O-(3,5-dichlorophenyl)hydroxylamine

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 3.5 grams (0.010 mole) of 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone (prepared in Step C of this Example) in 30 mL of ethanol is stirred, and a solution of 2.1 grams (0.012 mole) of O-(3,5-dichlorophenyl)hydroxylamine in 15 mL of ethanol is added dropwise. Upon completion of addition, the reaction mixture is heated to reflux, where it is stirred for about four hours. After this time the reaction mixture is cooled and concentrated under reduced pressure to a residue. The residue is dissolved in diethyl ether and washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline. Upon completion of addition the reaction mixture is heated to reflux where it is stirred for about four hours After this time the reaction mixture is cooled concentrated under reduced pressure to a residue The residue is dissolved in diethyl ether washed with two portions of an aqueous solution saturated with sodium chloride The organic layer is dried with sodium sulfate filtered The filtrate is concentrated under reduced pressure

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (50% in mineral oil), 4.0 grams (0.084 mole), is placed in a reaction vessel and washed with three portions of hexane. The sodium hydride is then stirred with 30 mL of N,N-dimethylformamide, and a solution of 13.7 grams (0.084 mole) of 3,5-dichlorophenol in 45 mL of N,N-dimethylformamide is added dropwise. Upon completion of addition, the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes. After this time the reaction mixture is cooled to about 2° C., and 13.4 grams (0.068 mole) of O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion. Upon completion of addition, the reaction mixture is stirred at about 2° C. for 10 minutes. The cooling medium is then removed, and the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 3.5 hours. After this time the reaction mixture is poured into about 1000 mL of ice-water. The resultant precipitate is collected by filtration and washed with water. The solid is dried and then is dissolved in ethyl acetate. The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding O-(3,5-dichlorophenyl)hydroxylamine. washed with three portions of hexane Upon completion of addition the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion Upon completion of addition the reaction mixture is stirred at about 2° C. for 10 minutes The cooling medium is then removed to warm to ambient temperature where it is stirred for about 3.5 hours After this time the reaction mixture is poured into about 1000 mL of ice-water The resultant precipitate is collected by filtration washed with water The solid is dried is dissolved in ethyl acetate The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride The organic layer is dried with sodium sulfate filtered The filtrate is concentrated under reduced pressure

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (50% in mineral oil), 4.0 grams (0.084 mole), is placed in a reaction vessel and washed with three portions of hexane. The sodium hydride is then stirred with 30 mL of N,N-dimethylformamide, and a solution of 13.7 grams (0.084 mole) of 3,5-dichlorophenol in 45 mL of N,N-dimethylformamide is added dropwise. Upon completion of addition, the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes. After this time the reaction mixture is cooled to about 2° C., and 13.4 grams (0.068 mole) of O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion. Upon completion of addition, the reaction mixture is stirred at about 2° C. for 10 minutes. The cooling medium is then removed, and the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 3.5 hours. After this time the reaction mixture is poured into about 1000 mL of ice-water. The resultant precipitate is collected by filtration and washed with water. The solid is dried and then is dissolved in ethyl acetate. The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding O-(3,5-dichlorophenyl)hydroxylamine. washed with three portions of hexane Upon completion of addition the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion Upon completion of addition the reaction mixture is stirred at about 2° C. for 10 minutes The cooling medium is then removed to warm to ambient temperature where it is stirred for about 3.5 hours After this time the reaction mixture is poured into about 1000 mL of ice-water The resultant precipitate is collected by filtration washed with water The solid is dried is dissolved in ethyl acetate The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride The organic layer is dried with sodium sulfate filtered The filtrate is concentrated under reduced pressure

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

Procedure: When the bridging group n is =NO--, 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal is prepared from 1,4-cyclohexanedione mono-ethylene ketal and cyanoguanidine, as previously described. The 2,4-diamino moieties are then protected by the reaction of 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal with pivalic anhydride in the presence of 4-dimethylaminopyridine, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal. The 6-ethylene ketal functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone. A second intermediate, an O-(phenyl)hydroxylamine, is prepared by the reaction of an appropriately substituted or unsubstituted phenol, for example, 3,5-dichlorophenol, with O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al (Tetrahedron, 28, 3833 (1972)). The so-prepared O-(phenyl)hydroxylamine, for example, O-(3,5-dichlorophenyl)hydroxylamine, is then reacted with the 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone in ethanol, yielding the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Treatment of the 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline with methanolic hydrochloric acid yields the targeted 2,4-diamino-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Example 12 provides a detailed description of how this reaction is conducted. prepared by the method of T

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 3.5 grams (0.010 mole) of 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone (prepared in Step C of this Example) in 30 mL of ethanol is stirred, and a solution of 2.1 grams (0.012 mole) of O-(3,5-dichlorophenyl)hydroxylamine in 15 mL of ethanol is added dropwise. Upon completion of addition, the reaction mixture is heated to reflux, where it is stirred for about four hours. After this time the reaction mixture is cooled and concentrated under reduced pressure to a residue. The residue is dissolved in diethyl ether and washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline. Upon completion of addition the reaction mixture is heated to reflux where it is stirred for about four hours After this time the reaction mixture is cooled concentrated under reduced pressure to a residue The residue is dissolved in diethyl ether washed with two portions of an aqueous solution saturated with sodium chloride The organic layer is dried with sodium sulfate filtered The filtrate is concentrated under reduced pressure

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (50% in mineral oil), 4.0 grams (0.084 mole), is placed in a reaction vessel and washed with three portions of hexane. The sodium hydride is then stirred with 30 mL of N,N-dimethylformamide, and a solution of 13.7 grams (0.084 mole) of 3,5-dichlorophenol in 45 mL of N,N-dimethylformamide is added dropwise. Upon completion of addition, the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes. After this time the reaction mixture is cooled to about 2° C., and 13.4 grams (0.068 mole) of O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion. Upon completion of addition, the reaction mixture is stirred at about 2° C. for 10 minutes. The cooling medium is then removed, and the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 3.5 hours. After this time the reaction mixture is poured into about 1000 mL of ice-water. The resultant precipitate is collected by filtration and washed with water. The solid is dried and then is dissolved in ethyl acetate. The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding O-(3,5-dichlorophenyl)hydroxylamine. washed with three portions of hexane Upon completion of addition the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion Upon completion of addition the reaction mixture is stirred at about 2° C. for 10 minutes The cooling medium is then removed to warm to ambient temperature where it is stirred for about 3.5 hours After this time the reaction mixture is poured into about 1000 mL of ice-water The resultant precipitate is collected by filtration washed with water The solid is dried is dissolved in ethyl acetate The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride The organic layer is dried with sodium sulfate filtered The filtrate is concentrated under reduced pressure

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

Procedure: When the bridging group n is =NO--, 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal is prepared from 1,4-cyclohexanedione mono-ethylene ketal and cyanoguanidine, as previously described. The 2,4-diamino moieties are then protected by the reaction of 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal with pivalic anhydride in the presence of 4-dimethylaminopyridine, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal. The 6-ethylene ketal functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 2,4-di[(1,1 -dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone. A second intermediate, an O-(phenyl)hydroxylamine, is prepared by the reaction of an appropriately substituted or unsubstituted phenol, for example, 3,5-dichlorophenol, with O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al (Tetrahedron, 28, 3833 (1972)). The so-prepared O-(phenyl)hydroxylamine, for example, O-(3,5-dichlorophenyl)hydroxylamine, is then reacted with the 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone in ethanol, yielding the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Treatment of the 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline with methanolic hydrochloric acid yields the targeted 2,4-diamino-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Example 12 provides a detailed description of how this reaction is conducted. prepared by the method of T

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

Procedure: A solution of 3.5 grams (0.010 mole) of 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone (prepared in Step C of this Example) in 30 mL of ethanol is stirred, and a solution of 2.1 grams (0.012 mole) of O-(3,5-dichlorophenyl)hydroxylamine in 15 mL of ethanol is added dropwise. Upon completion of addition, the reaction mixture is heated to reflux, where it is stirred for about four hours. After this time the reaction mixture is cooled and concentrated under reduced pressure to a residue. The residue is dissolved in diethyl ether and washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline. Upon completion of addition the reaction mixture is heated to reflux where it is stirred for about four hours After this time the reaction mixture is cooled concentrated under reduced pressure to a residue The residue is dissolved in diethyl ether washed with two portions of an aqueous solution saturated with sodium chloride The organic layer is dried with sodium sulfate filtered The filtrate is concentrated under reduced pressure

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (50% in mineral oil), 4.0 grams (0.084 mole), is placed in a reaction vessel and washed with three portions of hexane. The sodium hydride is then stirred with 30 mL of N,N-dimethylformamide, and a solution of 13.7 grams (0.084 mole) of 3,5-dichlorophenol in 45 mL of N,N-dimethylformamide is added dropwise. Upon completion of addition, the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes. After this time the reaction mixture is cooled to about 2° C., and 13.4 grams (0.068 mole) of O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion. Upon completion of addition, the reaction mixture is stirred at about 2° C. for 10 minutes. The cooling medium is then removed, and the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 3.5 hours. After this time the reaction mixture is poured into about 1000 mL of ice-water. The resultant precipitate is collected by filtration and washed with water. The solid is dried and then is dissolved in ethyl acetate. The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding O-(3,5-dichlorophenyl)hydroxylamine. washed with three portions of hexane Upon completion of addition the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion Upon completion of addition the reaction mixture is stirred at about 2° C. for 10 minutes The cooling medium is then removed to warm to ambient temperature where it is stirred for about 3.5 hours After this time the reaction mixture is poured into about 1000 mL of ice-water The resultant precipitate is collected by filtration washed with water The solid is dried is dissolved in ethyl acetate The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride The organic layer is dried with sodium sulfate filtered The filtrate is concentrated under reduced pressure

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

Procedure: When the bridging group n is =NO--, 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal is prepared from 1,4-cyclohexanedione mono-ethylene ketal and cyanoguanidine, as previously described. The 2,4-diamino moieties are then protected by the reaction of 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal with pivalic anhydride in the presence of 4-dimethylaminopyridine, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal. The 6-ethylene ketal functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone. A second intermediate, an O-(phenyl)hydroxylamine, is prepared by the reaction of an appropriately substituted or unsubstituted phenol, for example, 3,5-dichlorophenol, with O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al (Tetrahedron, 28, 3833 (1972)). The so-prepared O-(phenyl)hydroxylamine, for example, O-(3,5-dichlorophenyl)hydroxylamine, is then reacted with the 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone in ethanol, yielding the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Treatment of the 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline with methanolic hydrochloric acid yields the targeted 2,4-diamino-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Example 12 provides a detailed description of how this reaction is conducted. prepared by the method of T