1-[5-(2-Hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea → 3,4,5-Triacetoxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid methyl ester

HRID 1038337Notes

Reaction equation

HRID 1038337 reaction equation
[OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH3:4].[CH3:42][O:43][C:44](=[O:65])[C@H:45]1[O:51][C@:49](Br)(O)[C@H:48]([O:53][C:54](=[O:56])[CH3:55])[C@@H:47]([O:57][C:58](=[O:60])[CH3:59])[C@@H:46]1[O:61][C:62](=[O:64])[CH3:63]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:42][O:43][C:44]([CH:45]1[CH:46]([O:61][C:62](=[O:64])[CH3:63])[CH:47]([O:57][C:58](=[O:60])[CH3:59])[CH:48]([O:53][C:54](=[O:56])[CH3:55])[CH:49]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[C:23]5[N:27]([CH:28]=4)[C:26]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[CH:32][C:25]=4[S:24]5)=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH3:5])[O:51]1)=[O:65]

Participants

5

Reactant 2

HCID 461867861-[5-(2-Hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureaHCID 54062351methyl 2,3,4-tri-O-acetyl-1-bromo-alpha-d-glucopyranuronate

Product 1

HCID 667944213,4,5-Triacetoxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid methyl ester

Reagents, catalysts & solvents 2

HCID 178418647HCID 178418647, compoundCatalystHCID 1140TolueneSolvent

Procedure

To a stirred mixture of 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (1 equivalent) and silver carbonate (0.5-1 equivalent) in toluene at rt is added 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester (0.8-1.5 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is filtered and the filtrate is partitioned between water and either dichloromethane or a mixture of dichloromethane and isopropanol. The separated aqueous layer is further extracted with dichloromethane or a mixture of dichloromethane and isopropanol. The combined organic layers are washed with 2N aq sodium hydroxide dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 3,4,5-triacetoxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid methyl ester.

Workup

  1. filtrationThe mixture is filtered
  2. customthe filtrate is partitioned between water
  3. additioneither dichloromethane or a mixture of dichloromethane and isopropanol
  4. extractionThe separated aqueous layer is further extracted with dichloromethane
  5. additiona mixture of dichloromethane and isopropanol
  6. washThe combined organic layers are washed with 2N aq sodium hydroxide
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography

Sources & evidence

ORD record
ord-119e13a3e6924d43980fed37563873c9
Source dataset
uspto-grants-2013_10
Patent number
US08551963B2

Reaction notes

Loading…