Sodium hydride → HCID 178497599, compound

HRID 2370316Notes

Reaction equation

HRID 2370316 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+].[CH:14]([C:16]1[C:24]2[C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][C:19]=2[NH:18][N:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@@H:4]([NH:3][CH2:14][C:16]1[C:24]3[C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][C:19]=3[NH:18][N:17]=1)[CH2:5]2

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 5049666Sodium triacetoxyborohydrideHCID 12494972(R)-(+)-3-Aminoquinuclidine DihydrochlorideHCID 178497600HCID 178497600, compound

Product 1

HCID 178497599HCID 178497599, compoundYield 180%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred suspension of (R)-(+)-3-aminoquinuclidine dihydrochloride (916.0 mg, 4.6 mmol) in dichloromethane (60 mL) was added sodium hydride (368 mg, 9.2 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.15 mL) was added dropwise. Then methyl 3-formyl-1H-indazole-4-carboxylate (B1) (776 mg, 3.8 mmol) was added and the mixture continued to stir at room temperature for an additional 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 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 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (R)-methyl 3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate as a brown solid (2.15 g, quant. yield): 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, J=7.2, 0.7 Hz, 1H), 7.68 (dd, J=8.4, 0.7 Hz 1H), 7.36 (dd, J=8.3, 7.3 Hz, 1H), 4.30 (d, J=14.2 Hz, 1H), 4.25 (d, J=14.2 Hz, 1H), 3.96 (s, 3H), 3.28-3.25 (m, 1H), 3.12-3.07 (m, 1H), 2.99-2.91 (m, 4H), 2.73-2.69 (m, 1H), 2.19-2.12 (m, 1H), 2.04-2.00 (m, 1H), 1.80-1.74 (m, 1H), 1.65-1.57 (m, 1H), 1.52-1.46 (m, 1H). MS (ESI+) m/z 315 (M+H)

Workup

  1. stirringto stir at room temperature for an additional 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 dichloromethane/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-087cfe016b22478d95d0ab4526bf9fa8
Source dataset
uspto-grants-2014_04
Patent number
US08710047B2

Reaction notes

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