Acetic Acid → HCID 66899017, compound

HRID 2369882Notes

Reaction equation

HRID 2369882 reaction equation
Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.C[O-].[Na+].C(O)(=O)C.C([BH3-])#N.[Na+].[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:32]=1)[N:29]([CH2:37][CH:38]=O)[N:28]=[CH:27]2>CO>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:32]=1)[N:29]([CH2:37][CH2:38][NH:11][C@H:5]1[CH:6]3[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4]1)[N:28]=[CH:27]2

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 10942334Sodium MethoxideHCID 12494973(3S)-1-azabicyclo[2.2.2]octan-3-amine dihydrochlorideHCID 86672701HCID 86672701, compound

Product 1

HCID 66899017HCID 66899017, compoundYield 80.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

(S)-Quinuclidin-3-amine dihydrochloride (355 mg, 1.8 mmol) was stirred in MeOH (5 mL) at room temperature while sodium methoxide (25 wt % in MeOH, 0.8 mL, 3.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. Glacial acetic acid (0.2 mL, 4.1 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (224 mg, 3.6 mmol) was added, followed by methyl 5-chloro-1-(2-oxoethyl)-1H-indazole-7-carboxylate (472 mg, 1.9 mmol) from Step C above in MeOH (8 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated and absorbed onto silica gel and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 5-chloro-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate as a light yellow solid (525 mg, 77%): 1H NMR (500 MHz, CD3OD) δ 8.17 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 4.80 (t, J=6.5 Hz, 2H), 4.02 (s, 3H), 3.50-3.38 (m, 1H), 3.25-3.05 (m, 4H), 3.05-2.90 (m, 3H), 2.65-2.55 (m, 1H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 2H), 1.90-1.75 (m, 2H), 1.65-1.55 (m, 1H); MS (ESI+) m/z 363 (M+H).

Workup

  1. additionwas added dropwise
  2. stirringThe mixture was stirred at room temperature until the reaction
  3. customwas complete by TLC (1-2 h)
  4. concentrationThe reaction mixture was concentrated
  5. customabsorbed onto silica gel
  6. custompurified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-d39b15550084479f948e4e36eb78e22f
Source dataset
uspto-grants-2014_04
Patent number
US08710046B2

Reaction notes

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