Sodium Carbonate → 2-(1-((9-(2-hydroxyethyl)-2-(1H-indol-3-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol

HRID 1692876노트

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HRID 1692876 반응식
[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[N:14][C:13]2[C:8]1=[N:9][C:10](Cl)=[N:11][C:12]=2[N:27]1[CH2:32][CH2:31][O:30]CC1)(=O)[CH3:2].C1(S([N:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45](B(O)O)=[CH:44]2)(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[OH:30][CH2:31][CH2:32][N:27]1[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([C:23]([OH:26])([CH3:24])[CH3:25])[CH2:21][CH2:22]2)=[N:14][C:13]2[C:12]1=[N:11][C:10]([C:45]1[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[NH:43][CH:44]=1)=[N:9][C:8]=2[N:7]1[CH2:2][CH2:1][O:4][CH2:5][CH2:6]1

참가 물질

10

반응물 4

HCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 27762171-(phenylsulfonyl)-1H-indol-3-ylboronic acidHCID 866481532-(2-chloro-8-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-6-morpholino-9H-purin-9-yl)ethyl acetate

생성물 1

HCID 498209812-(1-((9-(2-hydroxyethyl)-2-(1H-indol-3-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol수율 40%

시약·촉매·용매 5

HCID 178418397HCID 178418397, 화합물촉매HCID 702Ethanol용매2회HCID 962Water용매HCID 1140Toluene용매HCID 8857Ethyl Acetate용매

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온도
95 °C

실험 절차

To a degassed suspension of 2-(2-chloro-8-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-6-morpholino-9H-purin-9-yl)ethyl acetate (110 mg, 0.23 mmol), 1-(phenylsulfonyl)-3-indoleboronic acid (83 mg, 0.27 mmol), 2 M Na2CO3 aqueous solution (0.23 mL, 0.46 mmol) in toluene (3 mL) and ethanol (1 mL) was added Pd(PPh3)4 (10 mg, 0.009 mmol). The suspension was then stirred under nitrogen at 95° C. for 18 hours. The reaction mixture was then diluted with EtOAc and water. The layers were then separated. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude mixture was filtered through a pad of silica gel (10% MeOH in DCM) and the filtrate was concentrated to give a yellow paste which was then taken up in ethanol (10 mL). To the solution was added a 1 M aqueous solution of NaOH (2 mL, 2 mmol). After 2 hours of stirring at 65° C., the reaction mixture was concentrated and purified by RP-HPLC to give 107 (32 mg, 40%). LCMS: M+H+=520.3. 1H-NMR (400 MHz, DMSO-d6): δ 11.5 (s, 1H), 8.54 (m, 1H), 8.20 (s, 1H), 8.11 (d, 1H), 7.44 (m, 1H), 7.14 (m, 2H), 4.44 (t, 2H), 4.27 (s, br, 4H), 3.85 (t, 2H), 3.78 (m, 4H), 3.72 (s, 3H), 2.91 (m, 2H), 1.98 (m, 2H), 1.67 (m, 2H), 1.21 (m, 3H), 1.01 (s, 6H)

후처리

  1. customThe layers were then separated
  2. extractionThe aqueous layer was extracted three times with EtOAc
  3. washThe combined organic extracts were washed with water
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. filtrationThe crude mixture was filtered through a pad of silica gel (10% MeOH in DCM)
  8. concentrationthe filtrate was concentrated
  9. customto give a yellow paste which
  10. stirringAfter 2 hours of stirring at 65° C.
  11. concentrationthe reaction mixture was concentrated
  12. custompurified by RP-HPLC

출처 및 근거

ORD 기록
ord-df8cecc2ac7d424db98a68aa64286120
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08158625B2

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