Citric Acid → Methyl(1R,2R,4S,5S,6R)-2-{[tert-butyl(dimethyl)silyl]oxy}-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate

HRID 1918273Notes

Reaction equation

HRID 1918273 reaction equation
[Si:1]([O:8][C@@H:9]1[CH2:14][C@H:13]2[C@H:11]([O:12]2)[C@H:10]1[CH:15]([F:20])[C:16]([O:18][CH3:19])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.C([Al](CC)CC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([OH:12])[C@@H:11]2[C@H:10]1[C@@:15]2([F:20])[C:16]([O:18][CH3:19])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 311Citric AcidHCID 2733832Lithium HexamethyldisilazideHCID 59434305Methyl((1r,2r,3r,5s)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-oxabicyclo[3.1.0]hex-2-yl)fluoroacetateHCID 86610617Triethylaluminum hexane

Product 1

HCID 11681051Methyl(1R,2R,4S,5S,6R)-2-{[tert-butyl(dimethyl)silyl]oxy}-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-50 °C

Procedure

A THF (270 mL) solution of the compound of Formula 13a thus obtained was cooled to −50° C., and 210 mL (197.40 mmol) of a 0.94 mol/L triethylaluminum hexane solution was added thereto over 30 minutes while keeping the internal temperature between −55° C. and −50° C. After stirring at −50° C. for 30 minutes, 143 mL (228.80 mmol) of a 1.6 mol/L lithium hexamethyldisilazide (LiHMDS) hexane solution was added thereto over 10 minutes while keeping the internal temperature between −50° C. and −40° C. After stirring at −50° C. for 2 hours the reaction mixture was added over 20 minutes to 265.08 g of a 25% citric acid aqueous solution cooled at 5° C. 270 mL of ethyl acetate was added to the reaction mixture, which was stirred and then separated. Extraction was carried out with 100 mL of ethyl acetate, the organic layers were combined, washed with 50 mL of water, and then concentrated under reduced pressure, thus giving 56.65 g of methyl (1R,2R,4S,5S,6R)-2-[(tert-butyl(dimethyl)silyl]oxy)-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate (14a) as a brown oily material.

Workup

  1. customthe internal temperature between −55° C. and −50° C
  2. waitover 10 minutes while keeping
  3. customthe internal temperature between −50° C. and −40° C
  4. stirringAfter stirring at −50° C. for 2 hours the reaction mixture
  5. temperaturecooled at 5° C
  6. stirringwas stirred
  7. customseparated
  8. extractionExtraction
  9. washwashed with 50 mL of water
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-84ac4302cc5e442da5c87de130f40f1c
Source dataset
uspto-grants-2013_12
Patent number
US08618312B2

Reaction notes

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