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【结 构 式】 
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【分子编号】39088 【品名】3-(hydroxyamino)propylphosphonic acid 【CA登记号】 |
【 分 子 式 】C3H10NO4P 【 分 子 量 】155.090502 【元素组成】C 23.23% H 6.5% N 9.03% O 41.26% P 19.97% |
合成路线1
该中间体在本合成路线中的序号：(I)1) The condensation of 1,3-dibromopropane (II) with diethyl phosphonate (III) gives diethyl 3-bromopropylphosphonate (IV), which by reaction with butyraldehyde oxime (V) by means of sodium ethoxide in ethanol is converted to diethyl 3-(butylideneamino)propylphosphonate-N-oxide (VI). Finally, this compound is hydrolyzed with HCl in refluxing acetic acid to obtain compound (I). 2) The condensation of (IV) with N-(p-methoxybenzyloxy)-p-toluenesulfonamide (VII) by means of sodium ethoxide in ethanol gives diethyl 3-[N-methoxybenzyloxy)-N-tosylamino]propyl phosphonate (VIII), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 3) The condensation of (IV) with methyl N-(benzyloxy)carbamate (IX) by means of sodium ethoxide in ethanol yields diethyl 3-(N-benzyloxy-N-methoxycarbonylamino)propylphosphonate (X), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 4) The condensation of (IV) with hydroxylamine by means of NaOH in MeOH-H2O gives diethyl 3-(N-hydroxylamino)propylphosphonate (XI), which is hydrolyzed with HCl in acetic acid to obtain compound (I).
| 【1】 Kuroda, Y.; et al.; US 4143135 . |
| 【2】 Prous, J.R.; Castaner, J.; FR-31564. Drugs Fut 1980, 5, 5, 239. |
| 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) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 | |
| (II) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (III) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (IV) | 39080 | diethyl 3-bromopropylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (V) | 39081 | butanal oxime | 110-69-0 | C4H9NO | 详情 | 详情 |
| (VI) | 39084 | (Z)butylidene[3-(diethoxyphosphoryl)propyl]ammoniumolate | C11H24NO4P | 详情 | 详情 | |
| (VII) | 39083 | N-[(4-methoxybenzyl)oxy]-4-methylbenzenesulfonamide | C15H17NO4S | 详情 | 详情 | |
| (VIII) | 39087 | diethyl 3-[[(4-methoxybenzyl)oxy][(4-methylphenyl)sulfonyl]amino]propylphosphonate | C22H32NO7PS | 详情 | 详情 | |
| (IX) | 39082 | methyl benzyloxycarbamate | C9H11NO3 | 详情 | 详情 | |
| (X) | 39086 | diethyl 3-[(benzyloxy)(methoxycarbonyl)amino]propylphosphonate | C16H26NO6P | 详情 | 详情 | |
| (XI) | 39085 | diethyl 3-(hydroxyamino)propylphosphonate | C7H18NO4P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)5) The condensation of 1-chloro-3-bromopropane (XII) with dibutyl phosphonate (XIII) affords dibutyl 3-chloropropylphosphonate (XIV), which by reaction with ethyl N-benzyloxycarbamate (A) is converted into dibutyl 3-(N-benzyloxy-N-ethoxycarbonylamino)propylphosphonate (XV). Finally, this compound is hydrolyzed with HCl in acetic acid to obtain compound (I). 6) The reaction of (XII) with diethyl phosphonate (III) yields diethyl 3-chloropropylphosphonate (XVI), which by condensation with ethyl N-ethoxycarbonyl-oxycarbamate (XVII) is converted into diethyl 3-(N-ethoxycarbonyloxy-N-ethoxycarbonylamino)propylphosphonate (XVIII). Finally, this compound is hydrolyzed with HCl in acetic acid to obtain compound (I).
| 【1】 Kuroda, Y.; et al.; US 4143135 . |
| 【2】 Prous, J.R.; Castaner, J.; FR-31564. Drugs Fut 1980, 5, 5, 239. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 39093 | ethyl benzyloxycarbamate | C10H13NO3 | 详情 | 详情 | |
| (I) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 | |
| (III) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (XII) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XIII) | 39089 | diethyl 3-chloropropylphosphonate | C7H16ClO3P | 详情 | 详情 | |
| (XIV) | 39091 | dibutyl 3-chloropropylphosphonate | C11H24ClO3P | 详情 | 详情 | |
| (XV) | 39095 | dibutyl 3-[(benzyloxy)(ethoxycarbonyl)amino]propylphosphonate | C21H36NO6P | 详情 | 详情 | |
| (XVI) | 39090 | dibutyl phosphonate | 1809-19-4 | C8H19O3P | 详情 | 详情 |
| (XVII) | 39092 | 1-[([[(ethoxycarbonyl)amino]oxy]carbonyl)oxy]ethane | C6H11NO5 | 详情 | 详情 | |
| (XVIII) | 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3
该中间体在本合成路线中的序号：(I)7) The condensation of dibutyl phosphonate (XIII) with N-(3-bromopropyl)-N-(p-methoxybenzyloxy)-p-toluenesulfonamide (XIX) by means of NaH in refluxing benzene gives dibutyl 3-[N-(p-methoxybenzyloxy)-N-tosylamino]propylphosphonate (XX), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 8) The condensation of (XIII) with isobutyl N-(p-methoxybenzyloxy)-N-(3-bromopropyl)carbamate (XXI) with NaH in refluxing benzene affords dibutyl 3-[N-(p-methoxybenzyloxy)-N-isobutoxycarbonylamino]propylphosphonate (XXII), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 9) The condensation of (XIII) with N-(3-bromopropyl)-N-benzyloxy-p-toluenesulfonamide (XXIII) with NaH in refluxing benzene gives dibutyl 3-(N-benzyloxy-N-tosylamino)propylphosphonate (XXIV), which is hydrolyzed with HCl in acetic acid to obtain compound (I).
| 【1】 Kuroda, Y.; et al.; US 4143135 . |
| 【2】 Prous, J.R.; Castaner, J.; FR-31564. Drugs Fut 1980, 5, 5, 239. |
| 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) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 | |
| (XIII) | 39089 | diethyl 3-chloropropylphosphonate | C7H16ClO3P | 详情 | 详情 | |
| (XIX) | 39096 | N-(3-bromopropyl)-N-[(4-methoxybenzyl)oxy]-4-methylbenzenesulfonamide | C18H22BrNO4S | 详情 | 详情 | |
| (XX) | 39098 | dibutyl 3-[[(4-methoxybenzyl)oxy][(4-methylphenyl)sulfonyl]amino]propylphosphonate | C26H40NO7PS | 详情 | 详情 | |
| (XXI) | 39097 | butyl 3-bromopropyl[(4-methoxybenzyl)oxy]carbamate | C16H24BrNO4 | 详情 | 详情 | |
| (XXII) | 39099 | dibutyl 3-[(butoxycarbonyl)[(4-methoxybenzyl)oxy]amino]propylphosphonate | C24H42NO7P | 详情 | 详情 | |
| (XXIII) | 39101 | N-(benzyloxy)-N-(3-bromopropyl)-4-methylbenzenesulfonamide | C17H20BrNO3S | 详情 | 详情 | |
| (XXIV) | 39100 | dibutyl 3-[(benzyloxy)[(4-methylphenyl)sulfonyl]amino]propylphosphonate | C25H38NO6PS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)10) The condensation of diethyl phosphonate (III) with N-(p-methoxybenzyloxy)-N-(3-chloropropyl)-p-toluenesulfonamide (XXV) by means of NaH in refluxing benzene gives (VIII), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 11) The condensation of (III) with N-(3-chloropropyl)-N-(benzyloxy)-p-toluenesulfonamide (XXVI) by means of NaH in refluxing benzene gives diethyl 3-(N-benzyloxy-N-tosylamino)propylphosphonate (XXVII), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 12) By reaction of 3-bromopropylphosphonic acid (XXVIII) with hydroxylamine by means of sodium methoxide in MeOH to obtain compound (I).
| 【1】 Kuroda, Y.; et al.; US 4143135 . |
| 【2】 Prous, J.R.; Castaner, J.; FR-31564. Drugs Fut 1980, 5, 5, 239. |
| 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) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 | |
| (III) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (VIII) | 39087 | diethyl 3-[[(4-methoxybenzyl)oxy][(4-methylphenyl)sulfonyl]amino]propylphosphonate | C22H32NO7PS | 详情 | 详情 | |
| (XXV) | 39102 | N-(3-chloropropyl)-N-[(4-methoxybenzyl)oxy]-4-methylbenzenesulfonamide | C18H22ClNO4S | 详情 | 详情 | |
| (XXVI) | 39103 | N-(benzyloxy)-N-(3-chloropropyl)-4-methylbenzenesulfonamide | C17H20ClNO3S | 详情 | 详情 | |
| (XXVII) | 39104 | diethyl 3-[(benzyloxy)[(4-methylphenyl)sulfonyl]amino]propylphosphonate | C21H30NO6PS | 详情 | 详情 | |
| (XXVIII) | 39105 | 3-bromopropylphosphonic acid | 1190-09-6 | C3H8BrO3P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)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6
该中间体在本合成路线中的序号：(VIII)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7
该中间体在本合成路线中的序号：(VIII)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8
该中间体在本合成路线中的序号：(VIII)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9
该中间体在本合成路线中的序号：(VIII)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 . |