Dimethylformamide → HCID 178515171, compound

HRID 1887513Notes

Reaction equation

HRID 1887513 reaction equation
N12CCC(CC1)[C@@H]([NH:9][CH2:10][C:11]1[C:19]3[C:18]([C:20]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][N:12]=1)C2.[Li+].[CH:24]([N:27](CC)[CH:28]([CH3:30])C)(C)[CH3:25].CCCP1(OP(CCC)(=O)OP([CH2:48][CH2:49][CH3:50])(=O)O1)=O.CN(C)C=[O:54]>>[N:27]12[CH2:48][CH2:49][CH:50]([CH2:30][CH2:28]1)[CH:25]([C@@H:9]1[C:20](=[O:54])[C:18]3[C:19]4=[C:14]([NH:13][N:12]=[C:11]4[CH2:10]1)[CH:15]=[N:16][CH:17]=3)[CH2:24]2

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 178524262HCID 178524262, compound

Product 1

HCID 178515171HCID 178515171, compound

Procedure

To a solution of crude lithium (R)-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate from Step B above in N,N-dimethylformamide (30 mL) was added N,N-diisopropylethylamine (5.7 mL, 34.4 mmol) followed by 1-propanephosphonic acid cyclic anhydride (T3P) (17 mL, 28.65 mmol) at 0° C. for 17 h. The solution was concentrated and purified by column chromatography (silica gel, 70:30:3 dichloromethane/methanol/concentrated ammonium hydroxide), SCX-2 column and preparative TLC (silica gel, 70:30:3 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (R)-7-(quinuclidin-3-yl)-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one. This material was dissolved in methanol and treated with HCl (1.25 M solution in methanol). The mixture was concentrated under reduced pressure. The residue was lyophilized from water to afford (R)-7-(quinuclidin-3-yl)-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one (373 mg, 23%) as a light-yellow solid. 1H NMR (500 MHz, D2O) δ 7.32 (d, J=8.3 Hz, 1H), 7.26 (dd, J=8.3, 6.9 Hz, 1H), 7.10 (d, J=6.9 Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.71 (d, J=16.8 Hz, 1H), 4.53 (t, J=8.9 Hz, 1H), 3.60 (dd, J=12.9, 10.6 Hz, 1H), 3.33-3.13 (m, 5H), 2.32 (br s, 1H), 2.13-2.07 (m, 1H), 2.03-1.85 (m, 3H). MS (ESI+) m/z 283 (M+H); HPLC>99% (AUC), tR 10.94 min.

Workup

  1. concentrationThe solution was concentrated
  2. custompurified by column chromatography (silica gel, 70:30:3 dichloromethane/methanol/concentrated ammonium hydroxide), SCX-2 column and preparative TLC (silica gel, 70:30:3 dichloromethane/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-6dc4c855496b441984c822021d8c633b
Source dataset
uspto-grants-2013_08
Patent number
US08501729B2

Reaction notes

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