tert-butyl N-[[2-(aminomethyl)-4-chlorophenyl]methyl]carbamate

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

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

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

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

Procedure: To a solution of tert-butyl 2-(azidomethyl)-4-chlorobenzylcarbamate (10.9 g, 36.73 mmol) in THF (60 ml) and water (6 ml) was added triphenylphospine (10.59 g, 40.40 mmol). The reaction was heated to 65 C. and stirred overnight at room temperature. The reaction was concentrated in vacuo and flashed with 4% (10% NH4OH/MeOH)/dichlor-omethane. A second purification using silica gel column chromatography with a careful gradient of 3 to 5% (10% NH4OH/MeOH)/dichloro methane gave the title compound. The reaction was heated to 65 C The reaction was concentrated in vacuo A second purification

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

Procedure: To a solution of tert-butyl 4-chloro-2-(hydroxymethyl)benzylcarbamate (10 g, 36.8 mmol) in anhydrous THF (100 ml) was added DPPA (8.3 ml, 38.6 mmol) and DBU (5.79 ml, 38.6 mmol). The mixture was stirred overnight and then was partitioned between ethyl acetate and water. The organic layer was washed with brine, and was concentrated in vacuo to a crude oil (14.6 g). Purification was accomplished by silica gel chromatography, eluting a gradient of ethyl acetate-hexane (10, 15, 20, 25, 50%) to give tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate. was partitioned between ethyl acetate and water The organic layer was washed with brine was concentrated in vacuo to a crude oil (14.6 g) Purification eluting a gradient of ethyl acetate-hexane (10, 15, 20, 25, 50%)

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

Procedure: To a solution of tert-Butyl 2-(aminomethyl)-4-chlorobenzylcarbamate (0.14 mmol, 37 mg), EDC (0.21 mmol, 40 mg), and Boc-D-Phe-Pro-OH (0.14 mmol, 50 mg), in 0.5 mL dimethylformamide, was added HOAT (0.15 mmol, 21 mg). The solution was stirred overnight and purified by prep HPLC to give N-(tert-Butoxyacetyl)-D-phenylalanyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide. Mass Spec ES (M+1)=615.2. purified by prep HPLC

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

Procedure: To a solution of tert-butyl 2-(azidomethyl)-4-chlorobenzylcarbamate (10.9 g, 36.73 mmol) in THF (60 ml) and water (6 ml) was added triphenylphospine (10.59 g, 40.40 mmol). The reaction was heated to 65 C and stirred overnight at room temperature. The reaction was concentrated in vacuo and flashed with 4% (10% NH4OH/MeOH)/dichlor-omethane. A second purification using silica gel column chromatography with a careful gradient of 3 to 5% (10% NH4OH/MeOH)/dichloro methane gave the title compound. The reaction was heated to 65 C The reaction was concentrated in vacuo A second purification

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

Procedure: To a solution of tert-butyl 2-(azidomethyl)-4-chlorobenzylcarbamate (10.9 g, 36.73 mmol) in THF (60 ml) and water (6 ml) was added triphenylphospine (10.59 g, 40.40 mmol). The reaction was heated to 65 C and stirred overnight at room temperature. The reaction was concentrated in vacuo and flashed with 4% (10% NH4OH/MeOH)/dichlor-omethane. A second purification using silica gel column chromatography with a careful gradient of 3 to 5% (10% NH4OH/MeOH)/dichloro methane gave the title compound. The reaction was heated to 65 C The reaction was concentrated in vacuo A second purification

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

Procedure: To a solution of tert-butyl 4-chloro-2-(hydroxymethyl)benzylcarbamate (10 g, 36.8 mmol) in anhydrous THF (100 ml) was added DPPA (8.3 ml, 38.6 mmol) and DBU (5.79 ml, 38.6 mmol). The mixture was stirred overnight and then was partitioned between ethyl acetate and water. The organic layer was washed with brine, and was concentrated in vacuo to a crude oil (14.6 g). Purification was accomplished by silica gel chromatography, eluting a gradient of ethyl acetate-hexane (10, 15, 20, 25, 50%) to give tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate. was partitioned between ethyl acetate and water The organic layer was washed with brine was concentrated in vacuo to a crude oil (14.6 g) Purification eluting a gradient of ethyl acetate-hexane (10, 15, 20, 25, 50%)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamine (0.52 g, 1.93 mmol) in dichloromethane (2 mL) was added diisopropylethylamine (0.34 mL, 1.95 mmol) and the solution was cooled to −78° C. Bromoacetyl bromide (0.19 mL, 2.12 mmol) was added slowly and after the addition was complete, the temperature was raised to 0° C. The reaction was complete in 15 min based on the disappearance of starting amine on silica gel TLC a 95:5 mixture of dichloromethane to methanol as mobile phase. The solvent was removed on a rotary evaporator to yield N-(2-(tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)bromoacetamide (0.75 g). after the addition the temperature was raised to 0° C The solvent was removed on a rotary evaporator

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

Procedure: A solution of 9-hydroxy-9-fluorenylcarbonyl-L-proline (1.8 g, 5.6 mmol) from step 2 above, 2-tert-butoxycarbonylaminomethyl-5-chlorobenzylamine (1.8 g, 6.8 mmol), N-methylmorpholine (12 drops), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (3.0 g, 6.7 mmol) in N,N-dimethylformamide (25 mL) was stirred at ambient temperature for 24 hours, concentrated in vacuo, and purified on silica gel (ethyl acetate-hexane, 1:2) to give 1-((9-hydroxy-9H-fluoren-9-yl)carbonyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide. HPLC=99%, R.T.=3.69 min, method A; M+1=576.2. concentrated in vacuo purified on silica gel (ethyl acetate-hexane, 1:2)

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

Procedure: A solution of 9-hydroxy-9-fluorenylcarbonyl-L-proline (1.8 g, 5.6 mmol) from step 2 above, 2-tert-butoxycarbonylaminomethyl-5-chlorobenzylamine (1.8 g, 6.8 mmol), N-methylmorpholine (12 drops), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (3.0 g, 6.7 mmol) in N,N-dimethylformamide (25 mL) was stirred at ambient temperature for 24 hours, concentrated in vacuo, and purified on silica gel (ethyl acetate-hexane, 1:2) to give 1-((9-hydroxy-9H-fluoren-9-yl)carbonyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide. HPLC=99%, R.T.=3.69 min, method A; M+1=576.2. concentrated in vacuo purified on silica gel (ethyl acetate-hexane, 1:2)