2,6-Difluorophenylboronic acid → tert-butyl 4-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate

HRID 1915865Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1915865
Br[C:2]1[S:3][C:4]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH:31]3[CH2:33][CH2:32]3)[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]2)=[O:8])[N:6]=1.O.O.[F-].[K+].[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[C:48]=1B(O)O>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[C:38]([O:37][C:35]([NH:34][C:4]1[S:3][C:2]([C:48]2[C:47]([F:46])=[CH:52][CH:51]=[CH:50][C:49]=2[F:53])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH:31]2[CH2:33][CH2:32]2)[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]1)=[O:8])=[O:36])([CH3:41])([CH3:40])[CH3:39]

Komponenten

6

Edukt 3

HCID 27343362,6-Difluorophenylboronic acidHCID 23708904Potassium fluoride dihydrateHCID 86680073tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate

Produkt 1

HCID 86680074tert-butyl 4-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylateAusbeute 44,8 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 71310864Tris(dibenzylideneacetone)dipalladium tri-tert-butyl phosphonium tetrafluoroborateKatalysatorHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A mixture of tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate (191 mg, 0.29 mmol), potassium fluoride dihydrate (90 mg, 0.96 mmol) and 2,6-difluoro-phenylboronic acid (137 mg, 0.87 mmol) in THF (3 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2) (35 mg, 0.029 mmol) was then added and the mixture degassed was heated in a microwave at 100° C. for 2 hr. The solvent was removed under reduced pressure. Water (5 mL) was added and the mixture extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to give tert-butyl 4-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate as an orange solid (95 mg, 0.13 mmol) which was dissolved in a solution of HCl in 1,4-dioxane (4 M, 0.7 mL, 2.73 mmol) and MeOH (0.2 mL) and stirred at 70° C. for 48 hr. The solvent was removed under reduced pressure and the residue dissolved in MeOH/DCM and passed through an SCX cartridge washing with DCM and MeOH and eluting with 1 N ammonia in MeOH. Purification by silica gel column chromatography (0-10% MeOH/DCM) gave 145 as a beige solid (35 mg, 25% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 7.87 (s, 1H), 7.38-7.28 (m, 1H), 7.08-6.97 (m, 2H), 6.20 (s, 2H), 3.71-3.56 (m, 3H), 3.46-3.35 (m, 4H), 3.12-3.06 (m, 2H), 1.25-1.19 (m, 2H), 1.06-0.97 (m, 2H). Alkyl NH not observed. LCMS (ES+) m/z 496 (M+1).

Aufarbeitung

  1. customwas degassed by gently bubbling nitrogen through the mixture for 15 min
  2. customthe mixture degassed
  3. customThe solvent was removed under reduced pressure
  4. additionWater (5 mL) was added
  5. extractionthe mixture extracted with EtOAc (2×20 mL)
  6. dry with materialThe combined organic layers were dried over MgSO4
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified via silica gel column chromatography (0-60% EtOAc/isohexane)

Quellen und Nachweise

ORD-Eintrag
ord-f7e6ba4f370248e88acbc8f029c94ab9
Quelldatensatz
uspto-grants-2013_12
Patentnummer
US08614206B2

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