Isopropanol → 8-Chloro-2-phenyl-3-[(1S)-1-[[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino]ethyl]-1(2H)-isoquinolinone

HRID 2406257Notes

Reaction equation

HRID 2406257 reaction equation
[NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CC(O)C.C(N(CC)CC)C>CCCCCCC>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2

Participants

6

Reactant 4

HCID 3776IsopropanolHCID 8471TriethylamineHCID 977406-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine2×HCID 66607319(S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one2×

Product 1

HCID 666077098-Chloro-2-phenyl-3-[(1S)-1-[[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino]ethyl]-1(2H)-isoquinolinoneYield 90.2%

Reagents, catalysts & solvents 1

HCID 8900HeptaneSolvent

Conditions

Temperature
2.5 °C

Procedure

3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) (150 g; 90% ee) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5° C., held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25° C. for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48° C. for two and half days to give 227 g (90.1%) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94% ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.

Workup

  1. temperatureat reflux for one day
  2. filtrationfiltered
  3. washThe cake was washed with heptane (450 mL; 3 vol)
  4. additionIPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added
  5. stirringthe resultant slurry stirred at 20-25° C. for three and half hours
  6. filtrationthen filtered
  7. washThe cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol)
  8. customvacuum dried at 48° C. for two and half days

Sources & evidence

ORD record
ord-106c5f3b38a941bd8d4805e65bb64853
Source dataset
uspto-grants-2014_08
Patent number
US08809349B2

Reaction notes

Loading…