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Intermediate 1 2-Chloro-3-nitrobenzyIbromide2-Chloro-3-nitrobenzoic acid (0.30 g, 1.5 mmol) was added to BH3 (IM, 4.0 mL, 4.0 mmol). The reaction was refluxed for 3 hours and then cooled to room temperature. The reaction was quenched with water and extracted with diethyl ether (3x15 mL). Purification on silica (100% dichloromethane) gave 0.28g, (99% yield) of the 2-chloro-3- nitrobenzylalcohol.
98%
Step 1. (2-Chloro-3-nitrophenyl)methanol; A 500-mL 3-necked round-bottom flask was charged with a solution of NaBH4 (4 g, 105.26 mmol, 2.10 equiv) in THF (100 mL). To this was added a solution of 2-chloro-3-nitrobenzoic acid (10 g, 49.75 mmol) in THF (100 mL) at 0 C. After 10 minutes, BF3.Et2O (15 mL) in THF (50 mL) was added dropwise over 10 minutes. The resulting solution was stirred at room temperature overnight. The reaction progress was monitored by TLC (DCM: MeOH=5:1). Upon completion, the reaction was quenched with water (500 mL) and extracted with ethyl acetate (3×300 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording (2-chloro-3-nitrophenyl)methanol as light yellow solid (9 g, 98%).
84%
In tetrahydrofuran; water;
Example 132 Synthesis of (2-chloro-3-nitrophenyl)methanol A borane-tetrahydrofuran complex (1.0 M, 20 ml) was added dropwise to a solution of 2-chloro-3-nitrobenzoic acid (5.0 g) in anhydrous tetrahydrofuran (30 ml) in a nitrogen atmosphere and the mixture was heated under reflux for 16 h. Water was added to the reaction mixture which was extracted with ethyl acetate; the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous-sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:2) to give 3.5 g of the titled compound (yield, 84%). 1H-NMR(CDCl3) δ: 2.04(1H, t, J=5.9 Hz), 4.88(2H, d, J=5.9 Hz), 7.45(1H, dd, J=7.9, 7.9 Hz), 7.72-7.82(2H,m)
61%
The following procedure for the synthesis of the intermediate 7-nitro-benzo[b]thiophene-2-carboxylic acid is a modification of the procedure in the chemical literature (L. K. A. Rahaman and R. M. Scrowston, J. Chem. Soc. Perkin Trans. I, 19, 1984, 385). 3-Nitro-2-chlorobenzoic acid (25.51 g, 126.56 mmol) was dissolved in anhydrous THF (400 mL) under a nitrogen atmosphere. The solution was cooled to -70 C. (internal temperature) under N2 flush. DIBAL-H (260 mL, 1.0M in hexanes) was added dropwise over about 11/2 h (internal temperature was maintained below -65 C.). The reaction was allowed to slowly warm to room temperature and was stirred 12 h. The reaction was cooled to -70 C. and 50 mL of MeOH was added dropwise. The reaction mixture was placed in an H2O/ice bath and a 1M Rochelle's salt solution was slowly added in. This solution was stirred for 1 h at room temperature, then filtered through diatomaceous earth. The THF was concentrated in vacuo and the remaining aqueous solution was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and evaporated to obtain 14.4 g (61%) of the desired 3-nitro-2-chlorobenzyl alcohol as a yellow solid.
43%
In tetrahydrofuran; hydrogenchloride; hexane;
EXAMPLE 9 2-Chloro-3-nitrobenzenemethanol A solution of 2-chloro-3-nitrobenzoic acid (1.0 g, 5.0 mmol) in tetrahydrofuran (10 mL) is cooled to 0 C. under an argon atmosphere. Boranetetrahydrofuran complex (6.4 mL of a 1.0 M solution) is added dropwise, maintaining a reaction temperature of less than 5 C. After the addition is complete, the reaction mixture is stirred for 6 hours at room temperature. It is then cooled in an ice bath and quenched by the addition of 10 mL of 1.0 N HCl. The reaction mixture is heated at reflux for 30 minutes and concentrated by distilling the THF. The remaining aqueous solution is extracted with methylene chloride, and the organic layer is washed with saturated aqueous bicarbonate and brine. Evaporation of the organic layer followed by recrystallization of the residue from hexane gives 2-chloro-3-nitrobenzenemethanol (0.4 g, 43%), mp=69-70 C.
With dimethylsulfide borane complex; triethylamine; In tetrahydrofuran; at 0℃; for 3h;Reflux;
General procedure: Triethylamine (94.3 g, 0.932 mol) and 10 N BH3·SMe2 in DMS (281 mL, 2.81 mol) were added to 2-bromo-4-nitro-benzoic acid 17 (230 g, 0.935 mol, sourced commercially) in THF (1.5 L) at 0 C, then the reaction mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool to rt, then slowly quenched with water (100 mL) and acidified with concd aq HCl to pH=1, heated at reflux for 30 min, then allowed to cool to rt. The mixture was extracted three times with DCM (3*500 mL), and the combined organic layers were evaporated and purified by flash chromatography, eluting with 17-33% EtOAc in petroleum ether, to afford the title compound (135.1 g, 62%) as a yellow solid;
With triethylamine; In tetrahydrofuran; water; ethyl acetate;
1-A. 2-Chloro-3-nitrobenzyl alcohol A mixture of 2-chloro-3-nitrobenzoic acid (2.01 g, 0.01 mol) and ethyl chloroformate (1.08 g, 0.01 mol) in 25 ml of dry tetrahydrofuran under argon at room temperature was treated with triethylamine (1.01 g, 0.01 mol) in 10 ml of tetrahydrofuran over a period of 15 minutes. After stirring for 1 hour, the solids were removed by filtration and the filtrate was treated dropwise with a solution of iodine borohydride (0.5 g, 0.013 mol) in 3 ml of water. Slight warming and copious gas evolution were noted. Solvent was removed in vacuo and the residue, dissolved in ethyl acetate, was washed with water, dilute sodium bicarbonate, water, 1N hydrochloric acid, water and saturated brine. The dried (magnesium sulfate) organic solution was concentrated in vacuo to give 1.69 g of crude solid product. Hexane trituration gave 1.5 g (80%) of product, melting point 67-70. Analysis for C7 H6 C1NO3:
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