tert-Butyl 2-(methylamino)ethylcarbamate

White to very pale yellow solid

Preparation 65Preparation 65: Synthesis of tert-butyl 2-(methylamino)ethylcarbamate (C)To a flask was added 20percent Pd(OH)Preparation 65: Synthesis of tert-butyl 2-(methylamino)ethylcarbamate (C)To a flask was added 20percent Pd(OH)In a flask, 20percent Pd (OH) 2 on carbon (3.1 g)MeOH (200 mL)Compound B (3.3 g, 12.5 mmol)And water (10 mL) were added while exposing to H 2 (40 psi). After 2.5 h, the reaction mixture was filtered through celite and concentrated under reduced pressure. Water was then added (50 mL) and the pH of the mixture was brought to 12 (by adding 1 N NaOH) and extracted with DCM (3 × 50 mL). CombinedThe organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure to give compound C (2.0 g, 11.7 mmol, 94percent) as a colorless oil.A mixture of tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.20 g, 4.54 mmol), 10percent Pd/C (0.90 g) and MeOH (60 ml) was stirred under a HSynthesis of tert-butyl 2-(methylainino)ethylcarbamate To a solution of tert-butyl 2-bromoethylcarbamate (9 g, 40.3 mmol) and methylamine (41.7 g, 403 rnrnol, 30percent in EtOll) in EtOll (80 mL) was added KI (140mg, 0.8 mmol). The mixture was heated to 50°C with stirring for 5 hours and then concentrated under reduce pressure, the residue was poured into water and extracted with EtOAc (3* 8OrnL). The organic phase was dried over Na2SO4, filtered and removal of solvent to give 4.3 g oil (used for next step without purification).LC-MS: CP-0007023-128: (ES, nz/z): 175 [M+ H1To a solution of di-tert-butyl dicarbonate (4.80g, 22.0mmol) in dry CHTo a solution of N-methylethylenediamine 1 (10.0 g, 135 mmol, 1.0 eq.) in anhydrous THF (70 mL), triethylamine (37.6 ml, 270 mmol, 2.0 eq.) was added under Ar atmosphere at room temperature. Synthesis of tert-bulyl 2-(methylainino)ethylcarbaniate To a solution of compound 16 (1.3 g, 4.22 mmol) in MeOll (30 mL) was added Pd/C (150 mg, 10percent). The suspension was agitated under an H2 atmosphere with stiff ing for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduce pressure to give an oil product (720 mg, 98percent).1HNMR: CP-0007023-117: ‘H-NMR (DMSO-d6, 500MHz): ö(ppm) 6.707 (s, 1H), 2.999-2.962 (q, J=6.5, 12.5 Hz, 2H), 2.488-2.461 (t, J=7, 13.5 Hz, 2H), 2.247 (s, 3H), 1.369 (s, 911).To a solution of benzoic acid (66.2 mg, 0.54 mmol) and /er/-butyl (2- (methylamino)ethyl)carbamate (97.5 mg, 1.03 equiv.) in DMF (3 mL) was added HATU (216.8 mg, 1.05 equiv.) and DIPEA (0.1 mL, 1.06 equiv.). The reaction mixture was stirred at ambient temperature for 16 hours, then diluted with EtOAc (20 mL) and washed with water (10 mL), 1M HC1 (10 mL), 1M NaOH (10 mL) and brine (10 mL). The combined organic extracts were dried (Na2S04) and concentrated to afford intermediate amide 1-52 (130.8 mg), which was then dissolved in 4M HC1 in dioxane (3 mL). After 1 hour, the reaction mixture was concentrated to afford the deprotected amine as a solid. This amine was suspended in DCM (3 mL) along with thiodiglycolic anhydride (60.4 mg, 0.97 equiv.), and DIPEA (0.17 mL, 2.1 equiv.) was added. The reaction mixture was stirred at ambient temperature for 2.5 hours, at which point HOSu (55.1 mg, 1.02 equiv.) and EDC (90 mg, 1.0 equiv.) were added. After 16 hours, the reaction mixture was diluted with DCM (20 mL) and washed with 1M HC1 (2 x 10 mL) and brine (8 mL). The organic extracts were dried (Na2S04) and concentrated to a residue, which was purified by silica gel chromatography (EtOAc) to afford 34.5 mg (18% yield) of 1-53. ESI-MS found 408.2. Ci8H22N306S (MH+) requires 408.1.Compound N1-methyl-N2-tert-butoxycarbonylethylenediamine (10.0 g, 57.4 mmol) was dissolved in tetrahydrofuran (100 ml), then triethylamine (8.4 ml, 60 mmol) was added. The resulting mixture was cooled to 0C. Then, ethyl bromoacetate (6.31 ml, 57.4 mmol) was added dropwise, and the reaction was continued after the dropwise addition. TLC monitoring was conducted until the reaction was completed. The reaction mixture was concentrated, water was added and then the resulting mixture was extracted with dichloromethane twice. The organic phase was washed with saturated aqueous solution of ammonium chloride, water and saturated saline respectively, dried over anhydrous sodium sulfate, filtered and concentrated, and then subjected to column chromatography, to obtain the target product (13.4 g). The product was dissolved in dichloromethane (20 ml), trifluoroacetic acid (10 ml) was added, and the mixture was reacted at room temperature for 8 hours, then concentrated under reduced pressure to give the crude trifluoroacetate (20.5 g) of compound 1A.A mixture of methyl 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (2 g, 3.96 mmol, 1 equiv.), tert-butyl N-[2-(methylamino)ethyl]carbamate (1.4 g, 7.91 mmol, 2.00 equiv.), XantPhos (686.6 mg, 1.19 mmol, 0.3 equiv.), Pd2(dba)3(362.2 mg, 0.40 mmol, 0.1 equiv.) and Cs2CO3(3.9 g, 11.87 mmol, 3 equiv.) in dioxane (30 mL, 89.53 equiv.) was stirred at 100C for 14 hr. The reaction mixture was filtered and the filtrate was concentrated to give the crude product which was purified by silica gel column chromatography, eluted with PE:EA (10:1 to 3:2) to afford methyl 4-[(2-[[(tert-butoxy)carbonyl]amino]ethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (630 mg, 26.59%) as a light yellow oil.1H NMR (400 MHz, Chloroform-d) delta 7.41 (t, J = 8.2 Hz, 1H), 7.34 - 7.26 (m, 3H), 7.18 (t, J = 8.7 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 5.39 (s, 2H), 5.28 (s, 1H), 3.78 (s, 3H), 3.38 (dd, J = 18.5, 5.7 Hz, 4H), 2.94 (s, 3H), 1.43 (s, 9H)K2CO3 (920 mg, 6.60 mmol) was added to compound 17 (1.50 g, 3.30 mmol) and tert-butyl(2-(methylamino)ethyl)carbamate (700 mg, 3.96 mmol) in CH3CN (40 mL) In the solution, the reaction was warmed to reflux and stirred overnight. Solid was washed with H2O (100mL) was stirred for 3hrs beating, the solid was filtered, then with cold ethanol (3mL x 2) solid was washed, dried in vacuo at 55 to give a red solid (2.5 g of), Yield: 87.01%.

Molecular Weight:174.24
XLogP3:0.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:174.136827821
Monoisotopic Mass:174.136827821
Topological Polar Surface Area:50.4
Heavy Atom Count:12
Complexity:141
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes