Hydrochloric Acid → 4-(5-(3-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile

HRID 1042278Notes

Reaction equation

HRID 1042278 reaction equation
[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.F[C:23]1[C:28]([C:29]2[C:30]3[NH:37][CH:36]=[CH:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[CH:27][CH:26]=[CH:25][N:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[N:32]1[C:31]2[CH:35]=[CH:36][NH:37][C:30]=2[C:29]([C:28]2[C:23]([NH:1][C:2]3[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[C:7]4[NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:34][CH:33]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 2733832Lithium HexamethyldisilazideHCID 596273664-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidineHCID 687254604-(5-Amino-6-methylisoquinolin-1-ylamino)benzonitrile

Product 1

HCID 251333314-(5-(3-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-(5-amino-6-methylisoquinolin-1-ylamino)benzonitrile (0.150 g, 0.55 mmol) and 4-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (0.13 g, 0.60 mmol) in anhydrous THF (10 mL) was stirred at RT and treated dropwise with lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.7 mL, 1.7 mmol) to give a dark suspension. After 1 h stirring, the mixture was treated with 1 N aq HCl (10 mL) and stirred at RT for 10 min. The reaction mixture was added to satd NaHCO3 (70 mL) and extracted with 3:1 CHCl3IPA (3×70 mL). The combined organic layers were washed with satd NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 70% to 90% EtOAc in CH2Cl2 to provide 50 mg. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 13 min. Fractions containing product were combined, concentrated in vacuo, and lyophilized to give 4-(5-(3-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile as a bright yellow solid. MS (ESI, pos. ion) m/z: 469.2 [M+H]+

Workup

  1. customto give a dark suspension
  2. stirringAfter 1 h stirring
  3. stirringstirred at RT for 10 min
  4. extractionextracted with 3:1 CHCl3IPA (3×70 mL)
  5. washThe combined organic layers were washed with satd NaCl (50 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customchromatographed through a Redi-Sep® pre-packed silica gel column (40 g)
  10. washeluting with a gradient of 70% to 90% EtOAc in CH2Cl2
  11. customto provide 50 mg
  12. customThe crude product was purified by reverse-phase preparative HPLC
  13. customover 13 min
  14. additionFractions containing product
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-45dd34347ecd432da80163173777b734
Source dataset
uspto-grants-2013_10
Patent number
US08557830B2

Reaction notes

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