Azetidine hydrochloride → HCID 71152506, compound

HRID 1497304Notes

Reaction equation

HRID 1497304 reaction equation
[F:1][CH:2]([F:16])[C@@H:3]1[C@@H:13]([OH:14])[C@@H:12]([F:15])[C@H:6]2[N:7]=[C:8](SC)[O:9][C@H:5]2[CH2:4]1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1>CCO>[NH3:7].[CH3:8][OH:9].[N:18]1([C:8]2[O:9][C@H:5]3[CH2:4][C@H:3]([CH:2]([F:16])[F:1])[C@@H:13]([OH:14])[C@@H:12]([F:15])[C@H:6]3[N:7]=2)[CH2:21][CH2:20][CH2:19]1

Participants

5

Reactant 2

HCID 12308726Azetidine hydrochlorideHCID 71152212HCID 71152212, compound

Product 2

HCID 21705897Ammonia methanolYield 10%HCID 71152506HCID 71152506, compoundYield 154.7%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of (3 aS,4S,5R,6S,7aS)-6-(difluoromethyl)-4-fluoro-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (46.5 mg, 0.182 mmol) in EtOH (3 mL) was added azetidine hydrochloride (51.2 mg, 0.547 mmol). The mixture was heated at reflux for 9 h. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 65% EtOAc in hexane and then 10% 1.8 M NH3 MeOH solution in DCM to give (3aS,4S,5R,6S,7aS)-2-(azetidin-1-yl)-6-(difluoromethyl)-4-fluoro-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (37.2 mg, 77%). MS m/z 265.1 (M+1, 100%); 1H NMR (500 MHz, MeOD) δ 6.16 (td, J=56.7 Hz, 1.8 Hz, 1H), 4.63-4.59 (m, 1H), 4.60 (dm, J=52.5 Hz, 1H), 4.03 (t, J=7.6 Hz, 4H), 3.88 (ddd, J=26.3 Hz, 7.1 Hz, 3.8 Hz, 1H), 3.61 (dd, J=29.4 Hz, 10.2 Hz, 1H), 2.45-2.30 (m, 4H), 1.94 (ddd, J=15.8 Hz, 10.8 Hz, 5.2 Hz, 1H); 13C NMR (100 MHz, MeOD) δ 165.68, 118.32 (t, J=238.5 Hz), 92.92 (d, J=179.3 Hz), 79.59, 68.84 (dd, J=18.8 Hz, 8.7 Hz), 64.22 (d, J=17.3 Hz), 51.87, 37.90 (td, J=19.7 Hz, 6.7 Hz), 22.41 (t, J=4.5 Hz), 17.77.

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 9 h
  3. customSolvent was evaporated
  4. customthe residue was purified by silica gel column chromatography
  5. washeluted with 65% EtOAc in hexane

Sources & evidence

ORD record
ord-b2e6f308ae33451f952ff87a3588c3fd
Source dataset
uspto-grants-2015_12
Patent number
US09199949B2

Reaction notes

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