埃索美拉唑镁的合成

2-羟甲基-3,5-二甲基-4-硝基吡啶经氯化亚砜氯化后得2-氯甲基-3,5-二甲基-4-硝基吡啶盐酸盐(3),3与5-甲氧基-2-巯基苯并咪唑缩合得5-甲氧基-2[(3,5-二甲基-4-硝基-2-吡啶基)甲硫基]-1H苯并咪唑(4),4经不对称氧化得5-甲氧基-2-[[(3,5-二甲基-4-硝基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(5),5再通过甲氧基化后得埃索美拉唑钠(6),最后6与氯化镁反应得埃索美拉唑镁,总收率约73.6％(以2-羟甲基-3,5-二甲基-4-硝基吡啶计).     

罗氟司特的合成

3,4-二羟基苯甲醛与二氟一氯甲烷醚化得到3-羟基-4-二氟甲氧基苯甲醛,与氯甲基环丙烷醚化得到3-环丙基甲氧基-4-二氟甲氧基苯甲醛,再经氧化、氯代后与4-氨基-3,5-二氯吡啶反应,制得慢性阻塞性肺病治疗药罗氟司特,总收率约23％.     

2-氯甲基-3，4-二甲氧基吡啶盐酸盐的制备

2-氯甲基 - 3,4-二甲氧基吡啶盐酸盐 (1 )是制备质子泵抑制剂泮托拉唑的重要中间体。文献 [1,2 ]以3-羟基 - 2 -甲基吡啶为起始原料 ,经氧化、硝化、醚化制得 6,再经乙酸化、水解、氯化制得 1。文献 [3] 报道以 3-甲氧基 - 2 -甲基 - 4-吡啶酮 (3)为起始原料 ,经氯化、氧化、醚化制得 6再制得 1。由于 3-羟基 - 2 -甲基吡啶没有国产品 ,而以国产麦芽酚 (2 -甲基 - 3-羟基 -γ-吡喃酮 ,2 )通过两步反应可制得 3。因此 ,参照文献[1～ 3] ,并对其工艺进行改进 ,制备了 1。文献[4 ] 报道3的制备是在 Ag2 O存在以下以 CH3I醚化 ,本文改用硫酸二…     

奥美拉唑产品中二种杂质的制备

为对奥美拉唑产品中的杂质进行定量控制,以2-巯基-5-甲氧基-IH-苯并咪唑和2-氯甲基-3,5-二甲基-4-甲氧基吡啶经缩合、氧化制得2个奥美拉唑杂质--5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基)甲磺酰基]-1H-苯并咪唑和5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基-1-氧化物)甲磺酰基]-1H-苯并咪唑,并经核磁共振和质谱确证结构.     

奥美拉唑的合成

2,3，5-三甲基吡啶经氧代、硝化、在乙酐中重排、水解及氯代制得2-氯甲基-3，5-二甲基-4-硝幕吡啶盐酸盐，与2-巯基-5-甲氧基苯并咪唑在甲醇钠作用下同时完成缩合、甲氧基化得到5-甲氧基-2-[（4-甲氧基-3，5-二甲基吡啶-2-基）甲硫基]-1H-苯并咪唑，最后氧化得到奥美拉唑，总收率约42％。     

5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸的合成

目的制备5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸。方法以2-甲基-6-氯-3-硝基吡啶为原料,经Williamson合成法制得2-甲基-6-甲氧基-3-硝基吡啶,再经Reissert合成法制得终产物。结果反应总收率33%,产物结构由1H-NMR光谱确证。结论该方法简单、原料价廉易得,后处理容易,副产物较少,适于工业化生产。     

H~+、K~+-ATP酶抑制剂Pantoprazole Sodium

合成反应是由3-甲氧基-2-甲基-4硝基吡啶-N-氧化物(Ⅰ)或4-氯-3-甲氧基-2-甲基吡啶-N-氧化物(Ⅱ)在热的甲醇中和甲醇钠反应产生3,4-二甲氧基-2-甲基吡啶-N-氧化物(Ⅲ),Ⅲ在90℃酸酐中异构化,并用NaOH水解转化为2-羟甲基-3,4-二甲氧基吡啶(Ⅳ),Ⅳ和SOCl_2在CH_2Cl_2起反应生成相应的2-氯甲基-3,4-二甲氧基吡啶鎓盐(Ⅴ);Ⅴ和5-二氟甲氧基-2-巯基苯并咪唑(Ⅵ),在热甲醇中通过NaOH缩合产生5-(二氟甲氧基)-2[[(3,4-二甲氧基-2-吡啶     

(6R,7R)-7-苯甲酰胺基-3-氯甲基-7-甲氧基-8-氧代-5-氧杂-1- 氮杂二环[4.2.0]辛-2-烯-2-羧酸二苯甲酯的合成

6-APA经酰化、氧化和羧基保护“一锅法”得到[2S-（2α，5α，6α）]-6-苯甲酰胺基-3，3-二甲基-4，7-二氧代-4-硫杂-1-氮杂二环[3．2．0]庚烷-2-羧酸二苯甲酯，再经重排、氯代、水解得[1R-[1α，5α]]-3-羟甲基-2-（7-氧代-3-苯基-4-氧杂-2,6-二氮杂二环[3．2．0]庚-2-烯-6-基）-3-丁烯酸二苯甲酯，与BF3·Et2O闭环后经氯加成、消除和甲氧基化等反应制得目标化合物，总收率约30％。     

艾司奥美拉唑钠有关物质的合成

目的合成艾司奥美拉唑钠产品中两个N-吡啶取代杂质,加强其质量控制。方法以奥美拉唑硫醚和2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐为起始原料,经取代反应得到奥美拉唑硫醚N-吡啶取代物(A),再经不对称氧化反应得到N-(4-甲氧基-3,5-二甲基-2-吡啶)甲基艾司奥美拉唑(B)。结果与结论目标化合物的结构经过质谱、核磁确证,纯度均大于98.0%,可用于艾司奥美拉唑钠产品研究质量控制的对照品。本工艺所用原料易得,成本低,纯度高。     

(2R,3S)-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐酸盐的合成

对甲氧基苯甲醛(3)和2-氨基乙醇进行还原胺化反应得2-(4-甲氧基苄胺基)乙醇(4),4和乙醛酸经成环反应得2-羟基-4-对甲氧基苄基吗啉-3-酮(5),5和三氟乙酐反应得6后与(R)-1-[3,5-二(三氟甲基)苯基]乙醇(7)缩合,再经结晶诱导不对称转化、格氏反应、氢化脱保护及成盐反应制得阿瑞吡坦关键中间体(2R,3S)-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐酸盐,总收率约18%(以3计)。     

Structural identification and characterization of potential impurities of pantoprazole sodium

Six impurities in pantoprazole sodium bulk drug substance were detected by a simple high performance liquid chromatographic method (HPLC) whose area percentage ranged from approximately 0.05 to 0.34%. Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the molecular weight of the impurities. A thorough study was undertaken to characterize these impurities. These impurities were synthesized, subsequently characterized and were co-injected with the sample containing impurities and found the retention time match of the spiked impurities. Based on their spectral data (IR, NMR and MS), these impurities were characterized as; 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (Impurity-I); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (Impurity-II); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-1-oxide-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole (Impurity-III); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1-((3,4-dimethoxy-2-pyridinyl)methyl)-1H-benzimidazole (Impurity-IV); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1-((3,4-dimethoxy-2-pyridinyl)methyl)-1H-benzimidazole (Impurity-V); 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-1-oxide-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (Impurity-VI). The formation of these impurities was proposed. The structure of the Impurity-II was unambiguously confirmed by single crystal X-ray diffraction (XRD) studies.     

泮托拉唑钠肠溶片在健康中国人体内的药动学研究及生物等效性评价

目的评价健康受试者单剂量口服两种泮托拉唑钠肠溶片的人体药动学与生物等效性。方法采用两种制剂两周期随机交叉试验设计,HPLC-UV法测定20名男性健康受试者单剂量口服40mg国产泮托拉唑钠肠溶片和进口泮托拉唑钠肠溶片后泮托拉唑的血药浓度。采用非室模型计算药动学参数。AUC,Cmax对数转换后进行方差分析并计算90%可信区间。结果国产和进口泮托拉唑钠肠溶片的药动学参数分别为：Cmax（3610±956）,（3466±1209）ng·mL^-1,tmax（3.00±0.40）,（3.00±0.46）h,AUC0–t（8140±5065）,（8390±5474）ng·h·mL^–1,AUC0–∞（8293±5094）,（8625±5606）ng·h·mL^–1。t1/2（1.61±0.28）,（1.85±0.27）h。结论国产和进口泮托拉唑钠肠溶片具有生物等效性。     

泮托拉唑钠冻干粉针剂生产工艺考察

目的:探讨泮托拉唑钠冻干粉针剂的生产工艺研究。方法:通过调节pH及加入适当比例的依地酸二钠(EDTA-2Na)使泮托拉唑钠冻干粉针达到良好的物理性质。结果:加入0.2%EDTA-2Na及配制好的泮托拉唑钠药液pH调到10.8～11,制成的粉针剂外观及溶液稳定性良好。结论:该方法较好地解决了泮托拉唑钠冻干粉针剂生产过程中出现的问题。     

利奈唑胺的合成

(S)-环氧氯丙烷(2)用叠氮钠开环得到(S)-1-叠氮基-3-氯-2-丙醇(3);另用3,4-二氟硝基苯(4)经与吗啉反应后以铁粉还原硝基,再与氯甲酸乙酯反应得到N-[3-氟-4- (4-吗啉基)苯基]氨基甲酸乙酯(7).3和7经环合反应制得(S)-3-[3-氟-4- (4-吗啉基)苯基]-5-叠氮甲基-1,3-噁唑烷-2-酮后,再经水合肼还原、氨基乙酰化得到抗菌剂利奈唑胺,总收率约40％(以4计).     

泮托拉唑隔日维持治疗内镜阴性胃食管反流病的疗效

目的评价泮托拉唑钠肠溶胶囊隔日维持治疗对内镜阴性胃食管反流病的疗效。方法 2008年3月-2010年3月,我院就诊的67例内镜阴性胃食管反流病患者,2个月基础治疗后,随机分为2组:隔日治疗组32例,常规治疗组35例。隔日治疗组隔日早餐前口服泮托拉唑钠肠溶胶囊40mg,常规治疗组每日早餐前口服泮托拉唑钠肠溶胶囊40mg。总观察时间为4个月,所有患者在治疗前及治疗后2、4个月进行反流性疾病问卷调查。结果两组患者第2个月RDQ评分比治疗前少(P<0.05),而第4个月RDQ评分与第2个月RDQ评分比较,差异无统计学意义(P>0.05)。两组RDQ评分比较,差异无统计学意义(P>0.05)。结论泮托拉唑钠肠溶胶囊隔日维持治疗可作为内镜阴性胃食管反流病维持治疗的手段。     

Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution.

The bioavailability of pantoprazole when administered as a suspension in sodium bicarbonate solution and as the oral tablet was studied. In an open-label, randomized, two-period crossover study, healthy fasting subjects received either one enteric-coated 40-mg pantoprazole tablet by mouth with 240 mL of water or 20 mL of a suspension prepared from one crushed pantoprazole tablet and 840 mg of sodium bicarbonate solution and administered via a nasogastric tube. Treatments were separated by a 48-hour washout period. Blood samples were collected at intervals up to 24 hours after drug administration for measurement of pantoprazole concentration by high-performance liquid chromatography (HPLC) and estimation of pharmacokinetic values. A separate study was conducted to determine pantoprazole's stability in the suspension for up to three months at 25, 5, and -20 degrees C; concentrations were measured by HPLC. Twelve subjects completed the study. The suspension yielded pantoprazole Cmax values similar to those of the tablet formulation, but the drug was 25% less bioavailable. There was no lag time for the suspension. The suspension was stable for up to two weeks at 5 degrees C and up to three months at -20 degrees C. A suspension of pantoprazole in sodium bicarbonate solution yielded a Cmax similar to that of the tablet formulation, and the drug was quickly absorbed. However, bio-availability was slightly lower with the suspension than with the tablet.     

泮托拉唑钠肠溶片在中国男性健康志愿者体内的药动学和相对生物利用度研究

目的:研究泮托拉唑钠肠溶试验片与参比片的药代动力学与相对生物利用度。方法:20名男性健康志愿者单剂量口服泮托拉唑钠试验和参比制剂各40mg;采用反相高效液相色谱法测定其血药浓度。用DAS软件计算药代动力学参数,考察其生物等效性。结果:泮托拉唑钠肠溶片在人体的药动学行为符合二房室开放模型,试验片与参比片的主要药代动力学参数:Tmax分别为(3.18±0.54)和(3.30±0.47)h;Cmax分别为(2.98±0.83)和(2.91±0.87)mg·L-1;T12分别为(1.86±0.41)和(1.72±0.48)h;AUC0-t分别为(9.51±3.71)和(9.77±4.55)mg·h·L-1;相对生物利用度为(102.3±19.6)%。结论:泮托拉唑钠肠溶片两种制剂具有生物等效性。     

注射用泮托拉唑钠的稳定性考察

目的:考察注射用泮托拉唑钠在4种输液中的稳定性。方法:采用高效液相色谱法测定注射用泮托拉唑钠与4种输液配伍 后在4h内的含量变化,并观察溶液外观;同时考察钾、镁、钙离子及pH值变化对注射用泮托拉唑钠稳定性的影响。结果:注射用泮 托拉唑钠在4种常用输液以及钾、镁、钙离子水溶液中于4h内其含量、外观、pH值、最大紫外吸收波长均无明显改变。溶液pH值 低于7．0时泮托拉唑钠极不稳定;pH值为7．0时,颜色可出现微黄变化,但含量降低不明显;溶液pH值在8．0以上时泮托拉唑钠 在4h内稳定。结论:注射用泮托拉唑钠在4种常用输液以及钾、镁、钙离子水溶液中于4h内可保持稳定,pH值对泮托拉唑钠溶液 的稳定性影响较大。     

Increasing sodium pantoprazole photostability by microencapsulation: Effect of the polymer and the preparation technique.

Pantoprazole sodium is a proton pump inhibitor, used in acid-related disorders, like peptic ulcers and gastroesophageal reflux. This drug is unstable in acid solution and in the presence of salts. The aim of this work was to study the photostability under UVC radiation of pantoprazole and to determine its kinetics. A methanol solution and the solid pantoprazole were evaluated by HPLC within 120min and 10 days, respectively. The work was also dedicated to evaluate and compare the ability of microencapsulation in stabilizing pantoprazole after UVC radiation. Pantoprazole-loaded microparticles prepared by emulsification/solvent evaporation or spray drying were compared. Pantoprazole was encapsulated using Eudragit S100((R)) or its blend with poly(epsilon-caprolactone) or HPMC. In methanol solution, pantoprazole was completely degraded after 120min and presented zero-order kinetics with t(1/2) of 6.48min. In the solid form, after 10 days, pantoprazole concentration was reduced to 27% following zero-order kinetic. The microparticles prepared only with Eudragit S100((R)) demonstrated an increase of the drug photostability. After 10 days of irradiation, 56 and 44% of the drug was stable when encapsulated by emulsification/solvent evaporation and spray drying, respectively. The use of polymer blends did not improve the pantoprazole photostability.     

Synthesis of 3-(3,4-dimethoxyphenyl)-1 H-1,2,4-triazole-5-thiol and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole derivatives exhibiting anti-inflammatory activity

New 1-acylderivatives of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazole (5c-f, 6d-f) were synthesized by the acylation of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazoles (3, 4) with acyl chlorides. The compounds 3, 4 were obtained by the alkylation of 3-(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-5-thiol (2) sodium salt with alkyl iodides. Compound 2 and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole (8) were prepared by the treatment of 3,4-dimethoxybenzoylthiosemicarbazide (1) with sodium hydroxide or acetyl chloride (and then sodium hydroxide), respectively. Related 2-acylamino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazoles (7c, e, f) were synthesized by the acylation of compound 8 with acyl chlorides. 3-(3,4-Dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thione (9) was N-acylated with acyl chlorides or S-methylated with iodomethane to give 1-acyl-3-(3,4-dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H- 1,2,4-triazole-5-thiones (10a, b) or 3-(3,4-dimethoxyphenyl)-5-methylthio-4-phenyl-4H-1,2,4-triazole (11) respectively. The synthesized compounds 6d, 7a, c, 10a, b, 11 exhibit anti-inflammatory activity.