1,2-双[双(2-乙氧基乙基)膦基]乙烷的合成改进

目的 合成1，2-双[双（2-乙氧基乙基）膦基]乙烷并进行工艺改进。方法 三乙氧基膦为原料，经与1，2-二溴乙烷加成，再经四氢铝锂还原得乙二膦，最后与乙烯基乙醚加成制得1，2-双[双（2-乙氧基乙基）膦基]乙烷。结果所得产物化学结构经红外光谱、核磁共振谱及质谱等确证。结论改进的合成工艺简便、合理且可行。     

2-(咪唑并[1,2-a]吡啶-3-基)乙酸的合成工艺改进

目的改进骨质疏松治疗药米诺膦酸的关键中间体2-(咪唑并[1,2-a]吡啶-3-基)乙酸的合成工艺。方法以反式-4-氧基-2-丁烯酸乙酯和2-氨基吡啶为起始原料,经环合、水解得到2-(咪唑并[1,2-a]吡啶-3-基)乙酸。结果与结论该合成方法首次以纯水替代有机溶剂作为反应溶剂,采用"一锅法"合成目标化合物,降低了该中间体的制备成本,而且环境友好,更适合于工业化生产。     

新型杂环双膦酸类化合物米诺膦酸的合成新工艺研究

目的是研究设计米诺膦酸合成新工艺。对国内外米诺膦酸合成工艺进行对比分析,设计新的合成路线,突出本工艺有特点。现合成2-氨基吡啶及2-(咪唑并[1,2-α]吡啶-3-基)乙酸乙酯,以上述两个物料为起始物料,制备咪唑并[1,2-α]吡啶-3-基)乙酸乙酯,再制备2-(咪唑并[1,2-α]吡啶基-3-基)乙酸,最后制备米诺膦酸原料,通过精制得米诺膦酸纯品。所设计工艺路线可行,在合成过程中生产成本低,收率高,可进行商业化生产,具有较广阔的应用前景。整个生产过程对起始物料及中间体均制定严格内控标准,所制备样品产品质量较好。     

N-[3',3'-双(膦羧基)丙基]-3-{4-[双(2-氯乙基)氨基]苯基}-3-氨基丙酰胺的合成及表征

目的合成N-[3’,3’-双(膦羧基)丙基]-3-{4-[双(2-氯乙基)氨基]苯基}-3-氨基丙酰胺,并进行体外骨靶向性实验。方法以3,3-双(二乙氧膦酰基)-1-硝基丙烷(1)为原料,经氢化还原,再与N-苄氧羰酰异苯丙氨酸氮芥(2)偶联,催化氢化还原得到化合物(4),用溴代三甲基硅烷脱去膦酸酯的烷基得到目标化合物T。用羟磷灰石晶体作为骨模型,测定偶联物T的趋骨性。结果和结论目标物T经1HNMRI、R、MS得到结构确证,体外骨靶向性实验显示,目标物T有良好的骨靶向性。     

脂蛋白酶A2抑制剂darapladib的合成工艺研究

目的改进脂蛋白酶A2抑制剂darapladib的合成方法。方法以对甲酰基苯硼酸(2)为原料,经醛胺缩合、氢化还原和Suzuki偶联一锅法合成N,N-二乙基-N’-(4’-三氟甲基-4-联苯基甲基)-1,2-乙二胺(4);以己二酸二甲酯(5)为原料,经Dieckmann缩合环化、杂环化和硫醚化制得[2-(4-氟苄硫基)-4-氧代-4,5,6,7-四氢-1H-环戊并嘧啶-1-基]乙酸(8);中间体8与4经酰胺化缩合制得darapladib。结果与结论 Darapladib及关键中间体的结构经1H-NMR谱确证,合成darapladib的4步反应总收率达49.8%(以己二酸二甲酯计)。本合成路线具有原料易得、工艺简单、收率高等优点,适合于规模化制备。     

端基含氰基的双半乳糖苷的设计和合成

目的合成端基含氰基的双半乳糖苷。方法以丙二酸二乙酯(4)为起始原料,经加成、保护、脱乙氧羰基、还原、加成、脱保护基、甲磺酰化、碘置换,再与已知的2-S-(2,3,4,6)-四-O-乙酰基-β-D-半乳吡喃糖基-2-异硫脲氢溴酸盐(1)作用,共9步反应,制得2-(4-氰基-2-氧杂正丁基)-1,3-二(2,3,4,6-四-O-乙酰基-β-D-半乳吡喃糖硫基)丙烷(3)。结果和结论合成的目标化合物(3)经1HNMR、IR和MS确证结构。     

(1-苯乙基哌啶-4-基)苯胺的制备

(1-苯乙基哌啶-4-基)苯胺(1)是合成阿片类镇痛药芬太尼(fentanyl)的重要中间体[1,2].文献[3]以β-苯乙胺和丙烯酸甲(乙)酯为原料,经Michael加成、Dieckmann缩合及酸性水解得N-苯乙基-4-哌啶酮(4),再与苯胺反应生成亚胺后由四氢锂铝还原得到1,总收率为30.5％～37.5％.4也可经三乙酰氧基硼氢化钠还原氨化[4]得到1.本研究改用雷尼镍催化下还原氨化,收率89.5％.改进后的总收率可提高至77.7％,且成本降低.1的合成路线见图1.     

一种克拉霉素关键中间体的合成工艺优化

目的研究克拉霉素关键中间体——（2＇4,″-O-双三甲基硅基）-红霉素A-9-[O-（1-乙氧基-1-甲乙基）]肟的＂一锅法＂合成工艺。方法以9-（E）-红霉素肟为原料,在内酰胺盐酸盐的催化下,与2-乙氧基丙烯进行醚化反应,再进行硅烷化,即经＂一锅法＂得到克拉霉素关键中间体。结果与结论目标物的结构经质谱、核磁共振谱确证。该合成路线收率良好（两步总收率为88%）、环境友好,为工业化生产克拉霉素提供了一种新的方法。     

N-金刚烷-2-基-N''''-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺的合成

目的 建立简便、经济的合成N-金刚烷-2-基-N'-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(SQ109)的方法.方法 以香叶醇、2-金刚烷酮为原料通过两条路线合成SQ109.第一条路线香叶醇经Mitsunobu反应、胺解反应得到香叶胺;2-金刚烷酮经亚胺化、硼氢化钠还原、催化氢化脱苄基得2-金刚烷胺.香叶胺经氯乙酰化,与2-金刚烷胺对接,再经红铝还原得到SQ109.第二条路线香叶醇首先转化成香叶基氯(12);2-金刚烷酮与乙二胺经亚胺化、硼氢化钠还原得到的中间产物11,11与香叶基氯12对接得到SQ109.结果与结论 路线1总收率38%,路线2总收率31%.两条合成路线均使用香叶醇与2-金刚烷酮代替了价格较高的香叶胺与2-金刚烷胺,从而降低了SQ109的合成成本.第二条路线,缩短了反应步骤,具有较大应用价值.     

N-金刚烷-2-基-N′-（3,7-二甲基-辛-2,6-二烯基）-乙烷-1,2-二胺的合成

目的建立简便、经济的合成N-金刚烷-2-基-N′-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(SQ109)的方法。方法以香叶醇、2-金刚烷酮为原料通过两条路线合成SQ109。第一条路线香叶醇经Mitsunobu反应、胺解反应得到香叶胺;2-金刚烷酮经亚胺化、硼氢化钠还原、催化氢化脱苄基得2-金刚烷胺。香叶胺经氯乙酰化,与2-金刚烷胺对接,再经红铝还原得到SQ109。第二条路线香叶醇首先转化成香叶基氯(12);2-金刚烷酮与乙二胺经亚胺化、硼氢化钠还原得到的中间产物11,11与香叶基氯12对接得到SQ109。结果与结论路线1总收率38%,路线2总收率31%。两条合成路线均使用香叶醇与2-金刚烷酮代替了价格较高的香叶胺与2-金刚烷胺,从而降低了SQ109的合成成本。第二条路线,缩短了反应步骤,具有较大应用价值。     

Synthesis and radiation stability of novel biologically active sulfur compounds derived from 1,2-bis(4-amino-5-mercapto-s-triazol-3-yl)ethane

Some novel 1,2-bis(s-triazolo[3,4b][1,3,4]thiadiazino-3-yl)ethane (4-7); 1,2-bis(s-triazolo[3,4b][1,3,4]thiadiazol-3-yl)ethane (16a,b) and 1,2-bis(s-triazolo[3,4b][1,3,4]thiadiazepino-3-yl)ethane (17) were synthesized via reaction of 1,2-bis(4-amino-5-mercapto-s-triazol-3-yl)ethane (3) with different reagents. Identification of the new compounds was established by elemental analyses, IR, 1H NMR and mass spectral data. Compounds 12, 13, 16b and 17 were promising antifungal activity. The biologically active compounds 13, 16b and 17 were radioresistant retaining their structures unchanged up to 40 k Gy. Radiosterilization of these compounds in the dry state may prove to be applicable.     

Synthesis and murine antineoplastic activity of bis[(carbamoyloxy)methyl] derivatives of pyrrolo[2,1-a]isoquinoline

The synthesis of 4,5-dihydropyrrolo[2,1-a]isoquinolines is reported. A key intermediate in the synthesis of 8-methoxy-4,5-dihydropyrrolo[2,1-a]isoquinolines, 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (6), was prepared by using a regiospecific phenolic cyclization reaction. The P388 lymphocytic activity is reported for 1,2-bis(hydroxymethyl)-5,6-dihydro-8-methoxy-3-methylpyrrolo [2,1-a]isoquinoline bis(isopropylcarbamate) (11a), 1,2-bis(hydroxymethyl)-5,6-dihydro-8-methoxy-3-methylpyrrolo[2,1-a ]isoquinoline bis(cyclohexylcarbamate) (11b), 1,2-bis(hydroxymethyl)-5,6-dihydro-3-methylpyrrolo[2,1-a]isoqui nol ine bis(methylcarbamate) (13a), 1,2-bis(hydroxymethyl)-5,6-dihydro-3-methylpyrrolo [2,1-a]isoquinoline bis(ethylcarbamate) (13b), and 1,2-bis(hydroxymethyl)-5,6-dihydroxy-3-methylpyrrolo[2,1-a]isoq uin oline bis(cyclohexylcarbamate) (13c); all of the compounds were active. Compound 11a was tested in an expanded tumor panel and was shown to be active against B16 melanocarcinoma, CD8F1 mammary, L1210 lymphoid leukemia, colon 38, and MX-1 human tumor breast xenograft systems.     

Ion-Pairing Interactions between 99MTc-Based Myocardial Imaging Agents and Oleic Acid

Purpose. The purpose was to test the hypothesis that ion-paired facilitated transport is of importance in successful myocardial uptake of cationic imaging complexes. In vitro ion-pairing interactions between oleic acid and seven cationic technetium-99m complexes based on the ligands l,2-bis[bis(2-ethoxyethyl) phosphino ethane] (tetrofosmin), l,2-bis(dimethyl phosphino ethane) (DMPE) and l,2-bis(diethyl phosphino ethane) (DEPE) has been studied. The complexes studied were: [^99mTc O₂ (tetrofosmin)₂]⁺ (commercially available as myocardial perfusion imaging kit, Myoview^®), [^99mTc O₂ (DMPE)₂]⁺, [^99mTc O₂ (DEPE)₂]⁺, [^99mTc C1₂ (DMPE)₂]⁺, [^99mTc C1₂ (DEPE)₂]⁺, [^99mTc (DMPE)₃]⁺ and [^99mTc (DEPE)₃]⁺. Methods. Ion-pairing interactions were monitored using a rotating diffusion cell containing a solid supported liquid membrane and by formation of lipid monolayers. Results. Depletion of complex from the donor phase into an isopropyl myristate model membrane was generally in proportion to distribution coefficient and transfer to the receptor compartment was in all cases very small. However, by the inclusion of 5%w/v oleic acid, which is used in myocardial metabolism, partitioning was enhanced by amounts which varied depending on the tendency to form complex/oleate ion-pairs. Transfer to the receptor compartment was increased for most complexes when given sufficient time to diffuse through the membrane. The complex [^99mTc O₂ (tetrofosmin)₂]⁺ appeared to form particularly stable ion-pairs with oleic acid. Monolayer formation also indicated ion-pairing interactions. Conclusions. The results suggested that whether or not a complex is taken up by the myocyte may depend on its ability to hitch a ride by ion-pairing with the myocytes energy source—a molecule of long chain fatty acid.     

Influence of alkyl chain ramification on estradiol receptor binding affinity and intrinsic activity of 1,2-dialkylated 1,2-bis(4- or 3-hydroxyphenyl)ethane estrogens and antiestrogens

The influence of a symmetrical introduction of CH3 substituents in the alpha or beta positions of the 1,2-dialkyl-1,2-bis(4-hydroxyphenyl)ethane estrogens hexestrol (ethyl, HES) and octestrol (n-propyl, OCES) [isopropyl (1), tert-butyl (2), sec-butyl (3), isobutyl (4)] and the 1,2-dialkyl-1,2-bis(3-hydroxyphenyl)ethane antiestrogens metahexestrol (ethyl, MetaHES) and metaoctestrol (n-propyl, MetaOCES) [isopropyl (5), tert-butyl (6), sec-butyl (7), isobutyl (8)] on estradiol receptor (E2R) binding affinity and intrinsic activity is described. The synthesis of compounds 1-8 was accomplished by reductive coupling of (a) the corresponding alpha-alkylbenzyl alcohols with TiCl3/LiAlH4 and separation of the meso diastereoisomers (compounds 2-4, 7, and 8), (b) alpha-tert-butyl-3-methoxybenzyl chloride with CoCl2/EtMgCl and isolation of the meso configurated isomer (6), and (c) the isopropyl phenyl ketones with TiCl4/Zn and subsequent hydrogenation of the corresponding cis-hex-3-enes (compounds 1 and 5). The binding affinity of 1-8 to the calf uterine E2R was measured relative to that of [3H]E2 by a competitive binding assay. Compounds 1 and 5 showed relative binding affinity (RBA) values exceeding those of HES and MetaHES, respectively. All other derivatives showed RBA values smaller than the corresponding parent compounds. The intrinsic activity was monitored in terms of uterotrophic and antiuterotrophic activity. It is striking that the introduction of a CH3 group in the alpha positions of MetaHES and MetaOCES led to compounds with full intrinsic activity (5-7), i.e., estrogens without antiestrogenic properties. No correlation between E2R binding affinity and intrinsic activity was found.     

Chemical behavior and in vitro activity of mixed phosphine gold(I) compounds on melanoma cell lines

(31)P nuclear magnetic resonance and electrospray ionization-mass spectrometry studies on the melanoma cytotoxic chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I), [Au(DPPP)(PPh 3)Cl], show partial decomposition that includes the novel dinuclear cation [Au 2(DPPP) 2Cl] (+); its structure was calculated by using the density functional theory (DFT). Unexpectedly, by using the diphosphine ligand 1,2-bis(diphenylphosphino)ethane (DIPHOS), [{AuCl(PPh 3)} 2(mu 2-DIPHOS)] was obtained. Its X-ray crystal structure shows a unique triangular coordination sphere in contrast to the T-shaped geometry of related Au(I)-DIPHOS compounds. Its cytotoxic activity in JR8, SK-Mel-5, and 2/60 melanoma cell lines is dose-dependent and lower than that of [Au(DPPP)(PPh 3)Cl] because of its nonchelating nature. An in vitro study of the effect of both Au compounds on the B16V melanoma cell line gives credence to this structure-activity relationship. IC 50 indicates that both Au species are 10 times more active in B16V than in JR8, SK-Mel-5, and 2/60. Oxidation of [Au(DPPP)(PPh 3)Cl] toward Au(III) compounds and phosphine-oxides is observed upon reaction with hypochlorite in water/dimethyl sulfoxide solution, mimicking endogenous hypochlorite. A related reaction involving the formation of [AuCl 4] (-) is thermodynamically feasible according to DFT calculations.     

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-compl exe s, Part I: Synthesis

The synthesis of the stereoisomeric 1,2-bis(3-hydroxyphenyl)ethylenediamines (1-4) from meso-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3-methoxybenzaldehyde by a diaza-Cope-rearrangement and subsequent ether cleavage with BBr3 and their conversion into the [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-complexes with K2PtCl4 (1-PtCl2 - 4-PtCl2) is described.     

Cellular pharmacology of mu-[1,2-bis(diphenylphosphino)ethane]bis[(1-thio-beta-D-gluco pyranosato-S)gold(I)]: a novel antitumor agent

SK&F 102912 (mu-[1,2-bis(diphenylphosphino)ethane]bis[(1-thio-beta-D- glucopyranosato-S)gold(I)], [(Autg)2(dppe)]) has shown reproducible and significant activity in transplantable murine tumor models and represents a structurally unique class of antineoplastic agents. A number of in vitro studies were performed to elucidate the cellular pharmacology of this gold-containing complex. [(Autg)2(dppe)] is a potent cytotoxic agent in vitro as demonstrated by its ability to inhibit the clonogenic capacity of a variety of tumor cell lines following a brief exposure to the drug. Cell-cycle analysis using HL-60 cells showed that low concentrations (2 microM) of [(Autg)2(dppe)] induced an S-phase block and higher concentrations induced a secondary block at the G1/S boundary. [(Autg)2(dppe)] had several effects on DNA metabolism and structure including preferential inhibition in cells of DNA synthesis (relative to RNA and protein synthesis) and the production of DNA single- and double-strand breaks as measured by alkaline elution. The cytoxic mechanism of this gold complex appears to be distinct from that of the monophosphine-gold complex auranofin.     

1,2-二羟基-5,8-双[[2-[(2-羟基乙基)氨基]乙基]氨基]-9,10-蒽二酮的合成和抗肿瘤活性

从1,2,5,8-四羟基蒽醌出发合成标题化合物(7)及其盐酸盐。波谱测定确认了其结构,体外筛选表明其具有较明显的抗小鼠 P 388白血病细胞活性。     

Tumor inhibiting [1,2-bis(difluorophenyl)ethylenediamine]dichloroplatinum (II) complexes, I: Synthesis.

The synthesis of the diastereomeric 1,2-bis(2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-difluorophenyl)ethylenediamine (meso, D/L 8-13) from meso 1,2-bis(2-hydroxyphenyl)ethylenediamine and the respective difluorobenzaldehyde by a diaza-Cope-rearrangement and their conversion into the [1,2-bis(2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-difluorophenyl)ethylenediamine]dihaloplatinum(II)- complexes (meso, D/L 8-13 PtCl2; meso D/L 9- and 11-PtI2) with K2PtHal4 (Hal = Cl, I) is described. From the diiodoplatinum(II)-complexes (meso D/L 9- and 11-PtI2) the better water soluble diaqua[1,2-bis(2,4- and 2,6-difluorophenyl)ethylenediamine]platinum(II) sulfates (meso, D/L 9- and 11-PtSO4) are obtained by reaction with Ag2SO4.