Diisopropylethylamine → 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol

HRID 1972471Notes

Reaction equation

HRID 1972471 reaction equation
[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][N:19]3[CH:24]4[CH2:25][CH:26]([OH:28])[CH2:27][CH:20]3[CH2:21][O:22][CH2:23]4)[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:29]([C:32]1[S:36][C:35]([S:37]([N:40]2[CH2:45][CH2:44][NH:43][C@@H:42]([CH2:46][N:47]3[CH:52]4[CH2:53][C:54](=[O:56])[CH2:55][CH:48]3[CH2:49][O:50][CH2:51]4)[CH2:41]2)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30].CCN(C(C)C)C(C)C.Cl[C:67]1[N:72]=[CH:71][C:70]([C:73]([OH:82])([C:78]([F:81])([F:80])[F:79])[C:74]([F:77])([F:76])[F:75])=[CH:69][N:68]=1>O1CCOCC1>[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:67]3[N:68]=[CH:69][C:70]([C:73]([OH:82])([C:74]([F:75])([F:76])[F:77])[C:78]([F:80])([F:81])[F:79])=[CH:71][N:72]=3)[C@@H:14]([CH2:18][N:19]3[CH:20]4[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]3[CH2:23][O:22][CH2:21]4)[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:29]([C:32]1[S:36][C:35]([S:37]([N:40]2[CH2:45][CH2:44][N:43]([C:67]3[N:68]=[CH:69][C:70]([C:73]([OH:82])([C:74]([F:75])([F:76])[F:77])[C:78]([F:80])([F:81])[F:79])=[CH:71][N:72]=3)[C@@H:42]([CH2:46][N:47]3[CH:48]4[CH2:55][C:54](=[O:56])[CH2:53][CH:52]3[CH2:51][O:50][CH2:49]4)[CH2:41]2)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 665826279-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-oneHCID 706562379-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-olHCID 866703482-(2-Chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol2×

Product 2

HCID 866703529-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-olHCID 866703539-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 20-mL vial was charged with 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.53 g, 1.9 mmol), Hünig's base (0.67 mL, 3.8 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.53 g, 1.88 mmol, Intermediate D) and dioxane (10 mL). The vial was, sealed and heated at 100° C. overnight. The crude reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.46 g) as a 1:1 mixture.

Workup

  1. customsealed
  2. customThe crude reaction
  3. concentrationwas concentrated onto silica gel
  4. custompurified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-c8bd9d0904cb4f1fbf2d468a8823330b
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

Loading…