Triethylamine → HCID 73068025, compound

HRID 1295368Notes

Reaction equation

HRID 1295368 reaction equation
[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:32])[C:16]([N:18]2[CH2:23][CH:22]3[C@@:20]([CH2:24][OH:25])([CH2:21]3)[C@@H:19]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.FC(F)(F)C1C=C(C(NC)C)C=C(C(F)(F)F)C=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1([C@@H]2NCC3[C@@]2(CO)C3)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]([N:15]([CH3:32])[C:16]([N:18]2[CH2:23][CH:22]3[C:20]([CH2:24][OH:25])([CH2:21]3)[CH:19]2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=1

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 220173563,5-Bis(trifluoromethyl)-alpha,N-dimethylbenzylamineHCID 69336509HCID 69336509, compoundHCID 86602054HCID 86602054, compound

Product 1

HCID 73068025HCID 73068025, compoundYield 57%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Mixture of 4 isomers, one being (1S,2S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid [(R)-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide. To a round bottom flask was added methylene chloride (8 mL), triethylamine (0.63 mL, 5.0 mmol), and [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (0.36 g, 1.2 mmol). The mixture was cooled to 0° C. and triphosgene (0.13 g, 0.49 mmol) in methylene chloride (3 mL) was added dropwise. The slurry was stirred for 16 hours at room temperature. To the reaction mixture was added racemic Intermediate 17 ((1S,2S)-2-phenyl-3-aza-bicyclo[3.1.0]hex-1-yl)-methanol (0.20 g, 1.1 mmol) and diisopropyl ethyl amine (0.19 mL, 1.2 mmol) in acetonitrile (8 mL). The reaction was heated to remove the methylene chloride and then refluxed for 2 hours. The solvent was removed at reduced pressure and the residue partitioned between 1N HCl and methylene chloride, the organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. The crude product was purified on a Biotage Flash 40 system eluted with 20% ETOAc/Hexanes to give the title compound as an oil which is a 1:1 mix of racemic diastereomers (0.29 g, 57% yield).

Workup

  1. temperatureThe reaction was heated
  2. customto remove the methylene chloride
  3. temperaturerefluxed for 2 hours
  4. customThe solvent was removed at reduced pressure
  5. customthe residue partitioned between 1N HCl and methylene chloride
  6. washthe organic phase was washed with brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated to an oil
  10. customThe crude product was purified on a Biotage Flash 40 system
  11. washeluted with 20% ETOAc/Hexanes

Sources & evidence

ORD record
ord-818f404eda4147149c49739ce9b91330
Source dataset
uspto-grants-2007_07
Patent number
US07241798B2

Reaction notes

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