Potassium Metaphosphate → (E)-1-(4-(5-(But-1-enyl)-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide

HRID 528849Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 528849
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:13])=[O:12])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2.[CH:55](/B(O)O)=[CH:56]\[CH2:57][CH3:58].[O-]P(=O)=O.[K+]>O1CCOCC1.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(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH:55](/[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:12])=[O:13])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2)=[CH:56]\[CH2:57][CH3:58]

Komponenten

7

Edukt 3

HCID 16133895Potassium MetaphosphateHCID 219091321-Butenylboronic acidHCID 710625451-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide

Produkt 1

HCID 86718889(E)-1-(4-(5-(But-1-enyl)-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamideAusbeute 71,2 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)KatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

To a sealed tube containing 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 16 mg, 0.019 mmol) in dioxane (1.0 mL) was added (E)-but-1-enylboronic acid (8 mg, 0.076 mmol), Pd2(dba)3 (9 mg, 10 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (9 mg, 0.019 mmol) and potassium metaphosphate (5 mg, 0.038 mmol). The reaction mixture was purged with nitrogen for 1 min and then heated at 90° C. for 16 h. The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg, 64%) as a pale yellow solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.06-8.05 (m, 1H), 7.94 (br s, 1H), 7.65-7.63 (m, 1H), 7.30-7.11 (m, 6.5H), 6.93 (d, J=7.0 Hz, 0.5H), 6.05-5.95 (m, 1H), 4.75-4.50 (m, 2H), 3.95-3.55 (m, 1H), 3.49-3.41 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.15-3.10 (m, 2H), 3.00-2.96 (m, 3H), 2.90-2.65 (m, 2H), 2.33 (s, 2H), 2.28 (s, 1H), 2.21-2.18 (m, 2H), 1.58-1.02 (m, 11 H), 1.03-0.95 (m, 5H), 0.93-0.87 (m, 3H), 0.77 (t, J=7.3 Hz, 2H), 0.69 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 813.3 (M+H)+.

Aufarbeitung

  1. customThe reaction mixture was purged with nitrogen for 1 min
  2. additionThe reaction mixture was then diluted with EtOAc and 1N aq. HCl solution
  3. customThe organic layer was separated
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by preparative HPLC

Quellen und Nachweise

ORD-Eintrag
ord-3a823cfc73e34b979eadb4eb48ce05d7
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09346795B2

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