Potassium Carbonate → [2-(2-{4-[3-(5-Tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester

HRID 1038329Notes

Reaction equation

HRID 1038329 reaction equation
[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34]Cl)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH2:42])C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:37][O:39][C:40](=[O:43])[CH2:41][NH:42][CH2:34][CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:25]2[N:26]3[CH:27]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=5)=[O:12])=[CH:15][CH:16]=4)[N:21]=[C:22]3[S:23][C:24]=2[CH:31]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 2723640Glycine ethyl ester, hydrochlorideHCID 667941831-(5-Tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-chloro-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea

Product 1

HCID 66794279[2-(2-{4-[3-(5-Tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 180AcetoneSolvent

Procedure

Alternatively, [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester is prepared in the following manner. To a stirred mixture of 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-chloro-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (1 equivalent), glycine ethyl ester hydrochloride (1-3 equivalents) and potassium carbonate (2-6 equivalents) in anhydrous acetone is added tetrabutylammonium iodide (0.1-1 equivalent) and the mixture is stirred and heated under reflux until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane. The combined extracts are washed with water or brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester.

Workup

  1. customAlternatively, [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester is prepared in the following manner
  2. temperatureheated
  3. temperatureunder reflux until the reaction
  4. customThe mixture is partitioned between water
  5. additioneither dichloromethane or a mixture of isopropanol and dichloromethane
  6. customThe organic layer is separated
  7. extractionthe aqueous layer is further extracted with dichloromethane
  8. additiona mixture of isopropanol and dichloromethane
  9. washThe combined extracts are washed with water or brine
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe residue is purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-f87f1372d3404e58bdb2468a95a29bc2
Source dataset
uspto-grants-2013_10
Patent number
US08551963B2

Reaction notes

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