目的 建立LC-MS/MS法检测2-且兑氧-D-核糖中基因毒性杂质甲磺酸甲酯和甲磺酸乙酯的方法.方法 选用C18色谱柱(以十八烷基硅烷键合硅胶为填充剂,250 mm ×4.6 mm,5μm),以甲醇-水(体积比30∶70)为流动相,流速为1.0 mL· min-1,分流比为30％,柱温为40℃,进样量为10 μL.采用APCI离子源检测扫描方式负离子模式检测.结果 甲磺酸甲酯和甲磺酸乙酯质量浓度在20～200 μg·L-1内与峰面积线性关系良好,甲磺酸甲酯和甲磺酸乙酯的检测限为4 μg·L-1,定量限为10 μg·L-1,甲磺酸甲酯和甲磺酸乙酯的回收率分别为104.8％(RSD=7.93％,n=9)和101.0％ (RSD =5.97％,n=9).结论 本方法灵敏、专属性强,适用于2-脱氧-D-核糖中基因毒性杂质甲磺酸甲酯和甲磺酸乙酯的检测.

Objective To synthesize three specified impurities as reference substances for strengthening quality control of fludarabine phosphate.Methods 6-Amino-9-(5-O-phosphono-β-D-arabinofuranosyl)-9H-purin-2-ol(impurity A)and 2-ethoxy-9-(5-O-phosphono-β-D-arabinofuranosyl)-9H-purin-6-amine(impurity F)were synthesized from 9-(5-O-phosphono-β-D-arabinofuranosyl)-2-fluoro-9H-purin-6-amine(fludarabine phosphate)through substitution reaction,and 9-(3,5-di-O-phosphono-β-D-arabinofuranosyl)-2-fluoro-9H-purin-6-amine(impurity C)was synthesized from 9-β-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine(impurity E)through phosphorylation and hydrolysis.Reversed-phase HPLC was used to purify the impurities.Results Three specified impurities of fludarabine phosphate were obtained,and their structures were identified by HR-MS and NMR.Conclusions The obtained compounds can be used as reference substances for the qualitative and quantitative analysis of fludarabine phosphate related substances.

Objective To prepare methyl(R)-o-chloromandelate(key intermediate for(S)-clopidogrel)and establish the optimal conditions.Methods Methyl 2-chlorobenzoylformate was transformed to methyl(R)-o-chloromandelate by enzyme system of alcohol dehydrogenase and coenzyme in Saccharomyces cerevisiae DM10.Effects of some factors on the asymmetric reduction,including substrate concentrations,initial pH,temperature and reaction time,were studied.Results and conclusion The optimal reaction conditions was obtained:10% inoculums of the conversion solution,substrate concentration was 1 g·L-1,the initial pH value was 6.5,temperature was set at 30 ℃,the reaction was maintained for 36 h,the conversion was 98.75% with the yield of 82.25% and enantiomeric excess of 95.1%.

A series of α-hydroxy esters were rapidly prepared (1.5 h) from α-keto esters via asymmetric transfer hydrogenation (ATH) in water by the use of surfactants for the first time. This green method, catalyzed by a water-soluble and recyclable Ru(II) complex, gave moderate to high enantioselectivities (up to 99.7% ee) with DTAB as an additive and HCOONa as the hydrogen source.

AbstractThe reaction occurs between 2 α‐iminoesters, which can be generated in situ from anilines and ester (II) or introduced directly.

Enantiopure tolvaptan, the first and only oral vasopressin antagonist for hyponatremia has been prepared by using an asymmetric transfer hydrogenation as a key step with HCOOH–Et3N or HCOONa–H2O as the hydrogen donor in open air. Good chemical yields with up to 99% enantioselectivity were obtained with a 1000:1 of S/C in an HCOONa–H2O system. The air and water stable catalysts provide a very promising prospect for industrial application.

Quinazoline derivatives were synthesized from α-iminoesters via a cascade imino-Diels-Alder and then oxidation reaction catalyzed with CuBr2. This method provided a new strategy for preparing quinazoline derivatives which may be useful in the synthesis of heterocyclic intermediates.

Vanadium-catalyzed oxidative kinetic resolution (OKR) of methyl o-chloromandelate 2a, key intermediate of the well-known oral antiplatelet agent (S)-clopidogrel, was achieved by ambient air for the first time. The air oxidation system, which was composed of vanadium and tridentate Schiff base ligands derived from amino alcohols and salicylaldehyde derivatives, afforded an efficient and economic approach to the target intermediate with high enantioselectivities (>99% ee).

A series of chiral tertiary aminonaphthol ligands were prepared from 2-naphthol, (S)-1-phenylethylamine, and aldehydes with diverse substituted groups. The results of asymmetric phenyl transfer to aromatic aldehydes catalyzed by these chiral ligands indicated that enantioselectivities were greatly influenced by the electronic and steric effects of the ligands.

The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C6H2SO2-DPEN as the catalyst and HCOOH-Et3N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition. The synthesis of (S)-Clopidogrel was also studied. (c) 2009 Elsevier B.V. All rights reserved.

Aim To prepare methyl(R)-o-chloromandelate(key intermediate for(S)-clopidogrel) by asymmetric hydrogenation and transfer hydrogenation.Methods Methyl(R)-o-chloromandelate was prepared by asymmetric hydrogenation and asymmetric transfer hydrogenation from methyl o-chlorobenzoylformate.Results and conclusion 64.8% ee was achieved for methyl(R)-o-chloromandelate by asymmetric hydrogenation while enantioselectivity was up to 92.6% ee for the key intermediate for(S)-clopidogrel under an optimal condition by asymmetric transfer hydrogenation.

Sciff bases 1 and 2, which were derived from chiral aminoalcohols, were used as ligands in Ti-catalyzed asymmetric alkynylation of aldehydes. Good enantioselectivities (up to 88% ee) and high chemical yields (80–90%) were obtained.