阿那曲唑合成工艺改进

目的改进芳香化酶抑制剂阿那曲唑的合成工艺。方法以3,5-二甲基苯甲酸为起始原料,经过酯化、溴化、氰化、甲基化、还原、氯代、N-烷基化和去氨基化合成阿那曲唑。结果产物结构经1H-NMR和MS确证。八步反应的总收率为24.2%。结论改进后的合成方法操作简便,适合工业化生产。     

B—内酰胺酶抑制剂—他唑巴坦酸的合成

他唑巴坦是新颖的内酰胺酶抑制剂,以6-APA为原料,经重氮化,溴代等反应制得关键中间体青霉烷酸二苯甲酯-1a-氧化物(4),与2-巯基苯并噻唑缩合后,经氯代得2-氨甲基-2a-甲基-6,6-二氢青霉烷酸二苯甲酯(6),该中间体再经缩合,氧化等步骤得到他唑巴坦酸,总收率16\3%,该法原料易得,反应条件温和,后处理方便,适合大量制备他唑巴坦酸.     

抗真菌药阿莫罗芬的合成

以叔戊基苯为原料 ,经羟甲基化、溴代 ,生成 4 溴甲基叔戊基苯 (2 ) ,再与甲基丙二酸二乙酯缩合 ,水解 ,脱羧 ,制得关键中间体 2 甲基 3 (4 叔戊基苯基 )丙酸 (3) ,与顺 2 ,6 二甲基吗啉成酰胺 ,还原得到阿莫罗芬 .     

β-内酰胺酶抑制剂——他唑巴坦酸的合成

他唑巴坦是新颍的β-内酰胺酶抑制剂,以6-APA为原料,经重氮化、溴代等反应制得关键中间体青霉烷酸二苯甲酯-1α-氧化物(4),与2-巯基苯并噻唑缩合后,经氯代得2β-氯甲基-2α-甲基-6,6-二氢青霉烷酸二苯甲酯(6),该中间体再经缩合、氧化等步骤得到他唑巴坦酸,总收率16.3%。该法原料易得,反应条件温和,后处理方便,适合大量制备他唑巴坦酸。     

青霉素扩环成头孢菌素的研究——Ⅱ.唑啉头孢菌素的合成

作者前曾报道3-溴甲基头孢烯酸二苯甲酯S-氧化物为一重要中间体,可供研制一一系列C_(10)-取代头孢菌素。本文用此中间体探讨唑啉头孢菌素的合成。 专利报道3-溴甲基头孢烯酸酯引入巯     

抗肿瘤药物阿那曲唑的合成方法改进

目的 改进抗肿瘤药物阿那曲唑的合成工艺。方法以1，3，5—三甲苯为起始原料，经过两步溴化、氰化、甲基化和N—烷基化5步反应合成阿那曲唑，在第二步和最后一步反应中使用相转移催化方法。结果 成功地合成阿那曲唑，总收率为28％。结论 改进后的合成方法反应时间明显缩短，操作方法大大简化，所有原料均国产化，更适合于工业化生产。     

抗真菌药阿莫罗芬中间体的合成研究

目的合成阿莫罗芬重要中间体.方法以苯为原料,经Friedel-Crafts烷基化和酰化制备叔戊基苯丙酮,再由叔戊基苯丙酮与甲醛,顺-2,6-二甲基吗啉通过Mannish反应制得顺4-[2-甲基-3-氧代-3-(对叔戊基苯基)丙基]-2,6二甲基吗啉这一重要中间体.结果总收率32.16%.结论目标化合物是合成阿莫罗芬的理想前体.     

硝酸依柏康唑的合成工艺改进

目的改进硝酸依柏康唑的合成方法。方法以3,5-二氯溴苄为起始原料经Wittig反应、氢化、水解、环合4步反应得到关键中间体2,4-二氯-10,11-二氢-5H-二苯并[a,d]环庚烯-5-酮,该中间体经还原、氯代、氮烃化、成盐4步反应合成硝酸依柏康唑。结果与结论目标化合物的结构经质谱、核磁共振氢谱确证。与原工艺路线相比,改进后的路线反应步骤短、操作简单、条件温和,易于工业化生产,总收率为26%(以3,5-二氯溴苄计)。     

β-溴代乙苯的制备

β-溴代乙苯是合成含β-苯乙基的药物及其它芳香族化合物的重要中间体,目前国内无商品供应。β-溴代乙苯的主要制法有苯与1,2—二溴乙烷的付一克烷化,β-苯乙醇的溴代,以及苯乙烯与溴化氢的反马氏加成等,其中以后者最为方便,因其所用原料一般,反应一步完成,收率高。     

高效液相色谱串联质谱法测定人体血浆中阿那曲唑的浓度

目的建立液质联用法来检测人体血浆中阿那曲唑的浓度。方法血浆样品经MTBE萃取后,选用来曲唑为内标。色谱柱为Thermo Hypurity C18柱(2.1 mm×150 mm,5μm);流动相为乙腈-0.1%甲酸(60∶40);流速为0.20 mL.min-1;采用ESI+MRM进行离子方式监测;源电压:3.6 kV;源温度:100℃;阿那曲唑和来曲唑的离子选择通道分别为:m/z294.69→225.41,286.25→217.60。结果阿那曲唑的线性范围为0.214~214 ng.mL-1,最低检测浓度为0.214 ng.mL-1,方法回收率在80%~120%,日内、日间RSD均<15%。结论本方法简单、灵敏,可以准确检测人体血浆中阿那曲唑的浓度。     

LC and LC–MS/MS study of forced decomposition behavior of anastrozole and establishment of validated stability-indicating analytical method for impurities estimation in low dose anastrozole tablets

Anastrozole tablets were subjected to different ICH prescribed stress conditions of thermal, hydrolysis, humidity, photolysis and oxidation stress. The drug was found to be stable for all the stressed conditions except for oxidation. Separation of anastrozole from its potential impurities, degradation products and five anastrozole related compounds as main impurities were achieved on Inertsil ODS-3V, 250 mm × 4.6 mm i.d, 5 μm analytical column using reversed phase high performance liquid chromatography (RP-HPLC). The elution of impurities employed time dependent gradient programmed mobile phase consisting of water as mobile phase-A and acetonitrile as mobile phase-B at column flow rates of 1 ml/min and at 215 nm UV detection. The same method was also extended to LC–MS/MS studies which were carried out to identify the degradation product. The method developed was established to have sufficient intermediate precision as similar separation was achieved on another instrument handled by a different operator. The LOQ for anastrozole related compound-A (RC-A), related compound-B (RC-B), related compound-C (RC-C), related compound-D (RC-D), related compound-E (RC-E) and anastrozole were 0.05, 0.03, 0.03, 0.06, 0.06 and 0.06 μg ml⁻¹ respectively. The linearity of the proposed method for all the above related compounds was investigated in the range of LOQ to 0.600 μg ml⁻¹ respectively. The specificity was established through peak purity testing using a photo-diode array detector. Method was validated according to ICH guidelines and statistical analysis of the data proved to be suitable for stability testing at quality control.     

Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer

Trastuzumab is a humanised IgG1 monoclonal antibody, which selectively binds to the human epidermal growth factor receptor 2 (HER2), inhibiting cell proliferation and survival in HER2-dependent tumours. In a randomised phase III trial in postmenopausal women with HER2 and hormone receptor (HR) co-positive metastatic breast cancer, median progression-free survival (primary endpoint) was significantly longer in patients receiving intravenous trastuzumab plus oral anastrozole than in those receiving anastrozole alone. Overall response rate and clinical benefit rate were also significantly higher, and median time to disease progression was significantly longer with trastuzumab plus anastrozole versus anastrozole alone. There were no reports of new or unexpected adverse events with trastuzumab plus anastrozole combination therapy in the randomised phase III trial. In a noncomparative phase II study of trastuzumab plus letrozole in postmenopausal women with HER2 and HR co-positive metastatic breast cancer, the majority of adverse events were mild or moderate in severity.     

不对称氢化、氢转移反应制备(R)-邻氯扁桃酸甲酯：(S)-氯吡格雷关键中间体的不对称合成

目的 用不对称氢化、氢转移方法制备合成(S)-氯吡格雷的关键中间体——(R)-邻氯扁桃酸甲酯。方法 以α-邻氯扁桃酮酸甲酯为起始原料,分别用不对称氢化和氢转移方法制备(R)-邻氯扁桃酸甲酯。结果与结论 使用不对称氢化方法制备(R)-邻氯扁桃酸甲酯,对映选择性为64.8% ,用氢转移方法,优化催化条件后目标产物的ee值高达92.6%,从而为(S)-氯吡格雷的不对称合成奠定了基础。     

Anastrozole in the management of breast cancer

Anastrozole (Arimidex, AstraZeneca) is a third-generation aromatase inhibitor which rapidly reduces oestradiol concentrations to below detectable levels. It is both potent and selective for the aromatase enzyme, with near-maximal suppression of serum oestrogens occurring at the clinical dose of 1 mg/day in postmenopausal women with advanced breast cancer. Anastrozole has also been shown to be a potent suppressor of intratumoural oestrogens, with responses comparable to those in serum. The results of two large, identically designed, randomised trials in postmenopausal women with advanced breast cancer who had progressed on tamoxifen showed that oral anastrozole 1 mg/day produced a statistically significant survival advantage over megestrol acetate 40 mg q.i.d. The median duration of survival was 26.7 months for anastrozole versus 22.5 months for megestrol acetate. Anastrozole was as well-tolerated as megestrol acetate, while weight gain was significantly increased in the megestrol acetate group compared with the anastrozole group. In another Phase III clinical trial involving 1021 postmenopausal women with advanced breast cancer, anastrozole showed a statistically significant advantage over tamoxifen in median time to progression in a combined analysis of 611 patients who were known to be oestrogen receptor- or progesterone receptor-positive. Anastrozole was as well-tolerated as tamoxifen, with a low rate of withdrawals (2%) due to drug-related adverse events. In addition, anastrozole was associated with fewer thromboembolic events and episodes of vaginal bleeding than tamoxifen. For women with hormone receptor-positive tumours who progress on tamoxifen, anastrozole is superior to megestrol acetate. In addition, anastrozole is a reasonable alternative to tamoxifen for first-line endocrine therapy of advanced breast cancer. Recent data confirm an emerging role for anastrozole as adjuvant therapy for primary breast cancer in postmenopausal patients. Anastrozole is also being investigated in the neoadjuvant setting.     

Anastrozole in the management of breast cancer

Anastrozole (Arimidex?, AstraZeneca) is a third-generation aromatase inhibitor which rapidly reduces oestradiol concentrations to below detectable levels. It is both potent and selective for the aromatase enzyme, with near-maximal suppression of serum oestrogens occurring at the clinical dose of 1 mg/day in postmenopausal women with advanced breast cancer. Anastrozole has also been shown to be a potent suppressor of intratumoural oestrogens, with responses comparable to those in serum. The results of two large, identically designed, randomised trials in postmenopausal women with advanced breast cancer who had progressed on tamoxifen showed that oral anastrozole 1 mg/day produced a statistically significant survival advantage over megestrol acetate 40 mg q.i.d. The median duration of survival was 26.7 months for anastrozole versus 22.5 months for megestrol acetate. Anastrozole was as well-tolerated as megestrol acetate, while weight gain was significantly increased in the megestrol acetate group compared with the anastrozole group. In another Phase III clinical trial involving 1021 postmenopausal women with advanced breast cancer, anastrozole showed a statistically significant advantage over tamoxifen in median time to progression in a combined analysis of 611 patients who were known to be oestrogen receptor- or progesterone receptor-positive. Anastrozole was as well-tolerated as tamoxifen, with a low rate of withdrawals (2%) due to drug-related adverse events. In addition, anastrozole was associated with fewer thromboembolic events and episodes of vaginal bleeding than tamoxifen. For women with hormone receptor-positive tumours who progress on tamoxifen, anastrozole is superior to megestrol acetate. In addition, anastrozole is a reasonable alternative to tamoxifen for first-line endocrine therapy of advanced breast cancer. Recent data confirm an emerging role for anastrozole as adjuvant therapy for primary breast cancer in postmenopausal patients. Anastrozole is also being investigated in the neoadjuvant setting.     

Is long-term adjuvant treatment of breast cancer with anastrozole indicated?

Background: Tamoxifen is the established adjuvant treatment for postmenopausal women with hormone-sensitive breast cancer. Objective: To determine whether the aromatase inhibitor anastrozole should replace tamoxifen as the adjuvant treatment in this cancer. Methods: Two recent trials of anastrozole and tamoxifen as adjuvant treatment were evaluated. Results/conclusion: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial showed that 5 years of adjuvant therapy with anastrozole reduced recurrence of breast cancer to a greater extent than did tamoxifen. The Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a showed that after 5 years of adjuvant treatment with tamoxifen more benefit was achieved by continuing with adjuvant anastrozole for 3 years than no further treatment. Although the long-term adjuvant treatment of hormone receptor positive breast cancer with anastrozole is indicated, questions remain as to how long the adjuvant treatment with anastrozole should continue.     

Anastrozole: a review of its use in postmenopausal women with early-stage breast cancer

Anastrozole (Arimidex) is an aromatase inhibitor approved in the EU, the US and in other countries worldwide for use as an adjuvant treatment in postmenopausal women with early-stage, hormone receptor-positive breast cancer. It is also approved in the EU and other countries worldwide for continuing adjuvant treatment in women who have already had 2-3 years of adjuvant tamoxifen treatment for breast cancer.Anastrozole is an effective primary adjuvant treatment for postmenopausal women with early-stage breast cancer. In patients with hormone receptor-positive tumours, 5 years of anastrozole treatment was more efficacious in reducing breast cancer recurrence than 5 years of tamoxifen, both in a head-to-head comparison and in switching trials when given after 2-3 years of tamoxifen treatment. The treatment benefits have now been shown to extend to 100 months following breast surgery. To date, overall survival was better in anastrozole than tamoxifen recipients in one switching trial and in a meta-analysis of three switching trials. There was no increased benefit in health-related quality of life with anastrozole over tamoxifen. In women who had received 5 years of tamoxifen treatment, continuation of treatment with anastrozole further reduced the risk of breast cancer recurrence. Ongoing head-to-head trials against other third-generation aromatase inhibitors will provide data as to its relative efficacy against these agents. Anastrozole is a generally well tolerated treatment for early-stage breast cancer. Like other aromatase inhibitors, its most important adverse effect was an increased risk of bone fractures, which for anastrozole was restricted to the treatment period. It is still unclear whether primary adjuvant treatment extended beyond 5 years is of benefit and whether primary adjuvant treatment with anastrozole for 5 years is preferable to switching to anastrozole after 2-3 years of tamoxifen treatment. However, the evidence to date establishes anastrozole as a valuable adjuvant and extended adjuvant treatment for postmenopausal women with hormone receptor-positive, early-stage breast cancer.     

Development and validation of an improved high-throughput method for the determination of anastrozole in human plasma by LC-MS/MS and atmospheric pressure chemical ionization

In the present study, an automated, 96-well format LC-MS/MS method for the determination of anastrozole in human plasma was developed and fully validated. Within method development procedure, atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI) were compared in terms of sensitivity and specificity, with the former proven to be more appropriate and thus being chosen for analyte ionization. In addition, the effect of declustering potential (DP) and collision energy (CE) in sensitivity was, as well, studied and compared between APCI and ESI source employment. Samples were treated with an acetonitrile (ACN) protein precipitation step followed by liquid-liquid extraction (LLE) with methyl t-butyl ether (MTBE) as the organic solvent, using omeprazole as the internal standard (IS). The statistical evaluation for the APCI protocol revealed excellent linearity, accuracy and precision values for the range of concentrations 0.100-100 ng/mL. The method proposed involves the lowest plasma volume so far reported (190 microL), as well as the shortest run time (1.6 min) and along with the employment of two robotic liquid handling systems enabled the rapid and reliable determination of anastrozole in a bioequivalence study (>1000 plasma samples) after per os administration of 1mg tablet within a 4-day period of time.