Diisopropylethylamine → HCID 86633225, compound

HRID 1511458Notes

Reaction equation

HRID 1511458 reaction equation
C[C@@:2]1([C:40]([OH:42])=O)[CH2:6][C@@H:5]([O:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[N:11]=[C:10]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)[CH:9]=2)[CH2:4][N:3]1C(=O)[C@@H](NC(NC(C)(C)C)=O)C(C)(C)C.FC(F)(F)C(O)=O.[NH2:50][C@@H](CCC)C(O)C(NC1CC1)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([O:7][CH:5]3[CH2:4][NH:3][CH:2]([C:40]([NH2:50])=[O:42])[CH2:6]3)=[CH:9][C:10]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[N:11]2)=[CH:16][CH:15]=1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 159087TriacetoxyperiodinaneHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68736379HCID 68736379, compoundHCID 68739448HCID 68739448, compound

Product 1

HCID 86633225HCID 86633225, compound

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

tert-butyl-(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxo-3-ylcarbamate (48 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (3.0 mL) was added. After stirring for 1 hour at room temperature, the reaction mixture was evaporated to dryness to give (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide trifluoroacetic acid salt as a white solid. A solution of (2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylic acid in dichloromethane/N,N-dimethylformamide (1:1, 6.0 mL) was added to the (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide trifluoroacetic acid salt, followed by O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (75 mg, 0.198 mmol) and diisopropylethylamine (0.1 mL, 0.7 mmol). After 24 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl, sodium bicarbonate, and brine. The ethyl acetate layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product was then dissolved in dry dichloromethane (10.0 mL) and Dess-Martin periodinane (112 mg, 0.264 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was quenched with 0.26M sodium thiosulfate in saturated sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layers were then washed with saturated sodium bicarbonate and brine. Purification by preparative HPLC gave (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((S)-1-cyclopropylamino)-1,2-dioxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide in >99% purity by HPLC.

Workup

  1. washwashed with 1N HCl, sodium bicarbonate, and brine
  2. dry with materialThe ethyl acetate layer was dried over magnesium sulfate
  3. filtrationfiltered
  4. customevaporated to dryness under reduced pressure
  5. dissolutionThe crude product was then dissolved in dry dichloromethane (10.0 mL)
  6. customthe reaction mixture was quenched with 0.26M sodium thiosulfate in saturated sodium bicarbonate
  7. extractionextracted with ethyl acetate
  8. washThe combined ethyl acetate layers were then washed with saturated sodium bicarbonate and brine
  9. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-415f5cce76004d449b3bb8d46edea3a8
Source dataset
uspto-grants-2012_07
Patent number
US08211897B2

Reaction notes

Loading…