Nitrogen → [1-(3-Fluoro-benzyl)-1h-indazol-5-yl]-(5-phenylsulfanylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-amine

HRID 1072071Notes

Reaction equation

HRID 1072071 reaction equation
Br[CH2:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10](Cl)=[N:9][CH:8]=[N:7]2.N#N.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=1)[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([NH2:45])=[CH:42][CH:43]=2)[CH:38]=[N:37]1>C(Cl)Cl.C(O)CCC.ClCCCl>[F:31][C:32]1[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=1)[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([NH:45][C:10]3[C:11]4=[C:3]([CH2:2][S:21][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:4]=[CH:5][N:6]4[N:7]=[CH:8][N:9]=3)=[CH:42][CH:43]=2)[CH:38]=[N:37]1

Participants

9

Reactant 5

HCID 947NitrogenHCID 7969ThiophenolHCID 81531DiisopropylethylamineHCID 71470731-(3-Fluorobenzyl)-1H-indazol-5-amineHCID 218743865-(Bromomethyl)-4-chloropyrrolo[2,1-f][1,2,4]triazine

Product 1

HCID 22390494[1-(3-Fluoro-benzyl)-1h-indazol-5-yl]-(5-phenylsulfanylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-amineYield 58%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 2631-ButanolSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (850 mg, 3.46 mmole) in DCM (30 mL) was sparged with N2 for 0.5 hr and then placed in a −20° C. bath. Thiophenol (384 μL, 1.0 equiv) and diisopropylethylamine (605 μL, 1.0 equiv) were added and the reaction was kept at −20° C. for 3 hr. After warming to RT, the reaction mixture was washed with water, dried (Na2SO4), and the solvent was removed. 1,2-Dichloroethane (10 mL), n-butanol (10 mL) and 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine (750 mg, 0.9 equiv) were added to the residue and this mixture was heated at 85° C. for 2.5 hr. The solvents were removed and the residue was taken up in DCM, washed with sat. aq NaHCO3 solution and dried (Na2SO4). Removal of the solvent followed by chromatography on silica gel using DCM containing 0 to 2% MeOH as eluent afforded [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-(5-phenylsulfanylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-amine (957 mg, 58%) as a foam. 1H NMR (CDCl3) δ 4.48 (s, 2H), 5.59 (s, 2H), 6.53 (d, 1H, J=3 Hz), 6.8-7.0 (m, 3H), 7.2-7.6 (m, 9H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d, 1H, J=2 Hz), 8.88 (br s, 1H); MS: 481 (M+H)+; HPLC Ret Time: 1.87 min (YMC S7 C18, 3.0×50 mm column, 2 min gradient, 5 mL/min). This was dissolved in chloroform (25 mL), cooled in an ice bath and m-chloro-perbenzoic acid (500 mg, 57 to 80%, 1 equiv) was added in small portions over 15 min. After 1 hr., the reaction was washed with 10% aqueous NaHSO3 solution, sat. aq. NaHCO3 solution (three times) and dried (Na2SO4). Removal of the solvent left the product as a foam (957 mg, 95%). 1H NMR (CDCl3) δ 4.28 (d, 1H, J=14 Hz), 4.53 (d, 1H, J=14 Hz), 5.60 (s, 2H), 6.13 (d, 1H, J=3 Hz), 6.8-7.6 (m, 11H), 7.71 (dd, 1H, J=2, 9 Hz), 7.98 (s, 1H), 8.05 (s, 1H), 8.14 (d, 1H, J=2 Hz); MS: 497 (M+H)+; HPLC Ret Time: 1.67 min (YMC S7 C18, 3.0×50 mm column, 2 min gradient, 5 mL/min).

Workup

  1. customplaced in a −20° C.
  2. washthe reaction mixture was washed with water
  3. dry with materialdried (Na2SO4)
  4. customthe solvent was removed
  5. temperaturethis mixture was heated at 85° C. for 2.5 hr
  6. customThe solvents were removed
  7. washwashed with sat. aq NaHCO3 solution
  8. dry with materialdried (Na2SO4)
  9. customRemoval of the solvent

Sources & evidence

ORD record
ord-99cd6a4174734796aed8780c2c3186fb
Source dataset
uspto-grants-2005_06
Patent number
US06908916B2

Reaction notes

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