Triethylamine → (R)-N-(6-Methylisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 250131Notes

Reaction equation

HRID 250131 reaction equation
Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C(N(CC)CC)C.[N:21]([C:24]1[N:25]=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2)=[C:22]=[S:23].C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH3:34][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24]([NH:21][C:22]1[O:13][C@:5]3([CH2:4][N:3]=1)[CH:10]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]1)[CH2:6]3)=[CH:33]2.[OH:13][C@:5]1([CH2:4][NH:3][C:22]([NH:21][C:24]2[N:25]=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=3)=[S:23])[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 12734DiisopropylcarbodiimideHCID 574766053-Isothiocyanato-6-methylisoquinolineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 2

HCID 58088264(R)-N-(6-Methylisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineHCID 86635294(S)-1-((3-hydroxyquinuclidin-3-yl)methyl)-3-(6-methylisoquinolin-3-yl)thiourea

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (65.8 mg, 0.285 mmol) in N,N-dimethylformamide (6 mL) was added triethylamine (0.090 mL, 0.63 mmol) and 3-isothiocyanato-6-methylisoquinoline (57 mg, 0.285 mmol). The suspension was placed into a preheated oil-bath and stirred at 70° C. for 2 h and 30 min. N,N′-diisopropylcarbodiimide (0.177 mL, 1.14 mmol) was then added and the mixture was stirred at 85° C. for 16 h. The mixture was concentrated and purified by silica gel chromatography (0-40% [9:1 methanol:ammonium hydroxide] in chloroform) followed by purification by reverse phase preparatory HPLC (0-40% TFA-methanol-water). The solution of product was filtered through UCT Clean-up CHQAX15M25 cartridge with MeOH (3×10 ml) and concentrated to afford the expected product, (S)-1-((3-hydroxyquinuclidin-3-yl)methyl)-3-(6-methylisoquinolin-3-yl)thiourea, as a tan gum. 1H NMR (400 MHz, MeOD) δ ppm 9.11 (s, 1H), 8.02 (d, J=8.53 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.47 (d, J=8.53 Hz, 1H), 4.47 (d, J=10.54 Hz, 1H), 4.31 (d, J=10.54 Hz, 1H), 4.10 (d, J=14.81 Hz, 1H), 3.92 (d, J=14.81 Hz, 1H), 3.53-3.71 (m, 2H), 3.27-3.51 (m, 3H), 2.84 (br.s, 1H), 2.55 (s, 3H), 2.48 (m, 1H), ) 2.10-2.30 (m, 3H). MS (LC/MS) R.T.=1.24; [M+H]+=323.2.

Workup

  1. customThe suspension was placed into a preheated oil-bath
  2. stirringthe mixture was stirred at 85° C. for 16 h
  3. concentrationThe mixture was concentrated
  4. custompurified by silica gel chromatography (0-40% [9:1 methanol:ammonium hydroxide] in chloroform)
  5. customfollowed by purification by reverse phase preparatory HPLC (0-40% TFA-methanol-water)
  6. filtrationThe solution of product was filtered through UCT Clean-up CHQAX15M25 cartridge with MeOH (3×10 ml)
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-c103ea4f9e67414aab6bc2d26e5b62e5
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

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