Chloromethyl ethyl ether → Methyl(1R,4S)-4-[(tert-Butoxycarbonyl)amino]-1-(ethoxymethyl)cyclopent-2-ene-1-carboxylate

Temperature

-78 °C

To a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (36.7 mL) was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (4.00 g, 1.66 mmol) in tetrahydrofuran (6.0 mL) at −78° C. The resulting light brown solution was stirred at −78° C. for 30 min before (chloromethoxy)ethane (1.88 g, 19.9 mol) was added in one portion. The mixture was stirred at −78° C. for 1 h and then kept in a freezer reading at −25° C. overnight. The reaction was then quenched with saturated NH4Cl (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (0 to 15% EtOAC in hexanes) to provide the desired product (3.29 g, 66%) as a cis/trans (3:2) mixture based on the analysis on reverse phase HPLC. MS calculated for C15H26NO5: (M+H) 300.2; found 200.2 (M+H-Boc).

1. additionwas added in one portion
2. waitkept in a freezer reading at −25° C. overnight
3. customThe reaction was then quenched with saturated NH4Cl (50 mL)
4. customThe organic layer was separated
5. extractionthe aqueous layer was extracted with CH2Cl2 three times
6. washThe combined organic layers were washed with brine
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated
10. custompurified by flash chromatography (0 to 15% EtOAC in hexanes)

ORD record

ord-fe3cf1098a0647b287d197cad4029bd0

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08563582B2