Diisopropylethylamine → HCID 69937553, compound

HRID 2168490Notes

Reaction equation

HRID 2168490 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O-:24])=O)[CH:15]=[CH:14]1)[CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([N:9]1[CH2:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16]([CH:15]=[CH:14]3)=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]1=[O:24])[CH2:2]2

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 86672698HCID 86672698, compound

Product 1

HCID 69937553HCID 69937553, compoundYield 24.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of lithium (R)-1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (574 mg, 1.7 mmol) from Step D above in DMF (8 mL) was cooled in an ice bath while N,N-diisopropylethylamine (1.3 g, 10.3 mmol) was added, followed by 1-propanephosphonic acid cyclic anhydride (T3P) (3.3 g, 10.3 mmol). The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with water and the aqueous phase was extracted with methylene chloride (3×) and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give (R)-2-(quinuclidin-3-yl)-2,3,4,5-tetrahydro-1H-[1,5]diazocino[3,2,1-hi]indol-1-one (127 mg, 24%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=6.6 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.20 (d, J=3.3 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.50 (d, J=3.0 Hz, 1H), 4.40-4.20 (m, 2H), 3.80-3.45 (m, 3H), 3.25-2.80 (m, 5H), 2.30-1.50 (m, 6H), 1.40-1.20 (m, 2H); MS (ESI+) m/z 310 (M+H).

Workup

  1. additionwas added
  2. customThe reaction was quenched with water
  3. extractionthe aqueous phase was extracted with methylene chloride (3×)
  4. washthe combined extracts were washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-a19bf60d64564f07a53df986f744e305
Source dataset
uspto-grants-2015_06
Patent number
US09045501B2

Reaction notes

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