3-amino-2,2-dimethylpropanamide

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methylpentylcarbamate (120 mg, 0.25 mmol), Et3N (1.5 mL), 2-hydroxypyridine (71.3 mg, 0.75 mmol), and 3-amino-2,2-dimethylpropanamide (87 mg, 0.75 mmol) was stirred at 80° C. overnight. The mixture was evaporated and purified by flash chromatography on silica gel to give tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (120 mg, 65%). MS: 646 (M++1) The mixture was evaporated purified by flash chromatography on silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methylpentylcarbamate (120 mg, 0.25 mmol), Et3N (1.5 mL), 2-hydroxypyridine (71.3 mg, 0.75 mmol), and 3-amino-2,2-dimethylpropanamide (87 mg, 0.75 mmol) was stirred at 80° C. overnight. The mixture was evaporated and purified by flash chromatography on silica gel to give tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (120 mg, 65%). MS: 646 (M++1) The mixture was evaporated purified by flash chromatography on silica gel

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

Procedure: To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.13 M) was added triphosgene (0.3 eq.) and then sodium hydroxide (1 M aq. solution, 3 eq.). The resulting mixture was stirred at RT for 2 h. The reaction was quenched with brine. The organic phase was separated and then added 3-amino-2,2-dimethylpropanamide (4 eq.). The resulting suspension was allowed to stir at RT for 16 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the filtrate concentrated in vacuo. The crude product thus obtained was purified further by way of column chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc) to afford the title compound as a colorless oil. The reaction was quenched with brine The organic phase was separated to stir at RT for 16 h The reaction was quenched with water extracted with EtOAc The combined organic extracts were washed with brine dried over MgSO4 filtered the filtrate concentrated in vacuo The crude product thus obtained was purified further by way of column chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc)

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

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

Procedure: The compound of step 5 (0.176 g, 0.30 mmol) was dissolved in 2.5 ml of anhydrous DCM at 0° C. 3-Amino-2,2-dimethyl-propionamide (0.044 g, 0.38 mmol), EDIA (0.13 ml, 0.75 mmol) and TBTU (0.120 g, 0.38 mmol) were added and the solution was stirred at room temperature for 60 h. EA (15 ml) was then added and the solution was washed with water, 1 N hydrochloric acid, a saturated solution of sodium hydrogencarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA/MOH, 100:0, then 97:5, then 95:5) to give 0.188 g of the title compound as a greenish-brown wax. the solution was washed with water, 1 N hydrochloric acid The organic phase was dried over magnesium sulfate filtered evaporated under reduced pressure The residue was purified by chromatography on silica gel (EA/MOH, 100:0

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 223 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.92 mmol) and 61 mg of 2-hydroxypyridine (0.64 mmol) were added to a solution of 367 mg of N-{(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in the above reaction (0.64 mmol) in triethylamine (6 ml), and the mixture was stirred at 80° C. for one hour. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 14 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 345 mg of (2S,4S,5S)-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-5-(2-nitrobenzenesulfonylamino)hexanoic acid (2-carbamoyl-2-methylpropyl)amide (yield: 78%). The reaction mixture was cooled concentrated under reduced pressure further stirred at 80° C. for 14 hours The reaction mixture was cooled water was added followed by extraction with methylene chloride Then, the organic layer was dried over anhydrous sodium sulfate After filtration the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 161 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.39 mmol) and 44 mg of 2-hydroxypyridine (0.46 mmol) were added to a solution of 263 mg of {(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}carbamic acid benzyl ester obtained in the above reaction (0.46 mmol) in triethylamine (4.6 ml), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 9 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=40/3) to obtain 166 mg of {(1S,2S,4S)-4-(2-carbamoyl-2-methylpropylcarbamoyl)-2-hydroxy-1-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-5-methylhexyl}carbamic acid benzyl ester (yield: 52%). The reaction mixture was cooled concentrated under reduced pressure further stirred at 80° C. for 9 hours The reaction mixture was cooled water was added followed by extraction with methylene chloride Then, the organic layer was dried over anhydrous magnesium sulfate After filtration the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=40/3)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 140 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.21 mmol) and 38 mg of 2-hydroxypyridine (0.40 mmol) were added to a solution of 205 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (1m) (0.40 mmol) in triethylamine (4 ml), and the mixture was stirred at 80° C. for four hours. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 14 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/methanol=40/3) to obtain 167 mg of the title compound (yield: 66%). The reaction mixture was cooled concentrated under reduced pressure further stirred at 80° C. for 14 hours The reaction mixture was cooled water was added followed by extraction with methylene chloride Then, the organic layer was dried over anhydrous magnesium sulfate After filtration the solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/methanol=40/3)

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

Procedure: The same procedure was employed as for amine 50, using 3-amino-2,2-dimethylpropanamide, to provide the product 51. The material was purified by prep HPLC (C18 30×100 mm column, 5-60% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) and lyophilized to give the formate salt the product as a white solid. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.11-7.21 (m, 3 H), 7.06 (d, J=8.1 Hz, 2 H), 6.88 (m, J=8.3 Hz, 2 H), 4.39 (d, J=9.3 Hz, 1H), 4.05-4.16 (m, 3 H), 3.94 (s, 2 H), 3.35-3.53 (m, 3 H), 3.23 (t, J=6.9 Hz, 2 H), 3.07 (s, 2 H), 2.20 (s, 3 H), 2.16-2.24 (m, 2 H), 2.14 (s, 3 H), 1.33 (s, 6 H); MS (ES+) [M+H]+=533.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methylpentylcarbamate (120 mg, 0.25 mmol), Et3N (1.5 mL), 2-hydroxypyridine (71.3 mg, 0.75 mmol), and 3-amino-2,2-dimethylpropanamide (87 mg, 0.75 mmol) was stirred at 80° C. overnight. The mixture was evaporated and purified by flash chromatography on silica gel to give tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (120 mg, 65%). MS: 646 (M++1) The mixture was evaporated purified by flash chromatography on silica gel

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

Procedure: To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.13 M) was added triphosgene (0.3 eq.) and then sodium hydroxide (1 M aq. solution, 3 eq.). The resulting mixture was stirred at RT for 2 h. The reaction was quenched with brine. The organic phase was separated and then added 3-amino-2,2-dimethylpropanamide (4 eq.). The resulting suspension was allowed to stir at RT for 16 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the filtrate concentrated in vacuo. The crude product thus obtained was purified further by way of column chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc) to afford the title compound as a colorless oil. The reaction was quenched with brine The organic phase was separated to stir at RT for 16 h The reaction was quenched with water extracted with EtOAc The combined organic extracts were washed with brine dried over MgSO4 filtered the filtrate concentrated in vacuo The crude product thus obtained was purified further by way of column chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc)