Diisopropylethylamine → n-{5-[(1r)-1-({3-Cyano-6-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide

HRID 2189872Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2189872
[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.NC(C1C=CC(F)=C([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])C=1)C.CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:13]1[C:12]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:23]=2)[CH3:21])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1)#[N:15]

Komponenten

5

Edukt 3

HCID 81531DiisopropylethylamineHCID 11646595(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrileHCID 67426606N-[5-(1-aminoethyl)-2-fluorophenyl]methanesulfonamide

Produkt 1

HCID 67425688n-{5-[(1r)-1-({3-Cyano-6-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamideAusbeute 20,2 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 2631-ButanolLösungsmittel

Reaktionsbedingungen

Temperatur
150 °C

Versuchsvorschrift

To a 10-ml microwave vessel was added, 2-chloro-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoronicotinonitrile (Method 1, 600 mg, 2.3 mmol), N-[5-(1-aminoethyl)-2-fluorophenyl]methanesulfonamide (Method 61, 500 mg, 2.3 mmol), DIEA (0.5 ml, 2.76 mmol), and n-butanol (5 ml). The vessel was sealed and subjected to microwave heating at 150° C. for 5 hours (CEM Discover System). The resulting mixture was then purified by silica gel chromatography using 5% MeOH/DCM. The racemic product obtained was then chirally purified by HPLC on Chiralcel OJ column (500×50 mm, 20 microns) using 50:25:25:0.1% of hexane/MeOH/EtOH/diethylamine at 118 ml/min. The chiral purification gave 220 mg of N-{5-[(1R)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide 1H NMR: δ 11.77-12.26 (br s, 1H), 9.51 (s, 1H), 9.34-9.48 (br s, 1H), 7.62 (d, J=10.55 Hz, 1H), 7.39 (d, J=8.29 Hz, 1H), 7.02-7.23 (m, 3H), 6.00 (s, 1H), 5.07-5.24 (m, 1H), 2.95 (s, 3H), 1.81-1.95 (m, 1H), 1.49 (d, J=7.54 Hz, 3H), 0.88-0.97 (m, 2H), 0.57-0.68 (m, 2H). MS: Calcd.: 473. Found: [M+H]+ 474 and 223 mg of N-{5-[(1S)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamidel; 1H NMR: 11.73-12.38 (br s, 1H), 9.42 (s, 1H), 8.41-9.12 (br s, 1H), 7.61 (d, J=11.30 Hz, 1H), 7.37 (d, J=7.54 Hz, 1H), 6.96-7.24 (m, 3H), 6.02 (s, 1H), 5.05-5.26 (m, 1H), 2.90 (s, 3H), 1.79-1.96 (m, 1H), 1.49 (d, J=6.78 Hz, 3H), 0.89-0.98 (m, 2H), 0.59-0.67 (m, 2H). MS: Calcd.: 473. Found: [M+H]+ 474.

Aufarbeitung

  1. additionTo a 10-ml microwave vessel was added
  2. customThe vessel was sealed
  3. customThe resulting mixture was then purified by silica gel chromatography
  4. customThe racemic product obtained
  5. customwas then chirally purified by HPLC on Chiralcel OJ column (500×50 mm, 20 microns)
  6. customThe chiral purification

Quellen und Nachweise

ORD-Eintrag
ord-421ad42dcd924662892b7579ab8ac717
Quelldatensatz
uspto-grants-2012_12
Patentnummer
US08324252B2

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