Benzoic Acid → (trans)-Benzyl 4-(benzoyloxy)-3-fluoropiperidine-1-carboxylate

HRID 876486Notes

Reaction equation

HRID 876486 reaction equation
[F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:38]([O:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3][C@H:2]1[F:1])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1

Participants

6

Reactant 4

HCID 243Benzoic AcidHCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 52324487(3R,4S)-Benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

Product 1

HCID 131731019(trans)-Benzyl 4-(benzoyloxy)-3-fluoropiperidine-1-carboxylateYield 89%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 of Example 94, Step 3D; 0.306 g, 1.21 mmol) was treated with triphenylphosphine (0.475 g, 1.81 mmol) and benzoic acid (0.221 g, 1.81 mmol) and the solids were dissolved in THF (5 mL), then cooled to 0° C. The solution was treated dropwise with diisopropyl azodicarboxylate (0.357 mL, 1.81 mmol) dissolved in THF (1 mL). The solution was warmed to ambient temperature with a bath and stirred for 7 days, then concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with saturated NH4Cl, water, 50% saturated NaHCO3, dried over Na2SO4 and concentrated in vacuo to a colorless oil. The oil was chromatographed on SiO2 eluting with 1:12 acetone/hexanes. The desired fraction was isolated to provide the desired product as a colorless oil (385 mg).

Workup

  1. temperatureThe solution was warmed to ambient temperature with a bath
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in CH2Cl2
  4. washwashed with saturated NH4Cl, water, 50% saturated NaHCO3
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo to a colorless oil
  7. customThe oil was chromatographed on SiO2 eluting with 1:12 acetone/hexanes
  8. customThe desired fraction was isolated

Sources & evidence

ORD record
ord-28cf530967e6475e9634e93f8086834c
Source dataset
uspto-grants-2015_03
Patent number
US08987251B2

Reaction notes

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