Triethylamine → 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

HRID 1972473Notes

Reaction equation

HRID 1972473 reaction equation
[F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@@H:16]2[CH2:21][N:22]2[CH:27]3[CH2:28][CH:29]([OH:31])[CH2:30][CH:23]2[CH2:24][O:25][CH2:26]3)=[N:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[F:34][C:35]([F:66])([F:65])[C:36]([C:42]1[CH:43]=[N:44][C:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][C@@H:49]2[CH2:54][N:55]2[CH:60]3[CH2:61][C:62](=[O:64])[CH2:63][CH:56]2[CH2:57][O:58][CH2:59]3)=[N:46][CH:47]=1)([OH:41])[C:37]([F:40])([F:39])[F:38].C(N(CC)CC)C.[Cl:74][C:75]1[N:80]=[CH:79][C:78]([S:81](Cl)(=[O:83])=[O:82])=[CH:77][CH:76]=1>C(Cl)Cl>[Cl:74][C:75]1[N:80]=[CH:79][C:78]([S:81]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[N:13]=[CH:14][C:9]([C:3]([OH:8])([C:2]([F:1])([F:32])[F:33])[C:4]([F:5])([F:6])[F:7])=[CH:10][N:11]=3)[C@@H:16]([CH2:21][N:22]3[CH:23]4[CH2:30][CH:29]([OH:31])[CH2:28][CH:27]3[CH2:26][O:25][CH2:24]4)[CH2:17]2)(=[O:83])=[O:82])=[CH:77][CH:76]=1.[Cl:74][C:75]1[N:80]=[CH:79][C:78]([S:81]([N:51]2[CH2:52][CH2:53][N:48]([C:45]3[N:46]=[CH:47][C:42]([C:36]([OH:41])([C:35]([F:34])([F:65])[F:66])[C:37]([F:39])([F:38])[F:40])=[CH:43][N:44]=3)[C@@H:49]([CH2:54][N:55]3[CH:56]4[CH2:63][C:62](=[O:64])[CH2:61][CH:60]3[CH2:59][O:58][CH2:57]4)[CH2:50]2)(=[O:83])=[O:82])=[CH:77][CH:76]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 27927922-Chloro-5-pyridinesulfonyl chlorideHCID 866703549-(((2R)-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 866703559-(((2R)-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 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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A 25-mL round-bottomed flask was charged with a 1:1 mixture of 9-(((2R)-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-(((2R)-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 (215 mg, 0.44 mmol), triethylamine (0.19 mL, 1.33 mmol) and CH2Cl2 (5 mL). 6-chloropyridine-3-sulfonyl chloride (94 mg, 0.44 mmol, Organic Process Research & Development 2009, 13, 875) was added as a solution in CH2Cl2 (2 mL) and the reaction was stirred at room temperature for 20 min. The reaction was then concentrated onto silica and purified via column chromatography (12 g silica gel, 0 to 100% EtOAc in hexanes) to give 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).

Workup

  1. concentrationThe reaction was then concentrated onto silica
  2. custompurified via column chromatography (12 g silica gel, 0 to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-961d4c351c674c17aa2e04121f73ec5d
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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