3-AMINOPHENYL N,N-DIMETHYLCARBAMATE, 97

6.2. Example 2(S)-3-(2-methyl-4-(5-methyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)piperazine-1-carboxamido)phenyl dimethylcarbamate A. Preparation of 3-aminophenyl-N, N-dimethylcarbamate: 3-nitrophenol (1.0 g, 7.2 mmol) was treated with pyridine (1.7 ml, 21.6 mmol), triethylamine (1.5 ml, 10.8 mmol), and N, N-dimethylchlorocarbamate (0.79 ml, 8.6 mmol) for 3 days. The reaction was quenched with HStarting materials 6 (1.00 g), Dimethylcarbamoyl chloride (0.77 g), Triethylamine (3 g) were added to the flask, 95 ° C reflux reaction overnight, Add 50 ml of dichloromethane dissolved, 75 ° C vacuum concentration, Plus 50 ml of dichloromethane re-dissolved, It was then washed three times with 0.5 M sodium hydroxide solution.The organic phase was mixed, Dried over anhydrous magnesium sulfate, A viscous mass was obtained by suction filtration. And dried in vacuo to give 1.23 g of a tan solid. 0.42 g of tan solid was weighed and mixed with stannous chloride (1.72 g), ethyl acetate (10 ml), absolute ethanol (10 ml), reacted at room temperature for 2 h and then at 50 ° C for 5 h. 50 ml of ethyl acetate was added to the mixture and washed once with 0.5 M sodium hydroxide solution. Several layers were collected and washed twice with saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 0.25 g Yellow solid. Yield: 55percent.A clean and dry 500 ml 4 neck round bottom flask was charged with DM SO (100 ml), 3-aminophenol (67.5 gm) and NaOH (24.7 gm). The reaction mixture was heated at 75 N, N-dimethylcarbamyl chloride (1.344g, 12.5 mmol) was added to the solution of3-nitrophenol (1.39 g, 10 mmol), triethylamine (2.1 mL, 15 mmol) and DMAP (122 mg, 1 mmol) in CH2Cl2 (30 mL) at room temperature under argon atmosphere. The mixturewas stirred overnight. The reaction mixture was diluted with CH2Cl2, washed with waterand brine, dried over MgSO4, and concentrated in vacuo. The crude product was usedwithout further purification.Iron powder (2.24 g, 40 mmol) was added to a solution of the crude material (10 mmol)in EtOH (20 mL) and glacial acetic acid (10 mL) was added. The mixture was heated at60 oC for 2 h and then cooled to room temperature. The mixture was diluted with waterand carefully neutralized with solid Na2CO3. The resulting solution was extracted withEtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo.The residue was purified by flash column chromatography to give the anilineA clean and dry 1000 ml 4 neck round bottom flask was charged with 3- aminophenyl dimethyl carbamate (50 gm), Calcium carbonate (50 gm) and acetone (300 ml). The reaction mixture was stirred for 5 min. Dimehtyl sulphate (128.3 gm) was added to the reaction mixture and stirred at 25 ' 30eC for 16 ' 18 hours. The reaction completion was confirmed by T LC analysis. (0197) The reaction mixture was filtered to remove calcium carbonate. Later cooled to 0 ' 5 · C and solid thus formed was collected to afford crude compound which was crystallized from isopropanol to provide pure neostigmine methyl sulfate. (0198) Y ield : 81 gm (84.6 %) (0199) M P : 142 - 145 - CA clean and dry 500 ml 4 neck round bottom flask was charged with DM SO (100 ml), 3-aminophenol (67.5 gm) and NaOH (24.7 gm). The reaction mixture was heated at 75 ' 80eC for 4 hours. 4-Nitrophenyl-N, N-dimethyl carbamate (100 g) was added portion wise at 75 ' 80eC along with 100 ml DM SO. The reaction temperature was raised to 110 ' 120 eC and maintained the reaction mixture at this temperature for 2 hours. The reaction completion was confirmed by T LC analysis. (0182) The reaction mixture was quenched with 1 % NaOH solution (1500 ml) and extracted with M DC. The M DC layer was washed with water, dried over sodium sulfate and concentrated to provide crude solid. The solid was recrystallized from toluene to afford pure 3-aminophenyl dimethyl carbamate. (0183) Y ield : 62 gm (72.2%) (0184) M P : 83 - 85 · C (Lit. MP: 80 - 86· C, FR 1498834)Compound 2 (0.20 g), Compound 7a (0.11 g), Bismuth chloride (0.15 g) was mixed, 10 ml of cyclohexane was added, Nitrogen atmosphere under room temperature for 10 minutes, And then reacted at 81 C for 36 h.After the reaction, 10 ml of water and 20 ml of ethyl acetate were added to the system. The aqueous phase and the organic phase were separated and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give brown Yellow oily liquid. The column was then eluted with a silica gel column gradient (eluent ethyl acetate / petroleum ether). 0.035 g of a yellow solid was obtained. Yield: 12%.General procedure: To a suspension of carboxylic acid (100mg) and DMAP (6 eq) in DCM (0.2 M) under nitrogen at -15C was added T3P (3 eq)dropwise over a period of 20 min. The resulting mixture was stirred at -15Cuntil a solution was obtained (2h) and the aniline (3 eq) was added dropwise.The reaction mixture was stirred at -15 C for 1h, slowly warmed to roomtemperature and stirred overnight. Saturated aq. NaHCO3 was thenadded and the aqueous layer extracted with EtOAc. The organic phase was washedwith saturated aq. NH4Cl (x 2), NaHCO3 and brine, driedover Na2SO4, filtered and concentrated under vacuum. Theresidue was dissolved in DCM and purified by flash chromatography (DCM/MeOH97/3 to 92/8).General procedure: To a suspension of carboxylic acid (100mg) and DMAP (6 eq) in DCM (0.2 M) under nitrogen at -15C was added T3P (3 eq)dropwise over a period of 20 min. The resulting mixture was stirred at -15Cuntil a solution was obtained (2h) and the aniline (3 eq) was added dropwise.The reaction mixture was stirred at -15 C for 1h, slowly warmed to roomtemperature and stirred overnight. Saturated aq. NaHCO3 was thenadded and the aqueous layer extracted with EtOAc. The organic phase was washedwith saturated aq. NH4Cl (x 2), NaHCO3 and brine, driedover Na2SO4, filtered and concentrated under vacuum. Theresidue was dissolved in DCM and purified by flash chromatography (DCM/MeOH97/3 to 92/8).

Molecular Weight:180.20
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:180.089877630
Monoisotopic Mass:180.089877630
Topological Polar Surface Area:55.6
Heavy Atom Count:13
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes