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

HRID 928158Notes

Reaction equation

HRID 928158 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.[C:33]([OH:38])([CH2:36][CH3:37])(C)C.C([O-])(O)=O.[Na+].C(Cl)(=O)C=C>C(Cl)Cl>[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:33](=[O:38])[CH:36]=[CH2:37])[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

6

Reactant 4

HCID 64052-Methyl-2-butanolHCID 13140Acryloyl chlorideHCID 516892Sodium BicarbonateHCID 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 33%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

(S)-2-(3-Aminopyrrolidin-1-yl)-9-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl) -9H-purin-6-amine (315 mg, 0.7 mmol) was dissolved in DCM:tert-pentyl alcohol (15 mL:1.5 mL) and sat. aq. NaHCO3 (6 mL) was added in one portion. The bi-phasic mixture was stirred vigorously and acryloyl chloride (90 μL, 1.1 mmol, 1.5 mol eq) was added in one portion and the resulting mixture was stirred at ambient temperature for 2 hr. The reaction was diluted with DCM (30 mL) and the organic layer was separated, and the product was extracted with more DCM:tert-pentyl alcohol (9:1, 30 mL). The combined organics were dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography with gradient of 100% ethyl acetate to 100 ethanol to give a crude purity at ˜90%. This crude was triturated with ethyl acetate:heptane (4:1, 15 mL). The resulting white solid was collected by filtration, washed with ethyl acetate:heptane (4:1, 10 mL) and dried to give the title product as a white solid (118 mg, 33% yield, ˜95% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (s, 1 H) 8.36 (d, J=6.72 Hz, 1 H) 7.91 (s, 1 H) 7.85 (d, J=8.80 Hz, 2 H) 6.87 (d, J=8.93 Hz, 2 H) 6.18-6.34 (m, 1 H) 6.03-6.15 (m, 1 H) 5.59 (dd, J=9.96, 2.02 Hz, 1 H) 4.62 (dt, J=13.33, 6.54 Hz, 1 H) 4.43 (d, J=5.14 Hz, 1 H) 3.71-3.87 (m, 1 H) 3.63 (dt, J=12.62, 6.46 Hz, 2 H) 3.43 (dd, J=11.25, 3.30 Hz, 1 H) 3.07 (m, J=4.65 Hz, 4 H) 2.45 (m, J=4.40 Hz, 4 H) 2.22 (s, 4 H) 1.89 (dd, J=11.37, 5.87 Hz, 1 H) 1.51 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C26H35N9O 490.2 (M+H)+.

Workup

  1. stirringthe resulting mixture was stirred at ambient temperature for 2 hr
  2. customthe organic layer was separated
  3. extractionthe product was extracted with more DCM:tert-pentyl alcohol (9:1, 30 mL)
  4. dry with materialThe combined organics were dried over Na2SO4
  5. customevaporated
  6. customto give a residue that
  7. customwas purified via silica flash chromatography with gradient of 100% ethyl acetate to 100 ethanol
  8. customto give a crude purity at ˜90%
  9. customThis crude was triturated with ethyl acetate:heptane (4:1, 15 mL)
  10. filtrationThe resulting white solid was collected by filtration
  11. washwashed with ethyl acetate:heptane (4:1, 10 mL)
  12. customdried

Sources & evidence

ORD record
ord-1c9810f6495e47eea3656db353fa89d5
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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