Sodium hydride → HCID 66772970, compound

HRID 2370321Notes

Reaction equation

HRID 2370321 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+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=3[C:23]([CH:34]=O)=[N:22]2)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=3[C:23]([CH2:34][NH:3][C@@H:4]3[CH:9]4[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]4)[CH2:5]3)=[N:22]2)=[CH:19][CH:20]=1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 5049666Sodium triacetoxyborohydrideHCID 12494972(R)-(+)-3-Aminoquinuclidine DihydrochlorideHCID 86636562HCID 86636562, compound

Product 1

HCID 66772970HCID 66772970, compoundYield 80.3%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred suspension of (R)-(+)-3-aminoquinuclidine dihydrochloride (360 mg, 1.8 mmol) in dichloromethane (15 mL) was added sodium hydride (144 mg, 3.6 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.15 mL) was added dropwise. Then methyl 1-(4-fluorophenyl)-3-formyl-1H-indazole-4-carboxylate (454 mg, 1.5 mmol) from Step A above was added and the mixture continued to stir at room temperature for an additional 4 h. Sodium triacetoxyborohydride (1.3 g, 6.0 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 1-(4-fluorophenyl)-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate as a light yellow oil (492 mg, 80%): 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=7.3 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.46 (t, J=7.9 Hz, 1H), 7.27-7.24 (m, 2H), 4.37 (d, J=14.1 Hz, 1H), 4.27 (d, J=14.1 Hz, 1H), 4.00 (s, 3H), 3.39-3.34 (m, 1H), 3.22-3.01 (m, 5H), 2.81 (dd, J=13.4, 2.3 Hz, 1H), 2.30-2.25 (m, 1H), 2.20-2.17 (m, 1H), 1.92-1.86 (m, 1H), 1.75-1.69 (m, 1H) 1.63-1.59 (m, 1H); MS (ESI+) m/z 409 (M+H).

Workup

  1. stirringto stir at room temperature for an additional 4 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-f69dce2e5ada4d239c2a58b9f8aa3d3c
Source dataset
uspto-grants-2014_04
Patent number
US08710047B2

Reaction notes

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