6-Methoxy-2-(4-Methoxyphenyl)benzo[b]thiophene-3-Carboxylic Acid Methyl Ester → Raloxifene Bismethyl Ether

HRID 850725Notes

Reaction equation

HRID 850725 reaction equation
CO[C:3]([C:5]1[C:6]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:4].[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:6]2[C:5]([C:3]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH2:31][CH2:30][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:38][CH:37]=3)=[O:4])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[S:8][C:7]=2[CH:18]=1

Participants

4

Reactant 2

HCID 543901236-Methoxy-2-(4-Methoxyphenyl)benzo[b]thiophene-3-Carboxylic Acid Methyl EsterHCID 178419641HCID 178419641, compound

Product 1

HCID 10767755Raloxifene Bismethyl EtherYield 31.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid methyl ester (202 mg, 0.615 mmol) in tetrahydrofuran (5 ml) under nitrogen at 5° C. is added, dropwise over 2 min via syringe a solution of 4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide (1.0 ml of 0.76 M solution, 0.76 mmol). Cooling is removed, and the reaction is allowed to stir at room temperature for 48 hours. It is then quenched by addition of saturated aqueous ammonium chloride (2 ml), and partitioned between methylene chloride and water. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated to an oil, which is chromatographed on silica (5:1:1 hexanes:dichloromethane:triethylamine) to afford recovered starting material (46.0 mg, 23%) and title compound. The latter is further purified by dissolution in methylene chloride, followed by washing with 1 N hydrochloric acid, then 1 N sodium hydroxide. Drying over magnesium sulfate, filtration and concentration furnished 97.4 mg of title compound (0.194 mmol, 32%, 41% based on recovered starting material). IR (CHCl3): 2932, 1647, 1597, 1475, 1252, 1163, 1029, 828 cm-1 ; 1H NMR (CDCl3) δ7.75 (d, 2H, J=8.7), 7.51 (d, 1H, J=8.7), 7.31 (m, 3H), 6.94 (dd, 1H, J=9.0, 2.4), 6.74 (m, 4 H), 4.07 (t, 2H, J=6.0), 3.87 (s, 3H), 3.73 (s, 3H), 2.72 (t, 2H, J=6.0), 2.47 (m, 4 H), 1.58 (m, 4 H), 1.42 (m, 2H); 13C NMR (CDCl3) d 193.2, 163.1, 159.8, 157.7, 142.5, 140.1, 134.1, 132.4, 130.7, 130. 5, 130.3, 126.1, 124.1, 114.8, 114.3, 114.1, 104.6, 66.3, 57.8, 55.7, 55.3, 55.2, 26.0, 24.2. Anal. Calcd. for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79; S, 6.39. Found: C, 71.56; H, 6.27; N, 2.82; S, 6.26.

Workup

  1. temperatureCooling
  2. customis removed
  3. customIt is then quenched by addition of saturated aqueous ammonium chloride (2 ml)
  4. custompartitioned between methylene chloride and water
  5. customThe organic phase is separated
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated to an oil, which
  9. customis chromatographed on silica (5:1:1 hexanes:dichloromethane:triethylamine)
  10. customto afford
  11. customrecovered
  12. customThe latter is further purified by dissolution in methylene chloride
  13. washby washing with 1 N hydrochloric acid
  14. dry with materialDrying over magnesium sulfate, filtration and concentration

Sources & evidence

ORD record
ord-a7011dbe24cf413ca2dce48301565cbc
Source dataset
uspto-grants-2000_01
Patent number
US06018056

Reaction notes

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