Diisopropylethylamine → (2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester

HRID 1257605Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1257605
[C:1]([NH:18][CH2:19][CH2:20][C:21](O)=[O:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[C:59]([NH:76][CH:77]2[CH2:82][CH2:81][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:79][CH2:78]2)=[C:60]2[CH:66]=[CH:65][N:64]([S:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)(=[O:69])=[O:68])[C:61]2=[N:62][CH:63]=1>CN(C=O)C>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1](=[O:2])[NH:18][CH2:19][CH2:20][C:21](=[O:22])[NH:57][C:58]3[C:59]([NH:76][CH:77]4[CH2:78][CH2:79][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:81][CH2:82]4)=[C:60]4[CH:66]=[CH:65][N:64]([S:67]([C:70]5[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=5)(=[O:69])=[O:68])[C:61]4=[N:62][CH:63]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1

Komponenten

6

Edukt 4

HCID 81531DiisopropylethylamineHCID 2724630N-Fluorenylmethoxycarbonyl-I2-alanineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 673456183-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile

Produkt 1

HCID 67345405(2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl esterAusbeute 97 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

Fmoc-beta-Alanine (3.1 g, 9.90 mmol), HATU (3.8 g, 9.90 mmol), and diisopropylethylamine (2.1 ml, 12.0 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (4.2 g, 9.90 mmol) in DMF (100 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml). the combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded (2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (6.89 g, 97%) as a white foam. LCMS (Method G, ESI): RT=0.85 min, m+H=718.5. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.14 (t, J=10.3 Hz), 7.84 (s), 7.75 (dd, J=15.2, 7.5 Hz), 7.60-7.54 (m), 7.50 (d, J=4.1 Hz), 7.44 (t, J=7.8 Hz), 7.37 (t, J=7.4 Hz), 7.28 (t, J=5.8 Hz), 6.52 (t, J=4.7 Hz), 5.50 (d, J=11.4 Hz), 4.70 (s), 4.40 (s), 4.33 (d, J=7.1 Hz), 4.19 (t, J=6.6 Hz), 3.64 (td, J=13.3, 6.7 Hz), 3.51 (d, J=21.9 Hz), 3.39 (d, J=5.4 Hz), 2.80-2.47 (m), 2.35 (s), 2.30-2.07 (m), 1.93 (d, J=12.0 Hz), 1.51 (dt, J=13.5, 6.8 Hz).

Aufarbeitung

  1. concentrationwas concentrated under reduced pressure
  2. customThe residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml)
  3. dry with materialthe combined organic layers were dried over Mg2SO4
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customPurification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2)

Quellen und Nachweise

ORD-Eintrag
ord-5fc5ca75c2244d9098538f60488cf4ce
Quelldatensatz
uspto-grants-2013_06
Patentnummer
US08461328B2

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