Sodium bis(trimethylsilyl)amide → HCID 178492382, compound

HRID 343221Notes

Reaction equation

HRID 343221 reaction equation
[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61]Br)=[N:53]1)=O)(C)(C)C>CN(C=O)C.C1COCC1>[NH:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:4]2=[O:34])=[N:53]1

Participants

6

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 108049513-(Bromomethyl)-1H-indazole, N1-BOC protectedHCID 676961852-(2,4-dioxo-5-pyrid-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide

Product 1

HCID 178492382HCID 178492382, compoundYield 50.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 0.35 g (0.77 mmol, 1.0 equiv) of 2-(2,4-dioxo-5-pyrid-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 36, in 7 mL of DMF is cooled in an ice/water bath. 0.85 mL (0.84 mmol, 1.1 equiv) of 1M NaN(TMS)2 in THF is added and the solution stirred at 0° C. for 10 min. A solution of 0.26 g (0.84 mmol, 1.1 equiv) of N-tert-butoxycarbonyl-3-bromomethyl-indazole in 3 mL of DMF is added and the resulting yellow solution stirred at RT for 1 h. The reaction is quenched with H2O, extracted with EtOAc (×3), washed with H2O (×2) and brine, dried over MgSO4 and concentrated to a brown oil. Purification by silica gel flash chromatography using EtOAc/hexane 1/1 as eluent followed by Si60 MPLC using EtOAc/hexane 1/1 as eluent gave 0.23 g of a white powder; low resolution MS (FAB) 689 (MH+). A portion of this compound is dissolved in 4N HCl in dioxane and stirred at 0° C. for 30 min, and then concentrated to a white foam. Purification by RP-18 MPLC using MeCN/H2O 3/2 containing 0.1% HCl as eluent gave 33 mg of the title compound HCl salt as an amorphous white powder: 1H NMR (d6 -DMSO, 400 MHz) δ8.47 (d, 1H, J=3.5), 8.0-7.0 (m, 15H), 4.79 (m,1H), 4.20 (m, 2H), 3.79 (s, 3H), 3.51 (dd, 1H, J=7, 15), 3.39 (dd, 1H, J=5, 15), 0.97 (dd, 6H, J=7, 14); low resolution MS (FAB)m/e 589 (MH+).

Workup

  1. stirringthe resulting yellow solution stirred at RT for 1 h
  2. customThe reaction is quenched with H2O
  3. extractionextracted with EtOAc (×3)
  4. washwashed with H2O (×2) and brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated to a brown oil
  7. customPurification by silica gel flash chromatography

Sources & evidence

ORD record
ord-3da2f72a821e4340808b7f2ecb7398a3
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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