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

HRID 2369864Notes

Reaction equation

HRID 2369864 reaction equation
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]

Participants

7

Reactant 4

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

Product 1

HCID 66899384(S)-methyl 5-chloro-3-methyl-1-((quinuclidin-3-ylamino)methyl)-1H-indole-7-carboxylateYield 106.3%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-744eb86e90b4403f970c353308197c77
Source dataset
uspto-grants-2014_04
Patent number
US08710046B2

Reaction notes

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