Cesium carbonate → tert-Butyl 3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidine-1-carboxylate

HRID 1639504Notes

Reaction equation

HRID 1639504 reaction equation
[CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:27]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)(=O)=O>CN(C=O)C>[CH2:3]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:27]4[CH2:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30]4)=[CH:11][CH:10]=3)[CH2:5]2)[CH2:1][O:2]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 10753243Tert-butyl 3-(methanesulfonyloxy)azetidine-1-carboxylateHCID 595635064-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenol

Product 1

HCID 59563505tert-Butyl 3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidine-1-carboxylateYield 74%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2A (0.77 g, 3.75 mmol) was dissolved in dry DMF (20 mL) and Cs2CO3 (2.44 g, 7.50 mmol) was added. The reaction mixture was stirred at room temperature for 10 min and then tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (1.88 g, 7.50 mmol) was added. The reaction mixture was thereafter stirred at 90° C. for 24 h. The mixture was filtered and the solvent was evaporated. The residue was dissolved in DMSO (6 mL) and purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer). The pure fractions were combined and concentrated. Dichloromethane was added and the solution was dried (phase separator) and concentrated. There was obtained 1.00 g (74%) of 3A as an oil which solidified on standing at room temperature. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 3.34 (s, 4H), 3.46 (s, 2H), 3.99 (dd, 2H), 4.28 (dd, 2H), 4.73 (s, 4H), 4.84 (m, 1H), 6.68 (d, 2H), 7.15 (d, 2H), MS (APCI+) m/z 361 [M+H]−.

Workup

  1. stirringThe reaction mixture was thereafter stirred at 90° C. for 24 h
  2. filtrationThe mixture was filtered
  3. customthe solvent was evaporated
  4. dissolutionThe residue was dissolved in DMSO (6 mL)
  5. custompurified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer)
  6. concentrationconcentrated
  7. additionDichloromethane was added
  8. customthe solution was dried (phase separator)
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-412eaa45161b45bda34f17e4ef94cd1c
Source dataset
uspto-grants-2012_02
Patent number
US08110566B2

Reaction notes

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