Methanol → Lapatinib

HRID 1847203Notes

Reaction equation

HRID 1847203 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].C[OH:43]>ClCCl.[Pd]>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:38]([O-:40])(=[O:43])=[O:39])=[CH:12][CH:11]=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

7

Reactant 3

HCID 887MethanolHCID 43405612-(Methylsulfonyl)ethanamineHCID 11181296(5-(4-(4-((3-Fluorobenzyl)oxy)-3-chloroanilino)-6-quinazolinyl)-2-furancarboxaldehyde

Product 2

HCID 85570p-ToluenesulfonateHCID 208908LapatinibYield 75%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 6344DichloromethaneSolvent

Procedure

The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-quinazolin-6-yl]-2-furaldehyde (20 g, 42.2 mmoL) in methanol (100 mL) and dichloromethane (60 mL) was charged with 2-aminoethylmethylsulfone (5.8 g, 46.4 mmoL) slowly under constant stirring at room temperature and then the reaction mixture was stirred for 2-4 hours until reaction completion. The reaction mixture was charged with 5% Pd—C (1 g) and stirred under hydrogen atmosphere (after evacuation) for 16-24 hours until reaction completion. The obtained mixture was filtered, washed with 3:1 mixture of methanol (40 mL) and dichloromethane (20 mL). The filtrate was distilled to low volume whereupon the obtained solution was slowly charged with a solution of p-toluenesulfonic acid monohydrate (8.8 g, 46.4 mmoL) in methanol (20 mL). The yellow solid which precipitated out was filtered and washed with 1:3 mixture of methanol (10 mL) and dichloromethane (30 mL). The solid obtained was dried under vacuum at 40-45° C. to furnish the monotosylate salt of Lapatinib (23.7 g, Yield=75%, 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. filtrationThe obtained mixture was filtered
  5. washwashed with 3:1 mixture of methanol (40 mL) and dichloromethane (20 mL)
  6. distillationThe filtrate was distilled to low volume whereupon the obtained solution
  7. additionwas slowly charged with a solution of p-toluenesulfonic acid monohydrate (8.8 g, 46.4 mmoL) in methanol (20 mL)
  8. customThe yellow solid which precipitated out
  9. filtrationwas filtered
  10. washwashed with 1:3 mixture of methanol (10 mL) and dichloromethane (30 mL)
  11. customThe solid obtained
  12. customwas dried under vacuum at 40-45° C.

Sources & evidence

ORD record
ord-f0ddca7a87534716b4265e45df40f459
Source dataset
uspto-grants-2015_02
Patent number
US08952154B2

Reaction notes

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