Dimethylformamide → HCID 70896246, compound

HRID 2369852Notes

Reaction equation

HRID 2369852 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]=[CH: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.CN(C)C=[O:55]>>[N:28]12[CH2:49][CH2:50][CH:51]([CH2:31][CH2:29]1)[CH:26]([C@H:10]1[NH:9][CH2:21][C:19]3=[C:20]4[C:15](=[CH:16][CH:17]=[CH:18]3)[CH:14]=[CH:13][N:12]4[C:11]1=[O:55])[CH2:25]2

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 66899275HCID 66899275, compound

Product 1

HCID 70896246HCID 70896246, compound

Procedure

To a stirred solution of crude lithium (R)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate from Step D above in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.3 mL, 13.8 mmol) followed by 1-propanephosphonic acid cyclic anhydride (T3P) (4.1 mL, 13.8 mmol) at room temperature and the mixture was stirred for 17 h. The reaction was quenched with water, extracted with methylene chloride (3×), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 60:30:10 methylene chloride/methanol/concentrated ammonium hydroxide) and preparative TLC (60:30:10 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (R)-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one. This material was dissolved in methanol and treated with HCl (1.25 M solution in methanol). The resulting hydrochloride salt was lyophilized from water to afford (R)-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one hydrochloride (377 mg, 21%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.85 (d, J=4.0 Hz, 1H), 7.77 (dd, J=4.3, 1.0 Hz, 1H), 7.45 (d, J=1.5, 1H), 7.14 (t, J=7.5 Hz, 1H), 6.57 (d, J=1.5, 1H), 4.72 (t, J=8.5 Hz, 1H), 4.50 (br s, 1H), 4.34 (br s, 1H), 3.91 (br s, 1H), 3.43-3.18 (m, 4H), 3.00 (t, J=8.0 Hz, 3H), 2.13 (d, J=1.0 Hz, 1H), 1.83-1.71 (m, 3H), 1.63 (t, J=11.0 Hz, 1H); MS (ESI+) m/z 296 (M+H).

Workup

  1. customThe reaction was quenched with water
  2. extractionextracted with methylene chloride (3×)
  3. washwashed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude material was purified by column chromatography (silica gel, 60:30:10 methylene chloride/methanol/concentrated ammonium hydroxide) and preparative TLC (60:30:10 methylene chloride/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-4f7036f9869e4415ba23aa3597a93a05
Source dataset
uspto-grants-2014_04
Patent number
US08710046B2

Reaction notes

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