(1S)-(+)-Camphor-10-sulphonic acid → 4-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyridin-2-yl]amide

HRID 492899Notes

Reaction equation

HRID 492899 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]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:40][CH:39]([N:41]([CH3:43])[CH3:42])[CH2:38]4)[CH2:33][CH2:32]3)=[O:30])[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>[F:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][C:54]([NH:56][C:57](=[S:58])[NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][CH:34]([N:37]5[CH2:38][CH:39]([N:41]([CH3:43])[CH3:42])[CH2:40]5)[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[CH:44][CH:45]=2)=[O:55])=[CH:51][CH:52]=1

Participants

5

Reactant 3

HCID 218580(1S)-(+)-Camphor-10-sulphonic acidHCID 231532482-(4-Fluorophenyl)acetyl isothiocyanateHCID 576773374-(3-Dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide

Product 1

HCID 576774114-[3-(Dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyridin-2-yl]amideYield 10.5%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

After adding (1S)-(+)-10-camphorsulfonic acid (90.7 mg) to a solution of 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (91.5 mg) in ethanol (2.0 ml), the mixture was stirred for 10 minutes at room temperature. Then, 2-(4-fluorophenyl)acetyl isothiocyanate (1.28 ml, 0.25 M solution in toluene) was added and stirring was carried out at room temperature for 50 minutes. The reaction mixture was 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 compounds were combined and concentrated. The residue was then purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were combined and concentrated, and then saturated aqueous sodium hydrogencarbonate was added to the 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, and the obtained precipitate was suspended in diethyl ether-hexane and filtered. The filtered solid was washed with diethyl ether. It was then dried by aspiration to provide the title compound (14.2 mg, 10.5%) as white powder.

Workup

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

Sources & evidence

ORD record
ord-64d24644241b4c88a24f588c3915155f
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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