Dimethylformamide → HCID 66772518, compound

HRID 1887523Notes

Reaction equation

HRID 1887523 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. ambient temperature 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 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 the crude material
  7. custompurified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-75cabc677a3149789c001de9f8ec735b
Source dataset
uspto-grants-2013_08
Patent number
US08501729B2

Reaction notes

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