4-(dipropylamino)-4-oxobutanoic acid

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

Procedure: To a solution of hydrocortisone (5 g, 0.014 mole) and N,N-di-n-propylsuccinamic acid (2.78 g, 0.014 mole) in 25 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.85 g, 0.014 mole). After the reaction was stirred 10 minutes, 25 ml dichloromethane was added to it to keep the suspension which had formed sufficiently fluid for stirring. After the reaction was stirred overnight, it was filtered. The residue was washed twice with CH2Cl2 and dried in the air to give 2.46 g (91% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to a residue which was dissolved in 25 ml hot THF. After the THF solution was filtered while hot, the resulting filtrate was diluted to 150 ml with Et2O. The product crystallized overnight and was filtered and dried to give 3.49 g of light brown crystals, which a preliminary NMR showed to be contaminated with solvent. The crystals were dried in vacuo (50° C., 2 hours) to give 2.81 g (37% yield) of the desired product: mp 157°-162° C.; NMR (CDCl3) δ5.64 (s, 1, O=C-CH=), 4.98 (m, 2, O=C-CH2O), 4.46 (m, 1, CHOH), 3.8-4.2 (m, 2, OH), 3.24 (t, 4, J=7 Hz, N CH2), 2.70 (s, 4, OCCH2CH2CO), 1.46 (s, 3, C-CH3), 0.96 (s, 3, C-CH3), 0.94 (m, 6, N(CH2CH2CH3)2), 2.9-0.8 (m, 21, CH, CH2); TLC (silica gel, 10% MeOH/Et2O) Rf 0.56; [α]25D=+127° (C=0.5, dioxane); IR (KBr) 3400 cm-1 (s) (OH), 1730, 1710, 1640 and 1610 cm-1 (s) (C=O). had formed sufficiently fluid for stirring After the reaction was stirred overnight it was filtered The residue was washed twice with CH2Cl2 dried in the air

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

Procedure: To a solution of hydrocortisone (5 g, 0.014 mole) and N,N-di-n-propylsuccinamic acid (2.78 g, 0.014 mole) in 25 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.85 g, 0.014 mole). After the reaction was stirred 10 minutes, 25 ml dichloromethane was added to it to keep the suspension which had formed sufficiently fluid for stirring. After the reaction was stirred overnight, it was filtered. The residue was washed twice with CH2Cl2 and dried in the air to give 2.46 g (91% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to a residue which was dissolved in 25 ml hot THF. After the THF solution was filtered while hot, the resulting filtrate was diluted to 150 ml with Et2O. The product crystallized overnight and was filtered and dried to give 3.49 g of light brown crystals, which a preliminary NMR showed to be contaminated with solvent. The crystals were dried in vacuo (50° C., 2 hours) to give 2.81 g (37% yield) of the desired product: mp 157°-162° C.; NMR (CDCl3) δ5.64 (s, 1, O=C-CH=), 4.98 (m, 2, O=C-CH2O), 4.46 (m, 1, CHOH), 3.8-4.2 (m, 2, OH), 3.24 (t, 4, J=7 Hz, N CH2), 2.70 (s, 4, OCCH2CH2CO), 1.46 (s, 3, C-CH3), 0.96 (s, 3, C-CH3), 0.94 (m, 6, N(CH2CH2CH3)2), 2.9-0.8 (m, 21, CH, CH2); TLC (silica gel, 10% MeOH/Et2O) Rf 0.56; [α]25D=+127° (C=0.5, dioxane); IR (KBr) 3400 cm-1 (s) (OH), 1730, 1710, 1640 and 1610 cm-1 (s) (C=O). had formed sufficiently fluid for stirring After the reaction was stirred overnight it was filtered The residue was washed twice with CH2Cl2 dried in the air

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

Procedure: To a solution of hydrocortisone (5 g, 0.014 mole) and N,N-di-n-propylsuccinamic acid (2.78 g, 0.014 mole) in 25 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.85 g, 0.014 mole). After the reaction was stirred 10 minutes, 25 ml dichloromethane was added to it to keep the suspension which had formed sufficiently fluid for stirring. After the reaction was stirred overnight, it was filtered. The residue was washed twice with CH2Cl2 and dried in the air to give 2.46 g (91% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to a residue which was dissolved in 25 ml hot THF. After the THF solution was filtered while hot, the resulting filtrate was diluted to 150 ml with Et2O. The product crystallized overnight and was filtered and dried to give 3.49 g of light brown crystals, which a preliminary NMR showed to be contaminated with solvent. The crystals were dried in vacuo (50° C., 2 hours) to give 2.81 g (37% yield) of the desired product: mp 157°-162° C.; NMR (CDCl3) δ5.64 (s, 1, O=C-CH=), 4.98 (m, 2, O=C-CH2O), 4.46 (m, 1, CHOH), 3.8-4.2 (m, 2, OH), 3.24 (t, 4, J=7 Hz, N CH2), 2.70 (s, 4, OCCH2CH2CO), 1.46 (s, 3, C-CH3), 0.96 (s, 3, C-CH3), 0.94 (m, 6, N(CH2CH2CH3)2), 2.9-0.8 (m, 21, CH, CH2); TLC (silica gel, 10% MeOH/Et2O) Rf 0.56; [α]25D=+127° (C=0.5, dioxane); IR (KBr) 3400 cm-1 (s) (OH), 1730, 1710, 1640 and 1610 cm-1 (s) (C=O). had formed sufficiently fluid for stirring After the reaction was stirred overnight it was filtered The residue was washed twice with CH2Cl2 dried in the air

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

Procedure: Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-(dipropylamino)-4-oxobutanoic acid to yield (3aR,4S,7aR)-methyl 4-(4-(dipropylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.771 min; LC/MS LC-MS Method III

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

Procedure: The reaction of 3-(N,N-dipropylcarbamoyl)propionic acid and diphenylphosphoryl azide in a solution of triethylamine and benzene provided a solution comprising 2-(N',N'-dipropylcarbamoyl)ethyl isocyanate (I.R.: 2280 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-[2-(N',N'-dipropylcarbamoyl)ethyl]carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 4.