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【结 构 式】 
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【分子编号】13925 【品名】2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 【CA登记号】83857-96-9 |
【 分 子 式 】C8H11ClN2O 【 分 子 量 】186.64092 【元素组成】C 51.48% H 5.94% Cl 19% N 15.01% O 8.57% |
合成路线1
该中间体在本合成路线中的序号：(V)Synthesis of imidazole (V) first entails the conversion of valeronitrile (I) to its imidate ester (II). Subsequent reaction with 1,3-dihydroxyacetone dimer and ammonia leads to imidazole (III). Chlorination with N-chlorosuccinimide yields the 4-chloroimidazole (IV). Oxidation with manganese dioxide finally yields imidazole-5-carboxaldehyde (V).
| 【1】 Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Santella, J.B.; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Timmermans, P.B.M.W.M.; Nonpeptide angiotensin II receptor antagonists: The discovery of a series of N-(biphenylmethyl)imidazoles as potent, orally-active antihypertensives. J Med Chem 1991, 34, 8, 2225-47. |
| 【2】 Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M.; DuP 753. Drugs Fut 1991, 16, 4, 305. |
| 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) | 13921 | Pentanenitrile; n-Valeronitrile | 110-59-8 | C5H9N | 详情 | 详情 |
| (II) | 13922 | Methyl pentanimidoate hydrocloride | C6H14ClNO | 详情 | 详情 | |
| (III) | 13923 | 2-Butyl-5-hydroxymethylimidazole; (2-Butyl-1H-imidazol-5-yl)methanol | 68283-19-2 | C8H14N2O | 详情 | 详情 |
| (IV) | 13924 | 2-Butyl-4-chloro-5-(hydroxymethyl)imidazole; (2-Butyl-4-chloro-1H-imidazol-5-yl)methanol | 79047-41-9 | C8H13ClN2O | 详情 | 详情 |
| (V) | 13925 | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde | 83857-96-9 | C8H11ClN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The compound is assembled by connecting the imidazole head (V) to the biphenyltetrazole tail (XI). The aldehyde (V) undergoes regioselective alkylation with bromide (XI). Subsequent reduction of the aldehyde group in the same pot yields adduct (XII). Deprotection in acid, followed by conversion to the potassium salt, yields DuP-753.
| 【1】 Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Santella, J.B.; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Timmermans, P.B.M.W.M.; Nonpeptide angiotensin II receptor antagonists: The discovery of a series of N-(biphenylmethyl)imidazoles as potent, orally-active antihypertensives. J Med Chem 1991, 34, 8, 2225-47. |
| 【2】 Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M.; DuP 753. Drugs Fut 1991, 16, 4, 305. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 13925 | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde | 83857-96-9 | C8H11ClN2O | 详情 | 详情 |
| (XI) | 13931 | 5-(4'-Bromo[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole | C32H23BrN4 | 详情 | 详情 | |
| (XII) | 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 |
合成路线3
该中间体在本合成路线中的序号：(XI)Several novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), a key intermediate in the synthesis of losartan, have been described: 1) Treatment of glycine methyl ester hydrochloride (I) with NaOH in methanol, followed by reaction with methyl pentanimidate (II), gives 2-butyl-4,5-dihydro-1H-imidazol-5-one (III), which is treated with POCl3 to give the 2-butyl-5-chloro-1H-imidazole (IV). Reaction of (IV) with POCl3 and DMF yields the enamine (V), which is finally hydrolyzed with water to 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), the desired intemediate in the synthesis of losartan. 2) Imidazolinone (III) can also be obtained by cyclization of chloroacetic acid methyl ester (VI), chloroacetyl chloride (VII) or bromoacetyl bromide (VIII) with pentanamidine (IX) by means of NaOH in methanol. 3) Alternatively, imidazolinone (III) can be treated with dimethylformamide dimethylacetal in dichloromethane yielding the enamine (X), which is finally treated with POCl3 and hydrolyzed with water. 4) The reaction of glycine (XI) with methyl pentanimidate (II) in NaOH/MeOH gives amidine (XII), which, without isolation, is treated with POCl3 and DMF at 100 C for 2 h, and then hydrolyzed with water to give the desired 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde. Methyl pentanimidate (II) is obtained treating a solution of valeronitrile in MeOH with HCl gas followed by neutralization with aqueous KOH and extraction with Et2O.
| 【1】 Kohr, J.; Griffiths, G.J.; Imwinkelried, R.; Hauck, M.B.; Roten, C.A.; Stucky, G.C.; Novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde: A key intermediate for the synthesis of the angiotensin II antagonist losartan. J Org Chem 1999, 64, 22, 8084. |
| 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) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (II) | 34050 | methyl pentanimidoate | C6H13NO | 详情 | 详情 | |
| (III) | 34051 | 2-butyl-3,5-dihydro-4H-imidazol-4-one | C7H12N2O | 详情 | 详情 | |
| (IV) | 34052 | 2-butyl-5-chloro-1H-imidazole | C7H11ClN2 | 详情 | 详情 | |
| (V) | 34053 | N-[(2-butyl-5-chloro-4H-imidazol-4-ylidene)methyl]-N,N-dimethylamine; (2-butyl-5-chloro-4H-imidazol-4-ylidene)-N,N-dimethylmethanamine | C10H16ClN3 | 详情 | 详情 | |
| (VI) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (IX) | 14576 | pentanimidamide | 109-51-3 | C5H12N2 | 详情 | 详情 |
| (X) | 34054 | 2-butyl-5-[(E)-(dimethylamino)methylidene]-3,5-dihydro-4H-imidazol-4-one | C10H17N3O | 详情 | 详情 | |
| (XI) | 13925 | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde | 83857-96-9 | C8H11ClN2O | 详情 | 详情 |
| (XII) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (XIII) | 34055 | 2-(pentanimidoylamino)acetic acid | C7H14N2O2 | 详情 | 详情 | |
| (XIV) | 13921 | Pentanenitrile; n-Valeronitrile | 110-59-8 | C5H9N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(XV)2) The condensation of 2-butyl-4-chloroimidazole-5-carbaldehyde (XV) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in DMF yields 4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzoic acid methyl ester (XVI), which is dechlorinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with 2-(2-thienylmethyl)malonic acid monomethyl ester (XVII) by means of piperidine/pyridine in toluene gives the previously described compound (XIV), which is finally saponified with KOH in ethanol.
| 【1】 Wittenberger, S.J.; Tasker, A.; Sorensen, B.K.; Donner, B.G.; 2-Butyl-4-iodoimidazole-5-carboxaldehyde: A versatile intermediate for the synthesis of highly functionalized imidazoles. Synth Commun 1993, 23, 22, 3231-48. |
| 【2】 Merlos, M.; Casas, A.; Graul, A.; Castaner, J.; Eprosartan. Drugs Fut 1997, 22, 10, 1079. |
| 【3】 Keenan, R.M.; Weinstock, J.; Finkelstein, J.A.; et al.; Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids. J Med Chem 1993, 36, 13, 1880-92. |
| 【4】 Weinstock, J.; Keenan, R.M.; Samanen, J.; et al.; 1-(Carboxybenzyl)imidazole-5-acrylic acids: Potent and selective angiotensin II receptor antagonists. J Med Chem 1991, 34, 4, 1514-7. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 14565 | methyl 4-(bromomethyl)benzoate | 2417-72-3 | C9H9BrO2 | 详情 | 详情 |
| (X) | 14567 | methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate | C17H20N2O3 | 详情 | 详情 | |
| (XIV) | 14571 | methyl 4-([2-butyl-5-[(E)-3-methoxy-3-oxo-2-(2-thienylmethyl)-1-propenyl]-1H-imidazol-1-yl]methyl)benzoate | C25H28N2O4S | 详情 | 详情 | |
| (XV) | 13925 | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde | 83857-96-9 | C8H11ClN2O | 详情 | 详情 |
| (XVI) | 14573 | methyl 4-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]benzoate | C17H19ClN2O3 | 详情 | 详情 | |
| (XVII) | 14574 | 3-methoxy-3-oxo-2-(2-thienylmethyl)propionic acid | C9H10O4S | 详情 | 详情 |