Sodium hydride → (S)-methyl 5-chloro-3-methyl-1-((quinuclidin-3-ylamino)methyl)-1H-indole-7-carboxylate

HRID 2168485Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2168485
Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:23]=1)[N:20]([CH2:28]C=O)[CH:19]=[C:18]2[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:23]=1)[N:20]([CH2:28][NH:3][C@H:4]1[CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]1)[CH:19]=[C:18]2[CH3:31]

Komponenten

7

Edukt 4

HCID 24758Sodium hydrideHCID 5049666Sodium triacetoxyborohydrideHCID 12494973(3S)-1-azabicyclo[2.2.2]octan-3-amine dihydrochlorideHCID 86672696HCID 86672696, Verbindung

Produkt 1

HCID 66899384(S)-methyl 5-chloro-3-methyl-1-((quinuclidin-3-ylamino)methyl)-1H-indole-7-carboxylateAusbeute 106,3 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 176Acetic AcidLösungsmittelHCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

To a stirred suspension of (S)-(−)-3-aminoquinuclidine dihydrochloride (621 mg, 3.1 mmol) in methylene chloride (20 mL) was added sodium hydride (250 mg, 6.2 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise and then methyl 5-chloro-3-methyl-1-(2-oxoethyl)-1H-indole-7-carboxylate (690 mg, 2.6 mmol) from Step D above was added and the mixture continued to stir at room temperature for 2 h. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 5-chloro-3-methyl-1-((quinuclidin-3-ylamino)methyl)-1H-indole-7-carboxylate (1.0 g, quantitative yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=1.0 Hz, 1H), 7.56 (d, J=1.0 Hz, 1H), 7.14 (s, 1H), 3.02-2.97 (m, 1H), 2.84-2.62 (m, 8H), 3.00-2.97 (m, 1H), 2.85-2.58 (m, 7H), 2.32 (s, 3H), 2.23-2.19 (dq, J=10.0, 2.0 Hz, 1H), 1.72-1.61 (m, 3H), 1.47-1.45 (m, 1H), 1.47-1.45 (m, 1H); MS (ESI+) m/z 362 (M+H).

Aufarbeitung

  1. stirringto stir at room temperature for 2 h
  2. stirringstirring
  3. waitwas continued overnight at room temperature
  4. customThe solvent was removed under reduced pressure
  5. customthe crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide)

Quellen und Nachweise

ORD-Eintrag
ord-2b3407ae119f45e6917699bbcdc5e7d5
Quelldatensatz
uspto-grants-2015_06
Patentnummer
US09045501B2

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