Potassium Carbonate → N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propyl)methanesulfonamide

HRID 914799Notes

Reaction equation

[OH:1][C:2]1[C:7]2=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:21][C:22]1[C:30](O)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH3:32])[NH:26]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[F:21][C:22]1[C:30]([O:1][C:2]2[C:7]3=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]3[N:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH3:32])[NH:26]2

Participants

Conditions

Temperature: 80 °C

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

customThe volatiles were removed
additionthe residue was diluted with dichloromethane
washwashed successively with cold NaHCO3 solution and brine
customdried
concentrationconcentrated in vacuo
customto afford the crude chloroimidate intermediate (610 mg), which
filtrationthe solid was filtered
concentrationThe filtrate was concentrated
customthe residue was purified by silica gel flash column chromatography
washeluting with 30% ethyl acetate/dichloromethane
customThe desired product was further purified by preparative HPLC

Sources & evidence

ORD record: ord-b21a9778185c4749a6bcfdb8c3661060
Source dataset: uspto-grants-2007_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07265113B2

Reaction notes

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