2-Amino-5-ethyl-pyridine

2-Amino-5-ethylpyridineDiethylzinc (24 mL of IM solution in hexane; 24 mmol) was added dropwise to a solution of 2-amino-5-bromopyridine (2.0 g, 11.6 mmol) and Pd(dppf)ClDiethylzinc (24 mL of IM solution in hexane, 24 mmol) was added dropwise to a solution of 2-amino-5-bromopyridine (2.0 g, 11.6 mmol) and Pd(dppf)Clb. 2-Amino-5-ethylpyridine A suspension of benzyl (5-ethyl-2-pyridyl)carbamate (1.9 g., 7.43 mmoles) and 10% palladium-on-carbon (0.4 g.) in ethanol (100 ml.) was shaken with hydrogen at a pressure of 3.5 kg./cm2 hours. The catalyst was removed by filtration and the filtrate concentrated to yield 2-amino-5-ethylpyridine (0.9 g., 99.4%) as a colorless oil.Step B 2-Amino-5-ethylpyridine Following the general method of K. Wachi and A. Terada (Chem. Pharm. Bull., 1980, 28, 465-472), a mixture 81 mg (0.29 mmoles) of 3-(5-ethyl-2-pyridinyl)-2, 2-dimethyl-2.3-dihydro-(4H)-1, 3-benzoxazin-4-one and 2.0 mL of concentrated hydrochloric acid was heated to reflux for 8 h. The reaction was cooled to room temperature and the solvent was evaporated. The residue was dissolved in 4 mL ethyl acetate and washed with 3*1 mL of a 1:1 mixture of 10% of aqueous sodium hydroxide solution and saturated aqueous sodium chloride. The organic solution was dried (sodium sulfate), decanted, and evaporated to give 26 mg (84% yield) of 2-amino-5-ethylpyridine as an amber oil. 1 H NMR (400 MHz, CD3 OD): delta 7.71 (bs, 1H), 7.34 (dd, 1H, J=8, 2 Hz), 6.53 (d, 1H, J=8 Hz), 2.48 (q, 2H, J=7 Hz), 1. 16 (t, 3H, J=7 Hz).General procedure: To an ethanol solution (20.0 mL) of the compound (880 mg) obtained in Reference Example 225 was added 10% palladium carbon (400 mg), and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 6 h The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (solvent; hexane/ethyl acetate=90/10 - 40/60) to give the title compound (585 mg). MS(ESI)m/z; 137[M+H]+General procedure: Different 03- and 05-substituted directing group were found to be suitable for the Zn(OAc)2.17H20- catalysed directed cleavage of I with iPrOH (lOa). Both electron-withdrawing (F, Cl, 000R, NO2, ON, OF3) and electron-donating (Alkyl, Ph, OR) groups in 03- and 05-position of the py-DG were evaluated (Example Table E2).To a solution of To a solution of 2-Amino-5-ethylpyridineDiethylzinc (24 mL of IM solution in hexane; 24 mmol) was added dropwise to a solution of 2-amino-5-bromopyridine (2.0 g, 11.6 mmol) and Pd(dppf)Cl2*CH2Cl2(225 mg, 0.28 mmol) in degassed dioxane (45 mL). The mixture was stirred at rt for 2 h, heated at reflux for 3 h and stirred at rt for 70 h under argon. The mixture was poured into NaCl (sat., aq.; 150 mL) and extracted with EtOAc (4x100 mL).The combined organic phases were washed with NaCl (sat., aq.; 100 mL), dried(Na2SO4) and concentrated. The residue was purified by chromatography(EtO Ac/heptane, then MeOH/EtOAc) to give the title compound. Yield: 1.40 g (99 %).1H NMR (DMSO-d6, 400 MHz) delta 7.74 (s, IH), 7.25 (dd, IH), 6.40 (d, IH)5 5.67 (br. s, 2H), 2.39 (q, 2H), 1.10 (t, 3H).Diethylzinc (24 mL of IM solution in hexane, 24 mmol) was added dropwise to a solution of 2-amino-5-bromopyridine (2.0 g, 11.6 mmol) and Pd(dppf)Cl2-CH2Cl2 (225 mg, 0.28 mmol) in degassed dioxane (45 mL). The mixture was stirred at rt for 2 h, then heated at reflux for 3 h and stirred at rt for 70 h under an argon atmosphere. The mixture was poured into NaCl (aq., sat.; 150 mL) and extracted with EtOAc (4x100 mL). The combined extracts were washed with NaCl (aq., sat.; 100 mL), dried (Na2SO4) and concentrated. The crude product was purified by chromatography (EtO Ac/heptane, then MeOH/EtOAc) to give the title compound (1.40 g, 99 %).1H NMR (DMSO-d6, 400 MHz) delta 7.74 (s, IH), 7.25 (dd, IH)5 6.40 (d, IH), 5.67 (br. s, 2H), 2.39 (q, 2H), 1.10 (t, 3H).The title compound (m.p. 155-156, 25.4% yield) was prepared from A solution of the dichloride of preparation 52 (1 EQ) in dimethylsulfoxide (1 ML. MMOL-1) was added to a solution of the appropriate amine HNR R2 (2eq) in DIMETHYLSULFOXIDE (0.75mL. MMOL-1). N-ETHYLDIISOPROPYLAMINE (1 EQ) was added and the reaction vessel sealed and shaken at 140rpm at 80C for 12 hours. The reaction mixture was then allowed to cool. A solution of test-butyl piperazine carboxylate or 33% methylamine in ethanol (5eq) in dimethylsulfoxide (0.66mL. mmol-1) followed by N-ethyldiisopropylamine (3eq) was then added to the reaction mixture and the reaction vessel sealed, heated to 120C and left for 18 hours. The reaction mixture was evaporated to dryness. When deprotection was required (ex 123 to 129), dichloromethane (2.5mL. mmol-1) and trifluoroacetic acid (2.5mL. mmol-1) were added and the reaction mixture sealed and stirred for 24 hours. The reaction mixture was concentrated in vacuo. The residues were purified using a Phenomenex Luna C18 2x15cm 5mum column eluting with ACETONITRILE : diethylamine to afford the title compounds.Production Example 329 4-Bromo-N-(5-ethylpyridin-2-yl)-2-fluorobenzamide 102 mg of the title compound was obtained as colorless crystals from 250 mg 4-bromo-2-fluorobenzoic acid and 153 mg 10% Palladium on carbon (300mg) was added to a solution of the amine of preparation 9 (1.7g, 14. 1 MMOL) in ethanol (80ML) and the reaction mixture stirred under 15psi of hydrogen for 18 hours. The reaction mixture was filtered through ARBOCELE and the filtrate concentrated in vacuo. The resulting oil was dissolved in DICHLOROMETHANE and washed with a solution of potassium fluoride (2X1 OML), the organic phase dried over magnesium sulphate, filtered and concentrated in vacuo to yield 650mg product. H NMR (400MHZ, CDC13) 8 : 1.16 (t, 3H), 2.48 (q, 2H), 4.35 (br s, 2H), 6.46 (d, 1 H), 7.26 (m, 1 H), 7.89 (m, 1 H)Production Example 327 5-Ethylpyridin-2-yl amine 0.25 g 5-vinylpyridin-2-yl amine (compound in Production Example 326) and 0.1 g of 10% palladium-carbon were stirred in 5 ML ethyl acetate at room temperature for 2 hours under hydrogen atmosphere.. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate), to give 0.24 g of the title compound as a pale yellow oil.1H-NMR (CDCl3) delta: 1.18(t, J=7.2Hz, 3H), 2.51(q, J=7.2Hz, 2H), 4.26(brs, 2H), 6.46(d, J=8.4Hz, 1H), 7.29(dd, J=8.4Hz, 1.8Hz, 1H), 7.91(d, J=1.8Hz, 1H)

Molecular Weight:122.17
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:122.084398327
Monoisotopic Mass:122.084398327
Topological Polar Surface Area:38.9
Heavy Atom Count:9
Complexity:83
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes