Dicyclohexylcarbodiimide → 8-Fluoro-isoquinoline-3-carboxylic acid{(s)-1-azabicyclo[2.2.2]oct-2-yl}-amide

HRID 2245286Notes

Reaction equation

HRID 2245286 reaction equation
C1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12]C2)CCCCC1.[F:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[N:24][C:23]([C:27]([OH:29])=O)=[CH:22]2.[CH2:30](N(C(C)C)C(C)C)C.OC1C2N=NNC=2C=CC=1.N12CCC(CC1)[C@H](N)C2>CN(C=O)C>[N:9]12[CH2:10][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH2:30][C@H:8]2[NH:7][C:27]([C:23]1[N:24]=[CH:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[F:16])=[O:29]

Participants

7

Reactant 5

HCID 10868DicyclohexylcarbodiimideHCID 81531Diisopropylethylamine2×HCID 719216(S)-quinuclidin-3-amineHCID 685453938-Fluoroisoquinoline-3-carboxylic acidHCID 178418300HCID 178418300, compound

Product 1

HCID 685505888-Fluoro-isoquinoline-3-carboxylic acid{(s)-1-azabicyclo[2.2.2]oct-2-yl}-amideYield 35%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Dicyclohexyl-carbodiimide (7.69 g, 30 mmol) is added to a solution of 8-fluoro-isoquinoline-3-carboxylic acid (5.1 g, 22.4 mmol), ethyl-diisopropyl-amine (4.6 ml, 26.88 mmol) and hydroxybenzotriazole (5.36 g, 33.6 mmol) in DMF (150 ml). The mixture is stirred for 2 hours at room temperature. (S)-(1-Aza-bicyclo[2.2.2]oct-3-yl)amine (4.46 g, 49.28 mmol) and ethyl-diisopropyl-amine (8.7 ml, 49.28 mmol) are added and the solution is stirred for another 18 hours at room temperature. The solvent is removed by evaporation and the residue is dissolved in methylenedichloride and washed with a saturated K2CO3 solution and brine. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by chromatography (CH2Cl2/MeOH/NH4OH, 92.5/7.5/0.75) to afford the desired compound (2.35 g). The product is recrystallized from ethanolic HCl to give 2 g. of the hydrochloric salt.

Workup

  1. stirringthe solution is stirred for another 18 hours at room temperature
  2. customThe solvent is removed by evaporation
  3. dissolutionthe residue is dissolved in methylenedichloride
  4. washwashed with a saturated K2CO3 solution and brine
  5. dry with materialThe organic layer is dried over MgSO4
  6. customevaporated
  7. customThe crude product is purified by chromatography (CH2Cl2/MeOH/NH4OH, 92.5/7.5/0.75)

Sources & evidence

ORD record
ord-71871602fe904859a754ca0db7e542e5
Source dataset
uspto-grants-2010_03
Patent number
US07683075B2

Reaction notes

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