1,2-Dichloroethane → [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoyl]piperidine-2-carboxylate

HRID 1754318Notes

Reaction equation

HRID 1754318 reaction equation
[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[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].Cl.[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][NH:54]1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][N:54]1[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH2:16][N:4]([C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=2[F:1])[CH:18]=1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1

Participants

6

Reactant 3

HCID 111,2-DichloroethaneHCID 867202763-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acidHCID 86720277[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride

Product 1

HCID 76285017[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoyl]piperidine-2-carboxylateYield 42%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

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 partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL)
  3. customthe solvent was removed in vacuo
  4. customPurification

Sources & evidence

ORD record
ord-9ff3d15b6812486cb8e0969ed4781114
Source dataset
uspto-grants-2015_10
Patent number
US09169245B2

Reaction notes

Loading…