Hydrazine hydrate (1:1) → (S)-[4-(2-Amino-pyridin-3-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester

HRID 2427271Notes

Reaction equation

HRID 2427271 reaction equation
[CH:1]([O:4][C:5](=[O:39])[NH:6][C@@H:7]1[CH2:38][C:10]2[N:11]([CH2:20][C:21]3[C:22]([N:27]4C(=O)C5C(=CC=CC=5)C4=O)=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O.NN>O1CCCC1.C(O)C>[CH:1]([O:4][C:5](=[O:39])[NH:6][C@@H:7]1[CH2:38][C:10]2[N:11]([CH2:20][C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]

Participants

5

Reactant 2

HCID 24654Hydrazine hydrate (1:1)HCID 59242747(S)-{7-cyano-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl}-carbamic acid isopropyl ester

Product 1

HCID 24963751(S)-[4-(2-Amino-pyridin-3-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl esterYield 84.9%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
24 °C

Procedure

Alternate procedure: Dissolve (S)-{7-cyano-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl}-carbamic acid isopropyl ester (20 g; 34.64 mmoles) in tetrahydrofuran (170 mL) and ethanol (30 mL). Add hydrazine monohydrate (3.37 mL, 69.29 mmoles) using a syringe pump over 30 min. Stir the mixture at 22/24° C. for 3 h and then filter. Wash the cake with additional tetrahydrofuran (50 ml). Evaporate the combined mother liquors and purify the resulting residue by silica gel chromatography eluting with dichloromethane/(2M NH3 in methanol/) (98:2). Combine the fractions containing pure product and evaporate the solvent. Dry the solid to constant weight and then add over ethanol (50 mL). Heat the mixture to reflux until complete dissolution occurs and then allow to cool to room temperature overnight. Filter the solid and dry under vacuum to constant weight to provide 11.45 g (84%) of the title compound. MS (m/z): 390 (M+1). Chiral HPLC: ee>98% (Isomer 1, Chiralpak AD, EtOH/0.2% dimethylethylamine)

Workup

  1. customover 30 min
  2. filtrationfilter
  3. washWash the cake with additional tetrahydrofuran (50 ml)
  4. customEvaporate the combined mother liquors
  5. custompurify the resulting residue by silica gel chromatography
  6. washeluting with dichloromethane/(2M NH3 in methanol/) (98:2)
  7. additionCombine the fractions containing pure product
  8. customevaporate the solvent
  9. customDry the solid to constant weight
  10. additionadd over ethanol (50 mL)
  11. temperatureHeat the mixture
  12. temperatureto reflux until complete dissolution
  13. temperatureto cool to room temperature overnight
  14. filtrationFilter the solid
  15. customdry under vacuum to constant weight

Sources & evidence

ORD record
ord-26c4066a40834520bd9ed5df79c00c31
Source dataset
uspto-grants-2011_06
Patent number
US07968587B2

Reaction notes

Loading…