Acetic Acid → GW3965 hydrochloride

HRID 1296961Notes

Reaction equation

HRID 1296961 reaction equation
[Cl:1][C:2]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([O:19]C)=[O:18])[CH:13]=[CH:14][CH:15]=1.[Li+].[OH-].CC(O)=O.Cl.CCOCC>O1CCCC1.O.CCOCC.O.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:21][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1

Participants

9

Reactant 4

HCID 176Acetic AcidHCID 3939Lithium Hydroxide2×HCID 10188816Methyl (3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)acetateHCID 10953452Ether hydrochloride

Product 1

HCID 16078973GW3965 hydrochlorideYield 110.6%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 22728543Water ethylacetateSolvent

Procedure

A solution of methyl (3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate (113 mg, 0.19 mmol) in 1.5 mL of tetrahydrofuran and 1 mL of water was treated with 1N aqueous LiOH (0.29 mL, 0.29 mmol). After stirring at room temperature for 2 hours, additional 1N aqueous LiOH (0.29 mL, 0.29 mmol) was added and stirring was continued for 2 hours. The reaction was neutralized with AcOH (66 μL, 0.58 mmol) and poured into H2O/EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative thin layer chromatography (silica gel, 1 mm plates, Merck 20×20 cm silica gel 60 F254) eluting with CH2Cl2:MeOH (95:5) to afford an oil. The oil was dissolved in Et2O and acidified with excess HCl/Et2O. The reaction was concentrated in vacuo and dried under reduced pressure to give 65 mg (56% yield) of the title compound as a white solid: H NMR (C5D5N, 400 MHz) δ 7.60–7.05 (m, 15 H), 7.01 (t, 1 H, J=7.6), 6.84 (dd, 1 H, J=8.4, 2.4), 4.32 (t, 1 H, J=7.6), 3.89 (s, 2 H), 3.77 (s, 2 H), 3.71 (t, 2 H, J=5.6), 3.16 (d, 2 H, J=7.6), 2.65 (t, 2 H, J=6.4), 1.88–1.78 (m, 2 H).

Workup

  1. stirringstirring
  2. waitwas continued for 2 hours
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (3×)
  5. washThe combined organic layers were washed with brine (1×)
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by preparative thin layer chromatography (silica gel, 1 mm plates, Merck 20×20 cm silica gel 60 F254)
  10. washeluting with CH2Cl2:MeOH (95:5)
  11. customto afford an oil
  12. concentrationThe reaction was concentrated in vacuo
  13. customdried under reduced pressure

Sources & evidence

ORD record
ord-a81ab5dea6b84634ab44f16116c93c2c
Source dataset
uspto-grants-2007_07
Patent number
US07247748B2

Reaction notes

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