Diisopropylethylamine → tert-butyl N-[2-bromo-4-[[5-[2-(tert-butoxycarbonylamino)-8-oxabicyclo[3.2.1]octan-5-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate

HRID 521871Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 521871
F[C:2]1([C:18]2[N:19]([CH3:26])[N:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]([OH:17])[CH2:4][CH2:3]1.[H][H].CCN(C(C)C)C(C)C.[Br:38][C:39]1[S:40][C:41]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[C:42]([C:44](O)=[O:45])[N:43]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1.CO.[Pd].C(Cl)Cl.O>[Br:38][C:39]1[S:40][C:41]([NH:47][C:48](=[O:49])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[C:42]([C:44](=[O:45])[NH:23][C:22]2[CH:21]=[N:20][N:19]([CH3:26])[C:18]=2[C:2]23[O:17][CH:5]([CH2:4][CH2:3]2)[CH:6]([NH:9][C:10]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:16])[CH2:7][CH2:8]3)[N:43]=1

Komponenten

11

Edukt 5

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 581821562-Bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylic acidHCID 86713008tert-butyl N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)carbamate2×HCID 178418361HCID 178418361, Verbindung

Produkt 1

HCID 86713819tert-butyl N-[2-bromo-4-[[5-[2-(tert-butoxycarbonylamino)-8-oxabicyclo[3.2.1]octan-5-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamateAusbeute 34 %

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 23938PalladiumKatalysatorHCID 887MethanolLösungsmittelHCID 962WaterLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

To a solution of tert-butyl N-[5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl]carbamate (210 mg, 0.565 mmol, intermediate 64) in THF (20 mL) and MeOH (20 mL) was added 10% palladium on carbon (20 mg). The reaction mixture was heated at 40° C. under a 400 psi atmosphere of hydrogen for 3 hr. After cooling to room temperature, the mixture was filtered through Celite®, washing with MeOH (50 mL) and concentrated under reduced pressure. To a solution of the residue in DCM (30 mL) was added DIPEA (2 mL, 1.40 mmol), 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (208 mg, 0.62 mmol, Example 22) and PyBOP (727 mg, 1.40 mmol) and the mixture was stirred at room temperature for 18 hr. Water (20 mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (80-100% EtOAc/isohexane) gave tert-butyl N-[2-bromo-4-[[5-[2-(tert-butoxycarbonylamino)-8-oxabicyclo[3.2.1]octan-5-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (120 mg, 34% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.40 (br s, 1H), 9.86 (br s, 1H), 8.12 (br s, 1H), 4.70-4.63 (m, 1H), 4.36-4.22 (m, 1H), 3.97-3.86 (m, 1H), 3.86 (s, 3H), 2.40-2.31 (m, 1H), 2.21-1.93 (m, 7H), 1.55 (s, 9H), 1.52 (s, 9H).

Aufarbeitung

  1. filtrationthe mixture was filtered through Celite®
  2. washwashing with MeOH (50 mL)
  3. concentrationconcentrated under reduced pressure
  4. extractionthe mixture was extracted with DCM (100 mL)
  5. customThe organic layer was passed through a phase separation cartridge
  6. concentrationconcentrated under reduced pressure
  7. customPurification via silica gel chromatography (80-100% EtOAc/isohexane)

Quellen und Nachweise

ORD-Eintrag
ord-ceb30ea113db47759825c663b6b0c634
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09328106B2

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