Hydrochloric Acid → [(S)-7-Cyano-4-((2R,3S)-3-hydroxy-1-methyl-pyrrolidin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester

HRID 449841Notes

Reaction equation

HRID 449841 reaction equation
C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=O)(C)(C)C.Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O1CCOCC1.ClCCl>[CH:33]([O:32][C:30](=[O:31])[NH:29][C@@H:27]1[CH2:28][C:16]2[N:15]([CH2:14][C@@H:9]3[C@@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[CH3:6])[C:23]3[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[C:17]=2[CH2:26]1)([CH3:35])[CH3:34]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 66933249(2R,3S)-2-((S)-7-Cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 44469962[(S)-7-Cyano-4-((2R,3S)-3-hydroxy-1-methyl-pyrrolidin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]-carbamic acid isopropyl esterYield 63%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of (2R,3S)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3.10 g, 6.42 mmol) in ethanol (20 mL) is treated with 4 N hydrogen chloride in 1,4-dioxane (20 mL) and stirred at room temperature for 3 h. The resulted solution is concentrated in vacuo and suspended in ethyl acetate (200 mL) and treated with 2 N aqueous sodium hydroxide (70 mL). The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The resulting residue is dissolved in chloroform (100 mL) and treated with formaldehyde (1.45 mL, 19.27 mmol) and sodium triacetoxyborohydride (4.25 g, 19.27 mmol). The resulting suspension is stirred overnight at room temperature. The suspension is treated with saturated sodium bicarbonate solution (40 mL) and stirred for 30 min. The resulting suspension is diluted with dichloromethane (100 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 1.6 g (63%) of the title compound. LC-ES/MS m/z 397.2 [M+H]+, TR=1.78 min.

Workup

  1. concentrationThe resulted solution is concentrated in vacuo
  2. additiontreated with 2 N aqueous sodium hydroxide (70 mL)
  3. washThe organic layer is washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. dissolutionThe resulting residue is dissolved in chloroform (100 mL)
  7. stirringThe resulting suspension is stirred overnight at room temperature
  8. stirringstirred for 30 min
  9. washwashed with water (3×100 mL) and brine
  10. dry with materialThe organic portion is dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated to dryness
  13. customThe resulting residue is purified by medium pressure liquid chromatography
  14. washeluting with methanol:chloroform (5:95)
  15. additionFractions containing pure product
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-fd4af974e0d647caba18aec5d44d7215
Source dataset
uspto-grants-2013_07
Patent number
US08486943B2

Reaction notes

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