benzene-1,2-dicarbohydrazide

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

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

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

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

Procedure: 71 ml. of a solution of anhydrous dimethylformamide containing 2 moles per liter of hydrazine hydrate (i.e. 0.142 mole) are added dropwise over a period of about 30 minutes at 0° C. to a suspension of 70.5 g. (0.128 mole) of tert-butyl 4-benzyloxycarbonyl-alphaphthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate in 150 ml. anhydrous dimethylformamide. The reaction mixture is allowed to warm up to ambient temperature, with magnetic stirring, and to the resulting clear solution are added 120 ml. of 1.203N hydrochloric acid over a period of 1.5 hours. A precipitate of phthalohydrazide is formed, which is filtered off and washed several times with water, whereupon the mother liquors are evaporated in vacuo (bath temperature: maximum 40° C.) and the residue is taken up in a mixture of acetone and diethyl ether. There are finally obtained 43.2 g. (yield 73.7%) of tert-butyl alpha-amino-4-benzyloxycarbonyl-1-thia-3-azaspiro[4.5]decane-2-acetate hydrochloride. to the resulting clear solution are added 120 ml

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

Procedure: To a solution of 338 mg (1.3 mmoles) of phthalhydrazide in 20 ml of DMF, 252 mg (1.83 mmoles) of K2CO3 and 400 mg (1.30 mmoles) of 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:2) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 70% yield. The obtained product is treated with MeJ under the same conditionto give N-methylated compound. To a solution of 295 mg (0.76 mmoles) of 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 20 ml of DMF, 0.066 ml (1.06 mmoles) of MeJ and 168 mg (1.22 mmoles) of K2CO3 are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:4) give 238 mg of 7-(2,2-Dimethyl-propyl)-6-(3-methyl-1,4dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield. The reaction mixture is quenched with ice-water extracted with AcOEt The combined extracts are washed with H2O, brine dried over MgSO4

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

Procedure: To a solution of 338 mg (1.3 mmoles) of phthalhydrazide in 20 ml of DMF, 252 mg (1.83 mmoles) of K2CO3 and 400 mg (1.30 mmoles) of 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:2) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 70% yield. The obtained product is treated with MeJ under the same conditionto give N-methylated compound. To a solution of 295 mg (0.76 mmoles) of 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 20 ml of DMF, 0.066 ml (1.06 mmoles) of MeJ and 168 mg (1.22 mmoles) of K2CO3 are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:4) give 238 mg of 7-(2,2-Dimethyl-propyl)-6-(3-methyl-1,4dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield. The reaction mixture is quenched with ice-water extracted with AcOEt The combined extracts are washed with H2O, brine dried over MgSO4

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

Procedure: The compound N-(4-benzyloxy-3,3-difluorobutyl)-phthalimide (68.5 g, 198.6 mmoles) and hydrazine hydrate (10 g, 200 mmoles) are stirred and heated overnight in ethanol (200 mL) at 90°-100° C. A mixture of concentrated HCl (94 mL) and ethanol (1130 mL) is added, and heating (90°-100° C.) is continued for 1.5 hours. After cooling (ice bath), phthalhydrazide is removed by filtration, and the filtrate is evaporated. The residue is taken up in water and extracted with ether (2×500 mL). After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals. These are dissolved in ethanol, the solution is filtered (Millipore organic) and the filtrate is evaporated to yield a residue which crystallizes on addition of ether: 34 g (68%). Evaporation of the ether extracts yields a partially crystalline material (20 g) consisting of starting material. Repetition of the hydrazine cleavage upon this mixture yields a second crop of 4-benzyloxy-3,3-difluorobutylamine (9.1 g). Total: 43.2 g (86.5%). is added heating (90°-100° C.) is removed by filtration the filtrate is evaporated extracted with ether (2×500 mL) After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals the solution is filtered (Millipore organic) the filtrate is evaporated to yield a residue which crystallizes on addition of ether Evaporation of the ether

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

Procedure: To a stirred solution of tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-phthalimido-propionate (3.9 g, 6.2 mmol) in a mixture of 78% methylene chloride/methanol (47 ml) was added hydrazine hydrate (3.9 ml, 125 mmol) and the mixture was stirred for five hours, at which time a solid precipitate of phthalhydrazide was observed to form. The material was filtered, washing with methylene chloride, to remove the precipitate. The filtrate was then evaporated on the rotovap and taken up in methylene chloride (80 ml) and transferred to a separatory funnel. After partitioning with an equal volume of water, the organic phase was collected and washed with an equal volume of brine. The aqueous phases were back extracted with methylene chloride (2×80 ml). The methylene chloride phases were combined, dried (MgSO4), filtered and condensed to provide tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate as a white semi-solid (3.0 g). to form The material was filtered washing with methylene chloride to remove the precipitate The filtrate was then evaporated on the rotovap transferred to a separatory funnel After partitioning with an equal volume of water the organic phase was collected washed with an equal volume of brine The aqueous phases were back extracted with methylene chloride (2×80 ml) dried (MgSO4) filtered condensed

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

Procedure: A mixture of 1-(2-phthalimidoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (5.2 gm., 0.015 mole) and 95% hydrazine (1.8 ml., 0.053 mole) in absolute ethanol (50 ml.) is refluxed for one hour. The reaction is cooled, water (37.8 ml.) and concentrated hydrochloric acid (37.5 ml.) are added. After refluxing for one half hour, the mixture is cooled in an ice bath and phthalhydrazide (2.85 gm., 0.0125 mole) is filtered off. The filtrate is concentrated and the residue is dissolved in water, made basic with saturated sodium carbonate and extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The residue containing the free base of the title compound is dissolved in a minimum amount of methanol and treated with ethereal hydrogen chloride. Recrystallization of the product from isopropanol gives 1-(2-aminoethyl)-5,7-dimethyl-1,8-naphthyridine-2(1H)-one hydrochloride melting at 253.5°-254.5° C. is refluxed for one hour The reaction is cooled After refluxing for one half hour the mixture is cooled in an ice bath The filtrate is concentrated the residue is dissolved in water extracted with methylene chloride The organic layer is dried over anhydrous sodium sulfate filtered evaporated The residue containing the free base of the title compound is dissolved in a minimum amount of methanol treated with ethereal hydrogen chloride Recrystallization of the product from isopropanol

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

Procedure: 71 ml. of a solution of anhydrous dimethylformamide containing 2 moles per liter of hydrazine hydrate (i.e. 0.142 mole) are added dropwise over a period of about 30 minutes at 0° C. to a suspension of 70.5 g. (0.128 mole) of tert-butyl 4-benzyloxycarbonyl-alphaphthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate in 150 ml. anhydrous dimethylformamide. The reaction mixture is allowed to warm up to ambient temperature, with magnetic stirring, and to the resulting clear solution are added 120 ml. of 1.203N hydrochloric acid over a period of 1.5 hours. A precipitate of phthalohydrazide is formed, which is filtered off and washed several times with water, whereupon the mother liquors are evaporated in vacuo (bath temperature: maximum 40° C.) and the residue is taken up in a mixture of acetone and diethyl ether. There are finally obtained 43.2 g. (yield 73.7%) of tert-butyl alpha-amino-4-benzyloxycarbonyl-1-thia-3-azaspiro[4.5]decane-2-acetate hydrochloride. to the resulting clear solution are added 120 ml

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

Procedure: To a solution of 338 mg (1.3 mmoles) of phthalhydrazide in 20 ml of DMF, 252 mg (1.83 mmoles) of K2CO3 and 400 mg (1.30 mmoles) of 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:2) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 70% yield. The obtained product is treated with MeJ under the same conditionto give N-methylated compound. To a solution of 295 mg (0.76 mmoles) of 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 20 ml of DMF, 0.066 ml (1.06 mmoles) of MeJ and 168 mg (1.22 mmoles) of K2CO3 are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:4) give 238 mg of 7-(2,2-Dimethyl-propyl)-6-(3-methyl-1,4dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield. The reaction mixture is quenched with ice-water extracted with AcOEt The combined extracts are washed with H2O, brine dried over MgSO4

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

Procedure: The compound N-(4-benzyloxy-3,3-difluorobutyl)-phthalimide (68.5 g, 198.6 mmoles) and hydrazine hydrate (10 g, 200 mmoles) are stirred and heated overnight in ethanol (200 mL) at 90°-100° C. A mixture of concentrated HCl (94 mL) and ethanol (1130 mL) is added, and heating (90°-100° C.) is continued for 1.5 hours. After cooling (ice bath), phthalhydrazide is removed by filtration, and the filtrate is evaporated. The residue is taken up in water and extracted with ether (2×500 mL). After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals. These are dissolved in ethanol, the solution is filtered (Millipore organic) and the filtrate is evaporated to yield a residue which crystallizes on addition of ether: 34 g (68%). Evaporation of the ether extracts yields a partially crystalline material (20 g) consisting of starting material. Repetition of the hydrazine cleavage upon this mixture yields a second crop of 4-benzyloxy-3,3-difluorobutylamine (9.1 g). Total: 43.2 g (86.5%). is added heating (90°-100° C.) is removed by filtration the filtrate is evaporated extracted with ether (2×500 mL) After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals the solution is filtered (Millipore organic) the filtrate is evaporated to yield a residue which crystallizes on addition of ether Evaporation of the ether