Triethylamine → HCID 86708521, compound

HRID 921659Notes

Reaction equation

HRID 921659 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.C(N(CC)CC)C.[Cl:38][C:39]1[C:44]([NH:45][C:46]2[N:51]=[C:50]([N:52]([CH:62]3[CH2:64][CH2:63]3)[CH2:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)[C:49]3=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]3[N:47]=2)=[CH:43][C:42]([C:70]#[N:71])=[CH:41][C:40]=1[N:72]1[CH2:77][CH2:76][C@@H:75]([NH:78][C:79](=[O:82])[O:80][CH3:81])[C@H:74](O)[CH2:73]1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][C@@H:76]1[C@@H:75]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH2:74][CH2:73][N:72]([C:40]2[CH:41]=[C:42]([C:70]#[N:71])[CH:43]=[C:44]([NH:45][C:46]3[N:51]=[C:50]([N:52]([CH:62]4[CH2:64][CH2:63]4)[CH2:53][C:54]4[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=4)[C:49]4=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]4[N:47]=3)[C:39]=2[Cl:38])[CH2:77]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 83693Boc-L-ValineHCID 2774761Tetramethylfluoroformamidinium hexafluorophosphateHCID 131732389(+/-)-methyl((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate

Product 1

HCID 86708521HCID 86708521, compoundYield 97.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (30.4 mg, 0.140 mmol), Tetramethylfluoroformamidinium hexafluorophosphate (37.0 mg, 0.140 mmol) and triethyl amine (0.039 mL, 0.280 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 h. (+/−)-methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (Example 171, 18 mg, 0.028 mmol) and DMAP (0.342 mg, 2.80 mol) were added and the reaction solution was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-30% ethyl acetate/dichloromethane). (+/−)-(R)-(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (23 mg) was obtained as a colorless oil.

Workup

  1. additionwere added
  2. washwashed with saturated sodium bicarbonate
  3. dry with materialThe organic layer was dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customthe crude product was purified by flash chromatography on silica gel using
  7. washan automated ISCO system (12 g column, eluting with 5-30% ethyl acetate/dichloromethane)

Sources & evidence

ORD record
ord-2ac3abd6bcbc4a739e28ea0cab5501b3
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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