Triethylamine → t-Butyl 4-(4-{2-fluoro-4-[3-(4-fluorophenyl)acetylthioureido]phenoxy}pyridin-2-ylcarbamoyl)piperidine-1-carboxylate

HRID 492681Notes

Reaction equation

HRID 492681 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:29])[CH:5]=[CH:4][N:3]=1.[C:30]([N:37]1[CH2:45][CH2:44][CH:40]([C:41](O)=[O:42])[CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.CCCCCC.O1CCCC1>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[S:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41]([CH:40]2[CH2:44][CH2:45][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:38][CH2:39]2)=[O:42])[CH:7]=1

Participants

9

Reactant 4

HCID 8471Triethylamine2×HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate2×HCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acid2×HCID 231530171-[4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl]-3-[(4-fluorophenyl)acetyl]thiourea

Product 1

HCID 23153119t-Butyl 4-(4-{2-fluoro-4-[3-(4-fluorophenyl)acetylthioureido]phenoxy}pyridin-2-ylcarbamoyl)piperidine-1-carboxylateYield 429.3%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent3×

Procedure

To a solution of 1-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]-3-[(4-fluorophenyl) acetyl]thiourea (84.6 mg, 0.204 mmol) in N,N-dimethylformamide (2.0 ml) were added Boc-isonipecotic acid (93.5 mg, 0.408 mmol), triethylamine (0.0853 ml, 0.612 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (180 mg, 0.408 mmol), followed by stirring at room temperature for 88 hrs. Boc-isonipecotic acid (93.5 mg, 0.408 mmol), triethylamine (0.0853 ml, 0.612 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (180 mg, 0.408 mmol) were further added thereto, followed by stirring at room temperature for 32.5 hrs. To the reaction mixture were added ethyl acetate (50 ml), tetrahydrofuran (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) to partition. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide (30 ml) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then subjected to silica gel column chromatography (Fuji Silysia BW-300; hexane:ethyl acetate=1:1, then ethyl acetate) to provide a crude product of the titled compound (548 mg) as a yellow oil.

Workup

  1. stirringby stirring at room temperature for 32.5 hrs
  2. customa saturated aqueous solution of sodium hydrogencarbonate (50 ml) to partition
  3. washThe organic layer was washed with a 1 N aqueous solution of sodium hydroxide (30 ml) and brine in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue, which

Sources & evidence

ORD record
ord-c7ed1df10b784423b7881cd977bc4086
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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