p-Toluenesulfonic acid monohydrate → Lapatinib

HRID 1847202Notes

Reaction equation

HRID 1847202 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39].O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CO.ClCCl.[Pd]>[CH3:53][C:43]1[CH:44]=[CH:45][C:46]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:47][CH:48]=1.[CH3:41][S:38]([CH2:37][CH2:36][NH:35][CH2:33][C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)[C:27]=3[CH:26]=2)=[CH:29][CH:30]=1)(=[O:40])=[O:39]

Participants

8

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 43405612-(Methylsulfonyl)ethanamineHCID 11181296(5-(4-(4-((3-Fluorobenzyl)oxy)-3-chloroanilino)-6-quinazolinyl)-2-furancarboxaldehyde

Product 2

HCID 85570p-ToluenesulfonateHCID 208908LapatinibYield 106%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolvent3×HCID 6344DichloromethaneSolvent2×

Procedure

The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5 g, 10.6 mmoL) in methanol (25 mL) and dichloromethane (25 mL) was charged with 2-aminoethylmethylsulfone (1.4 g, 11.2 mmoL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion and then the reaction mixture was charged with 5% Pd—C (500 mg) and stirred under hydrogen atmosphere (after evacuation) for 16-24 hours until reaction completion. The reaction mixture was further charged with methanol (25 mL) and dichloromethane (25 mL) and stirred for 12-16 hours. The obtained mixture was filtered, washed with 1:1 mixture of methanol (20 mL) and dichloromethane (20 mL). The yellow filtrate thus obtained was slowly charged with a solution of p-toluenesulfonic acid monohydrate (2.2 g, 11.2 mmoL) in methanol (5 mL). The yellow solid which precipitated out was filtered and washed with 1:1 mixture of methanol (20 mL) and dichloromethane (20 mL). The solid obtained was dried under vacuum at 40-45° C. to provide the monotosylate salt of Lapatinib (6.5 g, Yield=81%, HPLC purity>99%).

Workup

  1. stirringThe reaction mixture was stirred for 2-4 hours until reaction completion
  2. stirringstirred under hydrogen atmosphere (after evacuation) for 16-24 hours
  3. customuntil reaction completion
  4. stirringstirred for 12-16 hours
  5. filtrationThe obtained mixture was filtered
  6. washwashed with 1:1 mixture of methanol (20 mL) and dichloromethane (20 mL)
  7. customThe yellow filtrate thus obtained
  8. customThe yellow solid which precipitated out
  9. filtrationwas filtered
  10. washwashed with 1:1 mixture of methanol (20 mL) and dichloromethane (20 mL)
  11. customThe solid obtained
  12. customwas dried under vacuum at 40-45° C.

Sources & evidence

ORD record
ord-33d89d31bdb04a8da2ae9126a5c04175
Source dataset
uspto-grants-2015_02
Patent number
US08952154B2

Reaction notes

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