Hydrochloric Acid → 2-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide, dihydrochloride salt

HRID 1986077Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1986077
[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.F[C:38]1[N:53]=[CH:52][CH:51]=[CH:50][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH3:49])=[O:41].CN1C(=O)CCC1.Cl>O1CCOCC1>[ClH:1].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:53]=[CH:52][CH:51]=[CH:50][C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[CH3:49])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1

Komponenten

6

Edukt 4

HCID 313Hydrochloric Acid2×HCID 13387N-methyl-2-pyrrolidoneHCID 162230054-(4-(1h-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)nicotinamide, hydrochloride salt2×HCID 577213712-Fluoro-N-o-tolylnicotinamide

Produkt 1

HCID 1317274832-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide, dihydrochloride saltAusbeute 55,9 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.042 g, 0.17 mmol, Compound C of Example 1) and 2-fluoro-N-o-tolylnicotinamide (0.040 g, 0.17 mmol), in anhydrous 1,4-dioxane (0.22 mL) and anhydrous NMP (0.40 mL), was added HCl (4N in 1,4-dioxane, 0.18 mL, 0.72 mmol). The reaction mixture was heated in a sealed tube at 140° C. for 65 hours before being partitioned between chloroform and 10% LiCl (aq). The aqueous layer was extracted with chloroform and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to a tan solid that was dissolved in anhydrous THF (1 mL), cooled to 0° C. and treated with HCl (4N in 1,4-dioxane, 0.5 mL, 2.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.025 g, 29%) as a tan solid. 1H NMR (DMSO-d6) δ 12.74 (s, 1H), 10.89 (s, 1H), 10.26 (s, 1H), 8.10-8.50 (m, 4H), 7.10-7.70 (m, 7H), 6.95-7.05 (m, 1H), 6.65-6.75 (m, 1H), 6.45-6.53 (m, 1H), 2.19 (s, 3H);

Aufarbeitung

  1. custombefore being partitioned between chloroform and 10% LiCl (aq)
  2. extractionThe aqueous layer was extracted with chloroform
  3. concentrationthe combined organic layers were concentrated in vacuo
  4. customThe resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA)
  5. concentrationconcentrated in vacuo to a tan solid
  6. dissolutionthat was dissolved in anhydrous THF (1 mL)
  7. temperaturecooled to 0° C.

Quellen und Nachweise

ORD-Eintrag
ord-f37557b5d92740deb4a7fd5fd0ebc5f8
Quelldatensatz
uspto-grants-2009_06
Patentnummer
US07547782B2

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