Tributylphosphine → 1-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluorothiophen-2-yl)methoxy)pyridin-2(1H)-one

HRID 2202976Notes

Reaction equation

HRID 2202976 reaction equation
[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl-].[Cl-].[Ca+2]>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:26]5[S:27][C:23]([F:22])=[CH:24][CH:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 5

HCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 5284359Calcium ChlorideHCID 50896580(5-Fluorothiophen-2-yl)methanolHCID 896910841-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one

Product 1

HCID 896911571-(2-Cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluorothiophen-2-yl)methoxy)pyridin-2(1H)-oneYield 23.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg), (5-fluorothiophen-2-yl)methanol (376 mg), tributylphosphine (1.07 ml), 1,1′-(azodicarbonyl)dipiperidine (1.08 g) and THF (40 ml) was stirred at 60° C. under a dry atmosphere (CaCl2 tube) for 3 h. After solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (130 mg) as an off-white solid.

Workup

  1. customAfter solvent was evaporated
  2. customthe residue was purified by silica gel column chromatography (hexane/EtOAc
  3. extractionextracted with EtOAc
  4. customThe organic layer was separated
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-96f660aefe834a578c273a78b088803b
Source dataset
uspto-grants-2016_06
Patent number
US09365540B2

Reaction notes

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