Dimethylformamide → HCID 70896246, compound

HRID 2168473Notes

Reaction equation

HRID 2168473 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-a9da8a494d6444e8b591686a39a9b8b8
Source dataset
uspto-grants-2015_06
Patent number
US09045501B2

Reaction notes

Loading…