Ilomastat, CS-610, GM-6001, Galardin MPI, Galardin
伊洛马司他Chemical Name: 3-(N-Hydroxycarbamoyl)-2(R)-isobutylpropionyl-L-tryptophan methylamide
CAS No. 142880-36-2
项目整合开发状态: Preclinical
项目研究机构: Ligand (Originator), University of Florida (Originator), Arriva Pharmaceuticals (Licensee), Quick-Med Technologies (Licensee), Sankyo (Licensee)
合成路线:Scheme shows the synthesis of Galardin(TM) from the two starting materials,4-methyl-2-oxopentanoic acid sodium salt (I) and tert-butyloxycarbonyl-L-tryptophan (V).The pentanoic acid is protected as a benzyl ester and then condensed with the ylide methyl (triphenylphosphoranylidene)acetate to give methyl 3-benzyloxycarbonyl-5-methyl-2-hexenoate (III).Deprotection and reduction of (III) gives the key intermediate 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoic acid (IV) in high overall yield.The protected L-tryptophan starting material (V) is coupled with methylamine to give (VI),which is deprotected to give the second key intermediate,L-tryptophan methylamide hydrochloride (VII).Coupling of (IV) and (VII) gives the mixture of diastereomers 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide.Low-pressure column chromatography on silica gel gives 2(R)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide (VIII) in high yield.Direct hydroxaminolysis of the methyl ester (VIII) in methanol in the presence of potassium hydroxide gives crude Galardin(TM).Recrystallization gives the drug substance.
📌 参考资料/链接：
参考文献标题:Galardin (TM)
文献作者:Galardy,R.E.
参考来源:Drugs Fut 1993,18(12),1109
📄 详细内容
合成路线:Scheme shows the synthesis of Galardin(TM) from the two starting materials,4-methyl-2-oxopentanoic acid sodium salt (I) and tert-butyloxycarbonyl-L-tryptophan (V).The pentanoic acid is protected as a benzyl ester and then condensed with the ylide methyl (triphenylphosphoranylidene)acetate to give methyl 3-benzyloxycarbonyl-5-methyl-2-hexenoate (III).Deprotection and reduction of (III) gives the key intermediate 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoic acid (IV) in high overall yield.The protected L-tryptophan starting material (V) is coupled with methylamine to give (VI),which is deprotected to give the second key intermediate,L-tryptophan methylamide hydrochloride (VII).Coupling of (IV) and (VII) gives the mixture of diastereomers 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide.Low-pressure column chromatography on silica gel gives 2(R)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide (VIII) in high yield.Direct hydroxaminolysis of the methyl ester (VIII) in methanol in the presence of potassium hydroxide gives crude Galardin(TM).Recrystallization gives the drug substance.
参考文献标题:Matrix metalloproteinases: A review
文献作者:Bodden,M.K.; Engler,J.A.; Moore,W.G.I.; Windsor,L.J.; Birkedal-Hansen,H.; Birkedal-Hansen,B.; DeCarlo,A.
参考来源:Crit Rev Oral Biol Med 1993,4(2),197-250
产品链接: CAS No. 142880-36-2››