5-Chloro-2-pyrazinamine

Pale yellow powder

Method b:; 2-Amino-pyrazine (0.10 g, 1.05 mmol) and NCS (80 mg, 0.60 mmol) were added in a microwave tube with 1.5 mL of the anhydrous CHCl5-chloropyrazin-2-amine (P13).; Method a:; In a double necked dry flask equipped with condenser and dropping funnel, under nitrogen flow, were added 2-amino-pyrazine (0.50 g, 5.25 mmol) and 13 mL of anhydrous CHClA 250ml round bottom flask was charged with 2-aminopyrazine (1Og, O.lmol), N-chlorosuccinimide (14g, O.lmol) and dichloromethane (100ml) under nitrogen. The reaction mixture was refluxed for 5h, then allowed to cool to room temperature. The reaction mixture was filtered though a 1 cm thick celite pad, which was then thoroughly washed with dichloromethane. The EPO Step 1: [0383] A solution of 2-aminopyrazine (23.86 g, 0.2509 mol) in methylene chloride (420 mL) was cooled to 0° C. and then treated with N-chlorosuccinimide (33.50 g, 0.2509 mol). The reaction mixture was stirred at 0° C. for 24 h. The resulting dark reaction mixture was diluted with water (500 mL) and then concentrated in vacuo to remove methylene chloride. The aqueous layer was continuously extracted with ethyl acetate until product was absence from the aqueous layer as determined by thin layer chromatography. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 25percent ethyl acetate/hexanes) afforded 2-amino-5-chloropyrazine (2.66 g, 8.2percent) as a yellow solid: mp 126-128° C.; EI-HRMS m/e calcd for C4H4ClN3 (M+) 129.0094, found 129.0090. [0384] A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 200 mg, 0.56 mmol) and triphenylphosphine (192 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyrazine (145 mg, 1.12 mmol) and 2, 6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10percent aqueous hydrochloric acid solution (1.x.20 mL), a saturated aqueous sodium bicarbonate solution (1.x.20 mL) and water (1.x.20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (137 mg, 52percent) as a light yellow foam: [α]23589=-27.35° (c=0.49, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 470.0703, found 470.0705.Initial attempt showed that the reaction gave a lot of black polymers after a few (ii) Methyl 2-amino-5-chloro-3-carboxylate (3.75 g) was added to a solution of sodium hydroxide (2.0 g) in water (20 ml) and heated under reflux for 1.5 hours. The reaction mixture was cooled to 0 C. and the precipitate filtered off. This solid was redissolved in water (60 ml) with heating and the solution was filtered and acidified to pH 2 with 2M hydrochloric acid. The precipitate was filtered and washed with ice/water (2*20 ml) and dried. The resulting solid was suspended in diphenyl ether (15 ml) and heated under reflux in an argon atmosphere for 15 minutes. The reaction mixture was cooled to ambient temperature and diluted with n-hexane (15 ml). The precipitate so formed was filtered and washed with n-hexane (3*25 ml) to give 2-amino-5-chloropyrazine (1.78 g); 1 H NMR (d6 DMSO): 6.55 (br s, 2H), 7.67 (d, 1H), 7.95 (d, 1H); mass spectrum (+ve CI): 130 (M+H)+.To a solution of 48 (20 g, 0.157 mol) in DMF was added NIS (69.2 g, 0.31 mol) at 20C under N2. The reaction solution was heated to 75C and stirred for 16 h. TLC (PE: EtOAc =3:1 ) showed the reaction was completed. The reaction solution was extracted with EtOAc (200 ml. x 3) from water (300 ml_). The organic phase was washed with a.q. Na2S203 (300 ml.) and brine (300 ml_). Dried over Na2S04, filtered and purified by silica gel chromatography (gradient EtOAc : PE = from 1 :10 to 1 : 1 ) to give 49 (20 g, 50%). (0661) 1 H NMR 49 CDCIs Varian 400MHz: delta 4.83 - 5.23 (m, 2 H) 7.82 - 8.01 (m, 1 H).General procedure: A magnetically stirred solution of xanthate (2.0 equiv) and pyrazine (1.0 equiv) in 1, 2-dichloroethane (1.0mmol/mL according to the xanthate) was refluxed for 15min under a flow of nitrogen. Then dilauroyl peroxide (DLP) was added portionwise (20mol % according to the xanthate) every hour until total consumption of one substrate. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. Unless otherwise specified, the crude product was purified by flash chromatography on silica gel.General procedure: Sodium nitrite (3.4 g, 50 mmol, 1.3 eq.) was added in small portionsto 98% sulfuric acid (15 mL) ice bath, and the mixture was allowed towarm up and heated to 60. When getting clear, the solution wascooled in an ice bath again. A solution of 2-amino-pyrazine (9) (4 g, 39.3 mmol, 1 eq.) in 98% sulfuric acid (15 mL) was added dropwise.The reaction mixture was stirred at 40 for 1 h. After cooling to roomtemperature, it was slowly poured onto crushed ice and stirred until nonitrogen run out. The solution was adjusted to pH 6 with a 40% solutionof sodium hydroxide, resulting in lots of sodium sulfate which wasfiltered off whereafter. The filtrate was extracted with EA (50 mL×3), and the combined organics were dried (Na2SO4), filtered and concentratedin vacuo to give the product as a white precipitate (6.38 g, 53%).General procedure: Method B is a modification of Method A and was performed under nitrogen atmosphere andwith extended work-up. Substituted benzoyl chloride (1.5 mmol, 1.2 equiv) was placed into the askunder nitrogen, diluted with dry DCM (5 mL) and dry pyridine (400 mg, 5 mmol, 4 equiv) was added.The mixture was mixed for 5 min under nitrogen. Then, General procedure: Method B is a modification of Method A and was performed under nitrogen atmosphere andwith extended work-up. Substituted benzoyl chloride (1.5 mmol, 1.2 equiv) was placed into the askunder nitrogen, diluted with dry DCM (5 mL) and dry pyridine (400 mg, 5 mmol, 4 equiv) was added.The mixture was mixed for 5 min under nitrogen. Then, General procedure: Method B is a modification of Method A and was performed under nitrogen atmosphere andwith extended work-up. Substituted benzoyl chloride (1.5 mmol, 1.2 equiv) was placed into the askunder nitrogen, diluted with dry DCM (5 mL) and dry pyridine (400 mg, 5 mmol, 4 equiv) was added.The mixture was mixed for 5 min under nitrogen. Then,

Molecular Weight:129.55
XLogP3:0.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:129.0093748
Monoisotopic Mass:129.0093748
Topological Polar Surface Area:51.8
Heavy Atom Count:8
Complexity:77.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes