他米巴罗汀的合成

2,5-二甲基-2,5-己二醇经氯代后与苯进行Friedel-Crafts反应制得1,2,3,4-四氢-1,1,4,4-四甲基萘,再经硝化、还原、与4-氯甲酰基苯甲酸甲酯缩合、水解制得他米巴罗汀,总收率约20%.     

抗白血病药他米巴罗汀的合成工艺改进

目的 改进抗白血病药他米巴罗汀的合成工艺。方法 以2,5-二甲基-2,5-己二醇为起始原料,经傅克反应、水解、酰化、水解 4步反应制得目标化合物他米巴罗汀。结果与结论 目标化合物的结构经IR、1H-NMR、ESI-MS谱及元素分析确证,总收率为38.8%,该合成路线反应步骤短,操作简便,成本低廉,有利于工业化生产。     

枸橼酸托瑞米芬的合成工艺优化

目的枸橼酸托瑞米芬合成工艺优化。方法以4-羟基二苯甲酮为原料,经缩合,还原、氯代、成盐等四步合成枸橼酸托瑞米芬。结果反应总收率约为60.0%,产物经红外光谱、核磁共振、高分辩质谱确证结构。结论该优化合成工艺反应温和、操作简单、收率高、纯度好、污染小、易工业化生产。     

右兰索拉唑的合成工艺研究

目的 对右兰索拉唑的合成工艺进行研究。方法 以4-氯-2,3-二甲基吡啶-N-氧化物为起始原料,经酰化、水解、氯代、取代反应得到兰索拉唑硫醚,再进行不对称氧化、取代反应获得右兰索拉唑。结果 合成右兰索拉唑对映体过量值（ee值）为99.5%,总收率为21.6%。结论 改进后的工艺成本低、操作方法简单、后处理容易、收率高、产物纯度高、可用于工业放大生产。     

甲磺酸伊马替尼的合成工艺改进

目的改进甲磺酸伊马替尼的合成工艺。方法以4-[（4-甲基哌嗪-1-基）甲基]苯甲酰氯二盐酸盐与4-甲基-N3-[4-（3-吡啶基）嘧啶-2-基]-1,3苯二胺为起始原料,进行水相缩合反应得到伊马替尼游离碱,再与甲磺酸成盐,两步反应合成新型酪氨酸酶抑制剂类抗肿瘤药物伊马替尼。结果优化后的工艺成本低廉、后处理简便、产品纯度高、收率高,并且对环境污染小。纯度可达99.7%,且单一杂质〈0.1%。结论新工艺的总收率达81.5%,可工业化生产,前景广阔。目标产物结构经1H NMR,ESI-MS得到结构确证。     

吡非尼酮的合成及结构确证

目的：合成抗纤维化药物吡非尼酮。方法以2-氨基-5-甲基吡啶为原料,经重氮化水解为5-甲基-2（1H）-吡啶酮,再经N-芳基化反应得到吡非尼酮。结果合成的吡非尼酮经高分辨质谱、紫外吸收光谱、红外吸收光谱、核磁共振谱、质谱和热分析确证结构,总收率为49.0%,纯度≥99.9%。结论该合成工艺操作简便,收率高,纯度高,是合成吡非尼酮的较好方法。     

琥珀酸舒马曲坦的合成工艺改进

目的:改进琥珀酸舒马曲坦的合成工艺。方法:以4-肼基-N-甲基-苄基磺酰胺盐酸盐与4,4-二甲氧基-N,N-二甲基-丁胺为起始原料,改用多聚磷酸和磷酸二氢钠作为催化剂,后处理采用异丙醚和丙酮作为重结晶溶剂,经缩合、重排、环合、成盐的4步反应合成琥珀酸舒马曲坦。结果:获得纯度和收率均较满意的目标产物,总收率由文献报道的8.5%提高到12.7%。结论:此改进后的合成工艺成本低,操作简便易行,适于工业化生产。     

盐酸美金刚胺的合成工艺改进

目的改进盐酸美金刚胺的合成工艺。方法以1,3-二甲基金刚烷为原料,在叔丁醇、乙腈、浓硫酸存在下,经Ritter反应生成1-乙酰胺基-3,5-二甲基金刚烷,再以聚乙二醇为溶剂,加入氢氧化钠水解得到美金刚胺,然后在异丙醇溶剂中盐酸化得到盐酸美金刚胺。总收率：70%。结果合成了具有良好化学纯度的盐酸美金刚胺（纯度99.9%,总收率70%）。结论改进的工艺明显提高了反应收率,工艺条件温和,合成步骤简洁,适合工业化生产。     

药用1,3-二甲基戊胺盐酸盐的合成工艺改进

目的合成1,3-二甲基戊胺盐酸盐并改进其工艺。方法 以乙酰乙酸乙酯和2-溴丁烷为原料,经4步合成反应得到1,3-二甲基戊胺盐酸盐,并采用单因素考察法对合成工艺进行改进。结果1,3-二甲基戊胺盐酸盐各步反应的收率均>40%,产物总收率达到12.3%。结论产物结构经1 H-NMR和13 C-NMR确认为1,3-二甲基戊胺盐酸盐。     

吉非罗齐的合成

目的:合成吉非罗齐,并进行工艺改进。方法:以2 ,5-二甲基苯酚为起始原料,与1-氯-3-溴丙烷反应,得3-( 2 ,5-二甲基苯氧基)-1-氯丙烷,再与异丁酸钠锂作用,制得吉非罗齐。结果:通过两步反应制得产物,总收率4 3.8%。醚化反应经优化后收率较文献提高30 %以上。合成产物经红外光谱、核磁共振谱及质谱确证。结论:缩短了反应步骤,提高了反应收率。     

高效液相色谱法测定他米巴罗汀胶囊的含量

目的建立他米巴罗汀胶囊含量测定方法。方法采用高效液相色谱法(HPLC)进行测定,色谱柱为CEC-C8柱(150 mm×4.6 mm,5μm),流动相为乙腈-0.1%磷酸-甲醇(1∶1∶1),检测波长为235 nm。结果他米巴罗汀在2.51~40.12μg/mL浓度范围内,峰面积与浓度呈良好的线性关系,r=0.999 9;重复性试验的RSD为0.12%(n=6),最低检测限为0.2 ng,平均回收率为99.60%,他米巴罗汀主峰与辅料有良好分离。结论此法简单、灵敏、专属性强、重现性好,结果准确可靠,适用于他米巴罗汀胶囊的质量控制。     

贝沙罗汀的合成工艺研究

目的 研究贝沙罗汀的合成工艺。方法 以2,5-二甲基-2,5-己二醇为起始原料,经卤代、Friedel-Crafts烷基化反应、Friedel-Crafts酰化反应、Wittig反应、水解5步反应制得贝沙罗汀。结果与结论 目标化合物的结构经¹H-NMR和MS谱确证,总收率为37.2％。改进后的工艺操作简便,有利于工业化生产。     

吉非罗齐的合成

目的：合成吉非罗齐,并进行工艺改进。方法以２,５－二甲基苯酚为起始原料,与１－氯－３－溴丙烷反应,得３－（２,５－二甲基苯氧基）－１－氯丙烷,再与异丁酸钠锂作用,制得吉非罗齐。结果：通过两步反应制得产物,总收率４３．８％,醚化反应经优化后收率较文献提高３０％以上。合成产物经红外光谱,核磁共振谱及质谱确证。结论：缩短了反应步骤,提高了反应收率。     

Design,synthesis, and biological characterization of tamibarotene analogs as anticancer agents

In our efforts of developing novel compounds as potential anticancer agents, a series of tamibarotene analogs containing Zn²⁺‐binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC₅₀ of 1.8 ± 0.1 μm , thus suggesting that this could contribute to the improved antiproliferative activities of 7b . Pharmacokinetic studies revealed that compound 7b could release tamibarotene after administration and prolong the circulation time of tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.     

马来酸伊索拉定的合成

从２，５－二氯甲苯经４步反应合成新型抗溃疡药马来酸伊索拉定，总收率３５．４％。     

The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione: II. Dimethyl substitution accelerates pyrrole formation and protein crosslinking

3,4-Dimethyl-2,5-hexanedione and 2,5-hexanedione were reacted with model amines to yield N-substituted 2,3,4,5-tetramethylpyrroles and 2,5-dimethylpyrroles, respectively. When compared to the unsubstituted parent compound 2,5-hexanedione, 3,4-dimethyl-2,5-hexanedione was found to cyclize approximately eight times as rapidly on a molar basis at 37°C, with an activation energy of 3290 cal/mole less than 2,5-hexanedione. In addition, 1-benzyl-2,3,4,5-tetramethylpyrrole oxidized more readily than 1-benzyl-2,5-dimethylpyrrole with a difference in the half-wave potentials of 0.29 V. Both γ-diketones led to progressive crosslinking of proteins in vitro, with the dimethyl substitution accelerating this process by a factor of 40. The formation of pyrrolyl derivatives in vivo was demonstrated by the characteristic absorption spectra obtained following reaction of erythrocyte proteins from intoxicated rats with Ehrlich's reagent. There was progressive formation of protein-bound dimethylpyrroles following exposure to 2,5-hexanedione and formation of tetramethylpyrroles following exposure to 3,4-dimethyl-2,5-hexanedione in vivo. Preparations of axonal pads also demonstrated pyrrole derivatization in vivo. In addition, spectrin preparations of erythrocytes from intoxicated rats showed a large amount of high molecular weight protein (400,000 Da), corresponding to dimerized spectrin. Thus, 3,4-dimethyl-2,5-hexanedione, which is 20 to 30 times more potent on a molar basis than 2,5-hexanedione in leading to a neurofilamentous neuropathy, is associated with more rapid pyrrole formation and protein crosslinking in vitro, and it has been demonstrated that these processes occur in vivo. These observations support the hypothesis that pyrrole formation and autoxidation occur following exposure to γ-diketones, leading to covalent crosslinking of proteins in vivo, a process which may explain the pathogenesis of neurofilament accumulation in these neuropathies.     

Synthesis of fluorosugar analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole as antivirals with potentially increased glycosidic bond stability

The metabolic instability in vivo of the glycosidic bond of 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole , 2,5, 6-trichloro-1-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole, and 2-bromo-5, 6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3',5'-ditrityl derivatives, which were fluorinated with DAST and deprotected to yield 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole and 2,5, 6-trichloro-1-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low overall yield (5%) of 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5, 6-trichlorobenzimidazole was condensed with 1-bromo-3, 5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.     

Tamibarotene

Tamibarotene is a new synthetic retinoid drug recently approved for relapsed or refractory acute promyelocytic leukemia (APL) in Japan. It is a specific agonist for retinoic acid receptor alpha/beta. Compared to all-trans retinoic acid (ATRA), a natural retinoid indicated for a first-line treatment of APL, tamibarotene is chemically more stable and several times more potent as an inducer of differentiation in promyelocytic leukemia cells. In contrast to ATRA, whose plasma concentration declines considerably during daily administration, tamibarotene sustains plasma level probably due to a lower affinity for cellular retinoic acid binding protein. Furthermore, adverse side effects were milder than those of ATRA in clinical trials. Clinical trials held in Japan showed that tamibarotene had efficacy in APL patients who had relapsed from ATRA-induced complete remission. Recently, better understanding of the various mechanisms of action of retinoids has stimulated great interest in its potential use for treatment of various diseases. Tamibarotene is being investigated for treatment of multiple myeloma and Crohn's disease in clinical trials. This review focuses on tamibarotene's mechanisms of action, chemical properties, pharmacokinetics and its use in APL as well as its potential use in various disorders.     

Synthesis and analgesic activities of 2,5-dimethyl-2'-hydroxy-9alpha- and -beta-propyl-6,7-benzomorphans.

The 2,5-dimethyl-2'-hydroxy-9alpha- and-beta-propyl-6,7-benzomorphans were synthesized from 4-methyl-3-propylpyridine in five steps, in an overall yield of 14 and 5%, respectively. The required 4-methyl-3-propylpyridine was prepared in an overally yield of 34% by a four-step sequence. The benzomorphans were about as potent as, or more potent than, morphine in vivo.