Dimethylformamide → (R)-N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)tetrahydrofuran-2-carboxamide

HRID 468731

Reaktionsgleichung

Reaktionsgleichung von HRID 468731
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[O:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30](O)=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C@H:26]4[CH2:27][CH2:28][CH2:29][O:25]4)=[O:31])[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1

Komponenten

8

Edukt 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 2734707Tetrahydro-2-furoic acid, (+)-HCID 11038641((7-Azabenzotriazol-1-YL)oxy)tris(pyrrolidino)phosphonium hexafluorophosphateHCID 67974803N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide

Produkt 1

HCID 57411209(R)-N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)tetrahydrofuran-2-carboxamideAusbeute 65 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

To a mixture of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (62.4 mg, 0.167 mmol), (R)-(+)-tetrahydro-2-furoic acid (21.0 uL, 0.217 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (118.4 mg, 0.2284 mmol), and 4-dimethylaminopyridine (4.083 mg, 0.03342 mmol) was added N,N-dimethylformamide (2.0 mL, 26 mmol) and N,N-diisopropylethylamine (88 uL, 0.50 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over MgSO4, and filtered through a plug of silica gel, rinsing with ethyl acetate. The filtrate was concentrated and then purified via reverse phase HPLC and lyophilized to yield 45.0 mg (65%) of (R)—N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)tetrahydrofuran-2-carboxamide. LCMS (ESI): RT (min)=4.594, M+H=416.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.64 (s, 1H), 9.18 (s, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.68 (dd, J=11.6, 1.9 Hz, 2H), 7.64 (dd, J=8.3, 2.1 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 4.38 (dd, J=8.1, 5.6 Hz, 1H), 3.98 (dd, J=14.5, 6.8 Hz, 1H), 3.82 (dd, J=14.5, 6.9 Hz, 1H), 2.23 (s, 3H), 2.22-2.14 (m, 1H), 2.13-2.03 (m, 1H), 1.98 (td, J=12.6, 6.6 Hz, 1H), 1.86 (p, J=6.9 Hz, 2H), 0.95-0.77 (m, 4H).

Aufarbeitung

  1. washwashed twice with water and once with brine
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered through a plug of silica gel
  4. washrinsing with ethyl acetate
  5. concentrationThe filtrate was concentrated
  6. custompurified via reverse phase HPLC

Quellen und Nachweise

ORD-Eintrag
ord-bccdbb40738c455db1cda640cf5f0ddd
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08623889B2

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