(1S)-(+)-Camphor-10-sulphonic acid → 1-[1-(2-Dimethylaminoethyl)piperidin-4-yl]-3-[6-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyrimidin-4-yl]-1-methylurea

HRID 492877Notes

Reaction equation

HRID 492877 reaction equation
[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[C:19]([F:46])[CH:18]=1.[F:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55]([N:57]=[C:58]=[S:59])=[O:56])=[CH:50][CH:49]=1>C(O)C>[CH3:41][N:40]([CH3:42])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:44]=[CH:45][C:17]([NH:16][C:58]([NH:57][C:55](=[O:56])[CH2:54][C:51]4[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=4)=[S:59])=[CH:18][C:19]=3[F:46])[N:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1

Participants

5

Reactant 3

HCID 218580(1S)-(+)-Camphor-10-sulphonic acidHCID 231530283-[6-(4-Amino-2-fluorophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylureaHCID 231532482-(4-Fluorophenyl)acetyl isothiocyanate

Product 1

HCID 576773701-[1-(2-Dimethylaminoethyl)piperidin-4-yl]-3-[6-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyrimidin-4-yl]-1-methylureaYield 31.6%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

After adding (1S)-(+)-10-camphorsulfonic acid (101 mg) to a solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (110 mg) in ethanol (2.0 ml), the mixture was stirred for 15 minutes at room temperature. After adding 2-(4-fluorophenyl)acetyl isothiocyanate (3.06 ml, 0.25 M solution in toluene) thereto, the mixture was further stirred at room temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate (10 ml) and ethyl acetate (30 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated. Diethyl ether:hexane=1:1 was added to the obtained solid to produce a suspension. The precipitate was filtered and then washed with diethyl ether to provide the title compound (50.5 mg, 31.6%) as pale yellow powder.

Workup

  1. stirringthe mixture was further stirred at room temperature for 1 hour
  2. customThe reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate (10 ml) and ethyl acetate (30 ml)
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationThe dried organic layer was concentrated
  6. customthe residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  7. additionFractions containing the target compound
  8. concentrationwere concentrated
  9. additionDiethyl ether:hexane=1:1 was added to the obtained solid
  10. customto produce a suspension
  11. filtrationThe precipitate was filtered
  12. washwashed with diethyl ether

Sources & evidence

ORD record
ord-9210bba8a09a41c7948a916c89bebbbe
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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