CN102731407A - Method for preparing telmisartan - Google Patents

Method for preparing telmisartan Download PDF

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CN102731407A
CN102731407A CN2012102318965A CN201210231896A CN102731407A CN 102731407 A CN102731407 A CN 102731407A CN 2012102318965 A CN2012102318965 A CN 2012102318965A CN 201210231896 A CN201210231896 A CN 201210231896A CN 102731407 A CN102731407 A CN 102731407A
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telmisartan
reaction
ko
methyl
method
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吴绍伟
张达
沈磊
陶伟坚
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宁波九胜创新医药科技有限公司
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Abstract

The invention discloses a method for preparing telmisartan, which can be used for directly producing telmisartan by carrying out nucleophilic substitution reaction on 2-n-propyl-4-methyl-6-(1'-methyl benzimidazole-2-yl) benzimidazole and 4-brooethyl diphenyl-2-carboxylic acid under the action of acid-binding agent. The method is simple in operation, thus improving the yield of the final product and being suitable for the synthetic route of telmisartan in industrial production.

Description

ー种制备替米沙坦的方法 The method of preparing telmisartan species ー

技术领域 FIELD

[0001] 本发明涉及抗高血压药物的制备方法,具体地,本发明涉及替米沙坦(Telmisartan)的制备方法。 [0001] The present invention relates to a method of antihypertensive drugs, in particular, the present invention is directed to telmisartan (Telmisartan) preparation.

背景技术 Background technique

[0002] 替米沙坦是ー种新型非肽类血管紧张素(AT),其结构如下: [0002] Telmisartan is ー new type of non-peptide angiotensin (AT), the following structure:

[0003] [0003]

Figure CN102731407AD00031

[0004] 已有的替米沙坦的合成路线主要是以3-甲基-4-氨基苯甲酸甲酯为起始原料经N-酰化、硝化、还原、环合、酷水解、缩合反应得中间体2-正丙基-4-甲基-6-(1'_甲基苯并咪唑-2-基)苯并咪唑,与4-溴甲基联苯羧酸酯(R=CH3, C2H5, t-Bu)亲核取代得化合物IV,再水解为最終的替米沙坦(中国专利CN 1344712A)。 [0004] Telmisartan existing synthetic route mainly methyl-4-amino-benzoic acid methyl ester as the starting material was N- acylation, nitration, reduction, cyclization, hydrolysis cool, condensation reaction to give intermediate 2-n-propyl-4-methyl-6- (1'_ methyl-benzimidazol-2-yl) benzimidazole, 4-bromomethyl-biphenyl with carboxylic acid ester (R = CH3, C2H5, t-Bu) nucleophilic substitution to give to compound IV, and then hydrolyzed to the final telmisartan (Chinese Patent No. CN 1344712A). 该制备方法中,是用甲基、或こ基或叔丁基保护4-溴甲基联苯羧酸的羧基再与化合物I反应,再通过水解得到最终替米沙坦。 The preparation method, is protected carboxy 4-bromomethyl-biphenyl carboxylic acid with methyl, or t-butyl group or a ko reacted with compound I, and then by hydrolysis to give a final telmisartan. 但这个路线反应步数多,先上保护,后脱保护。 But the number of multi-step reaction route, the first protection, after deprotection. 总体收率不高,操作繁琐,不利于エ业化生产。 The overall yield is not high, complicated operation, is not conducive to Ester industry production.

反应式如下: The following reaction formula:

[0005] [0005]

Figure CN102731407AD00041

发明内容 SUMMARY

[0006] 本发明所要解决的技术问题是提供ー种制备替米沙坦的方法,本发明的方法简化了操作,提高了最终产品的收率,是适合エ业化生产的替米沙坦的合成路线。 [0006] The present invention solves the technical problem is to provide a kind of preparing telmisartan ー methods, the method of the invention simplifies operation, increasing the yield of the final product, it is suitable for industrialized production Ester telmisartan synthetic route.

[0007] 本发明解决上述技术问题所采用的技术方案是:ー种制备替米沙坦的方法,在反应溶剂中,加入式I所示的化合物I 2-正丙基-4-甲基-6-(I' -甲基苯并咪唑-2-基)苯并咪唑和式II所示的化合物II 4-溴甲基联苯-2-羧酸,加热升温,在缚酸剂的作用下,亲核反应至式I所示的2-正丙基-4-甲基-6-(I' -甲基苯并咪唑-2-基)苯并咪唑反应完全;反应液经分离纯化得到式III所示的替米沙坦; [0007] aspect of the present invention to solve the above technical problem is: The method of preparing telmisartan ー species, in a reaction solvent, the compound I of formula I is added 2-n-propyl-4-methyl - 6- (I '- methyl-benzimidazol-2-yl) benzimidazole, and a compound represented by formula II II-methylbiphenyl-2-carboxylic acid 4- bromo, heating up, the role of acid binding agent at , 2-n-propyl-nucleophilic reaction to the formula I 4-methyl -6- (I '- methyl-benzimidazol-2-yl) benzimidazole completion of the reaction; the reaction solution was separated to give the formula III telmisartan shown;

[0008] [0008]

Figure CN102731407AD00042

[0009] 其中,式I所示的2-正丙基-4-甲基-6-(Γ-甲基苯并咪唑-2-基)苯并咪唑、式II所示的4-溴甲基联苯-2-羧酸和缚酸剂的物质的量比为:1:1. Γ2.0:1. (Γ2. O。 [0009] wherein Formula I n-propyl-4-methyl-6- ([gamma] methyl-benzimidazol-2-yl) methyl 4-bromomethyl-benzimidazole, represented by formula II biphenyl-2-carboxylic acid-binding agent and the molar ratio of: 1:. 1 Γ2.0:. 1 (Γ2 O..

[0010] 上述技术方案中,去除了现有技术中的叔丁基、甲基、こ基保护,直接由4-溴甲基联苯-2-羧酸,它与化合物I经亲核取代反应直接生成目的产物III。 [0010] In the above technical solutions, in addition to the prior art tert-butyl, methyl, ko-protected by 4-bromomethyl-biphenyl-2-carboxylic acid, which compound I via direct nucleophilic substitution reaction directly generate the desired product III. 即,2-正丙基-4-甲基-6- (Γ-甲基苯并咪唑-2-基)苯并咪唑与4-溴甲基联苯-2-羧酸经亲核取代反应直接生成替米沙坦4'-[(1,4'-ニ甲基-2'-丙基[2,6'-ニ-IH-苯并咪唑]-I'基)甲基]-[1,I' _联苯]~2~羧酸。 I.e., 2-n-propyl-4-methyl-6- ([gamma] methyl-benzimidazol-2-yl) benzimidazole and 4-bromomethyl-biphenyl-2-carboxylic acid directly via a nucleophilic substitution reaction generating telmisartan 4 '- [(4'-methyl-2'-propyl ni [2,6' -IH- benzimidazol-ni] -I' yl) methyl] - [1, I '_ -biphenyl] ~ 2 ~ carboxylic acid.

[0011] 所述缚酸剂为有机碱,所述有机碱选自醇钠、三こ胺、三正丁胺和三丙基胺中的任 [0011] The acid binding agent is an organic base, the organic base is selected from sodium alkoxide, any one of three ko amine, tributylamine and tripropylamine of

意ー种。 Italian ー species.

[0012] 所述缚酸剂为无机碱,所述无机碱选自NaOH、KOH、CsOH, Ba (OH)2, Mg (OH)2,Ca (OH)2, KHCO3> K2CO3 > Na2CO3 和Cs2CO3 中的任意ー种。 [0012] The acid binding agent is an inorganic base, the inorganic base is selected from NaOH, KOH, CsOH, Ba (OH) 2, Mg (OH) 2, Ca (OH) 2, KHCO3> K2CO3> Na2CO3 and Cs2CO3 inー of any kind.

[0013] 所述亲核反应的温度为50_120°C,反应时间8-16小时。 [0013] The reaction temperature of nucleophilic 50_120 ° C, the reaction time is 8-16 hours.

[0014] 所述反应溶剂选自DMF、DMS0、ニ氧六环、卩比咯烷酮类、丁酮、2-甲基异丁基酮和こニ醇ニ甲醚中的任意ー种。 [0014] The reaction solvent is selected from DMF, DMS0, Ni oxygen dioxane, pyrrolidone type Jie, methyl ethyl ketone, methyl isobutyl ketone, and alcohols ko ni ni ether ー any species.

[0015] 所述反应液分离纯化的步骤为:将反应液加入到水中,调节pH值至2-3,析出固体,过滤烘干得到粗品,所得粗品用こ酸こ酯打浆一次,烘干后再用DMF重结晶得到式III所示的替米沙。 [0015] The purification step of separating the reaction liquid: The reaction mixture was added to water, adjusted to pH 2-3, the precipitated solid was filtered dried to give the crude product, the crude product was obtained ko ko acid ester beating once, after drying DMF then recrystallized Mischa shown for formula III.

[0016] 本发明与现有技术相比,具有如下优点: [0016] Compared with the prior art the present invention has the following advantages:

[0017] (I)本发明寻找到了一种新的用以生产药物替米沙坦的化学合成方法。 [0017] (I) of the present invention is to find a new method for the production of chemically synthesized drugs telmisartan. 本发明方法通过2-正丙基-4-甲基-6-(Γ -甲基苯并咪唑-2-基)苯并咪唑与4-溴甲基联苯-2-羧酸在缚酸剂的作用下,经亲核取代反应直接生成替米沙坦。 The method of the present invention by reacting 2-n-propyl-4-methyl -6- (Γ - methyl-benzimidazol-2-yl) benzimidazole and 4-bromomethyl-biphenyl-2-carboxylic acid in the acid-binding agent under the action, by a nucleophilic substitution reaction generated directly telmisartan. 该化学合成方法的路线更加合理,其反应条件更加温和。 The chemical synthesis route is more reasonable, more moderate reaction conditions.

[0018] (2)本发明的合成路线相对于现有技术步骤缩短,因此简化了生产操作,其他生产成本,包括时间、设备、辅料的成本也大大降低,因此更适用于エ业化生产。 [0018] (2) The synthesis route of the present invention with respect to prior art step is shortened, thus simplifying the production operation, other production costs, including the cost of time, equipment, materials is also greatly reduced, and therefore more suitable for industrialized production Ester.

[0019] (3)本发明制备方法提高了最终产品替米沙坦的收率,具有显著的经济效益。 Preparation of [0019] (3) The method of the present invention to improve the yield of the end product telmisartan, has significant economic benefits.

具体实施例: Specific Example:

[0020] 为了更好地理解本发明的内容,下面结合具体实施例作进ー步说明。 [0020] For a better understanding of the present invention, the following Examples with reference to specific embodiments as described further ー feed. 应理解,这些实施例仅用于对本发明进ー步说明,而不用于限制本发明的范围。 It should be understood that these examples are only intended to further illustrate the present invention into ー not intended to limit the scope of the present invention. 此外应理解,在阅读了本发明所述的内容后,该领域的技术人员对本发明作出一些非本质的改动或调整,仍属于本发明的保护范围。 Furthermore, it should be understood that, after reading the contents of the present invention, the skilled in the art to make some non-essential changes or adjustments to the present invention, still fall within the scope of the present invention.

[0021] 实施例I制备替米沙坦 [0021] Example I Preparation of telmisartan

[0022] 将式I所示的2-正丙基-4-甲基-6-(1'_甲基苯并咪唑-2-基)苯并咪唑(30. 4g, O. IOmol )、4_ 溴甲基联苯-2-羧酸(43. 6g, O. 15mol)、碳酸钾细粉(30g, O. 2mol)与DMSO 500ml混合,100°C下反应10小时,将反应液倒入冰水中,用稀盐酸缓慢调节至pH2_3,析出固体。 [0022] 2-n-propyl-4 of formula I is methyl-6- (1'_ methyl-benzimidazol-2-yl) benzimidazole (30. 4g, O. IOmol), 4_ bromomethyl-biphenyl-2-carboxylic acid (43. 6g, O. 15mol), finely powdered potassium carbonate (30g, O. 2mol) 500ml mixed with DMSO, reacted for 10 hours at 100 ° C, the reaction mixture was poured into ice water, dilute hydrochloric acid was slowly adjusted to pH2_3, to precipitate a solid. 过滤,70°C烘干得粗品,所得粗品用こ酸こ酯300ml加热打浆一次。 Filtered, 70 ° C dried to obtain a crude product, the crude product was obtained ko ko acid ester is heated 300ml beating again. 过滤,70°C烘干。 Filtered, 70 ° C dry. 以DMF重结晶得式III所示的替米沙坦44. 2g,收率:86. 5%。 44. 2g DMF to telmisartan Recrystallization of formula III, Yield: 865%.

[0023] 其中,所述DMSO可以用DMF、ニ氧六环、吡咯烷酮类、丁酮、2-甲基异丁基酮和こニ醇ニ甲醚中的任意ー种替换。 [0023] wherein, the DMSO can be of DMF, Ni oxygen dioxane, pyrrolidones, any ketone, methyl isobutyl ketone, and alcohols ko ni ni ether ー kinds of replacement.

[0024] 实施例2制备替米沙坦 [0024] Example 2 Preparation of telmisartan

[0025] 将式I所示的2-正丙基-4-甲基-6-(1'_甲基苯并咪唑-2-基)苯并咪唑(30. 4g,O. 10mol)、4_ 溴甲基联苯~2~ 羧酸(37. 83g,O. 13mol)、氢氧化钾(5. 6g,O. IOmol)与2-甲基异丁基酮500ml混合,80°C下反应16小吋,将反应液倒入冰水中,用稀盐酸缓慢调pH2-3,析出固体。 [0025] 2-n-propyl-4 of formula I is methyl-6- (1'_ methyl-benzimidazol-2-yl) benzimidazole (30. 4g, O. 10mol), 4_ bromomethylbiphenyl ~ 2 ~ carboxylic acid (37. 83g, O. 13mol), potassium hydroxide (5. 6g, O. IOmol) was mixed with methyl-isobutyl ketone 500ml, reaction at 80 ° C 16 small inches, the reaction mixture was poured into ice-water, adjusted pH 2-3 with dilute hydrochloric acid, slowly, to precipitate a solid. 过滤,70°C烘干得粗品,所得粗品用こ酸こ酯300ml加热打浆一次。 Filtered, 70 ° C dried to obtain a crude product, the crude product was obtained ko ko acid ester is heated 300ml beating again. 过滤,70°C烘干。 Filtered, 70 ° C dry. 以DMF重结晶得式III所示的替米沙坦38. Sg,收率:76%。 Telmisartan 38. Sg shown in DMF recrystallization of formula III, yield: 76%.

[0026] 其中,所述2-甲基异丁基酮可以用DMF、DMS0、ニ氧六环、吡咯烷酮类、丁酮和こニ醇ニ甲醚中的任意ー种替换。 [0026] wherein said methyl isobutyl ketone may be used DMF, DMS0, Ni oxygen dioxane, pyrrolidones, alcohols ni ni ko butanone and methyl ether of any species ー replacement.

[0027] 实施例3制备替米沙坦 [0027] Example 3 Preparation of telmisartan embodiment

[0028] 将式I所示的2-正丙基-4-甲基-6-(Γ-甲基苯并咪唑-2-基)苯并咪唑(30. 4gO. IOmol)、4_ 漠甲基联苯-2-竣酸(43. 6g, O. 15mol)、こ醇纳(13. 6g, O. 2mol)与N-甲基吡咯烷酮500ml混合,50摄氏度下反应10小吋,将反应液倒入冰水中,用稀盐酸缓慢调PH2-3,析出固体。 [0028] 2-n-propyl-4 of formula I is methyl-6- ([gamma] methyl-benzimidazol-2-yl) benzimidazole (30. 4gO. IOmol), 4_ desert methyl biphenyl-2-carboxylic acids (43. 6g, O. 15mol), sodium ko alcohol (13. 6g, O. 2mol) was mixed with N- methylpyrrolidone 500ml, reaction at 50 ° C for 10 hours inch, the reaction was poured into ice-water, adjusted pH 2-3 with dilute hydrochloric acid, slowly, to precipitate a solid. 过滤,70°C烘干得粗品,所得粗品用こ酸こ酯300ml加热打浆一次。 Filtered, 70 ° C dried to obtain a crude product, the crude product was obtained ko ko acid ester is heated 300ml beating again. 过滤, 70°C烘干。 Filtered, 70 ° C dry. 以DMF重结晶得式III所示的替米沙坦27. Ig,收率:54%。 Telmisartan 27. Ig recrystallization from DMF shown in formula III, yield: 54%.

[0029] 其中,所述N-甲基吡咯烷酮可以用DMF、DMS0、ニ氧六环、其他吡咯烷酮类、2-甲基异丁基酮、丁酮和こニ醇ニ甲醚中的任意ー种替换。 [0029] wherein said N- methylpyrrolidone may be used DMF, DMS0, Ni oxygen dioxane, other pyrrolidones, methyl isobutyl ketone, methyl ethyl ketone and alcohol ko ni ni ether any species ーreplace.

[0030] 实施例4制备替米沙坦 [0030] Example 4 Preparation of telmisartan embodiment

[0031] 将式I所示的2-正丙基-4-甲基-6-(1'_甲基苯并咪唑-2-基)苯并咪唑(30. 4g,O. 10mol)、4_ 溴甲基联苯-2-羧酸(43. 6g,O. 15mol)、三こ胺(12. Ig,O. 15mol)与こニ醇ニ甲醚500ml混合,100度下反应6小吋,将反应液倒入冰水中,用稀盐酸缓慢调PH2-3,析出固体。 [0031] 2-n-propyl-4 of formula I is methyl-6- (1'_ methyl-benzimidazol-2-yl) benzimidazole (30. 4g, O. 10mol), 4_ bromomethyl-biphenyl-2-carboxylic acid (43. 6g, O. 15mol), three ko amine (12. Ig, O. 15mol) with 500ml ether ko ni ni alcohol were mixed and reacted for 6 hours at 100 degrees inch, the reaction mixture was poured into ice-water, adjusted pH 2-3 with dilute hydrochloric acid, slowly, to precipitate a solid. 过滤,70°C烘干得粗品,所得粗品用こ酸こ酯300ml加热打浆一次。 Filtered, 70 ° C dried to obtain a crude product, the crude product was obtained ko ko acid ester is heated 300ml beating again. 过滤,70°C烘干。 Filtered, 70 ° C dry. 以DMF重结晶得式III所示的替米沙坦25. Ig,收率:50%。 Telmisartan 25. Ig recrystallization from DMF shown in formula III, yield: 50%.

[0032] 其中,所述こニ醇ニ甲醚可以用DMF、DMS0、ニ氧六环、吡咯烷酮类、2-甲基异丁基酮和丁酮中的任意一种替换。 [0032] wherein the ko ni ni ether alcohols may be used DMF, DMS0, Ni oxygen dioxane, pyrrolidones, methyl isobutyl ketone, methyl ethyl ketone, and any of one alternative.

[0033] 如上所述,便可较好地实现本发明。 [0033] As described above, the present invention can be better achieved.

Claims (7)

1. ー种制备替米沙坦的方法,其特征在于,所述方法为:在反应溶剂中,加入式I所示的化合物I和式II所示的化合物II,加热升温,在缚酸剂的作用下,亲核反应至所述化合物I反应完全;反应液经分离纯化得到式III所示的替米沙坦; 1. The method of telmisartan ー seed preparation, characterized in that the method is: in a reaction solvent, the compound of Formula I and II as shown in Formula I compound II, heating temperature, in an acid-binding agent under the action, a nucleophilic reaction to the completion of the reaction of compound I; the reaction solution was separated to obtain telmisartan of formula III;
Figure CN102731407AC00021
2.如权利要求I所述的制备替米沙坦的方法,其特征在于:加入的化合物I、化合物II和缚酸剂的物质的量比为:1:1. f2. 0:1.(T2. O。 2. A process for the preparation of telmisartan according to claim I, wherein: the added compound I, compound II and the ratio of acid binder substance is: 1: 1 f2 0:... 1 ( T2. O.
3.如权利要求2所述的制备替米沙坦的方法,其特征在于:所述缚酸剂为有机碱,所述有机碱选自醇钠、三こ胺、三正丁胺和三丙基胺中的任意ー种。 3. The method of preparing telmisartan according to claim 2, wherein: said acid binding agent is an organic base, the organic base is selected from sodium alkoxide, three ko amine, tri-n-butylamine and tripropyleneー any kind of amine.
4.如权利要求2所述的制备替米沙坦的方法,其特征在于:所述缚酸剂为无机碱,所述无机碱选自NaOH、KOH、CsOH, Ba (OH)2, Mg (OH)2, Ca (OH)2, KHCO3> K2C03、Na2CO3 和Cs2CO3 中的任意ー种。 4. The method of preparing telmisartan according to claim 2, wherein: said acid binding agent is an inorganic base, the inorganic base is selected from NaOH, KOH, CsOH, Ba (OH) 2, Mg ( OH) 2, Ca (OH) 2, KHCO3> K2C03, Na2CO3 or Cs2CO3 any ー species of.
5.如权利要求2所述的制备替米沙坦的方法,其特征在于,所述亲核反应的温度为50-120°C,反应时间8-16小时。 5. A process for the preparation of telmisartan according to claim 2, wherein the nucleophilic reaction temperature of 50-120 ° C, the reaction time is 8-16 hours.
6.如权利要求5所述的制备替米沙坦的方法,其特征在于,所述反应溶剂选自DMF、DMSO、ニ氧六环、吡咯烷酮类、丁酮、2-甲基异丁基酮和こニ醇ニ甲醚中的任意ー种。 6. A process for the preparation of telmisartan according to claim 5, characterized in that the reaction solvent is selected from DMF, DMSO, Ni oxygen dioxane, pyrrolidones, methyl ethyl ketone, methyl isobutyl ketone and any species ー ko ni ni ether of an alcohol.
7.如权利要求1-5任意一项所述的制备替米沙坦的方法,其特征在于,所述反应液分离纯化的步骤为:将反应液加入到水中,调节PH值至2-3,析出固体,过滤烘干得到粗品,所得粗品用こ酸こ酯打浆一次,烘干后再用DMF重结晶得到式III所示的替米沙坦。 7. The preparation according to any one of the telmisartan method as claimed in claim 1-5, wherein said step of separation and purification of the reaction solution as follows: The reaction mixture was added to water, adjusting the PH value to 2-3 , the precipitated solid was filtered dried to give the crude product, the crude product was obtained ko ko acid ester beating once, after drying recrystallized with DMF telmisartan of formula III.
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* Cited by examiner, † Cited by third party
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WO2019020104A1 (en) * 2017-07-28 2019-01-31 武汉朗来科技发展有限公司 Preparation and analysis methods for benzimidazole derivative

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
WO2014067237A1 (en) * 2012-10-31 2014-05-08 上海特化医药科技有限公司 Telmisartan preparation method and intermediate thereof
CN103787982A (en) * 2012-10-31 2014-05-14 上海特化医药科技有限公司 Telmisartan preparation method and intermediate of telmisartan
CN104768936A (en) * 2012-10-31 2015-07-08 上海特化医药科技有限公司 Enzalutamide polymorphic forms and its preparation
CN104768936B (en) * 2012-10-31 2017-07-28 上海特化医药科技有限公司 Prepare the method and its intermediate of Telmisartan
WO2019020104A1 (en) * 2017-07-28 2019-01-31 武汉朗来科技发展有限公司 Preparation and analysis methods for benzimidazole derivative
CN109305965A (en) * 2017-07-28 2019-02-05 武汉朗来科技发展有限公司 Benzimidizole derivatives preparation and analysis method

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