Benzyl Chloride → (1-Benzyl-1H-indazol-5-yl)-[5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine

HRID 1072095Notes

Reaction equation

HRID 1072095 reaction equation
BrCC1C=CN2C=1C(Cl)=NC=N2.C([O-])(O)=O.[Na+].Cl[C:19]1[C:24]2=[C:25]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:26]=[CH:27][N:23]2[N:22]=[CH:21][N:20]=1.[CH2:34]([N:41]1[C:49]2[C:44](=[CH:45][C:46]([NH2:50])=[CH:47][CH:48]=2)[CH:43]=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.FC1C=C(C=CC=1)CN1C2C(=CC(N)=CC=2)C=N1.C(Cl)C1C=CC=CC=1>COCCO.C(Cl)Cl.CC#N>[CH2:34]([N:41]1[C:49]2[C:44](=[CH:45][C:46]([NH:50][C:19]3[C:24]4=[C:25]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:26]=[CH:27][N:23]4[N:22]=[CH:21][N:20]=3)=[CH:47][CH:48]=2)[CH:43]=[N:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1

Participants

10

Reactant 6

HCID 7503Benzyl ChlorideHCID 2120691-(Phenylmethyl)-1H-indazol-5-amineHCID 516892Sodium Bicarbonate2×HCID 71470731-(3-Fluorobenzyl)-1H-indazol-5-amineHCID 218743865-(Bromomethyl)-4-chloropyrrolo[2,1-f][1,2,4]triazineHCID 223905494-Chloro-5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazine

Product 1

HCID 22390526(1-Benzyl-1H-indazol-5-yl)-[5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amineYield 21%

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×HCID 80192-MethoxyethanolSolvent

Procedure

A suspension of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (50 mg, 0.202 mmole and NaHCO3 (75 mg, 4.4 equiv) in 2-methoxyethanol (1.0 mL) under N2 was left stirring at RT for 6 hr. The reaction was diluted with DCM, extracted with water and dried (Na2SO4). Removal of the solvent left 4-chloro-5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazine (41 mg, 84%) as an oil. 1H NMR (CDCl3) δ 3.40 (s, 3H), 3.67 (m, 4H), 4.96 (s, 2H), 7.05 (d, 1H, J=3 Hz), 7.82 (d, 1H, J=1 Hz), 8.16 (s, 1H). A suspension of 4-chloro-5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazine (5 mg, 0.020 mmole), NaHCO3 (3 mg, 2 equiv) and 1-benzyl-1H-indazol-5-ylamine (4.5 mg, 1 equiv, prepared in the same manner as 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine but using benzyl chloride) in dry CH3CN (0.5 mL) was left stirring at RT for 2 hr. The reaction was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 0 to 1% MeOH) afforded the product as and oil (1.8 mg, 21%). 1H NMR (CDCl3) δ 3.16 (s, 3H), 3.63 (m, 4H), 4.83 (s, 2H), 5.53 (s, 2H), 6.48 (d, 1H, J=3 Hz), 7.1-7.5 (m, 8H), 7.88 s, 1H), 7.96 (s, 1H), 8.11 (s, 1H), 9.56 (s, 1H); MS: 429 (M+H)+; HPLC Ret Time: 2.58 min (YMC C18 S5, 4.6×50 mm, 3 min gradient (starting with 0% solvent B and ending with 70% solvent B), 4 mL/min.

Workup

  1. waitwas left
  2. extractionextracted with water
  3. dry with materialdried (Na2SO4)
  4. customRemoval of the solvent
  5. waitleft 4-chloro-5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazine (41 mg, 84%) as an oil
  6. waitwas left
  7. stirringstirring at RT for 2 hr
  8. washwashed with water
  9. dry with materialdried (Na2SO4)
  10. customRemoval of the solvent
  11. washfollowed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 0 to 1% MeOH)

Sources & evidence

ORD record
ord-50938ab0d8294d01905294883ff68de7
Source dataset
uspto-grants-2005_06
Patent number
US06908916B2

Reaction notes

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