N-ethylhydroxylamine;hydrochloride

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

Procedure: 2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate (13.5 g) was taken up in 20 ml of absolute ethanol and added to a solution containing ethyl hydroxylamine hydrochloride (11.03 g) and potassium t-butoxide (12.7 g) in 600 ml of absolute ethanol. The mixture was stirred at reflux under a nitrogen blanket for 18 hours then evaporated. The residue was taken up in chloroform and washed with brine, dried, and evaporated. Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane. Recrystallization from ether-cyclohexene gave 1.7 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine, as crystals, m.p. 102°-103° C., with softening at 88°0 C. added to a solution at reflux under a nitrogen blanket for 18 hours then evaporated washed with brine dried evaporated Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane Recrystallization from ether-cyclohexene

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

Procedure: A stirring solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 8.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 400 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight (16 hours) with continued stirring. The reaction was quenched with 500 ml of water and concentrated in vacuo to remove solvents. The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na2SO4) and concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated twice via preparative HPLC to give 2.65 g of 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-2-yl)-N-ethyl-N-hydroxypropanamide, as an oil. (16 hours) The reaction was quenched with 500 ml of water concentrated in vacuo to remove solvents The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1) The organic phase was washed with 500 ml of water dried (Na2SO4) concentrated in vacuo to an oil was separated twice via preparative HPLC

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

Procedure: 2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate (13.5 g) was taken up in 20 ml of absolute ethanol and added to a solution containing ethyl hydroxylamine hydrochloride (11.03 g) and potassium t-butoxide (12.7 g) in 600 ml of absolute ethanol. The mixture was stirred at reflux under a nitrogen blanket for 18 hours then evaporated. The residue was taken up in chloroform and washed with brine, dried, and evaporated. Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane. Recrystallization from ether-cyclohexene gave 1.7 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine, as crystals, m.p. 102°-103° C., with softening at 88°0 C. added to a solution at reflux under a nitrogen blanket for 18 hours then evaporated washed with brine dried evaporated Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane Recrystallization from ether-cyclohexene

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

Procedure: 2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate (13.5 g) was taken up in 20 ml of absolute ethanol and added to a solution containing ethyl hydroxylamine hydrochloride (11.03 g) and potassium t-butoxide (12.7 g) in 600 ml of absolute ethanol. The mixture was stirred at reflux under a nitrogen blanket for 18 hours then evaporated. The residue was taken up in chloroform and washed with brine, dried, and evaporated. Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane. Recrystallization from ether-cyclohexene gave 1.7 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine, as crystals, m.p. 102°-103° C., with softening at 88°0 C. added to a solution at reflux under a nitrogen blanket for 18 hours then evaporated washed with brine dried evaporated Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane Recrystallization from ether-cyclohexene

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

Procedure: A stirring solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 8.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 400 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight (16 hours) with continued stirring. The reaction was quenched with 500 ml of water and concentrated in vacuo to remove solvents. The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na2SO4) and concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated twice via preparative HPLC to give 2.65 g of 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-2-yl)-N-ethyl-N-hydroxypropanamide, as an oil. (16 hours) The reaction was quenched with 500 ml of water concentrated in vacuo to remove solvents The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1) The organic phase was washed with 500 ml of water dried (Na2SO4) concentrated in vacuo to an oil was separated twice via preparative HPLC

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

Procedure: A stirring solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 8.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 400 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight (16 hours) with continued stirring. The reaction was quenched with 500 ml of water and concentrated in vacuo to remove solvents. The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na2SO4) and concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated twice via preparative HPLC to give 2.65 g of 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-2-yl)-N-ethyl-N-hydroxypropanamide, as an oil. (16 hours) The reaction was quenched with 500 ml of water concentrated in vacuo to remove solvents The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1) The organic phase was washed with 500 ml of water dried (Na2SO4) concentrated in vacuo to an oil was separated twice via preparative HPLC

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-[(4-acetyl-2,6-dichlorophenyl)amino]pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Examples 144 and 145, Step 3) (20 mg, 0.50 mmol) in MeOH (1 mL) was added N-hydroxyethanamine HCl (24 mg, 0.25 Minot) and sodium acetate (21 mg, 0.25 mmol). The solution was heated to 85° C. for 1 hr then cooled to room temperature and extracted with 3:1 CHCl3/iPrOH and water. The organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (100% CH2Cl2 to 70% CH2Cl2 30% MeOH) provided the product as a mixture of rotamers and E/Z isomers. then cooled to room temperature extracted with 3:1 CHCl3/iPrOH and water The organic layers were dried with MgSO4 filtered concentrated under reduced pressure Purification by silica gel chromatography (100% CH2Cl2 to 70% CH2Cl2 30% MeOH) provided the product as a mixture of rotamers and E/Z isomers

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

Procedure: 2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate (13.5 g) was taken up in 20 ml of absolute ethanol and added to a solution containing ethyl hydroxylamine hydrochloride (11.03 g) and potassium t-butoxide (12.7 g) in 600 ml of absolute ethanol. The mixture was stirred at reflux under a nitrogen blanket for 18 hours then evaporated. The residue was taken up in chloroform and washed with brine, dried, and evaporated. Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane. Recrystallization from ether-cyclohexane gave 1.7 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine, as crystals, m.p 102-103° C., with softening at 88° C. added to a solution at reflux under a nitrogen blanket for 18 hours then evaporated washed with brine dried evaporated Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane Recrystallization from ether-cyclohexane

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

Procedure: 2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate (13.5 g) was taken up in 20 ml of absolute ethanol and added to a solution containing ethyl hydroxylamine hydrochloride (11.03 g) and potassium t-butoxide (12.7 g) in 600 ml of absolute ethanol. The mixture was stirred at reflux under a nitrogen blanket for 18 hours then evaporated. The residue was taken up in chloroform and washed with brine, dried, and evaporated. Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane. Recrystallization from ether-cyclohexene gave 1.7 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine, as crystals, m.p. 102°-103° C., with softening at 88°0 C. added to a solution at reflux under a nitrogen blanket for 18 hours then evaporated washed with brine dried evaporated Purification of the residual oil (HPLC, 9:1 DCM-methanol) gave an oil which crystallized from ether-hexane Recrystallization from ether-cyclohexene

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

Procedure: A stirring solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 8.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 400 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight (16 hours) with continued stirring. The reaction was quenched with 500 ml of water and concentrated in vacuo to remove solvents. The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na2SO4) and concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated twice via preparative HPLC to give 2.65 g of 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-2-yl)-N-ethyl-N-hydroxypropanamide, as an oil. (16 hours) The reaction was quenched with 500 ml of water concentrated in vacuo to remove solvents The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1) The organic phase was washed with 500 ml of water dried (Na2SO4) concentrated in vacuo to an oil was separated twice via preparative HPLC