Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → 1-Methyl-1-(1-methylpiperidin-4-yl)-3-{4-[4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}urea

HRID 492792Notes

Reaction equation

HRID 492792 reaction equation
[NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[CH:4][CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:42]1([CH2:48][C:49]([N:51]=[C:52]=[S:53])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>C(O)C.CCCCCC.C(OCC)C>[CH3:23][N:15]([CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[C:14]([NH:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([NH:1][C:52]([NH:51][C:49](=[O:50])[CH2:48][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[S:53])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)=[O:24]

Participants

8

Reactant 4

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 516892Sodium BicarbonateHCID 12454157Phenylacetyl isothiocyanateHCID 231535423-[4-(4-Aminophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Product 1

HCID 576776681-Methyl-1-(1-methylpiperidin-4-yl)-3-{4-[4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}ureaYield 2.2%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 3283Diethyl EtherSolventHCID 8058HexaneSolvent

Procedure

3-[4-(4-Aminophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (60 mg) was dissolved in ethanol (1 ml) while stirring, and then D-10-camphorsulfonic acid (39.3 mg) was added thereto under a nitrogen atmosphere, followed by stirring for 5 min. Phenylacetyl isothiocyanate (toluene solution, 1.82 M, 0.074 ml) was added thereto, followed by stirring further for 1.5 hrs. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine 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; hexane:ethyl acetate=1:5, then ethyl acetate). Fractions containing the crude product were concentrated to give a residue, which was then purified by LC-MS. The fractions containing the target compound were concentrated to give a residue, to which a saturated aqueous solution of sodium hydrogencarbonate was added to extract with ethyl acetate. The organic layer was separated, 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; ethyl acetate, then ethyl acetate:ethanol=9:1). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.3 ml)-hexane (0.1 ml) was then added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (2.0 mg, 2.2%) as a white solid.

Workup

  1. stirringby stirring for 5 min
  2. stirringby stirring further for 1.5 hrs
  3. customThe reaction mixture was partitioned between ethyl acetate (30 ml)
  4. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
  5. dry with materialdried over anhydrous sodium sulfate
  6. customThe solvent was evaporated
  7. customto give a residue, which
  8. customwas then purified by silica gel column chromatography (Fuji Silysia NH, eluent
  9. additionFractions containing the crude product
  10. concentrationwere concentrated
  11. customto give a residue, which
  12. customwas then purified by LC-MS
  13. additionThe fractions containing the target compound
  14. concentrationwere concentrated
  15. customto give a residue
  16. extractionto extract with ethyl acetate
  17. customThe organic layer was separated
  18. dry with materialdried over anhydrous sodium sulfate
  19. customThe solvent was evaporated
  20. customto give a residue, which
  21. customwas then purified by silica gel column chromatography (Fuji Silysia NH, eluent
  22. additionFractions containing the target compound
  23. concentrationwere concentrated
  24. customto give a residue
  25. filtrationThe solid was filtered off
  26. customdried under aeration

Sources & evidence

ORD record
ord-cde98ebd737c4ee78050a0079060e3b4
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

Loading…