Sodium hydride → (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate

HRID 2168496Notes

Reaction equation

HRID 2168496 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+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[C:40]([O:42][CH3:43])=[O:41])[CH:33]=[N:32]1>C1COCC1.C(O)(=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@H:4]([NH:3][CH2:29][CH2:30][N:31]1[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][C:38]=3[C:40]([O:42][CH3:43])=[O:41])[CH:33]=[N:32]1)[CH2:5]2

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 5049666Sodium triacetoxyborohydrideHCID 12494973(3S)-1-azabicyclo[2.2.2]octan-3-amine dihydrochlorideHCID 86672700methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate

Product 1

HCID 66899049(S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of (S)-(−)-3-aminoquinuclidine dihydrochloride (0.3 g, 1.3 mmol) in THF (13 mL) was added sodium hydride (0.1 g, 2.7 mmol) and the mixture was stirred for 1.5 h. Acetic acid (0.5 mL) and sodium triacetoxyborohydride (380 mg, 1.8 mmol) were added and stirred for 0.5 h. A solution of methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate (0.3 g, 1.3 mmol) from Step E above in THF (13 mL) was added dropwise, and the resulting suspension was stirred overnight at ambient temperature. The solvent was removed under reduced pressure, and the crude material was purified by preparative thin layer chromatography (90:9:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate: 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.03 (dd, J=8.0, 1.0 Hz, 1H), 7.85 (dd, J=7.0, 1.0 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 4.68-4.65 (m, 2H), 3.94 (s, 3H), 2.84-2.70 (m, 3H), 2.64-2.45 (m, 2H), 2.03-1.99 (m, 2H), 1.86-1.75 (m, 2H), 1.58-1.51 (m, 3H), 1.45-1.32 (m, 1H), 1.08-1.01 (m, 1H); MS (ESI+) m/z 329 (M+H).

Workup

  1. stirringstirred for 0.5 h
  2. stirringthe resulting suspension was stirred overnight at ambient temperature
  3. customThe solvent was removed under reduced pressure
  4. customthe crude material was purified by preparative thin layer chromatography (90:9:1 methylene chloride/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-a947718927fc4d0f8f11a9074f92d52b
Source dataset
uspto-grants-2015_06
Patent number
US09045501B2

Reaction notes

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