Triethylamine → 5-Chloro-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide

HRID 1354745Notes

Reaction equation

HRID 1354745 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[C:16]([N:23]1[CH:27]=[CH:26]N=[CH:24]1)(N1C=CN=C1)=[O:17].C(N(CC)CC)C.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2CCNC[CH:47]=2)=[N:40][CH:41]=1>C(#N)C.C1COCC1.C(Cl)(Cl)Cl>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16]([N:23]3[CH2:24][CH:47]=[C:42]([C:39]4[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][N:40]=4)[CH2:26][CH2:27]3)=[O:17])=[CH:3][CH:4]=2)[CH2:9]1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 211055245-Chloro-1',2',3',6'-tetrahydro-2,4'-bipyridineHCID 219165911-(4-aminophenyl)-N,N-dimethylpyrrolidin-3-amine

Product 1

HCID 588672045-Chloro-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic Acid [4-(3-dimethylamino-pyrrolidin-1-yl)phenyl]amide

Reagents, catalysts & solvents 3

HCID 6212ChloroformSolventHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Procedure

[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine (32 mg) and carbonyldiimidazole (27.1 mg) were dissolved in acetonitrile (1.5 ml), and the mixture was stirred for 3 hours. Triethylamine (63.4 μl) was added to a solution of 5-chloro-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridine (40.7 mg) in THF (1 ml) and chloroform (0.5 ml). After 15 minutes, the mixture was added dropwise to the first solution and stirred overnight. The mixture was concentrated and the residue was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate, filtered and concentrated. Contamination by the primary and/or secondary amine was removed by dissolving the residue in dichloromethane (1.5 ml) and adding the solution to a stirred suspension of polymer-bound p-toluenesulfonyl chloride (0.5 g) in dichloromethane (6 ml) and triethylamine (128 μl). After 3 hours, the resin was filtered off and washed several times with dichloromethane. The combined organic phases were concentrated. The residue was purified by chromatography (silica gel, mobile phase: ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 2%), later ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 3%). This resulted in the product with the molecular weight of 425.97 (C23H28ClN5O); MS (ESI): 426 (M+H+).

Workup

  1. waitAfter 15 minutes
  2. additionthe mixture was added dropwise to the first solution
  3. stirringstirred overnight
  4. concentrationThe mixture was concentrated
  5. customthe residue was partitioned between dichloromethane and water
  6. dry with materialThe organic phase was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customContamination by the primary and/or secondary amine was removed
  10. dissolutionby dissolving the residue in dichloromethane (1.5 ml)
  11. additionadding the solution
  12. additionto a stirred suspension of polymer-bound p-toluenesulfonyl chloride (0.5 g) in dichloromethane (6 ml) and triethylamine (128 μl)
  13. waitAfter 3 hours
  14. filtrationthe resin was filtered off
  15. washwashed several times with dichloromethane
  16. concentrationThe combined organic phases were concentrated
  17. customThe residue was purified by chromatography (silica gel, mobile phase
  18. customThis resulted in the product with the molecular weight of 425.97 (C23H28ClN5O)

Sources & evidence

ORD record
ord-10df67e345344ad6bb178ef340ce7f25
Source dataset
uspto-grants-2007_05
Patent number
US07223788B2

Reaction notes

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