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 1915865ノート

反応式

HRID 1915865 の反応式
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]

参加物

6

反応物 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

生成物 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-carboxylate収率 44.8%

試薬・触媒・溶媒 2

HCID 71310864Tris(dibenzylideneacetone)dipalladium tri-tert-butyl phosphonium tetrafluoroborate触媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
100 °C

実験手順

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).

後処理

  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)

出典と根拠

ORDレコード
ord-f7e6ba4f370248e88acbc8f029c94ab9
出典データセット
uspto-grants-2013_12
特許番号
US08614206B2

反応ノート

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