(1S)-(+)-Camphor-10-sulphonic acid → 4-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyrimidin-4-yl]amide

HRID 492901Notes

Reaction equation

HRID 492901 reaction equation
[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:43]=[CH:42][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]4[CH2:40][N:39]([CH3:41])[CH2:38]4)[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[C:19]([F:44])[CH:18]=1.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[F:44][C:19]1[CH:18]=[C:17]([NH:16][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=2)=[S:57])[CH:43]=[CH:42][C:20]=1[O:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]2[CH2:32][CH2:33][N:34]([CH:37]3[CH2:40][N:39]([CH3:41])[CH2:38]3)[CH2:35][CH2:36]2)=[O:30])[CH:23]=1

Participants

6

Reactant 3

HCID 218580(1S)-(+)-Camphor-10-sulphonic acidHCID 231532482-(4-Fluorophenyl)acetyl isothiocyanateHCID 576776494-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide

Product 1

HCID 576775214-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyrimidin-4-yl]amideYield 16.9%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 1140TolueneSolvent

Procedure

After adding (1S)-(+)-10-camphorsulfonic acid (29.4 mg) to a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (31.8 mg) in ethanol (1.5 ml), the mixture was stirred for 10 minutes at room temperature. A solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 0.634 ml) was added thereto, and stirring was carried out at room temperature for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated, and 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 residue. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was concentrated to provide the title compound (8.0 mg, 16.9%) as white powder.

Workup

  1. stirringstirring
  2. waitwas carried out at room temperature for 30 minutes
  3. customThe reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate
  4. washThe organic layer was washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationIt was then concentrated
  7. customthe residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system)
  8. additionFractions containing the target compound
  9. concentrationwere concentrated
  10. additionsaturated aqueous sodium hydrogencarbonate was added to the residue
  11. extractionThe mixture was then extracted with ethyl acetate
  12. washThe organic layer was washed with brine
  13. dry with materialdried over anhydrous sodium sulfate
  14. concentrationIt was concentrated

Sources & evidence

ORD record
ord-2e0f2de9c5404f908fd0ec78bd550c3e
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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