Citric Acid → HCID 11521293, compound

N-Boc-2-(3-hydroxy)benzylmorpholine, trifluoromethylsulfonate ester intermediate (a) (62 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL) and NMP (0.3 mL) under an atmosphere of nitrogen, at room temperature then iron (III) ac ethyl acetateetate (3 mg, 7.3 umol) was added in one portion to give an orange solution. To the reaction mixture was added ethylmagnesium chloride (2.0M solution in tetrahydrofuran, 0.11 mL, 0.22 mmol) dropwise over 2 minutes and the reaction stirred at room temperature for 30 minutes. Then more iron (III) ac ethyl acetateetate (6 mg, 14.6 umol) was added in one portion followed by ethylmagnesium chloride (2.0M solution in tetrahydrofuran, 0.24 mL, 0.48 mmol) dropwise over 3 minutes. After 30 minutes citric acid (10% w/w aqueous solution, 10 mL) and ethyl acetate (10 mL) was added and the mixture stirred vigorously for 5 minutes and left to stand for 18 hrs. The layers were separated and the aqueous layer extracted with ethyl acetate (10 mL). Combined organic layers were washed with water (10 mL), then brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (2.5 mL) and treated with TFA (1 mL) and stirred at room temperature for 3 hrs. The reaction was then poured through an SCX-2 column and washed with dichloromethane. The column was then washed with ammonia (2N, methanol) and the ammonia washes concentrated in vacuo. The residue was purified by preparative HPLC to yield the desired morpholine example 69 as an off-white solid (6 mg).

1. customto give an orange solution
2. stirringthe mixture stirred vigorously for 5 minutes
3. waitleft
4. waitto stand for 18 hrs
5. customThe layers were separated
6. extractionthe aqueous layer extracted with ethyl acetate (10 mL)
7. washCombined organic layers were washed with water (10 mL)
8. dry with materialbrine (10 mL), dried (MgSO4)
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. dissolutionThe residue was dissolved in dichloromethane (2.5 mL)
12. additiontreated with TFA (1 mL)
13. stirringstirred at room temperature for 3 hrs
14. additionThe reaction was then poured through an SCX-2 column
15. washwashed with dichloromethane
16. washThe column was then washed with ammonia (2N, methanol)
17. concentrationthe ammonia washes concentrated in vacuo
18. customThe residue was purified by preparative HPLC

ORD record

ord-010e99d044554f35a50eadb5d0ac3cf0

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07323466B2