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 1692876Notes

Reaction equation

HRID 1692876 reaction equation
[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

Participants

10

Reactant 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

Product 1

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

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolvent2×HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

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)

Workup

  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

Sources & evidence

ORD record
ord-df8cecc2ac7d424db98a68aa64286120
Source dataset
uspto-grants-2012_04
Patent number
US08158625B2

Reaction notes

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