Reaction #324428

Reaction equation

Na2CO3

title compound

(4-bromo-2-fluoro-benzylidene)-tert-butyl-amine

3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester

NaH

→

title compound

Yield 82.0%

3-(5-bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

Yield 82.0%

Solvents

H2O

AcOH

H2O

THF

DMF

Conditions

Workup

1. 1
   OtherTo a 0° C
2. 2
   Extractionthe reaction mixture was extracted with EtOAc (2×)
3. 3
   WashThe combined organic layers were washed with brine
4. 4
   Concentrationconcentrated
5. 5
   Otherto give a yellow liquid that
6. 6
   workup.WAITAfter 5 h
7. 7
   Extractionextracted with EtOAc (2×)
8. 8
   WashThe combined organic layers were washed with brine
9. 9
   Otherdried
10. 10
    OtherThe resulting solid was then triturated with 20% EtOAc in hexanes

Procedure

To a 0° C. DMF (720 mL) solution of the title compound of Step A (37.2 g, 144 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (25.0 g, 144 mmol) was added NaH (60 wt % in mineral oil, 7.50 g, 188 mmol) portionwise over 2 h. The reaction was then allowed to warm to rt. After 18 h, H2O was added and the reaction mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine and concentrated to give a yellow liquid that was treated with THF (360 mL), H2O (360 mL) and AcOH (25 mL). After 5 h, this solution was made basic with 5% Na2CO3 (aq.) and extracted with EtOAc (2×). The combined organic layers were washed with brine and dried. The resulting solid was then triturated with 20% EtOAc in hexanes to give 41.9 g (82%) of the title compound as a white solid. 1H NMR (CDCl3): 10.43 (s, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.26-7.23 (m, 1H), 6.77 (d, J=1.6 Hz, 1H), 5.01-4.95 (m, 1H), 4.39 (ddd, J=9.9, 6.3, 0.8 Hz, 2H), 4.08 (dd, J=6.4, 0.8 Hz, 2H), 1.46 (s, 9H).

Source