4-(2-isocyanoethyl)morpholine

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added at 22° to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine from Example 11 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of t-butyl methyl ether and 0.23 ml of water, stirred for 11/2 hrs. at 22°, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]propionyl]piperidine I, MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of t-butyl methyl ether 0.23 ml of water, stirred for 11/2 hrs at 22°, the suspension was diluted with 10 ml of hexane filtered the residue was dried at 22°/11 mbar, there

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

Procedure: A mixture of 66 mg (0.12 mmol) N-(4-Methoxy-phenyl)-N-(carboxypropyl-sulfonyl)-thieno[2,3-b]quinoline-4-carboxamide 17, 25 μl (0.17 mmol) 2-Morpholino-ethyl-isocyanide (MEI) and 21 mg (0.17 mmol) N-Hydroxysuccinimide (HOSu) was stirred overnight at room temperature. The solvent was removed under vacuum and the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid). The appropriate fractions were combined and evaporated to yield 75 mg of 18. The solvent was removed under vacuum the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid) evaporated

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

Procedure: A mixture of 140 mg (0.26 mmol) N-(4-Methoxy-phenyl)-N-(carboxypropyl-sulfonyl)-furo[2,3-b]quinoline-4-carboxamide 10, 54 μl (0.37 mmol) 2-Morpholino-ethyl-isocyanide (MEI) and 44 mg (0.37 mmol) N-Hydroxysuccinimide (HOSu) was stirred overnight at room temperature. The solvent was removed under vacuum and the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid). The appropriate fractions were combined and evaporated to yield 94 mg of 11. The solvent was removed under vacuum the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid) evaporated

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX) from Example 5 or 6 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride at 22° and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of tert-butyl methyl ether and 0.23 ml of water, stirred at 22° for 11/2 hrs., the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (X), MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of tert-butyl methyl ether 0.23 ml of water, stirred at 22° for 11/2 hrs , the suspension was diluted with 10 ml of hexane filtered the residue was dried at 22°/11 mbar, there

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added at 22° to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperdine from Example 11 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of t-butyl methyl ether and 0.23 ml of water, stirred for 1½ hrs. at 22°, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperdine I, MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of t-butyl methyl ether 0.23 ml of water, stirred for 1½ hrs at 22°, the suspension was diluted with 10 ml of hexane filtered the residue was dried at 22°/11 mbar, there

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added at 22° to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperdine from Example 11 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of t-butyl methyl ether and 0.23 ml of water, stirred for 1½ hrs. at 22°, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperdine I, MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of t-butyl methyl ether 0.23 ml of water, stirred for 1½ hrs at 22°, the suspension was diluted with 10 ml of hexane filtered the residue was dried at 22°/11 mbar, there

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX) from Example 5 or 6 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride at 22° and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of tert-butyl methyl ether and 0.23 ml of water, stirred at 22° for 1½ hrs., the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 220/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (X), MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of tert-butyl methyl ether 0.23 ml of water, stirred at 22° for 1½ hrs , the suspension was diluted with 10 ml of hexane filtered the residue was dried at 220/11 mbar, there

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX) from Example 5 or 6 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride at 22° and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of tert-butyl methyl ether and 0.23 ml of water, stirred at 22° for 1½ hrs., the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 220/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (X), MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of tert-butyl methyl ether 0.23 ml of water, stirred at 22° for 1½ hrs , the suspension was diluted with 10 ml of hexane filtered the residue was dried at 220/11 mbar, there

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added at 22° to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine from Example 11 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of t-butyl methyl ether and 0.23 ml of water, stirred for 11/2 hrs. at 22°, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]propionyl]piperidine I, MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of t-butyl methyl ether 0.23 ml of water, stirred for 11/2 hrs at 22°, the suspension was diluted with 10 ml of hexane filtered the residue was dried at 22°/11 mbar, there

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

Procedure: A mixture of 66 mg (0.12 mmol) N-(4-Methoxy-phenyl)-N-(carboxypropyl-sulfonyl)-thieno[2,3-b]quinoline-4-carboxamide 17, 25 μl (0.17 mmol) 2-Morpholino-ethyl-isocyanide (MEI) and 21 mg (0.17 mmol) N-Hydroxysuccinimide (HOSu) was stirred overnight at room temperature. The solvent was removed under vacuum and the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid). The appropriate fractions were combined and evaporated to yield 75 mg of 18. The solvent was removed under vacuum the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid) evaporated

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

Procedure: A mixture of 140 mg (0.26 mmol) N-(4-Methoxy-phenyl)-N-(carboxypropyl-sulfonyl)-furo[2,3-b]quinoline-4-carboxamide 10, 54 μl (0.37 mmol) 2-Morpholino-ethyl-isocyanide (MEI) and 44 mg (0.37 mmol) N-Hydroxysuccinimide (HOSu) was stirred overnight at room temperature. The solvent was removed under vacuum and the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid). The appropriate fractions were combined and evaporated to yield 94 mg of 11. The solvent was removed under vacuum the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid) evaporated

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

Procedure: 0.78 g of 2-morpholino-ethyl isocyanide was added to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX) from Example 5 or 6 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride at 22° and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of tert-butyl methyl ether and 0.23 ml of water, stirred at 22° for 11/2 hrs., the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (X), MS (EI): 436 (40%). stirred for 2 hrs The reaction mixture was washed with saturated NaHCO3 solution and with water evaporated The residue was dissolved in 20 ml of tert-butyl methyl ether 0.23 ml of water, stirred at 22° for 11/2 hrs , the suspension was diluted with 10 ml of hexane filtered the residue was dried at 22°/11 mbar, there