Nitrogen → 2-(4-((2-(1-Aminoisoquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide

HRID 1945707Notes

Reaction equation

HRID 1945707 reaction equation
Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[N:4][CH:3]=1.C([O-])(=O)C.[K+].N#N.Cl[C:21]1[N:22]=[C:23]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[C:24]2[S:29][C:28]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:33][CH2:32]3)=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C(Cl)Cl.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:21]2[N:22]=[C:23]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[C:24]3[S:29][C:28]([CH2:30][N:31]4[CH2:32][CH2:33][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:35][CH2:36]4)=[CH:27][C:25]=3[N:26]=2)=[CH:3][N:4]=1

Participants

12

Reactant 6

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 3118704-Bromo-1-isoquinolinamineHCID 517044Potassium AcetateHCID 574940122-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide

Product 1

HCID 596060662-(4-((2-(1-Aminoisoquinolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamideYield 16.2%

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent3×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
80 °C

Procedure

A mixture of 4-bromoisoquinolin-1-amine (126 mg, 0.565 mmol), bispinacol ester boronate (358 mg, 1.41 mmol), and potassium acetate (333 mg, 3.39 mmol) in 1,4-dioxane (4.6 mL) was sparged with N2 for 10 min. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (23.1 mg, 0.0282 mmol) was added. The mixture was sealed under N2 and heated at 80° C. for 20 h, diluted with DCM, the contents were filtered, washed with DCM, and concentrated. The crude product was mixed with 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (124 mg, 0.282 mmol), a 1 M solution of sodium carbonate (0.85 mL) and 1,4-dioxane (3.4 mL, 44 mmol). The mixture was sparged with N2 for 10 min. Palladium acetate (6.342 mg, 0.02825 mmol) and a 1.0 M solution of tri-tert-butylphosphine in toluene (0.0565 mL) were added. The mixture was sealed under N2 and heated at 85° C. for 6 h, diluted with DCM, the contents were filtered, and concentrated. The residue was purified with flash chromatography. The fractions containing the desired product were collected, concentrated, and purified with reverse-phase HPLC to give 108 (25 mg, 16%). LCMS: M+H+=467. 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=8.6, 1H), 8.67 (s, 1H), 7.85 (d, J=8.3, 1H), 7.71-7.64 (m, 1H), 7.53 (t, J=7.3, 1H), 7.34 (s, 1H), 7.10 (s, 1H), 5.29 (s, 2H), 5.20 (s, 1H), 4.10-3.99 (m, 4H), 3.87 (dd, J=9.1, 4.6, 6H), 2.61 (s, 8H), 1.24 (s, 6H)

Workup

  1. additionwas added
  2. customThe mixture was sealed under N2
  3. filtrationthe contents were filtered
  4. washwashed with DCM
  5. concentrationconcentrated
  6. customThe mixture was sparged with N2 for 10 min
  7. customThe mixture was sealed under N2
  8. temperatureheated at 85° C. for 6 h
  9. filtrationthe contents were filtered
  10. concentrationconcentrated
  11. customThe residue was purified with flash chromatography
  12. additionThe fractions containing the desired product
  13. customwere collected
  14. concentrationconcentrated
  15. custompurified with reverse-phase HPLC

Sources & evidence

ORD record
ord-fc02e923eb2e4f999db9793733db240f
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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