Diethyl Ether → 1-(3-Diethylaminopropyl)-3-{4-[2-fluoro-4-(3-phenylacetylureido)phenoxy]pyridin-2-yl}-1-methylurea

HRID 492808Notes

Reaction equation

HRID 492808 reaction equation
[CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][N:7]([CH3:26])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[F:25])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)C.CCCCCC>O1CCCC1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1.C(OCC)(=O)C>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:26])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:40])=[CH:20][C:19]=2[F:25])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:28]

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 8058HexaneHCID 12259960Phenylacetyl isocyanate2×HCID 231533361-(3-Diethylaminopropyl)-3-[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-1-methylurea

Product 1

HCID 576773561-(3-Diethylaminopropyl)-3-{4-[2-fluoro-4-(3-phenylacetylureido)phenoxy]pyridin-2-yl}-1-methylureaYield 5.9%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 11248939Pyrrolidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pyrimidin-4-yl}amideSolvent2×

Procedure

To a solution of 1-(3-diethylaminopropyl)-3-[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-1-methylurea (100 mg) in tetrahydrofuran (2.0 ml) was added a solution of phenylacetyl isocyanate in hexane (3.4 ml, Production Example 1), followed by stirring under a nitrogen atmosphere at room temperature for 30 min. A solution of phenylacetyl isocyanate in hexane (1.0 ml, Production Example 1) was further added thereto, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between a mixed solvent of ethyl acetate-tetrahydrofuran (1:1, 200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (15 ml). The organic layer was washed with a 1 N aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing a crude product were concentrated to give a residue, which was then dissolved in ethyl acetate and washed with a 1 N aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which diethyl ether (3 ml) and hexane (3 ml) were then added to precipitate a solid. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (8.3 mg, 5.9%) as colorless powder.

Workup

  1. stirringby stirring at room temperature for 30 min
  2. customThe reaction mixture was partitioned between a mixed solvent of ethyl acetate-tetrahydrofuran (1:1, 200 ml)
  3. washThe organic layer was washed with a 1 N aqueous solution of sodium hydroxide
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue, which
  7. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate)
  8. additionFractions containing a crude product
  9. concentrationwere concentrated
  10. customto give a residue, which
  11. washwashed with a 1 N aqueous solution of sodium hydroxide
  12. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  13. customThe solvent was evaporated
  14. customto give a residue
  15. customto precipitate a solid
  16. filtrationThe solid was filtered off
  17. washwashed with diethyl ether
  18. customdried under aeration

Sources & evidence

ORD record
ord-de2d959a402f45f6a74110964f842582
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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