Methanol → Regorafenib Monohydrate

HRID 404713Notes

Reaction equation

HRID 404713 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1(C)C=CC=CC=1.CO.C(Cl)(=O)C.[NH2:28][C:29]1[CH:45]=[CH:44][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH:42][CH3:43])=[O:41])[CH:35]=2)=[CH:31][C:30]=1[F:46]>O1CCCC1>[OH2:10].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:28][C:29]2[CH:45]=[CH:44][C:32]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH:42][CH3:43])=[O:41])[CH:35]=3)=[CH:31][C:30]=2[F:46])=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]

Participants

7

Reactant 5

HCID 887MethanolHCID 1140TolueneHCID 6367Acetyl chlorideHCID 27332651-Chloro-4-isocyanato-2-(trifluoromethyl) benzeneHCID 468352194-(4-Amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide

Product 1

HCID 24768591Regorafenib MonohydrateYield 150.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
20 °C

Procedure

A reaction flask with stirrer was charged with 20.0 g of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide and 180 g of tetrahydrofuran as solvent. A solution of 18.7 g of 4-chloro-3-trifluoromethyl-phenylisocyanate and 21.1 g of toluene was added dropwise within approximately 90 minutes at room temperature. The resulting solution was stirred for 3 hours to complete the reaction. After then 30 g of tetrahydrofuran and 7.8 g of methanol were added to the reaction mixture. Following 9.0 g of acetyl chloride were added dropwise within 15 minutes to the reaction mixture. After additional stirring for approximately 2 hours the suspension was filtered and the solid was washed with tetrahydofuran (18.2 g) and acetone (136.4 g). The solid was added to a mixture of acetone (268.6 g), water (55.8 g) and an aqueous sodium hydroxide solution (8.2 g, 45% w/w) at 40° C. The mixture was stirred for additional 30 minutes. Then the crystallization was initiated by seeding with crystals of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide monohydrate. After cooling to 20° C. 31.6 g of water were added. The suspension was cooled down to approx. 3° C. and stirred for 30 minutes. The product was filtered off, washed with a cold mixture of acetone (106 g) and water (44 g) and dried under reduced pressure (30° C., 80 mbar). In this way 31.8 g (83% of theory) of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide monohydrate were obtained as white crystals.

Workup

  1. customthe reaction
  2. additionwere added dropwise within 15 minutes to the reaction mixture
  3. stirringAfter additional stirring for approximately 2 hours the suspension
  4. filtrationwas filtered
  5. washthe solid was washed with tetrahydofuran (18.2 g) and acetone (136.4 g)
  6. additionThe solid was added to a mixture of acetone (268.6 g), water (55.8 g)
  7. customat 40° C
  8. stirringThe mixture was stirred for additional 30 minutes
  9. customThen the crystallization
  10. addition31.6 g of water were added
  11. temperatureThe suspension was cooled down to approx. 3° C.
  12. stirringstirred for 30 minutes
  13. filtrationThe product was filtered off
  14. washwashed with a cold mixture of acetone (106 g) and water (44 g)
  15. customdried under reduced pressure (30° C., 80 mbar)

Sources & evidence

ORD record
ord-c64961523439470fb9ce9a565966f049
Source dataset
uspto-grants-2014_06
Patent number
US08748622B2

Reaction notes

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