Tributylphosphine → 9-Chloro-6-[cyclopropyl(2,2-difluoroethoxy)methyl]-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

HRID 1399324Notes

Reaction equation

HRID 1399324 reaction equation
[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[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[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:61][CH:60]([F:63])[F:59])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 1361872,2-Difluoroethan-1-olHCID 57786088[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol

Product 1

HCID 577862759-Chloro-6-[cyclopropyl(2,2-difluoroethoxy)methyl]-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoleYield 48.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (183 mg, 0.433 mmol), 1,1′-(azodicarbonyl)dipiperidine (219 mg, 0.868 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.217 mL, 0.869 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2-difluoroethanol (0.272 mL, 4.30 mmol) was added to the reaction mixture. The mixture was stirred at 50° C. for 14 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (102 mg, 0.21 mmol, 48%) as colorless crystals.

Workup

  1. stirringThe mixture was stirred at 50° C. for 14 hr under nitrogen atmosphere
  2. concentrationThe mixture was concentrated in vacuo and diethyl ether
  3. additionwas added to the residue
  4. customThe solid was removed by filtration
  5. concentrationthe filtrate was concentrated in vacuo
  6. customThe residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane

Sources & evidence

ORD record
ord-e606d22df3264bf5903fc428fe2497b6
Source dataset
uspto-grants-2014_12
Patent number
US08901141B2

Reaction notes

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