3-Fluoro-4-nitrobenzenamine

Yellow to brown powder

Preparation of Compound 7; Compound 7; 58 g of 3-fluoroaniline and 58 mL of benzaldehyde were heated at 80°C during one hour. 200 mL of sulfuric acid were then added to the reaction mixture, cooled with an ice bath. After removing of the ice bath, the reaction mixture was further stirred at room temperature until complete dissolution of the solid. The reaction mixture was next cooled to 0°C with an ice bath and 36 mL of nitric acid in 120 mL of sulfuric acid were added dropwise, maintaining the temperature at 0°C. After one hour of stirring at 0°C, the solid was filtered off and poured into a saturated solution of potassium carbonate in water. Ethyl acetate was then added and the two layers were separated. The aqueous phase was extracted two more times with ethyl acetate. The organic phases were collected, dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 40percent ethyl acetate in hexane, yielding 28.65 g (35percent) of the desired intermediate A-2 3-fluoro-4-nitroaniline. 28.65 g of intermediate A-2 was dissolved in 230 mL of chlorhydric acid 36percent. The reaction mixture was cooled to 0°C with an ice bath and 13.7 g of sodium nitrite was added portion-wise. The reaction was maintained at 0°C during 1.5 hours, then mixed with 145 mL of a S02 saturated acetic acid solution, containing 10.5 mL of water and 9.3 g of CuC12. 2H20. After complete addition, the cooling bath was removed and the reaction mixture was stirred at room temperature during one hour, then poured onto ice. The solid was filtered off yielding 37.7 g of the intermediate B-2 3-fluoro-4-nitro- benzene sulfonyl chloride. To a solution of 53 g of intermediate C-1 (PG = Boc, R4 = isobutyl) in 500 mL of THF containing 42 mL of triethylamine was added portion-wise 37.7 g of intermediate B-2. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was dissolved in ethylacetate and extracted with water, then with a solution of HCI 5percent in water and with a K2CO3 solution in water. The organic layer was then dried over MgSO4 and evaporated. The crude compound was purified on silica gel yielding 53 g (65percent) of the desired intermediate 2-a [(lS, 2R)-3-[[(3-fluoro-4-nitrophenyl)- sulfonyl] (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester. 2 g of intermediate 2-a were dissolved in 50 mL of DMF and 1.85 mL of isopropyl- amine were added. The reaction mixture was stirred at 60°C overnight, then concentrated and the residue treated with a mixture of EtOAc and brine. The organic layer was then dried over MgS04 and evaporated to yield 2 g (91percent) of the desired intermediate 2-b [ (IS, 2R)-2-hydroxy-3- [ (2-methylpropyl) [ [3- (2-methylpropyl) amino-4- nitrophenyl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester, used without other purification in the next step. 2 g of intermediate 2-b were dissolved in 40 mL of methanol, then 1.5 g of ammonium formate and 0.2 g of palladium on charcoal (10percent) were added. The reaction mixture was stirred overnight at 60°C, then 0.5 g of ammonium formate and 0.2 g of palladium on charcoal were added. After three hours, the mixture was filtered on celite and evaporated. The residue was dissolved in 50 mL of DCM, washed with a solution of Na2CO3 in water, then brine, dried over MgS04 and evaporated to yield 1.3 g (68percent) of intermediate 2-c [(1S, 2R)-3-[[4-amino-3-[(2-methylpropyl) amino] phenyl] sulfonyl]- (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester, used without other purification in the next step. 1. 3 g of intermediate 2-c was dissolved in 20 mL of ethyl orthoformate. The reaction mixture was stirred at 80°C during 5 hours then concentrated. The residue was dissolved in ethyl acetate and washed with a solution of Na2C03 in water. The organic layer was dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 0 to 2percent methanol in DCM, yielding 0.8 g (70percent) of the desired intermediate 2-d [ S, 2R)-2-hydroxy-3-[(2-methylpropyl) [[l-(2-methylpropyl)- benzimidazol-6-yl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester. 2.6 g of intermediate 2-d was dissolved in 100 mL of HCI 5N in isopropanol. The reaction mixture was stirred at room temperature during 2 hours, then concentrated to yield 2.5 g (94percent) of the deprotected amine as an HCI salt, N-[(2R, 3S)-3-amino-2- hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[1-(2-methylpropyl) benzimidazol-6-yl] - sulfonamide, hydrochloride (2-e). 2.5 g of 2-e and 1.5 mL of triethylamine were dissolved in 60 mL of DCM. 3.05 g of 1-[[(3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-yl] oxycarbonyloxy] -2, 5- pyrrolidinedione were then added and the reaction mixture was stirred at room temperature during 4 hours. The reaction mixture was then washed with a solution of Na2CO3 in water, then brine, dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 5percent methanol in DCM, yielding 1.8 g (60percent) of the desired final compound [ (lS, 2R)-2-hydroxy-3- [ (2-methylpropyl) [ [1- (2-methyl- propyl) benzimidazol-6-yl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, [(3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-yl] ester (compound 7).A mixture of N-(3-fluoro-4-nitro-phenyl)-2, 2-dimethyl-propionamide (87.0 g, 0.36 mol) in CHDiphenylphosphorylazide (5.5 mmol, 1.5 g) was added to a solution of 3-fluoro-4- nitrobenzoic acid (5.4 mmol, [1] g) and triethylamine (5.6 mmol, 0.8 mL) in a 1: 1 mixture of [TERT-BUTYL] alcohol/dioxane (60 mL). The reaction mixture was refluxed for 2 days at 95 [C] and the solvent was evaporated to give an oily residue. The residue was taken up in ethyl acetate (100 mL) and washed with 10percent citric acid, IN NaOH, brine and H20. Evaporation of solvent afforded an orange residue that was subsequently purified by flash chromatography eluting with ethyl acetate/hexane to afford [(TERT-BUTOXY)-N- (3-FLUORO-4-] nitrophenyl) carboxamide (1. [75MMOL, ] 0.45g, yield 32percent). 3-Fluoro-4-nitroaniline (0.36 g, 2.3 mmol) was isolated as a byproduct. Treatment of [(TERT-BUTOXY)-N- (3-FLUORO-4-] nitrophenyl) carboxamide with trifluoroacetic acid in methylene chloride afforded additional [3-FLUORO-4-NITROANILINE.]

Molecular Weight:156.11
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:156.03350557
Monoisotopic Mass:156.03350557
Topological Polar Surface Area:71.8
Heavy Atom Count:11
Complexity:159
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes