-药物合成数据库

【药物名称】

化学结构式(Chemical Structure):

参考文献No.	35650
标题:	Phosphinate based inhibitors of matrix metalloproteases
作者:	Reiter, L.A. (Pfizer Inc.)
来源:	EP 0923585; JP 1999514673; WO 9803516

合成路线图解说明: 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No.	485779
标题:	Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket
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.
来源:	Bioorg Med Chem Lett 1999,9(2),127

合成路线图解说明: 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.