CN100384839C - Preparation process of [(substituted pyridyl) methyl] sulfenyl-1H-benzimidazole compound and its antimer zinc salt - Google Patents

Preparation process of [(substituted pyridyl) methyl] sulfenyl-1H-benzimidazole compound and its antimer zinc salt Download PDF

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CN100384839C
CN100384839C CN 200610023956 CN200610023956A CN100384839C CN 100384839 C CN100384839 C CN 100384839C CN 200610023956 CN200610023956 CN 200610023956 CN 200610023956 A CN200610023956 A CN 200610023956A CN 100384839 C CN100384839 C CN 100384839C
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methyl
sulfinyl
substituted pyridyl
zinc
benzimidazole
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CN1810804A (en )
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标 姜
王万军
赵小龙
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中国科学院上海有机化学研究所
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本发明涉及的是可作为质子泵抑制剂药物的[(取代的吡啶基)甲基]亚磺酰基-1H-苯并咪唑类化合物锌盐的制备方法,系在有机溶剂中和存在或不存在淬灭剂的情况下,[(取代的吡啶基)甲基]亚磺酰基-1H-苯并咪唑类化合物或其(S)-对映体和有机锌试剂反应获得。 The present invention relates to [(substituted pyridyl) methyl] sulfinyl -1H- benzimidazole-based compound prepared zinc salts can be used as a proton pump inhibitor medicament, in an organic solvent-based and the presence or absence of in the case where the quencher, [(substituted pyridyl) methyl] sulfinyl -1H- benzimidazole-based compound or the (S) - enantiomer of the reaction and obtain an organic zinc reagent. 本发明的方法简便,是一种适合工业化生产的方法。 The method of the present invention is simple, a process is suitable for industrial production.

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[(取代的吡狄)甲基]亚磺酖基-lf苯并咪唑类化合物及其对映体的锌盐的制备方法技术领域本发明涉及[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物的锌盐的制备方法。 [(Di-substituted pyrazolyl) methyl] sulfinyl benzimidazoles poison -lf group of compounds and zinc salt TECHNICAL FIELD The present invention relates to enantiomers [(substituted pyridyl) methyl] sulfinyl preparation of zinc salt -lf benzimidazole-based compound. 本发明还涉及[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物的(S)-对映体的锌盐的制备方法及包含[(取代的吡啶基)甲基]亚磺酰基-ig-苯并咪唑类化合物的锌盐和(S)-对映体的锌盐的药物组合物。 The present invention also relates to [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compound (S) - for the preparation of zinc salt and comprises enantiomer [(substituted pyridyl) methyl] -ig- sulfinyl benzimidazole-based compound and a zinc salt (S) - a pharmaceutical composition of zinc diastereomers. 背景技术具有如结构式(i)所示的[(取代的吡啶基)甲基]亚磺酰基-m-苯并咪唑类化合物,如奥美拉唑(i)、潘妥拉唑(n)、雷贝拉唑(m)和兰索拉唑(iv),和它们的(5)-对映体相应的镁盐,是一类可作为质子泵抑制剂的药物,特别是其中的奥美拉唑, 抑酸作用强,治愈率高、治愈时间短,可以消除难治性溃疡危象,而且安全可靠, 已成为胃及十二指肠溃疡及反流性食管炎的重要药物。 BACKGROUND OF THE INVENTION The structure of formula (i) shown in [(substituted pyridyl) methyl] sulfinyl -m- benzimidazoles, such as omeprazole (i), pantoprazole (n-), rabeprazole (m) and lansoprazole (IV), and their (5) - enantiomer corresponding magnesium salts, are a class of drugs can be used as proton pump inhibitors, in particular of omeprazole azole, acid-suppressing effect, high cure rate, short cure time, can eliminate intractable ulcers crisis, but also safe and reliable, has become a gastric and duodenal ulcers and reflux esophagitis important drug. 而奥美拉唑的单一对映体,(S)-奥美拉唑具有更好的药物动力学性质、对酸的抑制效果和安全性,生物利用度也更高,在不同个体中抑制变异度更小。 The single enantiomers of omeprazole, (S) - omeprazole with better pharmacokinetic properties, the inhibitory effect and safety of an acid, the bioavailability is higher, to suppress variation among different individuals degree smaller. 上述化合物的结构式如下:i r1 = "OCH3; r2 = -ch3; r3 = -och3; r4 = -ch3 奥美拉唑ii R1 = -ocf2h; R2 = R3 = _0ch3; R4 = _H 潘托拉唑iii r1 = -h; r2 = -ch3; r3 = -och2ch2ch2och3; r4 = -h 霣贝拉唑iv r1 = -h; r2 = -ch3; r3 = -och2cf3; r4 = -h 兰索拉唑。以奥美拉唑为例,这类化合物盐的制备方法己有相关报导。美国专利5714504描述了(5)-奥美拉唑的碱性盐,如钠盐、镁盐、锂盐、钾盐、钙盐和三 Structural formula of the above compounds are as follows: i r1 = "OCH3; r2 = -ch3; r3 = -och3; r4 = -ch3 omeprazole ii R1 = -ocf2h; R2 = R3 = _0ch3; R4 = _H pantoprazole iii r1 = -h; r2 = -ch3; r3 = -och2ch2ch2och3; r4 = -h rainstorm Bella oxadiazol iv r1 = -h; r2 = -ch3; r3 = -och2cf3; r4 = -h lansoprazole in Austria. esomeprazole example, preparation of a salt of such compounds have been reported in related U.S. Patent No. 5,714,504 describes (5) - omeprazole alkaline salt, such as sodium, magnesium, lithium, potassium, calcium salt and tri

烷基胺盐。 Alkyl amine salts. 其中除了报道了(5)-奥美拉唑自由碱的合成,仅仅描述了OS)-奥美拉唑钠盐和镁盐的制备方法。 Wherein the addition is reported (5) - Synthesis of the free base of omeprazole, describes only the OS) - Preparation of omeprazole sodium and magnesium salts. 世界专利WO 98/54171和WO 00/44744报道了(S)-奥美拉唑钾盐的制备方法。 World Patent WO 98/54171 and WO 00/44744 reported that (S) - Preparation of omeprazole potassium salt. 世界专利WO 2004/099182报道了(S)-奥美拉唑锌盐的制备方法,以(5)-奥美拉唑自由碱的碱性水溶液或者(5)-奥美拉唑碱金属盐的水溶液与无机酸或者有机酸的锌盐反应,得到(5)-奥美拉唑锌盐的沉淀。 World Patent WO 2004/099182 reported (S) - omeprazole preparation of zinc salt to (5) - an alkaline aqueous solution of free base omeprazole or (5) - an alkali metal salt of omeprazole and an aqueous solution of zinc salt of an inorganic acid or organic acid reaction, to give (5) - precipitated zinc salt of omeprazole. 中国专利CN 1683369 A报道了与世界专利WO 2004/099182完全相同的(S)-奥美拉唑锌盐的制备方法。 Chinese Patent CN 1683369 A world patent WO 2004/099182 reported identical (S) and - Preparation of zinc salt of omeprazole. 发明内容本发明的目的是提供一种有可能作为药用的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐的制备方法。 SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutically acceptable may be used as [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer of zinc Preparation. 这些化合物至少可以涉及目前己有报道可作为质子泵抑制剂类药物中的如奥美拉唑(I)、潘妥拉唑(II)、雷贝拉唑(III)和兰索拉唑(IV),和它们的(5)-对映体相应的锌盐等化合物中的任何一种。 These compounds may involve at least the current has been reported as a proton pump inhibitor class of drugs such as omeprazole (I), pantoprazole (II), rabeprazole (III) and lansoprazole (IV ), and their (5) - of any other enantiomeric corresponding zinc compound. 本发明的方法是一种以有机溶剂为反应介质,在简单和方便的反应条件下, 由[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物自由碱和它们的(5)-对映体自由碱与有机锌试剂反应制备[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(S)-对映体的锌盐的方法。 The method of the present invention is an organic solvent as a reaction medium, in a simple and convenient reaction conditions from [(substituted pyridyl) methyl] sulfinyl -lf benzimidazole-based compound and the free base thereof ( 5) - preparation of enantiomer free base with an organic zinc reagent [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compounds and their (S) - enantiomers method of zinc. 本发明描述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(S)-对映体的锌盐,指的是任何包括[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的阴离子和锌阳离子。 The present invention is described in [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compounds and their (S) - enantiomer of zinc, refers to any includes [(substituted pyridyl) methyl] -lf sulfinyl benzimidazoles and their compounds (5) - anions and zinc cations enantiomers. 例如:固体形式或者是溶液形式,晶体状态或者无定型状态。 For example: solid form or in form of a solution, a crystalline state or amorphous state. 可以是无水形式和/或者无溶剂形式和/ 或水合形式和/或含有溶剂形式。 It may be in anhydrous form and / or in the form of a solvent and / or a hydrated form and / or in the form of a solvent containing no. 本发明描述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物的(S)-对映体指的是其中完全不含有自由状态的(及)-对映体纯的[(取代的吡啶基)甲基] 亚磺酰基-lf苯并咪唑类化合物,例如:ee值为60。 The present invention is described in [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compound (S) - which does not contain free state (and) enantiomer refers to a - enantiomerically pure the [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf, for example: ee value of 60. /。 /. ,或者ee值为80"/。。在特定的条件下,(S)-对映体指的是ee值最少为95%,或者至少98%,或者至少99.0%, 或者至少99.5%。本发明描述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐,包含化学计量和非化学计量的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的阴离子和锌阳离子。[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的和锌的摩尔比率没有限定为1: l。在特定的具体实例中[(取代的吡啶基)甲基]亚磺酰基苯并咪唑类化合物和它们的(5)-对映体的锌盐,[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪哇类化合物和它们的(S)-对映体的阴离子和锌阳离子的摩尔比率为2: 1,即使在锌盐的形成过程中[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(s)-对映体或者有机锌试 Or ee value of 80 "/ .. Under certain conditions, (S) - enantiomer refers ee value is at least 95%, or at least 98%, or at least 99.0%, or at least 99.5% of the present invention. described [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer of zinc, comprising a non-stoichiometric and stoichiometric [(substituted pyridyl ) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - anions and zinc cations enantiomer [(substituted pyridyl) methyl] sulfinyl benzimidazole type compound -lf. and their (5) - and the molar ratio of zinc enantiomers is not limited to 1:. l in a particular example [(substituted pyridyl) methyl] sulfinyl benzimidazole compounds and their molar ratio of the enantiomers of anions and zinc cations - (5) - enantiomer of zinc, [(substituted pyridyl) methyl] sulfinyl benzimidazole wow -lf compounds and their (S) 2: 1, even in the formation of a zinc salt of [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compounds and their (s) - enantiomer or organozinc test 过量。本发明描述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(S)-对映体的锌盐,具有以下结构:其中R1, R2, 113和114独立地为氢、C卜2o的烷基、C卜2o的垸氧基或酯基、 卤素、苯基、三氟甲基或硝基。本发明描述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐,推荐以无定型态形式存在。与晶体形态相比,无定型态中更细小的粉末有可能获得更好的溶解性。本发明描述的制备[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐的方法包含以下步骤: Excess of the invention described [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compounds and their (S) - enantiomer of zinc, having the structure: wherein R1, R2, 113 and 114 are independently hydrogen, C 2o alkyl group Bu, C 2o the embankment Bu group or an ester group, halogen, phenyl, trifluoromethyl or nitro. the present invention is described in [(substituted pyridyl) methyl yl] -lf sulfinyl benzimidazoles and their compounds (5) - enantiomer of zinc, present in an amorphous state recommended form compared to crystalline form, in amorphous patterns finer powder possible to obtain better solubility of the present invention was prepared as described [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer method comprising zinc the following steps:

在有机溶剂中和室温下,[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物或者它们的(5)-对映体和有机锌试剂反应0.5~3小时,加入或不加入淬灭剂淬灭反应得到[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐。 In an organic solvent at room temperature, [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf thereof, or (5) - for 0.5 to 3 hours enantiomers and organozinc reagents, or added without the addition of quencher to quench the reaction to give [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer of zinc. 反应以后也可以通过分离得到[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐。 After the reaction can be obtained by isolating [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer of zinc. 所述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物具有以下结构:其中,R1, R2, RS或W独立地为氢、C卜2o的烷基、C卜2o的烷氧基或酯基、 卤素、苯基、三氟甲基或硝基;所述的有机锌试剂具有以下的结构:R5-Zn-R6,其中W和W独立地为有C卜6的烷基、C卜6的烯基、C卜6的炔基或者芳基;本发明中优先使用的是RS和R6 均为乙基的垸基锌试剂,即二乙基锌。 The [(substituted pyridyl) methyl] sulfinyl -lf benzimidazole-based compound has the structure: wherein, R1, R2, RS, or W is independently hydrogen, C 2o alkyl group Bu, C Bu 2o alkoxy or ester group, a halogen, a phenyl group, a trifluoromethyl group or a nitro group; an organic zinc reagent having the following structure: R5-Zn-R6, wherein W and W are independently C have Bu 6 alkyl, C 6 alkenyl Bu, C Bu 6 alkynyl group or an aryl group; in the present invention is preferably used in the RS and R6 are alkyl with ethyl zinc reagent, i.e. diethylzinc. 所述的淬灭剂是水、醇等质子性溶剂或者它们的混合物。 The quencher is a protic solvent such as water, alcohol and the like or mixtures thereof. 本发明中优先使用的淬灭剂是水。 Quenchers of the present invention is preferentially used is water. 所述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物或者它们的(5)-对映体、有机锌试剂和淬灭剂的摩尔比为1:0.5〜2:0〜1000;当采用淬灭剂时, 使用更多的淬灭剂对反应没有影响。 The [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf thereof, or (5) - enantiomer molar ratio of organozinc reagents and the quencher is from 1: 0.5~2 : 0~1000; when a quencher, the use of more quencher has no effect on the reaction. 采用淬灭剂还有利于分离未反应的有机锌试剂。 Using quenching also facilitates separation of unreacted organozinc reagent quencher. 推荐所述的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物或者它们 [(Substituted pyridyl) methyl] sulfinyl benzimidazole type compound or -lf thereof according to recommended

的(5)-对映体、有机锌试剂和淬灭剂的摩尔比为1:0.8~1.5:10~500。 (5) - enantiomer of the molar ratio, organozinc reagents and the quencher is from 1: 0.8 to 1.5: 10 to 500. 本发明描述的有机溶剂可以是二氯甲烷、氯仿、四氯化碳、己垸、苯、甲苯、 氯苯、硝基苯、二甲苯、乙醚、叔丁基醚、四氢呋喃和二氧六环或者它们的混合物。 The present invention describes the organic solvent may be dichloromethane, chloroform, carbon tetrachloride, hexyl embankment, benzene, toluene, chlorobenzene, nitrobenzene, xylene, diethyl ether, tert-butyl ether, tetrahydrofuran and dioxane, or mixtures thereof. 本发明中优先使用的有机溶剂是四氢呋喃。 The organic solvent is preferably used in the present invention is tetrahydrofuran. 所述的质子性溶剂可以是包括如甲醇、乙醇、丙醇或丁醇等在内的醇类。 The protic solvent may include alcohols such as methanol, ethanol, propanol, butanol, or the like, including. 采用本发明描述的方法,反应以后可以用过滤或者离心分离等的方法分离纯化,然后再进行洗涤和千燥。 Using the method described herein, may be isolated and purified by methods such as filtration or centrifugation after the reaction, and then washing was dry. 本发明中优先使用的分离方法是过滤。 The separation process of the invention is preferably used in filtering. 本发明所使用的[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物的(5)-对映体可以通过文献中巳知的方法如美国专利5714504等合成获得。 Used in the present invention [(substituted pyridyl) methyl] (5) -lf sulfinyl benzimidazole-based compound - can be synthesized as described in U.S. Patent No. 5,714,504 and the like to obtain enantiomers by methods known in the literature Pat. [(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(S)-对映体的锌盐作为胃酸分泌抑制剂是有效的,可用作抗溃疡药。 [(Substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compounds and their (S) - enantiomer of zinc is as effective inhibitors of gastric acid secretion, useful as antiulcer agents. 从更普遍的意义上讲, 它可用于治疗哺乳动物并且特别是人类中与胃酸有关的疾病,这些疾病包括例如反流性食管炎、胃炎、十二指肠炎、胃溃疡和十二指肠溃疡。 From a more general sense, it can be used for treating mammals, particularly humans, and gastric acid-related diseases. These diseases include, for example, reflux esophagitis, gastritis, duodenitis, gastric and duodenal ulcers . 此外,它可用于治疗其它的需要胃酸抑制作用的胃肠疾病,例如服用非甾类抗炎药(NSAID)的病人、患非溃疡性消化不良的病人、患胃食管回流疾病的病人及患胃泌素瘤的病人。 Further, it is useful for the treatment of other gastrointestinal disorders where gastric acid inhibitory effect, for example, patients taking nonsteroidal anti-inflammatory drug (NSAID), and patients suffering from non-ulcer dyspepsia, patients suffering from gastric and gastro-oesophageal reflux disease risk secretin tumor patients. [(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐也可用于特护病人、急性上胃肠出血的病人、术前和术后阻止胃酸吸入及治疗应激性溃疡。 [(Substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer before zinc may also be used intensive care patients, patients with acute upper gastrointestinal bleeding, and surgery postoperative prevent aspiration of gastric acid and treat stress ulceration. 此外,[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(S)-对映体的锌盐可用于治疗牛皮癣及治疗螺旋茵(Helicobacter)感染和与之有关的疾病。 In addition, [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf compounds and their (S) - and treatment of psoriasis Inn coil (of Helicobacter) and the infection therewith of zinc enantiomers useful for the treatment related diseases. [(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐也可用于治疗包括人类的哺乳动物的炎症。 [(Substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer of zinc may also be useful in treating inflammation comprising human mammal. 任何合适的给药途径都可用于提供给病人有效剂量的按本发明例如可以应用口服的制剂等。 Any suitable route of administration may be used to provide to a patient an effective dose of the formulation according to the invention may be applied, for example, orally, and the like. 剂型包括胶囊剂、片剂、分散体或悬浮液等。 Dosage forms include capsules, tablets, dispersions or suspensions and the like. 另外,本发明方法获得的包含[(取代的吡啶基)甲基]亚磺酰基-lf苯并咪唑类化合物和它们的(5)-对映体的锌盐作为活性组份与可药用载体、稀释剂或赋形剂及任选地其它治疗组份的药物组合物。 Further, the present invention obtained by the method comprising [(substituted pyridyl) methyl] sulfinyl benzimidazoles -lf and their compounds (5) - enantiomer of zinc as an active ingredient with a pharmaceutically acceptable carrier , diluent or excipient and optionally other parts of the pharmaceutical composition treatment groups. 本发明的方法是一种简便的合成方法,是一种适合工业化生产的方法。 The method of the present invention is a simple method of synthesis, it is a process suitable for industrial production. 具体实施方式以下再通过实施例形式的具体实施方式对本发明的上述内容作进一步的详细说明。 DETAILED DESCRIPTION The following further described in further detail by the foregoing the present invention DETAILED DESCRIPTION Embodiments of the form. 但不应将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容所实现的技术均属于本发明的范围。 However, this should not be understood that the present invention relating to the above-described range limited to the following examples, where the above-described technique based on the present invention are achieved within the scope of the present invention. 实施例l奥美拉唑锌盐的制备将奥美拉唑5克(14.5毫摩尔)溶于50毫升四氢呋喃中,缓缓加入二乙基锌0.98克(8毫摩尔),搅拌1〜2小时后,缓缓加入50毫升水,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12小时, 得到5.05克奥美拉唑锌盐,产率95%。 Example l Preparation of zinc salt of omeprazole omeprazole 5 g (14.5 mmol) dissolved in 50 ml of tetrahydrofuran, was slowly added diethylzinc 0.98 g (8 mmol), stirred for 1 to 2 hours after 50 ml of water was added slowly, stirring continued for 30 minutes to fully precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 5.05 g omeprazole zinc, 95% yield. 锌含量(质量/质量):10.01%。 Zinc content (mass / mass): 10.01%. 实施例2 (S)-奥美拉唑锌盐的制备将(5)-奥美拉唑5克(14.5毫摩尔,99%")溶于50毫升四氢呋喃中,缓缓加入二乙基锌0.98克(8毫摩尔),搅拌2小时后,缓缓加入50亳升水,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗漆,空气中40-45摄氏度干燥12 小时,得到5.05克(5)-奥美拉唑锌盐,产率95%。锌含量(质量/质量):9.28%。 HPLC纯度=99%,手性HPLC纯度-99.5W。实施例3潘托拉唑锌盐的制备将潘托拉唑5克(13毫摩尔)溶于50毫升二氯甲烷中,缓缓加入二乙基锌0.89克(7.2毫摩尔),搅拌2小时后,缓缓加入50毫升水和20毫升甲醇的混合物,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12小时,得到4.95克潘托拉唑锌盐,产率92%。锌含量(质量/质量): 8.36%。实施例4 (5)-潘托拉唑锌盐的制备将(S)-潘托拉唑5克(13毫摩尔,92% ee)溶于50毫升氯 Example 2 (S) - omeprazole preparation of the zinc salt (5) - omeprazole 5 g (14.5 mmol, 99% ") was dissolved in 50 ml of tetrahydrofuran, was slowly added diethylzinc 0.98 g (8 mmol), stirred for 2 hours, 50 ml of water was added slowly and continue stir for 30 minutes and the precipitated white solid was filtered off with suction, washed with methanol paint, air dried 40-45 ° C for 12 hours to give 5.05 g ( . 5) - omeprazole zinc, zinc content 95% yield (mass / mass): 9.28% HPLC purity = 99%, chiral HPLC purity zinc salt of pantoprazole -99.5W Example 3 embodiment. preparation of pantoprazole 5 g (13 mmol) dissolved in 50 ml of methylene chloride, diethyl zinc was added slowly 0.89 g (7.2 mmol), stirred for 2 hours, slowly added 50 ml of water and 20 mL of methanol, stirring was continued for 30 minutes to fully precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 4.95 Kepan zinc pantoprazole, yield 92% zinc content (mass / mass): 8.36% Example 4 (5) - preparation of zinc salt of pantoprazole the (S) - pantoprazole 5 g (13 mmol, 92% ee) was dissolved in 50 ml of chlorosulfonic 中,缓缓加入二乙基锌0.89克(7.2摩尔),搅拌2小时后,缓缓加入50毫升水和20毫升乙醇的混合物,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12小时,得到5.12克潘托拉唑锌盐,产率95%。锌含量(质量/质量):8.03%。 HPLC纯度-99X,手性HPLC纯度=92% 。实施例5雷贝拉唑锌盐的制备将雷贝拉唑5克(14毫摩尔)溶于50毫升甲苯中,缓缓加入二乙基锌0.95 克(7.7毫摩尔),搅拌2小时后,缓缓加入50毫升甲醇,继续充分搅拌30分钟, 析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12小时,得到5.00 克雷贝拉唑锌盐,产率91%。锌含量(质量/质量):9.87%。实施例6 (S)-雷贝拉唑锌盐的制备将(S)-雷贝拉唑5克(14毫摩尔,85%ee) 50毫升四氢呋喃中,缓缓加入二乙基锌0.95克(7.7摩尔),搅拌2小时后,缓缓加入50毫升乙醇,继续充分搅 In diethyl zinc was added slowly 0.89 g (7.2 mol), stirred for 2 hours, 50 ml of water and 20 ml of ethanol was added slowly, stirring was continued for 30 minutes to fully precipitated white solid was washed, filtered off with suction, methanol, 40-45 ° C air dried for 12 hours, to give 5.12 Kepan pantoprazole zinc, zinc content 95% yield (mass / mass):... 8.03% HPLC purity -99X, chiral HPLC purity = 92% embodiments Example 5 preparation of rabeprazole rabeprazole zinc salt 5 g (14 mmol) dissolved in 50 ml of toluene, diethyl zinc was added slowly 0.95 g (7.7 mmol), stirred for 2 hours, slowly slow addition of 50 ml of methanol, stirring was continued for 30 minutes to fully precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 5.00 rabeprazole zinc salt, yield 91% zinc content ( mass / mass): 9.87% Example. 6 (S) - preparation of zinc salt will rabeprazole (S) - rabeprazole 5 g (14 mmol, 85% ee) 50 ml of tetrahydrofuran, slowly diethylzinc was added 0.95 g (7.7 mol), stirred for 2 hours, 50 ml of ethanol was added slowly, stirring continued full 30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12小时, 得到4.91克雷贝拉唑锌盐,产率89%。锌含量(质量/质量):9.17%。 HPLC纯度=99%,手性HPLC纯度-85X。实施例7兰索拉唑锌盐的制备将兰索拉唑5克(13.5毫摩尔)溶于50毫升四氯化碳中,缓缓加入二乙基锌0.91克(7.4毫摩尔),搅拌2小时后,缓缓加入50毫升水,继续充分搅拌30 分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12小时,得到5,23克兰索拉唑锌盐,产率97%。 30 minutes, the precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 4.91 rabeprazole zinc, zinc content 89% yield (mass / mass):. 9.17% HPLC. purity = 99%, chiral HPLC purity -85X. azole zinc salt prepared in Example 7 lansoprazole the lansoprazole 5 g (13.5 mmol) dissolved in 50 ml of carbon tetrachloride was slowly added diethyl 0.91 g zinc group (7.4 mmol), stirred for 2 hours, 50 ml of water was added slowly, stirring continued for 30 minutes to fully precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 5 , 23 Crane esomeprazole zinc, 97% yield. 锌含量(质量/质量):10.13%。 Zinc content (mass / mass): 10.13%. 实施例8 (S)-兰索拉唑锌盐的制备10 Preparation of zinc salt of lansoprazole 10 - Example 8 (S)

将兰索拉唑5克(13.5毫摩尔,86%")溶于50毫升二氧六环中,缓缓加入二乙基锌0.91克(7.4毫摩尔),搅拌2小时后,缓缓加入50毫升水,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12 小时,得到5.11克兰索拉唑锌盐,产率95%。锌含量(质量/质量):9.39%。 HPLC纯度-99X,手性HPLC纯度二86X。实施例9 2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]-亚磺酰基]-1//-苯并咪唑锌盐的制备将2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]-亚磺酰基]-1//-苯并咪唑5克(16 毫摩尔)溶于50毫升四氨呋喃和10毫升己垸中,缓缓加入二乙基锌1.09克(8.8 毫摩尔),搅拌2小时后,缓缓加入50毫升水,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12小时,得到5.17克2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲萄-亚磺酰基]-l乐苯并咪唑锌盐,产率9 Lansoprazole 5 g (13.5 mmol, 86% ") in 50 ml dioxane, diethyl zinc was added slowly 0.91 g (7.4 mmol), stirred for 2 hours, added slowly 50 ml of water and continue stir for 30 minutes and the precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 5.11 Crane esomeprazole zinc, yield 95% zinc content (mass / mass ): 9.39% HPLC purity -99X, chiral HPLC purity titanium 86X Example 9 2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] - sulfinyl. acyl] -1 // - benzimidazol zinc salt of 2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] - sulfinyl] -1 / / - benzimidazole-5 g (16 mmol) in 50 ml furan and 10 ml of tetraamine has the embankment, diethyl zinc was added slowly 1.09 g (8.8 mmol), stirred for 2 hours, added slowly 50 ml of water and continue stir for 30 minutes and the precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 5.17 g 2 - [[(4-methoxy-3,5-dimethyl 2-pyridinyl) methyl grapes - sulfinyl] -l-benzimidazole Le zinc, yield 9 3%。锌含量(质量/质量):11.21%。实施例10 (5)-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲萄-亚磺酰基]-1界苯并咪唑锌盐的制备将(S)-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲萄-亚磺酰基]-l/f-苯并咪唑5克(16毫摩尔,92%ee)溶于50毫升四氢呋喃中,缓缓加入二乙基锌0.91克(7.4 毫摩尔),搅拌2小时后,缓缓加入50毫升水,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度千燥12小时,得到5.02克(5>2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲萄-亚磺酰基]-1//-苯并咪唑锌盐,产率90%。锌含量(质量/质量):9.39%。 HPLC纯度-99X,手性HPLC纯度=92%。实施例11 5-甲氧基-2-2[[[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲基]亚磺酰基]-lH-苯并咪唑锌盐的制备将5-甲氧基-2-2[[[3-甲基-4-(2, 2, 2-三氟乙氧基)-2-吡啶基]甲基]亚磺酰基]-lif-苯并咪唑5克(12.5毫摩尔)溶于50毫升四氢呋喃中 3% zinc content (mass / mass): 11.21% Example 10 (5) -2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl grapes - sulfinyl carbamoyl] -1 preparation boundary-benzimidazole the zinc salt (S) -2 - [[(4- methoxy-3,5-dimethyl-2-pyridinyl) methyl grapes - sulfinyl] -l / f- benzimidazol-5 g (16 mmol, 92% ee) was dissolved in 50 ml of tetrahydrofuran, was slowly added diethylzinc 0.91 g (7.4 mmol), stirred for 2 hours, 50 ml of water was added slowly stirring was continued for the full 30 minutes, the precipitated white solid was filtered off with suction, washed with methanol, air dry in 40-45 ° C for 12 hours to obtain 5.02 g (5> 2 - [[(4-methoxy-3,5- methyl-2-pyridinyl) methyl grapes - sulfinyl] -1 // - benzimidazol-zinc, zinc content 90% yield (mass / mass):.. 9.39% HPLC purity -99X, chiral HPLC purity = 92%. Example 11 5-methoxy--2-2 [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfonyl] lH-benzimidazole zinc salt of 5-methoxy--2-2 [[[3-methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridinyl yl] methyl] sulfinyl] -lif--benzimidazole 5 g (12.5 mmol) dissolved in 50 ml of tetrahydrofuran ,缓缓加入二乙基锌0.85克(6.9毫摩尔),搅拌2小时后,缓缓加入50毫升水,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中4045摄氏度干燥12小时,得到4.80克兰索拉唑锌盐,产率89%。 , Diethyl zinc was added slowly 0.85 g (6.9 mmol), stirred for 2 hours, 50 ml of water was added slowly, stirring continued for 30 minutes to fully precipitated white solid was filtered off with suction, washed with methanol, air dried 12 ° C 4045 hours, to give 4.80 Crane esomeprazole zinc salt, yield 89%. 锌含量(质量/质量):8.31%。 Zinc content (mass / mass): 8.31%.

实施例12 (5)- 5-甲氧基-2-2[[[3-甲基-4-(2, 2, 2-三氟乙氧基)-2-吡啶基]甲基]亚 -2-2-methoxy-5- [[[3-methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridinyl] methyl] - Example 12 (5) Embodiment

磺酰基]-l/f-苯并咪唑锌盐的制备将(5)-5-甲氧基-2-2[[[3-甲基-4-(2, 2, 2-三氟乙氧基)-2-吡啶基]甲基]亚磺酰基]-l/f-苯并咪唑5克(12.5毫摩尔,92%ee)溶于50毫升四氢呋喃中,缓缓加入二乙基锌0.85克(6.9毫摩尔),搅拌2小时后,缓缓加入50毫升水,继续充分搅拌30分钟,析出白色固体,抽滤,甲醇洗涤,空气中40-45摄氏度干燥12 小时,得到4.86克(S)-5-甲氧基-2-2[[[3-甲基-4-(2, 2, 2-三氟乙氧基)-2-吡啶萄甲基]亚磺酰基]-liZ-苯并咪唑锌盐,产率90%。 Sulfonyl] Preparation -l / f- benzimidazol-zinc salt of (5) -5-methoxy -2-2 [[[3-methyl-4- (2, 2-trifluoro-ethoxy yl) -2-pyridinyl] methyl] sulfinyl] -l / f- benzimidazol-5 g (12.5 mmol, 92% ee) was dissolved in 50 ml of tetrahydrofuran, was slowly added 0.85 g of diethyl zinc (6.9 mmol), stirred for 2 hours, 50 ml of water was added slowly and continue stir for 30 minutes and the precipitated white solid was filtered off with suction, washed with methanol, air dried 40-45 ° C for 12 hours to give 4.86 g (S) 5-methoxy--2-2 [[[3-methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridinyl grapes methyl] sulfinyl] -liZ- benzo zinc salt of imidazole, in 90% yield. 锌含量(质量/质量):8.47%。 Zinc content (mass / mass): 8.47%. HPLC 纯度=99 % ,手性HPLC纯度=92 % 。 HPLC purity = 99%, chiral HPLC purity = 92%.

Claims (8)

  1. 1、一种[(取代的吡啶基)甲基]亚磺酰基-1H-苯并咪唑类化合物或其(S)-对映体的锌盐的制备方法,其特征是包含以下步骤: 在有机溶剂中和室温下,[(取代的吡啶基)甲基]亚磺酰基-1H-苯并咪唑类化合物或者它们的(S)-对映体和有机锌试剂反应0.5~3小时,加入或不加入淬灭剂淬灭反应得到[(取代的吡啶基)甲基]亚磺酰基-1H-苯并咪唑类化合物和它们的(S)-对映体的锌盐; 所述的[(取代的吡啶基)甲基]亚磺酰基-1H-苯并咪唑类化合物或者它们的(S)-对映体、有机锌试剂和淬灭剂的摩尔比为1∶0.5~2∶0~1000; 所述的[(取代的吡啶基)甲基]亚磺酰基-1H-苯并咪唑类化合物具有以下结构: id="icf0001" file="C2006100239560002C1.gif" wi="75" he="24" top= "121" left = "59" img-content="drawing" img-format="tif" orientation="portrait" inline="no"/> 其中,R1,R2,R3或R4独立地为氢、C1~20的烷基、C1~20的烷氧基或酯 1 A [(substituted pyridyl) methyl] sulfinyl -1H- benzimidazole-based compound or the (S) - for the preparation of the zinc salt of enantiomer, characterized in comprising the steps of: organic solvent at room temperature, [(substituted pyridyl) methyl] sulfinyl -1H- benzimidazole-based compound thereof, or (S) - for 0.5 to 3 hours enantiomers and organozinc reagents, with or without [(said substituted; enantiomer zinc - quencher was added to quench the reaction to give [(substituted pyridyl) methyl] sulfinyl -1H- benzimidazole-based compound and their (S) pyridinyl) methyl] sulfinyl -1H- benzimidazole-based compound thereof, or (S) - enantiomer of the molar ratio, organozinc reagents and the quencher is 0.5 ~ 2-0 ~ 1000; the described [(substituted pyridyl) methyl] sulfinyl -1H- benzimidazole-based compound having the structure: id = "icf0001" file = "C2006100239560002C1.gif" wi = "75" he = "24" top = "121" left = "59" img-content = "drawing" img-format = "tif" orientation = "portrait" inline = "no" /> wherein, R1, R2, R3 and R4 are independently hydrogen, C1 ~ 20 alkyl group, alkoxy group or a C1 - ester 20 基、卤素、苯基、三氟甲基或硝基; 所述的有机锌试剂具有以下的结构:R5-Zn-R6,其中R5和R6独立地为有C1~6的烷基; 所述的淬灭剂是质子性溶剂或者它们的混合物。 Group, halogen, phenyl, nitro or trifluoromethyl; organozinc reagent having the following structure: R5-Zn-R6, wherein R5 and R6 are independently C1 ~ 6 alkyl; said quencher is a protic solvent or a mixture thereof.
  2. 2、 如权利要求1所述的方法,其特征是所述的[(取代的吡啶基)甲基]亚磺酰基-1^苯并咪唑类化合物和它们的(5)-对映体的锌盐是以无定型态形式存在。 2. The method as claimed in claim 1, characterized in that the [(substituted pyridyl) methyl] -1 ^ sulfinyl benzimidazoles and their compounds (5) - enantiomer zinc salt is present in an amorphous form.
  3. 3、 如权利要求1所述的方法,其特征是所述的有机溶剂是二氯甲烷、氯仿、四氯化碳、己烷、苯、甲苯、氯苯、硝基苯、二甲苯、乙醚、叔丁基醚、四氢呋喃、 二氧六环或者它们的混合物。 3. The method of claim 1, wherein said organic solvent is dichloromethane, chloroform, carbon tetrachloride, hexane, benzene, toluene, chlorobenzene, nitrobenzene, xylene, diethyl ether, tert-butyl ether, tetrahydrofuran, dioxane, or mixtures thereof.
  4. 4、 如权利要求3所述的方法,其特征是所述的有机溶剂是四氢呋喃。 4. The method as claimed in claim 3, wherein said organic solvent is tetrahydrofuran.
  5. 5、 如权利要求1所述的方法,其特征是所述的有机锌试剂是二乙基锌。 5. The method as claimed in claim 1, characterized in that said organozinc reagent is diethylzinc.
  6. 6、 如权利要求1所述的方法,其特征是所述的质子性溶剂是水、甲醇、乙醇、 丙醇或丁醇。 6. The method as claimed in claim 1, wherein said protic solvent is water, methanol, ethanol, propanol or butanol.
  7. 7、 如权利要求6所述的方法,其特征是所述的淬灭剂是水。 7. The method as claimed in claim 6, wherein the quenching agent is water.
  8. 8、 如权利要求1所述的方法,其特征是反应后通过过滤或者离心分离,然后再进行洗涤和干燥。 8. A method as claimed in claim 1, wherein after the reaction by filtration or centrifugation, washed and then dried.
CN 200610023956 2006-02-17 2006-02-17 Preparation process of [(substituted pyridyl) methyl] sulfenyl-1H-benzimidazole compound and its antimer zinc salt CN100384839C (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054171A1 (en) 1997-05-30 1998-12-03 Astra Aktiebolag Novel form of s-omeprazole
WO2000044744A1 (en) 1999-01-28 2000-08-03 Astrazeneca Ab Potassium salt of ($i(s))-omeprazole
CN1683369A (en) 2005-03-15 2005-10-19 天津市轩宏医药技术有限公司 S-omeprazole zinc salt and its preparing method and use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054171A1 (en) 1997-05-30 1998-12-03 Astra Aktiebolag Novel form of s-omeprazole
WO2000044744A1 (en) 1999-01-28 2000-08-03 Astrazeneca Ab Potassium salt of ($i(s))-omeprazole
CN1683369A (en) 2005-03-15 2005-10-19 天津市轩宏医药技术有限公司 S-omeprazole zinc salt and its preparing method and use

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