新产品编号:327983
Chemical Name: (4-Benzylbenzyl)[2(S)-[N-[2,2-dimethyl-1(S)-(N-methylcarbamoyl)propyl]carbamoyl]-4-phenylbutyl]phosphinic acid
CAS No. 202976-34-9
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:Michael addition of bis(trimethylsilyl)phosphonite (II) to benzyl 2-phenethylacrylate (I) afforded phosphinic acid (III).4-Benzoylbenzyl bromide (IV) was reduced using triethylsilane and trifluoroacetic acid to give 4-benzylbenzyl bromide (V).Subsequent Arbuzov reaction of phosphinic acid (III) with bromide (V) generated the disubstituted phosphinic acid (VI),which was protected as the methyl ester (VII) employing trimethylsilyl diazomethane.Hydrogenolysis of the benzyl ester of (VII) then yielded carboxylic acid (VIII).This was coupled with (S)-tert-leucinamide (IX) by means of BOP to furnish the corresponding diamide (X).Alternatively,acid (VIII) was treated with N-hydroxysuccinimide (NHS) and EDC,and the resulting succinimidyl ester (XI) was coupled with amine (IX) to produce (X).The methyl phosphinate ester (X) was then deprotected by treatment with aqueous trifluoroacetic acid,and the required (S,S)-diastereoisomer was isolated by reverse phase flash chromatography.
📌 参考资料/链接：
参考文献标题:Phosphinate based inhibitors of matrix metalloproteases
文献作者:Reiter,L.A.(Pfizer Inc.)
参考来源:EP 0923585; JP 1999514673; WO 9803516
📄 详细内容
合成路线:Michael addition of bis(trimethylsilyl)phosphonite (II) to benzyl 2-phenethylacrylate (I) afforded phosphinic acid (III).4-Benzoylbenzyl bromide (IV) was reduced using triethylsilane and trifluoroacetic acid to give 4-benzylbenzyl bromide (V).Subsequent Arbuzov reaction of phosphinic acid (III) with bromide (V) generated the disubstituted phosphinic acid (VI),which was protected as the methyl ester (VII) employing trimethylsilyl diazomethane.Hydrogenolysis of the benzyl ester of (VII) then yielded carboxylic acid (VIII).This was coupled with (S)-tert-leucinamide (IX) by means of BOP to furnish the corresponding diamide (X).Alternatively,acid (VIII) was treated with N-hydroxysuccinimide (NHS) and EDC,and the resulting succinimidyl ester (XI) was coupled with amine (IX) to produce (X).The methyl phosphinate ester (X) was then deprotected by treatment with aqueous trifluoroacetic acid,and the required (S,S)-diastereoisomer was isolated by reverse phase flash chromatography.
参考文献标题:Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket
文献作者:Reiter,L.A.; Rizzi,J.P.; Pandit,J.; Lasut,M.J.; McGahee,S.M.; Parikh,V.D.; Blake,J.F.; Danley,D.E.; Laird,E.R.; Lopez-Anaya,A.; Lopresti-Morrow,L.L.; Mansour.M,N.; Martinelli,G.J.; Mitchell,P.G.; Owens,B.S.; Pauly,T.A.; et al.
参考来源:Bioorg Med Chem Lett 1999,9(2),127