Pyridine → Sunitinib

HRID 1500387Notes

Reaction equation

HRID 1500387 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](O)=[O:20])[C:14]=1[CH3:22].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH2:45])[CH3:41]>CN(C=O)C.CN(C)C1C=CN=CC=1.CO.O>[CH3:41][CH2:40][N:42]([CH2:43][CH2:44][NH:45][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2/[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]/2=[O:11])[NH:17][C:16]=1[CH3:18])=[O:20])[CH2:46][CH3:47]

Participants

9

Reactant 4

HCID 1049PyridineHCID 73974-Toluenesulfonyl chlorideHCID 60993N,N-DiethylethylenediamineHCID 10979489Sunitinib acid2×

Product 1

HCID 5329102Sunitinib

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent4×

Conditions

Temperature
17 °C

Procedure

A mixture of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene) methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (70 g) in DMF (1050 mL) was cooled to 15-19° C. To this mixture p-toluene sulfonyl chloride (133.4 g) in DMF (350 mL) was added in 15 min. 4-dimethylamino pyridine (81.3 g) in DMF (350 mL) was added in 15 min and pyridine (36.9 g) was added in 15 min at 15-19° C. The reaction mixture was stirred at the same temperature over a period of 60-90 minutes. The reaction mass was cooled to 13-16° C. To the above reaction mixture N, N-diethyl ethylene diamine (81.3 g) in DMF (350 mL) was added in 10 min at 13-16° C. The reaction mass was maintained under stirring for a period of 30 minutes at the same temperature. The progress of the rection was monitored by HPLC with a limit of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid not more than 5.0%. After the completion of reaction 28 mL of water was charged and DMF was distilled off under vacuum. 1050 mL of 5% sodium bicarbonate solution was charged under stirring. The pH of the above solution was adjusted to 12-13 by 50% NaOH solution. Ethyl acetate was charged and it was stirred for 5 min. The organic layer were separated and treated with 1% NaOH, and brine solution followed by separation of the ethyl acetate fraction and distillation off under vacuum below 50° C. The residue was treated with 30% methanol in water to isolate the material. It was treated with methanol to obtain sunitinib base. The obtained solid was dried under vacuum at 55 -65° C. over for a period of 5 hrs. Yield: 65.6 g of Sunitinib base with ˜0.5% des ethyl sunitinib.

Workup

  1. temperatureThe reaction mass was cooled to 13-16° C
  2. temperatureThe reaction mass was maintained
  3. stirringunder stirring for a period of 30 minutes at the same temperature
  4. additionwas charged
  5. distillationDMF was distilled off under vacuum
  6. addition1050 mL of 5% sodium bicarbonate solution was charged
  7. stirringunder stirring
  8. additionEthyl acetate was charged
  9. stirringit was stirred for 5 min
  10. customThe organic layer were separated
  11. additiontreated with 1% NaOH, and brine solution
  12. customfollowed by separation of the ethyl acetate fraction and distillation off under vacuum below 50° C
  13. additionThe residue was treated with 30% methanol in water
  14. customto isolate the material

Sources & evidence

ORD record
ord-a9e37c0a718043ed8b79cc627dd4f327
Source dataset
uspto-grants-2015_12
Patent number
US09206163B2

Reaction notes

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