Phenylacetyl chloride → 4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pirimidin-4-yl}amide

HRID 492771Notes

Reaction equation

HRID 492771 reaction equation
[C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:42]=[CH:41][C:19]([O:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:35][CH2:34][CH:33]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([F:43])[CH:17]=1.CCCCCC>C(#N)C.C(OCC)C>[F:43][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:42]=[CH:41][C:19]=1[O:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:29])[CH:22]=1

Participants

7

Reactant 4

HCID 7679Phenylacetyl chlorideHCID 8058HexaneHCID 516872Potassium thiocyanateHCID 576776564-(Pyrrolidin-1-yl)piperidin-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide

Product 1

HCID 576775064-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pirimidin-4-yl}amideYield 11.5%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolvent2×

Procedure

2-Phenylacetyl chloride (0.053 ml) was dissolved in acetonitrile (4 ml) under a nitrogen atmosphere, and then potassium thiocyanate (77.7 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. 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, to which was added a solution of 4-(pyrrolidin-1-yl)piperidin-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (49.0 mg) in acetonitrile (5 ml) under a nitrogen atmosphere, followed by stirring at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1). The resultant crude product was purified again by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (0.5 ml)-hexane (1.0 ml). The solid was filtered off and dried under aeration to provide the titled compound (8.1 mg, 11.5%) as a white solid.

Workup

  1. customat 60° C.
  2. custompartitioned between ethyl acetate
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue
  7. stirringby stirring at room temperature for 1 hr
  8. customThe reaction mixture was partitioned between ethyl acetate and water
  9. washThe organic layer was washed with brine
  10. dry with materialdried over anhydrous sodium sulfate
  11. customThe solvent was evaporated under a reduced pressure
  12. customto give a residue, which
  13. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1)
  14. customThe resultant crude product was purified again by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1)
  15. additionFractions containing the target compound
  16. concentrationwere concentrated
  17. customto give a residue, which
  18. filtrationThe solid was filtered off
  19. customdried under aeration

Sources & evidence

ORD record
ord-4493839b3a3d49a599dfdafe7420678a
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

Loading…