Hexane → (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol

HRID 1912989Notes

Reaction equation

HRID 1912989 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[C:10]=2[F:18])[CH:7]=1.[Li][CH2:21]CCC.CCCCCC.C[Si](C)(C)[O:33][C@@H:34]1[C@@H:39]([O:40][Si](C)(C)C)[C@H:38]([O:45][Si](C)(C)C)[C@@H:37]([CH2:50][O:51][Si](C)(C)C)[O:36][C:35]1=[O:56]>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([C@@:35]2([O:56][CH3:21])[C@H:34]([OH:33])[C@@H:39]([OH:40])[C@H:38]([OH:45])[C@@H:37]([CH2:50][OH:51])[O:36]2)=[CH:7][C:6]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[C:10]=1[F:18]

Participants

7

Reactant 4

HCID 8058HexaneHCID 10994280(3R,4S,5R,6R)-3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-onHCID 866851071-[(5-Bromo-2-chloro-phenyl)methyl]-2,3-difluoro-4-methoxy-benzeneHCID 178418339Butyllithium

Product 1

HCID 86685109(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

1-[(5-bromo-2-chloro-phenyl)methyl]-2,3-difluoro-4-methoxy-benzene 2e (3.55 g, 10.2 mmol) was dissolved in 30 mL mixed solution (THF and toluene, v:v=1:2) and cooled to −78° C., followed by dropwise addition of a solution of nBuLi in n-hexane (4.9 mL, 12.26 mmol). After stirring for 1 hour at −78° C., a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-one 2f (5.24 g, 11.22 mmol, prepared according to the method in WO2010048358) in toluene (30 mL) was added. The reaction mixture was stirred for 3 hours at −78° C. Thereafter, the reaction mixture was concentrated under reduced pressure after 30 mL saturated sodium carbonate solution were added. The residue was dissolved in 30 mL saturated sodium chloride solution and extracted with ethyl acetate (50 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 2g (1.31 g, white solid), yield: 27.9%. MS m/z (ESI): 429.1 [M−31]

Workup

  1. additionwas added
  2. stirringThe reaction mixture was stirred for 3 hours at −78° C
  3. concentrationThereafter, the reaction mixture was concentrated under reduced pressure after 30 mL saturated sodium carbonate solution
  4. additionwere added
  5. dissolutionThe residue was dissolved in 30 mL saturated sodium chloride solution
  6. extractionextracted with ethyl acetate (50 mL×3)
  7. extractionthe organic extract
  8. dry with materialdried over anhydrous magnesium sulfate
  9. filtrationfiltered
  10. concentrationThe filtrate was concentrated under reduced pressure
  11. customthe resulting residue was purified by silica gel chromatography with elution system

Sources & evidence

ORD record
ord-7cf755666da14294a869a9515fd9bea4
Source dataset
uspto-grants-2013_12
Patent number
US08609622B2

Reaction notes

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