tert-butyl N-[2-[(4-chlorophenyl)methylamino]ethyl]carbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol) was added at room temperature to a solution of tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and Hunig's base (0.2 mL, 1.2 mmol, 1.5 eq.) in dichloromethane (1.6 mL). The reaction was allowed to stir overnight. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography to afford benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate as foam (167 mg, 38%). MS (ESI) m/e (M+H+) 531. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) was added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl 2-aminoethylcarbamate (4.5 mL, 28.5 mmol, 1.2 eq.) and acetic acid (2.5 mL) in dichloroethane (20 mL). The reaction mixture was allowed to stir overnight before being quenched with 0.5M HCl (30 mL). The mixture was then extracted with dichloromethane one time and then brine was added. The precipitate was filtered and dried to give tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%), MS (ESI) m/e (M+H+) 285. before being quenched with 0.5M HCl (30 mL) The mixture was then extracted with dichloromethane one time brine was added The precipitate was filtered dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol) was added at room temperature to a solution of tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and Hunig's base (0.2 mL, 1.2 mmol, 1.5 eq.) in dichloromethane (1.6 mL). The reaction was allowed to stir overnight. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography to afford benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate as foam (167 mg, 38%). MS (ESI) m/e (M+H+) 531. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol) was added at room temperature to a solution of tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and Hunig's base (0.2 mL, 1.2 mmol, 1.5 eq.) in dichloromethane (1.6 mL). The reaction was allowed to stir overnight. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography to afford benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate as foam (167 mg, 38%). MS (ESI) m/e (M+H+) 531. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) was added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl 2-aminoethylcarbamate (4.5 mL, 28.5 mmol, 1.2 eq.) and acetic acid (2.5 mL) in dichloroethane (20 mL). The reaction mixture was allowed to stir overnight before being quenched with 0.5M HCl (30 mL). The mixture was then extracted with dichloromethane one time and then brine was added. The precipitate was filtered and dried to give tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%), MS (ESI) m/e (M+H+) 285. before being quenched with 0.5M HCl (30 mL) The mixture was then extracted with dichloromethane one time brine was added The precipitate was filtered dried

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol) was added at room temperature to a solution of tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and Hunig's base (0.2 mL, 1.2 mmol, 1.5 eq.) in dichloromethane (1.6 mL). The reaction was allowed to stir overnight. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography to afford benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate as foam (167 mg, 38%). MS (ESI) m/e (M+H+) 531. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) was added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl 2-aminoethylcarbamate (4.5 mL, 28.5 mmol, 1.2 eq.) and acetic acid (2.5 mL) in dichloroethane (20 mL). The reaction mixture was allowed to stir overnight before being quenched with 0.5M HCl (30 mL). The mixture was then extracted with dichloromethane one time and then brine was added. The precipitate was filtered and dried to give tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%), MS (ESI) m/e (M+H+) 285. before being quenched with 0.5M HCl (30 mL) The mixture was then extracted with dichloromethane one time brine was added The precipitate was filtered dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 4-pyridin-4-yl-benzoic acid hydrochloride salt (100 mg, 0.502 mmol), [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester (143 mg, 0.502 mmol), HOBt (77 mg, 0.502 mmol), and EDCI (56 mg, 0.552 mmol) were dissolved in 1.7 mL DMF, then treated with triethyl amine (77 μL, 0.552 mmol) to room temperature. The reaction was allowed to stir overnight to completion and partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with hexanes/ethyl acetate gradients plus 2% triethylamine) to afford the {2-[(4-chlorobenzyl)-(4-pyridin-4-yl-benzoyl)-amino]-ethyl}-carbamic acid tert-butyl ester as a colorless oil (184 mg, 93%). 1H NMR (CDCl3, 400 MHz) δ 8.68 (d, J=4.8 Hz, 2H), 7.65 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.48 (d, J=4.4 Hz, 2H), 7.34 (m, 2H), 7.13 (m, 2H), 4.91 (m, 1H), 4.59 (brs, 2H), 3.62 (m, 2H), 3.44 (m, 2H), 1.46 (s, 9H). LCMS (APCI+) m/z 466 [M+H]+; Rt=3.19 min. partitioned between ethyl acetate and diluted NaHCO3 solution The aqueous was extracted with ethyl acetate The organic was washed with water, brine dried over MgSO4 filtered concentrated in vacuo The residue was purified by chromatography (silica gel eluted with hexanes/ethyl acetate gradients plus 2% triethylamine)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The (2-amino-ethyl)-carbamic acid tert-butyl ester (5.00 g, 31.2 mmol) and 4-chloro-benzaldehyde (4.61 g, 32.77 mmol) were dissolved in 60 mL of 1,2-dichloroethane at room temperature. The reaction mixture was allowed to stir for 40 minutes prior to treatment with sodium triacetoxyborohydride (9.90 g, 46.8 mmol). The mixture was allowed to stir overnight to completion and quenched with a saturated NaHCO3 solution. The aqueous was extracted with DCM, separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with hexanes/EtOAc plus 2% triethyl amine) to afford the pure [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester as a viscous yellow oil (5.38 g, 61%). 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.92 (brs, 1H), 3.75 (s, 2H), 3.23 (appd, J=5.6 Hz, 2H), 2.73 (appt, J=6.0 Hz, 2H), 1.44 (s, 9H), 1.36 (brs, 1H). LCMS (APCI+) m/z 285 [M+H]+; Rt=2.30 min. to stir overnight to completion quenched with a saturated NaHCO3 solution The aqueous was extracted with DCM separated dried over MgSO4 concentrated in vacuo The residue was purified by chromatography (silica gel eluted with hexanes/EtOAc plus 2% triethyl amine)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step 1-Quinazolin-4-yl-piperidine-4-carbonyl chloride hydrochloride (197 mg, 0.63 mmol) was added to a solution of [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol) in DCM (6.5 mL) cooled in an ice bath. After being stirred for 12 hours, the mixture was partitioned between DCM (50 mL) and H2O (80 mL) containing 1 mL of 1.0 M HCl. The DCM layer was drained off and the acidic aqueous layer was extracted 3 more times with DCM. The combined DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using EtOAc as eluent to give {2-[(4-chlorobenzyl)-(1-quinazolin-4-yl-piperidine-4-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (190 mg). cooled in an ice bath the mixture was partitioned between DCM (50 mL) and H2O (80 mL) containing 1 mL of 1.0 M HCl the acidic aqueous layer was extracted 3 more times with DCM The combined DCM extracts were dried (Na2SO4) filtered concentrated in vacuo The crude material was chromatographed (SiO2)