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To a stirred solution of 3-chloro-5-nitrobenzoic acid (5.00 g; 24.8 mmol; ABCR GmbH & CO. KG) in THF (48 mL) at 0°C was added a 1M solution of borane-THF complex in THF (99.2 mL; 99.2 mmol). The mixture was allowed to react at RT overnight. Then, MeOH was cautiously added to the stirred mixture while cooling with an ice bath. The batch was diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (IN) and saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography hexane / ethyl acetate 50 percent to 100 percent) to give the pure product (4.22 g; 22.5 mmol). NMR (400MHz, CDC13, 300K) δ = 8.13 (m, 2H), 7.71 (s, 1H), 4.81 (m, 2H), 2.00 (br, 1H).
Reference：
[1] Tetrahedron Letters, 2003, vol. 44, # 29, p. 5477 - 5481
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 9, p. 1111 - 1118
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 11, p. 2897 - 2905
4
[ 90390-46-8 ]
[ 79944-62-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
With sodium nitrite In hydrogenchloride; water; ethyl acetate
(iii) 3-Chloro-5-nitrobenzyl alcohol To a suspension of 3-amino-5-nitrobenzyl alcohol (103.8 g, 0.62 mol; from step (ii) above) in 1.0 L of 6N HCl at -5° C. was added sodium nitrite (47.1 g, 0.68 mol) in H2O (400 mL) over 45 min. The resulting solution was stirred at -5° C. for 1 h prior to the addition of a mixture of copper(II)chloride (125.0 g, 0.93 mol) and copper(I)chloride (0.74 g, 0.007 mol) in 6N HCl (1.0 L) over 1 h while maintaining the temperature at less than 0° C. The resulting solution was warmed to 60-70° C. for 2.5 h then cooled to room temperature and extracted with Et2O (6x). The organics were washed with brine (2x), dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. Flash chromatography on silica gel eluding with Hex:EtOAc (4:1) gave 81.7 g (70percent) of the sub-title compound as an off white solid. The sub-title compound could be further purified by crystallization from CH2Cl2. Mp: 74-75° C. 1H NMR (300 MHz, CDCl3) δ8.14 (s, 2H), 7.72 (s, 1H), 4.83 (d, 2H, J=7 Hz), 2.18 (t, 1H, J=7 Hz)
Reference：
[1] Patent: US2002/68730, 2002, A1,
5
[ 71022-43-0 ]
[ 79944-62-0 ]
Reference：
[1] Tetrahedron Letters, 2003, vol. 44, # 29, p. 5477 - 5481
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 9, p. 1111 - 1118
c) 3-Chloro-5-nitro -benzaldehyde; To a solution of oxalyl chloride (14.42 ml, 0.167 mol) in dry DCM (130 ml) at -780C is added dropwise dry DMSO (26.4 ml, 0.373 mol) in dry DCM (130 ml) over 45 minutes, maintaining the reaction temperature below -700C, under nitrogen. The solution is stirred at - 78C for 2 hours. A solution of (3-chloro-5-nitro-phenyl)Hnethanol (1.67 g, 8.90 mmol) in dry DCM (5 ml) is added dropwise over 15 minutes. The reaction mixture is stirred at -780C for 2 hours. Triethylamine (53.47 ml, 0.38 mol) is added dropwise to the reaction mixture over 15 minutes, atbelow -7O0C. The reaction mixture is left in the cooling-bath and allowed to warm to room temperature slowly, then stirred overnight. The reaction mixture is quenched with water and the organic layer is separated. The aqueous is extracted with DCM, the combined organic layers are washed with water, brine, dried over MgSO4. After filtration, the solvent is removed under reduced pressure to give the crude titled compound as a red-brown solid.
General procedure: To a stirring solution of 2,3-difluoro-5-nitrobenzoic acid (Butt Park Ltd.; 9.00 g; 44.3 mmol) in THF at 0C was added a 1M solution of borane-tetrahydrofuran complex in THF (177.3 mL; 177.3 mmol). The mixture was allowed to react at RT overnight. Then, MeOH was cautiously added to the stirred mixture while cooling with an ice bath. The batch was diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (IN) and saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography (hexane to hexane / ethyl acetate 1 :2) to give the pure product (8.20 g; 43.4 mmol). NMR (400MHz, CDC13, 300K) delta = 8.26 (m, 1H), 8.03 (m, 1H), 4.89 (br, 2H), 2.13 (br, 1H).
b) (3-Chloro-5-nitro-phenyl)-methanol; A solution of 3-diloro-5-nitro-benzoic add methyl ester (19.0 g, 0.08 mol) in dry toluene (200 ml) is flushed with argon. The colorless solution is cooled to-78C and treated with a solution of 1.5M DIBAL (129.2 ml, 0.19 mol) in toluene over 1 hour, maintaining the reaction temperature below -75C. The reaction mixture is stirred at below -78C for 1 hour then slowly allowed to warm to 100C. The reaction mixture is cooled over an ice -bath and quenched by dropwise addition of 1M HCI (100 ml). The reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over MgSO4. After filtration, the solvent is evaporated under reduced pressure to give the crude titled compound as a yellow solid.
With sodium nitrite; In hydrogenchloride; water; ethyl acetate;
(iii) 3-Chloro-5-nitrobenzyl alcohol To a suspension of 3-amino-5-nitrobenzyl alcohol (103.8 g, 0.62 mol; from step (ii) above) in 1.0 L of 6N HCl at -5 C. was added sodium nitrite (47.1 g, 0.68 mol) in H2O (400 mL) over 45 min. The resulting solution was stirred at -5 C. for 1 h prior to the addition of a mixture of copper(II)chloride (125.0 g, 0.93 mol) and copper(I)chloride (0.74 g, 0.007 mol) in 6N HCl (1.0 L) over 1 h while maintaining the temperature at less than 0 C. The resulting solution was warmed to 60-70 C. for 2.5 h then cooled to room temperature and extracted with Et2O (6x). The organics were washed with brine (2x), dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. Flash chromatography on silica gel eluding with Hex:EtOAc (4:1) gave 81.7 g (70%) of the sub-title compound as an off white solid. The sub-title compound could be further purified by crystallization from CH2Cl2. Mp: 74-75 C. 1H NMR (300 MHz, CDCl3) delta8.14 (s, 2H), 7.72 (s, 1H), 4.83 (d, 2H, J=7 Hz), 2.18 (t, 1H, J=7 Hz)
With formaldehyd;platinum (IV) oxide; In ethanol; water; ethyl acetate;
(i) 3-Chloro-5-N,N-dimethylaminobenzyl Alcohol To a solution of <strong>[79944-62-0]3-chloro-5-nitrobenzyl alcohol</strong> (12.5 g, 66.6 mmol) in EtOH (750 mL) was added platinum(IV) oxide (1.25 g). The resulting suspension was purged with hydrogen for 3 h. Formaldehyde solution (37 wt % in H2O, 97 mL, 1.3 mol) was added and the mixture was stirred under a hydrogen atmosphere for 18 h. The solution was filtered through a pad of Celite and concentrated in vacuo to give the crude product. Flash chromatography on silica gel, eluding with Hex:EtOAc (7:3), gave 8.2 g (66%) of the sub-title compound as an oil. 1H NMR (300 MHz; CDCl3): delta 6.67 (s, 1H), 6.55-6.63 (m, 2H), 4.58 (d, 2H, J=7 Hz), 2.96 (s, 6H), 1.74 (t, 1H, J=7 Hz). CI-MS: (M+1) 185 m/z.
Structural formula STR46 Step 1. Synthesis of 3-chloro-5-nitrobenzyl methanesulfonate To a solution of 92 mg of <strong>[79944-62-0]3-chloro-5-nitrobenzyl alcohol</strong> in 3 ml of chloroform, 0.3 ml of triethylamine and 0.1 ml of methanesulfonyl chloride were added at room temperature, followed by stirring for 40 minutes, addition of saturated aqueous sodium bicarbonate solution and further stirring for 30 minutes. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate solution and then brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 119 mg of the title compound was obtained as an oil.
To a stirred solution of 3-chloro-5-nitrobenzoic acid (5.00 g; 24.8 mmol; ABCR GmbH & CO. KG) in THF (48 mL) at 0C was added a 1M solution of borane-THF complex in THF (99.2 mL; 99.2 mmol). The mixture was allowed to react at RT overnight. Then, MeOH was cautiously added to the stirred mixture while cooling with an ice bath. The batch was diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (IN) and saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography hexane / ethyl acetate 50 % to 100 %) to give the pure product (4.22 g; 22.5 mmol). NMR (400MHz, CDC13, 300K) delta = 8.13 (m, 2H), 7.71 (s, 1H), 4.81 (m, 2H), 2.00 (br, 1H).
1-chloro-3-(chloromethyl)-5-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.4 g
With thionyl chloride; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 20℃;
To a stirring solution of <strong>[79944-62-0](3-chloro-5-nitrophenyl)methanol</strong> (4.20 g; 22.4 mmol) in DCM (67 mL) and NMP (9 mL) at RT was added dropwise thionyl chloride (4.1 mL; 60.0 mmol). The mixture was allowed to react at RT overnight. Then, the mixture was poured into aqueous sodium bicarbonate solution / saturated aqueous sodium chloride solution / ice. The batch was stirred for 15 minutes before it was extracted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated to give the crude product (6.40 g) that was used without further purification. NMR (400MHz, CDCI3, 300K) delta = 8.17 (m, 2H), 7.72 (s, 1H), 4.62 (s, 2H).
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