Water → 2-[3-(6-Fluoro-1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-trifluoromethoxy-phenyl)-acetamide

HRID 343164Notes

Reaction equation

HRID 343164 reaction equation
[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:24]([CH3:26])[CH3:25])[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4](=[O:37])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:49][C:50]1[C:58]2[C:53](=[CH:54][C:55]([F:59])=[CH:56][CH:57]=2)[N:52]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[N:51]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[F:59][C:55]1[CH:54]=[C:53]2[C:58]([C:50]([CH2:49][CH:3]3[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:24]([CH3:26])[CH3:25])[C:13]4[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=4)=[O:11])[C:7]4[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=4[N:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:4]3=[O:37])=[N:51][N:52]2[C:60]([O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[O:61])=[CH:57][CH:56]=1

Participants

7

Reactant 4

HCID 962WaterHCID 3251421Potassium bis(trimethylsilyl)amideHCID 10568325Tert-butyl 3-(bromomethyl)-6-fluoro-1H-indazole-1-carboxylateHCID 676963332-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-trifluoromethoxy-phenyl) acetamide

Product 1

HCID 867535932-[3-(6-Fluoro-1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-trifluoromethoxy-phenyl)-acetamideYield 26.9%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 250 mg of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-trifluoromethoxy-phenyl) acetamide, prepared as in Part C, in 5 mL of dry DMF at 0° C. is added 1.5 mL of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture is stirred for 30 min at 0° C. and a solution of 170 mg of 3-Bromomethyl-6-fluoro-1-tert-butoxycarbonyl-indazole in 3 mL of dry DMF is added dropwise. The reaction mixture is stirred overnight at RT, poured into water and the product extracted with ethyl acetate (2×15 mL). The solvent is removed in vacuo and the residue is purified by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent to afford 100 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ7.98-6.95 (m,16H) 5.07 (m, 1H), 4.30 (m, 3H), 3.86 (dd, 1H, J=16.5, 6.4), 3.65 (dd, 1H,J=16.5,6.4), 1.69 (s, 9H), 1.13 (d, 6H, J=6.8).

Workup

  1. stirringThe reaction mixture is stirred overnight at RT
  2. extractionthe product extracted with ethyl acetate (2×15 mL)
  3. customThe solvent is removed in vacuo
  4. customthe residue is purified by silica gel flash column chromatography

Sources & evidence

ORD record
ord-f0397ef8588c4b829f27b64e96247391
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

Loading…