A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug.
A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug.
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来自妥拉唑啉（一种含咪唑啉药物）亚硝化的重氮离子级联。
DOI：
10.1021/tx700317g
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发表时间：
2008
影响因子：
4.1
通讯作者：
Geddam,Sailaja
中科院分区：
文献类型：
--
作者：
Loeppky,RichardN;Shi,Jianzheng;Barnes,CharlesL;Geddam,Sailaja
妥拉唑啉（1-苄基咪唑啉）是一种代表性的含咪唑啉药物，在乙酸中容易与亚硝酸盐反应，生成复杂的产物混合物。当使用8倍过量的HNO 2时，已经鉴定出14种化合物为这种转化的产物。产物包括N-亚硝基酰胺、酯、醇和苯乙酸，被合理化为反应性重氮离子级联反应的产物。当反应进行时，用CH_2Cl_2萃取混合物，可以从亚硝化反应中分离出N-亚硝基妥拉唑啉，产率较高。它的亚硝化反应速度比妥拉苏林快得多（50倍），生成肟[1-（N-亚硝基-2-咪唑啉基）亚苄基]羟胺，该产物也可以由妥拉苏林与亚硝酸异丙酯反应以高产率制备。在低底物浓度和亚硝酸盐浓度下，主要反应产物为N-亚硝基妥拉唑啉及其分解产物N-2-羟乙基苯乙酰胺、肟、苯乙酸和2-羟乙基苯乙酸。在pH 3.4和37 °C下测定了三种缓冲体系中妥拉唑啉的亚硝化速率（kobs= 6.25 × 10−5s− 1，在0.5 M醋酸盐缓冲液中，10 mM [NO2−] = 250 mM）。由于N-亚硝基妥拉唑啉表现出直接作用的诱变剂和致癌物的化学性质，我们已经使用的速率数据，以估计其在亚硝酸盐浓度<3 mM的形成水平。粗略检查羟甲唑啉，相关药物的亚硝化化学，主要集中在其富含电子的芳香环。
Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2is used. The products, which includeN-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions.N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2as the transformation progresses. It nitrosates much more rapidly (50×) than tolazoline to give, among other products, the oxime [1-(N-nitroso-2-imidazolinyl)benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products areN-nitrosotolazoline, its decomposition productN-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37 °C (kobs= 6.25 × 10−5s−1in 0.5 M acetate buffer with a 10 ∗ [NO2−] = 250 mM). BecauseN-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations <3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.