Lithium hydroxide, monohydrate → 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid

HRID 1754317Notes

Reaction equation

HRID 1754317 reaction equation
[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]C)=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].O.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6]

Participants

6

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 86720275(R)-methyl 3-(((2-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoate

Product 1

HCID 867202763-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acidYield 88.1%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of methyl 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate (4.12 g, 10 mmol) in tetrahydrofuran (45 mL) and methanol (45 mL) was added lithium hydroxide hydrate (839 mg, 20 mmol) in water (18 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified using an SCX-2 cartridge eluting sequentially with methanol and 7 N methanolic ammonia. The product was triturated with THF (×5) and diethyl ether to give 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (3.51 g, 88%) as a white solid. To a solution of 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (76 mg, 0.19 mmol) in DMF (2 mL) was then added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride (Int 6, 93 mg, 0.19 mmol), followed by DMAP (11 mg, 0.1 mmol) and EDC (72 mg, 0.37 mmol). The mixture was allowed to stir at room temperature for 5 hours, and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (66 mg, 42%).

Workup

  1. customThe solvent was removed in vacuo
  2. customthe residue was purified
  3. washeluting sequentially with methanol and 7 N methanolic ammonia
  4. customThe product was triturated with THF (×5) and diethyl ether

Sources & evidence

ORD record
ord-e3d8345d46b849cc9a248a162f879fbc
Source dataset
uspto-grants-2015_10
Patent number
US09169245B2

Reaction notes

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