Ethyl orthoformate → tert-butyl 4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate

HRID 1468869Notes

Reaction equation

HRID 1468869 reaction equation
[NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].[CH:28](OCC)(OCC)OCC.[N-:38]=[N+:39]=[N-:40].[Na+]>C(O)(=O)C>[F:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[N:1]1[CH:28]=[N:40][N:39]=[N:38]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]1

Participants

5

Reactant 3

HCID 31214Ethyl orthoformateHCID 33557Sodium AzideHCID 86717803tert-butyl 4-((1R,2R)-2-((4-amino-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate

Product 1

HCID 71140737tert-butyl 4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidine-1-carboxylateYield 91%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
100 °C

Procedure

A solution of tert-butyl 4-((1R,2R)-2-((4-amino-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step B product, 400 mg, 1.06 mmol), triethyl orthoformate (880 uL, 5.28 mmol), and sodium azide (344 mg, 5.28 mmol) in acetic acid (4.3 mL) that had been placed under an inert atmosphere was heat in a sealed vial at 100° C. for 3 hrs. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting crude was partitioned between EtOAc (20 mL) and water (20 mL) and the layers were cut. The aqueous phase was extracted with EtOAc (20 mL×2) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica column (KP-Sil 25 g SNAP column, Biotage system) eluting with a range of 20-60% EtOAc/Hex over 12 CV to give the desired compound (415 mg, 91%). LC/MS (m/z): 432 (M+H)+.

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. concentrationconcentrated under reduced pressure
  3. customThe resulting crude was partitioned between EtOAc (20 mL) and water (20 mL)
  4. extractionThe aqueous phase was extracted with EtOAc (20 mL×2)
  5. dry with materialthe combined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. washeluting with a range of 20-60% EtOAc/Hex over 12 CV

Sources & evidence

ORD record
ord-f604f390faa447d3b1d2e443ac66082a
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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