Triethylamine → HCID 117720490, compound

HRID 1854581Notes

Reaction equation

HRID 1854581 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.Cl.[OH:44][CH2:45][C@H:46]1[CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2[CH2:56][CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[C@H:48]([CH3:62])[NH:47]1>C(#N)C>[Cl:1][C:2]1[C:3]([CH2:10][C:11]([N:47]2[C@@H:46]([CH2:45][OH:44])[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][C:53]=3[CH2:56][CH2:57][C:58]([OH:60])([CH3:59])[CH3:61])[C@@H:48]2[CH3:62])=[O:13])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]#[N:9]

Participants

6

Reactant 4

HCID 8471Triethylamine4×HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate2×HCID 68147289Benzeneacetic acid, 2-chloro-6-cyano-2×HCID 117720355HCID 117720355, compound2×

Product 1

HCID 117720490HCID 117720490, compoundYield 21.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent4×

Procedure

In a vial slurry 2-(2-chloro-6-cyano-phenyl)acetic acid (75.4 mg, 0.37 mmol) in acetonitrile (0.3 mL). Add triethylamine (114 μL, 0.82 mmol) and stir until the solids dissolve. Add 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (165 mg, 0.51 mmol) and stir at ambient temperature for 10 min. In a separate flask slurry 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride (102 mg, 0.34 mol) in acetonitrile (0.3 mL). Add triethylamine (227 μL, 1.63 mmol) and a precipitate forms. Stir 10 min at ambient temperature. Transfer the 2-(2-chloro-6-cyano-phenyl)acetic acid, acetonitrile, triethylamine, and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate reaction mixture from the vial to the flask containing the 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride, acetonitrile and triethylamine reaction mixture. Rinse with acetonitrile (0.9 mL) and stir the homogeneous reaction mixture at ambient temperature overnight. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the ethyl acetate extracts with water, saturated sodium bicarbonate solution and brine. Dry the extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (0-60% gradient) to give a residue. Purify by reverse phase chromatography on C18 modified silica to yield the title compound as a green oil (34 mg, 0.08 mmol): (m/z): 441.2 (M+1).

Workup

  1. dissolutiondissolve
  2. additioncontaining
  3. washRinse with acetonitrile (0.9 mL)
  4. stirringstir the homogeneous reaction mixture at ambient temperature overnight
  5. additionDilute the reaction mixture with water
  6. extractionextract with ethyl acetate
  7. washWash the ethyl acetate
  8. dry with materialDry the extracts over sodium sulfate
  9. filtrationfilter
  10. concentrationconcentrate under reduced pressure
  11. customPurify the residue by silica gel chromatography
  12. washeluting with ethyl acetate
  13. customhexanes (0-60% gradient) to give a residue
  14. customPurify by reverse phase chromatography on C18 modified silica

Sources & evidence

ORD record
ord-61ebc5f816664605ae617f2edac09614
Source dataset
uspto-grants-2015_02
Patent number
US08962654B2

Reaction notes

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