3-(3-CYANO-4-FLUOROPHENYL)-1-PROPENE synthesis

Yield:943247-49-2 61%

Reaction Conditions:

tetrakis(triphenylphosphine) palladium⁽⁰⁾ in N,N-dimethyl-formamide at 20 - 50;

Steps:

27

Example 27: 5-Propyl-N-l,3-thiazol-2-yl-lH-indazol-3-amineH₂, Pd/C, EtOH[0333] To a stirred solution of 5-bromo-2-fluorobenzonitrile (1.50 g, 7.50 mmol) in DMF (20 mL) were added allyl tributyltin (3.73 g, 11.25 mmol) and tetrakis(triphenylphosphine)palladium (433 mg, 0.375 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred at 50⁰C overnight. After cooling, the mixture was diluted with EtOAc, washed with IN HCl, H₂O, and brine, dried (MgSO₄), filtered, and concentrated in vacuo. The crude oil was passed through a short NH-SiO₂ column, and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (hexane/EtOAc=20: 1 to 10:1) gave 739 mg (61 %) of 5-allyl-2-fluorobenzonitrile (compound 27A) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 3.39 (d, 2H, 7=6.59 Hz) 5.02 - 5.23 (m, 2H) 5.79 - 6.01 (m, IH) 7.14 (t, IH, 7=8.57 Hz) 7.35 - 7.50 (m, 2H) [0334] To a stirred solution of 5-allyl-2-fluorobenzonitrile (0.74 g, 4.57 mmol) in n-BuOH (30 mL) was added hydrazine monohydrate (0.67 mL, 13.8 mmol). The mixture was stirred under reflux overnight, and concentrated in vacuo. The residue was diluted with EtOAc, washed with H2O and brine, dried (MgSO₄), filtered, and concentrated in vacuo. The precipitate was collected, and washed with hexane to give the mixture of 5-allyl-lH-indazol- 3-arnine (compound 27B) and 5-propyl-lH-indazol-3-amine (compound 27C) (2:5). The mixture was dissolved with ethanol (2 itiL). Palladium charcoal (80 mg) was added to the solution, and the mixture was stirred for 4 h under hydrogen atmosphere at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 83.2 mg (10%) of compound 27C as a colorless solid. ¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, 3H, /=7.25 Hz) 1.60 - 1.77 (m, 2H) 2.61 - 2.76 (m, 2H) 4.05 (brs, 2H) 7.16 - 7.23 (m, 2H) 7.33 (s, IH) 8.75 (brs, IH). MS (ES) [m+H] calc'd for Ci₀Hi₃N₃, 176; found 176. [0335] N-(5-Propyl-lH-indazol-3-yl)thiourea (compound 27D) was prepared in 100% yield from 5-propyl-lH~indazol-3-amine according to a procedure analogous to that outlined in Example 9. 1H NMR (300 MHz, CDCl₃) 6 0.96 (t, 3H, /=7.38 Hz) 1.61 - 1.77 (m, 2H) 2.71 (t, 2H, /=7.57 Hz) 6.81 (brs, IH) 7.28 - 7.37 (m, 2H) 7.41 (s, IH) 8.32 (brs, IH) 9.36 (brs, IH) 9.55 (brs, IH). MS (ES) [m+H] calc'd for C_nHi₄N₄S, 235; found 235. [0336] The title compound was prepared in 29% yield from /V-(5-propyl-lH-indazol-3- yl)thiourea according to a procedure analogous to that outlined in Example 7. ¹H NMR (300 MHz, DMSO-J₆) 5 0.92 (t, 3H, /=7.38 Hz) 1.55 - 1.72 (m, 2H) 2.63 (t, 2H, /=7.57 Hz) 6.96 (d, IH, /=3.41 Hz) 7.21 (dd, IH, /=8.33, 1.14 Hz) 7.31 (d, IH, /=8.71 Hz) 7.34 (d, IH, /=3.79 Hz) 7.89 (s, IH) 11.18 (s, IH) 12.18 (s, IH). MS (ES) [m+H] calc'd for Ci₃Hj₄N₄S, 259; found 259.

References:

WO2007/75847,2007,A2 Location in patent:Page/Page column 108-109