2-PICOLINYLHYDRAZIDE

A mixture of ethyl pyridin-2-carboxylate (90 gm) and hydrazine hydrate (60 gm) in ethanol (400 ml) was stirred at 80° C over a period of 4 h. Solvent was evaporated and to provide a crude mass. The mass was stirred with diethyl ether and the suspension was filtered and the wet cake washed with small quantity of ethanol (50 ml) to provide title compound in 76 gm quantity (93percent) as a white solid.Mass: m/z: 138.0 (M+l)Step-1:Preparation 3: 2- (5-Bromometh yl- 1 , 3, 4-thiadiazol-2- yl) -pyridine :Step- 1 : Pyridin-2-carboxylic acid hydrazide:A mixture of ethyl pyridin-2-carboxylate (90 gm) and hydrazine (60 gm) in ethanol (400 ml) was stirred at 80°C over a period of 4 h. Solvent was evaporated under vacuum to provide a crude mass. The crude mass was stirred with diethyl ether and the suspension was filtered and the wet cake washed with small quantity of ethanol (50 ml) to provide title compound in 76 gm quantity (93percent) as a white solid.Mass: m/z: 138 (M+l).To a round-bottom flask was added ethyl picolinate (2.5 mL, 18.52mmol) in ethanol (12 mL) followed by hydrazine monohydrate (1.74 mL, 55.56mmol). The mixture was refluxed for 2h. Ethanol was evaporated after reaction mixture cooled down. The light yellow crude product was washed with diethyl ether (15 mL x 2). Final product as a white solid (2.3 g, 90percent) was collected by vacuum filtration and dried under vacuum. Preparation of pyridine 2-carboxylic acid hydrazinePicolinohydrazide 5 was synthesized by theaddition of a solution containing 50 mmol of hydrazine dissolved in 40 ml ofethanol to 10 mmol of ethyl picolinate 4 and reuxed for 10 h. Then, the volume ofthe solvent was reduced to 10 ml and cooled to room temperature when a whitesolid as the product was precipitated. The crude product was recrystallized inethanol to obtain picolinohydrazide in a yield of 74 percent [22] (Scheme 2).EXAMPLE 58 General procedure: An ethanol (300 ml) suspension of salicylic acid(13.8 g; 0.1 mol) and strongly acidic ion-exchange resin, Amberlyst-15 (5 g) were stirred with refluxing for three days.Insoluble catalyst was separated by filtration, and washed withethanol (3 20 ml). Combined ethanol filtrates were mixed with hydrazine hydrate (20 ml; 20.5 g; 0.4 mol) and refluxed with slowsolvent distillation using the modified Hickman still apparatus(Scheme 3). After 3 h of refluxing, the volume of the reaction mixturewas reduced to about 50 ml and white precipitate started toform. The white suspension was cooled to room temperature andthen left at 5 C for 1 h. Insoluble product was separated by filtration, washed with ice cold ethanol, and dried on air to give pureproduct (13.2 g; 87percent).To a 500 mL three neck round-bottomed flask equipped with a mechanical stirrer, a reflux condenser, and a nitrogen inlet/outlet was added methyl picolinate (40 g, 0.292 mol), hydrazine hydrate (17.5 g, 0.35 mol) and ethanol (120 mL). The resulting mixture was heated under reflux for 1 h. The solvent was removed under reduced pressure and the resulting residue dried to give the product 40 g (0.292 mol, 100percent) as a white solid. Add to the reaction flask2-picolinic acid (12.31 g, 100 mmol) and methanol (100 ml) were added dropwise 2 mL of concentrated sulfuric acid, Heated to reflux for 12 h. After cooling to room temperature, 20 mL of deionized water was added, and most of the methanol was removed under reduced pressure by a rotary evaporator, followed by extraction with ethyl acetate (100 mL x 5).The resulting organic liquid was dried in anhydrous, filtered, and the solvent was distilled off under reduced pressure. The resulting colorless transparent liquid was dried in a vacuum oven at 50C for 24 hours.To the above-mentioned intermediate was added 100 mL of methanol and 30 mL of 85percent hydrazine hydrate, stirred and refluxed for 12 h.After cooling, the mixture was poured into 200 mL of deionized water and extracted with dichloromethane (100 mL x 5).The resulting organic phase was dried over anhydrous MgSO4 and dried to remove the solid. The resulting filtrate was concentrated, added dropwise to 200 mL of vigorously stirred n-hexane, and stirring was continued for 30 min.The resulting white solid was washed with n-hexane and dried in a vacuum oven at 50 ° C for 24 h to give the product as a white solid, 2-pyridinecarboxylic acid hydrazide (2.0 g, 14.6 mmol) in 14.6percent yield.General procedure: The obtained compounds II was dissolved with ethanol (90 mL) and hydrazine hydrate (85percent, 30 mL), then the mixture was heated to reflux for 6 h. After the reaction was completed, ethanol and the excess of hydrazine hydrate were distilled out under a reduced pressure, and a white product was left. The crude product was recrystallized from ethanol to afford white crystals III.

An impurity of Isoniazid (I821450), which is an antibiotic for treatment of Mycobacterium tuberculosis and inhibits mycolic acid biosynthesis. Intermediate used for the synthesis of analogs of antitumor agent 1-acetyl-2-picolinoylhydrazine.

Molecular Weight:137.14
XLogP3:-0.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:137.058911855
Monoisotopic Mass:137.058911855
Topological Polar Surface Area:68
Heavy Atom Count:10
Complexity:126
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes