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【结 构 式】 
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【分子编号】16109 【品名】1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide 【CA登记号】589-15-1 |
【 分 子 式 】C7H6Br2 【 分 子 量 】249.93264 【元素组成】C 33.64% H 2.42% Br 63.94% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 2-butyl-4-chloroimidazole-5-carbaldehyde (I) with 4-bromobenzyl bromide (II) by means of K2CO3 in dimethylacetamide gives 1-(4-bromobenzyl)-2-butyl-4-chloroimidazole-5-carbaldehyde (III), which is reduced with NaBH4 in methanol yielding the corresponding carbinol (IV). The condensation of (IV) with the phenylboronic acid (VI) by means of Pd(OAc)2 and PPh3 affords the biphenyl derivative (VI), which is finally detritylated with H2SO4 in acetonitrile. The intermediate phenylboronic acid (V) has been obtained as follows: The protection of 5-phenyltetrazole (VII) with trityl chloride and TEA in THF gives 5-phenyl-2-(triphenylmethyl)tetrazole (VII), which is then treated with isopropyl borate and BuLi in THF.
| 【1】 Larsen, R.D.; et al.; Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist. J Org Chem 1994, 59, 21, 6391. |
| 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) | 13925 | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde | 83857-96-9 | C8H11ClN2O | 详情 | 详情 |
| (II) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (III) | 36350 | 1-(4-bromobenzyl)-2-butyl-4-chloro-1H-imidazole-5-carbaldehyde | C15H16BrClN2O | 详情 | 详情 | |
| (IV) | 36351 | [1-(4-bromobenzyl)-2-butyl-4-chloro-1H-imidazol-5-yl]methanol | C15H18BrClN2O | 详情 | 详情 | |
| (V) | 36352 | 2-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)phenylboronic acid | C26H21BN4O2 | 详情 | 详情 | |
| (VI) | 13932 | (2-Butyl-4-chloro-1-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl)methanol | C41H37ClN6O | 详情 | 详情 | |
| (VII) | 36353 | 5-phenyl-2H-1,2,3,4-tetraazole | 18039-42-4 | C7H6N4 | 详情 | 详情 |
| (VIII) | 36354 | 5-phenyl-2-trityl-2H-1,2,3,4-tetraazole | C26H20N4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The arylation of 1,2,4-triazol-4-amine (I) with 4-fluorobenzonitrile (II) by means of NaH in DMSO gives 4-(1,2,4-triazol-4-ylamino)benzonitrile (III), which is then condensed with 4-bromobenzyl bromide (III) by means of K2CO3 in acetonitrile.
| 【1】 Mealy, N.; Castaner, J.; YM-511. Drugs Fut 1996, 21, 7, 716. |
| 【2】 Okada, M.; Kawaminami, E.; Yoden, T.; Kudo, M.; Isomura, Y. (Yamanouchi Pharmaceutical Co., Ltd.); Triazolylated tertiary amine cpds. or salts thereof. EP 0641785; JP 1993505096; US 5674886; WO 9305027 . |
| 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) | 16106 | 4H-1,2,4-triazol-4-amine; 4-Amino-4H-1,2,4-triazole; 4H-1,2,4-triazol-4-ylamine; 4-Amino-1,2,4-triazole | 584-13-4 | C2H4N4 | 详情 | 详情 |
| (II) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (III) | 16108 | 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile | C9H7N5 | 详情 | 详情 | |
| (IV) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Treatment of triethyl phosphoacetate (I) with NaH and 4-bromobenzyl bromide (II) in DMF provides the 2-substituted triethyl phosphoacetate (III), which then undergoes reaction with formaldehyde and K2CO3 to afford acrylate derivative (IV). Michael condensation of (IV) with phosphinic acid (V) in N,O-bistrimethylsilylacetamide (BSA) yields intermediate (VI), which then undergoes Suzuki condensation in toluene with phenylboronic acid (VII) and NaHCO3 in MeOH catalyzed by Pd(PPh3)4 to give (VIII). Hydrolysis of ethyl ester (VIII) by means of NaOH in EtOH furnishes carboxylic acid (IX), which is then coupled to L-alanine (X) by means of BOP and DIEA or Et3N in DMF to yield methyl ester (XI). Compound (XI) is then hydrolyzed by treatment with NaOH or LiOH in EtOH and, finally, the Z-protecting group is removed with BBr3 in dichloromethane.
| 【1】 Chen, H.; Noble, F.; Coric, P.; Fournie-Zaluski, M.-C.; Roques, B.P.; Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics. Proceedings of the National Academy of Sciences of the United States of America 1998, 95, 20, 12028. |
| 【2】 Noble, F.; Morthé, A.; Chen, H.; et al.; Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors: Synthesis, biological properties, and antinociceptive activities. J Med Chem 2000, 43, 7, 1398. |
| 【3】 Fournie-Zaluski, M.-C.; Chen, H.; Roques, B.P. (INSERM (Institut National de la Sante et de la Recherche Medicale)); Novel (alpha-aminophosphino) peptide derivs., method for making same and therapeutic applications thereof. EP 1009750; WO 9818803 . |
| 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) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (II) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (III) | 42984 | ethyl 3-(4-bromophenyl)-2-(diethoxyphosphoryl)propanoate | C15H22BrO5P | 详情 | 详情 | |
| (IV) | 42985 | ethyl 2-(4-bromobenzyl)acrylate | C12H13BrO2 | 详情 | 详情 | |
| (V) | 42986 | 1-[[(benzyloxy)carbonyl]amino]ethylphosphinic acid | C10H14NO4P | 详情 | 详情 | |
| (VI) | 42987 | 1-[[(benzyloxy)carbonyl]amino]ethyl[2-(4-bromobenzyl)-3-ethoxy-3-oxopropyl]phosphinic acid | C22H27BrNO6P | 详情 | 详情 | |
| (VII) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (VIII) | 42988 | 1-[[(benzyloxy)carbonyl]amino]ethyl[2-([1,1'-biphenyl]-4-ylmethyl)-3-ethoxy-3-oxopropyl]phosphinic acid; 4-(2-[[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]methyl]-3-ethoxy-3-oxopropyl)-1,1'-biphenyl | C28H32NO6P | 详情 | 详情 | |
| (IX) | 42989 | 3-[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]-2-([1,1'-biphenyl]-4-ylmethyl)propionic acid | C26H28NO6P | 详情 | 详情 | |
| (X) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (XI) | 42990 | 1-[[(benzyloxy)carbonyl]amino]ethyl(2-([1,1'-biphenyl]-4-ylmethyl)-3-[[(1S)-2-methoxy-1-methyl-2-oxoethyl]amino]-3-oxopropyl)phosphinic acid; 4-(2-[[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]methyl]-3-[[(1S)-2-methoxy-1-methyl-2-oxoethyl]amino]-3-oxopropyl)-1,1'-biphenyl | C30H35N2O7P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The alkylation of 4-(dimethoxymethyl)pyridine (I) with 4-bromobenzyl bromide (II) in the presence of n-butyllithium, followed by ketal hydrolysis with formic acid provided the diaryl ethanone (III). Further alkylation of (III) with 4-chlorophenacyl bromide (IV) employing sodium hexamethyldisilazide yielded diketone (V), which was cyclized in the presence of ammonium acetate in boiling AcOH to produce pyrrole (VI). Finally, Suzuki coupling of (VI) with 3-methoxybenzeneboronic acid (VII) by means of Pd(PPh3)4 furnished the title compound.
| 【1】 McMillan, M.; Cudaback, E.; Misra-Press, A.; et al.; Synthesis and biological studies of a novel inhibitor of NF-kappaB. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 213. |
| 【2】 de Laszlo, S.E.; Kim, D.; Chang, L.L.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. US 5776954 . |
| 【3】 De Laszlo, S.E.; Chang, L.L.; Kim, D.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. EP 0859771; JP 1999514651; WO 9716442 . |
| 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) | 29418 | 4-(dimethoxymethyl)pyridinemethoxy(4-pyridinyl)methyl methyl ether | C8H11NO2 | 详情 | 详情 | |
| (II) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (III) | 29423 | 2-(4-bromophenyl)-1-(4-pyridinyl)-1-ethanone | C13H10BrNO | 详情 | 详情 | |
| (IV) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (V) | 29424 | 2-(4-bromophenyl)-4-(4-chlorophenyl)-1-(4-pyridinyl)-1,4-butanedione | C21H15BrClNO2 | 详情 | 详情 | |
| (VI) | 29425 | 4-[3-(4-bromophenyl)-5-(4-chlorophenyl)-1H-pyrrol-2-yl]pyridine | C21H14BrClN2 | 详情 | 详情 | |
| (VII) | 29426 | 3-methoxyphenylboronic acid | 10365-98-7 | C7H9BO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)Treatment of acetonitrile derivative (I) with dibromoethane (II) in toluene in the presence of NaNH2 affords bromo compound (III), which is then condensed with imidazole derivative (IV) by means of Et3N in DMF to provide compound (V). Hydrolysis of the cyano group of (V) with aqueous H2SO4 yields amide derivative (VI), which is finally subjected to alkyl quaternization by reaction with bromobenzyl bromide (VI) in acetone to furnish the desired product.
| 【1】 Miyachi, H.; Kiyota, H.; Segawa, M.; Design, synthesis and antimuscarinic activity of some imidazolium derivatives. Bioorg Med Chem Lett 1999, 9, 20, 3003. |
| 【2】 Miyachi, H.; Okazaki, K.; Kiyota, H.; Segawa, M. (Kyorin Pharmaceutical Co., Ltd.); Novel imidazole deriv. and process for producing the same. EP 0733621; US 5932607; US 6103747; WO 9515951 . |
| 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) | 14493 | alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile | 86-29-3 | C14H11N | 详情 | 详情 |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 26217 | 4-Bromo-2,2-diphenylbutyronitrile; 4-Bromo-2,2-diphenylbutanenitrile | 39186-58-8 | C16H14BrN | 详情 | 详情 |
| (IV) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
| (V) | 26218 | 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanenitrile | C20H19N3 | 详情 | 详情 | |
| (VI) | 47152 | 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide | 170105-16-5 | C20H21N3O | 详情 | 详情 |
| (VII) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)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7
该中间体在本合成路线中的序号：(IV)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8
该中间体在本合成路线中的序号：(IV)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 |
合成路线9
该中间体在本合成路线中的序号：(II)4-Chloro-5-formyl-2-phenylimidazole (I) is alkylated with 4-bromobenzyl bromide (II) in the presence of K2CO3 in DMF to produce the N-bromobenzyl imidazole (III). Subsequent Suzuki coupling between aryl bromide (III) and 5-isobutyl-2-[(N-tert-butyl)sulfonamido]thiophene-3-boronic acid (IV) affords the thienylphenyl derivative (V). The N-tert-butyl group is then removed by treatment with trifluoroacetic acid in the presence of anisole, yielding sulfonamide (VI). Displacement of the chloro substituent of (VI) with MeOH/NaOH furnishes the 4-methoxy imidazole (VII). Finally, condensation of sulfonamide (VII) with ethyl isocyanate gives rise to the target N-sulfonyl urea compound.
| 【1】 Wiemer, G.; Heitsch, H. (Aventis Pharma Deutschland GmbH); 1-(p-Thienylbenzyl)-imidazoles as angiotensin-(1-7) receptor agonists, method for the production and the utilization thereof and pharmaceutical preparations containing said cpds.. EP 1185527; JP 2002544130; US 6235766; US 6429222; WO 0068226 . |
| 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) | 63250 | 4-chloro-2-phenyl-1H-imidazole-5-carbaldehyde | C10H7ClN2O | 详情 | 详情 | |
| (II) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (III) | 63251 | 1-(4-bromobenzyl)-4-chloro-2-phenyl-1H-imidazole-5-carbaldehyde | C17H12BrClN2O | 详情 | 详情 | |
| (IV) | 63252 | 2-[(tert-butylamino)sulfonyl]-5-isobutyl-3-thienylboronic acid | C12H22BNO4S2 | 详情 | 详情 | |
| (V) | 63253 | N-(tert-butyl)-3-{4-[(4-chloro-5-formyl-2-phenyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thiophenesulfonamide | C29H32ClN3O3S2 | 详情 | 详情 | |
| (VI) | 63254 | 3-{4-[(4-chloro-5-formyl-2-phenyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thiophenesulfonamide | C25H24ClN3O3S2 | 详情 | 详情 | |
| (VII) | 63255 | 3-{4-[(5-formyl-4-methoxy-2-phenyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thiophenesulfonamide | C26H27N3O4S2 | 详情 | 详情 |