盐酸肼

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 15.9 g hydrazine hydrochloride and 18.4 ml hydrazine hydrate are added under stirring to 22.5 g of the product of step (a) in 20 ml n-propanol and the obtained reaction mixture is heated under reflux for 5 hours. The mixture is concentrated, treated with 500 ml H2O, filtered and washed with H2O (fraction A). The mother liquor is extracted with ethyl acetate and the extract evaporated. To the residue (7.5 g) are added 100 ml n-propanol and 20 ml triethylamine and the mixture is stirred and heated at reflux. The reaction is followed by thin layer chromatography. After approximately 15 hours when all of the β-product is converted into the 8α-product, H2O is added and the mixture is filtered. The filter cake is combined with fraction A and recrystallized twice from hot ethanol to afford the heading compound, m.p. 235°-240°, which is the pure α-isomer by NMR. the obtained reaction mixture is heated under reflux for 5 hours The mixture is concentrated treated with 500 ml H2O filtered washed with H2O (fraction A) The mother liquor is extracted with ethyl acetate the extract evaporated To the residue (7.5 g) are added 100 ml n-propanol and 20 ml triethylamine heated at reflux is added the mixture is filtered recrystallized twice from hot ethanol to afford the heading compound, m.p. 235°-240°, which

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 2-((5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (9.0 mg, 0.037 mmol) and palladium-black (10 mg) in 7 M methanolic ammonia (2 mL) was added hydrazine hydrochloride (0.250 mL, 6.87 mmol) dropwise. After 1 h at ambient temperature the reaction was virtually complete by TLC (dichloromethane:7 M methanolic ammonia, 3:1, visualised with UV and Erlichs). The supernatant solution was filtered through a small pad of celite and the palladium was washed twice with methanol and also filtered through celite. The combined filtrates were concentrated under reduced pressure and the resulting residue triturated with chloroform and dichloromethane. Lyophilization of the residue gave 2-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (4 mg, 63%) as a white solid. 1H NMR (D2O) δ 8.16 (s, 1H), 7.58 (s, 1H), 4.12 (s, 2H), 3.79-3.70 (m, 4H), 2.85 (s, 2H), 2.15 (s, 3H). +ESMS Found 298.1346 (M+H+) C12H20N5O2S requires 298.1338. The supernatant solution was filtered through a small pad of celite the palladium was washed twice with methanol also filtered through celite The combined filtrates were concentrated under reduced pressure the resulting residue triturated with chloroform and dichloromethane

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2,3-Dioxo-1-p-tolylpiperidine-4-carbonitrile (3.56 g, 15.597 mmol) was added to anhydrous ethanol (52.0 mL) and dissolved by heating to 60° C. After adding hydrazine hydrochloride (1.06 mL, 21.836 mmol) and glacial acetic acid (1.34 mL, 23.396 mmol) room temperature, reaction was carried out for 2 days. After removing ethanol by distillation, the produced solid was filtered and then acetic acid was completely removed by washing with NaHCO3 twice or more times. A target compound (3.25 g, 13.414 mmol, 86.0%) was yielded as white solid. dissolved After adding After removing ethanol by distillation the produced solid was filtered acetic acid was completely removed by washing with NaHCO3 twice

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 452 mg (1.84 mmol) of mCPBA is added under argon to a stirring solution of 486 mg (1.67 mmol) of 6-((2,4-difluorophenyl)(methyl)amino)-2-(methylthio)nicotinonitrile in 15 mL of dichloromethane. The reaction medium is stirred 30 min at room temperature before adding an ethyl acetate fraction. The organic phase is washed with a NaHCO3 saturated solution, dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved again in 6 mL of propanol and 164 μL (3.38 mmol) of hydrazine hydrochloride in water is added. The mixture is heated at 90° C. for 6 hours before being diluted in water and extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 328 mg of N6-(2,4-difluorophenyl)-N6-methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (70%). The organic phase is washed with a NaHCO3 saturated solution dried on magnesium sulfate dry evaporated The crude reaction product The mixture is heated at 90° C. for 6 hours extracted with ethyl acetate The organic phase is dried on magnesium sulfate dry evaporated before being purified by silica gel chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 769 mg (3.12 mmol) of m-chloroperbenzoic acid (mCPBA) is added under argon to a stiring solution of 786 mg (2.83 mmol) of 6-(2,4-difluorophenylamino)-2-(methylthio)nicotinonitrile in 25 mL of dichloromethane. The reaction medium is stirred 1 hour at room temperature before adding a fraction of ethyl acetate and washed this organic phase with a NaHCO3 saturated solution. The combined organic phases are dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved again in 10 mL of propanol and 2 equivalents of hydrazine hydrochloride in water are added. The mixture is heated at 90° C. for 6 hours before being diluted in water and extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 495 mg of N6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (67%). washed this organic phase with a NaHCO3 saturated solution The combined organic phases are dried on magnesium sulfate dry evaporated The crude reaction product The mixture is heated at 90° C. for 6 hours extracted with ethyl acetate The organic phase is dried on magnesium sulfate dry evaporated before being purified by silica gel chromatography

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-Boc-3-cyano-4-pyrrolidinone (5 g, 23.78 mmol) and hydrazine monohydrochloride (1.629 g, 23.78 mmol) were dissolved in ethanol (140 ml). The mixture was heated to 60° C. for 3 h. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 (50 mL) was added slowly, remaining water was extracted four times with ethyl acetate. The organic phase was dried over Na2SO4 (anhydrous). The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/MeOH/aqueous ammonia (gradient from 0 to 10%) to give the title product as a yellow foam. LC-MS: 224.99 (M+1). The mixture was cooled to 0° C. was extracted four times with ethyl acetate The organic phase was dried over Na2SO4 (anhydrous) The residue was purified by column chromatography on silica gel Biotage 40M eluting with EtOAc/MeOH/aqueous ammonia (gradient from 0 to 10%)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-Boc-3-cyano-4-pyrrolidinone (5 g, 23.78 mmol) and hydrazine monohydrochloride (1.629 g, 23.78 mmol) were dissolved in ethanol (140 ml). The mixture was heated to 60° C. for 3 h. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 (50 mL) was added slowly, remaining water was extracted four times with ethyl acetate. The organic phase was dried over Na2SO4 (anhydrous). The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/MeOH/aqueous ammonia (gradient from 0 to 10%) to give the title product as a yellow foam. LC-MS: 224.99 (M+1). The mixture was cooled to 0° C. was extracted four times with ethyl acetate The organic phase was dried over Na2SO4 (anhydrous) The residue was purified by column chromatography on silica gel Biotage 40M eluting with EtOAc/MeOH/aqueous ammonia (gradient from 0 to 10%)

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1.8M LDA in THF (30.0 mL, 54.00 mmol) was added to tetrahydrofuran (60 mL) and cooled to −78° C. Acetonitrile (2.82 mL, 54.00 mmol) was added drop-wise over 15 mins. A solution of methyl 3-(3-(methylcarbamoyl)phenyl)propanoate (2.99 g, 13.5 mmol) in tetrahydrofuran (10 ml) was added. The resulting mixture stirred at −78° C. for 10 mins. The reaction mixture was warmed to 5° C. and stirred for 30 mins, hydrazine hydrochloride (3.70 g, 54.00 mmol) and ethanol (60.0 mL) were added and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was cooled and evaporated to dryness. The residue was dissolved in methanol (50 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH fractions were evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 3-(2-(5-amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide (0.450 g, 13.64%) as a yellow oil. The reaction mixture was warmed to 5° C. stirred for 30 mins the reaction mixture heated at 80° C. for 18 h The reaction mixture was cooled evaporated to dryness The residue was dissolved in methanol (50 ml) the crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness to afford an oil The crude product was purified by silica column chromatography eluting with a gradient of 0 to 10% MeOH in DCM Pure fractions were evaporated to dryness

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 452 mg (1.84 mmol) of mCPBA is added under argon to a stirring solution of 486 mg (1.67 mmol) of 6-((2,4-difluorophenyl)(methyl)amino)-2-(methylthio)nicotinonitrile in 15 mL of dichloromethane. The reaction medium is stirred 30 min at room temperature before adding an ethyl acetate fraction. The organic phase is washed with a NaHCO3 saturated solution, dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved again in 6 mL of propanol and 164 μL (3.38 mmol) of hydrazine hydrochloride in water is added. The mixture is heated at 90° C. for 6 hours before being diluted in water and extracted with ethyl acetate. the organic phase is dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 328 mg of N6-(2,4-difluorophenyl)-N6-methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (70%). The organic phase is washed with a NaHCO3 saturated solution dried on magnesium sulfate dry evaporated The crude reaction product The mixture is heated at 90° C. for 6 hours extracted with ethyl acetate the organic phase is dried on magnesium sulfate dry evaporated before being purified by silica gel chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 769 mg (3.12 mmol) of m-chloroperbenzoic acid (mCPBA) is added under argon to a stirring solution of 786 mg (2.83 mmol) of 6-(2,4-difluorophenylamino)-2-(methylthio)nicotinonitrile in 25 mL of dichloromethane. The reaction medium is stirred 1 hour at room temperature before adding a fraction of ethyl acetate and washed this organic phase with a NaHCO3 saturated solution. The combined organic phases are dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved again in 10 mL of propanol and 2 equivalents of hydrazine hydrochloride in water are added. The mixture is heated at 90° C. for 6 hours before being diluted in water and extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 495 mg of N6-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (67%). washed this organic phase with a NaHCO3 saturated solution The combined organic phases are dried on magnesium sulfate dry evaporated The crude reaction product The mixture is heated at 90° C. for 6 hours extracted with ethyl acetate The organic phase is dried on magnesium sulfate dry evaporated before being purified by silica gel chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of the hydrazine hydrochloride of Step 1 (70 g) in toluene (1.2 L) was added Et3N (107 mL) followed by 4-chlorobenzyl chloride (61 g). The resulting mixture was heated at reflux for 2 hours. The reaction mixture was cooled and Et2O (1.2 L) was added. The triethylammonium hydrochloride salt was filtered off, and the filtrate concentrated under vacuum. The crude residue was purified by chromatography on a bed of silica gel eluting with hexane-EtOAc (6:4) to afford the pure title product as an oil. The resulting mixture was heated at reflux for 2 hours The reaction mixture was cooled The triethylammonium hydrochloride salt was filtered off the filtrate concentrated under vacuum The crude residue was purified by chromatography on a bed of silica gel eluting with hexane-EtOAc (6:4)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedure described in Example 162B], 2-cyclopropanecarbonyl-3-oxo-3-pyrimidin-5-yl-propionic acid ethyl ester and hydrazine.hydrochloride gave the title compound as white solid (39%). MS: 259.1 (MH+).