1,3-Dibromopropane → N-[3-(5-methyl-4-phenoxy-pyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propyl]-methanesulfonamide

HRID 914798Notes

Reaction equation

HRID 914798 reaction equation
[O:1]([C:8]1[C:13]2=[C:14]([CH3:18])[C:15]([OH:17])=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22]Br.C([O-])([O-])=O.[K+].[K+].[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>CN(C=O)C.ClCCl>[CH3:18][C:14]1[C:15]([O:17][CH2:20][CH2:21][CH2:22][NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:16][N:12]2[C:13]=1[C:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N:9][CH:10]=[N:11]2

Participants

7

Reactant 4

HCID 80011,3-DibromopropaneHCID 11430Potassium Carbonate2×HCID 72879MethanesulfonamideHCID 219458735-Methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazin-6-ol

Product 1

HCID 22508873N-[3-(5-methyl-4-phenoxy-pyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propyl]-methanesulfonamideYield 81%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 4-phenoxy-5-methyl-6-hydroxypyrrolo-[2,1-f][1,2,4]triazine (1.05 g, 4.35 mmol), 1,3-dibromopropane (4.0 g, 20 mmol), and K2CO3 (3 g, 22 mmol) was heated at 70° C. for 2 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, eluting from dichloromethane to 20% ethyl acetate/dichioromethane) to afford the crude intermediate (1.35 g, 86% yield). This intermediate (1.3 g, 3.59 mmol) was heated with methanesulfonamide (2.0 g, 21 mmol) and K2CO3 (4 g, 29 mmol) in DMF (15 mL) for 2 h. The mixture was cooled, diluted with dichloromethane, washed twice with 5% Na2CO3 solution, dried and concentrated. The residue was purified by flash column chromatography (silica gel, 20% ethyl acetate/dichloromethane) to afford N-[3-(5-methyl-4-phenoxy-pyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide (1.1 g, 81%) as a white solid. MS: (M+H)+=377. B. The compound from Step A above was treated with methanesulfonamide by a procedure similar to that described forthe preparation of Example 24 to obtain N-[3-(4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide. (64% yield). MS: (M+H)+=301. C. A mixture of N-[3-(4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide (530 mg, 1.77 mmol) and POC13 was heated at 80° C. for 1.5 h. The volatiles were removed and the residue was diluted with dichloromethane, washed successively with cold NaHCO3 solution and brine, dried, and concentrated in vacuo to afford the crude chloroimidate intermediate (610 mg), which was heated with 4-fluoro-2-methyl-1H-indol-5-ol (495 mg, 3.0 mmol) and K2CO3 (3.0 g, 22 mmol) in DMF (8 mL) at 80-85° C. for 2 h. The mixture was diluted with dichloromethane and the solid was filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography eluting with 30% ethyl acetate/dichloromethane. The desired product was further purified by preparative HPLC to afford the title compound (290 mg, 34% yield) as a tan solid. HRMS (M+H)+ Calcd. For C20H22FN5O4S: 447.1376. Found: 448.1476. 1H NMR (CDCl3) δ 7.75 (s, 1H), 7.24 (s, 1H), 7.03 (d, 1H, J=8.32 Hz), 6.88 (m, 1H), 4.04 (t, 2H, J=5.72 Hz), 3.31 (t, 2H, J=6.16 Hz), 2.90 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H), 2.04 (m, 2H). Anal. Calcd. For C20H21FN4O4S:1.0 H2O:0.18 TFA: C 50.57; H 4.73; N 14.61; S 6.80. Found: C 50.44; H 4.87; N 14.51; S 6.70.

Workup

  1. customThe solvent was removed in vacuo
  2. customThe residue was purified by flash column chromatography (silica gel, eluting from dichloromethane to 20% ethyl acetate/dichioromethane)
  3. customto afford the crude intermediate (1.35 g, 86% yield)
  4. temperatureThe mixture was cooled
  5. washwashed twice with 5% Na2CO3 solution
  6. customdried
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography (silica gel, 20% ethyl acetate/dichloromethane)

Sources & evidence

ORD record
ord-abfed993bf9442cb973f516e9f92f048
Source dataset
uspto-grants-2007_09
Patent number
US07265113B2

Reaction notes

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