Diisopropylethylamine → ((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester

HRID 1185259Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1185259
[Br:1][C:2]1[S:3][C:4]([NH:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:17]([O:24][C:25](=[O:41])[NH:26][C@@H:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]2[N:35]([CH3:40])[N:36]=[CH:37][C:38]=2[NH2:39])[CH2:29][CH2:28]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:42]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([O:24][C:25](=[O:41])[NH:26][C@@H:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]2[N:35]([CH3:40])[N:36]=[CH:37][C:38]=2[NH:39][C:7]([C:5]2[N:6]=[C:2]([Br:1])[S:3][C:4]=2[NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:42])[CH3:15])=[O:12])=[O:9])[CH2:29][CH2:28]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1

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 58465005(R)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamateHCID 674388042-Bromo-5-(isopropoxycarbonylamino)-thiazole-4-carboxylic acid

Produkt 1

HCID 58464869((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl esterAusbeute 99,7 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

To a stirred solution of 2-bromo-5-(isopropoxycarbonylamino)-thiazole-4-carboxylic acid (650.0 mg, 2.01 mmol) and [(R)-1-(4-amino-2-methyl-2H-pyrazol-3-yl)-azepan-4-yl]-carbamic acid benzyl ester (828.9 mg, 2.41 mmol, 1.2 eq.) in anhydrous N,N-dimethylformamide (22 mL) was added HATU (1.07 g, 2.81 mmol, 1.4 eq.) followed by N,N-diisopropylethylamine (0.88 mL, 5.03 mmol, 2.5 eq.), and the reaction mixture was stirred at RT under N2 for 7 days. The reaction mixture was diluted with ethyl acetate (150 mL). The organic layer was washed with 50% brine/water, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via flash column chromatography eluted with 45 to 100% ethyl acetate/heptane to give 1.30 g (79.7%) of ((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester as a tacky gel. 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.33 (s, 5H), 5.09 (s, 2H), 4.98 (s, 1H), 3.89 (s, 1H), 3.72 (s, 3H), 3.36-3.21 (m, 2H), 3.16-3.03 (m, 2H), 2.19-2.01 (m, 2H), 2.00-1.61 (m, 4H), 1.51 (s, 9H)

Aufarbeitung

  1. washThe organic layer was washed with 50% brine/water, water and brine
  2. dry with materialdried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe crude was purified via flash column chromatography
  6. washeluted with 45 to 100% ethyl acetate/heptane

Quellen und Nachweise

ORD-Eintrag
ord-5cc4132662634c26832c81d63f33a438
Quelldatensatz
uspto-grants-2014_03
Patentnummer
US08669361B2

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