Ethyl orthoformate → benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate

HRID 1850751Notes

Reaction equation

HRID 1850751 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH3:30])[C:5]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)=[N:6][CH:7]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[CH:35](OCC)(OCC)OCC>C(O)(=O)C>[CH3:30][C:4]1[C:5]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:16][CH2:15]2)=[N:6][CH:7]=[C:2]([N:1]2[CH:35]=[N:33][N:32]=[N:31]2)[CH:3]=1

Participants

5

Reactant 3

HCID 31214Ethyl orthoformateHCID 33557Sodium AzideHCID 70856037benzyl 4-((1R,2S)-2-{2-[(5-amino-3-methylpyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate

Product 1

HCID 66563379benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of benzyl 4-((1R,2S)-2-{-[(5-amino-3-methylpyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (1.20 g, 2.93 mmol) in acetic acid (50 mL) was added sodium azide (762 mg, 11.72 mmol) followed by triethyl orthoformate (1.95 mL, 11.72 mmol) and the resulting solution was heated to 60° C. and stirred for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between NaHCO3 and ethyl acetate. The aqueous was again extracted with ethyl acetate (100 mL). The organics were combined, washed by brine, dried on sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (40 M+ silica gel) using a gradient eluant of 0-100% ethyl acetate in hexane (800 ml) to afford the title compound. LC/MS (m/z): 463 (M+H)+.

Workup

  1. customThe volatiles were removed in vacuo
  2. customthe residue was partitioned between NaHCO3 and ethyl acetate
  3. extractionThe aqueous was again extracted with ethyl acetate (100 mL)
  4. washwashed by brine
  5. customdried on sodium sulfate
  6. filtrationfiltered
  7. concentrationthe filtrate concentrated under reduced pressure
  8. customThe residue was purified on Biotage column (40 M+ silica gel)

Sources & evidence

ORD record
ord-5f2c0ec0d9a94b4e8071035787d3341a
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

Loading…