2-Chloro-5-nitrophenol

Light Brown Crystalline Solid

Reference Example 27; 2-chloro-5-nitro-phenol; A saturated solution of sodium nitrite (1.8 g, 26.0 mmol) in water (12 mL) was added dropwise to a suspension of 2-amino-5-nitro-phenol (2.0 g, 13.0 mmol) in concentrated hydrochloric acid (10 mL) at 0° C. and stirred for 30 min. In another flask, copper (I) chloride (5.15 g, 52.0 mmol) and concentrated hydrochloric acid (20 mL) were heated to between 60 and 70° C. and the diazonium salt solution was added dropwise to this over a period of 30 min. The reaction mixture was heated to 80° C. and stirred for 15 min. It was then cooled to room temperature and ethyl acetate (50 mL) was added and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2.x.50 mL). The combined organic phases were washed with water (4.x.50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (100-200 mesh) using 5percent ethyl acetate in petroleum ether as eluent to afford 2-chloro-5-nitro-phenol (2.08 g, 92percent) as a crystalline yellow solid.A saturated solution of sodium nitrite (1.8 g, 26.0 mmol) in water (12 mL) was added dropwise to a suspension of 2-amino-5-nitro-phenol (2.0 g, 13.0 mmol) in concentrated hydrochloric acid (10 mL) at 0 10 g of 2-amino-5-nitrophenol 2 (0.064 mol, 1 equiv) wasadded to 33 ml of 37percent HCl at 0–5 C and reaction mixture was allowedto stir for 10 min. Then, a solution of NaNO2 (4.9 g, 0.071 mol, 1.1 equiv) in 15 ml H2O was added dropwise over 1–1.5 h. The resulting reaction mixture was added in portions to15 ml of stirred suspension of CuCl (6.2 g, 0.064 mol, 1 equiv) in20percent aqueous HCl solution within 1 h. The resulting precipitatewas filtered, washed with H2O and dried in vauco to give 8.5 gcrude brown-yellow solid in a yield of 75percent. Mp: 126–128 C, ESIMS:172.2 [MH], C6H4ClNO3 [173.55].Preparation To a stirred solution of l-chloro-2-methoxy-4-nitrobenzene (20 g, 106.6 mmol) in dichloromethane (500 mL) at -78 °C under a flow of Nitrogen gas, a solution of BBrA mixture of 2-chloro-5-nitroanisole (101.86 g, 543 mmol), and 48 percent hydrobromic acid (500 ml) in acetic acid (500 ml) was heated at reflux for 3 days. Further 48 percent hydrobromic acid (200 ml) was added after 48 hours. The mixture was cooled and poured ontoice/water (3 litres). The resultant solid was removed by filtration. The solid was taken up into INNaOH(1 litre), and washed with EtOAc (3 x 500 ml). The aqueous layer was acidified by the addition of conc. HCl with cooling. The mixture was extracted with EtOAc (3 x 500 ml), the combined EtOAc layers washed with water (500 ml), sat. NaCl (500 ml), dried overNa2SO4, filtered and evaporated to give a beige solid (51 g, 54percent).'H NMR (400 MHz, DMSO-d6) 11.29(1H, s), 7.77(1H, d, J2.5), 7.67(1H, dd, J8. 7 and 2.5), 7.63 (1H, d, J8.7).5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30 percent sulfuric acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0°C. After 15 mins, this solution was added slowly to dilute sulfuric acid (50 percent, 250 ml) at 110 °C. Stirring was continued for 15 min. The reaction mixture was cooled to RT, ice water was added, extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The phenol product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24.0 percent. [00153] K2CO3 (23.84 g, 0.172 mol) was added to 2-chloro-5- nitrophenol (10.0 g, 0.058 mol) in acetonitrile (100 ml) at RT. After cooling to 0 °C, methyl iodide (19.6 g, 0.138 mol) was added slowly and the reaction mixture stirred at RT overnight. Water (100 ml) was added and the aqueous layer extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography to yield the ANISOLE (6.0 g, 55.55percent). [00154] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 °C and the temperature was slowly raised to 50 ° C. Stirring was continued for 2 h. After cooling to RT, the reaction mixture was basified with 50 percent NAOH solution, extracted by ethyl acetate, washed with water, then brine and dried over NA2SO4. 3-METHOXY-4-CHLOROANILINE was obtained upon concentration and was purified further by column chromatography. Yield : 4.0 g, 79.36 percent. [00155] To 3-METHOXY-4-CHLOROANILINE (2.0 g, 0.0126 mol) in trichloroethylene (30 ml) was added BC13 (2.18 g, 1 M solution in DCM, 0.0188 mol) AT 0 °C. After stirring for 10 min, 4-CYANOPYRIDINE (1.6 g, 0.0153 mol) and AIC13 (2.35 g, 0.018 mol) were added and the temperature was raised to RT, with further stirring for 30 min. The temperature was raised further to 85 °C and maintained at the same temperature for 1 h. DCM was distilled off and the solution was stirred at 115 °C for 4 h and then at RT over night. 3N HCI was added at RT and the reaction mixture REFLUXED for 1.5 h. The reaction mixture was allowed to cool and made basic using NAOH (6 N), diluted with water and extracted with DCM, washed with water, brine and dried over NA2SO4. The crude title compound was obtained upon concentration and was purified by column chromatography. Yield : 0.50 g, 15 percent.5-NITRO-2-CHLORO aniline (50.0 g, 0.289 mol) in 30 percent sulfuric acid (300 ml) was stirred at RT FOR 2 h. Sodium nitrite (21.0 g, 0.304 mol) in water (50 ml) was added slowly at 0°C and maintained at this temperature for 15 min. This diazotized solution was added slowly to dilute sulfuric acid (50 percent, 250 ML) at 110 °C. Stirring was continued for 15 min. After cooling to RT, ice water was added, the mixture extracted with ethylacetate, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 12.0 g, 24. 0 percent. [00162] To K2CO3 (23.84 g, 0.172 mol) and 2-chloro-5-nitrophenol (10.0 g, 0.0576 mol) in ACETONITRILE (100 ml) was added methyl iodide (19.60 g, 0.138 mol) at 0°C. The reaction mixture was warmed to RT and stirred overnight. Water was added and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 6.0 g, 55. 55 percent. [00163] 2-CHLORO-5-NITRO ANISOLE (6.0 g, 0.032 mol) in MEOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCI (110 ml) at 40 °C and the temperature was slowly raised to 50 ° C. Stirring was continued for 2h, the reaction cooled to RT, basified with 50 percent NAOH solution and extracted by ethyl acetate. The organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 4.0 g, 79.36 percent. [00164] To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4- chloro aniline (3.0 g, 0.0190 mol) in benzene (50 ML) was added trimethylacetylchloride (2.75 g, 0.022 mol) slowly at 0 °C. The temperature was raised to RT and stirred overnight. The reaction mixture was added to ice and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over NA2SO4 and concentrated. Yield : 3.7 g, 80.43 percent. [00165] To N-PIVALOYL-3-METHOXY-4-CHLOROANILINE (1.50 g, 0.0062 mol) in THF (30 ML) was added n-butyl lithium (1.0 g, 0.0156 mol) at 0 °C and the reaction stirred for 2 hr. After cooling to-70 °C, methyl isonicotinate (1.3 g, 0.0094 mol) in THF (12 ml) was added slowly. The reaction was warmed to rt and stirred overnight and then quenched with water and extracted with ether. The water layer was further extracted and the combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield 0.50 g, 23. 25 percent. [00166] The protected ketone from step 5 (0.500g, 0. 0014MOL) was suspended in concentrated HCI (5 ml) at RT, then the temperature was raised to 95 °C and the mixture stirred over night. The mixture was cooled to RT, basified with 20 percent NAOH solution and extracted with DCM. The combined organic layer was washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.140 g, 37.33percent).

Molecular Weight:173.55
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:172.9879707
Monoisotopic Mass:172.9879707
Topological Polar Surface Area:66
Heavy Atom Count:11
Complexity:158
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes