Dimethylformamide → HCID 70896171, compound

HRID 2369857Notes

Reaction equation

HRID 2369857 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 66899360HCID 66899360, compound

Product 1

HCID 70896171HCID 70896171, compound

Procedure

To a stirred solution of crude lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate from Step D above in N,N-dimethylformamide (15 mL) was added N,N-diisopropylethylamine (4.3 mL, 26.1 mmol) followed by 1-propanephosphonic acid cyclic anhydride (T3P) (7.8 mL, 26.1 mmol) and the reaction was stirred at room temperature 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) to afford (S)-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) and the mixture was concentrated under reduced pressure. The residue was lyophilized from water to afford (S)-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one hydrochloride (800 mg, 62%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.93 (d, J=4.0 Hz, 1H), 7.77 (dd, J=4.5, 1.0 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 4.71 (br s, 1H), 4.53 (br s, 1H), 4.46 (d, J=5.5 Hz, 1H), 4.08 (br s, 1H), 4.00-3.96 (m, 1H), 3.86-3.69 (m, 3H), 3.46-3.31 (m, 3H), 2.51 (q, J=5.5 Hz, 1H), 2.26 (br s, 1H), 2.19-1.98 (m, 3H); 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)

Sources & evidence

ORD record
ord-9c928b65e09a4bc0a33e09d283b2c37f
Source dataset
uspto-grants-2014_04
Patent number
US08710046B2

Reaction notes

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