Diisopropylethylamine → tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate

HRID 1486046Notes

Reaction equation

HRID 1486046 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:28])OC(C)(C)C)[C@H:17]([CH3:29])[N:16]([C:30](=[O:36])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]1=3)=[C:7]([O:41][CH3:42])[CH:6]=[CH:5]2.[C:43]([N:50]([CH3:56])[C@H:51](C(O)=O)[CH3:52])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:28])[C@@H:51]([N:50]([CH3:56])[C:43](=[O:44])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH3:52])[C@H:17]([CH3:29])[N:16]([C:30](=[O:36])[CH2:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]1=3)=[C:7]([O:41][CH3:42])[CH:6]=[CH:5]2

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 7009590(2S)-2-(((tert-butoxy)carbonyl)(methyl)amino)propanoic acidHCID 131736771tert-butyl(3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate

Product 1

HCID 118292666tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamateYield 95.3%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A rt solution of tert-butyl(3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (75 mg, 114 μmol) in 4 M HCl in 1,4-dioxane (568 μl) was stirred for 1.5 h then concentrated. This material was taken up in DMF (380 μl) and Boc-N-methyl-L-alanine (25.5 mg, 125 μmol), N,N-diisopropylethylamine (78.9 μl, 456 μmol), and HBTU (47.6 mg, 125 μmol) were added. The reaction was stirred at rt for 20 min, then diluted with EtOAc, washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (81 mg, 95%) as a white solid. MS m/z 767/769 (M+Na)+

Workup

  1. concentrationthen concentrated
  2. washwashed with sat. aq. NaHCO3 and sat. aq. NaCl
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-fcfb31434ffd4b9cb34d5192e3f8fd83
Source dataset
uspto-grants-2016_08
Patent number
US09422331B2

Reaction notes

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