Methanol → Lapatinib

HRID 1847205Notes

Reaction equation

HRID 1847205 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 93%

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 (10 g, 21.1 mmoL) in dichloromethane (100 mL) was charged with a solution of 2-aminoethylmethylsulfone (5.8 g, 46.4 mmoL) in methanol (50 mL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion. The reaction mixture was charged with 5% Pd—C (1.5 g) and stirred under hydrogen atmosphere using balloon pressure for 12-16 hours until reaction completion. The obtained mixture was filtered through Celite® pad and rinsed with methanol (30 mL) and dichloromethane (10 mL) mixture. The filtrate was distilled to a low volume and the solution was charged with toluene (50 mL) followed by addition of the solution of p-toluenesulfonic acid monohydrate (4.8 g, 25.3 mmoL) in methanol (25 mL). The yellow solid precipitated out was filtered after 2-8 hours and washed with 1:1 mixture of methanol and toluene (40 mL). The solid obtained was dried under vacuum at 40-45° C. to provide the monotosylate salt of Lapatinib (11.4 g, Yield=93%, HPLC purity>99%).

Workup

  1. stirringThe reaction mixture was stirred for 2-4 hours until reaction completion
  2. stirringstirred under hydrogen atmosphere
  3. customfor 12-16 hours
  4. customuntil reaction completion
  5. filtrationThe obtained mixture was filtered through Celite® pad
  6. washrinsed with methanol (30 mL) and dichloromethane (10 mL) mixture
  7. distillationThe filtrate was distilled to a low volume
  8. additionthe solution was charged with toluene (50 mL)
  9. additionfollowed by addition of the solution of p-toluenesulfonic acid monohydrate (4.8 g, 25.3 mmoL) in methanol (25 mL)
  10. customThe yellow solid precipitated out
  11. filtrationwas filtered after 2-8 hours
  12. washwashed with 1:1 mixture of methanol and toluene (40 mL)
  13. customThe solid obtained
  14. customwas dried under vacuum at 40-45° C.

Sources & evidence

ORD record
ord-0ab6602bcd794f969b0940190bed5d15
Source dataset
uspto-grants-2015_02
Patent number
US08952154B2

Reaction notes

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