1H-Indazole-6-boronic acid → 6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

HRID 2400523노트

반응식

HRID 2400523 반응식
Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](B(O)O)[CH:27]=2)[CH:22]=[N:21]1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(Cl)Cl.O.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>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)[CH:27]=2)[CH:22]=[N:21]1

참가 물질

8

반응물 2

HCID 247286171H-Indazole-6-boronic acidHCID 866424656-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

생성물 1

HCID 462396696-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine수율 39.1%

시약·촉매·용매 5

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매HCID 6344Dichloromethane용매HCID 10340Sodium Carbonate용매HCID 312751,4-Dioxane용매

반응 조건

온도
135 °C

실험 절차

A mixture of impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (195 mg), from above, and 1H-indazol-6-ylboronic acid (159 mg, 0.650 mmol) in 1 M aqueous sodium carbonate (1.3 mL) and 1,4-dioxane (3.5 mL) was sparged with nitrogen while stirring for 5 min. Tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.060 mmol) was then added and the resulting mixture heated under microwave irradiation at 135° C. for 30 min. After this time, the reaction was diluted with methylene chloride (30 mL) and water (20 mL), and filtered through diatomaceous earth. The filtrate layers were separated and the aqueous phase was extracted with a mixture of 9:1 methylene chloride/methanol (100 mL). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by chromatography (silica, gradient, methylene chloride to 8:2 methylene chloride/methanol), then trituration with acetonitrile to afford 6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (5) (85 mg, 35%) as a yellow solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 9.95 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.75 (dd, J=8.7, 1.2 Hz, 1H), 7.62 (s, 1H), 4.52 (m, 1H), 1.47 (d, J=6.6 Hz, 6H); ESI MS m/z 359.4 [M+H]+; HPLC, 5.37 min, >99% (AUC).

후처리

  1. filtrationfiltered through diatomaceous earth
  2. customThe filtrate layers were separated
  3. extractionthe aqueous phase was extracted with a mixture of 9:1 methylene chloride/methanol (100 mL)
  4. concentrationThe combined organic layers were concentrated under reduced pressure
  5. customthe resulting residue was purified by chromatography (silica, gradient, methylene chloride to 8:2 methylene chloride/methanol)

출처 및 근거

ORD 기록
ord-87599335931141489452882f64264a8d
출처 데이터셋
uspto-grants-2014_08
특허 번호
US08796270B2

반응 노트

불러오는 중…