利用过二硫酸盐氧化消除2-碘双氢非那雄胺制备非那雄胺

系统考察了不同碱及氧化剂对2-碘二双氢非那雄胺(2a)氧化消除反应的影响,实验结果表明,当以K2S2O8为氧化剂时,反应效果最佳.以K2S2O8为氧化剂,探索了溶剂、K2S2O8用量、温度、时间对反应的影响,获得最佳反应条件为:四氢呋喃(THF)为溶剂,室温反应10 h,K2S2O8与2-碘二双氢非那雄胺(2a)的投料比为2∶1.在该最优化条件下,非那雄胺(3a)收率为96%,纯度为99.6%.同时,该条件也适用于2-碘-3-氧代-4-氮杂-5α-雄甾-17β-甲酸(2b)和2-碘-3-氧代-4-氮杂-5α-雄甾-17β-甲酸甲酯(2c)的氧化消除反应,得到相应目标产物收率和纯度均高.本方法具有反应条件温和、产品收率和纯度均高且对环境友好等优点.     

2,6-二溴-4-氨基吡啶的合成

从时间分辨荧光免疫分析双功能螯合剂合成需要出发,设计了2,6-二溴-4-氨基吡啶的合成路线.以2,6-二溴吡啶为起始原料,经过氧化、硝化和还原三步合成了该化合物,通过红外光谱、元素分析和熔点测定对其进行了表征.证明了该结构和合成方法的可靠性,并分别探讨了各步产物合成反应条件的影响,具有一定的参考价值.     

2-二氟溴甲基-1,3-苯并噻唑的简便合成

本文应用二氟溴乙酸作为二氟溴甲基的合成子,实现了2 巯基芳胺与二氟溴乙酸的缩合反应合成2-二氟溴甲基-1,3-苯并噻唑。该反应以5当量二氟溴乙酸,氯苯为溶剂,于100 ℃下与2-巯基芳胺反应18~40 h,产率高达88%。目标产物通过核磁共振和高分辨质谱表征。该反应条件温和,是对现有合成2-二氟溴甲基-1,3-苯并噻唑的良好补充。     

a-碘代烯酰基二硫缩烯酮与炔类化合物的 Sonogashira反应

烯炔化合物是药物和天然产物的重要骨架,其合成方法一直受到有机合成化学家们的重视。近年来,Sonogashira反应一直是合成烯炔化合物的重要方法。本文以ɑ-碘代烯酰基二硫缩烯酮与端炔类化合物,考察了钯催化剂种类与用量、碱种类与用量、溶剂、底物结构等对偶联反应的影响,通过Sonogashira偶联反应,合成了一系列的ɑ-芳炔基烯酰基二硫缩烯酮类化合物,通过核磁共振、质谱分析对所得化合物进行了表征,并对该反应机理进行了探讨。     

镍催化的丁二烯、醛、炔和氢氯二茂锆的多组分偶联反应合成1,4-二烯

1,4-二烯结构广泛存在于一系列具有生物活性的化合物分子中,其构建是有机合成中的重要研究领域之一.使用简单易得的原料合成1,4-二烯具有重要的研究意义.发展了镍催化的1,3-丁二烯、醛、炔和氢氯二茂锆的多组分偶联反应,用于高效合成1,4-二烯产物.该反应的原料均简单易得,其中1,3-丁二烯更是大宗化工产品.通过简单的炔烃氢锆化反应现场制备烯基锆试剂直接参与反应,无需分离纯化.反应以优秀的区域选择性和立体选择性合成了一系列(E,E)-1,4-二烯产物.简单温和的反应条件使该方法具有广泛的底物适用范围和优秀的官能团兼容性.该反应提供了一种合成1,4-二烯产物的高效且实用的方法.     

水相中3,5-二芳基异噁唑衍生物的微波辐射合成

微波辐射下,以芳香醛和芳香酮为起始原料合成2,4,6-三芳基吡喃盐,在NaOH水溶液中与盐酸羟胺发生开环、缩环和脱苯甲酰基反应,一步生成3,5-二芳基异噁唑衍生物。考察了微波辐射功率和辐射时间对目标产物收率的影响,2,4,6-三芳基吡喃盐与盐酸羟胺反应生成3,5-二芳基异噁唑衍生物的最佳微波辐射功率为600W,辐射时间为8min,最大收率为83%。该法不仅避免了使用高氯酸造成的环境污染,而且以水作为反应介质,使后处理简便。该工艺具有操作安全、反应条件温和和产率高等优点,是一种环境友好的合成工艺。产物经元素分析、1HNMR和MS测试技术表征了其结构。     

5,5-二甲基-2-磷杂-1,3-二噁烷-2-基烯丙基磷酸酯的制备

以新戊二醇、三氯氧磷、烯丙醇和金属钠为原料,经过2步反应合成了新型反应型阻燃化合物5,5-二甲基-2-磷杂-1,3-二噁烷-2-基烯丙基磷酸酯。 采用元素分析、FTIR、MS和1H NMR等测试技术对其结构进行了表征。 对合成工艺进行了探讨,当n（Na）∶n（烯丙醇）=1∶2,于冰水浴反应2 h,再于30 ℃反应6 h时,产率可达55.5%。 TG分析显示,该化合物的起始分解温度为130.2 ℃,800 ℃时仍有23%的残炭率,说明该化合物具有较好的热稳定性和成炭性。     

微波辐射下水相中3, 5-二芳基异噁唑衍生物的合成

微波辐射下,以芳香醛和芳香酮为起始原料首先合成2,4,6-三芳基吡喃盐,再在NaOH水溶液中与盐酸羟胺发生开环、缩环和脱苯甲酰基反应,一步生成3,5-二芳基异噁唑衍生物。 考察了微波辐射功率和辐射时间对目标产物收率的影响,2,4,6-三芳基吡喃盐与盐酸羟胺反应生成3,5-二芳基异噁唑衍生物的最佳微波辐射功率为600 W,辐射时间为8 min,最大收率为83%。 该法不仅避免了使用高氯酸造成的环境污染,而且以水作为反应介质,使后处理简便。 该工艺具有操作安全、反应条件温和和产率高等优点,是一种环境友好的合成工艺。 产物经元素分析、1H NMR和MS测试技术表征了其结构。     

2,3-二氯-5,6-二氰基-1,4-苯醌促进的3,4-二氢嘧啶硫酮的氧化偶联反应合成1,2-二嘧啶基二硫醚

在室温、空气气氛下,以2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)为氧化剂,快速实现了3,4-二氢嘧啶-2-硫酮的氧化偶联芳构化反应,以较高产率合成了系列1,2-二嘧啶基二硫醚.该法与已知的合成1,2-二嘧啶基二硫醚的方法相比,具有反应温度低、反应时间短及产率高的优点.通过1H NMR,13C NMR,HRMS及X射线单晶衍射对其结构进行了表征,并简要探讨了其结构特性和反应机理.     

离子液体中钯催化合成cis-1,2-二卤代-1,7-辛二烯的反应研究

发展了一种以PdBr2为催化剂,以[Bmim]X/HXaq为溶剂,炔卤与5-己烯-1-醇进行交叉偶联反应的新方法,以中等及优良的产率(73%~94%)合成了系列cis-1,2-二卤代-1,7-辛二烯衍生物.反应表现出较高的区域选择性和立体选择性.并且该偶联反应合成途径简捷、反应条件温和,可为cis-1,2-二卤代烯烃类化合物的合成提供简便的途径.     

The structure of Genin G(12-O-benzoyl-desacetylmetaplexigenin) and H (di-O-benzoyl-viminolon) from the stems of Sarcostemma viminale (L.) R. Br

The following structures for the two new genins G and H from Sarcostemma viminale have been deduced. Genin G is shown to be 12-O-benzoyl-deacetylmetaplcxigenin ( 3 ). On the basis of physical data, its behaviour in KOH-methanol solution and its positive test with alcaline silver-diammine solution, the structure of 3β, 8β, 14β, 17β-tetrahydroxy-12β, 21-dibenzoyloxy-20-oxo-17α-pregn-5-ene ( 4 ) is proposed for genin H. This substance therefore contains a dihydroxyacetone group like some corticoids (e.g. Cortisol), but with different stereochemistry at C-14 and C-17.     

Cardenolide and pregnane derivatives from the roots of Trachycalymma fimbriatum (Weimark) Bullock. Glycosides and aglycones. 322

The roots of Trachycalymma fimbriatum (WEIMARCK ) BULLOCK contain both cardenolide and pregnaneglycosides. Elimination of 2-deoxysugars by mild acid hydrolysis gave a mixture from which some anhydroderivatives and the following compounds could be isolated: uzarigenin ( l ), ascleposide = 3-O-(6-deoxy-β-D -allopyranosyl)-uzarigenin ( 4 ), coroglaucigenin ( 6 ) and two pregnane derivatives (H and J). Compound H could be identified as 3β,14β-dihydroxy5α, 17α-pregnan-20-one ( 10 ). Compound J is probably a new substance, for which we tentatively assign structure 18 , i.e. 3β8β,14β-trihydroxy-5α,17α-pregnan-20-one. We suspect H and J to be artefacts produced from the corresponding 17b-derivatives during acid hydrolysis. 17-iso-H is probably a precursor in the biosynthesis of uzarigenin. The cardenolides of Trachycalymma fimbriatum are the same as found in Asclepias glaucophylla, a closely related species, while the pregnane derivatives of the latter are distinctly higher hydroxylated.     

Insights into the Synthesis of Steroidal A‐Ring Olefins

The classical synthesis, followed by purification of the steroidal A‐ring Δ¹‐olefin, 5α‐androst‐1‐en‐17‐one ( 5 ), from the Δ¹‐3‐keto enone, (5α,17β)‐3‐oxo‐5‐androst‐1‐en‐17‐yl acetate ( 1 ), through a strategy involving the reaction of Δ¹‐3‐hydroxy allylic alcohol, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ), with SOCl₂, was revisited in order to prepare and biologically evaluate 5 as aromatase inhibitor for breast cancer treatment. Surprisingly, the followed strategy also afforded the isomeric Δ²‐olefin 6 as a by‐product, which could only be detected on the basis of NMR analysis. Optimization of the purification and detection procedures allowed us to reach 96% purity required for biological assays of compound 5 . The same synthetic strategy was applied, using the Δ⁴‐3‐keto enone, 3‐oxoandrost‐4‐en‐17β‐yl acetate ( 8 ), as starting material, to prepare the potent aromatase inhibitor Δ⁴‐olefin, androst‐4‐en‐17‐one ( 15 ). Unexpectedly, a different aromatase inhibitor, the Δ^3,5‐diene, androst‐3,5‐dien‐17‐one ( 12 ), was formed. To overcome this drawback, another strategy was developed for the preparation of 15 from 8 . The data now presented show the unequal reactivity of the two steroidal A‐ring Δ¹‐ and Δ⁴‐3‐hydroxy allylic alcohol intermediates, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ) and 3β‐hydroxyandrost‐4‐en‐17β‐yl acetate ( 9 ), towards SOCl₂, and provides a new strategy for the preparation of the aromatase inhibitor 12 . Additionally, a new pathway to prepare compound 15 was achieved, which avoids the formation of undesirable by‐products.     

Diastereoselective hydroformylation of Δ4-steroids with rhodium–phosphite catalysts

The hydroformylation of two steroidal substrates, namely 17β-acetoxyandrost-4-ene 1 and 3β,17β-diacetoxyandrost-4-ene 2, with a rhodium tris(O-tert-butylphenyl)phosphite catalyst was investigated. In both cases, the major reaction product was 4β-formyl-17β-acetoxy-5β-androstane 3, which was isolated and characterized by X-ray diffraction and NMR techniques. This reaction is the first example of catalytic carbonylation to the β face of a steroid backbone. The effect of reaction temperature, the pressure at which the reaction was completed and the ligand:Rh ratio on the regio- and stereoselectivity of the reaction is also discussed.     

Copper-mediated regio- and stereoselective 12β-hydroxylation of steroids with molecular oxygen and an unexpected 12β-chlorination

It is shown, that copper(I) complexes of 17-(2-iminomethyl)pyridino steroids (17-IMPY steroids) can react with molecular oxygen followed by a regio- and stereoselective γ-hydroxylation in 12β-position. After decomplexation and hydrolysis of the IMPY group 12β-hydroxy-17-ketones are available in practical useful yields. IMPY compounds are simple to prepare by condensation of oxo compounds with (2-aminomethyl)pyridine. In the cases of 17-IMPY steroids the yields in the hydroxylation procedure of an unactivated CH₂ group are higher by starting with copper(II) complexes, reduction with benzoin/triethylamine in acetone and reaction with molecular oxygen in comparison to the direct reaction of copper(I) complexes with molecular oxygen in acetone. Employing the procedure in dichloromethane as solvent starting with copper(II) complexes surprisingly the 12β-chloro compound could be isolated next to the hydroxylation product. This regio- and stereoselective γ-chlorination takes place also in acetone, when triethylammonium chloride is added to the reaction mixture. Oxygen is necessary for this reaction. The mechanistic and stereochemical aspects of these new reactions are discussed. Comparison of the different yields of steroids with different A-ring [3-methoxy-estra-1,3,5(10)-triene and 3β-hydroxy-androst-5-ene] pointed out to a subtle influence of the molecular structure far from the reaction centre on these reactions. The successful hydroxylation of the IMPY derivative of 3β-hydroxy-androst-5-ene-17-one shows the tolerance of a homoallylic system against this oxidation procedure. By Oppenauer oxidation 12β-hydroxy-androst-4-ene-3,17-dione is available. The hydroxylation procedure opens a short way to 12β-hydroxy-17-oxo steroids, which are difficult to obtain by other routes.     

Synthesis of 2-(β-D-ribofuranosyl)pyrimidines,A new class of C-nucleosides

A new C-glycosyl precursor for C-nucleoside synthesis, 2,5-anhydroallonamidine hydrochloride ( 4 ) was prepared and utilized in a Traube type synthesis to prepare 2-(β-D-ribofuranosyl)pyrimidines, a new class of C-nucleosides. The anomeric configuration of 4 was confirmed by single-crystal X-ray analysis. Reaction of 4 with ethyl acetoacetate gave 6-methyl-2-(β-D-ribofuranosyl)pyrimidin-4-(1H)-one ( 5 ). Reaction of 4 with diethyl sodio oxaloacetate gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxylic acid ( 6 ). Esterification of 6 with ethanolic hydrogen-chloride gave the corresponding ester 7 which when treated with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxamide ( 8 ). Condensation of 2,5-anhydroallonamidine hydrochloride ( 4 ) with ethyl 4-(dimethylamino)-2-oxo-3-butenoate ( 9 ), gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboxylate ( 10 ). Treatment of 10 with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ). Single-crystal X-ray analysis confirmed the β-anomeric configuration of 11. Acetylation of 11 followed by treatment with phosphorus pentasulfide and subsequent deprotection with sodium methoxide gave 2-(β-D-ribofuranosyl)pyrimidine-4-thiocarboxamide ( 14 ). Dehydration of the acetylated amide 12 with phosphorous oxychloride provided 2-(β-D-ribofuranosyl)pyrimidine-4-carbonitrile ( 15 ). Treatment of 15 with sodium ethoxide gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboximidate ( 16 ), which was converted to 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamidine hydrochloride ( 17 ) by treatment with ethanolic ammonia and ammonium chloride. Treatment of 16 with hydroxylamine yielded 2-(β-D-ribofuranosyl)pyrimidine-4-N-hydroxycarboxamidine ( 18 ). Treatment of 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ) with phosphorus oxychloride gave the corresponding 5′-phosphate, 19 , Coupling of 19 with AMP using the carbonyldiimidazole activation procedure gave the corresponding NAD analog, 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide-(5′ ? 5′)-adenosine pyrophosphate ( 20 ).     

An Unusual Occurrence in the Reaction of 4-Azasteroid Derivatives with N-Fluorodibenzenesulfonimide and Lithium Diisopropylamide

The reaction of N,N-diethyl-3-oxo-4-methyl-4-aza-5-androstane-17β-carboxamide(1) with N-fluorodibenzenesulfonimide(NFA) and lithium diisopropylamide(LDA) was studied.Under absolute anhydrous and anaerobic conditions,the formation of 5(2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxylic acid methyl ester) can be rationalized by participating in the expected nucleophilic substitution reaction.Not in absolute anhydrous and anaerobic conditions,the formation of 10(N-di-isopropyl-N'-aryl-sulfonamides(C12H20N2O2S) and 11(N-diethyl-3-oxo-4-methyl-4-aza-5-androstene-17β-carboxamide) can be rationalized by assuming that the situ genera-ted carbanion 2 followed by a single electron transfer mechanism.5,10 and 11 were characterized.10 was a new compound and determined by X-ray single-crystal diffraction.Crystal data for 10:space group C2/c with a = 14.783(2),b = 7.6193(11),c = 24.663(3) ,β = 98.688(3)o,V = 2746.1(7) nm3,Mr = 256.36,Z = 8,Dc = 1.240 g/cm3,μ = 0.229 mm-1,F(000) = 1104,R = 0.0511 and wR = 0.1268.There exist intramolecular H-bonds which result in a supramolecular framework of the title compound.The formation mechanisms of 10 and 11 were also discussed briefly.     

5α-androstano [3,2-b]pyridines, 5α-androstano[17,16-b]pyridines and androst-4 and 5-eno[17,16-b]pyridines

A new synthesis of 5α-androstano[3,2-b]pyridin-17β-ol acetate (VIa) and 17-methyl-5α-androstano[3,2-b]pyridin-17β-ol (VIb), first reported by Shimizu, Ohta, Ueno, and Takegoshi, was achieved. The analogous 5α - androstano[17,16-b]pyridin-3β-ol (XII), 5α-androstano[17,16-b]pyridin-3-one (XIVa), and androst-4-eno[17,16-b]pyridin-3-one (XIVb) were also prepared. An illustration of the method follows. Condensation of 3β-hydroxy-5α-androstan-17-one (VIIa) with 3-(2-furyl)acrolein afforded 16-[3-(2-furyl)-2-propenylidene]-3β-hydroxy-5α-androstan-17-one (VIIIa), the oxime (IXa) of which was thermally cyclized to 5α-androstano[17,16-b]-6′-(2-furyl)pyridin-3β-ol (Xa). 3β-Hydroxy-5α-androstano[17,16-b]pyridine-6′-carboxylic acid (XI) was obtained by ozonolysis of Xa. Thermal decarboxylation of XI gave XII. Cinnamaldehyde was used in place of 3-(2-furyl)acrolein to give the corresponding phenylpyridines.     

Glykoside von Marsdenia erecta R. Br. 2. Mitteilung: Versuche zur Strukturbestimmung der Genine. Glykoside und Aglykone, 330. Mitteilung

Structures for the genins of the ester glycosides of Marsdenia erecta are suggested. They are based on the behaviour in alkaline hydrolysis of these ester glycosides, their NMR. and mass spectra and ORD. data. All genins are derived from three acyl-free pregnane derivatives, i.e. drevogenin-P ( 1 ), 17 β-marsdenin ( 3 ) and marsectohexol ( 7 ). The structure of 1 is known, 3 and 7 are new compounds, i.e. 3 = 3β,8β,11α,12β,14β-pentahydroxy-Δ⁵-pregnen-20-one and 7 = 3β,8β,11α,12β,14β,20ξ-hexahydroxy-Δ⁵-pregnene. Formulae 13–17 were attributed to the acyl-genins A-1, A-2, A-3, A-4 and A-5, but only two of them were pure compounds, i.e. acyl-genin A-3 = 11,12-di-O-tiglyl-17β-marsdenin ( 15 ) and acyl-genin A-5 = 11,12-di-O-acetyl-marsectohexoi ( 17 ). Acyl-genin A-1 is a mixture of the two esters 13a + 13b derived from drevogenin-P, and similarly acyl-genin A-2 is a mixture of the esters 14a + 14b derived from 17β-marsdenin. The poorly characterised acyl-genin A-4 is most probably a mixture of the esters 16a + 16b , also derived from 17β-marsdenin.     

Solid phase analytical derivatization of anthropogenic and natural phenolic estrogen mimics with pentafluoropyridine for gas chromatography-mass spectrometry

A simple, low cost, fast and sensitive method is reported for the determination of the four endocrine disrupting chemicals (EDCs) 4-tert-butylphenol, 4-tert-octylphenol, bisphenol A and 17β-estradiol using pentafluoropyridine as the derivatizing reagent. These EDCs were determined by simultaneous extraction and derivatization in a solid phase analytical derivatization (SPAD) technique without the aid of any phase transfer catalyst (PTC) or an ion-pair mechanism. Recoveries of analytes as their tetrafluoropyridyl derivatives from water ranged from 71% for 4-tert-butylphenol to 106% for 17β-estradiol; from urine they ranged from 61% for 17β-estradiol to 91% for 4-tert-octylphenol; and from humic acids solution the ranged from 59% for 17β-estradiol to 104% for 4-tert-octylphenol in humic acid solutions. Calibration curves were constructed from a matrix of human male urine in the range 1-40 ng/mL and had coefficients of correlation greater than 0.99. For 4-tert-butylphenol, bisphenol A and 17β-estradiol the limits of quantitation were 5 ng/mL and for 4-tert-octylphenol it was 1 ng/mL. This method was applied to determine EDCs and detected 4-tert-octylphenol, bisphenol A and 17β-estradiol in concentrations comparable to those found in the literature. The method offers advantages in speed of analysis, reduced reagent and specificity of derivatization.