Lithium Chloride → HCID 86713888、化合物

HRID 521963

反応式

HRID 521963 の反応式
Br[C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][C:46]=1[Sn](CCCC)(CCCC)CCCC.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:25]([O:24][C:22]([NH:21][C@H:18]1[C@@H:17]([F:29])[CH2:16][O:15][C@H:14]([C:13]2[N:12]([CH3:30])[N:11]=[CH:10][C:9]=2[NH:8][C:7]([C:5]2[N:6]=[C:2]([C:46]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[F:40])[S:3][C:4]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:20][CH2:19]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]

参加物

7

反応物 3

HCID 433294Lithium Chloride2 回HCID 222736013-Fluoro-4-(tributylstannyl)pyridine2 回HCID 86713830tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate2 回

生成物 1

HCID 86713888HCID 86713888、化合物

試薬・触媒・溶媒 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)触媒2 回HCID 178418397HCID 178418397、化合物触媒2 回HCID 312751,4-Dioxane溶媒

反応条件

温度
135 °C

実験手順

A mixture of tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (100 mg, 0.16 mmol, intermediate 88), 3-fluoro-4-tri-n-butylstannyl pyridine (93 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (9.3 mg, 0.008 mmol), copper (I) iodide (9 mg, 0.047 mmol) and lithium chloride (21 mg, 0.48 mmol) in dioxane (1.5 mL) was degassed by bubbling nitrogen gas through it for 5 min. The mixture was heated at 135° C. under microwave irradiation for 45 min. After cooling to room temperature, more 3-fluoro-4-tri-n-butylstannyl pyridine (93 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (9.3 mg, 0.008 mmol), copper (I) iodide (9 mg, 0.047 mmol) and lithium chloride (21 mg, 0.48 mmol) were added and the mixture was degassed by bubbling nitrogen gas through it for 5 min. The mixture was heated at 135° C. for 45 min, cooled to room temperature, filtered through celite and the filtrate concentrated under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl N-[4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(3-fluoro-4-pyridyl)thiazol-5-yl]carbamate as a pale brown solid. This solid was stirred in a solution of HCl (4.0 M in dioxane, 3 mL) and MeOH (0.5 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure. Purification via preparative HPLC gave 182 as the formate salt as a pale pink solid (26 mg, 33%). 1H NMR (400 MHz, d6-DMSO) δ 9.27 (s, 1H), 8.43 (d, J=2.8 Hz, 1H), 8.28-8.23 (m, 1H), 8.00 (s, 1H), 7.78-7.72 (m, 1H), 7.47 (s, 1H), 7.42 (br s, 2H), 4.78-4.58 (m, 2H), 3.99-3.85 (m, 1H), 3.79-3.67 (m, 1H), 3.49 (s, 3H), 3.17-3.02 (m, 1H), 1.90-1.80 (m, 1H), 1.67-1.51 (m, 2H), 1.41 (d, J=13.1 Hz, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 450 (M+1).

後処理

  1. customwas degassed
  2. customby bubbling nitrogen gas through it for 5 min
  3. temperatureAfter cooling to room temperature
  4. customthe mixture was degassed
  5. customby bubbling nitrogen gas through it for 5 min
  6. temperatureThe mixture was heated at 135° C. for 45 min
  7. temperaturecooled to room temperature
  8. filtrationfiltered through celite
  9. concentrationthe filtrate concentrated under reduced pressure
  10. customPurification via silica gel column chromatography (0-80% EtOAc/isohexane)

出典と根拠

ORDレコード
ord-447be63c7eaa4a6d89877e42b133e3af
出典データセット
uspto-grants-2016_05
特許番号
US09328106B2

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