Methanol → 1-{[(5S,7S)-2-oxo-3-({1-[5-(trifluoromethyl)-3-pyridinyl]-1H-1,2,3-triazol-4-yl}methyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile

HRID 715520Notes

Reaction equation

HRID 715520 reaction equation
[O:1]=[C:2]1[N:6]([CH2:7][C:8]#[CH:9])[CH2:5][C@@:4]2([CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][N:16]3[C:20]4[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH2:10]2)[O:3]1.[N:27]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)=[N+:28]=[N-:29].[O:40]=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[CH3:53][OH:54]>C(O)(C)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].CC#N.O>[C:53]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:54].[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[N:29]=[N:28][N:27]([C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=3)[CH:9]=2)[CH2:5][C@@:4]2([CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][N:16]3[C:20]4[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH2:10]2)[O:3]1

Participants

10

Reactant 4

HCID 887MethanolHCID 212903563-Azido-5-(trifluoromethyl)pyridineHCID 23667548Sodium AscorbateHCID 867175871-{[(5S,7S)-2-oxo-3-(2-propyn-1-yl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile

Product 2

HCID 6422Trifluoroacetic acidYield 0.1%HCID 712275731-{[(5S,7S)-2-oxo-3-({1-[5-(trifluoromethyl)-3-pyridinyl]-1H-1,2,3-triazol-4-yl}methyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrileYield 9.2%

Reagents, catalysts & solvents 4

HCID 24463Copper sulfate pentahydrateCatalystHCID 962WaterSolvent2×HCID 6386tert-ButanolSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

To a light orange solution of 1-{[(5S,7S)-2-oxo-3-(2-propyn-1-yl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (0.100 g, 0.287 mmol) (93:7 trans:cis) in tert-butanol (1.435 mL) and water (1.435 mL) in a vial was added 3-azido-5-(trifluoromethyl)pyridine (0.054 g, 0.287 mmol), sodium L-ascorbate (0.011 g, 0.057 mmol), copper(II) sulfate pentahydrate (0.014 g, 0.057 mmol), and water (1.435 mL). After 18 h, 1 mL of MeOH was added and the mixture was vacuum filtered using a small Buchner funnel. The filtrate was filtered through Acrodisc CR 25 mm syringe filter with 0.2 um PTFE membrane and purified by Gilson prep HPLC: 25-45% CH3CN/H2O, 0.1% TFA, 30×150 mm Sunfire C18, 25 mL/min, 15 min to yield the TFA salt of 1-{[(5S,7S)-2-oxo-3-({1-[5-(trifluoromethyl)-3-pyridinyl]-1H-1,2,3-triazol-4-yl}methyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an orange foam (18.1 mg, 9.2% yield). MS (m/z) 537 (M+H+).

Workup

  1. filtrationfiltered
  2. filtrationThe filtrate was filtered through Acrodisc CR 25 mm syringe
  3. filtrationfilter with 0.2 um PTFE membrane
  4. custompurified by Gilson prep HPLC

Sources & evidence

ORD record
ord-40988763f0e641c99faeb3580029e5e0
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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