Potassium Phosphate, Tribasic → HCID 53329356, compound

HRID 1028998Notes

Reaction equation

HRID 1028998 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.I[C:70]1[C:75]([CH3:76])=[CH:74][CH:73]=[CH:72][C:71]=1[C:77]1[N:81]2[CH:82]=[CH:83][CH:84]=[CH:85][C:80]2=[CH:79][N:78]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:79]1[N:78]=[C:77]([C:71]2[CH:72]=[CH:73][CH:74]=[C:75]([CH3:76])[C:70]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH2:26])[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16]3)[N:81]2[CH:82]=[CH:83][CH:84]=[CH:85][C:80]=12

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 67347968HCID 67347968, compoundHCID 673479953-Morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine

Product 1

HCID 53329356HCID 53329356, compound

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
140 °C

Procedure

A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.236 g, 0.664 mmol, prepared as in Example 2, Step 1-2), potassium phosphate (0.564 g, 2.66 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.063 g, 0.133 mmol), Pd2(dba)3 (0.030 g, 0.033 mmol), and 3-(2-iodo-3-methylphenyl)imidazo[1,5-a]pyridine (0.222 g, 0.664 mmol). The vessel was evacuated and flushed with nitrogen three times before dioxane (4.43 mL) and water (2.215 mL) (each degassed by bubbling nitrogen gas through the solution for 10 min prior to addition) were added. The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 15 min. The reaction mixture was diluted with 10:1 saturated ammonium chloride/ammonium hydroxide and extracted with EtOAc. The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:20 2M NH3 in MeOH/DCM. The fractions containing the product (with some impurities) were combined and concentrated. The solid was dissolved in MeOH and filtered to remove some of the impurity. The remainder of the sample was purified by reverse-phase preparative HPLC with 0.1% TFA in CH3CN/H2O, gradient 5-70% over 20 min to provide 6-(2-(imidazo[1,5-a]pyridin-3-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine. The purified compound was partitioned between DCM and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 6-(2-(imidazo[1,5-a]pyridin-3-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. MS (ESI, pos. ion) m/z: 436 (M+1).

Workup

  1. customA glass microwave reaction vessel
  2. customThe vessel was evacuated
  3. customflushed with nitrogen three times before dioxane (4.43 mL) and water (2.215 mL) (
  4. customeach degassed
  5. customby bubbling nitrogen gas through the solution for 10 min
  6. additionto addition)
  7. additionwere added
  8. additionThe reaction mixture was diluted with 10:1 saturated ammonium chloride/ammonium hydroxide
  9. extractionextracted with EtOAc
  10. washThe combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide, water, saturated sodium chloride
  11. dry with materialdried over sodium sulfate
  12. filtrationThe solution was filtered
  13. concentrationconcentrated in vacuo
  14. customto give the crude material
  15. customThe crude material was purified by silica gel chromatography
  16. washby eluting with 1:20 2M NH3 in MeOH/DCM
  17. additionThe fractions containing the product (with some impurities)
  18. concentrationconcentrated
  19. dissolutionThe solid was dissolved in MeOH
  20. filtrationfiltered
  21. customto remove some of the impurity
  22. customThe remainder of the sample was purified by reverse-phase preparative HPLC with 0.1% TFA in CH3CN/H2O, gradient 5-70% over 20 min

Sources & evidence

ORD record
ord-a6e2edc9462f4140898e7972551581b4
Source dataset
uspto-grants-2014_05
Patent number
US08735384B2

Reaction notes

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