3-(Bromomethyl)-1H-indazole, N1-BOC protected → 3-(6-[(benzyl-isopropyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester

HRID 900106Notes

Reaction equation

HRID 900106 reaction equation
[CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([CH2:52]Br)=[N:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([CH2:52][CH:19]2[C:18]3[N:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:16][N:17]=3)[C:13]3[CH:28]=[CH:29][CH:30]=[CH:31][C:12]=3[N:11]([CH2:10][C:9](=[O:32])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:33]([CH3:35])[CH3:34])[C:20]2=[O:21])=[N:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]

Participants

3

Reactant 2

HCID 108049513-(Bromomethyl)-1H-indazole, N1-BOC protectedHCID 58957935N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide

Product 1

HCID 693126163-(6-[(benzyl-isopropyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl esterYield 6.1%

Procedure

Following the procedure described in Example 3(A), Step A, N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 10) (210 mg, 0.451 mmol) was alkylated with 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (150 mg, 0.473 mmol). The reaction was diluted with a pH 6.8 buffer solution and the aqueous solution was washed with EtOAc. The organic solution was washed with brine (3×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (2×) by preparative chromatography eluting with 5% acetone in CH2Cl2 followed by medium pressure chromatography eluting with a solvent gradient (2% acetone in CH2Cl2 to 14% acetone in CH2Cl2) to provide 19.1 mg of 3-{6-[(benzyl-isopropyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD2Cl2) δ 8.05 (m, 1H), 7.12-7.71 (m, 15H), 7.03 (m, 1H), 6.92 (d, 1H), 5.21 (d) and 4.90 (d, total 1H), 4.61-4.72 (m, 2H), 4.49 (s, 1H), 4.43 (t, 1H), 4.25-4.32 (m, 1H), 3.96-4.15 (m, 2H), 1.61 (d, 9H), 1.16 (dd, 3H), 1.04 (dd, 3H); MS 696.4 (M+1).

Workup

  1. washthe aqueous solution was washed with EtOAc
  2. washThe organic solution was washed with brine (3×)
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified (2×) by preparative chromatography
  7. washeluting with 5% acetone in CH2Cl2
  8. washeluting with a solvent gradient (2% acetone in CH2Cl2 to 14% acetone in CH2Cl2)

Sources & evidence

ORD record
ord-5d27cd28e21e4b2bb810fe0c702ae0c8
Source dataset
uspto-grants-2008_04
Patent number
US07358242B2

Reaction notes

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