Tetrahydrofuran → (s,e)-n-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-8-methyl-3-(3-morpholinoprop-1-enyl)-6,7,8,9-tetrahydro-5h-imidazo[1,5-a][1,4]diazepine-1-carboxamide

HRID 535964Notes

Reaction equation

HRID 535964 reaction equation
[Si](OC[CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:17]2[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH2:22][C:16]2=[C:15]([C:24]([NH:26][C@@H:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([NH:30][CH3:31])=[O:29])=[O:25])[N:14]=1)(C(C)(C)C)(C)C.CC[CH2:38][CH2:39][N+:40](CCCC)(CCCC)[CH2:41][CH2:42]CC.[F-].C1C[O:57]CC1>>[CH3:35][C:32]([CH3:34])([CH3:33])[C@H:27]([NH:26][C:24]([C:15]1[N:14]=[C:13](/[CH:12]=[CH:11]/[CH2:10][N:40]2[CH2:41][CH2:42][O:57][CH2:38][CH2:39]2)[N:17]2[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH2:22][C:16]=12)=[O:25])[C:28]([NH:30][CH3:31])=[O:29]

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 2724141Tetrabutylammonium FluorideHCID 57635634HCID 57635634, compound

Product 1

HCID 57635710(s,e)-n-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-8-methyl-3-(3-morpholinoprop-1-enyl)-6,7,8,9-tetrahydro-5h-imidazo[1,5-a][1,4]diazepine-1-carboxamideYield 70%

Procedure

Compound 47A (0.126 g, 0.25 mmol) was dissolved in THF and TBAF (1M in THF, 0.50 mL, 0.50 mmol) solution was added. The resulting mixture was stirred for 18 h. The mixture was concentrated, diluted with NaCl saturated solution and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep LC/MS using 5-95% gradient of acetonitrile/water with 0.1% formic acid. The resulting material was purified by ion exchange chromatography using a Strata SPE SCX column to remove t-butyl dimethylsilane impurity. Compound 514 (0.070 g, 70%) was isolated as a free base. 1H-NMR (400 MHz, CDCl3) δ: 1.07 (s, 9H), 1.85 (m, 3H), 2.37 (s, 3H), 2.53 (m, 2H), 2.80 (d, 3H), 2.95 (m, 2H), 3.82 (t, 2H), 4.06 (m, 2H), 4.29 (m, 3H), 5.93 (m, 1H), 6.34 (d, 1H), 6.73 (m, 1H), 7.86 (m, 1H); LCMS (+ESI) m/z 392.2 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated
  2. additiondiluted with NaCl saturated solution
  3. extractionextracted with DCM
  4. dry with materialThe organic layer was dried over anhydrous Na2SO4
  5. concentrationconcentrated
  6. customThe residue was purified by Prep LC/MS
  7. customThe resulting material was purified by ion exchange chromatography
  8. customto remove t-butyl dimethylsilane impurity

Sources & evidence

ORD record
ord-e087da93b00f4985a133c17e99a9bb54
Source dataset
uspto-grants-2014_10
Patent number
US08859538B2

Reaction notes

Loading…