4-Toluenesulfonyl chloride → tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate

HRID 2369362Notes

Reaction equation

HRID 2369362 reaction equation
[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl-].[Cl-].[Ca+2].[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.[Cl-].[Na+].O>[N:37]([C@@H:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@H:10]1[F:15])=[N+:38]=[N-:39].[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]

Participants

10

Reactant 5

HCID 73974-Toluenesulfonyl chlorideHCID 8471TriethylamineHCID 33557Sodium AzideHCID 5284359Calcium ChlorideHCID 40152152tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate

Product 2

HCID 40152152tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylateHCID 73977892HCID 73977892, compound

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×HCID 57417360Sodium chloride; waterSolvent2×

Procedure

To a solution of 0.60 g (2.74 mmol) of cis-1-Boc-3-fluoro-4-hydroxypiperidine 3 in 15 mL DCM was added 0.42 g (4.11 mmol) of triethylamine and 37 mg (0.3 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) at rt. Then a solution of 0.57 g (3.01 mmol) of p-toluenesulfonyl chloride in 2 mL of DCM was added under a dry atmosphere (CaCl2-tube) at rt. After stirring for 15 h at rt, the solution was poured in brine (20 mL) and extracted with DCM (3×25 mL). After drying over MgSO4, filtration and evaporation of the solvent, the crude mixture was used as such in the next step without further purification. The obtained tosylate was dissolved in 5 mL of dry DMSO and 0.36 g (5.48 mmol) of NaN3 was added. The mixture was stirred under N2-atmosphere at 90° C. for 15 h. After cooling, the mixture was poured in brine (10 mL) and extracted with EtOAc. The combined extract were washed with brine, dried over MgSO4, filtered and evaporated in vacuo. trans-4-Azido-1-Boc-3-fluoropiperidine 4 was obtained as a colorless oil in 92% yield from 4-hydroxypiperidine 3 and was sufficiently pure for further use. 1H NMR (CDCl3): δ 1.43 (9H, s); 1.44-1.64 (1H, m); 1.97 (1H, ddd, J=4.3 Hz, 8.4 Hz, 18.0 Hz); 2.99 (1H, ddd, J=3.3 Hz, 10.5 Hz, 13.8 Hz); 3.00-3.15 (2H, m); 3.57-3.68 (1H, m); 3.79 (1H, dt, J=13.8 Hz, J=4.4 Hz); 4.00-4.19 (1H, m); 4.33 (tdd, J=47.9 Hz, J=8.3 Hz, J=4.4 Hz). 19F NMR (CDCl3): δ −188.1 (1F, d(br), J=47.4 Hz). 13C NMR (CDCl3): δ 28.3 (4×), 41.2 (br), 45.5 (br), 61.4 (d, J=20.7 Hz), 80.6, 88.9 (d, J=182.3 Hz), 154.4. IR (ATR, cm−1): ν=2099, 1693, 1417, 1236, 1161, 1141. MS (ES+) m/z (%): 227 (M+H+, 100).

Workup

  1. extractionextracted with DCM (3×25 mL)
  2. dry with materialAfter drying over MgSO4, filtration and evaporation of the solvent
  3. customwithout further purification
  4. dissolutionThe obtained tosylate was dissolved in 5 mL of dry DMSO
  5. stirringThe mixture was stirred under N2-atmosphere at 90° C. for 15 h
  6. temperatureAfter cooling
  7. extractionextracted with EtOAc
  8. extractionThe combined extract
  9. washwere washed with brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. customevaporated in vacuo

Sources & evidence

ORD record
ord-35db4b087b554f0289b87fcfa80e6aea
Source dataset
uspto-grants-2014_04
Patent number
US08703958B2

Reaction notes

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