Tetrahydrofuran → (S)-7-(quinuclidin-3-yl)-8,9-dihydro-[1,4]diazepino[6,7,1-hi]indazol-6(7H)-one

HRID 2168498Notes

Reaction equation

HRID 2168498 reaction equation
N12CCC(CC1)[C@H]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O-])=O)[CH:14]=[N:13]1)C2.[Li+].[CH:25]([N:28](CC)[CH:29]([CH3:31])C)(C)[CH3:26].CCCP1(OP(CCC)(=O)OP([CH2:49][CH2:50][CH3:51])(=O)O1)=O.C1C[O:55]CC1>>[N:28]12[CH2:49][CH2:50][CH:51]([CH2:31][CH2:29]1)[CH:26]([C@@H:16]1[C:17](=[O:55])[CH:18]=[C:19]3[CH:21]=[N:9][CH:10]=[CH:11][N:12]4[C:20]3=[C:15]1[CH2:14][NH:13]4)[CH2:25]2

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 66899683lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate

Product 1

HCID 70896244(S)-7-(quinuclidin-3-yl)-8,9-dihydro-[1,4]diazepino[6,7,1-hi]indazol-6(7H)-oneYield 63%

Procedure

To a suspension of lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate (360 mg, 1.1 mmol) from Step G above in THF (50 mL) was added N,N-diisopropylethylamine (1.2 mL, 6.7 mmol) and the mixture was stirred at ambient temperature for 10 min. To the above reaction mixture was added 1-propanephosphonic acid cyclic anhydride (T3P) (3.6 g, 5.6 mmol) and the reaction was stirred for 2.5 h. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL), extracted with ethyl acetate (3×250 mL), and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude solid was purified by SCX-2 resin to afford (S)-7-(quinuclidin-3-yl)-8,9-dihydro-[1,4]diazepino[6,7,1-hi]indazol-6(7H)-one (207 mg, 63%): 1H NMR (500 MHz, CD3OD) δ 8.17 (dd, J=7.5, 1.0 Hz, 1H), 8.15 (s, 1H), 8.00 (dd, J=8.0, 1.0 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 4.80-4.75 (m, 2H), 4.70-3.80 (m 3H), 3.38-3.34 (m, 1H), 3.20-3.05 (m, 2H), 2.96-2.85 (m, 3H), 2.14-2.00 (m, 1H), 1.95-1.65 (m, 4H); MS (ESI+) m/z 297 (M+H).

Workup

  1. stirringthe reaction was stirred for 2.5 h
  2. customThe reaction was quenched with saturated aqueous sodium bicarbonate (100 mL)
  3. extractionextracted with ethyl acetate (3×250 mL)
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude solid was purified by SCX-2 resin

Sources & evidence

ORD record
ord-5e20355a43874054abc48369319e11e3
Source dataset
uspto-grants-2015_06
Patent number
US09045501B2

Reaction notes

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