Diisopropylethylamine → 4-{2-Butyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoic Acid

HRID 1472257Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1472257
C([S:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.C[O:49][C:50](=[O:71])[C:51]1[CH:56]=[CH:55][C:54]([CH2:57][N:58]2[C:62]([CH2:63][NH2:64])=[CH:61][N:60]=[C:59]2[CH2:65][CH2:66][CH2:67][CH3:68])=[C:53]([F:69])[C:52]=1[F:70]>CN(C=O)C>[CH2:65]([C:59]1[N:58]([CH2:57][C:54]2[CH:55]=[CH:56][C:51]([C:50]([OH:71])=[O:49])=[C:52]([F:70])[C:53]=2[F:69])[C:62]([CH2:63][NH:64][C:6](=[O:8])[C@@H:5]([SH:4])[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:61][N:60]=1)[CH2:66][CH2:67][CH3:68]

Komponenten

6

Edukt 4

HCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 14505484(S)-2-(Acetylthio)-4-methylpentanoic acidHCID 669685314-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt

Produkt 1

HCID 529130354-{2-Butyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoic AcidAusbeute 23,8 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel2×

Versuchsvorschrift

(S)-2-Acetylsulfanyl-4-methylpentanoic acid (205 mg, 1.1 mmol) was dissolved in DMF (8.1 mL, 104 mmol). HATU (409 mg, 1.1 mmol) and DIPEA (170 μL, 1.0 mmol) were added and the mixture was stirred at room temperature for 30 minutes. 4-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt (401 mg, 1.0 mmol) was dissolved in DMF (1 ml) with DIPEA (170 pt, 1.0 mmol) and added. to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water, and the mixture extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude residue was then redissolved in 1:1 MeOH:NaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with acetic acid and the mixture was concentrated. The product was purified by preparative HPLC (2-90%) to yield 108 mg of the title compound as a white solid. MS m/z: [M+H] calcd for C22H29F2N3O3S, 454.19; found 454.2. 1H-NMR (DMSO): 8.44 (1H, t), 7.59 (1H, t), 7.25 (1H, s), 6.62 (1H, t), 5.56 (2H, s), 4.24 (2H, m), 3.14 (2H, q), 2.79 (2H, t), 2.72 (1H, d), 1.2-1.6 (7H, m), 0.78 (6H, d), 0.71 (3H, d).

Aufarbeitung

  1. additionadded
  2. stirringThe mixture was stirred at room temperature for 2 hours
  3. customThe reaction was then quenched with water
  4. extractionthe mixture extracted with EtOAc
  5. washwashed with saturated aqueous NaCl
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. dissolutionThe crude residue was then redissolved in 1:1 MeOH
  10. stirringNaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour
  11. customThe reaction was quenched with acetic acid
  12. concentrationthe mixture was concentrated
  13. customThe product was purified by preparative HPLC (2-90%)

Quellen und Nachweise

ORD-Eintrag
ord-5745deaadc38488b9ce6d8c3a0b437da
Quelldatensatz
uspto-grants-2015_04
Patentnummer
US09012485B2

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