Gemopatrilat, BMS-189921
1H-阿氮平-1-醋酸,六氢-6-[[(2S)-2-巰基-1-氧基-3-苯基丙基]氨基]-2,2-二甲基-7-氧基-,(6S)-Chemical Name: 2-[2,2-Dimethyl-7-oxo-6(S)-[3-phenyl-2(S)-sulfanylpropanamido]hexahydro-1H-azepin-1-yl]acetic acid
CAS No. 160135-92-2
项目整合开发状态: Phase II
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:(S)-6-Hydroxy-2-phthalimidohexanoic acid (I) was converted to benzyl ester (II) by treatment with benzyl bromide and Cs2CO3.Subsequent Swern oxidation of the alcohol function of (II) followed by reaction of the resulting aldehyde (III) with Me3Al afforded secondary alcohol (IV).A new Swern oxidation of (IV) provided ketone (V).Introduction of a further methyl group to give the tertiary alcohol (VI) was achieved by means of methyltitanium trichloride,generated in situ from MeLi and TiCl4.Azide (VII) was then obtained by treatment of (VI) with Me3SiN3 and BF3-Et2O.Palladium-catalyzed hydrogenation effected both reduction of the azide to amine and hydrogenolysis of the benzyl ester.Then,EDC-mediated cyclization of the intermediate amino acid gave azepinone (VIII).
合成路线:Removal of phthaloyl protecting group of (VIII) provided amine (IX),which was protected as the tert-butyl carbamate (X) with Boc2O.Alkylation at the lactam nitrogen atom of (X) was then achieved employing LiN(SiMe3)2 and ethyl bromoacetate to afford (XI),which was deprotected under acidic conditions to furnish amine (XII).Alternatively,amine (IX) could be protected using a N-trityl group.Coupling of amine (XII) with 2-(acetylthio)benzenepropanoic acid (XIII) using either BOP or EDC as the condensing reagents produced amide (XIV).Finally,both ethyl ester and acetyl thioester of (XIV) were hydrolyzed with NaOH to yield the title compound.
📌 参考资料/链接：
参考文献标题:Dual action inhibitors
文献作者:Karanewsky,D.S.; Barrish,J.C.; Petrillo,E.W.Jr.; Robl,J.A.; Ryono,D.E.(Bristol-Myers Squibb Co.)
参考来源:EP 0599444; US 5552397
📄 详细内容
合成路线:(S)-6-Hydroxy-2-phthalimidohexanoic acid (I) was converted to benzyl ester (II) by treatment with benzyl bromide and Cs2CO3.Subsequent Swern oxidation of the alcohol function of (II) followed by reaction of the resulting aldehyde (III) with Me3Al afforded secondary alcohol (IV).A new Swern oxidation of (IV) provided ketone (V).Introduction of a further methyl group to give the tertiary alcohol (VI) was achieved by means of methyltitanium trichloride,generated in situ from MeLi and TiCl4.Azide (VII) was then obtained by treatment of (VI) with Me3SiN3 and BF3-Et2O.Palladium-catalyzed hydrogenation effected both reduction of the azide to amine and hydrogenolysis of the benzyl ester.Then,EDC-mediated cyclization of the intermediate amino acid gave azepinone (VIII).
合成路线:Removal of phthaloyl protecting group of (VIII) provided amine (IX),which was protected as the tert-butyl carbamate (X) with Boc2O.Alkylation at the lactam nitrogen atom of (X) was then achieved employing LiN(SiMe3)2 and ethyl bromoacetate to afford (XI),which was deprotected under acidic conditions to furnish amine (XII).Alternatively,amine (IX) could be protected using a N-trityl group.Coupling of amine (XII) with 2-(acetylthio)benzenepropanoic acid (XIII) using either BOP or EDC as the condensing reagents produced amide (XIV).Finally,both ethyl ester and acetyl thioester of (XIV) were hydrolyzed with NaOH to yield the title compound.
参考文献标题:Vasopeptidase inhibitors: Incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides
文献作者:Robl,J.A.; Sulsky,R.; Sieber-McMaster,E.; Ryono,D.E.; Cimarusti,M.P.; Simpkins,L.M.; Karanewsky,D.S.; Chao,S.; Asaad,M.M.; Seymour,A.A.; Fox,M.E.; Smith,P.L.; Trippodo,N.C.
参考来源:J Med Chem 1999,42(2),305
产品链接: CAS No. 160135-92-2››