|
【结 构 式】 
|
【分子编号】35764 【品名】4-nitro-1H-imidazole 【CA登记号】3034-38-6 |
【 分 子 式 】C3H3N3O2 【 分 子 量 】113.07584 【元素组成】C 31.87% H 2.67% N 37.16% O 28.3% |
合成路线1
该中间体在本合成路线中的序号：(X)4-Methoxyphenylacetic acid (VII) was esterified with EtOH and p-toluenesulfonic acid. The resulting ethyl ester (VIII) was brominated by means of N-bromosuccinimide to produce bromoester (IX), which was condensed with 4-nitroimidazole (X) yielding (XI). Reduction of the nitro group of (XI) by catalytic hydrogenation over Pd/C gave amine (XII). This was coupled with acid (VI) by means of EDC and HOBt to afford amide (XIII). Then, hydrolysis of the methyl ester of (XIII) with LiOH gave rise to carboxylic acid (XIV). Finally, coupling of (XIV) with 4-methylpiperidine (XV) generated the title compound.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (VII) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (VIII) | 38805 | methyl 2-(4-methoxyphenyl)acetate | 23786-14-3 | C10H12O3 | 详情 | 详情 |
| (IX) | 38806 | methyl 2-bromo-2-(4-methoxyphenyl)acetate | C10H11BrO3 | 详情 | 详情 | |
| (X) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XI) | 38807 | methyl 2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)acetate | C13H13N3O5 | 详情 | 详情 | |
| (XII) | 38808 | methyl 2-(4-amino-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C13H15N3O3 | 详情 | 详情 | |
| (XIII) | 38809 | methyl 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C32H41N5O8 | 详情 | 详情 | |
| (XIV) | 38810 | 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetic acid | C31H39N5O8 | 详情 | 详情 | |
| (XV) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)4-Methoxyphenylacetic acid (XI) was esterified using EtOH and p-toluenesulfonic acid, and then brominated with NBS to give bromoester (XII). Coupling of (XII) with 4-nitroimidazole (XIII) afforded adduct (XIV), which was alkylated using iodomethane and NaH to yield (XVa-b). Hydrolysis of the ester group of (XVa-b) with LiOH gave the corresponding carboxylic acid, which was converted to acid chloride (XVIa-b) by means of treatment with oxalyl chloride. Reaction of (XVI) with the lithium salt of the chiral oxazolidinone (XVII) provided a diastereomeric mixture of N-acyloxazolidinones, which were separated by silica gel chromatography. Removal of the chiral auxiliary from the desired isomer (XVIII) under basic conditions, followed by treatment with oxalyl chloride provided acid chloride (XIX). Further reaction of (XIX) with pyrrolidine (XX) produced amide (XXI). Reduction of the nitro group of (XXI) using hydrogen and Pd/C generated the aminoimidazole derivative (XXII). This was coupled with the N-Boc-dipeptide (X) affording amide (XXIII). The Boc protecting group of (XXIII) was then cleaved by treatment with trifluoroacetic acid, and the title compound was finally isolated as the dihydrochloride salt.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVa) | 35766 | ethyl (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoate | C15H17N3O5 | 详情 | 详情 | |
| (XVIa) | 35767 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XVIb) | 35768 | (2S)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XVb) | 35769 | ethyl (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoate | C15H17N3O5 | 详情 | 详情 | |
| (X) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (XI) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (XII) | 35763 | ethyl 2-bromo-2-(4-methoxyphenyl)acetate | 77053-56-6 | C11H13BrO3 | 详情 | 详情 |
| (XIII) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XIV) | 35765 | ethyl 2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)acetate | C14H15N3O5 | 详情 | 详情 | |
| (XVII) | 35770 | C10H10LiNO2 | 详情 | 详情 | ||
| (XVIII) | 35771 | (4R,5S)-3-[(2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C23H22N4O6 | 详情 | 详情 | |
| (XIX) | 35767 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XX) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XXI) | 35772 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)-1-(1-pyrrolidinyl)-1-propanone | C17H20N4O4 | 详情 | 详情 | |
| (XXII) | 35773 | (2R)-2-(4-amino-1H-imidazol-1-yl)-2-(4-methoxyphenyl)-1-(1-pyrrolidinyl)-1-propanone | C17H22N4O2 | 详情 | 详情 | |
| (XXIII) | 35774 | tert-butyl 2-([(1R)-1-[([1-[(1R)-1-(4-methoxyphenyl)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-imidazol-4-yl]amino)carbonyl]-4-phenylbutyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C37H50N6O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Alkylation of 4-nitroimidazole (XII) by means of ethyl bromoacetate (XIII) gave ethyl 2-(4-nitro-1-imidazolyl)acetate (XIV). Reduction of (XIV) to the corresponding amine (XV) was effected by catalytic hydrogenation over Pd/C. Coupling of (XV) with dipeptide (XI) gave (XVI), which was hydrolyzed to carboxylic acid (XVII) using LiOH. This was finally coupled with proline amide (XIX), (obtained by treatment of L-proline (XVIII) with benzylamine and CDI), to furnish the title compound.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (XI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (XII) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XIV) | 38800 | ethyl 2-(4-nitro-1H-imidazol-1-yl)acetate | C7H9N3O4 | 详情 | 详情 | |
| (XV) | 38801 | ethyl 2-(4-amino-1H-imidazol-1-yl)acetate | C7H11N3O2 | 详情 | 详情 | |
| (XVI) | 38802 | ethyl 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetate | C27H39N5O6 | 详情 | 详情 | |
| (XVII) | 38803 | 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetic acid | C25H35N5O6 | 详情 | 详情 | |
| (XVIII) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (XIX) | 38804 | (2S)-N-benzyl-2-pyrrolidinecarboxamide | C12H16N2O | 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 nitration of imidazole (I) with HNO3 and H2SO4 at 100 °C gives 4-nitroimidazole (II) , which by a second nitration with HNO3 and Ac2O, and optionally AcOH, affords 1,4-dinitroimidazole (III) . Rearrangement of dinitroimidazole intermediate (III) in refluxing xylene or chlorobenzene generates 2,4-dinitroimidazole (IV), which then undergoes selective nitro group displacement with HCl in refluxing chlorobenzene/water to yield 2-chloro-4-nitroimidazole (V) . Condensation of imidazole (V) with epoxide (VI) by means of Et3N in hot ethyl acetate gives the adduct (VII), which is hydrolyzed using K2CO3 in MeOH providing the vicinal diol (VIII). Selective monomesylation of diol (VIII) by means of MsCl in the presence of pyridine affords the primary mesylate (IX), which is then treated with DBU in ethyl acetate to give epoxide (X). Finally, this compound is cyclized with the 4-substitutedphenol (XI) by means of NaH in DMF .
| 【1】 Wuellner, G., Herkenrath, F.-W., Juelich, A., Yamada, Y., Kawabe, S.(Dynamit Nobel GmbH Explosivstoff- and Systemtechnik; Asahi Kasei Chemicals Corp.; Otsuka Pharmaceutical Co., Ltd.). Methods for the production of 2-halo-4-nitroimidazole and intermediates thereof. CN 102131787, EP 2323990, JP 2012500183, WO 2010021409. |
| 【2】 Wüllner, G., Herkenrath, F.-W., Jülich, A. (Dynamit Nobel GmbH Explosivstoff-and Systemtechnik). Method for the production of 2-halogeno-4-nitroimidazole. WO 2010143007. |
| 【3】 Tsubouchi, H., Sasaki, H., Haraguchi, Y. et al. Synthesis and antituberculous activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. 45th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Dec 16-19, Washington, D.C.) 2005, Abst F-1473. |
| 【4】 Tsubouchi, H., Itoya, M., Hasegawa, T. et al. (Otsuka Pharmaceutical Co., Ltd.). 2,3-Dihydroimidazo[2,1-b]oxazole compounds. CN 10253262, EP 1555267, JP 2004149527, US 006094767, US 7262212, WO 2004033463. |
| 【5】 Sasaki, H., Haraguchi, Y., Itotani, M. et al. Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. J Med Chem 2006, 49(26): 7854-60. |
| 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) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (II) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (III) | 57884 | 1,4-dinitro-1H-imidazole | 19182-81-1 | C3H2N4O4 | 详情 | 详情 |
| (IV) | 56023 | 2,4-dinitro-1H-imidazole | 5213-49-0 | C3H2N4O4 | 详情 | 详情 |
| (V) | 67892 | 2-Chloro-4-nitroimidazole;2-Chloro-4-nitro-1H-imidazole | 57531-37-0 | C3H2ClN3O2 | 详情 | 详情 |
| (VI) | 67893 | (S)-(2-methyloxiran-2-yl)methyl 4-nitrobenzoate | 118200-96-7 | C11H11NO5 | 详情 | 详情 |
| (VII) | 67895 | (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxy-2-methylpropyl 4-nitrobenzoate | C14H13ClN4O7 | 详情 | 详情 | |
| (VIII) | 67897 | (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methylpropane-1,2-diol | C7H10ClN3O4 | 详情 | 详情 | |
| (IX) | 67896 | (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxy-2-methylpropyl methanesulfonate | C8H12ClN3O6S | 详情 | 详情 | |
| (X) | 67898 | (S)-2-chloro-1-((2-methyloxiran-2-yl)methyl)-4-nitro-1H-imidazole | C7H8ClN3O3 | 详情 | 详情 | |
| (XI) | 67894 | 4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)phenol | C18H18F3NO3 | 详情 | 详情 |