3-(Trifluoromethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazine → 1-[4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

HRID 1400051Notes

Reaction equation

HRID 1400051 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[F:27][C:28]([F:39])([F:38])[C:29]1[N:33]2[CH2:34][CH2:35][NH:36][CH2:37][C:32]2=[N:31][N:30]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:36]4[CH2:35][CH2:34][N:33]5[C:29]([C:28]([F:39])([F:27])[F:38])=[N:30][N:31]=[C:32]5[CH2:37]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 3

HCID 101764893-(Trifluoromethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazineHCID 23676156Sodium t-butoxideHCID 53432548tert-Butyl 1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate2×

Product 1

HCID 675151121-[4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl esterYield 62%

Reagents, catalysts & solvents 3

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 400 mg, 1.18 mmol) in anhydrous toluene (5 mL) were added Pd2(dba)3 (5.4 mg, 0.006 mmol), BINAP (11.0 mg, 0.018 mmol), sodium tert-butoxide (227 mg, 2.34 mmol) and 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (prepared by the procedure as described in reference J. Med. Chem., 2005, 48, 141-151) (340 mg, 1.77 mmol) at r.t. and reaction mixture was refluxed for 6 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 6:4 EtOAc:Pet. ether) to afford the title compound as white solid (330 mg, 62%).

Workup

  1. customprepared by the procedure
  2. custom, 2005, 48, 141-151) (340 mg, 1.77 mmol) at r.t. and reaction mixture
  3. temperaturewas refluxed for 6 h
  4. customReaction mixture
  5. concentrationwas then concentrated
  6. customthe crude product was purified by column chromatography (silica gel, 6:4 EtOAc:Pet. ether)

Sources & evidence

ORD record
ord-97e06dc4b872439fb722c1c88980a439
Source dataset
uspto-grants-2014_12
Patent number
US08906913B2

Reaction notes

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