9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one → (1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol

HRID 1972487Notes

Reaction equation

HRID 1972487 reaction equation
[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][C:36](=[O:38])[CH2:37][CH:30]2[CH2:31][O:32][CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].[CH3:39][Mg]Br>C1COCC1>[CH3:39][C:36]1([OH:38])[CH2:35][C@H:34]2[N:29]([CH2:28][C@H:11]3[CH2:10][N:9]([S:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)(=[O:7])=[O:8])[CH2:14][CH2:13][N:12]3[C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C@H:30]([CH2:31][O:32][CH2:33]2)[CH2:37]1

Participants

4

Reactant 2

HCID 665823999-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-oneHCID 178418573HCID 178418573, compound2×

Product 1

HCID 70655259(1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A 25-mL round-bottomed flask was cooled to 0° C. and charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg, 0.087 mmol, Example 106) and THF (5 mL). Methylmagnesium bromide was added (3.0M in THF, 0.15 mL, 0.44 mmol, Sigma-Aldrich, St. Louis, Mo.) and after 20 min another 0.5 equivalent of methylmagnesium bromide was added. The reaction was then quenched with MeOH (50 mL), concentrated onto silica gel, and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc). The material was purified further via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give (1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (10 mg) as a mixture of two isomers.

Workup

  1. customThe reaction was then quenched with MeOH (50 mL)
  2. concentrationconcentrated onto silica gel
  3. custompurified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc)
  4. customThe material was purified further via reverse-phase preparative HPLC
  5. washeluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min)

Sources & evidence

ORD record
ord-77581dca516c423cacbf371d8f9df648
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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