3-CHLORO-2-HYDRAZINO-1,2-DIHYDROPYRAZINE HYDROCHLORIDE

Step 1 : To a solution of 2, 3-dichloropyrazine (150 g, 1 .01 mol) in EtOH (700 mL) was added hydrazine monohydrate (124.53g, 2.11 mmol, 85percent in water). The reaction mixture was heated under reflux overnight. The reaction mixture was cooled and the precipitate was filtered. The resulting solid was washed with water (100 mL, two times), then cold EtOH (150 ml, two times) and dried under reduced pressure to give the 2-chloro-3-hydrazinylpyrazine (140 g, yield 96percent) .2, 3-Dichloropyrazine A-1 (15 g; 100.68 mmol) and hydrazine hydrate 65percent (15.509 ml; 201.37 mmol) are dissolved in 45 ml ethanol and stirred for 1 h at 80° C. While cooling down, a precipitate is formed. It is slurred up with a small amount of water and filtered off. 2, 3-Dichloropyrazine A-1 (15 g; 100.68 mmol) and hydrazine hydrate 65percent (15.509 ml; 201.37 mmol) are dissolved in 45 ml ethanol and stirred for 1 h at 80° C. 2, 3-dichloropyrazine (1000 g, 6.7 mol) and hydrazine monohydrate (700 g, 14 mol) were dissolved in absolute ethanol (2 L) and refluxed under N[00114] 2, 3-Dichloropyrazine (25 g) and anhydrous hydrazine (21 ml) were dissolved in pyridine (100 mL) and heated to 60 A 100 mL round bottom flask was charged with 2, 3-dichloropyrazine (10 g, 67.6 mmol), hydrazine hydrate (6.76 g, 135 mmol) and ethanol (40 mL). The resulting mixture was stirred at reflux for 3 h. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 2:1). Work-up: the reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with water (30 mL x 2) and dried, to afford 8.4 g (87percent) of the product as a yellow solid.Hydrazine hydrate (20 mL, 43.6 mmol) was slowly added dropwise to a solution of 2, 3-dichloropyrazine (3.2 g, 21.8 mmol) in ethanol (600 mL).The temperature was raised to reflux for 1.5 hours, and the mixture was dried under reduced pressure.The solid is added to the water and filtered.The solid was recrystallized twice in ethanol to give a yellow solid(2.68 g, yield 85percent).STEP1 Preparation of 2-chloro-3-hydrazinylpyrazine 2, 3-dichloro-pyrazine (25 g) was dissolved in ethanol (500 mL), Hydrazine monohydrate (16.7 mL) was added, And the mixture was stirred under reflux for 1 hour and a half. Water was added to the reaction solution, and the precipitated solid was dried under reduced pressure after filtering off the resulting solid to give the title compound as white crystals by recrystallization from ethanol (18.12g, 74percent).2, 3-Dichloropyrazine (2 mL, 13 mmol) was dissolved in 95percent ethanol (4 mL) and to this was added, dropwise and with stirring, hydrazine anhydrous (2 mL, 67 mmol). During the addition of the hydrazine the solution became warm and yellowish. Following cooling of this mixture in an ice bath, the resulting material was isolated by filtration, washed with cold aqueous 95percent ethanol to riled 1-(3-chloropyrazin-2-yl)hydrazine (1.42 g, 73percent yield) as white crystals. No further purification was done. MS m/z: 145.0 (M+1).2, 3-Dichloropyrazine (2 g, 13.42 mmol), hydrazine (1.324 g, 26.8 mmol) and ethanol (40 ml) were combined and the reaction mixture was stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature and the yellow flakes were filtered off. The solid was washed with a small amount of water and dried. The mother liquor was concentrated to afford a yellow solid triturated with a small amount of water and dried. The 2 solids were combined to afford title product 471 (1.15 g, 59percent) as yellow solid. MS (m/z): 145.0 (M+H).2, 3-Dichloropyrazine A-1 (15 g; 100.68 mmol) and hydrazine hydrate 65 percent (15.509 ml; 201.37 mmol) are dissolved in 45 ml ethanol and stirred for 1 h at 80 °C. While cooling down, a precipitate is formed. It is slurred up with a small amount of water and filtered off. It is washed with water and then dried to afford the product. Yield: 93percent (13.6 g; 94.07mmol) HPLC-MS: (M+H)2, 3-Dichloropyrazine (2 mL, 13 mmol) was dissolved in 95percent ethanol (4 niL) and to this was added, dropwise and with stirring, hydrazine anhydrous (2 mL, 67 mmol). During the addition of the hydrazine the solution became warm and yellowish. Following cooling of this mixture in an ice bath, the resulting material was isolated by filtration, washed with cold aqueous 95percent ethanol to riled l-(3-chloropyrazin-2-yl)hydrazine (1.42 g, 73percent yield) as white crystals. No further purification was done. MS m/z: 145.0 (M+l).Compound 49A is added to trimethyl orthoformate, The temperature was raised to reflux for 10 hours, cooled to room temperature, and filtered.Obtaining Compound 49B Solid(2 g, yield 70%).To Add trifluoroacetic anhydride to the flask, use ethyl acetate as a solvent, stir in an ice bath, add ethyl acetate to intermediate b (5g, 0.0346mol) and sonicate to mix thoroughly, then slowly add trifluoroacetic anhydride. , Stir in an ice bath, check the progress of the reaction by spotting the plate. After the reaction, the solution was directly extracted with NaOH solution and ethyl acetate, and the organic phase was collected to be rotary-evaporated to obtain an oil. After drying, 10.9 g of a gray solid was obtained with a yield of 93.3%.Reference Example 146-2 Preparation of cis-N'-(3-chloropyrazin-2-yl)-3-(trifluoromethyl)cyclohexanecarbohydrazide cis, racemate and Reference Example 147-2 trans-N'-(3-chloropyrazin-2-yl)-3-(trifluoromethyl)cyclohexanecarbohydrazide trans, racemate To a mixture of 3-trifluoromethylcyclohexanecarboxylic acid (516 mg), 1-hydroxybenzotriazole (429 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (621 mg), and chloroform (13 mL) in a 50 mL eggplant flask was added Reference Example 23-2 Preparation of N'-(3-chloropyrazin-2-yl)-2-ethylpiperidine-1-carbohydrazide racemate To a 100 mL eggplant flask were added 2-ethylpiperidine-1-carbonylchloride (509 mg) prepared in the Reference Example 23-3, diisopropylethylamine (1.11 g), acetonitrile (10 mL), and (2) To a 100 mL eggplant flask were added the above slightly red oil of (S)-2-methylpiperidine-1-carbonylchloride (0.53 g), diisopropylethylamine (1.57 mL), and dichloromethane (20 mL), Reference Example 146-2 Preparation of cis-N'-(3-chloropyrazin-2-yl)-3-(trifluoromethyl)cyclohexanecarbohydrazide cis, racemate and Reference Example 147-2 trans-N'-(3-chloropyrazin-2-yl)-3-(trifluoromethyl)cyclohexanecarbohydrazide trans, racemate To a mixture of 3-trifluoromethylcyclohexanecarboxylic acid (516 mg), 1-hydroxybenzotriazole (429 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (621 mg), and chloroform (13 mL) in a 50 mL eggplant flask was added (2) To a 100 mL eggplant flask were added the yellow oil (1.65 g) prepared in the above step,

Molecular Weight:144.56
XLogP3:0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:144.0202739
Monoisotopic Mass:144.0202739
Topological Polar Surface Area:63.8
Heavy Atom Count:9
Complexity:88.6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes