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【结 构 式】 
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【分子编号】14576 【品名】pentanimidamide 【CA登记号】109-51-3 |
【 分 子 式 】C5H12N2 【 分 子 量 】100.16376 【元素组成】C 59.96% H 12.08% N 27.97% |
合成路线1
该中间体在本合成路线中的序号：(IX)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2
该中间体在本合成路线中的序号：(XVI)3) The cyclization of 1,3-dihydroxyacetone (XV) with pentanamidine (XVI) in liquid ammonia gives 2-butyl-5-(hydroxymethyl)imidazole (XVII), which is acetylated with acetic anhydride yielding 5 (acetoxymethyl)-1-acetyl-2-butylimidazole (XVIII). The condensation of (XVIII) with methyl 4-(hydroxymethyl)benzoate (XIX) by means of trifluoroacetic anhydride and diisopropylethylamine in dichloromethane affords 4-[5-(acetoxymethyl)-2-butylimidazol-1-ylmethyl)benzoic acid methyl ester (XX), which is hydrolyzed with NaOH in methanol/water giving 4-[2-butyl-5-(hydroxymethyl)imidazol-1-ylmethyl)benzoic acid (XXI). The controlled oxidation of (XXI) with activated MnO2 in toluene/dichloromethane yields the corresponding aldehyde (XXII), which is condensed with methyl 3-(2-thienyl)propionate (XI) with LDA in THF affording (XXIII). The acetylation of (XXIII) with acetic anhydride and DMAP gives the corresponding acetate (XXIV), which is treated with DBU as before yielding the propenoate (XXV). Finally, this compound is hydrolyzed with NaOH as already described.
| 【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】 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. |
| 【4】 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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 14568 | methyl 3-(2-thienyl)propanoate | 16862-05-8 | C8H10O2S | 详情 | 详情 |
| (XV) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (XVI) | 14576 | pentanimidamide | 109-51-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 13923 | 2-Butyl-5-hydroxymethylimidazole; (2-Butyl-1H-imidazol-5-yl)methanol | 68283-19-2 | C8H14N2O | 详情 | 详情 |
| (XVIII) | 14578 | (1-acetyl-2-butyl-1H-imidazol-5-yl)methyl acetate | 136701-34-3 | C12H18N2O3 | 详情 | 详情 |
| (XIX) | 14579 | methyl 4-(hydroxymethyl)benzoate; Methyl 4-hydroxymethylbenzoate | 6908-41-4 | C9H10O3 | 详情 | 详情 |
| (XX) | 14580 | methyl 4-([5-[(acetoxy)methyl]-2-butyl-1H-imidazol-1-yl]methyl)benzoate | C19H24N2O4 | 详情 | 详情 | |
| (XXI) | 14581 | 4-[[2-butyl-5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzoic acid | C16H20N2O3 | 详情 | 详情 | |
| (XXII) | 14582 | 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid | C16H18N2O3 | 详情 | 详情 | |
| (XXIII) | 14583 | 4-([2-butyl-5-[1-hydroxy-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-1H-imidazol-1-yl]methyl)benzoic acid | C24H28N2O5S | 详情 | 详情 | |
| (XXIV) | 14584 | 4-([5-[1-(acetoxy)-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-2-butyl-1H-imidazol-1-yl]methyl)benzoic acid | C26H30N2O6S | 详情 | 详情 | |
| (XXV) | 14585 | 4-([2-butyl-5-[(E)-3-methoxy-3-oxo-2-(2-thienylmethyl)-1-propenyl]-1H-imidazol-1-yl]methyl)benzoic acid | C24H26N2O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIV)An asymmetric synthesis of the (Z)(R)-enantioner has also been reported. Treatment of bromide (XXI) with NaOEt in Et2O provided ethyl methylenecyclopropanecarboxylate (XXII). Saponification of the ester group of (XXII) afforded racemic acid (XXIII) which, after activation as the mixed anhydride with isobutyl chloroformate, was coupled with (R)-phenylglycinol (XXIV) to yield a mixture of diastereomeric amides (XXV) and (XXVI). Chromatographic separation of the desired (R,R)-diastereoisomer (XXV) was followed by acid hydrolysis to furnish the (R)-acid (XXVII), which was subsequently esterified to (XXVIII) in ethanolic HCl. Addition of Br2 to (XXVIII) produced a mixture of (1S,2S)- and (1S,2R)-dibromoesters (XXIX). Further reduction of (XXIX) to alcohols (XXX) with DIBALH was followed by acetylation with Ac2O in pyridine yielding (XXXI). The alkylation-elimination procedure of the resulting bromides (XXXI) with adenine (V) afforded a mixture of (Z)(R) (XXXII) and (E)(R)- (XXXIII) olefins. Finally, deacetylation with ammonia in MeOH gave a mixture of the target (Z)(R)-compound and the corresponding E-isomer (XXXIV), which were not separed but used for analytical confirmation of the configuration of the title compound.
| 【1】 Qiu, Y.-L.; et al.; (Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New nucleoside analogues with a broad-spectrum antiviral activity. J Med Chem 1998, 41, 1, 10. |
| 【2】 Qiu, Y.-L.; Hempel, A.; Camerman, N.; Camerman, A.; Geiser, F.; Ptak, R.G.; Breitenbach, J.M.; Kira, T.; Li, L.; Gullen, E.; Cheng, Y.C.; Drach, J.C.; Zemlicka, J.; (R)-(-)- and (S)-(+)-synadenol: Synthesis, absolute configuration, and enantioselectivity of antiviral effect. J Med Chem 1998, 41, 26, 5257. |
| 【3】 Zemilicka, J.; Qiu, Y.-L.; A new efficient synthesis of antiviral methylenecyclopropane analogs of purine nucleosides. Synthesis 1998, 10, 1447-1452. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 21768 | ethyl 2-bromo-2-methylcyclopropanecarboxylate | C7H11BrO2 | 详情 | 详情 | |
| (XXII) | 21769 | ethyl 2-methylenecyclopropanecarboxylate | C7H10O2 | 详情 | 详情 | |
| (XXIII) | 21770 | 2-methylenecyclopropanecarboxylic acid | C5H6O2 | 详情 | 详情 | |
| (XXIV) | 14576 | pentanimidamide | 109-51-3 | C5H12N2 | 详情 | 详情 |
| (XXV) | 21772 | (1R)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide | C13H15NO2 | 详情 | 详情 | |
| (XXVI) | 21773 | (1S)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide | C13H15NO2 | 详情 | 详情 | |
| (XXVII) | 21774 | (1R)-2-methylenecyclopropanecarboxylic acid | C5H6O2 | 详情 | 详情 | |
| (XXVIII) | 21775 | ethyl (1R)-2-methylenecyclopropanecarboxylate | C7H10O2 | 详情 | 详情 | |
| (XXIX) | 21776 | ethyl (1S)-2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (XXX) | 21777 | [(1S)-2-bromo-2-(bromomethyl)cyclopropyl]methanol | C5H8Br2O | 详情 | 详情 | |
| (XXXI) | 21778 | [(1S)-2-bromo-2-(bromomethyl)cyclopropyl]methyl acetate | C7H10Br2O2 | 详情 | 详情 | |
| (XXXII) | 21779 | [(1R)-2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H13N5O2 | 详情 | 详情 | |
| (XXXIII) | 21780 | [(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H13N5O2 | 详情 | 详情 | |
| (XXXIV) | 21781 | [(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 |