(1S)-(+)-Camphor-10-sulphonic acid → 1-[1-(2-Dimethylaminoethyl)piperidin-4-yl]-3-[4-(4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyridin-2-yl]-1-methylurea

HRID 492897Notes

Reaction equation

HRID 492897 reaction equation
[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[CH:19][CH:18]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]4[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=4)=[S:58])=[CH:45][CH:44]=3)[CH:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1

Participants

5

Reactant 3

HCID 218580(1S)-(+)-Camphor-10-sulphonic acidHCID 231531743-[4-(4-Aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylureaHCID 231532482-(4-Fluorophenyl)acetyl isothiocyanate

Product 1

HCID 576774361-[1-(2-Dimethylaminoethyl)piperidin-4-yl]-3-[4-(4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyridin-2-yl]-1-methylureaYield 14.8%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

After adding (1S)-(+)-10-camphorsulfonic acid (119 mg) to a solution of 3-[4-(4-aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (121 mg) in ethanol (2.0 ml), the mixture was stirred for 10 minutes at room temperature. Next, 2-(4-fluorophenyl)acetyl isothiocyanate (2.34 ml, 0.25 M solution in toluene) was added thereto and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were combined and concentrated. The residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were concentrated, and saturated aqueous sodium hydrogencarbonate was added to the resultant residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated to provide the title compound (26.3 mg, 14.8%) as white powder.

Workup

  1. stirringthe mixture was stirred at room temperature for 50 minutes
  2. customThe reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate
  3. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate
  6. additionFractions containing the target compound
  7. concentrationconcentrated
  8. customThe residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system)
  9. additionFractions containing the target compound
  10. concentrationwere concentrated
  11. additionsaturated aqueous sodium hydrogencarbonate was added to the resultant residue
  12. extractionThe mixture was extracted with ethyl acetate
  13. washthe organic layer was washed with brine
  14. dry with materialdried over anhydrous sodium sulfate
  15. concentrationIt was then concentrated

Sources & evidence

ORD record
ord-e7953e9f50694d0b85c2cf7a2a252102
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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