GV-228869

Chemical Name: 4,6-Dichloro-3-[2(E)-[N-[4-(ureidomethyl)phenyl]carbamoyl]vinyl]-1H-indole-2-carboxylic acid sodium salt
CAS No. 182314-66-5, 182314-64-3 (free acid)
项目整合开发状态: Preclinical
项目研究机构: GlaxoSmithKline (Originator)
合成路线:The known indole-2-carboxylate intermediate (I) was protected as the N-benzenesulfonyl derivative (II) using benzenesulfonyl chloride and NaH,and the tert-butyl ester group of (II) was subsequently cleaved by means of formic acid.The resulting carboxylic acid (III) was activated as the 2-pyridyl thioester (IV) upon treatment with 2,2'-dipyridyl disulfide and triphenylphosphine.Selective protection of 4-aminobenzyl amine (V) with Boc2O produced the amino carbamate (VI).This was coupled with pyridyl thioester (IV) in refluxing THF to yield amide (VII).Subsequent removal of the N-Boc group of (VII) with trifluoroacetic acid afforded the free amino derivative (VIII),which was converted to the required urea (IX) upon treatment with trimethylsilyl isocyanate.Further hydrolysis of the benzenesulfonyl group of (IX) with ethanolic NaOH furnished the deprotected indole (X).

合成路线:In a more direct route,4-aminobenzyl amine (V) was treated with trimethylsilyl isocyanate to yield amino urea (XVI).This was subsequently coupled with pyridyl thioester (XIII) to furnish the previously described intermediate (X).

合成路线:Hydrolysis of the ethyl ester function of (X) by means of LiOH,followed by acidic workup,gave rise to carboxylic acid (XI),which was finally isolated as the title sodium salt by treatment with aqueous NaOH and subsequent freeze drying.Alternatively,hydrolysis of ethyl ester (X) with NaOH in isopropanol-water provided directly the target sodium salt.