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Triethylamine → N-(4-(4-(1-benzyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

HRID 2246478
Notes
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Reaction equation

HRID 2246478 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16](=[O:36])[N:17]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:19][CH:20]=3)=[CH:11][C:10]=2[F:37])[CH:5]=[CH:4][N:3]=1.[CH3:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41]C.ClC(OC1C=CC=CC=1)=[O:47].N1CCCC1>C1COCC1>[CH2:29]([N:17]1[C:16](=[O:36])[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41]([N:40]4[CH2:43][CH2:44][CH2:38][CH2:39]4)=[O:47])[CH:7]=3)=[C:10]([F:37])[CH:11]=2)=[CH:20][N:19]=[C:18]1[NH:21][C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 31268PyrrolidineHCID 592183715-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one

Product 1

HCID 59218374N-(4-(4-(1-benzyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide
Yield 11.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

5-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-benzyl-2-(4-fluorophenylamino)pyrimidin-4(3H)-one (238 mg, 0.478 mmol) was dissolved in THF (4.0 ml) and Et3N (0.17 ml, 1220 μmol) and phenyl chloroformate (0.13 ml, 1.0 mmol) were added. The reaction was stirred under nitrogen, and after 40 minutes, pyrrolidine (0.60 ml, 7.2 mmol) was added. Stirring was continued at room temperature, until LCMS analysis indicated the formation of the product. The reaction was quenched with saturated ammonium chloride (10 ml) and extracted with DCM (3×20 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (30:1->20:1 DCM/MeOH). The fractions with product were collected, concentrated, and washed with Et2O and then with acetone. The suspension was filtered, and the solid was collected and dried in vacuo to afford the desired title compound N-(4-(4-(1-benzyl-2-(4-fluorophenylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (33.2 mg, 0.0558 mmol, 4% over 3 steps). MS (ESI pos. ion) m/z: 595 (MH+). Calc'd exact mass for C33H25F2N6O3: 594. 1HNMR (400 MHz, CDCl3): 8.06 (d, J=6.4 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J=1.2 Hz, 1H), 7.68 (dd, J=10.4 Hz, 2.0 Hz, 1H), 7.51-7.39 (m, 6H), 7.22 (t, J=8.0 Hz, 1H), 7.15 (dd, J=9.2 Hz, 5.2 Hz, 2H), 7.06-6.99 (m, 3H), 6.57 (dd, J=5.2 Hz, 3.2 Hz, 1H), 6.44 (s, 1H), 5.49 (s, 2H), 3.49-3.43 (m, 4H), 1.99-1.94 (m, 4H).

Workup

  1. stirringStirring
  2. customwas continued at room temperature, until LCMS analysis
  3. customThe reaction was quenched with saturated ammonium chloride (10 ml)
  4. extractionextracted with DCM (3×20 ml)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified on a silica gel column (30:1->20:1 DCM/MeOH)
  9. customThe fractions with product were collected
  10. concentrationconcentrated
  11. washwashed with Et2O
  12. filtrationThe suspension was filtered
  13. customthe solid was collected
  14. customdried in vacuo

Sources & evidence

ORD record
ord-a5d4e9e49ce24f5f9ca41722f5291a00
Source dataset
uspto-grants-2010_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07687522B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes