Hydrochloric Acid → HCID 67682288, Verbindung

HRID 1751592Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1751592
[F:1][C:2]1([F:59])[C:14]2[CH:13]=[C:12]([C:15]3[NH:19][C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4C(OC(C)(C)C)=O)=[N:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:32]1[CH:33]=[CH:34][C:35]3[N:39]=[C:38]([C@@H:40]4[C@@H:45]5[CH2:46][C@@H:42]([CH2:43][CH2:44]5)[N:41]4[C:47](=[O:57])[C@@H](NC(OC)=O)C(C)C)[NH:37][C:36]=3[CH:58]=1)=[CH:6][CH:7]=2.Cl.O1C[CH2:65][O:64][CH2:63]C1.[CH3:67][O:68][C:69]([NH:71][C@H:72]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:73]([OH:75])=O)=[O:70].CCOC([C:87](C#N)=[N:88]OC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N([CH:115]([CH3:117])[CH3:116])CC)(C)C.C[OH:119]>>[CH3:65][O:64][C:63]([NH:88][C@@H:87]([CH:115]([CH3:116])[CH3:117])[C:47]([N:41]1[C@H:40]([C:38]2[NH:37][C:36]3[CH:58]=[C:32]([C:5]4[CH:4]=[C:3]5[C:8]([C:9]6[CH:10]=[CH:11][C:12]([C:15]7[NH:19][C:18]([C@@H:20]8[CH2:24][CH2:23][CH2:22][N:21]8[C:73](=[O:75])[C@H:72]([NH:71][C:69](=[O:70])[O:68][CH3:67])[C:76]8[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=8)=[N:17][CH:16]=7)=[CH:13][C:14]=6[C:2]5([F:59])[F:1])=[CH:7][CH:6]=4)[CH:33]=[CH:34][C:35]=3[N:39]=2)[C@@H:45]2[CH2:46][C@H:42]1[CH2:43][CH2:44]2)=[O:57])=[O:119]

Komponenten

8

Edukt 7

HCID 313Hydrochloric AcidHCID 887MethanolHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 67682549HCID 67682549, VerbindungHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Produkt 1

HCID 67682288HCID 67682288, VerbindungAusbeute 24 %

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

A solution of (S)-tert-butyl 2-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (106 mg, 0.13 mmol), methanol (1.5 mL), and 4M HCl in dioxane (1.5 mL, 6 mmol) was stirred at room temperature. The reaction was thoroughly concentrated after thirty minutes. The resulting residue was dissolved in a 4:1 dichloromethane:dimethylformamide solution (1.3 mL). To this solution was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (28 mg, 0.13 mmol) and COMU (56 mg, 0.13 mmol) and the reaction was cooled to 0° C. Diisopropylethylamine (0.092 mL, 0.53 mmol) was added and the reaction was stirred at 0° C. for twenty minutes. The reaction was quenched by the addition of formic acid (0.05 mL) and thoroughly concentrated. The resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA) to yield methyl (R)-2-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (28 mg, 24%). LCMS-ESI+: calculated for C50H50F2N8O6: 897.0; observed [M+1]+: 898.1.

Aufarbeitung

  1. concentrationThe reaction was thoroughly concentrated after thirty minutes
  2. dissolutionThe resulting residue was dissolved in a 4:1 dichloromethane
  3. customThe reaction was quenched by the addition of formic acid (0.05 mL)
  4. concentrationthoroughly concentrated
  5. customThe resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA)

Quellen und Nachweise

ORD-Eintrag
ord-7ade1a5c5c244eeaba637272cf298a1d
Quelldatensatz
uspto-grants-2015_10
Patentnummer
US09156823B2

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