Cesium carbonate → (S)-2-(3-(hydroxymethyl)-4-(8-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyridin-2-yl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one

HRID 1024069노트

반응식

HRID 1024069 반응식
Br[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][C@@H:19]3[CH3:28])=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O:32][CH2:33][C:34]1[C:35]([N:49]2[CH2:61][CH2:60][N:52]3[C:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=4[CH:59]=[C:51]3[C:50]2=[O:62])=[N:36][CH:37]=[CH:38][C:39]=1B1OC(C)(C)C(C)(C)O1)(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.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].O1CCOCC1>[OH:32][CH2:33][C:34]1[C:35]([N:49]2[CH2:61][CH2:60][N:52]3[C:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=4[CH:59]=[C:51]3[C:50]2=[O:62])=[N:36][CH:37]=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:20][C@@H:19]3[CH3:28])=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1

참가 물질

8

반응물 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 86684143(2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetateHCID 86684147(S)-6-Bromo-N-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine

생성물 1

HCID 71557302(S)-2-(3-(hydroxymethyl)-4-(8-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyridin-2-yl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one수율 13.4%

시약·촉매·용매 3

HCID 962Water촉매HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 312751,4-Dioxane용매

반응 조건

온도
130 °C

실험 절차

A sealed tube was charged with 115e (156 mg, 0.35 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 114e (134 mg, 0.35 mmol), Pd2(dba)3 (64 mg, 0.070 mmol), PCy3 (40 mg, 0.14 mmol), cesium carbonate (228 mg, 0.70 mmol), water (1 drop), and dioxane (9 mL). After three cycles of vacuum/argon flush, the mixture was heated at 130° C. for 16 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol and further purified with reverse-phase prep-HPLC to afford 115 (31 mg, 13%). MS-ESI: [M+H]+ 661.3. 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.25 (d, J=5.0 Hz, 1H), 8.19 (d, J=0.5 Hz, 1H), 7.95 (s, 1H), 7.68 (d, J=1.0 Hz, 1H), 7.48-7.44 (m, 3H), 6.58 (s, 1H), 4.76 (t, J=5.0 Hz, 1H), 4.58-4.54 (m, 3H), 4.49-4.46 (m, 1H), 4.43-4.36 (m, 2H), 4.30-4.05 (m, 3H), 3.94-3.87 (m, 2H), 3.42-3.37 (m, 1H), 3.24-3.19 (m, 1H), 3.00-2.96 (m, 1H), 2.66-2.57 (m, 3H), 2.47-2.43 (m, 3H), 2.28-2.26 (m, 1H), 2.12-2.09 (m, 1H), 1.79-1.68 (m, 4H), 1.00 (d, J=6.5 Hz, 3H).

후처리

  1. customAfter three cycles of vacuum/argon flush
  2. temperatureIt was then cooled to room temperature
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. customthe resulting residue was purified by silica-gel column chromatography
  6. washeluting with 40:1 dichloromethane/methanol
  7. customfurther purified with reverse-phase prep-HPLC

출처 및 근거

ORD 기록
ord-11ca0454997e45cab333722d09a2215b
출처 데이터셋
uspto-grants-2014_05
특허 번호
US08722676B2

반응 노트

불러오는 중…