Acetic Acid → HCID 130473006, compound

HRID 2279952Notes

Reaction equation

HRID 2279952 reaction equation
Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([O:11][C:12](=[O:21])[CH:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4]2.[CH:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH:32]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=2)[CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][N+:37]([O-:41])=[CH:36][C:35]=2[Cl:42])=[O:30])=[CH:26][CH:25]=1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:40][C:39]1[CH:38]=[N+:37]([O-:41])[CH:36]=[C:35]([Cl:42])[C:34]=1[CH2:33][CH:32]([O:31][C:29]([C:27]1[S:28][C:24]([CH2:22][NH:20][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:21])[O:11][C@@H:5]2[CH:6]3[CH2:7][CH2:8][N:3]([CH2:10][CH2:9]3)[CH2:4]2)=[CH:25][CH:26]=1)=[O:30])[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 67425463(R)-Quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochlorideHCID 118117315HCID 118117315, compound2×

Product 1

HCID 130473006HCID 130473006, compoundYield 25%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of [(3R)-quinuclidin-3-yl]2-amino-2-phenylacetate bis hydrochloride salt (273 mg, 0.82 mmol) in ethanol (10 mL) was added the single enantiomer 2 of [2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)ethyl] 5-formylthiophene-2-carboxylate (Intermediate 75, 135 mg, 0.27 mmol) and acetic acid (40 μL, 0.68 mmol). The resulting mixture was stirred at room temperature for 16 h. Sodium cyanoborohydride (45 mg, 0.68 mmol) was added and the reaction mixture was stirred at room temperature for a further 24 h. The solvent was removed by evaporation under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (3 mL) and ethyl acetate (3 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×3 mL). The aqueous phase was basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (2×3 mL). The combined organic fractions were extracted with 1 M aqueous hydrochloric acid (2 mL). Brine (2 mL) was added and the aqueous layer was extracted with chloroform (5 mL and 2 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (2 mL), passed through a hydrophobic frit and the solvent was removed by evaporation under reduced pressure. Purification by preparative HPLC gave the title compound as an off-white solid (50 mg, 25%).

Workup

  1. stirringthe reaction mixture was stirred at room temperature for a further 24 h
  2. customThe solvent was removed by evaporation under reduced pressure
  3. customthe residue was partitioned between 1 M aqueous hydrochloric acid (3 mL) and ethyl acetate (3 mL)
  4. customThe layers were separated
  5. extractionthe aqueous phase was extracted with ethyl acetate (2×3 mL)
  6. extractionextracted with ethyl acetate (2×3 mL)
  7. extractionThe combined organic fractions were extracted with 1 M aqueous hydrochloric acid (2 mL)
  8. additionBrine (2 mL) was added
  9. extractionthe aqueous layer was extracted with chloroform (5 mL and 2 mL)
  10. washThe combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (2 mL)
  11. customthe solvent was removed by evaporation under reduced pressure
  12. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-9f5b1fc470ba45b2870d16bee0cb81b3
Source dataset
uspto-grants-2015_09
Patent number
US09133185B2

Reaction notes

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