tert-butyl N-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethylamino]ethyl]carbamate

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of bis(2-tert-butoxycarbonylaminoethyl)amine (0.01 mol), 4-cyanobenzyl-bromide (0.01 mol), K2CO3 (0.05 mol), and CH3CN (70 mL) was heated at 60° C. for 10 hours. The resultant bis(2-tert-butoxycarbonylaminoethyl)amino-4-methylphenylcyanide was deprotected using HCl/ether, condensed with 2-acetyl pyridine (0.01 mol) in MeOH, and then reduced by NaBH4. After sequential treatments with pyridine-2-carboxaldehyde, NaBH4, and HCl, compound 110 was obtained in 75% overall yield.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diethylenetriamine (0.42 g; 4.1 mmol) in tetrahydrofuran (THF; 5 ml) is stirred at 0° C. under nitrogen for 20 minutes. A solution of 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile (Boc-ON; 2.04 g; 8.2 mmol) in THF (5 ml) is then added dropwise and the reaction mixture is stirred at 0° C. for 1 hour. The solvent is eliminated at reduced pressure and the resulting residue is purified by silica gel column chromatography with methanol-ammonium hydroxide 100:3. 1.2 g (yield 96%) of an oil having the following characteristics is thus obtained: the resulting residue is purified by silica gel column chromatography with methanol-ammonium hydroxide 100:3

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

Procedure: To a solusion of 1,1′-oxalyldiimidazole (1.52 g) in N,N-dimethylformamide (16 ml) was added 1-methyl-N5-trityl-1H-pyrazole-4,5-diamine (1.42 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a solution of di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (4.55 g) in N,N-dimethylformamide (4 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 day and then allowed to stand at room temperature for 9 days. To the reaction mixture were added ethyl acetate (50 ml) and methylene chloride (20 ml). The resulting precipitate was collected by filtration and dried in vacuo to give di-tert-butyl [({2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-oxoacetyl}imino)bis(2,1-ethanediyl)]biscarbamate (1.79 g) as a solid. The mother liquor was washed successively with water, 5% aqueous citric acid solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crystalline residue was washed with a mixed solvent of methylene chloride and diethyl ether, dried in vacuo and combined with the former solid to give di-tert-butyl [({2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-oxoacetyl}imino)bis(2,1-ethanediyl)]biscarbamate (2.44 g). cooling cooling the mixture was stirred at room temperature for 1 day to stand at room temperature for 9 days The resulting precipitate was collected by filtration dried in vacuo

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

Procedure: To a solusion of 1,1′-oxalyldiimidazole (1.52 g) in N,N-dimethylformamide (16 ml) was added 1-methyl-N5-trityl-1H-pyrazole-4,5-diamine (1.42 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a solution of di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (4.55 g) in N,N-dimethylformamide (4 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 day and then allowed to stand at room temperature for 9 days. To the reaction mixture were added ethyl acetate (50 ml) and methylene chloride (20 ml). The resulting precipitate was collected by filtration and dried in vacuo to give di-tert-butyl [({2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-oxoacetyl}imino)bis(2,1-ethanediyl)]biscarbamate (1.79 g) as a solid. The mother liquor was washed successively with water, 5% aqueous citric acid solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crystalline residue was washed with a mixed solvent of methylene chloride and diethyl ether, dried in vacuo and combined with the former solid to give di-tert-butyl [({2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-oxoacetyl}imino)bis(2,1-ethanediyl)]biscarbamate (2.44 g). cooling cooling the mixture was stirred at room temperature for 1 day to stand at room temperature for 9 days The resulting precipitate was collected by filtration dried in vacuo

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

Procedure: To a solution of di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (2.13 g) and 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (1.91 g) in chloroform (10 ml) was added triethylamine (0.558 ml), and the mixture was stirred under reflux. After 9 hours, additional di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (1.82 g) was added to the reaction mixture, and the mixture was stirred under reflux for 1 day. To the reaction mixture was added diethyl ether, and the solution was washed successively with 5% aqueous citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride/methanol (20:1) to give di-tert-butyl {[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxocyclobut-1-en-1-yl)imino]bis(2,1-ethanediyl)}biscarbamate (1.84 g) as a solid. under reflux the mixture was stirred under reflux for 1 day the solution was washed successively with 5% aqueous citric acid solution, water and brine The organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was chromatographed on silica gel eluting with methylene chloride/methanol (20:1)

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

Procedure: To a solution of di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (2.13 g) and 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (1.91 g) in chloroform (10 ml) was added triethylamine (0.558 ml), and the mixture was stirred under reflux. After 9 hours, additional di-tert-butyl [iminobis(2,1-ethanediyl)]biscarbamate (1.82 g) was added to the reaction mixture, and the mixture was stirred under reflux for 1 day. To the reaction mixture was added diethyl ether, and the solution was washed successively with 5% aqueous citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride/methanol (20:1) to give di-tert-butyl {[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxocyclobut-1-en-1-yl)imino]bis(2,1-ethanediyl)}biscarbamate (1.84 g) as a solid. under reflux the mixture was stirred under reflux for 1 day the solution was washed successively with 5% aqueous citric acid solution, water and brine The organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was chromatographed on silica gel eluting with methylene chloride/methanol (20:1)

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 carbonyldiimidazole (204 mg, 1.25 mmol) in DCM (20 mL) was added tert-butyl N-[(1S)-4-amino-1-{[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}butyl]carbamate CXV (687 mg, 1.20 mmol) and stirred at r.t. for 1 h. To this mixture was added tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X (436 mg, 1.44 mmol) and the reaction was stirred overnight at r.t. The mixture was diluted DCM and washed with 1 M HCl, brine, dried over MgSO4 and purified on a silica gel column (100:1→70:1→50:1 CHCl3/MeOH) to give product tert-butyl N-[2-({[(4S)-4-{[(tert-butoxy)carbonyl]amino}-4-{[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}butyl]carbamoyl} (2-{[(tert-butoxy)carbonyl]amino}ethyl)amino)ethyl]carbamate CXVI (500 mg, 0.55 mmol, 44% yield). ESIMS found for C44H61F3N8O9 m/z 904 (M+H). the reaction was stirred overnight at r.t washed with 1 M HCl, brine dried over MgSO4 purified on a silica gel column (100:1→70:1→50:1 CHCl3/MeOH)

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

Procedure: To a solution of CDMT (2.22 g, 12.62 mmol) in DCM (40 mL) and cooled to 0° C. was added N-methylmorpholine (1.38 mL, 12.63 mmol). The mixture was stirred for 10 min before adding (4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentanoic acid (3.0 g, 11.48 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was crystallized from DCM/hexane to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate XIV (4.91 g, 8.98 mmol, 72% yield). 1H NMR (DMSO-d6) 1.35-1.47 (m, 27H), 1.80-1.91 (m, 1H), 2.19-2.32 (m, 1H), 2.33-2.42 (m, 1H), 2.46-2.57 (m, 1H), 3.11-3.38 (m, 6H), 3.40-3.53 (m, 1H), 3.54-3.62 (m, 1H), 3.73 (s, 3H), 4.26-4.38 (m, 1H), 4.99-5.09 (brs, 1H), 5.31-5.46 (m, 2H); ESIMS found for C25H46N4O9 m/z 547 (M+H). The solution was stirred for 60 min at 0° C the mixture stirred at r.t. overnight The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine dried over anhydrous MgSO4 The crude product was crystallized from DCM/hexane

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

Procedure: To a solution of CDMT (37 mg, 0.20 mmol) in DCM (10 mL) and cooled to 0° C. was added N-methylmorpholine (0.023 mL, 0.20 mmol). The mixture was stirred for min before adding (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoic acid (110 mg, 0.18 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was then purified on a silica gel column (100:1 CHCl3/MeOH) and finally crystallized from ethyl ether/hexane to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}ethyl]carbamate XI (110 mg, 0.13 mmol, 72% yield). 1H NMR (CDCl3) 1.43 (s, 18H), 1.50 (s, 9H), 1.69 (brs, 2H), 2.03 (brs, 2H), 2.78 (brs, 2H), 3.23 (brs, 2H), 3.46 (brs, 4H), 4.60 (brs, 4H), 4.96-5.11 (m, 1H), 5.98-6.14 (m, 1H), 6.91-7.01 (m, 1H), 7.28-7.38 (m, 3H), 7.47-7.58 (m, 3H), 7.88-8.03 (m, 2H), 8.12 (d, J=7 Hz, 1H), 8.52 (s, 1H), 8.81 (brs, 1H), 9.31 (brs, 1H); 19F NMR (DMSO-d6) −61.75 (s, 3F); ESIMS found for C43H58F3N7O9 m/z 874 (M+H). The solution was stirred for 60 min at 0° C the mixture stirred at r.t. overnight The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine dried over anhydrous MgSO4 The crude product was then purified on a silica gel column (100:1 CHCl3/MeOH) finally crystallized from ethyl ether/hexane

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

Procedure: To a solution of CDMT (2.22 g, 12.62 mmol) in DCM (40 mL) and cooled to 0° C. was added N-methylmorpholine (1.38 mL, 12.63 mmol). The mixture was stirred for 10 min before adding (4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentanoic acid (3.0 g, 11.48 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate XIV was then added and the mixture stirred at room temperature overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was crystallized from DCM/hexane to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate (XV) (4.91 g, 8.98 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 1.35-1.47 (m, 27H), 1.80-1.91 (m, 1H), 2.19-2.32 (m, 1H), 2.33-2.42 (m, 1H), 2.46-2.57 (m, 1H), 3.11-3.38 (m, 6H), 3.40-3.53 (m, 1H), 3.54-3.62 (m, 1H), 3.73 (s, 3H), 4.26-4.38 (m, 1H), 4.99-5.09 (brs, 1H), 5.31-5.46 (m, 2H); ESIMS found for C25H46N4O9 m/z 547 (M+H). The solution was stirred for 60 min at 0° C the mixture stirred at room temperature overnight The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine dried over anhydrous MgSO4 The crude product was crystallized from DCM/hexane