3,3,3-trifluoro-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid

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

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

Procedure: 1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (570 mg, 2.83 mmol), 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid (826 mg, 3.40 mmol), HATU (1.29 g, 3.40 mmol) and N-methylmorpholine (685 μl, 6.23 mmol) were suspended in 20 mL of dichloromethane and stirred overnight. The reaction mixture was diluted with more dichloromethane and the solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain the title compound in a 47% yield (562 mg) as a white solid. the solution was washed with water and brine dried over magnesium sulphate filtered the solvent was removed in vacuum The product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid

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

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

Procedure: To a stirred solution of 338 (294 mg, 1.209 mmol) in THF (10 mL) at 0° C. under nitrogen was added sequentially NMM (159.5 μL, 1.451 mmol) neat via syringe and ethyl chloroformate (138.7 μL, 1.451 mmol) neat by syringe. After 45 min the resulting suspension was filtered through GF/F filter paper with THF and the filtrate was isolated and stirred at 0° C. under nitrogen. A solution of NaBH4 (45.74 mg, 1.209 mmol) in H2O (2 mL) was added and the cooling bath was removed. After about 15 min, the reaction was concentrated and the residue was resuspended in Et2O (30 mL) and H2O (30 mL) with stirring. After stirring for 5 min the layers were separated and the organic phase washed brine (1×30 mL). The organic phase was (MgSO4), filtered and concentrated to afford 240 mg (86%) of tert-butyl 1,1,1-trifluoro-3-hydroxypropan-2-ylcarbamate (340) as a white solid. After 45 min the resulting suspension was filtered through GF/F filter paper with THF the filtrate was isolated the cooling bath was removed the reaction was concentrated H2O (30 mL) with stirring After stirring for 5 min the layers were separated the organic phase washed brine (1×30 mL) filtered concentrated

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

Procedure: To a stirred solution of 338 (294 mg, 1.209 mmol) in THF (10 mL) at 0° C. under nitrogen was added sequentially NMM (159.5 μL, 1.451 mmol) neat via syringe and ethyl chloroformate (138.7 μL, 1.451 mmol) neat by syringe. After 45 min the resulting suspension was filtered through GF/F filter paper with THF and the filtrate was isolated and stirred at 0° C. under nitrogen. A solution of NaBH4 (45.74 mg, 1.209 mmol) in H2O (2 mL) was added and the cooling bath was removed. After about 15 min, the reaction was concentrated and the residue was resuspended in Et2O (30 mL) and H2O (30 mL) with stirring. After stirring for 5 min the layers were separated and the organic phase washed brine (1×30 mL). The organic phase was (MgSO4), filtered and concentrated to afford 240 mg (86%) of tert-butyl 1,1,1-trifluoro-3-hydroxypropan-2-ylcarbamate (340) as a white solid. After 45 min the resulting suspension was filtered through GF/F filter paper with THF the filtrate was isolated the cooling bath was removed the reaction was concentrated H2O (30 mL) with stirring After stirring for 5 min the layers were separated the organic phase washed brine (1×30 mL) filtered concentrated

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

Procedure: TBTU (6.87 g, 21.4 mmol) was added to a stirred suspension of 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid, which is commercially available, in DCM (50 mL). NMM (4.4 mL, 40 mmol) and 3-hydroxyazetidinol hydrochloride (2.48 g, 22.6 mmol) were added. The mixture was stirred at rt for 4 h. The turbid solution was diluted with DCM (70 mL) and washed with NaHCO3 solution (saturated, 1×100, 2×20 mL). After drying (Na2SO4) the solvent was evaporated under reduced pressure. The residue was stirred at rt with isohexanes (60 mL) to yield the title product (3.97 g, 97%) as a colourless powder. 1H NMR (500 MHz, DMSO-d6) δ 7.86-8.05 (1H), 5.71-5.87 (1H), 4.86-5.03 (1H), 4.27-4.54 (2H), 4.04-4.15 (1H), 3.78-3.97 (1H), 3.56-3.68 (1H), 1.38-1.4 (9H). Ratio of rotamers ˜6:4. washed with NaHCO3 solution (saturated, 1×100, 2×20 mL) After drying (Na2SO4) the solvent was evaporated under reduced pressure The residue was stirred at rt with isohexanes (60 mL)

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

Procedure: The title compound was prepared from 2-(5-aminomethyl-2-trifluoromethyl-phenylamino)-6-methoxy-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide and 2-tert.butoxycarbonylamino-3,3,3-trifluoro-propionic acid with TBTU, and TEA in THF_in analogy to example 3e.

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

Procedure: 1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (570 mg, 2.83 mmol), 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid (826 mg, 3.40 mmol), HATU (1.29 g, 3.40 mmol) and N-methylmorpholine (685 μl, 6.23 mmol) were suspended in 20 mL of dichloromethane and stirred overnight. The reaction mixture was diluted with more dichloromethane and the solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain the title compound in a 47% yield (562 mg) as a white solid. the solution was washed with water and brine dried over magnesium sulphate filtered the solvent was removed in vacuum The product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid