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

HRID 1720362Notes

Reaction equation

HRID 1720362 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]([CH3:27])([CH3:26])[OH: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>[OH:25][C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][C@@H:15]([S:39][CH2:38][C:50]1([CH2:49][C:53]([O:52][CH3:51])=[O:46])[CH2:37][CH2:35]1)[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:10]=1)([CH3:27])[CH3:26]

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 15 (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 methanesulphonyl chloride (3.6 mL, 46.6 mmol) dropwise. The solution was stirred 1.5 hours with a mechanical stirrer while maintaining the temperature between -42° C. and -35° C.; then it was cooled to -45° C. The thiol of Step 10 (7.84 g, 48.9 mmol) was added followed by dropwise addition of DMF (15 mL). The potassium tert-butoxide in THF solution (56 mL, 1.75M, 97.9 mmol) was added to the reaction mixture within 20 minutes using a syringe pump. Stirring 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. NH4Cl (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. temperaturewhile maintaining the temperature between -42° C. and -35° C.
  2. stirringStirring
  3. waitcontinued for 5 hours
  4. temperaturewith slow warming from -35° C. to -22° C.
  5. customgiving a very thick translucid gel
  6. customThe reaction was quenched with saturated aq. NH4Cl (250 mL) and EtOAc (300 mL)
  7. extractionThe product was extracted with EtOAc
  8. washwashed with H2O and brine
  9. dry with materialdried over MgSO4
  10. customPurification by flash chromatography (20% to 30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-7735000bc5ff45df8f5f3305c01d7331
Source dataset
uspto-grants-1996_04
Patent number
US05506227

Reaction notes

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