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2-Trityl-5-methyl tetrazole → (R)-N-((S)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

HRID 238805
Notes
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Reaction equation

HRID 238805 reaction equation
[CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[Li]CCCC.[F:31][C:32]1[CH:33]=[C:34]([C:45]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[N:46][S@@:47]([C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])[CH:35]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:37]=1>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([C@@:45]([NH:46][S@@:47]([C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])([C:53]2[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=2)[CH2:1][C:2]2[N:3]=[N:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH:35]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:41])[F:42])[CH:37]=1.[F:31][C:32]1[CH:33]=[C:34]([C@:45]([NH:46][S@@:47]([C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])([C:53]2[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=2)[CH2:1][C:2]2[N:3]=[N:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH:35]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:41])[F:42])[CH:37]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 109583602-Trityl-5-methyl tetrazoleHCID 86613040(R)-N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamideHCID 178418339Butyllithium

Product 2

HCID 86613056(R)-N-((S)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide
HCID 86613057
(R)-N-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 5-methyl-2-trityl-2H-tetrazole (0.90 g, 2.76 mmol) in dry THF (20 mL) at −78° C. under argon was added dropwise n-BuLi (2.5 M in hexane, 1.2 mL, 3 mmol). The resulting solution was stirred at −78° C. for 1 h, followed by the dropwise addition of a solution of (R)—N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide, prepared as described in Procedure 3, 4 and 5, (0.40 g, 0.91 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. to −70° C. overnight. The reaction mixture was quenched by addition of sat. NH4Cl and the aqueous layer was extracted with Et2O (2×) and the combined organic layers were washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO flash chromatography (silica gel, hexanes/EtOAc) to give (R)—N—((S)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as the fast eluting diastereomer (90 mg, 13% yield) and (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as the slow eluting diastereomer (85 mg, 12% yield).

Workup

  1. customprepared
  2. stirringThe reaction mixture was stirred at −78° C. to −70° C. overnight
  3. customThe reaction mixture was quenched by addition of sat. NH4Cl
  4. extractionthe aqueous layer was extracted with Et2O (2×)
  5. washthe combined organic layers were washed with H2O, sat. NaCl
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by ISCO flash chromatography (silica gel, hexanes/EtOAc)

Sources & evidence

ORD record
ord-43ae424e14884dfa82ec62bdcc0a5723
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08642576B2

Reaction notes

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