Potassium Phosphate, Tribasic → 9-tert-butyl-2-isobutyramido-3-methoxy-13-(2-thienyl)-5,6,9,10,11,12-hexahydro-8H-azepino[4',3':4,5]pyrrolo[2,1-a]isoquinolin-8-one

HRID 1971650Notes

Reaction equation

HRID 1971650 reaction equation
[C:1]([N:5]1[CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:31])([CH3:4])([CH3:3])[CH3:2].[C:32]([NH2:37])(=[O:36])[CH:33]([CH3:35])[CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C(O)(C)(C)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:5]1[CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH:37][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:31])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 68424IsobutyramideHCID 11953610Di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphaneHCID 581248529-tert-butyl-2-bromo-3-methoxy-13-(2-thienyl)-5,6,9,10,11,12-hexahydro-8H-azepino[4',3':4,5]pyrrolo[2,1-a]isoquinolin-8-one

Product 1

HCID 509388529-tert-butyl-2-isobutyramido-3-methoxy-13-(2-thienyl)-5,6,9,10,11,12-hexahydro-8H-azepino[4',3':4,5]pyrrolo[2,1-a]isoquinolin-8-oneYield 47.4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 250 mg of 3d, 110 mg of isobutyramide, 230 mg of K3PO4, 15 mg of Pd2 dba3 and 20 mg of di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine in 3 ml of degassed tert-butanol was heated under nitrogen atmosphere for 16 hr at 100° C. The reaction mixture was cooled and diluted with 20 ml of water. The product was extracted into ethyl acetate. The extract was washed with water, dried, concentrated and the product was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 120 mg of 3f. The sample was crystallized from ethyl acetate; MS-ESI: [M+1] 506.25. NMR (CDCl3) δ 1.18 (d, 6, isoC3H7), 1.58 (s, 9, tertC4H9), 1.89 (m, 2, CH2), 2.44 (m, 1, CH), 2.58 (t, 2, CH2), 3.01 (t, 2, CH2), 3.42 (t, 2, CH2), 3.86 (s, 3, OCH3), 4.50 (t, 2, CH2), 6.70 (s, 1 ArH) and 7.46 (bs, 1, ArH), 7.00, 7.18 and 7.38 (3×m, 3, thiophene-H), 8.08 (bs, 1, NH).

Workup

  1. temperatureThe reaction mixture was cooled
  2. extractionThe product was extracted into ethyl acetate
  3. washThe extract was washed with water
  4. customdried
  5. concentrationconcentrated
  6. customthe product was purified by chromatography over silica gel

Sources & evidence

ORD record
ord-e3fadb57a1ab4bf5ba3726b3b1ad3676
Source dataset
uspto-grants-2013_04
Patent number
US08431564B2

Reaction notes

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