Hydrochloric Acid → HCID 178485822, Verbindung

HRID 333496

Reaktionsgleichung

Reaktionsgleichung von HRID 333496
[CH3:1][O:2][C:3](=[O:55])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][C@H:46]([CH3:48])[NH:45][CH2:44][C@H:43]5[CH3:49])=[CH:40][CH:41]=4)=[O:35])=[CH:29][C:28]=3[O:50][C:51]([F:54])([F:53])[F:52])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.[CH3:65][NH:66][C:67](Cl)=[O:68].Cl>C(Cl)Cl.CC(N(C)C)=O.O>[CH3:1][O:2][C:3](=[O:55])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][C@H:46]([CH3:48])[N:45]([C:67](=[O:68])[NH:66][CH3:65])[CH2:44][C@H:43]5[CH3:49])=[CH:40][CH:41]=4)=[O:35])=[CH:29][C:28]=3[O:50][C:51]([F:54])([F:52])[F:53])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]

Komponenten

8

Edukt 4

HCID 313Hydrochloric AcidHCID 80931Methylcarbamoyl chloride2×HCID 81531DiisopropylethylamineHCID 178502383((S)-1-{(S)-2-[4-(4'-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2'-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Produkt 1

HCID 178485822HCID 178485822, Verbindung

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 31374DimethylacetamideLösungsmittel2×

Versuchsvorschrift

To a solution of ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (62.8 g, 74.1 mmol; Preparation 3) and N,N-diisopropylethylamine (20.1 mL, 115.2 mmol) in DCM (750 mL) was slowly added 1 M methylaminoformyl chloride in DMA (68.4 mL) over 10 min at 10-15° C. After 50 min, 1 M methylaminoformyl chloride in DMA (3.6 mL) was added and the reaction mixture was stirred overnight. To the reaction mixture was added water (750 mL) and 1 N HCl (40 mL). The organic layer was washed with water, dried over Na2SO4, and evaporated. Methanol (300 mL) and 2 N LiOH (10 mL) were added to the crude product and the reaction mixture was stirred for 30 min. Water (110 mL) was added slowly to the reaction mixture. Seeds of crystalline title product were added after 50 mL of water. The reaction mixture was stirred for 2 days and then methanol (60 mL) and water (24 mL) were added. After 30 min, the mixture was filtered. The solid was washed with 2:1 methanol:water (120 mL), and dried under vacuum at 35° C. overnight to provide the title compound (54 g).

Aufarbeitung

  1. customover 10 min
  2. customat 10-15° C
  3. washThe organic layer was washed with water
  4. dry with materialdried over Na2SO4
  5. customevaporated
  6. additionMethanol (300 mL) and 2 N LiOH (10 mL) were added to the crude product
  7. stirringthe reaction mixture was stirred for 30 min
  8. additionWater (110 mL) was added slowly to the reaction mixture
  9. additionSeeds of crystalline title product were added after 50 mL of water
  10. stirringThe reaction mixture was stirred for 2 days
  11. additionmethanol (60 mL) and water (24 mL) were added
  12. waitAfter 30 min
  13. filtrationthe mixture was filtered
  14. washThe solid was washed with 2:1 methanol
  15. dry with materialwater (120 mL), and dried under vacuum at 35° C. overnight

Quellen und Nachweise

ORD-Eintrag
ord-8032d1dff32a452cb61789e14c9045ac
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08883135B2

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