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With hydrogen;palladium 10% on activated carbon; In water; ethyl acetate; under 760.051 Torr;
(3-Aminophenyl)carbamic acid tert-butyl ester (1.0 g) was dissolved in ethyl acetate (30ml) and treated with aqueous formaldehyde (37% wt, 443 mul) and palladium on carbon (10%, 350 mg). The reaction mixture was hydrogen- ated under a balloon of hydrogen overnight at atmospheric pressure. The cata- lyst was removed by filtration through Celite under nitrogen and the volatiles were removed by evaporation. The residue was purified by chromatography using the Biotage system on a 10 g silica cartridge eluting with a mixture of ethyl acetate and cyclohexane (1 :19 increasing to 1 :1) to give (3-methylamino- phenyl)carbamic acid tert-butyl ester (500 mg). LCMS (Method A) Rt 2.45 (M+H+) 2231H NMR (300MHz) (CDCI3) delta 7.2 (t, 1 H) 6.8 (br s, 1H) 6.5 (dd, 1 H) 6.4 (br s, 1 H), 6.3 (dd, 1 H) 3.7 (br s, 1 H) 2.8 (s, 3H) 1.5 (s, 9H)
To a solution of 4'-fluorobiphenyl-3-sulphonyl chloride (245 mg) in pyridine (5 ml) was added a solution of <strong>[1134328-09-8](3-methylaminophenyl)carbamic acid tert-butyl ester</strong> (Intermediate 1 , 200 mg) in pyridine (2 ml), and the resultant mixture was stirred at room temperature for 3 hours. The pyridine was removed by evaporation under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4), fil- tered and the volatiles were removed by evaporation. The residue was purified by HPLC eluting with a mixture of water and acetonitrile (each containing 0.1% formic acid) from 20 to 98% acetonitrile over 25 minutes to give {3-[N-(4'- Fluorobiphenyl-3-sulphonyl)-N-methylamino]-phenyl}carbamic acid tert-butyl ester as a white solid (220 mg).LCMS (Method A) Rt 4.26 (M-H) 4551H NMR (300MHz) (CDCI3) delta 7.75 (dd, 1 H) 7.7 (br s, 1 H) 7.6-7.5 (m, 2H) 7.5-7.4 (m, 2H) 7.35 (d, 1 H) 7.2 (m, 2H) 7.15 (t, 2H) 6.75 (dd, 1 H) 6.5 (br s, 1 H) 3.2 (S, 3H) 1.5 (S1 9H)
With triethylamine; In acetonitrile; at 20.0℃; for 4.0h;
Ethanesulfonyl chloride (1.28 mL; 13.5 mmol) was added into a solution of <strong>[1134328-09-8]tert-butyl (3-(methylamino)phenyl)carbamate</strong> (2 g, 9 mmol), triethymaine (3.79 mL, , 26.99 mmol) in ACN (100 mL) at room temperature. The solution was stirred at room temperature for 4h00. Water was added and the reaction mixture was extracted with DCM. The organic layer was separated and dried over MgSO4, filtered and the solventwas evaporated.The residue (3.2g) was purified by silica gel chromatography (Irregular SiOH, 40jim,80g, Mobile phase: gradient from 90%: DCM, 10% Heptane to 97% DCM, 3% MeOH,0.3% NH4OH. The fractions were combined and the solvent was evaporated to give2.55g of an impure fraction which was repurified by silica gel chromatography(Irregular SiOH, 40jim, 80g, Mobile phase: gradient from 70%: DCM, 30% Heptane to97% DCM, 3% MeOH, 0.3% NH4OH. The fractions were combined and the solventwas evaporated to give 1.24g (39%, 88% of purity based on LC/MS) of intermediate642 (39% pure at 88%).
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