Sodium Hydroxide → N-(3-Iodo-4-methyl-phenyl)-6-[4-(4-methoxy-phenyl)-piperazin-1-yl]-nicotinamide

HRID 2190635Notes

Reaction equation

HRID 2190635 reaction equation
Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[OH-].[Na+].C(N(C(C)C)CC)(C)C.Cl[C:29]1[CH:45]=[CH:44][C:32]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[C:38]([I:43])[CH:37]=2)=[O:34])=[CH:31][N:30]=1.Cl.COC1C=CC(N2CCNCC2)=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:43][C:38]1[CH:37]=[C:36]([NH:35][C:33](=[O:34])[C:32]2[CH:44]=[CH:45][C:29]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)[CH2:12][CH2:13]3)=[N:30][CH:31]=2)[CH:41]=[CH:40][C:39]=1[CH3:42]

Participants

8

Reactant 5

HCID 14798Sodium HydroxideHCID 81531Diisopropylethylamine2×HCID 27237001-(4-Methoxyphenyl)-piperazine, dihydrochlorideHCID 79255626-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamideHCID 122011971-(4-Methoxyphenyl)piperazine hydrochloride

Product 1

HCID 59318182N-(3-Iodo-4-methyl-phenyl)-6-[4-(4-methoxy-phenyl)-piperazin-1-yl]-nicotinamide

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

4-methoxyphenyl piperazine dihydrochloride (110 mg, 0.41 mmol) was partitioned between CH2Cl2 and 2N aq. NaOH. The aqueous layer was extracted twice more with CH2Cl2 and the combined organic layer was dried and concentrated. The residue was dissolved in dioxane (6 mL). The solution was then treated with diisopropyl ethylamine (0.07 mL, 0.41 mmol), a catalytic amount of DMAP and 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (50 mg, 0.13 mmol). The mixture was heated in a sealed tube at 120° C. for 22 hr. The mixture was then cooled, followed addition of another portion of 4-methoxyphenyl piperazine hydrochloride (110 mg, 0.41 mmol) and diisopropyl ethyl amine (0.14 mL, 0.82 mmol). The mixture was stirred at 120° C. for 3 more days then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column with 20-40% EtOAc in hexanes to afford the product. HRMS m/z calcd for C24H25N4O2I [M+H]+: 529.1095. Found: 529.1098.

Workup

  1. extractionThe aqueous layer was extracted twice more with CH2Cl2
  2. customthe combined organic layer was dried
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in dioxane (6 mL)
  5. temperatureThe mixture was then cooled
  6. temperaturethen cooled
  7. custompartitioned between EtOAc and aq. saturated Na2CO3
  8. dry with materialThe organic layer was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was chromatographed on a silica gel column with 20-40% EtOAc in hexanes
  12. customto afford the product

Sources & evidence

ORD record
ord-0e384de5a2e243248fa4d140a5a3d237
Source dataset
uspto-grants-2012_12
Patent number
US08324385B2

Reaction notes

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