Reaction #1726686

Reaction equation

2A

4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenol

Cs2CO3

tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate

→

3A

Yield 74.0%

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

Yield 74.0%

Solvents

DMF

Conditions

Workup

1. 1
   workup.STIRRINGThe reaction mixture was thereafter stirred at 90° C. for 24 h
2. 2
   FiltrationThe mixture was filtered
3. 3
   Otherthe solvent was evaporated
4. 4
   workup.DISSOLUTIONThe residue was dissolved in DMSO (6 mL)
5. 5
   Otherpurified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer)
6. 6
   Concentrationconcentrated
7. 7
   workup.ADDITIONDichloromethane was added
8. 8
   Otherthe solution was dried (phase separator)
9. 9
   Concentrationconcentrated

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]−.

Source