Acrylic Acid → (S)-N-(1-(9-isopropyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

HRID 928159Notes

Reaction equation

HRID 928159 reaction equation
[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:42](O)(=[O:45])[CH:43]=[CH2:44].CCCP(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:16]([N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:42](=[O:45])[CH:43]=[CH2:44])[CH2:3]1)=[N:8][C:9]=2[NH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)([CH3:18])[CH3:17]

Participants

9

Reactant 5

HCID 6581Acrylic AcidHCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 16167369Propylphosphoric anhydrideHCID 118073535(S)-2-(3-Aminopyrrolidin-1-yl)-9-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-9H-purin-6-amine

Product 1

HCID 118073537(S)-N-(1-(9-isopropyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)acrylamideYield 34.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-2-(3-Aminopyrrolidin-1-yl)-9-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl) -9H-purin-6-amine (436 mg, 1 mmol) was suspended in DMF (3.3 mL). DIPEA (0.53 mL, 3 mmol, 3 mol eq) and acrylic acid (73 μL, 1.05 mmol, 1.05 mol eq) were added to give a suspension. Propylphosphonic anhydride (CAS 68957-94-8, 50% in DMF, 0.7 mL, 1.2 mmol, 1.2 mol eq) was added in one portion. The reaction mixture warmed up slightly to afford a solution. After 15 min, aqueous Na2CO3 (1 M, 2 mL, 2 mmol) was added and stirred for 30 min. Water (10 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with water (3×10 mL), dried over Na2SO4 and evaporated to give a light yellow foamy solid, which was purified by SFC (Column ZymorSpher HADP 150×21.2 mm I.D., 5 μm particles. Modifier: ethanol. Gradient 21% (hold 2 min) to 24% (hold 1 min) at 1.5% per min. Flow rate (58 mL/min) to give the title product (167 mg, 34% yield, >95% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (s, 1 H) 8.36 (d, J=6.85 Hz, 1 H) 7.91 (s, 1 H) 7.85 (d, J=9.05 Hz, 2 H) 6.87 (d, J=9.05 Hz, 2 H) 6.19-6.32 (m, 1 H) 6.05-6.16 (m, 1 H) 5.59 (dd, J=10.09, 2.38 Hz, 1 H) 4.62 (quin, J=6.72 Hz, 1 H) 4.34-4.48 (m, 1 H) 3.76 (dd, J=11.31, 6.30 Hz, 1 H) 3.54-3.70 (m, 2 H) 3.43 (dd, J=11.19, 3.85 Hz, 1 H) 2.93-3.14 (m, 4 H) 2.39-2.47 (m, 4 H) 2.22 (s, 3 H) 2.12-2.20 (m, 1 H) 1.83-1.95 (m, 1 H) 1.51 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C26H35N9O 490.4 (M+H)+.

Workup

  1. customto give a suspension
  2. temperatureThe reaction mixture warmed up slightly
  3. customto afford a solution
  4. customThe organic layer was separated
  5. washwashed with water (3×10 mL)
  6. dry with materialdried over Na2SO4
  7. customevaporated
  8. customto give a light yellow foamy solid, which
  9. customwas purified by SFC (Column ZymorSpher HADP 150×21.2 mm I.D
  10. customGradient 21% (hold 2 min)
  11. customto 24% (hold 1 min)

Sources & evidence

ORD record
ord-5a231b23738d423a9b59a825d1f00124
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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