tert-butyl 3-(methylamino)propanoate

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: A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 125 mg of tert-butyl 3-(methylamino)propanoate, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 209 mg of methyl 4-{2-[4-({[2-({3-[(3-tert-butoxy-3-oxopropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow formed solid. The reaction mixture was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography (hexane-chloroform)

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

Procedure: A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 125 mg of tert-butyl 3-(methylamino)propanoate, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 209 mg of methyl 4-{2-[4-({[2-({3-[(3-tert-butoxy-3-oxopropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow foamed solid. The reaction mixture was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography (hexane-chloroform)

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

Procedure: A 33% solution of methylamine in EtOH (62 ml) is cooled to 0°. A solution of tert-butyl acrylate (12.8 g) in EtOH (50 ml) is added dropwise over 2.5 hours. This mixture is allowed to reach room temperature over night. All volatiles are removed under reduced pressure and the residue chromatographed on silicagel using first EtOAc and then EtOAc/MeOH 1:1 as eluent. 7.81 g of a slightly yellow oil are obtained. TLC (silicagel, EtOAc/MeOH 1:1): rf 0.13. to reach room temperature over night All volatiles are removed under reduced pressure the residue chromatographed on silicagel 7.81 g of a slightly yellow oil are obtained

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

Procedure: A 33% solution of methylamine in EtOH (62 ml) is cooled to 0°. A solution of tert-butyl acrylate (12.8 g) in EtOH (50 ml) is added dropwise over 2.5 hours. This mixture is allowed to reach room temperature over night. All volatiles are removed under reduced pressure and the residue chromatographed on silicagel using first EtOAc and then EtOAc/MeOH 1:1 as eluent. 7.81 g of a slightly yellow oil are obtained. TLC (silicagel, EtOAc/MeOH 1:1): rf 0.13. to reach room temperature over night All volatiles are removed under reduced pressure the residue chromatographed on silicagel 7.81 g of a slightly yellow oil are obtained

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

Procedure: The title compound was prepared by a method analogous to that described in Steps B and C of Example 2, using ethyl 4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate and tert-butyl 3-(methylamino)propanoate. MS (M+1) 554.5.

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

Procedure: The title compound was prepared by a method analogous to that described in Steps B and C of Example 2, using ethyl 4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate and tert-butyl 3-(methylamino)propanoate. MS (M+1) 554.5.

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

Procedure: A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), tert-butyl N-methyl-beta-alaninate (1.34 g; 8.41 mmol; 1.20 eq.) (prepared as described by Howard N., I. et al. in Bioorg. Med. Chem. 11 (2003), 3083-3099) and potassium carbonate (1.94 g; 14.02 mmol; 2 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for 16 hours. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over sodium sulfate and concentration in vacuo gave title compound as a slightly yellow oil (1.9 g; 92%). 1H NMR (CDCl3) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (t, J=8.9 Hz, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%). at RT for 16 hours The acetonitrile was evaporated in vacuo the resulting mixture diluted with water Extraction with EtOAc washing with NaCl sat. solution drying over sodium sulfate and concentration in vacuo

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

Procedure: A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), tert-butyl N-methyl-beta-alaninate (1.34 g; 8.41 mmol; 1.20 eq.) (prepared as described by Howard N., I. et al. in Bioorg. Med. Chem. 11 (2003), 3083-3099) and potassium carbonate (1.94 g; 14.02 mmol; 2 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for 16 hours. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over sodium sulfate and concentration in vacuo gave title compound as a slightly yellow oil (1.9 g; 92%). 1H NMR (CDCl3) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (t, J=8.9 Hz, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%). at RT for 16 hours The acetonitrile was evaporated in vacuo the resulting mixture diluted with water Extraction with EtOAc washing with NaCl sat. solution drying over sodium sulfate and concentration in vacuo

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

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

Procedure: The title compound was prepared according the general procedure 10, starting from 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 24 Step 1, 750 mg, 3.5 mmol) and tert-butyl N-methyl-beta-alaninate (670 mg, 4.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (ddd, J=8.6, 2.6, 1.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.45 (m, 1H), 3.53 (s, 2H), 2.60 (t, J=6.7 Hz, 2H), 2.38 (t, J=6.7 Hz, 2H), 2.12 (s, 3H), 1.40 (s, 9H). LC/MS (Method B): 293.3 (M+H)+. HPLC (Method A) Rt 2.61 min (Purity: 96.2%). It was isolated as a pale yellow oil