Hexamethylphosphoramide → HCID 86706129, compound

Temperature

-78 °C

Into an oven dried, argon purged flask tetrahydrofuran (50 mL) was added and the solution was cooled with an ice bath. A 1.8 M solution of lithium diisopropylamide (7.2 mL, 13 mmol) in tetrahydrofuran/heptane/ethylbenzene was added. The resulting solution was cooled to −78° C., and treated dropwise with methyl tetrahydro-2H-pyran-4-carboxylate (Sigma-Aldrich) (1.20 mL. 1.30 g, 9 mmol) followed by hexamethylphosphoramide (1.56 mL, 1.61 g, 9 mmol). The resulting solution was warmed to 0° C., stirred for 20 min., cooled to −78° C., and treated dropwise with pre-cooled (0° C.) solution of 1,2-dichloro-ethyne (ca. 10 mmol). The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature. After 4 hours at room temperature, the reaction mixture was poured into crushed ice and extracted with diethyl ether (200 mL) (5 mL of brine was added to support the separation). The organic phase was separated and washed with water (200 mL). This water phase was extracted with diethyl ether (100 mL). The combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered through a 2 cm layer of silica gel (silica gel layer was washed with 50 mL of ethyl acetate), and then concentrated under reduced pressure. The crude product was subjected to silica gel chromatography (gradient from 0-15% ethyl acetate in iso-hexanes) to afford the title compound (1.22 g, 67%) as a colorless oil. Rf=0.48, 30% ethyl acetate in iso-hexanes, phosphomolybdic acid in ethanol. LCMS (m/z) 203.2/205.3 [M+H]′ Tr=3.12 min (Gemini 5u C18 110 Å, 50×4.60 mm 5 micron column, 3.5 min, 2 ml/min, 5-100% acetonitrile/water, 0.1% acetic acid modifier gradient). 1H NMR (400 MHz, CDCl3): δ 3.79-3.65 (m, 4H), 3.72 (s, 3H), 1.97 (m, 2H), 1.78 (m, 2H).

1. customInto an oven dried
2. additionargon purged flask tetrahydrofuran (50 mL) was added
3. temperaturethe solution was cooled with an ice bath
4. temperatureThe resulting solution was warmed to 0° C.
5. temperaturecooled to −78° C.
6. additiontreated dropwise
7. stirringThe reaction mixture was stirred at −78° C. for 30 min
8. temperatureto warm to room temperature
9. waitAfter 4 hours at room temperature
10. additionthe reaction mixture was poured
11. custominto crushed ice
12. extractionextracted with diethyl ether (200 mL) (5 mL of brine
13. additionwas added
14. customthe separation)
15. customThe organic phase was separated
16. washwashed with water (200 mL)
17. extractionThis water phase was extracted with diethyl ether (100 mL)
18. washThe combined organic fractions were washed with brine (100 mL)
19. dry with materialdried over magnesium sulfate
20. filtrationfiltered through a 2 cm layer of silica gel (silica gel layer was washed with 50 mL of ethyl acetate)
21. concentrationconcentrated under reduced pressure

ORD record

ord-fb6c801698ae4fe5a8e1959aa69f59d1

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09062092B2