Bromhydrol → (+/-)-6-Methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-[[trans-2-(1-Piperidyl)cyclohexyl]oxy]phenyl Ketone

HRID 1387002Notes

Reaction equation

HRID 1387002 reaction equation
[N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)[S:30][C:29]=2[CH:47]=1.[Br-].[Al+3].[Br-].[Br-]>S(Cl)(Cl)=O.CN(C=O)C>[N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([C:32]3[C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:47][C:29]=4[S:30][C:31]=3[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 166749BromhydrolHCID 106894206-Methoxy-2-[4-(2-(1-pyrrolidinyl)ethoxy)phenyl]benzo[b]thiopheneHCID 183975244-[[trans-2-(1-Piperidyl)cyclohexyl]oxy]benzoic acid

Product 1

HCID 18397560(+/-)-6-Methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-[[trans-2-(1-Piperidyl)cyclohexyl]oxy]phenyl Ketone

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 24386Thionyl ChlorideSolvent

Procedure

1.698 g (5.60 mmol) of 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzoic acid (Part C) was dissolved in 30 mL of thionyl chloride at room temperature. To this was added 434 μL (5.60 mmol) of DMF as a catalyst. The mixture was stirred for 3 days at room temperature. The thionyl chloride was removed under reduced pressure and the residue was treated with dry benzene to remove azeotropically the residual thionyl chloride and then placed under high vacuum. The crude acid chloride was suspended in 50 mL of anhydrous dichloroethane, and to this was added 1.799 g (5.09 mmol) of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B). After cooling the slurry to 0° C., aluminum bromide (6.79 g, 25.4 mmol) was added, producing a dark red mixture. The ice bath was removed and the reaction mixture was stirred at room temperature for 6 h. The mixture was poured into 100 mL of cooled (0° C.) 2.0 N NaOH. The aqueous layer was extracted with EtOAc (3×400 mL). The combined organic layers were washed with 300 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified using PrepLC (8% of (10% concd NH4OH in MeOH) in CH2Cl2).

Workup

  1. customThe thionyl chloride was removed under reduced pressure
  2. additionthe residue was treated with dry benzene
  3. customto remove azeotropically the residual thionyl chloride
  4. temperatureAfter cooling the slurry to 0° C.
  5. customproducing a dark red mixture
  6. customThe ice bath was removed
  7. stirringthe reaction mixture was stirred at room temperature for 6 h
  8. additionThe mixture was poured into 100 mL
  9. temperatureof cooled (0° C.) 2.0 N NaOH
  10. extractionThe aqueous layer was extracted with EtOAc (3×400 mL)
  11. washThe combined organic layers were washed with 300 mL of brine
  12. dry with materialdried over MgSO4
  13. concentrationconcentrated under reduced pressure
  14. customThe crude product was purified

Sources & evidence

ORD record
ord-0f7d149910594dafa1b68c9f07a8cd31
Source dataset
uspto-grants-2001_07
Patent number
US06265575B1

Reaction notes

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