Hydrochloric Acid → [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-benzyloxy-3-formyl-benzoate

HRID 1529539Notes

Reaction equation

HRID 1529539 reaction equation
[CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[OH:33].Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:33][C@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:31][C:30]1[C:29]([Cl:49])=[CH:28][N+:27]([O-:50])=[CH:26][C:25]=1[Cl:24])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71092687HCID 71092687, compoundHCID 86720697Methyl 2-(benzyloxy)-3-formylbenzoate

Product 1

HCID 86720698[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-benzyloxy-3-formyl-benzoateYield 90.2%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of methyl 2-(benzyloxy)-3-formylbenzoate (598 mg, 2.21 mmol) in THF (4 mL) and MeOH (2 mL) and a solution of 4 N NaOH (1.10 mL, 4.43 mmol) was added at 0° C. and the reaction mixture stirred for 30 minutes. 2N HCl was then added at 0° C. to adjust the pH to ˜2. After concentration in vacuo, the residue was azeotroped with toluene to dryness. The crude solid was dissolved in DMF (4.4 mL). To half of this solution (2.2 mL, 1.1 mmol) was added (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (553 mg, 1.32 mmol), 4-(dimethylamino)-pyridine (67 mg, 0.55 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (422 mg, 2.2 mmol and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (100 mL), the organic phase washed with sat. NaHCO3 (2×50 mL). The phases were separated over a hydrophobic frit and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% EtOAc in isohexane to give the title compound as a white solid (784 mg, 54% over two steps).

Workup

  1. concentrationAfter concentration in vacuo
  2. customthe residue was azeotroped with toluene to dryness
  3. dissolutionThe crude solid was dissolved in DMF (4.4 mL)
  4. stirringthe resulting mixture was stirred at room temperature for 4 hours
  5. washthe organic phase washed with sat. NaHCO3 (2×50 mL)
  6. customThe phases were separated over a hydrophobic frit
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified via silica gel chromatography
  9. washeluting with 0-100% EtOAc in isohexane

Sources & evidence

ORD record
ord-79271b01a91a47ad82faa47c474751f2
Source dataset
uspto-grants-2015_07
Patent number
US09090606B2

Reaction notes

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