diethyl 2-aminononanedioate

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

Procedure: Diethyl 2-aminononanedioate (5.0 g) was heated with benzaldehyde (2.15 g) in benzene (10 ml) under reflux for 12/3 hours, removing the water formed by means of a Dean and Stark apparatus. The benzene was evaporated in vacuo and the residual oil was taken up in dry tetrahydrofuran (20 ml), stirred under dry nitrogen, treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen began. Thereafter, reaction was allowed to proceed at room temperature. When effervescence had ceased, the pale yellow-brown solution was cooled in ice-water and, with continued stirring, treated with methyl iodide (6.83 g); the cooling bath was removed after 15 minutes and the mixture was set aside at room temperature overnight. The resulting suspension of solid was diluted with ether (100 ml) and shaken with ice-cold water (100 ml), and the ethereal phase was washed with H2O, dried over sodium sulphate, and evaporated, to leave crude diethyl 2-(benzylideneamino)2-methylnonanedioate (6.4 g) as a yellow oil. under reflux for 12/3 hours removing the water formed by means of a Dean and Stark apparatus The benzene was evaporated in vacuo treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen Thereafter, reaction to proceed at room temperature the cooling bath was removed after 15 minutes The resulting suspension of solid was diluted with ether (100 ml) shaken with ice-cold water (100 ml) the ethereal phase was washed with H2O dried over sodium sulphate evaporated

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

Procedure: Diethyl 2-aminononanedioate (5.0 g) was heated with benzaldehyde (2.15 g) in benzene (10 ml) under reflux for 12/3 hours, removing the water formed by means of a Dean and Stark apparatus. The benzene was evaporated in vacuo and the residual oil was taken up in dry tetrahydrofuran (20 ml), stirred under dry nitrogen, treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen began. Thereafter, reaction was allowed to proceed at room temperature. When effervescence had ceased, the pale yellow-brown solution was cooled in ice-water and, with continued stirring, treated with methyl iodide (6.83 g); the cooling bath was removed after 15 minutes and the mixture was set aside at room temperature overnight. The resulting suspension of solid was diluted with ether (100 ml) and shaken with ice-cold water (100 ml), and the ethereal phase was washed with H2O, dried over sodium sulphate, and evaporated, to leave crude diethyl 2-(benzylideneamino)2-methylnonanedioate (6.4 g) as a yellow oil. under reflux for 12/3 hours removing the water formed by means of a Dean and Stark apparatus The benzene was evaporated in vacuo treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen Thereafter, reaction to proceed at room temperature the cooling bath was removed after 15 minutes The resulting suspension of solid was diluted with ether (100 ml) shaken with ice-cold water (100 ml) the ethereal phase was washed with H2O dried over sodium sulphate evaporated

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

Procedure: The above aminodiester was alternatively prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C. with stirring, and set aside at room temperature for 3 hours, giving diethyl 2-(3-oxooctylamino)nonanedioate as a colourless oil, δ2.3(4H, multiplet, --CH2 --CO2Et and NCH2CH2CO--), 3.16(1H, triplet, EtO2C--CHR--N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, --O--CH2 --CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 31/2 hours at room temperature, and concentrated at 40° C. in vacuo. The residue, dissolved in water, was brought to pH5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxy-octylamino)nonanedioate as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed by p-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.

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

Procedure: Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml)) and the mixture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H, singlet, --COCH3), 4.17(6H, multiplet, 3×--OCH2 --CH3). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2 hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 11/2 hours, cooled, and poured into ice-water, adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114°-115°/0.02-0.03 mm. the mixture was refluxed for 27 hours the product was extracted into ether the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H the cooled solution was washed with ether evaporated to dryness in vacuo The residual colourless glass was dissolved in the minimum quantity of absolute ethanol added dropwise to a stirred cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g) refluxed for 11/2 hours cooled poured into ice-water The mixture was extracted with ether the dried extract was concentrated distilled

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

Procedure: Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml)) and the mixture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H, singlet, --COCH3), 4.17(6H, multiplet, 3×--OCH2 --CH3). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2 hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 11/2 hours, cooled, and poured into ice-water, adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114°-115°/0.02-0.03 mm. the mixture was refluxed for 27 hours the product was extracted into ether the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H the cooled solution was washed with ether evaporated to dryness in vacuo The residual colourless glass was dissolved in the minimum quantity of absolute ethanol added dropwise to a stirred cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g) refluxed for 11/2 hours cooled poured into ice-water The mixture was extracted with ether the dried extract was concentrated distilled

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

Procedure: Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C., with stirring, and set aside at room temperature for 3 h., giving diethyl 2-(3-oxoctylamino) nonanedioate as a colourless oil, 2.3(4H, multiplet, --CH2 --CO2Et and NCH2CH2CO--), 3.16(1H, triplet, EtO2C--CHR--N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, --O--CH2 --CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 ml) in absolute ethanol (70 ml), then kept for 31/2 h. at room temperature, and concentrated at 40° C. in vacuo. The residue dissolved in water, was brought to pH 5 with N hydrochloric acid and extracted throughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxyoctylamino)nonanedioate as a colourless oil. giving diethyl 2-(3-oxoctylamino) nonanedioate as a colourless oil, 2.3(4H 2 h. at room temperature concentrated at 40° C. in vacuo The residue dissolved in water extracted throughly with chloroform the extract was washed with water dried evaporated

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

Procedure: The above aminodiester was alternatively prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C. with stirring, and set aside at room temperature for 3 hours, giving diethyl 2-(3-oxooctylamino)nonanedioate as a colourless oil, δ2.3(4H, multiplet, -CH2 -CO2Et and NCH2CH2CO-), 3.16(1H, triplet, EtO2C-CHR-N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, -O-CH2 -CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 31/2 hours at room temperature and concentrated at 40° C. in vacuo. The residue, dissolved in water, was brought to pH 5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxy-octylamino)nonanedioate as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed by p-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.

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

Procedure: Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml)) and the mixture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H, singlet, --COCH3), 4.17(6H, multiplet, 3×--OCH2 --CH3). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2 hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 11/2 hours, cooled, and poured into ice-water adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114°-115°/0.02--0.3 mm. the mixture was refluxed for 27 hours the product was extracted into ether the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H the cooled solution was washed with ether evaporated to dryness in vacuo The residual colourless glass was dissolved in the minimum quantity of absolute ethanol added dropwise to a stirred cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g) refluxed for 11/2 hours cooled poured into ice-water adjusting the pH to 9 with aqueous sodium hydroxide The mixture was extracted with ether the dried extract was concentrated distilled

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

Procedure: Diethyl 2-aminononanedioate (5.0 g) was heated with benzaldehyde (2.15 g) in benzene (10 ml) under reflux for 12/3 hr, removing the water formed by means of a Dean and Stark apparatus. The benzene was evaporated in vacuo and the residual oil was taken up in dry tetrahydrofuran (20 ml), stirred under dry nitrogen, treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen began. Thereafter reaction was allowed to procede at room temperature. When effervescence had ceased, the pale yellow-brown solution was cooled in ice-water and, with continued stirring, treated with methyl iodide (6.83 g); the cooling bath was removed after 15 min and the mixture was set aside at room temperature overnight. The resulting suspension of solid was diluted with ether (100 ml) and shaken with ice-cold water (100 ml), and the ethereal phase was washed with H2O, dried over sodium sulphate, and evaporated, to leave crude diethyl 2-(benzylideneamino)-2-methylnonanedioate (6.4 g) as a yellow oil. under reflux for 12/3 hr removing the water formed by means of a Dean and Stark apparatus The benzene was evaporated in vacuo treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen Thereafter reaction to procede at room temperature the cooling bath was removed after 15 min The resulting suspension of solid was diluted with ether (100 ml) shaken with ice-cold water (100 ml) the ethereal phase was washed with H2O dried over sodium sulphate evaporated

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

Procedure: A stirred solution of diethyl 2-aminononanedioate (10 g) in ethanol (77 ml) was cooled in ice-water and treated with 2N hydrochloric acid (38.6 ml) followed by a solution of potassium cyanate (6.255 g) in water (20 ml). The cooling bath was removed and the suspension was stirred for 7 hours at room temperature then set aside overnight. The ethanol was evaporated in vacuo and the residue was shaken with water and chloroform; the chloroform phase was separated, washed with water and dried (MgSO4), and the chloroform was evaporated to give an oil which was heated on the steam bath for 6 hours. The resulting oil crystallised on standing at room temperature. The crystals were stirred with ether and collected, affording pure diethyl 2-ureidononanedioate, m.p. 79°-80° C. The cooling bath was removed then set aside overnight The ethanol was evaporated in vacuo the residue was shaken with water and chloroform the chloroform phase was separated washed with water dried (MgSO4) the chloroform was evaporated to give an oil which was heated on the steam bath for 6 hours The resulting oil crystallised on standing at room temperature The crystals were stirred with ether collected

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

Procedure: Diethyl 2-aminononanedioate (5.0 g) was heated with benzaldehyde (2.15 g) in benzene (10 ml) under reflux for 12/3 hours, removing the water formed by means of a Dean and Stark apparatus. The benzene was evaporated in vacuo and the residual oil was taken up in dry tetrahydrofuran (20 ml), stirred under dry nitrogen, treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen began. Thereafter, reaction was allowed to proceed at room temperature. When effervescence had ceased, the pale yellow-brown solution was cooled in icewater and, with continued stirring, treated with methyl iodide (6.83 g); the cooling bath was removed after 15 minutes and the mixture was set aside at room temperature overnight. The resulting suspension of solid ws diluted with ether (100 ml) and skaken with ice-cold water (100 ml), and the ethereal phase was washed with H2O, dried over sodium sulphate, and evaporated, to leave crude diethyl 2-(benzylideneamino)-2-methylnonanedioate (6.4 g) as a yellow oil. under reflux for 12/3 hours removing the water formed by means of a Dean and Stark apparatus The benzene was evaporated in vacuo treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen Thereafter, reaction to proceed at room temperature the pale yellow-brown solution was cooled in icewater and, with continued stirring the cooling bath was removed after 15 minutes The resulting suspension of solid ws diluted with ether (100 ml) the ethereal phase was washed with H2O dried over sodium sulphate evaporated

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

Procedure: The above aminodiester was alternatively prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C. with stirring, and set aside at room temperature for 3 hours, giving diethyl 2-(3-oxooctyl amino)nonanedioate as a colourless oil, δ2.3 (4H, multiplet, --CH2 --CO2Et and NCH2CH2CH--), 3.16(1H, triplet, EtO2C--CHR--N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, --O--CH2 --CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 31/2 hours at room temperature, and concentrated at 40° C. in vacuo. The residue, dissolved in water, was brought to pH 5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxy-octylamino)nonanediote as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed by p-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.