Lithium Chloride → HCID 86713888, 화합물

HRID 521963

반응식

HRID 521963 반응식
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]

참가 물질

7

반응물 3

HCID 433294Lithium Chloride2회HCID 222736013-Fluoro-4-(tributylstannyl)pyridine2회HCID 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]carbamate2회

생성물 1

HCID 86713888HCID 86713888, 화합물

시약·촉매·용매 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매2회HCID 178418397HCID 178418397, 화합물촉매2회HCID 312751,4-Dioxane용매

반응 조건

온도
135 °C

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-447be63c7eaa4a6d89877e42b133e3af
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09328106B2

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