Dimethylformamide → LY-2452473

HRID 2427280Notes

Reaction equation

HRID 2427280 reaction equation
Cl.[NH2:2][C@@H:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1.CN(C=O)C.C(N(CC)CC)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>CCCCCCC>[CH:40]([O:39][C:37](=[O:38])[NH:2][C@@H:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)([CH3:42])[CH3:41]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 7917Isopropyl chloroformateHCID 8471TriethylamineHCID 67252403HCID 67252403, compound

Product 1

HCID 24963749LY-2452473Yield 84.5%

Reagents, catalysts & solvents 1

HCID 8900HeptaneSolvent

Conditions

Temperature
0 °C

Procedure

Equip a 2 L reaction flask with a cooling bath, air stirrer, temperature probe, and addition funnel Charge the flask with (S)-2-amino-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile hydrochloride (62.8 g, 0.218 moles), DMF (188 mL), and triethylamine (33.4 mL, 0.240 mol). Cool the resulting solution to 0° C. using an ice/acetone bath. While maintaining the temp at <10° C., add isopropyl chloroformate (218 mL, 0.218 mol, 1 M in toluene) drop-wise via an addition funnel. When the addition is complete, remove the cooling bath was removed and allow the mixture to warm to ambient temperature. After 1 hour, analyze by HPLC to indicate the reaction is complete, and pour the mixture into a solution of deionized water (1256 mL) and EtOAc (1884 mL). Separate the layers, filter the organic layer, and re-wash with a 1:1 water:brine solution, then dry over Na2SO4. Concentrate in vacuo at 55° C. to about 15 volumes, and allow the resulting to cool to ambient temperature, affording a white precipitate. Add heptane (628 mL) and stir for 20 min. Concentrate the mixture back to about 15 volumes. Filter the solids, wash with heptane, and dry to give the titled compound as a fluffy white solid (68.9 g, 84.5%). 1H NMR (500 MHz, DMSO-d6), δ 8.49 (dd, 1H), 7.86 (d, 1H, J=1.5), 7.71-7.75 (m, 1H), 7.60 (d, 1H, J=9.0), 7.57 (d, 1H, J=9.0), 7.36 (dd, 1H), 7.28-7.26 (m, 1H), 7.14 (d, 1H, J=7.5), 5.44 (s, 2H), 4.79-4.72 (m, 1H), 4.71-4.66 (m, 1H), 3.22-3.20 (m, 1H), 3.16-3.12 (m, 1H), 2.73-2.66 (m, 2H), 1.16 (dd, 6H).

Workup

  1. customEquip
  2. customa 2 L reaction flask with a cooling bath, air stirrer
  3. additiontemperature probe, and addition funnel
  4. temperatureWhile maintaining the temp at <10° C.
  5. additionWhen the addition
  6. customremove the cooling bath
  7. customwas removed
  8. temperatureto warm to ambient temperature
  9. additionpour the mixture into a solution of deionized water (1256 mL) and EtOAc (1884 mL)
  10. customSeparate the layers
  11. filtrationfilter the organic layer
  12. washre-wash with a 1:1 water
  13. dry with materialbrine solution, then dry over Na2SO4
  14. concentrationConcentrate in vacuo at 55° C. to about 15 volumes
  15. temperatureto cool to ambient temperature
  16. customaffording a white precipitate
  17. concentrationConcentrate the mixture back to about 15 volumes
  18. filtrationFilter the solids
  19. washwash with heptane
  20. customdry

Sources & evidence

ORD record
ord-7b6c05431a984647b1c5979c6c8ef4eb
Source dataset
uspto-grants-2011_06
Patent number
US07968587B2

Reaction notes

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