Dichloromethane → (S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-(isopropylamino)nicotinonitrile

HRID 75906

Reaktionsgleichung

Reaktionsgleichung von HRID 75906
[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16](I)[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC[N:32](C(C)C)[CH:33]([CH3:35])[CH3:34].C(N)(C)C.C(Cl)Cl>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16]([NH:32][CH:33]([CH3:35])[CH3:34])[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1

Komponenten

6

Edukt 4

HCID 6344DichloromethaneHCID 6363IsopropylamineHCID 81531DiisopropylethylamineHCID 67456774(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile

Produkt 1

HCID 11524930(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-(isopropylamino)nicotinonitrileAusbeute 51 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 2631-ButanolLösungsmittel

Reaktionsbedingungen

Temperatur
185 °C

Versuchsvorschrift

To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile (Example 134, 0.07 g, 0.14 mmol) and DIEA (0.023 g, 0.18 mol) in n-BuOH (1.5 ml) was added isopropylamine (0.16 g, 2.7 mmol). The reaction was then heated to 185° C. under microwave conditions (1 hour×4 cycles). The reaction was then cooled to room temperature, DCM (10 ml) was added, and washed with 10% aqueous Na2S2O3. The organic layer was then dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.031 g, 51%). 1H NMR (400 MHz, CD3OD) δ 7.36-7.33 (m, 2H), 7.04-7.00 (m, 2H), 5.99-5.59 (br s, 1H), 5.14 (s, 1H), 4.29-4.23 (m, 1H), 1.87-1.83 (m, 1H), 1.52 (d, J=7.0 Hz, 3H), 1.25 (d, J=6.2 Hz, 6H), 0.95-0.94 (m, 2H), 0.65-0.63 (m, 2H). MS: Calcd.: 437. Found: [M+H]+ 438.

Aufarbeitung

  1. temperatureThe reaction was then cooled to room temperature
  2. washwashed with 10% aqueous Na2S2O3
  3. dry with materialThe organic layer was then dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe resulting oil was purified by reverse-phase column chromatography (5-50% ACN)

Quellen und Nachweise

ORD-Eintrag
ord-e49870e38b0b4050a79114c13bc10cff
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08835465B2

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