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。方法以三乙氧基膦为原料,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。     

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。     

2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

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。     

N-(双膦羧次甲基)-6-(5-氟-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基)-6-氧代-己酰胺的合成及其初步的骨靶向性研究

目的合成N-（双膦羧次甲基）-6（5-氟-2，4-二氧代3，4-二氢-2H-嘧啶-1-基）-6-氧代-己酰胺，并进行初步体外骨靶向性实验。方法以5-氟尿嘧啶为原料，经硅烷化、缩合、氢解3步合成6-（5-氟-2，4-二氧代-3，4-二氢-2H-嘧啶-1-基）-6-氧代-己酸（2），用二氯亚砜氯化后再与含氨基的偕二膦酸酯偶联，最后再用溴代三甲基硅烷特异性解离掉膦酸酯得到目标化合物L，并采用羟磷灰石晶体吸附实验考察目标物的骨靶向性。结果合成了目标物L，并利用^-1H—NMR、IR和MS进行了结构确证。结论体外骨靶向性实验结果显示目标物L有较好的骨靶向性。     

2-正丁基-4-氯-5-甲酰基咪唑的合成新路线

目的：合成抗高血压药氯沙坦的关键中间体2-正丁基-4-氯-5-甲酰基咪唑。方法：戊腈与甲醇在甲醇钠的作用下加成得到1-甲氧基-1-亚胺戊烷（2）,经取代、环合得到目标化合物2-正丁基-4-氯-5-甲酰基咪唑（1）。结论：本工艺具有试剂易得,反应条件温和,收率高（59.02%）的特点,适合工业化生产。     

抗肿瘤药物舒尼替尼的新合成方法

目的 研究抗肿瘤药物舒尼替尼的新合成路线。方法 以4-氟-2-碘苯胺（3）为原料,经氯乙酰化、膦酰化、Horner-Emmons-Wittig反应得N-[2-(二乙胺基)乙基]-5-[(E)-2-(4-氟-2-碘代-苯胺基甲酰基)-乙烯基]-2,4-二甲基-1H-吡咯-3-甲酰胺（6）;6在醋酸钯和三乙胺的作用下,通过分子内5-exo型环合反应得舒尼替尼。结果与结论 新中间体及舒尼替尼结构经核磁共振谱和质谱确证,合成路线未见报道。     

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。     

咪达那新的合成工艺研究

目的 对咪达那新的合成工艺进行研究。方法 以二苯乙腈为起始原料,与1,2-二溴乙烷经相转移反应生成4-溴-2,2-二苯基丁腈（1）,化合物1在三乙胺存在下,于N,N-二甲基甲酰胺–二甲基亚砜中与2-甲基咪唑反应,生成4-(2-甲基-1H-咪唑-1-基)-2,2-二苯基丁腈（2）,化合物2在70%硫酸溶液中,经水解、精制得咪达那新。结果 该合成工艺总收率为40.2%,终产物质量分数为99.9%。结论 工艺改进后,简化了操作过程,提高了咪达那新的收率。     

多靶点叶酸拮抗剂—培美曲唑的合成

目的改进多靶点叶酸拮抗剂-培美曲唑的合成工艺。方法以4-溴苯甲酸乙酯和3-丁炔-1-醇为起始原料,经钯（0）催化偶联、氧化、溴代,再同2,4-二氨基吡啶环合,得到4-[2-（2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基）乙基]苯甲酸甲酯（4）。4经皂化、酸化,同L-谷氨酸二乙酯部分缩合,得到N-[4-[2-（2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基）乙基]苯甲酰基]-L-谷氨酸二甲酯（2）。2和对甲苯磺酸成盐,再经皂化、酸化,得到培美曲唑（pemetrexed,1）。培美曲唑经中和,冷冻干燥,得到临床应用的培美曲唑二钠盐。结果与结论改进了培美曲唑的合成工艺,产物经^1H-NMR、MS确证结构,总收率为39.2%（文献收率36.8%）。     

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.     

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.     

Automated commercial synthesis system for preparation of O‐(2‐[18F]fluoroethyl)‐L‐tyrosine by direct nucleophilic displacement on a resin column

A slightly modified automated commercial synthesis system for preparation of O‐(2‐[¹⁸F]fluoroethyl)‐l‐tyrosine (FET), an amino acid tracer for tumor imaging with positron emission tomography, is described. Direct nucleophilic fluorination of [¹⁸F]fluoride with 1,2‐di(4‐methylphenylsulfonyloxy)ethane on a quaternary 4‐(4‐methylpiperidinyl)‐pyridinium functionalized polystyrene anion exchange resin gave 1‐[¹⁸F]‐2‐(4‐methylphenylsulfonyloxy)ethane, then [¹⁸F]fluoroalkylation of l‐tyrosine yielded FET. The overall radiochemical yield with no decay correction was about 8–10%, the whole synthesis time was about 52 min, and the radiochemical purity was above 95%. Copyright © 2003 John Wiley & Sons, Ltd.     

Comparison of the Disposition of Ester Prodrugs of the Antiviral Agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA] in Caco-2 Monolayers

Purpose. To evaluate the potential of several bis-ester prodrugs of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) to enhance the oral absorption of PMEA. Methods. Caco-2 monolayers were used to estimate intestinal transport and metabolism of the bis(pivaloyloxymethyl)-ester [bis(POM)-] and a series of bis(S-acyl-2-thioethyl)-esters [bis(SATE)-] of PMEA. An LC-MS method was used for the identification of unknown metabolites which were formed from the SATE-esters. Results. During transport across Caco-2 monolayers, all esters were extensively degraded as could be concluded from the appearance of the mono-ester and free PMEA in apical as well as basolateral compartments. Incubation of SATE-esters with the monolayers resulted in the formation of two additional metabolites, which were identified as 2-thioethyl-PMEA and its dimerisation product. All ester prodrugs resulted in enhanced transepithelial transport of total PMEA (i.e. the bis-esters and their corresponding metabolites, including PMEA), but significant differences could be observed between the various esters. Transport of total PMEA ranged from 0.4 ± 0.1 % for the bis[S(methyl) ATE]-ester to 15.3 ± 0.9% for the more lipophilic bis[S(phenyl)ATE]-PMEA. A relationship between total transport of the esters and their lipophilicity (as estimated by their octanol/water partition coefficient) was established (r² = 0.87). Incubation of prodrug esters with homogenates from Caco-2 cells showed large differences in susceptibility of the compounds to esterases, the half-lives of the bis-esters varying from 4.3 ± 0.3 min for the bis[S(phenyl)ATE]-PMEA to 41.5 ± 0.8 min for its methyl analogue. In addition, intracellularly formed PMEA was observed to be further converted by the cells to the diphosphorylated PMEA (PMEApp). Conclusions. Several SATE-esters of PMEA can be considered as potential alternatives to bis(POM)-PMEA, due to enhanced epithelial transport, sufficient chemical and enzymatic stability and adequate release of PMEA. Toxicological studies as well as in vivo experiments are required in order to further explore the potential of those SATE-esters as prodrugs for oral delivery of PMEA.     

Synthesis of Brostallicin (PNU‐166196A) Labelled with 2H and 14C

Brostallicin (PNU‐166196A), a DNA minor groove binder, has been labelled with ²H and ¹⁴C. The preparation of the deuterium specifically labelled [²H₄]brostallicin was achieved according to a nine‐step sequence starting from 1,2‐diamino[1,1,2,2‐²H₄]ethane (1) . [¹⁴C]Brostallicin was obtained via a four‐step procedure in 31% overall radiochemical yield starting from 1‐methyl‐4‐nitropyrrole‐2‐[¹⁴C]carboxylic acid (9) . Copyright © 2002 John Wiley & Sons, Ltd.     

N‐Arylation of indoles with 4‐[18F]fluoroiodobenzene: synthesis of 18F‐labelled σ2 receptor ligands for positron emission tomography (PET)

The palladium‐mediated N‐arylation of indoles with 4‐[¹⁸F]fluoroiodobenzene as a novel radiolabelling method has been developed. Optimized reaction conditions were elaborated by variation of different catalyst systems (CuI/1,2‐diamines and Pd₂(dba)₃/phosphine ligands), bases and solvents in the reaction of indole with 4‐[¹⁸F]fluoroiodobenzene. Optimized reaction conditions (Pd₂(dba)₃/(2‐(dicyclohexyl‐phosphino)‐2′‐(N,N‐dimethylamino)‐biphenyl, NaOBu^t, toluene, 100°C for 20 min) were applied for the synthesis of ¹⁸F‐labelled σ₂ receptor ligands [¹⁸F]‐11 and [¹⁸F]‐13 which were obtained in 91 and 84% radiochemical yields, respectively. Copyright © 2004 John Wiley & Sons, Ltd.     

A mechanistic study of the metabolism of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD) to 2,2-bis(p-chlorophenyl)acetic acid (DDA)

The metabolism of [1-²H]-1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD-d) and [1-²H]-1-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU-d) and their corresponding non-deuterated isomers DDD and DDMU was studied in female Swiss mice over a 96-hr period. The only detected urinary metabolite of DDD-d and DDD was 2,2-bis(p-chlorophenyl)acetic acid (DDA). Animals administered DDD excreted ～2.4-fold more DDA than those treated with DDD-d over the total collection period. The initial (0–36 hr) linear excretion rates of DDA for DDD and DDD-d were 17.1 and 5.5 μg/hr respectively. DDMU- and DDMU-d-treated mice excreted significant quantities of DDA, 2,2-bis(p-chlorophenyl)ethanol (DDOH) and 2,2-bis(p-chlorophenyl)ethanal (DDCHO). The only quantitative difference between DDMU and DDMU-d was that the non-deuterated isomer afforded ～1.8 times more DDA over the 96-hr collection. The initial (0–36 hr) linear excretion rates of DDMU and DDMU-d were 10.7 and 6.2 μg/hr respectively. The qualitative and quantitative results are consistent with DDD being metabolized to DDA via enzyme-mediated hydroxylation on the C-1 side chain carbon.     

Synthesis and biological evaluation of a novel asymmetrical 99mTc‐nitrido complex of metronidazole derivative

The novel dithiocarbamate derivative of metronidazole, potassium 2‐(2‐methyl‐5‐nitro‐1H‐imidazolyl)‐ethyl‐dithiocarbamate (MNIE‐DTC), was synthesized as the pharmacophore‐containing bifunctional ligand. The corresponding asymmetrical ^99mTc‐nitrido complex, expected as a tumor hypoxia marker, had been successfully obtained by the addition of the biphosphine ligand PNP5 (PNP5 = N‐ethoxethyl‐N,N‐bis[2‐(bis(3‐methoxypropyl)phosphino)ethyl]‐amine) and the dithiocarbamate ligand (MNIE‐DTC) to the ^99mTc‐nitrido precursor solution at 100°C for 15 min. The radiochemical purity of the product was above 95% as measured by thin‐layer chromatography and high‐performance liquid chromatography. In vitro studies showed that the complex possessed good stability under physiological conditions. Its partition coefficient studies indicated that it was a lipophilic complex. The electrophoresis results showed that the complex was cationic. Biological evaluation of the complex [^99mTcN(PNP5)(MNIE‐DTC)]⁺ performed in Kunming mice bearing H22 tumor showed that the complex had a moderate tumor uptake (0.57±0.06%ID/g at 1h), and the ratios of tumor/blood and tumor/muscle were 2.46 and 1.31 at 1h p.i., and reached 4.52 and 2.86 at 4h p.i., respectively. Copyright © 2007 John Wiley & Sons, Ltd.