Diisopropylethylamine → (1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

HRID 417726Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 417726
[CH3:1][O:2][C:3]([NH:5][C:6](=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][NH:85]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:43][O:44][C:45](=[O:89])[NH:46][CH:47]([C:51]([N:53]1[CH2:57][CH2:56][CH2:55][CH:54]1[C:58]1[NH:59][C:60]([C:63]2[CH:72]=[CH:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([C:73]4[CH:78]=[CH:77][C:76]([C:79]5[NH:80][C:81]([CH:84]6[CH2:88][CH2:87][CH2:86][N:85]6[C:7](=[O:9])[C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[C:10]6[CH2:15][CH2:14][O:13][CH2:12][CH2:11]6)=[N:82][CH:83]=5)=[CH:75][CH:74]=4)[CH:69]=3)[CH:64]=2)=[CH:61][N:62]=1)=[O:52])[CH:48]([CH3:50])[CH3:49]

Komponenten

7

Edukt 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59611013Methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acidHCID 66620476{2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride

Produkt 1

HCID 66620834(1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl esterAusbeute 50 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittel2×HCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (1M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 mmol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0.11 mmol). After stirring for 5 minutes, a solution of {2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 μL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield {1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%).

Aufarbeitung

  1. stirringThe reaction was stirred for 1 hour at room temperature
  2. washThe organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. custompurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Quellen und Nachweise

ORD-Eintrag
ord-7e2bf4670288419982b4a52054eb2493
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08088368B2

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