Triethylamine → Lapatinib

HRID 2093285Notes

Reaction equation

HRID 2093285 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37].C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 4311764Sodium borohydrideHCID 43405612-(Methylsulfonyl)ethanamineHCID 11181296(5-(4-(4-((3-Fluorobenzyl)oxy)-3-chloroanilino)-6-quinazolinyl)-2-furancarboxaldehyde

Product 1

HCID 208908Lapatinib

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

The title compound was prepared according to Procedure D as follows. The 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (12.58 g, 24.7 mmol) was added to a solution of 2-methanesulphonyl-ethylamine (4.55 g, 37.0 mmol) and triethylamine (2.0 ml, 27.2 mmol) in 125 ml of tetrahydrofuran and 125 ml of methanol. After stirring 3 hours, the solution was cooled in an ice bath and sodium borohydride (2.42 g, 64.0 mmol) was added in five portions over a 20 minute period. The reaction mixture was stirred overnight at room temperature and then quenched with the dropwise addition of 250 ml of water. The solution was concentrated in vacuo to remove the organic solvents and the residual oily solution was extracted with 1 l of ethyl acetate. The organic solution was washed with 1M sodium hydroxide and brine and then dried with sodium sulfate. The solution was concentrated in vacuo to a very small volume and solid crystallized out. The suspension was filtered with a small volume of ethyl acetate, washed with ether and dried in a vacuum oven at 65 C to give 10.0 g (70%) of free base as an off white solid. 1H NMR 400 MHz (DMSO-d6) δ 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H+).

Workup

  1. temperaturethe solution was cooled in an ice bath
  2. stirringThe reaction mixture was stirred overnight at room temperature
  3. customquenched with the dropwise addition of 250 ml of water
  4. concentrationThe solution was concentrated in vacuo
  5. customto remove the organic solvents
  6. extractionthe residual oily solution was extracted with 1 l of ethyl acetate
  7. washThe organic solution was washed with 1M sodium hydroxide and brine
  8. dry with materialdried with sodium sulfate
  9. concentrationThe solution was concentrated in vacuo to a very small volume and solid
  10. customcrystallized out
  11. filtrationThe suspension was filtered with a small volume of ethyl acetate
  12. washwashed with ether
  13. customdried in a vacuum oven at 65 C

Sources & evidence

ORD record
ord-745b6728f1dd4863b12df91c4d1aca12
Source dataset
uspto-grants-2013_05
Patent number
US08444988B2

Reaction notes

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