Ethanol → 9-(((2S)-4-((6-amino-3-pyridinyl)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 1972474Notes

Reaction equation

HRID 1972474 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]3[CH:39]4[CH2:40][CH:41]([OH:43])[CH2:42][CH:35]3[CH2:36][O:37][CH2:38]4)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:45]1[N:50]=[CH:49][C:48]([S:51]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[N:65]=[CH:64][C:63]([C:66]([OH:75])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])=[CH:62][N:61]=3)[C@@H:56]([CH2:76][N:77]3[CH:82]4[CH2:83][C:84](=[O:86])[CH2:85][CH:78]3[CH2:79][O:80][CH2:81]4)[CH2:55]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1.[OH-].[NH4+].CCO>O.CCOC(C)=O>[NH2:50][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]3[CH:39]4[CH2:40][CH:41]([OH:43])[CH2:42][CH:35]3[CH2:36][O:37][CH2:38]4)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:7][C:45]1[N:50]=[CH:49][C:48]([S:51]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[N:65]=[CH:64][C:63]([C:66]([OH:75])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])=[CH:62][N:61]=3)[C@@H:56]([CH2:76][N:77]3[CH:82]4[CH2:83][C:84](=[O:86])[CH2:85][CH:78]3[CH2:79][O:80][CH2:81]4)[CH2:55]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1

Participants

8

Reactant 4

HCID 702EthanolHCID 14923Ammonium HydroxideHCID 866703569-(((2S)-4-((6-chloro-3-pyridinyl)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 866703579-(((2S)-4-((6-chloro-3-pyridinyl)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

Product 2

HCID 866703589-(((2S)-4-((6-amino-3-pyridinyl)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 866703599-(((2S)-4-((6-amino-3-pyridinyl)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 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

A 30-mL sealed tube was charged with 9-(((2S)-4-((6-chloro-3-pyridinyl)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-((6-chloro-3-pyridinyl)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 (50 mg, 0.076 mmol), ammonium hydroxide (266 mg, 7.59 mmol) and EtOH (5 mL) and was heated to 150° C. o/n. The reaction was diluted with water (50 mL) and EtOAc (100 mL) and the organic layer was separated, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (10% to 100% over 15 min) to give 9-(((2S)-4-((6-amino-3-pyridinyl)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) (12 mg) and 9-(((2S)-4-((6-amino-3-pyridinyl)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 (10 mg).

Workup

  1. customA 30-mL sealed tube
  2. customthe organic layer was separated
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe resulting residue was purified via reverse-phase preparative HPLC
  7. washeluting with 0.1% TFA in CH3CN/H2O (10% to 100% over 15 min)

Sources & evidence

ORD record
ord-c66d5eed4b394a4a8e1c045da518dd2b
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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