Tributylphosphine → 9-Chloro-6-[1-(2,2-difluoroethoxy)propyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

HRID 1628827Notes

Reaction equation

HRID 1628827 reaction equation
[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][CH:60]([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 13831Tributylphosphine2×HCID 730421,1'-(Azodicarbonyl)dipiperidine2×HCID 1361872,2-Difluoroethan-1-ol2×HCID 57786288HCID 57786288, compound

Product 1

HCID 577863639-Chloro-6-[1-(2,2-difluoroethoxy)propyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (111.0 mg, 0.287 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 10 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. To the mixture was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 30 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 1.5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (50.0 mg, 0.111 mmol, 39).

Workup

  1. waitAfter 30 min
  2. stirringThe reaction mixture was stirred at 60° C. for 1.5 hrs
  3. concentrationThe mixture was concentrated
  4. additionTo the residue was added diethyl ether
  5. customthe precipitate was removed by filtration
  6. customThe residue was purified by silica gel column chromatography
  7. washeluting with a 0-40% ethyl acetate/n-hexane gradient mixture
  8. customto give the mixture

Sources & evidence

ORD record
ord-dca564dc31e74084bc46acf8a9cac649
Source dataset
uspto-grants-2014_07
Patent number
US08785460B2

Reaction notes

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