Hydrochloric Acid → HCID 59475968, compound

A cold solution of n-BuLi (2.5 M in hexane, 163 mL, 0.408 mol) precooled to −78° C. can be added dropwise under argon to a stirred solution of 4-bromo-1-chloro-2-((4-cyclopropylphenyl)methyl)benzene (100 g, 0.340 mol) in anhydrous THF/toluene (1:2 (v/v), 660 mL) at −78° C. at such a rate as to keep the internal temperature below −70° C. The mixture is then stirred for another 40 min after the addition. The reaction mixture is transferred by a cannula to a stirred solution of (3R,4S,5R,6R)-3,4,5-tris-(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (206 g, 0.442 mol) in toluene (660 mL) at −78° C. at a rate as to keep the internal temperature below −70° C. The reaction mixture is then stirred at −78° C. for 3 h until the starting materials are consumed before quenching slowly with a solution of hydrochloric acid (36˜38%, 62.3 mL, 0.747 mol) in methanol (440 mL), so the reaction temperature does not exceed −45° C. The reaction mixture is gradually warmed to room temperature and stirred overnight. The mixture is neutralized with aqueous solution of saturated sodium bicarbonate to pH 7.5. The organic layer is separated and the aqueous phase is extracted with ethyl acetate (2×1.2 L). The combined organic layers can be washed with brine (2×1.0 L), dried over sodium sulfate, and concentrated. The residue is then dissolved in hot toluene (200 mL), to which n-hexane (2.0 L) is poured in with rapid stirring. The mixture is stirred for another 1 h and filtered. The solid is dried under vacuum to give the crude product, which can be used in the next step without further purification.

1. customprecooled to −78° C.
2. customthe internal temperature below −70° C
3. additionafter the addition
4. customthe internal temperature below −70° C
5. stirringThe reaction mixture is then stirred at −78° C. for 3 h until the starting materials
6. customare consumed
7. customdoes not exceed −45° C
8. stirringstirred overnight
9. customThe organic layer is separated
10. extractionthe aqueous phase is extracted with ethyl acetate (2×1.2 L)
11. washThe combined organic layers can be washed with brine (2×1.0 L)
12. dry with materialdried over sodium sulfate
13. concentrationconcentrated
14. dissolutionThe residue is then dissolved in hot toluene (200 mL), to which n-hexane (2.0 L)
15. additionis poured in with rapid stirring
16. stirringThe mixture is stirred for another 1 h
17. filtrationfiltered
18. customThe solid is dried under vacuum

ORD record

ord-b8aaba02af594d8da2f8a8858eee77d3

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09006403B2