(PYRAZIN-2-YLMETHYL)AMINE

The synthesis of 2-aminomethyl pyradine(2-AMPZ) was carried out by a method shown below, byreference to the method described in literature (JP A 2001-894594). 2-cyanopyradine used was from Sigma-Aldrich Co.LLC.1.05 g of 2-cyanopyradine (10 mmol) and 100mg of60 wt percent-Ni/5i02 were placed in an autoclave (5U53 16) with20 mL of toluene and replaced with argon gas. This waspressurized with hydrogen gas to 50 atm, stirred at 140°C. for4 hours. The reaction solution was filtered and concentratedto give 2-aminomethyl pyradine (2-AMPZ) quantitatively.10152] ‘H-NMR spectrum (399.78 MHz, CDC13):ö8.60-8.45 (m, 3H), 4.07 (s, 2H), 1.79 (br, 2H)Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1, 4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 °C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98percent) as a brown oil. MS m/z (ESI): 110 [M+1]Step 6Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1, 4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave.2-cyano-pyrazol 1g (10.5 g, 100 mmol) was dissolved in 150 mL 1, 4- dioxane was added 1.0 g Raney nickel in 250 mL autoclave at 60 , 40 atm of hydrogen the reaction was stirred for 8 hours. Filtered, and the filtrate was concentrated under reduced pressure, to give C- pyridin-2-yl - methylamine 1h (10.7 g, brown oil). Yield: 98percent.Pyrazine-2-carbonitrile (19 g, 180 mmol) was dissolved in 1, 4-dioxane (280 mL), and then Raney nickel (1.9 g) was added. The reaction mixture was reacted in hydrogen atmosphere at 60°C for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (1) (19 g, 98.9percent) as a brown oil. 1H MR (400 MHz, DMSO-dB. A suspension of 2-(pyrazin-2-ylmethyl)isoindoline-1 , 3-dione (3.56 g, 14.9 mmol) in 5 N aqueous sodium hydroxide (180 mL) was heated at reflux for 1 h, allowed to cool to ambient temperature extracted with dichloromethane (4 x 50 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford pyrazin-2-ylmethanamine as a yellow oil in 67percent yield (1.09 g), which was used without further purification: The synthesis of 2-aminomethyl pyradine(2-AMPZ) was carried out by a method shown below, byreference to the method described in literature (JP A 2001-894594). 2-cyanopyradine used was from Sigma-Aldrich Co.LLC.1.05 g of 2-cyanopyradine (10 mmol) and 100mg of60 wt %-Ni/5i02 were placed in an autoclave (5U53 16) with20 mL of toluene and replaced with argon gas. This waspressurized with hydrogen gas to 50 atm, stirred at 140C. for4 hours. The reaction solution was filtered and concentratedto give 2-aminomethyl pyradine (2-AMPZ) quantitatively.10152] 'H-NMR spectrum (399.78 MHz, CDC13):oe8.60-8.45 (m, 3H), 4.07 (s, 2H), 1.79 (br, 2H)Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1, 4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1]Step 6 C-Pyrazin-2-yl-methylamine Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1, 4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60 C and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1].Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1, 4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60 C. and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1].2-cyano-pyrazol 1g (10.5 g, 100 mmol) was dissolved in 150 mL 1, 4- dioxane was added 1.0 g Raney nickel in 250 mL autoclave at 60 , 40 atm of hydrogen the reaction was stirred for 8 hours. Filtered, and the filtrate was concentrated under reduced pressure, to give C- pyridin-2-yl - methylamine 1h (10.7 g, brown oil). Yield: 98%.Pyrazine-2-carbonitrile (19 g, 180 mmol) was dissolved in 1, 4-dioxane (280 mL), and then Raney nickel (1.9 g) was added. The reaction mixture was reacted in hydrogen atmosphere at 60C for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (1) (19 g, 98.9%) as a brown oil. 1H MR (400 MHz, DMSO-d6): delta 871 (s, 1H), 8.54-8.53 (m, 2H), 8.48 (d, J = 2.4Hz, 1H), 3.86 (s, 2H), 1.97 (br, 2H).Preparation 53; C-Pyrazin-2-yl-methylamine; In a Parr bottle, charge pyrazine-2-carbonitrile (1 g) in absolute ethanol (10mol). Add 10% Pd-C (w/w, 0.4g) and place on a Parr Hydrogenation Apparatus under 50 psig hydrogen at ambient temperature for sixteen hours. Filter the mixture through a pad of Celite. Purify material on SCX column. Use crude basic material in next step without further purification.Example 8. Synthesis of the primary amine, pyrazin-2-ylmethanaminechromatography 17 3. TFA / CH2CI2 18[0096] Raney nickel catalyst was carefully washed with THF and methanol making sure that the catalyst remained moist. The weight of the moist catalyst was 2.5 g after washing. This material was added to a solution of pyrazinecarbonitrile (17) (3.0 g) in 7N methanolic ammonia (120 mL). The mixture was shaken under a 50 p.s.i. atmosphere of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to provide the crude title compound. Purification was accomplished by conversion of the crude amine to the tert-butyl carbamate with excess di-fert-butyl dicarbonate in methylene chloride. Column chromatography (70:27:3 hexanes:ethyl acetate:methanol) provided 0.5O g of pure tert-butyl pyrazin-2-ylmethylcarbamate. Pure pyrazin-2- ylmethanamine (18) was obtained as the TFA salt from deprotection of the carbamate with 1:1 TFA / CH2Cl2. EPO Example 8 Synthesis of the primary amine, pyrazin-2-ylmethanamine Raney nickel catalyst was carefully washed with THF and methanol making sure that the catalyst remained moist. The weight of the moist catalyst was 2.5 g after washing. This material was added to a solution of pyrazinecarbonitrile (17) (3.0 g) in 7N methanolic ammonia (120 mL). The mixture was shaken under a 50 p.s.i. atmosphere of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to provide the crude title compound. Purification was accomplished by conversion of the crude amine to the tert-butyl carbamate with excess di-tert-butyl dicarbonate in methylene chloride. Column chromatography (70:27:3 hexanes:ethyl acetate:methanol) provided 0.50 g of pure tert-butyl pyrazin-2-ylmethylcarbamate.Raney nickel catalyst was carefully washed with THF and methanol making sure that the catalyst remained moist. The weight of the moist catalyst was 2.5 g after washing. This material was added to a solution of pyrazinecarbonitrile (17) (3.0 g) in 7N methanolic ammonia (120 mL). The mixture was shaken under a 50 p.s.i. atmosphere of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to provide the crude title compound. Purification was accomplished by conversion of the crude amine to the tert-butyl carbamate with excess di-terf-butyl dicarbonate in methylene chloride. Column chromatography (70:27:3 hexanes:ethyl acetate methanol) provided 0.50 g of pure tert-butyl pyrazin-2-ylmethylcarbamate. Pure pyrazin-2-yhnethanamine (18) was obtained as the TFA salt from deprotection of the carbamate with 1:1 TFA / CH2Cl2.The synthesis of EXAMPLE 157 Preparation of Compound 334 in Table 13 An analogous reaction to that described in general scheme 5, starting with General procedure: A solution of the Example 5 (12 mg, 0.021 mmol), diphenylcarbonate (5 mg, 0.023 mmol)) and DMAP (15 mg, 0.123 mmol) in 3 mL acetonitrile was allowed to stir at rt for 16 hrs. (1-Methyl-1H-pyrazol-5-yl)methanamine (6.8 mg, 0.062 mmol) was added and the mixture was further stirred at rt for 1 hr. LC/MS showed completion of the reaction. The solvent was evaporated under reduced pressure and the residue was dissolved in 3 mL methanol and purified using HPLC to afford Example 75. 1H NMR (400 MHz, Methanol-d4) delta 7.74 (d, J=8.5 Hz, 1H), 7.49-7.20 (m, 3H), 7.20-7.03 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 6.37 (d, J=1.9 Hz, 1H), 6.00-5.68 (m, 2H), 5.38-5.16 (m, 2H), 4.21-3.90 (m, 2H), 3.82-3.47 (m, 3H), 3.46-3.18 (m, 11H), 3.10 (dd, J=15.0, 10.7 Hz, 1H), 2.93-2.60 (m, 3H), 2.58-2.15 (m, 3H), 2.15-1.64 (m, 6H), 1.52-1.17 (m, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C37H45ClN6O5S: 721.29; found: 721.91.General procedure: According general method, to a solution of compoundS1(579 mg, 1 mmol) and different amines (1.2eq) in CH2Cl2 wasslowly added triethylamine (0.1 mL). The reaction mixture wasstirred at room temperature for 3 h, and then diluted with water, the reaction mixture was extracted with DCM (20 mL 3). Theorganic layers were combined, then washed with brine, dried with anhydrous sodium sulfate and concentrated in vacuo. Using columnchromatography (petroleum ether/EtOAc) purified the crude residueby afforded the target compounds M1-M33 with 75e85%yields..

Molecular Weight:109.13
XLogP3:-1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:109.063997236
Monoisotopic Mass:109.063997236
Topological Polar Surface Area:51.8
Heavy Atom Count:8
Complexity:64.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes