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With potassium carbonate; In dimethyl sulfoxide; at 75℃;
A solution of <strong>[19745-07-4]2,5-dichloropyrazine</strong> (1.03 g, 6.91 mmol) in DMSO (10 mL) was treated sequentially with K2C03(s) (2.867 g, 20.74 mmol) and tert-butyl piperazine-1-carboxylate (1.288 g, 6.9 14 mmol), then stirred overnight at 75 °C. After cooling to ambient temperature, the mixture was partitioned between EtOAc (10 mL) and water (20 mL). After phase separation, the organic extracts were concentrated in vacuo to provide the title compound (1.928 g, 93percent yield). MS (apci) m/z = 199.1 (M-Boc). ?HNIVIR(CDC13) 8.07 (m, 1H), 7.86 (m, 1H), 3.56 (s, 8H), 1.48 (s, 9H).
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1h;
To an NMP (7.5 ml) solution of 1.51 g of <strong>[19745-07-4]2,5-dichloropyrazine</strong> were added 2.00 g of 1-(t-butoxycarbonyl)piperazine and 2.00 g of potassium carbonate, followed by 1 hour of stirring under heating at 100°C. The mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 2.73 g of 2-chloro-5-(4-t-butoxycarbonylpiperazin-1-yl)pyrazine. Using this compound, 2-chloro-5-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrazine was obtained in a similar manner to Example 14 as colorless crystals.
With hydrazine; In ethanol; at 20 - 80℃; for 2.75h;
[Referential Example 11] 1-(5-Methoxy-2-pyrazinyl)-5-(2-pyridyl)-1H-pyrazole-3-carboxylic acid; [Show Image] [Show Image] 1) 5-Chloro-2-hydrazinopyrazine; A solution of 5-chloro-2-hydroxpyrazine (1.84 g) synthesized from aminopyrazine by the method of Palamidessi et al. (J.Org.Chem., vol.29, pp 2491-2492, 1964) in phosphorus oxychloride (28ml) was placed in a sealed tube, and the solution was stirred at an outer temperature of 130°C for 6 hours. After cooling with air, ice cold water and dichloromethane were added to the reaction liquid, then the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hydrazine monohydrate (1.39 ml) was added to a solution of the residue in ethanol (14 ml), and the mixture was stirred at room temperature for 150 minutes and for another 15 minutes at 80°C. After cooling with air, the reaction liquid was evaporated under reduced pressure, and to the residue was added water and a mixed solvent of chloroform and methanol (1:10), then the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 5-chloro-2-hydrazinopyrazine(0.325 g, 16percent) as a solid. 1H-NMR (400 MHz, DMSO-d6)delta: 4.32 (2H, br s), 7.92 (1H, s), 7.99 (1H, s), 8.13 (1H, s). EI-MSm/z: 144 (M+).
1.6 g
With hydrazine hydrate; In ethanol; at 80℃; for 16h;Inert atmosphere;
A mixture of A-63 (10.00 g, 67.12 mmol) in EtOH (80 mL) was stirred under N2 at 80 C for 16 hours. The mixture was concentrated to give the crude product, which was triturated from H20 (20 mL) to give A-64 (1.60 g, 11.07 mmol) as a solid. 1H NMR (400MHz, CDCI3) _ = 8.10 - 8.01 (m, 2H), 6.03 (br s, 1H), 3.85 (br s, 2H).
With hydrogenchloride; sodium nitrite; In water; at -10 - 20℃; for 4h;
Step 2: Synthesis of 2,5-dichloropyrazine To a stirred solution of 5-chloropyrazin-2-amine (1 g, 7.751 mmol) in conc. HCl (10 mL) was added aq. solution sodium nitrite (1.1 g, 15.89 mmol) at -10° C. over a period of 1 h, stirred for 1 h 0° C. and then at RT for 2 h. Progress of reaction was monitored by TLC. After reaction completion reaction mass neutralised with 50percent NaOH solution and extracted with DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Crude was purified by silica gel (100-200 mesh) column chromatography using 2percent ethyl acetate in hexane as eluent to yield 2,5-dichloropyrazine (0.59 g, 15percent) as colourless oil. MS: 184.1 [M-1]
With tert.-butylnitrite; copper(l) chloride; copper dichloride; In acetonitrile; at -10 - 65℃; for 3h;
Step 2: Preparation of 2,5-dichloropyrazine; 5-Chloropyrazin-2-amine (5.0 g, 38.6 mmol) was dissolved in acetonitrile (77 ml) under a balloon of N2. The copper(I) chloride (5.7 g, 57.9 mmol) and copper(ET) chloride (7.8 g, 57.9 mmol) were added and the slurry cooled to -1O 0C with an ice:acetone bath. t-Butyl nitrite (9.15g, 89 mmol, 90percent) was added dropwise and the solution allowed to warm to RT. The solution was stirred for 30 minutes until rapid gas evolution ceased. The mixture was heated to 65 0C for 2.5 hours. The mixture was cooled to RT and filtered through a 1.5 inch pad of celilte packed into a 465 ml frit. The pad was washed with DCM (200 ml x 4), the wash fractions containing the desired material combined, filtered, and concentrated in vacuo. <n="55"/>The residue was purified by chromatography on silica gel with 2percent etheI.euro.pentane to yield the title compound.
With hydrogenchloride; sodium nitrite; In water; at 0 - 20℃; for 3h;
Step 2: 2,5-Dichloropyrazine; 5-Chloro-2-pyrazinamine (product of E1, step 1) (2.41g, 18.6mmole) was dissolved in concentrated hydrochloric acid (24ml), cooled in an ice-acetone bath and treated with a solution of sodium nitrite (2.63g, 38.1 mmole) in water (1 8ml) dropwise over a period of 1 hour. The mixture was cooled in an ice-water bath and left to stir for 1 hour. The mixture was allowed to warm to room temperature over 1 hour, neutralised by addition of sodium hydroxide solution (2M) and extracted with dichloromethane ( x 4). The dichloromethane layers were combined, dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography (1: 9 ethyl acetate: pentane) to afford the title compound (0.33g). 1H NMR (CDCl3) 8.40 (2H, s).
With hydrogenchloride; sodium nitrite; In water; at 0 - 20℃; for 3h;ice-acetone bath;
5-CHLORO-2-PYRAZINAMINE (D47, Step 1) (2.41 g, 18.6 MMOL) was dissolved in concentrated hydrochloric acid (24 ML), cooled in an ice-acetone bath and treated with a solution of sodium nitrite (2.63 g, 38.1 MMOL) in water (18 ML) dropwise over a period of 1 hour. The mixture was cooled in an ice-water bath and left to stir for 1 hour. The mixture was allowed to warm to room temperature over 1 hour, neutralised by addition of sodium hydroxide solution (2M) and extracted with dichloromethane. The DICHLOROMETHANE layers were combined, dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate: pentane (1: 9) to afford the title compound (0.33 g);'H NMR (CDCI3) 8.40 (2H, s).
With hydrogenchloride; sodium nitrite; In water; at 0 - 20℃; for 4h;Ic;
Description 5 2,5-Dichloropyrazine (D5); 5-Chloro-2-pyrazinamine (D4) (753 mg, 5.81 mmol) was dissolved in concentrated hydrochloric acid (8 ml), cooled in an ice-acetone bath and treated with a solution of sodium nitrite (822 mg, 11.9 mmol) in water (6 ml) dropwise over a period of 1 hour. The mixture was transferred to an ice-water bath and left to stir for 1 hour. The mixture was allowed to warm to room temperature over 2 hours, neutralised by addition of an aqueous 50percent sodium hydroxide solution and extracted with dichloromethane (x 4). The dichloromethane layers were combined, dried under magnesium sulfate and evaporated. The resulting residue was purified by Biotage column chromatography eluting with 10percent ethyl acetate in pentane to afford the title compound (112 mg). 1H NMR (CDCI3) 8.40 (2H, s).
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