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

HRID 1986077Notes

Reaction equation

HRID 1986077 reaction equation
[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

Participants

6

Reactant 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

Product 1

HCID 1317274832-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide, dihydrochloride saltYield 55.9%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

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);

Workup

  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.

Sources & evidence

ORD record
ord-f37557b5d92740deb4a7fd5fd0ebc5f8
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

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