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Cesium carbonate → (S)-6-tert-Butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl) phthalazin-1(2H)-one

HRID 1185158
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HRID 1185158 반응식
Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][CH:7]=1.C([O:30][CH2:31][C:32]1[C:33]([N:47]2[N:56]=[CH:55][C:54]3[C:49](=[C:50]([F:61])[CH:51]=[C:52]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:53]=3)[C:48]2=[O:62])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O.O1CCOCC1>[C:57]([C:52]1[CH:53]=[C:54]2[C:49](=[C:50]([F:61])[CH:51]=1)[C:48](=[O:62])[N:47]([C:33]1[C:32]([CH2:31][OH:30])=[C:37]([C:2]3[CH:3]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][N:19]([CH:22]6[CH2:25][O:24][CH2:23]6)[CH2:18][C@@H:17]5[CH3:26])=[CH:12][N:11]=4)[C:5](=[O:8])[NH:6][CH:7]=3)[CH:36]=[CH:35][N:34]=1)[N:56]=[CH:55]2)([CH3:60])([CH3:58])[CH3:59]
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참가 물질

8

반응물 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 86683972(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetateHCID 86684015(S)-5-Chloro-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one

생성물 1

HCID 86684016
(S)-6-tert-Butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl) phthalazin-1(2H)-one
수율 18%

시약·촉매·용매 3

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

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온도
120 °C

실험 절차

A sealed tube equipped with a magnetic stirrer was charged with 138c (150 mg, 0.40 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (495.6 mg, 1.2 mmol), Pd2(dba)3 (36.6 mg, 0.040 mmol), P(cy)3(44.6 mg, 0.16 mmol), Cs2CO3 (391.2 mg, 1.2 mmol), dioxane (8 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 120° C. for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 ethyl acetate/methanol and further purified by reverse-phase prep-HPLC to afford 138 (48 mg, 18%) as a yellow solid. MS-ESI: [M+H]+ 667.3. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.55 (d, J=3.0 Hz, 1H), 8.44 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.79 (dd, J=1.0 Hz, 13.0 Hz, 1H), 7.54 (d, J=5.0 Hz, 1H), 7.39 (dd, J=2.5 Hz, 9.0 Hz, 1H), 7.26-7.23 (m, 2H), 4.97-4.95 (m, 1H), 4.58-4.54 (m, 2H), 4.48-4.46 (m, 1H), 4.43-4.41 (m, 1H), 4.38-4.37 (m, 2H), 3.69-3.68 (m, 1H), 3.41-3.39 (m, 1H), 3.11-3.09 (m, 1H), 2.97-2.93 (m, 1H), 2.56-2.54 (m, 1H), 2.35-2.32 (m, 2H), 2.21-2.17 (m, 1H), 1.40 (s, 9H), 0.94 (d, J=6.5 Hz, 3H),

후처리

  1. customA sealed tube equipped with a magnetic stirrer
  2. customAfter three cycles of vacuum/argon flush
  3. temperatureAfter this time the reaction was cooled to room temperature
  4. filtrationIt was then filtered
  5. customthe filtrate was evaporated under reduced pressure
  6. customThe residue was purified by silica-gel column chromatography
  7. washeluting with 40:1 ethyl acetate/methanol
  8. customfurther purified by reverse-phase prep-HPLC

출처 및 근거

ORD 기록
ord-f7d0fbcbf8dd4fe8ae2aedbc2dab32fe
출처 데이터셋
uspto-grants-2014_03
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08669251B2

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