Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → 4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyrimidin-4-yl]amide

HRID 492856Notes

Reaction equation

HRID 492856 reaction equation
[NH2:1][C:2]1[CH:28]=[CH:27][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][CH:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[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)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:29][C:4]1[CH:3]=[C:2]([NH:1][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:28]=[CH:27][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][CH:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1

Participants

8

Reactant 4

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 516892Sodium BicarbonateHCID 231532482-(4-Fluorophenyl)acetyl isothiocyanateHCID 576776564-(Pyrrolidin-1-yl)piperidin-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide

Product 1

HCID 576776274-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyrimidin-4-yl]amideYield 34%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

After suspending a crude product of 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (88.4 mg) in ethanol (3 ml), D-10-camphorsulfonic acid (51.3 mg) was added and the mixture was stirred for 5 minutes. A 0.2 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (1.3 ml) was added thereto and the mixture was stirred for 62 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and then the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:9). Fractions containing the target compound were concentrated, and then diethyl ether (1 ml) and hexane (1.5 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (44.7 mg, 34%) as pale pink powder.

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for 62 hours
  3. customfor partition
  4. washthe organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml)
  5. dry with materialdried over anhydrous sodium sulfate
  6. distillationThe solvent was distilled off under reduced pressure
  7. customthe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:9)
  8. additionFractions containing the target compound
  9. concentrationwere concentrated
  10. additiondiethyl ether (1 ml) and hexane (1.5 ml) were added to the resultant residue
  11. customto produce a suspension
  12. filtrationAfter filtering the solid, it
  13. customdrying

Sources & evidence

ORD record
ord-3f8b1beb236a43eaa0a96cb9993f14f6
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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