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 1024069ノート

反応式

HRID 1024069 の反応式
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

参加物

8

反応物 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

生成物 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)-one収率 13.4%

試薬・触媒・溶媒 3

HCID 962Water触媒HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
130 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-11ca0454997e45cab333722d09a2215b
出典データセット
uspto-grants-2014_05
特許番号
US08722676B2

反応ノート

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