Dimethylformamide → HCID 66772518, compound

HRID 1644267Notes

Reaction equation

HRID 1644267 reaction equation
[CH2:1]([N:8]1[C:16]2[CH:15]=CC=[C:12]([C:17]([O-])=O)[C:11]=2[C:10]([CH2:20][CH2:21]N[C@H]2C3CCN(CC3)C2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH:32]([N:35]([CH2:39][CH3:40])[CH:36]([CH3:38])C)([CH3:34])C.[CH3:41]CCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)(O)[O-].[Na+].[CH3:64][N:65]([CH:67]=[O:68])C>[Cl-].[Na+].O>[CH2:1]([N:8]1[C:16]2=[CH:15][CH:64]=[N:65][C:67](=[O:68])[C:12]3=[C:11]2[C:10]([CH2:20][CH2:21][C@H:17]3[CH:40]2[CH:41]3[CH2:34][CH2:32][N:35]([CH2:36][CH2:38]3)[CH2:39]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 516892Sodium BicarbonateHCID 66772990HCID 66772990, compound

Product 1

HCID 66772518HCID 66772518, compoundYield 66%

Reagents, catalysts & solvents 1

HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of the crude lithium (S)-1-benzyl-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-4-carboxylate (509 mg, 1.24 mmol) from Step D above in DMF (25 mL) was added N,N-diisopropylethylamine (1.22 mL, 7.44 mmol) at 0° C. To the above reaction was added 1-propanephosphonic acid cyclic anhydride (T3P) (50% in ethyl acetate, 3.94 g, 6.2 mmol) and the mixture was stirred at 0° C. for 1.5 h. The reaction mixture was treated with brine (25 mL) and saturated aqueous solution of sodium bicarbonate (25 mL). The compound was extracted with dichloromethane (4×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-2-benzyl-7-(quinuclidin-3-yl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one (316 mg, 66%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.98-7.95 (m, 1H), 7.45-7.43 (m, 2H), 7.32-7.25 (m, 3H), 7.119-7.15 (m, 2H), 5.57 (s, 2H), 4.85-4.68 (1H), 4.20-3.90 (m, 2H), 3.45-3.38 (m, 1H), 3.35-2.90 (m, 7H), 2.25-2.15 (m, 1H), 1.95-1.55 (m, 4H); MS (ESI+) m/z 387 (M+H).

Workup

  1. customTo the above reaction
  2. extractionThe compound was extracted with dichloromethane (4×100 mL)
  3. washthe combined organic layers were washed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-a2dafd61fb7b45c5ac62dc6ce02426ac
Source dataset
uspto-grants-2012_02
Patent number
US08124600B2

Reaction notes

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