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

HRID 493003Notes

Reaction equation

HRID 493003 reaction equation
[NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[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.C1(C)C=CC=CC=1>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)=[S:58])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1

Participants

6

Reactant 3

HCID 218580(1S)-(+)-Camphor-10-sulphonic acidHCID 231532482-(4-Fluorophenyl)acetyl isothiocyanateHCID 576775554-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide

Product 1

HCID 576773814-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyrimidin-4-yl]amide

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 1140TolueneSolvent

Procedure

4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (31 mg) was dissolved in ethanol (1 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (47 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.448 ml) was added thereto, followed by stirring for 15 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, ethyl acetate, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated under reduced pressure to give a residue, which was then purified by LC-MS. Fractions containing the target compound were concentrated to give a residue, which was then partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (0.9 mg) as a colorless oil.

Workup

  1. stirringby stirring for 15 hrs
  2. customThe reaction mixture was partitioned between ethyl acetate (50 ml)
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue, which
  7. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent
  8. additionFractions containing the target compound
  9. concentrationwere concentrated under reduced pressure
  10. customto give a residue, which
  11. customwas then purified by LC-MS
  12. additionFractions containing the target compound
  13. concentrationwere concentrated
  14. customto give a residue, which
  15. customwas then partitioned between ethyl acetate (50 ml)
  16. washThe organic layer was washed with brine (30 ml)
  17. dry with materialdried over anhydrous sodium sulfate
  18. customThe solvent was evaporated

Sources & evidence

ORD record
ord-12579c2a184a438fb1664454b281e649
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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