Diisopropylethylamine → tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate

HRID 521853Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 521853
[F:1][C:2]([F:25])([F:24])[C:3]([NH:5][CH:6]1[CH2:12][CH2:11][C:10](F)([C:13]2[N:14]([CH3:21])[N:15]=[CH:16][C:17]=2[N+:18]([O-])=O)[CH2:9][CH2:8][CH:7]1[OH:23])=[O:4].[H][H].CCN(C(C)C)C(C)C.[C:37]([O:41][C:42]([NH:44][C:45]1[S:49][C:48]([C:50]2[C:55]([F:56])=[CH:54][CH:53]=[CH:52][C:51]=2[F:57])=[N:47][C:46]=1[C:58](O)=[O:59])=[O:43])([CH3:40])([CH3:39])[CH3:38].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1.CO.[Pd].C(Cl)Cl>[F:57][C:51]1[CH:52]=[CH:53][CH:54]=[C:55]([F:56])[C:50]=1[C:48]1[S:49][C:45]([NH:44][C:42](=[O:43])[O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[C:46]([C:58](=[O:59])[NH:18][C:17]2[CH:16]=[N:15][N:14]([CH3:21])[C:13]=2[C:10]23[O:23][CH:7]([CH2:8][CH2:9]2)[CH:6]([NH:5][C:3](=[O:4])[C:2]([F:25])([F:24])[F:1])[CH2:12][CH2:11]3)[N:47]=1

Komponenten

10

Edukt 5

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 867138002,2,2-trifluoro-N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)acetamideHCID 178418361HCID 178418361, Verbindung

Produkt 1

HCID 86713799tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 23938PalladiumKatalysatorHCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

To a solution of 2,2,2-trifluoro-N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)acetamide (120 mg, 0.32 mmol) in THF (10 mL) and MeOH (10 mL) was added 10% palladium on carbon (12 mg). The reaction mixture was heated at 40° C. under a 400 psi atmosphere of hydrogen for 3 hr, cooled to room temperature, filtered through Celite®, washing with methanol (50 mL) and concentrated under reduced pressure. The procedure was repeated using the same conditions except with additional aqueous HCl (2 M, 2 mL). To a solution of the residue in DCM (20 mL) was added DIPEA (1.00 mL, 5.74 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (123 mg, 0.46 mmol) and PyBOP (409 mg, 0.78 mmol) and the mixture was stirred at room temperature for 16 hr. The reaction was quenched with water (20 mL) and extracted with DCM (150 mL). The organic layer was washed saturated solution of NaHCO3 (30 mL) and water (30 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel chromatography (80-100% EtOAc/isohexane) gave tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate as an off-white solid (58 mg, 27% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 10.39 (s, 1H), 8.33 (s, 1H), 7.39-7.33 (m, 1H), 7.18-7.10 (m, 2H), 5.91 (d, J=7.7 Hz, 1H), 4.89-4.83 (m, 1H), 4.47-4.38 (m, 1H), 3.86 (s, 3H), 2.47-2.38 (m, 1H), 2.27-1.90 (m, 7H), 1.55 (s, 9H).

Aufarbeitung

  1. filtrationfiltered through Celite®
  2. washwashing with methanol (50 mL)
  3. concentrationconcentrated under reduced pressure
  4. customThe reaction was quenched with water (20 mL)
  5. extractionextracted with DCM (150 mL)
  6. washThe organic layer was washed saturated solution of NaHCO3 (30 mL) and water (30 mL)
  7. customseparated
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated under reduced pressure
  10. customPurification via silica gel chromatography (80-100% EtOAc/isohexane)

Quellen und Nachweise

ORD-Eintrag
ord-a731bc7eb65c4acab555b920797fbf68
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09328106B2

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