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【结 构 式】 
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【分子编号】26542 【品名】3,5-dichloroaniline 【CA登记号】626-43-7 |
【 分 子 式 】C6H5Cl2N 【 分 子 量 】162.01784 【元素组成】C 44.48% H 3.11% Cl 43.76% N 8.65% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound has been obtained by two related ways: 1) The sulfonation of 3,5-dichloroaniline (I) with chlorosulfonic acid gives 2-amino-4,6-dichlorobenzenesulfonyl chloride (II), which is condensed with 3-bromobenzylamine (III) by means of TEA yielding the corresponding sulfonamide (IV). The cyclization of (IV) with glyoxylic acid (A) in ethanol/sulfuric acid affords the esterified benzothiadiazine-3-carboxylate (V), which is finally hydrolyzed with aqueous NaOH. 2) The reaction of sulfonyl chloride (II) with liquid ammonia gives the corresponding sulfonamide (VI), which is cyclized with glyoxylic acid (A) as before yielding the benzothiadiazine (VII). Finally the alkylation of (VII) with 3-bromobenzyl bromide (VIII) by means of NaH affords the already reported benzothiadiazine-3-carboxylate (V). 3) The enantiomers of the title compound have been obtained in optically pure form by preparative liquid chromatography on a Pirkle-type chiral phase column.
| 【1】 Shot, J.H.; Biermacher, U.; Synthesis of potential diuretic agents. II. Dichloro-derivatives of 1,2,4-benzothiadiazine-1,1-dioxide. J Am Chem Soc 1960, 2, 1135-38. |
| 【2】 Mignani, S.; et al.; 2H-3,4-Dihydro-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid derivatives, a novel family of glycine antagonists of the NMDA receptor channel complex. Drugs Fut 1995, 20, 11, 1133. |
| 【3】 Jimonet, P.; et al.; Synthesis and SAR of 2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid derivatives as novel potent glycine antagonists of the NMDA receptor-channel complex. Bioorg Med Chem Lett 1994, 4, 23, 2735. |
| 【4】 Boireau, A.; Malgouris, C.; Burgevin, M.C.; et al.; Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro. Eur J Pharmacol 1996, 300, 3, 237. |
| 【5】 Doble, A.; Boireau, A.; et al.; RPR 104632, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor-channel complex. Can J Physiol Pharmacol 1994, 72, Suppl. 1, 333. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (I) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (II) | 41179 | 2-amino-4,6-dichlorobenzenesulfonyl chloride | C6H4Cl3NO2S | 详情 | 详情 | |
| (III) | 41180 | (3-bromophenyl)methanamine; 3-bromobenzylamine | C7H8BrN | 详情 | 详情 | |
| (IV) | 41181 | 2-amino-N-(3-bromobenzyl)-4,6-dichlorobenzenesulfonamide | C13H11BrCl2N2O2S | 详情 | 详情 | |
| (V) | 41182 | ethyl 2-(3-bromobenzyl)-6,8-dichloro-1,1-dioxo-1,2,3,4-tetrahydro-1lambda(6),2,4-benzothiadiazine-3-carboxylate | C17H15BrCl2N2O4S | 详情 | 详情 | |
| (VI) | 41183 | 2-amino-4,6-dichlorobenzenesulfonamide | C6H6Cl2N2O2S | 详情 | 详情 | |
| (VII) | 41184 | ethyl 6,8-dichloro-1,1-dioxo-1,2,3,4-tetrahydro-1lambda(6),2,4-benzothiadiazine-3-carboxylate | C10H10Cl2N2O4S | 详情 | 详情 | |
| (VIII) | 20466 | 1-bromo-3-(bromomethyl)benzene | 823-78-9 | C7H6Br2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Treatment of 3,5-dichloroaniline (I) with thiophosgene afforded the corresponding aryl isothiocyanate (II). Ritter reaction of 3-ethyl-3-pentanol (III) using NaCN and H2SO4 produced formamide (IV), which was hydrolyzed to amine (V) with NaOH. Then, condensation of isothiocyanate (II) with amine (V) yielded thiourea (VI). Subsequent removal of H2S in (VI) by treatment with PPh3, CCl4 and Et3N gave carbodiimide (VII). Finally, addition of cyanamide to (VII) in the presence of i-Pr2NEt furnished the required cyanoguanidine.
| 【1】 Yoshiizumi, K.; Seko, N.; Nishimura, N.; Ikeda, S.; Yoshino, K.; Kondo, H.; Tanizawa, K.; Biologically selective potassium channel openers having 1,1-diethylpropyl group. Bioorg Med Chem Lett 1998, 8, 23, 3397. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 | |
| (I) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (II) | 26543 | 1,3-dichloro-5-isothiocyanatobenzene | 6590-93-8 | C7H3Cl2NS | 详情 | 详情 |
| (III) | 26537 | 3-ethyl-3-pentanol | 597-49-9 | C7H16O | 详情 | 详情 |
| (IV) | 26538 | 1,1-diethylpropylformamide | C8H17NO | 详情 | 详情 | |
| (V) | 26539 | 1,1-diethylpropylamine | C7H17N | 详情 | 详情 | |
| (VI) | 26544 | N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)thiourea | C14H20Cl2N2S | 详情 | 详情 | |
| (VII) | 26545 | N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)carbodiimide | C14H18Cl2N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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4
该中间体在本合成路线中的序号：(VII)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5
该中间体在本合成路线中的序号：(I)Diazotization of 3,5-dichloroaniline (I), followed by reduction of the resultant diazonium salt provides hydrazine (II). Subsequent reaction of 3,5-dichlorophenylhydrazine (II) with ethyl pyruvate (III) under Fischer reaction conditions gives rise to indole (IV). Vilsmeier formylation of (IV) using N-methylformanilide and phosphoryl chloride produces aldehyde (V). This is reductively aminated with methyl glycinate and NaBH(OAc)3 to afford aminoester (VI). Condensation of (VI) with phenyl isocyanate, followed by cyclization in the presence of Et3N leads to hydantoin (VII). Finally, ester (VII) is hydrolyzed employing LiOH to furnish the target indolecarboxylic acid.
| 【1】 Jansen, M.; Potschka, H.; Brandt, C.; Loscher, W.; Dannhardt, G.; Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor. J Med Chem 2003, 46, 1, 64. |
| 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) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (II) | 28066 | 1-(3,5-dichlorophenyl)hydrazine | 39943-56-1 | C6H6Cl2N2 | 详情 | 详情 |
| (III) | 12135 | ethyl 2-oxopropanoate; Ethyl pyruvate | 617-35-6 | C5H8O3 | 详情 | 详情 |
| (IV) | 32142 | ethyl 4,6-dichloro-1H-indole-2-carboxylate | C11H9Cl2NO2 | 详情 | 详情 | |
| (V) | 32144 | ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate | C12H9Cl2NO3 | 详情 | 详情 | |
| (VI) | 64389 | ethyl 4,6-dichloro-3-({[2-(methyloxy)-2-oxoethyl]amino}methyl)-1H-indole-2-carboxylate | C15H16Cl2N2O4 | 详情 | 详情 | |
| (VII) | 64390 | ethyl 4,6-dichloro-3-[(2,4-dioxo-3-phenyl-1-imidazolidinyl)methyl]-1H-indole-2-carboxylate | C21H17Cl2N3O4 | 详情 | 详情 |