【药物名称】BIRT-0377, BIRT-377
化学结构式(Chemical Structure):
参考文献No.37311
标题:Small molecules useful in the treatment of inflammatory disease
作者:Bormann, B.J.; Frye, L.L.; Wu, J.-P.; Kelly, T.A. (Boehringer Ingelheim Pharmaceuticals Inc.)
来源:EP 0966447; WO 9839303
合成路线图解说明:

The reaction of N-(tert-butoxycarbonyl)-L-alanine (I) with benzaldehyde dimethylacetal (II) by means of SOCl2 and ZnCl2 gives the oxazolidinone (III), which is alkylated with 4-bromobenzyl bromide (IV) and KHMDS in THF to yield the alkylated compound (V). The opening of the oxazolidinone ring of (V) with HBr/HOAc, followed by esterification with EtOH/HCl, affords the aminopropionic ester (VI), which is cyclized again with 3,5-dichlorophenyl isocyanate (VII) by means of Na2CO3 to provide imidazolidinedione (VIII). Finally, this compound is methylated with Me-I and NaHMDS to give the target compound.

参考文献No.594298
标题:Self-regeneration of stereocenters: A practical enantiospecific synthesis of LFA-1 antagonist BIRT-377
作者:Yee, N.K.
来源:Org Lett 2000,2(18),2781
合成路线图解说明:

The reaction of N-(tert-butoxycarbonyl)-D-alanine (I) with 3,5-dichloroaniline (II) by means of isobutyl chloroformate and NMM gives the corresponding protected amide (III), which is deprotected with TFA to yield alaninamide (IV). The cyclization of (IV) with pivalaldehyde (V) in hot toluene affords the imidazolidinone (VI), which is acylated with TFAA and TEA in THF to provide the trifluoroacetyl derivative (VII). The alkylation of (VII) with 4-bromobenzyl bromide (VIII) and LHMDS in THF gives the benzyl derivative (IX), which is treated first with benzyl trimethylammonium chloride and NaOH and then with 6N HCl (or t-BuOK in THF/water) to yield the propionamide derivative (X). The cyclization of (X) with methyl chloroformate and TEA in THF affords the imidazolidinedione (XI), which is finally methylated with methyl iodide and LHMDS to provide the target compound.

参考文献No.611043
标题:An improved synthesis of chiral alpha-(4-bromobenzyl)alanine ethyl ester and its application to the synthesis of LFA-1 antagonist BIRT-377
作者:Kapadia, S.R.; Spero, D.M.; Eriksson, M.
来源:J Org Chem 2001,66(5),1903
合成路线图解说明:

The reaction of N-(tert-butoxycarbonyl)-L-alanine (I) with benzaldehyde dimethylacetal (II) by means of SOCl2 and ZnCl2 gives the oxazolidinone (III), which is alkylated with 4-bromobenzyl bromide (IV) and KHMDS in THF to yield the alkylated compound (V). The opening of the oxazolidinone ring of (V) with HBr/HOAc, followed by esterification with EtOH/HCl, affords the aminopropionic ester (VI), which is cyclized again with 3,5-dichlorophenyl isocyanate (VII) by means of Na2CO3 to provide imidazolidinedione (VIII). Finally, this compound is methylated with Me-I and NaHMDS to give the target compound.

参考文献No.613035
标题:Small molecule antagonists of LFA-1 mediated cell adhesion
作者:Emeigh, J.E.; et al.
来源:221st ACS Natl Meet (April 1 2001, San Diego) 2001,Abst MEDI 256
合成路线图解说明:

The reaction of N-(tert-butoxycarbonyl)-L-alanine (I) with benzaldehyde dimethylacetal (II) by means of SOCl2 and ZnCl2 gives the oxazolidinone (III), which is alkylated with 4-bromobenzyl bromide (IV) and KHMDS in THF to yield the alkylated compound (V). The opening of the oxazolidinone ring of (V) with HBr/HOAc, followed by esterification with EtOH/HCl, affords the aminopropionic ester (VI), which is cyclized again with 3,5-dichlorophenyl isocyanate (VII) by means of Na2CO3 to provide imidazolidinedione (VIII). Finally, this compound is methylated with Me-I and NaHMDS to give the target compound.

参考文献No.618171
标题:Crystallization-induced asymmetric transformations and self-regeneration of stereocenters (SROSC): Enantiospecific synthesis of alpha-benzylalanine and hydantoin BIRT-377
作者:Farina, V.; Napolitano, E.
来源:Tetrahedron Lett 2001,42(18),3231
合成路线图解说明:

The reaction of N-(tert-butoxycarbonyl)-L-alanine (I) with biphenyl-4-carbaldehyde (II) by means of oxalyl chloride and ZnCl2 or TsOH gives the oxazolidinone (III), which is alkylated with 4-bromobenzyl bromide (IV) and LHMDS in THF, yielding the alkylated compound (V). The opening of the oxazolidinone ring of (V) with LiOMe and NaHSO3 affords the aminopropionic ester (VI), which is cyclized again with 3,5-dichloroaniline (VII) by means of NaOMe in refluxing toluene to provide imidazolidinedione (VIII). Finally, this compound is methylated with MeI, NaOH and tetrabutylammonium bisulfate to give the target compound.

参考文献No.624342
标题:An improved synthesis of N-aryl-hydantoin LFA-1 antagonists via the enantiospecific alkylation of a isobutyraldehyde-derived imidazolidinone template
作者:Frutos, R.P.; et al.
来源:Tetrahedron Asymmetry 2001,12(1),101
合成路线图解说明:

The reaction of N-(tert-butoxycarbonyl)-D-alanine (I) with 3,5-dichloroaniline (II) by means of isobutyl chloroformate and NMM gives the corresponding protected amide (III), which is deprotected with TFA to yield alaninamide (IV). The cyclization of (IV) with pivalaldehyde (V) in hot toluene affords the imidazolidinone (VI), which is acylated with TFAA and TEA in THF to provide the trifluoroacetyl derivative (VII). The alkylation of (VII) with 4-bromobenzyl bromide (VIII) and LHMDS in THF gives the benzyl derivative (IX), which is treated first with benzyl trimethylammonium chloride and NaOH and then with 6N HCl (or t-BuOK in THF/water) to yield the propionamide derivative (X). The cyclization of (X) with methyl chloroformate and TEA in THF affords the imidazolidinedione (XI), which is finally methylated with methyl iodide and LHMDS to provide the target compound.

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