Tetrahydrofuran → tert-Butyl (3R)-3-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate

HRID 496661Notes

Reaction equation

HRID 496661 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19](CC)CC.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH:25]([CH3:27])[CH3:26].[N-]=[N+]=[N-].[Na+].[CH2:36]1[CH2:40]OC[CH2:37]1>O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:19][C:29]([O:28][CH2:24][C:25]2[CH:27]=[CH:40][CH:36]=[CH:37][CH:26]=2)=[O:30])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 5

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 33557Sodium AzideHCID 62365Isobutyl chloroformateHCID 27356471-((Tert-butoxy)carbonyl)piperidine-3-carboxylic acid

Product 1

HCID 51656152tert-Butyl (3R)-3-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of piperidine-1,3-dicarboxyli acid 1-tert butyl ester (1.23 g, 5.37 mmol) in THF (40 ml) at 0° C. was added Et3N (1.90 ml, 13.4 mmol), isobutylchloroformate (1.40 ml, 10.74 mmol). After 1 hr of stirring, sodium azide (6.28 g, 96.7 mmol) in water (21 ml) was added and the reaction mixture stirred for 30 min. EtOAc (80 ml) was added. The organic layer was separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The IR (film) of the crude acyl azide had an absorption at 2137(N3), 1693(C═O) cm−1. The crude residue was dissolved in dry benzene (100 ml) and heated at 60° C. for 70 min. After removal of benzene, the IR of the crude isocyanate (film) 2994, 2865, 2263, 1698, 1422, 1377, 1241, 1169 cm−1; The crude mixture was dissolved in toluene (10 ml), BnOH (0.7 ml) was added. The mixture was heated at 110° C. for 48 hr (monitored by IR until the absorption at 2263 cm−1 completely disappeared). After removal of the solvent, the residue was purified by silica gel chromatography (20% EtOAc in hexane) to give a colorless oil (1.02 g, 57% for three steps). 1H-NMR (300 MHz, CDCl3) δ 7.20 (m, 5H), 5.15 (s, 2H), 4.90 (broad s, 1H), 3.75 (broad s, 1H), 3.60 (m, 1H), 3.40-3.20 (m, 3H), 2.85 (m, 1H), 1.78-1.50 (m, 2), 1.45 (s, 9H) ppm; IR (film) 3321, 2979, 2858, 1692 (with two shoulders), 1540, 1431, 1234, 1154 cm−1; LRMS (calculated for C18H25N2O4) 334. found (M-BOC)+ 234, (M-BOC+1)+ 235.

Workup

  1. stirringthe reaction mixture stirred for 30 min
  2. customThe organic layer was separated
  3. washwashed with water
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customan absorption at 2137(N3), 1693(C═O) cm−1
  8. dissolutionThe crude residue was dissolved in dry benzene (100 ml)
  9. customAfter removal of benzene
  10. dissolutionThe crude mixture was dissolved in toluene (10 ml)
  11. additionBnOH (0.7 ml) was added
  12. temperatureThe mixture was heated at 110° C. for 48 hr (
  13. custommonitored by IR until the absorption at 2263 cm−1
  14. customAfter removal of the solvent
  15. customthe residue was purified by silica gel chromatography (20% EtOAc in hexane)
  16. customto give a colorless oil (1.02 g, 57% for three steps)

Sources & evidence

ORD record
ord-0cb920bb95c74dba8fb2113d79a490d8
Source dataset
uspto-grants-2005_09
Patent number
US06946477B2

Reaction notes

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