Diisopropylethylamine → 2,2-Diallyl-3-isobutyl-N4-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-succinamide

HRID 273283

Reaktionsgleichung

Reaktionsgleichung von HRID 273283
[CH2:1]([C:4]([CH:11]([C:16](=[O:37])[NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:19]1)[CH2:12][CH:13]([CH3:15])[CH3:14])([CH2:8][CH:9]=[CH2:10])[C:5](O)=[O:6])[CH:2]=[CH2:3].C[N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([C:4]([CH2:8][CH:9]=[CH2:10])([CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:16]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:19]1)=[O:37])[C:5]([NH2:39])=[O:6])[CH:2]=[CH2:3]

Komponenten

7

Edukt 3

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 222882322-Allyl-2-[3-methyl-1-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e] [1,4]diazepin-3-ylcarbamoyl)-butyl]-pent-4-enoic acid

Produkt 1

HCID 221352682,2-Diallyl-3-isobutyl-N4-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-succinamideAusbeute 48 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

A solution of compound 29 (300 mg, 0.54 mmol) in 50 ml TFA/CH2Cl2 (1:1) was stirred for 2 hr at ambient temperature, then concentrated under vacuum. Two cycles of toluene addition and removal of volatiles gave 250 mg of 30 as a white solid (92%) which was used in the next step without purification. ESI ES+=502.3 (M+1) Step 3: Preparation of 2,2-Diallyl-3-isobutyl-N4-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-succinamide 31. To a solution of 30 (250 mg, 0.5 mmol) in 30 ml DMF was added HATU (250 mg, 0.66 mmol) and DIEA (400 uL, 2.2 mmol). After stirring for 2 hrs, ammonia gas was bubbled into the solution for 5 minutes using a glass inlet tube. The mixture was then stirred at ambient temperature overnight. Water was added (10 mL) and the solvent was removed under vacuum to give a yellow oil which was taken up in ethyl acetate and water (1:1). The organic layer was washed twice with water and then brine, and dried over Na2SO4. After filtration and concentration, the crude product was purified using silica gel chromatography (CH2Cl2/methanol 10:0.5) to give compound 31 (120 mg) as a white solid (48%). 1H NMR (CDCl3) 0.95-0.88 (dd, 6H), 1.32-1.28 (m, 1H), 1.64-1.50 (m, 1H), 1.90-1.80 (m, 1H), 2.35-2.00 (m, 1H), 2.80-2.54 (m, 4H), 3.48 (s, 3H), 5.38-5.14 (m, 5H), 5.54-5.51 (d, 1H), 5.90-5.78 (m, 2H), 7.65-7.25 (m, 9H), 8.52 (s, 1H). ESI ES+=523.2 (M+Na). Step 4: Preparation of 1-[(1R)-3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopent-3-enecarboxylic amide 32. To a solution of 31 (110 mg, 0.22 mmol) in 20 ml of toluene and CH2Cl2 (1:1) at 100 degree was added (bis(tricyclohexylphosphine)-benzylidine ruthenium (IV) dichloride) (24 mg, 0.029 mmol). The mixture was stirred at 100 degree for 4 hrs and another 24 mg Grubbs' catalyst was added. The mixture was then stirred at 100 degree for another 4 hrs. Then the solution was cooled to RT, after which 100 mg of charcoal was added. The mixture was filtered through celite to provide a slightly yellow solution, then concentrated. The residue was purified in silica gel chromatography with CH2Cl2/methanol (10:0.5) to give 48 mg of 32 (46%). 1H NMR (CDCl3) 0.97-0.90 (dd, 6H), 1.30-1.25 (m, 1H), 1.65-1.57 (m, 1H), 2.00-1.85 (m, 1H), 2.40-2.30 (d, 1H), 2.80-2.65 (m, 2H), 3.00-2.80 (d, 1H), 3.40-3.20 (m, 1H), 3.47 (s, 3H), 5.40-5.20 (s, 1H), 5.52-5.49 (d, 1H), 5.80-5.71 (m, 2H), 7.63-7.20 (m, 9H), 7.90 (s, 1H). API AP+ 473.1 (M+1).

Aufarbeitung

  1. customwas used in the next step without purification
  2. customESI ES+=502.3 (M+1) Step 3: Preparation of 2,2-Diallyl-3-isobutyl-N4-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-succinamide 31
  3. customammonia gas was bubbled into the solution for 5 minutes
  4. stirringThe mixture was then stirred at ambient temperature overnight
  5. additionWater was added (10 mL)
  6. customthe solvent was removed under vacuum
  7. customto give a yellow oil which
  8. washThe organic layer was washed twice with water
  9. dry with materialbrine, and dried over Na2SO4
  10. filtrationAfter filtration and concentration
  11. customthe crude product was purified

Quellen und Nachweise

ORD-Eintrag
ord-b181f6f60eb04b4396c2ada3c5781db7
Quelldatensatz
uspto-grants-2008_11
Patentnummer
US07456278B2

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