulfuric acid In tetrahydrofuran at 10 - 66℃; for 4 h;
Tetrahydrofuran (99.7g) and sodium borohydride (15.2g, 0.4mol) were added to the reaction flask at 10-25°C.A solution of 2-bromo-5-iodobenzoic acid (109.4 g, 0.34 mol, prepared in Example 2) in tetrahydrofuran (151 g) was slowly added dropwise.At 10-30°C, a solution of sulfuric acid (16.4 g) in tetrahydrofuran (25 g) was added dropwise to the reaction vessel. After the addition was completed, the reaction was performed at room temperature for 2 hours. Then, it was heated to reflux 66°C, refluxed for 2 hours, and then lowered to room temperature. 5percent hydrochloric acid (235 g) was slowly added dropwise and THF was distilled off under reduced pressure (-0.01 MPa).Add 326.7 g of MTBE and 222.7 g of water to dissolve the solid, cool to 15-25°C, separate the layers, and evaporate the organic layer under reduced pressure (-0.095 MPa).Toluene (108.8 g) and water (108.8 g) were added and the mixture was warmed to 60°C for 1 h, reduced to 18-22°C and filtered. After drying, 89.1 g of an off-white solid product was obtained with a measured content of >99percent and a yield of 85.1percent.
84%
With diborane In tetrahydrofuran at 0 - 20℃; for 4 h; Irradiation; Inert atmosphere
To a 5000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-5-iodobenzoic acid (200 g, 61 1.78 mmol, 1.00 equiv) and tetrahydrofuran (1500 mL), followed by the addition of borane (1834 mL, 3.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 4 h at room temperature, quenched by the addition of 4000 mL of water/ice, and then extracted with 2x2000 mL of ethyl acetate. The combined organic layer was washed with 2x2000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was diluted with 500 mL of PE. The solids were collected by filtration to afford 160 g (84percent) of (2-bromo-5-iodophenyl)methanol as a white solid.
Step 2: (2-bromo-5-iodophenyl)methanolTo a solution of 2-bromo-5-iodobenzaldehyde (12.4 g, 40 mmol) in MeOH (50 mL) was added NaBH4 (3 g, 80 mmol) at 0 °C. After the addition, the reaction solution was stirred at rt for 30 minutes. The reaction solution was diluted with water (20 mL) and EtOAc (60 mL). The organic layer was separated and dried over anhydrous Na2S04. After removal of solvent, the residue was purified with column chromatography to afford (2-bromo-5- iodophenyl)methanol (3.5 g, 1 1 .2 mmol, 28 percent yield) as a white solid.
Example I; 4-Bromo-3-hvdroxymethyl-1-iodo-benzene; Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid in CH2CI2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product. Yield: 47.O g (99percent of theory)
Preparation of 4-bromo-3-hydroxymethyl-1-iodo-benzene [0245] Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2Cl2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product. [0246] Yield: 47.0 g (99percent of theory)
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 1h;Cooling with ice;
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2CI2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiB (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2S04) and the solvent is evaporated under reduced pressure to give the crude product. Yield: 47.0 g (99percent of theory)
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Example Il; 4-Bromo-3-chloromethyl-1-iodo-benzene; Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo- benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. <n="30"/>Yield: 41.0 g (82percent of theory)
82%
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Thionyl chloride (13 mL) is added to a suspension of <strong>[946525-30-0]4-bromo-3-hydroxymethyl-1-iodo-benzene</strong> (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. Yield: 41.0 g (82percent of theory)
41.0 g
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Example II 4Bromo-3-chloromethyl-1 -iodo-benzeneThionyl chloride (13 mL) is added to a suspension of 4-bromo3-hydroxymethyl-1-iodo- benzene (47.0 g) in dichloromethane (100 mL) containing DMF (01 mL). The mixture isstirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried.Yi&d: 41.0 g (82percent of theory)
41 g
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;
Thionyl chloride (13 mL) is added to a suspension of <strong>[946525-30-0]4-bromo-3-hydroxymethyl-1-iodo-benzene</strong> (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. [0077] Yield: 41.0 g (82percent of theory)
41.0 g
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3-hydroxymethyl-l-iodo- benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. Yield: 41.0 g (82percent of theory)
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Preparation of 4-bromo-3-chloromethyl-1-iodo-benzene Thionyl chloride (13 mL) is added to a suspension of <strong>[946525-30-0]4-bromo-3-hydroxymethyl-1-iodo-benzene</strong> (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. Yield: 41.0 g (82percent of theory)
41 g
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Preparation of 4-bromo-3-chloromethyl-1-iodo-benzene Thionyl chloride (13 mL) is added to a suspension of <strong>[946525-30-0]4-bromo-3-hydroxymethyl-1-iodo-benzene</strong> (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. Yield: 41.0 g (82percent of theory)
41 g
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;
Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3 -hydro ymethyl- 1 -iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. Yield: 41.0 g (82percent of theory)
41 g
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3 -hydro xymethyl- 1 -iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried. Yield: 41.0 g (82percent of theory)
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 0.5h;
Step 3: (2-bromo-5-iodobenzyloxy)(tert-butyl)dimethylsilaneTo a solution of <strong>[946525-30-0](2-bromo-5-iodophenyl)methanol</strong> (3.5 g, 1 1 .2 mmol) and imidazole (1 .53g, 22.4 mmol) in DCM (85 mL) was added TBSCI (2.03 g, 13.4 mmol) at 0 °C. The solution was stirred at room temperature for 30 minutes and then diluted with water (20 mL) The organic layer was washed with brine (20 mL) and dried over anhydrous Na2S04. After removal of solvent, the crude product was purified with flash column chromatography to afford (2-bromo-5-iodobenzyloxy)(tert-butyl)dimethylsilane (4.48 g, 10.5 mmol, 94 percent yield) as a colorless oil.
With 1H-imidazole; In dichloromethane; at 20℃; for 0.2h;
To a stirred solution of 2-bromo-5-iodobenzylalcohol (10 g, 32 mmol) (Compound (8-1)) in dichloromethane (200 mL) was added imidazole followed by TBDMS-Cl at room temperature. The mixture was stirred at room temperature for about 2 h and partitioned between dichloromethane (additional 100 mL) and water (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2-bromo-5-iodobenzyloxy)(tert-butyl)dimethylsilane, Compound (8-2), which was used in next step without further purification
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 0.5h;
Step 2: (2-bromo-5-iodophenyl)methanolTo a solution of <strong>[1032231-24-5]2-bromo-5-iodobenzaldehyde</strong> (12.4 g, 40 mmol) in MeOH (50 mL) was added NaBH4 (3 g, 80 mmol) at 0 °C. After the addition, the reaction solution was stirred at rt for 30 minutes. The reaction solution was diluted with water (20 mL) and EtOAc (60 mL). The organic layer was separated and dried over anhydrous Na2S04. After removal of solvent, the residue was purified with column chromatography to afford (2-bromo-5- iodophenyl)methanol (3.5 g, 1 1 .2 mmol, 28 percent yield) as a white solid.
With sodium tetrahydroborate; sulfuric acid; In tetrahydrofuran; at 10 - 66℃; for 4h;
Tetrahydrofuran (99.7g) and sodium borohydride (15.2g, 0.4mol) were added to the reaction flask at 10-25°C.A solution of 2-bromo-5-iodobenzoic acid (109.4 g, 0.34 mol, prepared in Example 2) in tetrahydrofuran (151 g) was slowly added dropwise.At 10-30°C, a solution of sulfuric acid (16.4 g) in tetrahydrofuran (25 g) was added dropwise to the reaction vessel. After the addition was completed, the reaction was performed at room temperature for 2 hours. Then, it was heated to reflux 66°C, refluxed for 2 hours, and then lowered to room temperature. 5percent hydrochloric acid (235 g) was slowly added dropwise and THF was distilled off under reduced pressure (-0.01 MPa).Add 326.7 g of MTBE and 222.7 g of water to dissolve the solid, cool to 15-25°C, separate the layers, and evaporate the organic layer under reduced pressure (-0.095 MPa).Toluene (108.8 g) and water (108.8 g) were added and the mixture was warmed to 60°C for 1 h, reduced to 18-22°C and filtered. After drying, 89.1 g of an off-white solid product was obtained with a measured content of >99percent and a yield of 85.1percent.
84%
With diborane; In tetrahydrofuran; at 0 - 20℃; for 4h;Irradiation; Inert atmosphere;
To a 5000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-5-iodobenzoic acid (200 g, 61 1.78 mmol, 1.00 equiv) and tetrahydrofuran (1500 mL), followed by the addition of borane (1834 mL, 3.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 4 h at room temperature, quenched by the addition of 4000 mL of water/ice, and then extracted with 2x2000 mL of ethyl acetate. The combined organic layer was washed with 2x2000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was diluted with 500 mL of PE. The solids were collected by filtration to afford 160 g (84percent) of (2-bromo-5-iodophenyl)methanol as a white solid.
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2Cl2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product. [0074] Yield: 47.0 g (99percent of theory)
Example I 4-Bromo-3-hydroxvmethyl- 1 iodo-benzeneOxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo5-iodo-benzoic acid (49.5 g) in CH2CI2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h Then the solution is concentrated under reduced pressure and the residue is dissolved in THE (100 mL). The resulting solution is cooled in an ice-bath andLiBH4 (3A g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product.Yield: 47.0 g (99percent of theory)
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2C12 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and L1BH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2S04) and the solvent is evaporated under reduced pressure to give the crude product. Yield: 47.0 g (99percent of theory)
Preparation of 4-bromo-3-hydroxymethyl-1-iodo-benzene Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2Cl2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product. Yield: 47.0 g (99percent of theory)
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2CI2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and L1BH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2S04) and the solvent is evaporated under reduced pressure to give the crude product. Yield: 47.0 g (99percent of theory)
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2Cl2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product. Yield: 47.0 g (99percent of theory)
1-(4-bromo-3-(hydroxymethyl)phenyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of <strong>[946525-30-0]2-bromo-5-iodobenzyl alcohol</strong> (5.0 g, 16.0 mmol) (Compound (8-1)) in dry THF (40 mL) was added a 2 M solution of isopropylmagnesium chloride in THF (17.6 mL, 35.2 mmol) while maintaining the internal temperature below about ?10° C. A white suspension was formed after 5 min. The mixture was stirred for about 1 h at or below about ?10° C. and then was added N-methoxy-N-methylacetamide (3.73 mL, 35.2 mmol) dropwise over a period of about 3 min. The reaction mixture was allowed to warm to about 20° C. over 1 h. The reaction mixture was cooled to about 0° C., quenched with 3N HCl (25 mL), and diluted with tert-butylmethyl ether (50 mL). The resulting biphasic mixture was stirred and the layers separated. The organic layer was washed with 1M HCl (50 mL) followed by water (50 mL) and concentrated under reduced pressure to afford Compound (M-a) as a crude product mixture which was used in next step without further purification. 1H NMR (400 MHz, CDCl3) delta 8.07 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 4.79 (s, 2H), 2.59 (s, 3H)
(2-bromo-5-iodophenyl)methyl methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;Inert atmosphere;
To a 3000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[946525-30-0](2-bromo-5-iodophenyl)methanol</strong> (160 g, 51 1.30 mmol, 1.00 equiv), dichloromethane (1500 mL) and TEA (103.2 g, 1.02 mol, 2.00 equiv), followed by the addition of methanesulfonyl chloride (81.6 g, 712.35 mmol, 1.40 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 30 min at room temperature, quenched by the addition of 1000 mL of water/ice, and then extracted with 2x1500 mL of dichloromethane. The combined organic layer was washed with 1x1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 200 g (crude) of (2-bromo-5-iodophenyl)methyl methanesulfonate as a light yellow solid.
With camphor-10-sulfonic acid; In dichloromethane; for 0.666667h;
A 100 mL single-necked flask was charged with 1 (5 g, 0.016 mol), camphorsulfonic acid (350 mg, 1.5 mmol) and dissolved in 50 mL of methylene chloride. THP-OH (3 ml, 0.032 mol) was added slowly and stirred for 40 minutes. The reaction was complete by TLC and concentrated directly to give Intermediate 2 (3 g, 47percent yield).
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