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

HRID 1754317노트

반응식

HRID 1754317 반응식
[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]

참가 물질

6

반응물 2

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

생성물 1

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

시약·촉매·용매 3

HCID 887Methanol용매HCID 962Water용매HCID 8028Tetrahydrofuran용매

실험 절차

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%).

후처리

  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

출처 및 근거

ORD 기록
ord-e3d8345d46b849cc9a248a162f879fbc
출처 데이터셋
uspto-grants-2015_10
특허 번호
US09169245B2

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