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【结 构 式】 
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【药物名称】FR-900098 【化学名称】3-(N-Acetyl-N-hydroxyamino)propylphosphonic acid 【CA登记号】66508-32-5 【 分 子 式 】C5H12NO5P 【 分 子 量 】197.12889 |
【开发单位】Fujisawa (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases |
合成路线1
The title compound was originally isolated from the fermentation broths of Streptomyces rubellomurinus. The chemical synthesis of this compound was further described. Treatment of O-benzyl hydroxylamine (I) with TsCl in pyridine afforded N-(benzyloxy)-p-toluenesulfonamide (II). A closely related procedure used O-(p-methoxy-benzyl)hydroxylamine. Diethyl (3-bromopropyl)phosphonate (V) was obtained by alkylation of the sodium salt of diethyl phosphonate (III) with 1,3-dibromopropane (IV). Related procedures used dibutyl phosphonate or 1-bromo-3-chloropropane instead of (III) or (IV). The condensation of protected hydroxylamine (II) with bromide (V) in the presence of NaH furnished adduct (VI). Alternatively, intermediate (VI) was prepared by first alkylation of N-(benzyloxy)-p-toluenesulfonamide (II) with 1,3-dibromopropane (IV) to give (VII), and then condensation of bromide (VII) with the sodium salt of diethyl phosphonate (III). Hydrolysis of (VI) with HCl in HOAc gave rise to 3-(N-hydroxyamino)propylphosphonic acid (VIII). This was finally acetylated with Ac2O in NaOH.
| 【1】 Takashi, K.; et al.; Studies on phosphonic acid antibiotics. I. Structure and synthesis 3-(N-acetyl-N-hydroxyamino) propylphosphonic acid (FR-900098) and its N-formyl analog (FR-31564). Tetrahedron Lett 1980, 21, 1, 95. |
| 【2】 Iguchi, E.; et al.; Studies on new phosphonic acid antibiotics II. Taxonomic studies on producing organisms of the phosphonic acid and related compounds. J Antibiot 1980, 33, 1, 18. |
| 【3】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 . |
| 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) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (II) | 39517 | N-(benzyloxy)-4-methylbenzenesulfonamide | C14H15NO3S | 详情 | 详情 | |
| (III) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (IV) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (V) | 39080 | diethyl 3-bromopropylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (VI) | 39104 | diethyl 3-[(benzyloxy)[(4-methylphenyl)sulfonyl]amino]propylphosphonate | C21H30NO6PS | 详情 | 详情 | |
| (VII) | 39517 | N-(benzyloxy)-4-methylbenzenesulfonamide | C14H15NO3S | 详情 | 详情 | |
| (VIII) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 |
合成路线2
Isobutyl N-hydroxycarbamate (IX) was O-alkylated with 4-methoxybenzyl bromide (X) using NaOEt to give (XI). Subsequent N-alkylation with 1,3-dibromopropane (IV) produced bromide (XII), which was condensed with the sodium salt of dibutyl phosphonate (XIII) to furnish adduct (XIV). Acid hydrolysis of (XIV) then gave intermediate (VIII).
| 【1】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (VIII) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 | |
| (IX) | 42012 | isobutyl hydroxycarbamate | C5H11NO3 | 详情 | 详情 | |
| (X) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (XI) | 42013 | isobutyl (4-methoxybenzyl)oxycarbamate | C13H19NO4 | 详情 | 详情 | |
| (XII) | 42014 | isobutyl 3-bromopropyl[(4-methoxybenzyl)oxy]carbamate | C16H24BrNO4 | 详情 | 详情 | |
| (XIII) | 39090 | dibutyl phosphonate | 1809-19-4 | C8H19O3P | 详情 | 详情 |
| (XIV) | 42015 | dibutyl 3-[(isobutoxycarbonyl)[(4-methoxybenzyl)oxy]amino]propylphosphonate | C24H42NO7P | 详情 | 详情 |
合成路线3
The condensation of hydroxylamine with two equivalents of ethyl chloroformate (XV) afforded (XVI). The potassium salt of (XVI) was then alkylated with bromopropyl phosphonate (V) to yield (XVII), which was subsequently hydrolyzed to the intermediate (VIII) using HCl in HOAc.
| 【1】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 . |
| 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) | 39080 | diethyl 3-bromopropylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (VIII) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 | |
| (XV) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (XVI) | 39092 | 1-[([[(ethoxycarbonyl)amino]oxy]carbonyl)oxy]ethane | C6H11NO5 | 详情 | 详情 | |
| (XVII) | 39094 | 4-ethoxy-8-(ethoxycarbonyl)-4,10-dioxo-3,9,11-trioxa-8-aza-4lambda(5)-phosphatridecane | C13H26NO8P | 详情 | 详情 |
合成路线4
The condensation of bromopropyl phosphonate (V) with hydroxylamine gave (XVIII). This was then subjected to acid hydrolysis to produce (VIII).
| 【1】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 . |
合成路线5
Butyraldehyde oxime (XIX) was alkylated with bromopropyl phosphonate (V) to give the imine N-oxide (XX), which was then hydrolyzed under acidic conditions. A closely related procedure used octanaldehyde oxime instead of (XIX).
| 【1】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 . |