Tetrahydrofuran → Methyl 1-(((1(R)-(3-(((2-tetrahydropyranyl)oxy)methyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetate

HRID 2226983Notes

Reaction equation

HRID 2226983 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C@@H:15](O)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1.C(N([CH:35]([CH3:37])C)CC)(C)C.[CH3:38][S:39](Cl)(=O)=O.CC(C)([O-:46])C.[K+].[CH2:49]1[CH2:53][O:52][CH2:51][CH2:50]1>CC#N.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C@H:15]([S:39][CH2:38][C:50]2([CH2:49][C:53]([O:52][CH3:51])=[O:46])[CH2:37][CH2:35]2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1

Participants

8

Reactant 5

HCID 8028TetrahydrofuranHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 186552462-(3-(3-((2-Tetrahydropyranyl)oxymethyl) phenyl)-3(S)-hydroxypropyl)-alpha,alpha-dimethylbenzenemethanolHCID 23665647Potassium tert-butoxide

Product 1

HCID 18655247Methyl 1-(((1(R)-(3-(((2-tetrahydropyranyl)oxy)methyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetateYield 68%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent

Conditions

Temperature
-45 °C

Procedure

The diol of Step 13 (17.9 g, 46.6 mmol) was dissolved in CH3CN (40 mL) and DMF (10 mL) and cooled to -42° C. under nitrogen. Diisopropylethylamine (8.5 mL, 48.9 mmol) was added followed by methanesulfonyl chloride (3.6 mL, 46.6 mmol) dropwise. The solution was stirred 1.5 hours with a mechanical stirring while maintaining the temperature between -42° and -35° C.; then it was cooled to -45° C. The thiol of Step 8 (7.84 g, 48.9 mmol) was added followed by dropwise addition of DMF (15 mL). Potassium tert-butoxide in THF (56 mL, 1.75 M, 97.9 mmol) was added to the reaction mixture over 20 minutes using a syringe pump. Stirring was continued for 5 hours with slow warming from -35° C. to -22° C., giving a very thick translucid gel. The reaction was quenched with saturated aq. NH4CI (250 mL) and EtOAc (300 mL). The product was extracted with EtOAc, washed with H2O and brine, and dried over MgSO4. Purification by flash chromatography (20% to 30% EtOAc in hexanes) gave 16.8 g (68%) of the title compound.

Workup

  1. stirringa mechanical stirring
  2. temperaturewhile maintaining the temperature between -42° and -35° C.
  3. stirringStirring
  4. waitwas continued for 5 hours
  5. temperaturewith slow warming from -35° C. to -22° C.
  6. customgiving a very thick translucid gel
  7. customThe reaction was quenched with saturated aq. NH4CI (250 mL) and EtOAc (300 mL)
  8. extractionThe product was extracted with EtOAc
  9. washwashed with H2O and brine
  10. dry with materialdried over MgSO4
  11. customPurification by flash chromatography (20% to 30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-3f191f6793ec4b19a3dc138a58617c8c
Source dataset
uspto-grants-1994_09
Patent number
US05350760

Reaction notes

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