Pyrrolidine → N-(4-((6-Cyano-7-(((2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl)oxy)-4-quinolyl)oxy)phenyl)-N'-(thiazol-2-yl)urea

HRID 1433723Notes

Reaction equation

HRID 1433723 reaction equation
[NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]4[CH2:23][O:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(O[C:33](=[O:40])[NH:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1.[NH:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1>CS(C)=O.CN(C)C=O.CO.C(OCC)(=O)C.O>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][C@H:21]([OH:22])[CH2:23][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[O:40])=[CH:25][CH:24]=1)#[N:18]

Participants

10

Reactant 4

HCID 31268PyrrolidineHCID 651148phenyl N-(1,3-thiazol-2-yl)carbamateHCID 21939870Tetrahydrofuran ethyl acetateHCID 865914804-(4-Aminophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline

Product 1

HCID 86591481N-(4-((6-Cyano-7-(((2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl)oxy)-4-quinolyl)oxy)phenyl)-N'-(thiazol-2-yl)ureaYield 9%

Reagents, catalysts & solvents 5

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

4-(4-Aminophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline (322 mg, 0.966 mmol) and thiazol-2-ylcarbamic acid phenyl ester (255 mg, 1.26 mmol) were heated and stirred in dimethylsulfoxide (2 ml) at 85° C. for 4 hours. The reaction solution was distributed between an ethyl acetate-tetrahydrofuran mixed solvent and water, the organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the drying agent was filtered off and the filtrate distilled off under reduced pressure. The obtained product and pyrrolidine (343 mg, 4.83 mmol) were stirred in dimethylformamide (3 ml) at room temperature for 15 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=15:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (45 mg, 0.085 mmol, 9%) as light yellow crystals.

Workup

  1. washthe organic layer was washed with water and saturated brine
  2. dry with materialdried over anhydrous magnesium sulfate
  3. filtrationthe drying agent was filtered off
  4. distillationthe filtrate distilled off under reduced pressure
  5. washthe organic layer was washed with water and saturated brine
  6. dry with materialdried over anhydrous magnesium sulfate
  7. filtrationthe drying agent was filtered off
  8. distillationthe filtrate was distilled off under reduced pressure
  9. customThe obtained crude product
  10. additionthe fraction containing the target substance
  11. concentrationwas concentrated
  12. additionthe suspension was diluted with hexane
  13. filtrationthe crystals were filtered out
  14. washwashed with hexane
  15. customblow-dried

Sources & evidence

ORD record
ord-71bc92c578724f22828bbdcd2c18a85b
Source dataset
uspto-grants-2009_11
Patent number
US07612092B2

Reaction notes

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