Hydrochloric Acid → 2-(Aminomethyl)-4-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)pyrimidine-5-carboxamide, trihydrochloride salt

HRID 1986109Notes

Reaction equation

HRID 1986109 reaction equation
[ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:35]#[N:36])[N:19]=3)=[CH:13][C:12]=2[F:37])[CH:7]=[CH:6][N:5]=1.Cl>CO.C1COCC1.CCOCC.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[ClH:1].[NH2:36][CH2:35][C:20]1[N:19]=[C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=3)=[C:12]([F:37])[CH:13]=2)[C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[O:25])=[CH:22][N:21]=1

Participants

7

Reactant 2

HCID 313Hydrochloric Acid2×HCID 1317274934-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-2-cyano-n-(2,4-difluorophenyl)pyrimidine-5-carboxamide, dihydrochloride salt

Product 1

HCID 1317274942-(Aminomethyl)-4-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-n-(2,4-difluorophenyl)pyrimidine-5-carboxamide, trihydrochloride saltYield 110.4%

Reagents, catalysts & solvents 4

HCID 9942167Palladium hydroxideCatalystHCID 887MethanolSolventHCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-2-cyano-N-(2,4-difluorophenyl)pyrimidine-5-carboxamide, dihydrochloride salt (48 mg, 0.092 mmol) in methanol (1 mL) was added 1 N HCl in ether (30 μL, 0.03 mmol), and 20% palladium hydroxide on carbon (48 mg). The suspension was purged with hydrogen and was stirred 2 h. Additional palladium hydroxide (38 mg) and methanol (1 mL) was added and the mixture was stirred an additional 4 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and treated with Amberlyst A-21 ion exchange resin, filtered and concentrated in vacuo to give the freebase. The residue was dissolved in anhydrous THF (2 mL), and acidified with 1N HCl in ether. The reaction mixture was stirred for 10 min, the solvent was removed in vacuo and the solid was triturated in ether to afford the amine (20 mg, 39%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.99 (s, 1H), 10.78 (s, 1H), 9.16 (s, 1H), 8.48 (br s, 2H), 8.17 (dd, 1H, J=12.9, 2.4 Hz), 7.99 (d, 1H, J=7.2 Hz), 7.87 (br s, 2H), 7.62 (m, 2H), 7.43 (m, 2H), 7.20 (m, 1H), 6.70 (dd, 1H, J=7.2, 2.4 Hz), 6.21 (d, 1H, J=2.3 Hz), 4.21 (m, 2H); MS(ESI+) m/z 482 (M+H)+.

Workup

  1. customThe suspension was purged with hydrogen
  2. additionAdditional palladium hydroxide (38 mg) and methanol (1 mL) was added
  3. stirringthe mixture was stirred an additional 4 h
  4. filtrationThe mixture was filtered through Celite®
  5. concentrationthe filtrate concentrated in vacuo
  6. customThe resultant residue was purified by preparative (RP) HPLC (gradient from 34% to 90% aqueous methanol with 0.1% TFA)
  7. additiontreated with Amberlyst A-21 ion exchange resin
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give the freebase
  11. stirringThe reaction mixture was stirred for 10 min
  12. customthe solvent was removed in vacuo
  13. customthe solid was triturated in ether

Sources & evidence

ORD record
ord-b920a1899f1d45c698e9224481fbc673
Source dataset
uspto-grants-2009_06
Patent number
US07547782B2

Reaction notes

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