Water → Ethyl 2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-sulfanyl]phenoxy}-2-methylpropanoate

HRID 1766129Notes

Reaction equation

HRID 1766129 reaction equation
O.Cl[S:3]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)(=O)=O.Cl[Si](Cl)(C)C.S(Cl)(Cl)(=O)=O.O[CH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[N:35][C:34]=1[CH2:48][OH:49]>C(OC(C)C)(=O)C.[Zn].COCCOC>[OH:49][CH2:48][C:34]1[N:35]=[C:36]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)[S:37][C:33]=1[CH2:32][S:3][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1

Participants

9

Reactant 5

HCID 962WaterHCID 6398Dichlorodimethylsilane2×HCID 24648Sulfuryl chlorideHCID 11974006(2-(4-(Trifluoromethyl)phenyl)thiazole-4,5-diyl)dimethanolHCID 17951805Ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate

Product 1

HCID 11975785Ethyl 2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-sulfanyl]phenoxy}-2-methylpropanoate

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 7915Isopropyl AcetateSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred suspension of zinc dust (0.75 wt, 3.5 eq) in isopropyl acetate (5 vols), add a solution of DME (0.5 vol) and water (0.5 eq). Heat the resulting solution from room temperature to 40° C. Treat the reaction mixture with a solution of ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate (1.0 wt, 1.0 eq) and dichlorodimethylsilane (0.32 wt, 0.75 eq) in isopropyl acetate (3 vols) over a period of 2 h as this addition is mildly exothermic. After the addition is complete, increase the process temperature to 60° C. Treat the suspension at 60° C. slowly with neat dichlorodimethylsilane (0.95 wt, 2.3 eq) over a period of 1 h. When the reduction of the sulfonylchloride is deemed complete (by HPLC), treat the reaction mixture with {5-Hydroxymethyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol (1.04 wt, 1.1 eq) in one portion at 60° C. After the addition is complete, increase the process temperature to 89° C. and stir the reaction mixture at this temperature for 3 to 5 h then cool to ambient temperature. Filter the reaction mixture to remove unreacted zinc residue, wash the filtrate with water (2×8 vols) and concentrate the organic layer to about 3.5 volumes via vacuum distillation at 40–45° C. Dissolve the resultant, somewhat syrupy, residue in ethanol (2 vols) and treat the resulting solution with iso-octane (2 vols). Cool the clear yellow-tinted solution to ambient temperature to induce crystallization of the product. Collect the solid via filtration. Wash the wet cake with iso-octane/EtOH (9:1, 1 vol) and dry under vacuum (˜21 Torr) at 60° C. for 12 h to afford the title compound as an off-white solid.

Workup

  1. temperatureHeat the resulting solution from room temperature to 40° C
  2. additionas this addition
  3. additionAfter the addition
  4. additionAfter the addition
  5. temperatureincrease the process temperature to 89° C.
  6. temperaturethen cool to ambient temperature
  7. filtrationFilter the reaction mixture
  8. customto remove unreacted zinc residue
  9. washwash the filtrate with water (2×8 vols)
  10. concentrationconcentrate the organic layer to about 3.5 volumes
  11. distillationvia vacuum distillation at 40–45° C
  12. dissolutionDissolve the resultant
  13. additionsomewhat syrupy, residue in ethanol (2 vols) and treat the resulting solution with iso-octane (2 vols)
  14. temperatureCool the clear yellow-tinted solution to ambient temperature
  15. customcrystallization of the product
  16. customCollect the solid
  17. filtrationvia filtration
  18. washWash the wet cake with iso-octane/EtOH (9:1, 1 vol)
  19. customdry under vacuum (˜21 Torr) at 60° C. for 12 h

Sources & evidence

ORD record
ord-90fb55c885b048e3ae0d325ec1c7b836
Source dataset
uspto-grants-2007_06
Patent number
US07229998B2

Reaction notes

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