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

HRID 1255052Notes

Reaction equation

HRID 1255052 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-05fe12a088884b589a45e4ca8cf088e5
Source dataset
uspto-grants-2013_06
Patent number
US08455646B2

Reaction notes

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