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【结 构 式】 
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【分子编号】47933 【品名】(5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione 【CA登记号】 |
【 分 子 式 】C17H13BrCl2N2O2 【 分 子 量 】428.1119 【元素组成】C 47.69% H 3.06% Br 18.66% Cl 16.56% N 6.54% O 7.47% |
合成路线1
该中间体在本合成路线中的序号：(XI)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.
| 【1】 Frutos, R.P.; et al.; An improved synthesis of N-aryl-hydantoin LFA-1 antagonists via the enantiospecific alkylation of a isobutyraldehyde-derived imidazolidinone template. Tetrahedron Asymmetry 2001, 12, 1, 101. |
| 【2】 Yee, N.K.; Self-regeneration of stereocenters: A practical enantiospecific synthesis of LFA-1 antagonist BIRT-377. Org Lett 2000, 2, 18, 2781. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (III) | 47927 | tert-butyl (1R)-2-(3,5-dichloroanilino)-1-methyl-2-oxoethylcarbamate | C14H18Cl2N2O3 | 详情 | 详情 | |
| (IV) | 47928 | (2R)-2-amino-N-(3,5-dichlorophenyl)propanamide | C9H10Cl2N2O | 详情 | 详情 | |
| (V) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VI) | 47929 | (2S,5R)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-4-imidazolidinone | C14H18Cl2N2O | 详情 | 详情 | |
| (VII) | 47930 | (2R,5R)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-4-imidazolidinone | C16H17Cl2F3N2O2 | 详情 | 详情 | |
| (VIII) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (IX) | 47931 | (2R,5R)-5-(4-bromobenzyl)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-4-imidazolidinone | C23H22BrCl2F3N2O2 | 详情 | 详情 | |
| (X) | 47932 | (2R)-2-amino-3-(4-bromophenyl)-N-(3,5-dichlorophenyl)-2-methylpropanamide | C16H15BrCl2N2O | 详情 | 详情 | |
| (XI) | 47933 | (5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione | C17H13BrCl2N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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.
| 【1】 Farina, V.; Napolitano, E.; Crystallization-induced asymmetric transformations and self-regeneration of stereocenters (SROSC): Enantiospecific synthesis of alpha-benzylalanine and hydantoin BIRT-377. Tetrahedron Lett 2001, 42, 18, 3231. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (II) | 28446 | [1,1'-biphenyl]-4-carbaldehyde | 3218-36-8 | C13H10O | 详情 | 详情 |
| (III) | 47938 | tert-butyl (2S,4S)-2-[1,1'-biphenyl]-4-yl-4-methyl-5-oxo-1,3-oxazolidine-3-carboxylate | C21H23NO4 | 详情 | 详情 | |
| (IV) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (V) | 47939 | tert-butyl (2S,4S)-2-[1,1'-biphenyl]-4-yl-4-(4-bromobenzyl)-4-methyl-5-oxo-1,3-oxazolidine-3-carboxylate | C28H28BrNO4 | 详情 | 详情 | |
| (VI) | 47940 | methyl (2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]-2-methylpropanoate | C16H22BrNO4 | 详情 | 详情 | |
| (VII) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (VIII) | 47933 | (5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione | C17H13BrCl2N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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.
| 【1】 Kapadia, S.R.; et al.; An improved synthesis of chiral alpha-(4-bromobenzyl)alanine ethyl ester and its application to the synthesis of LFA-1 antagonist BIRT-377. J Org Chem 2001, 66, 5, 1903. |
| 【2】 Emeigh, J.E.; et al.; Small molecule antagonists of LFA-1 mediated cell adhesion. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 256. |
| 【3】 Bormann, B.J.; Frye, L.L.; Wu, J.-P.; Kelly, T.A. (Boehringer Ingelheim Pharmaceuticals Inc.); Small molecules useful in the treatment of inflammatory disease. EP 0966447; WO 9839303 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (II) | 27515 | Methoxy(phenyl)methyl methyl ether; Dimethylacetal benzaldehyde; Benzaldehyde dimethylacetal | 1125-88-8 | C9H12O2 | 详情 | 详情 |
| (III) | 47934 | tert-butyl (2S,4S)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate | C15H19NO4 | 详情 | 详情 | |
| (IV) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (V) | 47935 | tert-butyl (2S,4S)-4-(4-bromobenzyl)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate | C22H24BrNO4 | 详情 | 详情 | |
| (VI) | 47936 | ethyl (2S)-2-amino-3-(4-bromophenyl)-2-methylpropanoate | C12H16BrNO2 | 详情 | 详情 | |
| (VII) | 47937 | 1,3-dichloro-5-isocyanatobenzene; 3,5-dichlorophenyl isocyanate | C7H3Cl2NO | 详情 | 详情 | |
| (VIII) | 47933 | (5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione | C17H13BrCl2N2O2 | 详情 | 详情 |