2-amino-N-tert-butylacetamide

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

Procedure: which comprises the following steps: Condensing N-(5-oxo-L-prolyl)-L-histidine hydrazide by means of the azide method with L-tryptophan benzyl ester and treating the resulting compound with hydrazine hydrate to obtain N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan hydrazide (II); treating N-[O-benzyl-N-carboxy-L-tyrosyl]glycine N-benzyl ester with ethyl chloroformate to obtain the corresponding mixed anhydride which is reacted with t-butyl carbazate to obtain the corresponding 2-carboxyhydrazide t-butyl ester which is hydrogenolyzed to N-L-tyrosylglycine 2-carboxyhydrazide t-butyl ester, and condensing the latter with N-carboxy-L-seryl N-benzyl ester 2,4-dinitrophenyl ester followed by hydrogenolysis of the reaction product to obtain N-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide t-butyl ester (III); condensing N-carboxy-L-proline N-benzyl ester with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, treating the resulting product with ammonia and then hydrogenolyzing, to obtain 2-[(L-prolyl)amino]acetamide, which is condensed with N-carboxy-NG -nitro-L-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide and N-hydroxysuccinimide to obtain N-[N-(N-carboxy-NG -nitro-L-arginyl)-L-prolyl)]glycinamide N-t-butyl ester (IV); or alternatively condensing L-proline methyl ester with N-carboxy-NG -nitro-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide, condensing the resulting product with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, and treating the resulting product with ammonia to obtain the same compound IV as above; treating said compound IV with acid and then with N-carboxy-L-leucine N-benzyl ester 2,4,5-trichlorophenyl ester and hydrogenolyzing the resulting product in acetic acid, to obtain N-[N-[N-(N-L-leucyl)-L-arginyl]-L-prolyl]-glycinamide diacetate (V); condensing compound II with compound III by means of the azide method to obtain the hexapeptide N-[N-[N-[N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophyl]-L-seryl]-L-tyrosyl]glycine 2-carboxyhydrazide t-butyl ester, or condensing N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan with compound III in the presence of dicyclohexylcarbodiimide to obtain the same hexapeptide as above, and deprotecting and converting the latter to its trifluoroacetate salt (VI); and condensing compound V with compound VI by means of the azide method, to obtain the decapeptide of formula I which is isolated as the diacetate salt and optionally converted to other pharmaceutically acceptable salts.

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

Procedure: which comprises the following steps: Condensing N-(5-oxo-L-prolyl)-L-histidine hydrazide by means of the azide method with L-tryptophan benzyl ester and treating the resulting compound with hydrazine hydrate to obtain N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan hydrazide (II); treating N-[O-benzyl-N-carboxy-L-tyrosyl]glycine N-benzyl ester with ethyl chloroformate to obtain the corresponding mixed anhydride which is reacted with t-butyl carbazate to obtain the corresponding 2-carboxyhydrazide t-butyl ester which is hydrogenolyzed to N-L-tyrosylglycine 2-carboxyhydrazide t-butyl ester, and condensing the latter with N-carboxy-L-seryl N-benzyl ester 2,4-dinitrophenyl ester followed by hydrogenolysis of the reaction product to obtain N-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide t-butyl ester (III); condensing N-carboxy-L-proline N-benzyl ester with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, treating the resulting product with ammonia and then hydrogenolyzing, to obtain 2-[(L-prolyl)amino]acetamide, which is condensed with N-carboxy-NG -nitro-L-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide and N-hydroxysuccinimide to obtain N-[N-(N-carboxy-NG -nitro-L-arginyl)-L-prolyl)]glycinamide N-t-butyl ester (IV); or alternatively condensing L-proline methyl ester with N-carboxy-NG -nitro-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide, condensing the resulting product with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, and treating the resulting product with ammonia to obtain the same compound IV as above; treating said compound IV with acid and then with N-carboxy-L-leucine N-benzyl ester 2,4,5-trichlorophenyl ester and hydrogenolyzing the resulting product in acetic acid, to obtain N-[N-[N-(N-L-leucyl)-L-arginyl]-L-prolyl]-glycinamide diacetate (V); condensing compound II with compound III by means of the azide method to obtain the hexapeptide N-[N-[N-[N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophyl]-L-seryl]-L-tyrosyl]glycine 2-carboxyhydrazide t-butyl ester, or condensing N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan with compound III in the presence of dicyclohexylcarbodiimide to obtain the same hexapeptide as above, and deprotecting and converting the latter to its trifluoroacetate salt (VI); and condensing compound V with compound VI by means of the azide method, to obtain the decapeptide of formula I which is isolated as the diacetate salt and optionally converted to other pharmaceutically acceptable salts.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A neat mixture of 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one (100 mg, 0.25 mmol) and 2-amino-N-tert-butyl acetamide (INTERMEDIATE I.2) (32 mg, 2.46 mmol) was heated at 120° C. for 3 h. The reaction mixture was cooled and partitioned between ethyl acetate and sat. NH4Cl (aq.). The organic layer was washed with brine (1×20 mL), dried (MgSO4) and concentrated in vacuo to afford N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1H-isoquinolin-2-yl)acetamide (120 mg, 0.23 mmol, 94%) which was used in the next step without further purification. The reaction mixture was cooled partitioned between ethyl acetate and sat. NH4Cl (aq.) The organic layer was washed with brine (1×20 mL) dried (MgSO4) concentrated in vacuo

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

Procedure: A suspension of 5-bromoisatoic anhydride (1.2 g, 5.0 mmol) and 2-amino-N-tert-butylacetamide (INTERMEDIATE I.2) (0.78 g, 6.0 mmol) in acetonitrile (8 mL) was stirred at room temperature for 20 h. The white suspension was filtered, and the white precipitate washed cold EtOH to give 2-amino-5-bromo-N-(tert-butylcarbamoylmethyl)benzamide (1.06 g, 3.22 mmol, 65%). The white suspension was filtered the white precipitate washed cold EtOH

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

Procedure: which comprises the following steps: Condensing N-(5-oxo-L-prolyl)-L-histidine hydrazide by means of the azide method with L-tryptophan benzyl ester and treating the resulting compound with hydrazine hydrate to obtain N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan hydrazide (II); treating N-[O-benzyl-N-carboxy-L-tyrosyl]glycine N-benzyl ester with ethyl chloroformate to obtain the corresponding mixed anhydride which is reacted with t-butyl carbazate to obtain the corresponding 2-carboxyhydrazide t-butyl ester which is hydrogenolyzed to N-L-tyrosylglycine 2-carboxyhydrazide t-butyl ester, and condensing the latter with N-carboxy-L-seryl N-benzyl ester 2,4-dinitrophenyl ester followed by hydrogenolysis of the reaction product to obtain N-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide t-butyl ester (III); condensing N-carboxy-L-proline N-benzyl ester with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, treating the resulting product with ammonia and then hydrogenolyzing, to obtain 2-[(L-prolyl)amino]acetamide, which is condensed with N-carboxy-NG -nitro-L-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide and N-hydroxysuccinimide to obtain N-[N-(N-carboxy-NG -nitro-L-arginyl)-L-prolyl)]glycinamide N-t-butyl ester (IV); or alternatively condensing L-proline methyl ester with N-carboxy-NG -nitro-arginine N-t-butyl ester in the presence of dicyclohexylcarbodiimide, condensing the resulting product with glycine ethyl ester in the presence of dicyclohexylcarbodiimide, and treating the resulting product with ammonia to obtain the same compound IV as above; treating said compound IV with acid and then with N-carboxy-L-leucine N-benzyl ester 2,4,5-trichlorophenyl ester and hydrogenolyzing the resulting product in acetic acid, to obtain N-[N-[N-(N-L-leucyl)-L-arginyl]-L-prolyl]-glycinamide diacetate (V); condensing compound II with compound III by means of the azide method to obtain the hexapeptide N-[N-[N-[N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophyl]-L-seryl]-L-tyrosyl]glycine 2-carboxyhydrazide t-butyl ester, or condensing N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan with compound III in the presence of dicyclohexylcarbodiimide to obtain the same hexapeptide as above, and deprotecting and converting the latter to its trifluoroacetate salt (VI); and condensing compound V with compound VI by means of the azide method, to obtain the decapeptide of formula I which is isolated as the diacetate salt and optionally converted to other pharmaceutically acceptable salts.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A neat mixture of 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one (100 mg, 0.25 mmol) and 2-amino-N-tert-butyl acetamide (INTERMEDIATE I.2) (32 mg, 2.46 mmol) was heated at 120° C. for 3 h. The reaction mixture was cooled and partitioned between ethyl acetate and sat. NH4Cl (aq.). The organic layer was washed with brine (1×20 mL), dried (MgSO4) and concentrated in vacuo to afford N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1H-isoquinolin-2-yl)acetamide (120 mg, 0.23 mmol, 94%) which was used in the next step without further purification. The reaction mixture was cooled partitioned between ethyl acetate and sat. NH4Cl (aq.) The organic layer was washed with brine (1×20 mL) dried (MgSO4) concentrated in vacuo