Sodium Carbonate → 1-((2-(isoquinolin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine

HRID 1945708Notes

Reaction equation

HRID 1945708 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:27]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[C:31]=2[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:27]1[C:36]2[C:31](=[C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1

Participants

5

Reactant 3

HCID 10340Sodium CarbonateHCID 599474Isoquinoline-5-boronic acidHCID 575067401-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine

Product 1

HCID 596057931-((2-(isoquinolin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amineYield 50%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
130 °C

Procedure

A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.630 g, 1.59 mmol), isoquinoline-5-boronic acid (0.331 g, 1.91 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.056 g, 0.08 mmol), 1 N aqueous sodium carbonate solution (2.5 mL) and acetonitrile (7.5 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in methanol and filtered through celite. The filtrates were concentrated then purified by chromatography (C-18 reverse phase column, 5 to 95% acetonitrile in water containing 0.1% TFA). The fractions containing the desired product were concentrated then dissolved in MeOH/dichloromethane, basified with solid sodium carbonate then filtered and concentrated to furnish 109 (0.386 g, 50%) as a white foam. MS m/e 489 [M+H]; 1H NMR (300 MHz, MeOH-d4) δ ppm 1.61-1.91 (m, 2 H) 1.99-2.15 (m, 2 H) 2.17-2.36 (m, 2 H) 2.88 (s, 6 H) 3.04-3.28 (m, 3 H) 3.73-3.87 (m, 4 H) 3.91 (s, 2 H) 3.96-4.07 (m, 4 H) 7.33 (s, 1 H) 7.69-7.83 (m, 1 H) 8.18 (d, J=8.3 Hz, 1 H) 8.30 (d, J=7.2 Hz, 1 H) 8.43 (d, J=6.4 Hz, 1 H) 8.57 (d, J=6.0 Hz, 1 H) 9.28 (s, 1 H)

Workup

  1. customThe vessel was evacuated
  2. additionback-filled with argon three times
  3. customthen sealed
  4. temperatureThe reaction mixture was cooled
  5. concentrationconcentrated
  6. dissolutionredissolved in methanol
  7. filtrationfiltered through celite
  8. concentrationThe filtrates were concentrated
  9. customthen purified by chromatography (C-18 reverse phase column, 5 to 95% acetonitrile in water containing 0.1% TFA)
  10. additionThe fractions containing the desired product
  11. concentrationwere concentrated
  12. dissolutionthen dissolved in MeOH/dichloromethane
  13. filtrationthen filtered
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-c9d2f52d438f484aa1a0d4c6715084fe
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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