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【结 构 式】 
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【分子编号】37311 【品名】Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate 【CA登记号】33513-44-9 |
【 分 子 式 】C7H4Na2O7S2 【 分 子 量 】310.216096 【元素组成】C 27.1% H 1.3% Na 14.82% O 36.1% S 20.67% |
合成路线1
该中间体在本合成路线中的序号：(III)Reduction of 2-methyl-2-nitropropane (I) with either zinc and acetic acid or aluminum and HgCl2 afforded the corresponding hydroxylamine (II). Subsequent condensation of (II) with aldehyde (III) furnished the title nitrone.
| 【1】 Carney, J.M. (Oklahoma Medical Research Foundation; University of Kentucky); 2,4-Disulfonyl phenyl butyl nitrone, its salts, and their use as pharmaceuticals. WO 9517876 . |
| 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) | 37310 | 2-methyl-2-nitropropane | 594-70-7 | C4H9NO2 | 详情 | 详情 |
| (II) | 35455 | N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane | C4H11NO | 详情 | 详情 | |
| (III) | 37311 | Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate | 33513-44-9 | C7H4Na2O7S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)NXY-059 is synthesized by condensation of N-tert-butylhydroxylamine (I) or its acetate or hydrochloride salts and disodium benzaldehyde-2,4-disulfonate (II) directly in refluxing MeOH or mixtures of MeOH/water or i-PrOH/MeOH/water or by means of MeONa in refluxing MeOH/water or i-PrOH/MeOH/water. N-tert-butylhydroxylamine (I) can be prepared as follows: a) Reduction of 2-methyl-2-nitropropane (III) with either Zn in HOAc/EtOH or aluminum foil and HgCl2 in EtOH/ether/H2O. b) Condensation of benzaldehyde (IV) with tert-butyl-amine (V) in refluxing toluene provides N-benzylidene-N-tert-butylamine (VI), which is oxidized with meta-chloroperbenzoic acid and Na2CO3 in water/toluene/ EtOH to furnish the phenyloxaziridine derivative (VII). Finally, the oxaziridine ring of (VII) is opened by treatment with H2SO4/HOAc in EtOH/H2O. c) Heating of the phenyloxaziridine derivative (VII) at 130 C gives N-tert-butylphenylnitrone (VIII), which is finally treated with H2SO4/HOAc in toluene. Disodium benzaldehyde-2,4-disulfonate (II) can be obtained as follows: a) Heating of 2,4-dichlorobenzaldehyde (IX) with sodium sulfite at 170 °C in water in water, followed by oxidation with sodium hypochlorite. b) Reaction of 2,4-dichlorobenzal chloride (X) with sodium sulfite and Na2CO3 or NaHCO3 at 170 C in water, followed by oxidation with sodium hypochlorite.
| 【1】 Leeson, P.A.; del Fresno, M.; Castañer, J.; Sorbera, L.A.; NXY-059. Drugs Fut 2002, 27, 3, 240. |
| 【2】 Carney, J.M. (Oklahoma Medical Research Foundation; University of Kentucky); 2,4-Disulfo phenyl butyl nitrone, its salts and their use as pharmaceuticals. US 5780510 . |
| 【3】 Carney, J.M. (Oklahoma Medical Research Foundation; University of Kentucky); 2,4-Disulfonyl phenyl butyl nitrone, its salts, and their use as pharmaceuticals. WO 9517876 . |
| 【4】 Metz, H.J. (Aventis Pharma AG); Process for the preparation of alkali metal and alkaline earth salts of benzaldehyde-2,4-disulfonic acid. DE 3434038; US 4715995 . |
| 【5】 Metz, H.J. (Aventis Pharma AG); Process for the preparation of alkali metal and alkaline earth salts of benzaldehyde-2,4-di-sulfonic acid. DE 3434079; US 4710322 . |
| 【6】 Blixt, J. (AstraZeneca AB); Novel salts of N-tert-butylhydroxylamine. WO 0002848 . |
| 【7】 Kruk, H.; McGinley, J.; Pouhov, S.; Blixt, J.; Vajda, J. (AstraZeneca AB; Centaur Pharmaceuticals, Inc.); Novel process for the preparation of alpha-(2,4-disulfophenyl)-N-tert-butylnitrone and pharmaceutically acceptable salts thereof. WO 0151460 . |
| 【8】 Wilcox, A.; Blixt, J.; Kruk, H.; Larsson, U.; McGinley, J.; Pouhov, S.; Vajda, J. (AstraZeneca AB; Centaur Pharmaceuticals, Inc.); Novel process for the preparation of alpha-(2,4-disulfophenyl)-N-tert-butylnitrone and pharmaceutically acceptable salts thereof. WO 0151461 . |
| 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) | 35455 | N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane | C4H11NO | 详情 | 详情 | |
| (II) | 37311 | Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate | 33513-44-9 | C7H4Na2O7S2 | 详情 | 详情 |
| (III) | 37310 | 2-methyl-2-nitropropane | 594-70-7 | C4H9NO2 | 详情 | 详情 |
| (IV) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (V) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
| (VI) | 52176 | N-(tert-butyl)-N-[(Z)-benzylidene]amine; 2-methyl-N-[(Z)-benzylidene]-2-propanamine | C11H15N | 详情 | 详情 | |
| (VII) | 52177 | 2-(tert-butyl)-3-phenyl-1,2-oxaziridine | C11H15NO | 详情 | 详情 | |
| (VIII) | 52178 | tert-butyl[(Z)-benzylidene]ammoniumolate | C11H15NO | 详情 | 详情 | |
| (IX) | 22196 | 2,4-dichlorobenzaldehyde | 874-42-0 | C7H4Cl2O | 详情 | 详情 |
| (X) | 52179 | 2,4-dichloro-1-(dichloromethyl)benzene | C7H4Cl4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The reaction of 2,4-dichlorophenyl bromide (I) with 14CO2 (II) by means of BuLi in ethyl ether gives the labeled 2,4-dichlorobenzoic acid (III), which is reduced with LiAlH4 in the same solvent to yield 2,4-dichlorobenzyl alcohol (IV). The oxidation of (IV) with lead tetraacetate affords 2,4-dichlorobenzaldehyde (V), which is condensed with sodium sulfite in water at 160 C in a pressure vessel to provide the disulfonate (VI). Finally, the aldehyde group of (VI) is condensed with N-tert-butylhydroxylamine (VII) in hot acetic acid to give rise to the target imine oxide.
| 【1】 Johansson, R.; Werner, R.; Syntheses of two [14C]-labeled disodium 4-[(N-tert-butylimino)methyl]benzene-1,3-disulfonate N-oxides. J Label Compd Radiopharm 2000, 43, 13, 1265. |
| 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) | 53307 | 1-Bromo-2,4-dichlorobenzene | 1193-72-2 | C6H3BrCl2 | 详情 | 详情 |
| (III) | 33443 | 2,4-dichlorobenzoic carboxylic acid; 2,4-dichlorobenzoic acid | 50-84-0 | C7H4Cl2O2 | 详情 | 详情 |
| (III) | 53308 | 2,4-dichlorobenzoic acid | 50-84-0 | C7H4Cl2O2 | 详情 | 详情 |
| (IV) | 53309 | (2,4-dichlorophenyl)methanol | 1777-82-8 | C7H6Cl2O | 详情 | 详情 |
| (IV) | 53310 | 2,4-Dichlorobenzyl alcohol | 1777-82-8 | C7H6Cl2O | 详情 | 详情 |
| (V) | 22196 | 2,4-dichlorobenzaldehyde | 874-42-0 | C7H4Cl2O | 详情 | 详情 |
| (V) | 53311 | 2,4-dichlorobenzaldehyde | 874-42-0 | C7H4Cl2O | 详情 | 详情 |
| (VI) | 37311 | Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate | 33513-44-9 | C7H4Na2O7S2 | 详情 | 详情 |
| (VI) | 53312 | disodium 4-formyl-1,3-benzenedisulfonate | 119557-95-8 | C7H4Na2O7S2 | 详情 | 详情 |
| (VII) | 36455 | (1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one | C13H13NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The reaction of 14C-labeled acetone (I) with O-benzylhydroxylamine (II) and pyridine in refluxing ethanol gives the corresponding oxime (III), which is methylated with MeLi and BF3.Et2O in toluene to yield labeled N-tert-butyl-O-benzylhydroxylamine (IV). The deprotection of (IV) by hydrogenation with H2 over Pd/C in methanol affords N-tert-butylhydroxylamine (V), which is finally condensed with benzaldehyde 2,4-disulfonic acid sodium salt (VI) in HOAc/water to give rise to the target imine oxide.
| 【1】 Johansson, R.; Werner, R.; Syntheses of two [14C]-labeled disodium 4-[(N-tert-butylimino)methyl]benzene-1,3-disulfonate N-oxides. J Label Compd Radiopharm 2000, 43, 13, 1265. |
| 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) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (II) | 53313 | acetone | 67-64-1 | C3H6O | 详情 | 详情 |
| (III) | 53314 | acetone O-benzyloxime | n/a | C10H13NO | 详情 | 详情 |
| (III) | 53315 | acetone O-benzyloxime | n/a | C10H13NO | 详情 | 详情 |
| (IV) | 53316 | 1-{[(tert-butylamino)oxy]methyl}benzene; O-benzyl-N-(tert-butyl)hydroxylamine | n/a | C11H17NO | 详情 | 详情 |
| (IV) | 53317 | O-benzyl-N-(tert-butyl)hydroxylamine; 1-{[(tert-butylamino)oxy]methyl}benzene | n/a | C11H17NO | 详情 | 详情 |
| (V) | 35455 | N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane | C4H11NO | 详情 | 详情 | |
| (V) | 53318 | 2-(hydroxyamino)-2-methylpropane; N-(tert-butyl)hydroxylamine | 16649-50-6 | C4H11NO | 详情 | 详情 |
| (VI) | 37311 | Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate | 33513-44-9 | C7H4Na2O7S2 | 详情 | 详情 |