Dicyclohexylcarbodiimide → 4-{[(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)oxycarbonyl]-phenylamino-methyl}-benzoic acid methyl ester

HRID 77019Notes

Reaction equation

HRID 77019 reaction equation
[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].C(N(C(C)C)C(C)C)C.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:56]12[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]1)[C@@H:58](O)[CH2:57]2>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:12]([O:14][C@@H:58]2[CH:59]3[CH2:62][CH2:63][N:56]([CH2:61][CH2:60]3)[CH2:57]2)=[O:13])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1

Participants

6

Reactant 4

HCID 10868Dicyclohexylcarbodiimide2×HCID 757711-Hydroxybenzotriazole2×HCID 914043-Quinuclidinol, (-)-2×HCID 67425011N-ethyl-N-isopropylpropan-2-amine 2-(4-(methoxycarbonyl)phenyl)-2-(phenylamino)acetate

Product 1

HCID 594011274-{[(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)oxycarbonyl]-phenylamino-methyl}-benzoic acid methyl esterYield 21%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

N-Ethyl-N-isopropylpropan-2-amine 2-(4-(methoxycarbonyl)phenyl)-2-(phenylamino)acetate (I94) (212 mg, 0.51 mmol), DCC (158 mg, 0.77 mmol), and HOBT (117 mg, 0.77 mmol) are dissolved in dry THF (5 mL). (R)-Quinuclidin-3-ol (195 mg, 1.53 mmol) is added and the mixture is stirred at RT for 2 days. A second portion of DCC (79 mg, 0.38 mmol), HOBT (58.7 mg, 0.38 mmol) and (R)-quinuclidin-3-ol (98 mg, 0.77 mmol) are added and the mixture is further stirred for 24 hours. Then THF is evaporated, the residue is dissolved in EtOAc and washed with NaHCO3, water and brine. The organic phase is dried (Na2SO4), filtered and evaporated. The crude is purified by preparative HPLC. The recovered fractions are evaporated, dissolved in EtOAc and washed with sat. NaHCO3. The organic phase is dried (Na2SO4), filtered and evaporated to afford the desired compound as a colorless oil (42 mg, 21% yield, mixture of diastereoisomers).

Workup

  1. stirringthe mixture is further stirred for 24 hours
  2. customThen THF is evaporated
  3. dissolutionthe residue is dissolved in EtOAc
  4. washwashed with NaHCO3, water and brine
  5. dry with materialThe organic phase is dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated
  8. customThe crude is purified by preparative HPLC
  9. customThe recovered fractions are evaporated
  10. dissolutiondissolved in EtOAc
  11. washwashed with sat. NaHCO3
  12. dry with materialThe organic phase is dried (Na2SO4)
  13. filtrationfiltered
  14. customevaporated

Sources & evidence

ORD record
ord-053149529fe2486694c57e1e39da6e07
Source dataset
uspto-grants-2014_09
Patent number
US08835682B2

Reaction notes

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