Benzyl chloroformate → 4-Cbz-Morpholine-3-carboxylic acid

Temperature

5 °C

Morpholine-3-carboxylic acid (10 g, 76 mmol) was dissolved in water (50 ml) and cooled to 5° C. A solution of 50% sodium hydroxide (6.10 g, 76 mmol) was added and the reaction mixture was cooled back to 5° C. An additional portion of 50% sodium hydroxide (7.93 g, 99 mmol) was then diluted to 22 mL with water and added to an addition funnel. Benzyl chloroformate (65.3 ml, 458 mmol) was added to a separate addition funnel and the two reagents were simultaneously added dropwise over about 30 minutes while maintaining the reaction temperature below 10° C. The pH of the mixture was about 6 when the addition was completed. Additional 50% NaOH (1.13 g, 14.3 mmol) was added to adjust pH to 9. The reaction was stirred at 10-15° C. for 2 hours. The reaction mixture was extracted with hexanes (2×30 ml) to remove excess benzyl chloroformate. EtOAc (50 ml) was added into the aqueous phase. The mixture was acidified to pH of about 0 with concentrated HCl (10 g). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×100 ml). The combined organic solution was concentrated to afford an oil. The product was further dried under high vacuum overnight to afford 21.2 g of crude 4-(benzyloxycarbonyl)morpholine-3-carboxylic acid which was used in the next step without further purification. [M−H] calculated for C13H15NO5, 264. found, 264

1. temperaturethe reaction mixture was cooled back to 5° C
2. additionadded to an addition funnel
3. additionthe two reagents were simultaneously added dropwise over about 30 minutes
4. temperaturewhile maintaining the reaction temperature below 10° C
5. additionthe addition
6. extractionThe reaction mixture was extracted with hexanes (2×30 ml)
7. customto remove excess benzyl chloroformate
8. additionEtOAc (50 ml) was added into the aqueous phase
9. customThe organic phase was separated
10. extractionthe aqueous phase was extracted with EtOAc (3×100 ml)
11. concentrationThe combined organic solution was concentrated
12. customto afford an oil
13. customThe product was further dried under high vacuum overnight

ORD record

ord-8beaf7db167c40a696294231edfc3219

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08268819B2