CN102766138A - Preparation method of azilsartan - Google Patents

Preparation method of azilsartan Download PDF

Info

Publication number
CN102766138A
CN102766138A CN2012102544059A CN201210254405A CN102766138A CN 102766138 A CN102766138 A CN 102766138A CN 2012102544059 A CN2012102544059 A CN 2012102544059A CN 201210254405 A CN201210254405 A CN 201210254405A CN 102766138 A CN102766138 A CN 102766138A
Authority
CN
China
Prior art keywords
methyl
carboxylate
benzimidazole
azilsartan
ko
Prior art date
Application number
CN2012102544059A
Other languages
Chinese (zh)
Other versions
CN102766138B (en
Inventor
陈林
Original Assignee
上海凯谱林医药开发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海凯谱林医药开发有限公司 filed Critical 上海凯谱林医药开发有限公司
Priority to CN201210254405.9A priority Critical patent/CN102766138B/en
Publication of CN102766138A publication Critical patent/CN102766138A/en
Application granted granted Critical
Publication of CN102766138B publication Critical patent/CN102766138B/en

Links

Abstract

The invention relates to a preparation method of azilsartan, comprising the following steps of: (1) preparing ethoxybenzimidazole-7-methyl carboxylate; (2) preparing 2-cyan-4'-bromomethyl biphenyl; (3) dissolving the ethoxybenzimidazole-7-methyl carboxylate and the 2-cyan-4'-bromomethyl biphenyl into ethanol; adding potassium carbonate to react to obtain 1-[(2'-cyan diphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-methyl carboxylate; (4) suspending the 1-[(2'-cyan diphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-methyl carboxylate in water; adding hydroxylamine hydrochloride, sodium hydroxide and tetrabutylammonium fluoride; heating and reflowing, and then cooling; adding the sodium hydroxide and ethyl chloroformate, heating and reflowing to obtain azilsartan methyl ester; and (5) hydrolyzing the azilsartan methyl ester to obtain a product. The preparation method of the azilsartan, disclosed by the invention, has the advantages of being short in process route, high in yield, and safe and reliable; and the purity of the azilsartan obtained by using the method is high.

Description

ー种阿齐沙坦的制备方法 The method of producing ー of azilsartan

技术领域 FIELD

[0001] 本发明属于治疗高血压药物的制备领域,特别涉及ー种阿齐沙坦的制备方法。 [0001] The present invention belongs to the field of medicament for treating hypertension, in particular, it relates to a method of azilsartan ー species. 背景技术 Background technique

[0002] 阿齐沙坦是ー款治疗高血压症的血管紧张素II受体拮抗剂药物,多用于治疗高血压症,也是目前唯一处于末期临床的血管紧张素II受体拮抗剂(沙坦类)药物。 [0002] azilsartan is an angiotensin ー models treat hypertension II receptor antagonist drug used for the treatment of hypertension, is the only in the late clinical angiotensin II receptor antagonists (losartan class) drugs. 该药物由日本武田制药公司在2012年上市,其临床阶段的疗效显著。 In 2012, the drug is marketed by Takeda Pharmaceuticals, a significant effect clinical phase. 根据著名的药物情报机构Thomson Reuters Pharma的预测,该药物2016年的年销售额会超过3亿美元,该中间体还可以用于坎地沙坦,阿奇沙坦酯等药物的合成,市场上对该类中间体的需求日益増大。 According to well-known pharmaceutical intelligence agency Thomson Reuters Pharma projections, the drug annual sales in 2016 of more than $ 300 million, the intermediates can also be used for the synthesis of candesartan, Archie medoxomil and other drugs on the market the growing demand for this class of intermediates zo large. 是合成包括盐酸法舒地尔等多种药物的重要中间体,并且其在抗氧剂、发泡剂、化妆品,乳化剤,含能材料等方面有广泛应用,具有很大的市场潜カ。 Is an important intermediate synthesis include fasudil hydrochloride Erdeng more drugs, and which has wide application in antioxidants, foaming agents, cosmetics, emulsified Ji, energetic materials, etc., have great market potential ka.

[0003] 1996年US5583141专利报道采用阿奇沙坦甲酯作为原料,经过最后ー步水解,直接得到阿奇沙坦,但是具体方法,及其之前的具体エ艺,没有公布。 [0003] In 1996 US5583141 patent reports using azithromycin candesartan ester as the starting material, after the final hydrolysis step ー, losartan azithromycin directly, but the specific method, and particularly prior arts Ester, not disclosed. 2006年的PCT2006015134专利报道以2-羧基-3-硝基-甲酸甲酯为原料,经过酰化,还原,关环三步,合成中间体1_[ (2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯;该专利采用的エ艺与上ー篇类似,在第一歩中使用的ニ氯亚砜,和第二步中使用了叠氮化钠,都属于较为危险的化工原料,在使用中増加了生产的的危险性,不利于エ业的安全。 Patent reports in 2006 PCT2006015134 nitro-2-carboxy-3 - carboxylic acid methyl ester as starting material, acylation, reduction, cyclization three steps, the synthesis of Intermediate 1_ [(2'-cyanobiphenyl-4-yl ) methyl] -2-ko-benzimidazole-7-carboxylate; ester arts of the patent with the use of similar articles ー, Ni-chloro sulfoxide ho used in the first, the second step, and using sodium azide, are all the more dangerous chemicals, in use, the risk of increase in production is not conducive Ester security industry. 2011年的PCT2011145100专利报道用3-硝基邻苯ニ甲酸作为起始原料,经过酯化,酰化,重排,烷基化,脱保护,还原,关环等七步反应,合成中间体1_[ (2' -氰基联苯-4-基)甲基]-2-乙氧基苯并咪唑-7-羧酸甲酯;该专利涉及的路线较长,エ艺周期长,原料种类多,合成成本高,收率较低,特别是对于第二步中使用的ニ氯亚砜,和第三步中使用的叠氮化钠,属于较为危险的化工原料,在使用中増加了生产的危险性,不利于エ业的安全。 Patent reports 2011 PCT2011145100 Ni with 3-nitro-phthalic acid as a starting material, after esterification, acylation, rearrangement, alkylation, deprotection, reduction, cyclization and other seven-step reaction, synthetic intermediates 1_ [(2 '- cyanobiphenyl-4-yl) methyl] -2-ethoxy-benzimidazole-7-carboxylate; long line according to the patent, ester arts long period, multiple types of raw materials , synthesis of high cost, low yield, particularly for Ni thionyl chloride used in the second step, sodium azide and used in the third step, is more dangerous chemicals, in use, to increase in the production danger, is not conducive to Ester security industry.

发明内容 SUMMARY

[0004] 本发明所要解决的技术问题是提供ー种阿齐沙坦的制备方法,该方法的エ艺路线短,生产周期短,合成成本低,避免了ニ氯亚砜和叠氮化钠等危险品的使用,安全可靠;得到的产品纯度高,为98. (T99. 5%。 [0004] The present invention solves the technical problem is to provide a method of azilsartan ー species, the short-line process Ester arts, short production period, low cost synthesis, thionyl chloride avoid Ni and sodium azide use of dangerous goods, safety and reliability; high purity product obtained as 98. (T99 5%..

[0005] 本发明的ー种阿齐沙坦的制备方法,包括: Preparation Method [0005] ー azilsartan species present invention, comprising:

[0006] (I)こ氧基苯并咪唑-7-羧酸甲酯 [0006] (I) ko-benzimidazole-7-carboxylate

[0007] 按摩尔比I: f 1:3将2,3- ニ氨基苯甲酸甲酯和原碳酸四こ酷溶解到醋酸中,于2(T30°C加入四丁基氟化铵,加热回流反应1(T16小时后冷却至室温,然后蒸去溶剂醋酸,将得到的粗产品用水打浆过滤,固体用こ醇重结晶,干燥,得到こ氧基苯并咪唑-7-羧酸甲酷; [0007] The molar ratio of I: f 1: 3 mixture of 2,3-Ni-aminobenzoate and cool ko four orthocarbonate was dissolved in acetic acid, in 2 (T30 ° C was added tetrabutylammonium fluoride was heated at reflux after the reaction 1 (T16 hour cooled to room temperature, the acetic acid solvent was then distilled off and the resulting crude product was slurried with water filtration, ko solid was recrystallized from an alcohol, and dried to give ko-benzimidazole-7- carboxylic acid a cool;

[0008] (2) 2-氰基-4'-溴甲基联苯的合成 [0008] (2) Synthesis of 2-cyano-4'-bromomethyl-biphenyl

[0009] 将2-氰基-4 '-甲基联苯溶于ニ氯甲烷中,分批加入N-溴代琥珀酰亚胺,室温下搅拌4-8小时,反应结束后,经水洗、蒸馏、石油醚打浆,然后过滤、干燥,得到2-氰基-4'-溴甲基联苯,该粗品无需进行进ー步纯化; [0009] 2-cyano-4 '- Ni-biphenyl was dissolved in methylene chloride, was added portionwise N- bromosuccinimide, with stirring at room temperature for 4-8 hours, after the reaction, washed with water, distillation, beating petroleum ether, then filtered and dried to give 2-cyano-4'-bromo-biphenyl, the crude product was carried further without purification into ー;

[0010] (3)1-[(2/ -氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的合成 [0010] (3) 1 - [(2 / - cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate in

[0011] 按摩尔比I: f 1:2将上述こ氧基苯并咪唑-7-羧酸甲酯和2-氰基-4' _溴甲基联苯溶解到こ醇中,加入碳酸钾,回流8〜16小时,然后蒸掉こ醇、加水打浆,再过滤、用こ醇重结晶得到1_[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酷; [0011] The molar ratio of I: f 1: 2 the above-ko-benzimidazole-7-carboxylate and 2-cyano-4 '_ ko bromomethyl-biphenyl was dissolved in an alcohol, potassium carbonate refluxed for 8~16 hours, and then distilled off ko alcohol, slurried with water, filtered again, to give 1 _ [(2'-cyanobiphenyl-4-yl) methyl] -2- alcohol recrystallized with ko ko pentoxybenzene benzimidazole-7-carboxylic acid A cool;

[0012] (4)将上述1_[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯悬浮于水中,加入盐酸羟胺、氢氧化钠和四丁基氟化铵,加热回流1(T16小时后冷却,然后加入氢氧化钠,再于2(T30°C加入氯甲酸こ酷,加热回流8〜16小时后冷却析出固体,最后过滤、水洗、干燥得到阿奇沙坦甲酯; [0012] (4) The above 1 _ [(2'-cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate was suspended in water, was added hydroxylamine hydrochloride, sodium hydroxide and tetrabutylammonium fluoride was heated at reflux for 1 (T16 h after cooling, followed by addition of sodium hydroxide, and then at 2 (T30 ° C ko cool chloroformate, heated at reflux for 8~16 hours and then cooled to precipitate a solid, finally filtered, washed with water, and dried to give azithromycin medoxomil ester;

[0013] (5)将上述阿奇沙坦甲酯悬浮于水中,加入氢氧化锂水溶液,室温搅拌12-16小吋,于冰水浴下调节PH值为2-4后过滤,最后用こ醇重结晶得到白色晶体,即为阿齐沙坦,纯度为98〜99%。 [0013] (5) The above methyl ester was suspended in water Archie Chastain, aqueous lithium hydroxide solution was added, stirred at room temperature 12-16 inch small, ice-water bath and filtered after adjusting the PH value 2-4, and finally with an alcohol ko recrystallization yielded white crystals, namely azilsartan purity of 98~99%.

[0014] 步骤(I)中所述的四丁基氟化铵的用量为2,3_ ニ氨基苯甲酸甲酯摩尔量的5〜20%。 [0014] Step (I) in an amount according to tetrabutylammonium fluoride in an amount of 5~20 mole% of methyl anthranilate 2,3_ ni.

[0015] 步骤(2)中所述的N-溴代琥珀酰亚胺与2-氰基-4'-甲基联苯的摩尔比为I〜2:I。 [0015] Step (2) in the molar ratio of N- bromosuccinimide and 2-cyano-4'-methylbiphenyl was I~2: I.

[0016] 步骤(3)中所述的碳酸钾与こ氧基苯并咪唑-7-羧酸甲酯的摩尔比为:T5: I。 The molar ratio of carboxylate [0016] Step (3) in the group potassium carbonate and ko is a benzimidazole-7: T5: I.

[0017] 步骤(4)中所述的盐酸羟胺与1-[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的摩尔比为4〜8: I。 [0017] Step (4) above with hydroxylamine hydrochloride 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate in molar ratio of 4~8: I.

[0018] 步骤(4)中所述的加热回流1(T16小时前所加入的氢氧化钠与1_[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的摩尔比为4〜8:1。 [0018] Step (4) was heated to reflux in claim 1 (T16 hour before addition of sodium hydroxide and 1 _ [(2'-cyanobiphenyl-4-yl) methyl] -2-ko pentoxybenzene the molar ratio of benzimidazole-7-carboxylate of 4 to 8: 1.

[0019] 步骤(4)中所述的四丁基氟化铵的用量为1_[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯摩尔量的5-20%。 [0019] Step (4) in the amount of tetrabutylammonium fluoride 1 _ [(2'-cyanobiphenyl-4-yl) methyl] -2-benzimidazole-7-yloxy ko 5 to 20% molar amount of the carboxylic acid methyl ester.

[0020] 步骤(4)中所述的加热回流1(T16小时后所加入的氢氧化钠与1_[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的摩尔比为1:1 ;氯甲酸こ酯与1-[(2/ -氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的摩尔比为1:1。 After [0020] Step (4) was heated to reflux in claim 1 (h T16 added sodium hydroxide 1 _ [(2'-cyanobiphenyl-4-yl) methyl] -2-ko pentoxybenzene the molar ratio of benzimidazole-7-carboxylate is 1: 1; ko chloroformate ester with 1 - [(2 / - cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole the molar ratio of 7-carboxylate is 1: 1.

[0021] 步骤(5)中所述的氢氧化锂水溶液的质量浓度为20%,氢氧化锂水溶液中氢氧化锂的含量为阿奇沙坦甲酯摩尔量的2飞倍。 [0021] Step (5) concentration in the aqueous solution of lithium hydroxide was 20%, the content of the lithium hydroxide aqueous solution of lithium hydroxide to 2-fold fly Archie medoxomil ester molar amount.

[0022] 步骤(5)中所述的调节pH值为采用稀盐酸调节。 [0022] Step (5) in said adjusted to pH adjustment using dilute hydrochloric acid.

[0023] 本发明的合成路线如下: [0023] The synthetic routes of the present invention are as follows:

[0024] [0024]

Figure CN102766138AD00061

[0025] 本发明的合成产品阿齐沙坦的表征: [0025] Synthesis of the product of the present invention is characterized azilsartan:

[0026] 下面通过核磁共振氢谱,质谱,高效气相色谱、熔点测定等方法对本发明合成的化合物阿齐沙坦进行表征。 [0026] Next, by the method of nuclear magnetic resonance spectra, mass spectra, high gas chromatography, melting point measurement and the like of the present invention synthesized compounds were characterized azilsartan.

[0027] I、核磁共振氢谱数据如下: [0027] I, H NMR data was as follows:

[0028] H-NMR (400MHz, DMS0_d6) : 8 I. 47 (3H, t, J=7. 0),4. 67 (2H, q, J=7. 0),5. 77 (2H, s),7. 07-7. 70(11H, m)。 [0028] H-NMR (400MHz, DMS0_d6): 8 I. 47 (3H, t, J = 7 0.), 4 67 (2H, q, J = 7 0.), 5 77 (2H, s.. ), 7. 07-7. 70 (11H, m).

[0029] 其中化学位移5 =1. 47 (3H)和4. 76 (2H)咪唑环上こ氧基的氢;5. 77 (2H)是苄位的氢,7. 07-7. 70 (IlH)是芳香环上的氢。 [0029] where ko hydrogen group on the chemical shift 5 = 1 47 (3H) and 4. 76 (2H) imidazole ring;.. 5 77 (2H) is a benzylic hydrogen, 707-770 (. ILH) is hydrogen on the aromatic ring. 核磁共振氢谱测定结果确定为阿齐沙坦。 Hydrogen nuclear magnetic resonance spectroscopy result determined azilsartan.

[0030] 2.质谱仪测定数据如下: [0030] 2. The mass spectrometer data was as follows:

[0031] ESI-MS (m/z,%) 457。 [0031] ESI-MS (m / z,%) 457.

[0032] 该化合物分子量为456. 14,谱图中出现457 [M+H]+的信号。 [0032] The molecular weight of the compound 456. 14, 457 [M + H] + signal spectrum appears. 质谱测定结果确定为阿齐沙坦。 Mass spectrometry results are decided as azilsartan.

[0033] 3、高效气相色谱:[0034]纯度为 98. 0〜99. 5%。 [0033] 3, high GC: [0034] 0~99 98. 5% purity.

[0035] 4、熔点分析: [0035] 4, mp Analysis:

[0036]熔点为 192_194で。 [0036] mp 192_194 で.

[0037] 综合分析上述核磁共振氢谱,质谱,高效气相色谱、熔点測定,表明本发明合成的最終产品为阿齐沙坦,并纯度合格。 [0037] The comprehensive analysis of the above-described hydrogen spectra, mass spectra, high gas chromatography, nuclear magnetic resonance melting point determination, the present invention indicates that the final product is synthesized azilsartan, and acceptable purity. 其结构式为: Its structural formula is:

[0038] [0038]

Figure CN102766138AD00071

[0039] 其中收率为46. 5〜63. 5%。 [0039] 46. 5~63 wherein Yield 5%.

[0040] 本发明以2,3- ニ氨基苯甲酸甲酷,原碳酸四こ酷,2-氰基-4' -甲基联苯为原料,以醋酸,ニ氯甲烧,こ醇,水为溶剂,通过五步反应,得到目标产品阿齐沙坦,并经液相色谱、核磁谱图、质谱进行数据表征。 [0040] In the present invention, 2,3-diaminobenzoic acid methyl ni cool, cool orthocarbonate four ko, 2-cyano-4 '- methyl-biphenyl as a raw material, acetic acid, ni chloroformate burning, ko alcohol, water as solvent, by five steps to give the title product azilsartan, and data characterizing by liquid chromatography, NMR spectrum, mass spectrum. 本发明エ艺路线段短,生产周期短,合成成本低;避免了以往专利中二氯亚砜和叠氮化钠等危险品的使用,使得エ艺更加温和,可靠,安全;本发明产品的收率高(为46. 5〜63. 5%),产品纯度高(为98. 0〜99. 5%)。 The present invention is a short route segment Ester arts, short production period, low cost synthesis; patent avoids the use of dangerous goods thionyl chloride and sodium azide in the past, so that more moderate Ester arts, reliable, safe; product of the present invention yield (46. of 5~63. 5%), high purity (98.3 0~99. 5%).

[0041] 有益效果: [0041] beneficial effects:

[0042] I、本发明的制备方法中避免了ニ氯亚砜和叠氮化钠等危险品的使用,使得エ艺更加温和,可靠,安全,并降低了成本;且多次回收こ醇,ニ氯甲烷等溶剂,降低了有毒试剂的排放和处理成本,符合国家绿色环保号召;另外,本发明可以实现对该产品大規模生产,满足国内外市场对该产品的大量需求; [0042] I, the production method of the present invention avoids the use of Ni thionyl chloride and sodium azide and other dangerous goods, such Ester arts milder, reliable, safe, and reduced cost; ko alcohol and recycled many times, ni solvent such as methylene chloride, to reduce the emission of toxic reagents and processing costs, called green line with the state; Further, the present invention can be mass production of the products to meet the needs of a large number of domestic and international market for this product;

[0043] 2、本发明使用中间体1_[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酷,经过ー锅法和水解,得到最终产品阿奇沙坦;与现有技术相比,可大幅降低生产成本和周期,节约了成本; [0043] 2, the present invention is Intermediate 1 _ [(2'-cyanobiphenyl-4-yl) methyl] -2-benzimidazole ko 7-carboxylic acid A cool, and after pot process ーhydrolysis, to give the final product azithromycin losartan; compared with the prior art, it can significantly reduce production costs and cycle cost savings;

[0044] 3、在本发明的生产过程中,中间体和最終产品纯度都能达到95%以上,均能满足市场要求,且收率高,为46. 5〜63. 5% ;得到的产品阿奇沙坦纯度高达98. 0^99. 5%。 [0044] 3, in the production process of the present invention, the intermediates and final product purity can be over 95%, can meet the market requirements, and high yield is 46. 5% 5~63;. The resulting product Archie losartan purity of up to 98.0 ^ 99.5%.

具体实施方式 Detailed ways

[0045] 下面结合具体实施例,进ー步阐述本发明。 [0045] The following embodiments with reference to specific embodiments, further illustrate the present invention into ー. 应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。 It should be understood that these embodiments are illustrative only and the present invention is not intended to limit the scope of the invention. 此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。 Furthermore, it should be understood that, after reading the teachings of the present invention, those skilled in the art that various changes or modifications may be made to the present invention, and these equivalents also fall within the scope of the appended claims of the present application as defined.

[0046] 实施例I [0046] Example I

[0047] (I)こ氧基苯并咪唑-7-羧酸甲酯 [0047] (I) ko-benzimidazole-7-carboxylate

[0048] 将2, 3- ニ氨基苯甲酸甲酯(166. 18g, Imol)与原碳酸四こ酉旨(192. 3g, ImoI)溶解在醋酸中(2L),于20°C加入四丁基氟化铵(13g,5%mol),升温回流反应10小时,冷却至室温,蒸去溶剂醋酸,粗产品用水打浆过滤,固体用こ醇重结晶,干燥,得到こ氧基苯并咪唑-7-羧酸甲酯(202. 6g,收率92%); [0048] The 2, 3-ni-aminobenzoate (166. 18g, Imol) and orthocarbonate four unitary purpose ko (192. 3g, ImoI) was dissolved in acetic acid (2L), at 20 ° C was added tetrabutylammonium yl ammonium fluoride (13g, 5% mol), heated at reflux for 10 hours, cooled to room temperature, the acetic acid solvent was evaporated, the crude product was filtered slurried with water, ko solid was recrystallized from an alcohol, and dried to give ko-benzimidazole - 7- carboxylate (202. 6g, 92% yield);

[0049] (2) 2-氰基-4'-溴甲基联苯的合成[0050] 将2-氰基-4'-甲基联苯(193g,lmol)溶于ニ氯甲烷中(2L),室温分批加入N-溴代琥珀酰亚胺(178g,lmol),室温下搅拌4小时,反应结束后,经水洗、蒸馏、石油醚打浆,过滤,干燥,得到2-氰基-4'-溴甲基联苯,该粗品无需进行进ー步纯化(243. 3g,收率89. 4%); [0049] (2) Synthesis of 2-cyano-4'-bromomethyl-biphenyl [0050] 2-cyano-4'-methylbiphenyl (193g, lmol) was dissolved in methylene chloride ni (2L ) at room temperature was added portionwise N- bromosuccinimide (178g, lmol), stirred at room temperature for 4 hours. after completion of the reaction, washed with water, distillation, refining petroleum ether, filtered and dried to give 2-cyano-4 '- bromo-biphenyl, the crude product was carried forward without further purification ー (243. 3g, 89. 4% yield);

[0051] (3)1-[(2/ -氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的合成 [0051] (3) 1 - [(2 / - cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate in

[0052] 将こ氧基苯并咪唑-7-羧酸甲酯(22g,0. lmol)和2_氰基-4'-溴甲基联苯(27. 2g, 0. lmol)溶解在こ醇中(300mL),加入碳酸钾(41. 4g, 0. 3mol),回流8小吋,蒸掉こ醇,加水打楽■,过滤,こ醇重结晶得到1_[ (2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯(32. Ig,收率78%); [0052] The ko-benzimidazole-7-carboxylate (22g, 0. Lmol) and 2_-cyano-4'-bromomethylbiphenyl (27. 2g, 0. lmol) was dissolved in ko alcohol (300 mL), was added potassium carbonate (41. 4g, 0. 3mol), refluxed for 8 hours inch, ko alcohol was distilled off, water was added playing yue ■, filtered, and recrystallized from an alcohol to give 1_ ko [(2'-cyanobiphenyl phen-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate (32. Ig, 78% yield);

[0053] (4)将ト[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯(20. 6g, 0. 05mol)悬浮于水中(250mL),加入盐酸轻月安(13. 9g, 0. 2mol)和氢氧化钠(8g, 0. 2mol),再加入四丁基氟化铵(0. 65g, 2. 5mmol),回流10小时,冷却,再加入氢氧化钠(2g, 0. 05mol),20°C加入氯甲酸こ酯(5. 4g, 0. 05mol),再回流8小时,冷却洗出固体,过滤,水洗,干燥得到阿奇沙坦甲酯(17.4g,74%); [0053] (4) The Suites [(2'-cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate (20. 6g, 0. 05mol) is suspended in water (250mL), hydrochloric acid was added safety light month (13. 9g, 0. 2mol) and sodium hydroxide (8g, 0. 2mol), was added tetrabutylammonium fluoride (0. 65g, 2. 5mmol) , refluxed for 10 hours, cooled, and then was added sodium hydroxide (2g, 0. 05mol), 20 ° C ko chloroformate ester (5. 4g, 0. 05mol), then refluxed for 8 hours, cooled to wash the solid was filtered, washed with water, and dried to give losartan azithromycin ester (17.4g, 74%);

[0054] (5)将阿奇沙坦甲酯(10g,21. 3mmol)悬浮于水中(45mL),加入质量浓度为20%的氢氧化锂水溶液(5. OmL, 41. 6mmol),室温搅拌16小时。 [0054] (5) the methyl ester Archie Losartan (10g, 21. 3mmol) was suspended in water (45mL), added to a concentration of 20% by mass aqueous solution of lithium hydroxide (5. OmL, 41. 6mmol), stirred at room temperature 16 hours. 冰水浴下用稀盐酸酸化到pH=3,过滤得到产品阿奇沙坦,こ醇重结晶得到白色晶体,纯度为98、9%(9. 50g,收率98%)。 Under ice-water bath and acidified with dilute hydrochloric acid to pH = 3, the product was filtered to give azithromycin losartan, ko recrystallized from an alcohol to give white crystals, with a purity of 98,9% (9. 50g, yield 98%).

[0055] 实施例2 [0055] Example 2

[0056] (I)こ氧基苯并咪唑-7-羧酸甲酯 [0056] (I) ko-benzimidazole-7-carboxylate

[0057] 将2, 3- ニ氨基苯甲酸甲酯(166. 18g, lmol)与原碳酸四こ酉旨(384. 6g, 2mol)溶解在醋酸中(2L),于20°C加入四丁基氟化铵(13g,5%mol),升温回流反应10小时,冷却至室温,蒸去溶剂醋酸,粗产品用水打浆过滤,固体用こ醇重结晶,干燥,得到こ氧基苯并咪唑-7-羧酸甲酯(204. 8g,收率93%); [0057] The 2, 3-ni-aminobenzoate (166. 18g, lmol) orthocarbonate and four unitary purpose ko (384. 6g, 2mol) was dissolved in acetic acid (2L), at 20 ° C was added tetrabutylammonium yl ammonium fluoride (13g, 5% mol), heated at reflux for 10 hours, cooled to room temperature, the acetic acid solvent was evaporated, the crude product was filtered slurried with water, ko solid was recrystallized from an alcohol, and dried to give ko-benzimidazole - 7- carboxylate (204. 8g, yield 93%);

[0058] (2) 2-氰基-4'-溴甲基联苯的合成 [0058] (2) Synthesis of 2-cyano-4'-bromomethyl-biphenyl

[0059] 将2-氰基-4' -甲基联苯(193g,lmol)溶于ニ氯甲烷中(2L),室温分批加入N-溴代琥珀酰亚胺(356g,2mol),室温下搅拌4小吋,反应结束后,经水洗,蒸馏,石油醚打浆,过滤,干燥,得到2-氰基-4'-溴甲基联苯,该粗品无需进行进ー步纯化(244. 9g,收率90%); [0059] 2-cyano-4 '- methyl-biphenyl (193g, lmol) was dissolved in methylene chloride ni (2L), at room temperature was added portionwise N- bromosuccinimide (356g, 2mol), room temperature for 4 inches under stirring, after the reaction, washed with water, distillation, refining petroleum ether, filtered and dried to give 2-cyano-4'-bromo-biphenyl, the crude product was carried further without purification into ー (244. 9g , yield 90%);

[0060] (3)1-[(2/ -氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的合成 [0060] (3) 1 - [(2 / - cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate in

[0061] 将こ氧基苯并咪唑-7-羧酸甲酯(22g,0. lmol)和2_氰基-4'-溴甲基联苯(27. 2g, 0. I lmol)溶解在こ醇中(300mL),加入碳酸钾(41. 4g, 0. 3mol),回流8小时,蒸掉こ醇,加水打楽■,过滤,こ醇重结晶得到1_[ (2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酷(32. 9g,收率80%); [0061] The ko-benzimidazole-7-carboxylate (22g, 0. Lmol) and 2_-cyano-4'-bromomethylbiphenyl (27. 2g, 0. I lmol) was dissolved in ko alcohol (300 mL), was added potassium carbonate (41. 4g, 0. 3mol), refluxed for 8 hours, ko alcohol was distilled off, water was added playing yue ■, filtered, and recrystallized from an alcohol to give 1_ ko [(2'-cyanobiphenyl phen-4-yl) methyl] -2-ko-benzimidazole-7- carboxylic acid A cool (32. 9g, 80% yield);

[0062] (4)将ト[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯(20. 6g, 0. 05mol)悬浮于水中(250mL),加入盐酸轻月安(13. 9g, 0. 2mol)和氢氧化钠(8g, 0. 2mol),再加入四丁基氟化铵(I. 3g, 5mmol),回流10小时,冷却,再加入氢氧化钠(2g, 0. 05mol),20°C加入氯甲酸こ酯(5. 4g, 0. 05mol),再回流8小时,冷却洗出固体,过滤,水洗,干燥得到阿奇沙坦甲酯(18. 3g,78%); [0062] (4) The Suites [(2'-cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate (20. 6g, 0. 05mol) is suspended in water (250mL), hydrochloric acid was added safety light month (13. 9g, 0. 2mol) and sodium hydroxide (8g, 0. 2mol), was added tetrabutylammonium fluoride (I. 3g, 5mmol), reflux 10 hours, cooled, and then was added sodium hydroxide (2g, 0. 05mol), 20 ° C ko chloroformate ester (5. 4g, 0. 05mol), then refluxed for 8 hours, cooled to wash the solid was filtered, washed with water, Archie dried to give methyl losartan (18. 3g, 78%);

[0063] (5)将阿奇沙坦甲酯(10g,21. 3mmol)悬浮于水中(45mL),加入质量浓度为20%的氢氧化锂水溶液(IOmL, 83. 2mmol)(同上),室温搅拌16小时。 [0063] (5) the methyl ester Archie Losartan (10g, 21. 3mmol) was suspended in water (45mL), added to a concentration of 20% by mass lithium hydroxide aqueous solution (IOmL, 83. 2mmol) (supra), room temperature stirred for 16 hours. 冰水浴下用稀盐酸酸化到pH=3,过滤得到产品阿奇沙坦,こ醇重结晶得到白色晶体,纯度为98、9%(9.56g,收率98. 6%)。 Under ice-water bath and acidified with dilute hydrochloric acid to pH = 3, the product was filtered to give azithromycin losartan, ko recrystallized from an alcohol to give white crystals, with a purity of 98,9% (9.56g, yield 98.6%).

[0064] 实施例3 [0064] Example 3

[0065] (I)こ氧基苯并咪唑-7-羧酸甲酯 [0065] (I) ko-benzimidazole-7-carboxylate

[0066] 将2, 3- ニ氨基苯甲酸甲酯(166. 18g, lmol)与原碳酸四こ酉旨(384. 6g, 2mol)溶解在醋酸中(2L),于30°C加入四丁基氟化铵(13g,5%mol),升温回流反应16小时,冷却至室温,蒸去溶剂醋酸,粗产品用水打浆过滤,固体用こ醇重结晶,干燥,得到こ氧基苯并咪唑-7-羧酸甲酯(211. 4g,收率96%); [0066] The 2, 3-ni-aminobenzoate (166. 18g, lmol) orthocarbonate and four unitary purpose ko (384. 6g, 2mol) was dissolved in acetic acid (2L), at 30 ° C was added tetrabutylammonium yl ammonium fluoride (13g, 5% mol), heated at reflux for 16 hours, cooled to room temperature, the acetic acid solvent was evaporated, the crude product was filtered slurried with water, solid was recrystallized ko alcohol, and dried to give ko-benzimidazole - 7- carboxylate (211. 4g, yield 96%);

[0067] (2) 2-氰基-4'-溴甲基联苯的合成 [0067] (2) Synthesis of 2-cyano-4'-bromomethyl-biphenyl

[0068] 将2-氰基-4' -甲基联苯(193g,lmol)溶于ニ氯甲烷中(2L),室温分批加入N-溴代琥珀酰亚胺(356g,2mol),室温下搅拌8小吋,反应结束后,经水洗,蒸馏,石油醚打浆,过滤,干燥,得到2-氰基-4'-溴甲基联苯,该粗品无需进行进ー步纯化(255. Sg,收率94%); [0068] 2-cyano-4 '- methyl-biphenyl (193g, lmol) was dissolved in methylene chloride ni (2L), at room temperature was added portionwise N- bromosuccinimide (356g, 2mol), room temperature inch under stirring for 8 hours, after the reaction, washed with water, distillation, refining petroleum ether, filtered and dried to give 2-cyano-4'-bromo-biphenyl, the crude product was carried further without purification into ー (255. Sg 94% yield);

[0069] (3)1-[(2/ -氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的合成 [0069] (3) 1 - [(2 / - cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate in

[0070] 将こ氧基苯并咪唑-7-羧酸甲酯(22g,0. lmol)和2_氰基-4'-溴甲基联苯(27. 2g, 0. 13mol)溶解在こ醇中(300mL),加入碳酸钾(41. 4g, 0. 3mol),回流8小时,蒸掉こ醇,加水打楽■,过滤,こ醇重结晶得到1_[ (2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酷(34. 5g,收率84%); [0070] The ko-benzimidazole-7-carboxylate (22g, 0. Lmol) and 2_-cyano-4'-bromomethylbiphenyl (27. 2g, 0. 13mol) was dissolved in ko alcohol (300 mL), was added potassium carbonate (41. 4g, 0. 3mol), refluxed for 8 hours, ko alcohol was distilled off, water was added playing yue ■, filtered, and recrystallized from an alcohol to give 1_ ko [(2'-cyanobiphenyl 4-yl) methyl] -2-ko-benzimidazole-7- carboxylic acid A cool (34. 5g, 84% yield);

[0071] (4)将1_[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯(20. 6g, 0. 05mol)悬浮于水中(250mL),加入盐酸轻胺(27. 8g, 0. 4mol)和氢氧化钠(16g, 0. 4mol),再加入四丁基氟化铵(I. 3g, 5mmol),回流10小时,冷却,再加入氢氧化钠(2g, 0. 05mol),20°C加入氯甲酸こ酯(5. 4g, 0. 05mol),再回流8小时,冷却洗出固体,过滤,水洗,干燥得到阿奇沙坦甲酯(19. 2g,82%); [0071] (4) _ 1 [(2'-cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate (20. 6g, 0. 05mol) is suspended in water (250mL), was added light hydrochloride (27. 8g, 0. 4mol) and sodium hydroxide (16g, 0. 4mol), was added tetrabutylammonium fluoride (I. 3g, 5mmol), refluxed for 10 hours, cooled, and then was added sodium hydroxide (2g, 0. 05mol), 20 ° C ko chloroformate ester (5. 4g, 0. 05mol), then refluxed for 8 hours, cooled to wash the solid was filtered, washed with water, dried Archie losartan obtained methyl (19. 2g, 82%);

[0072] (5)将阿奇沙坦甲酯(10g,21. 3mmol)悬浮于水中(45mL),加入质量浓度为20%的氢氧化锂水溶液(IOmL, 83. 2mmol),室温搅拌16小时。 [0072] (5) the methyl ester Archie Losartan (10g, 21. 3mmol) was suspended in water (45mL), added to a concentration of 20% by mass lithium hydroxide aqueous solution (IOmL, 83. 2mmol), stirred for 16 hours at room temperature . 冰水浴下用稀盐酸酸化到pH=3,过滤得到产品阿奇沙坦,こ醇重结晶得到白色晶体,纯度为98、9%(9. 56g,收率98. 6%)。 Under ice-water bath and acidified with dilute hydrochloric acid to pH = 3, the product was filtered to give azithromycin losartan, ko recrystallized from an alcohol to give white crystals, with a purity of 98,9% (9. 56g, 98.6% yield).

[0073] 实施例4 [0073] Example 4

[0074] (I)こ氧基苯并咪唑-7-羧酸甲酯 [0074] (I) ko-benzimidazole-7-carboxylate

[0075] 将2, 3- ニ氨基苯甲酸甲酯(166. 18g, lmol)与原碳酸四こ酉旨(384. 6g, 2mol)溶解在醋酸中(2L),于30°C加入四丁基氟化铵(13g,5%mol),升温回流反应16小时,冷却至室温,蒸去溶剂醋酸,粗产品用水打浆过滤,固体用こ醇重结晶,干燥,得到こ氧基苯并咪唑-7-羧酸甲酯(211. 4g,收率96%); [0075] The 2, 3-ni-aminobenzoate (166. 18g, lmol) orthocarbonate and four unitary purpose ko (384. 6g, 2mol) was dissolved in acetic acid (2L), at 30 ° C was added tetrabutylammonium yl ammonium fluoride (13g, 5% mol), heated at reflux for 16 hours, cooled to room temperature, the acetic acid solvent was evaporated, the crude product was filtered slurried with water, solid was recrystallized ko alcohol, and dried to give ko-benzimidazole - 7- carboxylate (211. 4g, yield 96%);

[0076] (2) 2-氰基-4'-溴甲基联苯的合成 [0076] (2) Synthesis of 2-cyano-4'-bromomethyl-biphenyl

[0077] 将2-氰基-4' -甲基联苯(193g,lmol)溶于ニ氯甲烷中(2L),室温分批加入N-溴代琥珀酰亚胺(356g,2mol),室温下搅拌8小吋,反应结束后,经水洗,蒸馏,石油醚打浆,过滤,干燥,得到2-氰基-4'-溴甲基联苯,该粗品无需进行进ー步纯化(255. Sg,收率94%); [0077] 2-cyano-4 '- methyl-biphenyl (193g, lmol) was dissolved in methylene chloride ni (2L), at room temperature was added portionwise N- bromosuccinimide (356g, 2mol), room temperature inch under stirring for 8 hours, after the reaction, washed with water, distillation, refining petroleum ether, filtered and dried to give 2-cyano-4'-bromo-biphenyl, the crude product was carried further without purification into ー (255. Sg 94% yield);

[0078] (3)1-[(2/ -氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的合成 [0078] (3) 1 - [(2 / - cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate in

[0079] 将こ氧基苯并咪唑-7-羧酸甲酯(22g,0. lmol)和2_氰基-4'-溴甲基联苯(27. 2g, 0. 13mol)溶解在こ醇中(300mL),加入碳酸钾(41. 4g, 0. 3mol),回流8小时,蒸掉こ醇,加水打楽■,过滤,こ醇重结晶得到1_[ (2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酷(34. 5g,收率84%); [0079] The ko-benzimidazole-7-carboxylate (22g, 0. Lmol) and 2_-cyano-4'-bromomethylbiphenyl (27. 2g, 0. 13mol) was dissolved in ko alcohol (300 mL), was added potassium carbonate (41. 4g, 0. 3mol), refluxed for 8 hours, ko alcohol was distilled off, water was added playing yue ■, filtered, and recrystallized from an alcohol to give 1_ ko [(2'-cyanobiphenyl 4-yl) methyl] -2-ko-benzimidazole-7- carboxylic acid A cool (34. 5g, 84% yield);

[0080] (4)将ト[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯(20. 6g, 0. 05mol)悬浮于水中(250mL),加入盐酸轻胺(27. 8g, 0. 4mol)和氢氧化钠(16g, 0. 4mol),再加入四丁基氟化铵(I. 95g, 7. 5mmol),回流10小时,冷却,再加入氢氧化钠(2g, 0. 05mol),20°C加入氯甲酸こ酯(5. 4g, 0. 05mol),再回流16小时,冷却洗出固体,过滤,水洗,干燥得到阿奇沙坦甲酯(19.9g,85%); [0080] (4) The Suites [(2'-cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate (20. 6g, 0. 05mol) is suspended in water (250mL), was added light hydrochloride (27. 8g, 0. 4mol) and sodium hydroxide (16g, 0. 4mol), was added tetrabutylammonium fluoride (I. 95g, 7. 5mmol), refluxed for 10 hours, cooled, and then was added sodium hydroxide (2g, 0. 05mol), 20 ° C ko chloroformate ester (5. 4g, 0. 05mol), then refluxed for 16 hours, cooled to wash the solid was filtered, washed with water , and dried to give losartan azithromycin ester (19.9g, 85%);

[0081] (5)将阿奇沙坦甲酯(10g,21. 3mmol)悬浮于水中(45mL),加入质量浓度为20%的氢氧化锂水溶液(IOmL, 83. 2mmol),室温搅拌16小时。 [0081] (5) the methyl ester Archie Losartan (10g, 21. 3mmol) was suspended in water (45mL), added to a concentration of 20% by mass lithium hydroxide aqueous solution (IOmL, 83. 2mmol), stirred for 16 hours at room temperature . 冰水浴下用稀盐酸酸化到pH=3,过滤得到产品阿奇沙坦,こ醇重结晶得到白色晶体,纯度为98、9%(9. 56g,收率98. 6%)。 Under ice-water bath and acidified with dilute hydrochloric acid to pH = 3, the product was filtered to give azithromycin losartan, ko recrystallized from an alcohol to give white crystals, with a purity of 98,9% (9. 56g, 98.6% yield).

[0082] 实施例5 [0082] Example 5

[0083] (I)こ氧基苯并咪唑-7-羧酸甲酯 [0083] (I) ko-benzimidazole-7-carboxylate

[0084] 将2, 3- ニ氨基苯甲酸甲酯(166. 18g, lmol)与原碳酸四こ酉旨(576. 9g, 3mol)溶解在醋酸中(2L),于30°C加入四丁基氟化铵(13g,5%mol),升温回流反应16小时,冷却至室温,蒸去溶剂醋酸,粗产品用水打浆过滤,固体用こ醇重结晶,干燥,得到こ氧基苯并咪唑-7-羧酸甲酯(211. 4g,收率96%); [0084] The 2, 3-ni-aminobenzoate (166. 18g, lmol) orthocarbonate and four unitary purpose ko (576. 9g, 3mol) was dissolved in acetic acid (2L), at 30 ° C was added tetrabutylammonium yl ammonium fluoride (13g, 5% mol), heated at reflux for 16 hours, cooled to room temperature, the acetic acid solvent was evaporated, the crude product was filtered slurried with water, solid was recrystallized ko alcohol, and dried to give ko-benzimidazole - 7- carboxylate (211. 4g, yield 96%);

[0085] (2) 2-氰基-4'-溴甲基联苯的合成 [0085] (2) Synthesis of 2-cyano-4'-bromomethyl-biphenyl

[0086] 将2-氰基-4' -甲基联苯(193g,lmol)溶于ニ氯甲烷中(2L),室温分批加入N-溴代琥珀酰亚胺(356g,2mol),室温下搅拌8小吋,反应结束后,经水洗,蒸馏,石油醚打浆,过滤,干燥,得到2-氰基-4'-溴甲基联苯,该粗品无需进行进ー步纯化(255. Sg,收率94%); [0086] 2-cyano-4 '- methyl-biphenyl (193g, lmol) was dissolved in methylene chloride ni (2L), at room temperature was added portionwise N- bromosuccinimide (356g, 2mol), room temperature inch under stirring for 8 hours, after the reaction, washed with water, distillation, refining petroleum ether, filtered and dried to give 2-cyano-4'-bromo-biphenyl, the crude product was carried further without purification into ー (255. Sg 94% yield);

[0087] (3)1-[(2/ -氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯的合成 [0087] (3) 1 - [(2 / - cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate in

[0088] 将こ氧基苯并咪唑-7-羧酸甲酯(22g,0. lmol)和2_氰基-4'-溴甲基联苯(27. 2g, 0. 2mol)溶解在こ醇中(300mL),加入碳酸钾(69g, 0. 5mol),回流16小时,蒸掉こ醇,加水打楽■,过滤,こ醇重结晶得到1_[ (2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯(34. 5g,收率84%); [0088] The ko-benzimidazole-7-carboxylate (22g, 0. Lmol) and 2_-cyano-4'-bromomethylbiphenyl (27. 2g, 0. 2mol) was dissolved in ko alcohol (300 mL), was added potassium carbonate (69g, 0. 5mol), refluxed for 16 hours, ko alcohol distilled off, water was added playing yue ■, filtered, and recrystallized from an alcohol to give 1_ ko [(2'-cyanobiphenyl -4 - yl) methyl] -2-ko-benzimidazole-7-carboxylate (34. 5g, 84% yield);

[0089] (4)将ト[(2'-氰基联苯-4-基)甲基]-2-こ氧基苯并咪唑-7-羧酸甲酯(20. 6g, 0. 05mol)悬浮于水中(250mL),加入盐酸轻胺(27. 8g, 0. 4mol)和氢氧化钠(16g, 0. 4mol),再加入四丁基氟化铵(2. 6g, IOmmol),回流10小时,冷却,再加入氢氧化钠(2g,0.05mol),20°C加入氯甲酸こ酯(5. 4g,0. 05mol),再回流16小时,冷却洗出固体,过滤,水洗,干燥得到阿奇沙坦甲酯(19.9g,85%); [0089] (4) The Suites [(2'-cyanobiphenyl-4-yl) methyl] -2-ko-benzimidazole-7-carboxylate (20. 6g, 0. 05mol) is suspended in water (250mL), was added light hydrochloride (27. 8g, 0. 4mol) and sodium hydroxide (16g, 0. 4mol), was added tetrabutylammonium fluoride (2. 6g, IOmmol), refluxed for 10 hours, cooled, and then was added sodium hydroxide (2g, 0.05mol), 20 ° C ko chloroformate ester (5. 4g, 0. 05mol), then refluxed for 16 hours, cooled to wash the solid was filtered, washed with water, and dried to give Archie losartan ester (19.9g, 85%);

[0090] (5)将阿奇沙坦甲酯(10g,21. 3mmol)悬浮于水中(45mL),加入质量浓度为20%的氢氧化锂水溶液(IOmL, 83. 2mmol),室温搅拌16小时。 [0090] (5) the methyl ester Archie Losartan (10g, 21. 3mmol) was suspended in water (45mL), added to a concentration of 20% by mass lithium hydroxide aqueous solution (IOmL, 83. 2mmol), stirred for 16 hours at room temperature . 冰水浴下用稀盐酸酸化到pH=3,过滤得到产品阿奇沙坦,こ醇重结晶得到白色晶体,纯度为98、9%(9. 56g,收率98. 6%)。 Under ice-water bath and acidified with dilute hydrochloric acid to pH = 3, the product was filtered to give azithromycin losartan, ko recrystallized from an alcohol to give white crystals, with a purity of 98,9% (9. 56g, 98.6% yield).

Claims (10)

1. 一种阿齐沙坦的制备方法,包括: (1)按摩尔比I: f 1:3将2,3-二氨基苯甲酸甲酯和原碳酸四乙酯溶解到醋酸中,于2(T30°C加入四丁基氟化铵,加热回流反应1(Γ16小时后冷却至室温,然后蒸去醋酸,将得到的粗产品用水打浆过滤,最后用乙醇重结晶、干燥,得到乙氧基苯并咪唑-7-羧酸甲酯; (2)将2-氰基-4 '-甲基联苯溶于二氯甲烷中,分批加入N-溴代琥珀酰亚胺,室温下搅拌4-8小时,反应结束后,经水洗、蒸馏、石油醚打浆,然后过滤、干燥,得到2-氰基-4' _溴甲基联苯; (3)按摩尔比I: f 1:2将上述乙氧基苯并咪唑-7-羧酸甲酯和2-氰基-4'-溴甲基联苯溶解到乙醇中,加入碳酸钾,加热回流8〜16小时,然后蒸掉乙醇、加水打浆,再过滤、用乙醇重结晶得到1_[(2'-氰基联苯-4-基)甲基]-2-乙氧基苯并咪唑-7-羧酸甲酯; (4)将上述1-[(2'-氰基联苯-4-基)甲基]-2-乙氧基苯并 1. A method of preparing azilsartan, comprising: (1) a molar ratio of I: f 1: 3 by dissolving 2,3-diamino-benzoic acid methyl ester and tetraethyl orthocarbonate into acetate, in 2 (T30 ° C was added tetrabutylammonium fluoride was heated at reflux for reaction 1 (Γ16 hours, cool to room temperature, acetic acid was distilled off and the resulting crude product was slurried with water filtration, and finally recrystallized from ethanol, and dried to give an ethoxy benzimidazole-7-carboxylate; (2) 2-cyano-4 '- methyl-biphenyl was dissolved in dichloromethane, was added portionwise N- bromosuccinimide, with stirring at room temperature for 4 8 hours, after the reaction, washed with water, distillation, beating petroleum ether, then filtered and dried to give 2-cyano-4 '_ bromomethyl-biphenyl; (3) the molar ratio of I: f 1: 2 to the above-ethoxy-benzimidazole-7-carboxylate and 2-cyano-4'-bromomethyl-biphenyl was dissolved in ethanol, and potassium carbonate, heated under reflux for 8~16 hours, and then ethanol was evaporated, water was added beating, and then filtered to give 1 _ [(2'-cyanobiphenyl-4-yl) methyl] -2-ethoxy-benzimidazole-7-carboxylate was recrystallized from ethanol; (4) the above 1 - [(2'-cyanobiphenyl-4-yl) methyl] -2-ethoxy-benzo 唑-7-羧酸甲酯悬浮于水中,加入盐酸羟胺、氢氧化钠和四丁基氟化铵,加热回流1(Γ16小时后冷却,然后加入氢氧化钠,再于2(T30°C加入氯甲酸乙酯,加热回流8〜16小时后冷却析出固体,最后过滤、水洗、干燥得到阿奇沙坦甲酯; (5)将上述阿奇沙坦甲酯悬浮于水中,加入氢氧化锂水溶液,室温搅拌12-16小时,于冰水浴下调节PH值为2-4后过滤,最后用乙醇重结晶,得到阿齐沙坦。 -7-carboxylate was suspended in water, was added hydroxylamine hydrochloride, sodium hydroxide, and tetrabutylammonium fluoride, heated to reflux (Γ16 h after cooling, followed by addition of sodium hydroxide was added to 2 (T30 ° C of ethyl chloroformate was heated under reflux for 8~16 hours and then cooled to precipitate solid was finally filtered, washed with water, and dried to give losartan azithromycin ester; (5) the above methyl ester was suspended in water Archie losartan, an aqueous solution of lithium hydroxide the mixture was stirred at room temperature for 12-16 hours, ice-water bath by filtration after adjusting the PH value 2-4, and finally recrystallized from ethanol to give azilsartan.
2.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(I)中所述的四丁基氟化铵的用量为2,3- 二氨基苯甲酸甲酯摩尔量的5〜20%。 The method of preparing azilsartan of claim I, wherein: the amount of the step (I), the tetrabutylammonium fluoride is 2,3-diamino benzoic acid methyl ester an amount of 5~20 mole%.
3.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(2)中所述的N-溴代琥珀酰亚胺与2-氰基-4'-甲基联苯的摩尔比为广2:1。 The method of preparing azilsartan of claim I, wherein: the step (2) in the N- bromosuccinimide with 2-cyano-4'-methyl the molar ratio of biphenyl was widely 2: 1.
4.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(3)中所述的碳酸钾与乙氧基苯并咪唑-7-羧酸甲酯的摩尔比为:Γ5:1。 The method of preparing azilsartan of claim I, wherein: the molar ratio in step (3) with potassium carbonate in the ethoxy-benzimidazole-7-carboxylate It is: Γ5: 1.
5.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(4)中所述的盐酸羟胺与1_[(2'-氰基联苯-4-基)甲基]-2-乙氧基苯并咪唑-7-羧酸甲酯的摩尔比为4 〜8:1。 The method of preparing azilsartan of claim I, wherein: step (4) with hydroxylamine hydrochloride in the _ 1 [(2'-cyanobiphenyl-4-yl) methyl molar ratio yl] -2-ethoxy-benzimidazole-7-carboxylate 4 ~ 8: 1.
6.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(4)中所述的加热回流10〜16小时前所加入的氢氧化钠与1-[(2'-氰基联苯-4-基)甲基]-2-乙氧基苯并咪唑-7-羧酸甲酯的摩尔比为Γ8: I。 The method of preparing azilsartan of claim I, wherein: step (4) heating at reflux for 10~16 hours before the addition of sodium hydroxide and 1 - [(2 '- cyanobiphenyl-4-ylmethyl molar ratio of carboxylate)] -2-ethoxy-benzimidazole-7 is Γ8: I.
7.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(4)中所述的四丁基氟化铵的用量为1_[(2'-氰基联苯-4-基)甲基]-2-乙氧基苯并咪唑-7-羧酸甲酯摩尔量的5-20%。 The method of preparing azilsartan of claim I, wherein: step (4) in the amount of tetrabutylammonium fluoride 1 _ [(2'-cyanobiphenyl 4-yl) methyl] -2-ethoxy-benzimidazole-7-carboxylate 5 to 20% molar amount.
8.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(4)中所述的加热回流1(Γ16小时后所加入的氢氧化钠与1-[(2'-氰基联苯-4-基)甲基]-2-乙氧基苯并咪唑-7-羧酸甲酯的摩尔比为1:1 ;氯甲酸乙酯与1-[(2'-氰基联苯-4-基)甲基]-2-乙氧基苯并咪唑-7-羧酸甲酯的摩尔比为1:1。 8. A method of preparing azilsartan of claim I, wherein: step (4) of the heating reflux for 1 (Γ16 hour and the sodium hydroxide was added 1 - [(2 '- cyano-4-ylmethyl-biphenyl molar ratio)] -2-ethoxy-benzimidazole-7-carboxylate is 1: 1; ethyl chloroformate and 1 - [(2'- molar ratio of 4-methyl-2-ethoxy-benzimidazole-7-carboxylate-cyanobiphenyl)] of 1: 1.
9.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(5)中所述的氢氧化锂水溶液的质量浓度为20%,氢氧化锂水溶液中氢氧化锂的含量为阿奇沙坦甲酯摩尔量的2飞倍。 9. A method of preparing azilsartan of claim I, wherein: the concentration step (5) in the aqueous lithium hydroxide solution was 20% aqueous solution of lithium hydroxide lithium hydroxide in an amount of 2 times the Archie fly molar amount of methyl losartan.
10.根据权利要求I所述的一种阿齐沙坦的制备方法,其特征在于:步骤(5)中所述的调节pH值为采用稀盐酸调节。 10. The method of preparing azilsartan of claim I, wherein: the step (5) in said adjusted to pH adjustment using dilute hydrochloric acid.
CN201210254405.9A 2012-07-23 2012-07-23 A kind of preparation method of Azilsartan CN102766138B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210254405.9A CN102766138B (en) 2012-07-23 2012-07-23 A kind of preparation method of Azilsartan

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210254405.9A CN102766138B (en) 2012-07-23 2012-07-23 A kind of preparation method of Azilsartan

Publications (2)

Publication Number Publication Date
CN102766138A true CN102766138A (en) 2012-11-07
CN102766138B CN102766138B (en) 2017-10-24

Family

ID=47093746

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210254405.9A CN102766138B (en) 2012-07-23 2012-07-23 A kind of preparation method of Azilsartan

Country Status (1)

Country Link
CN (1) CN102766138B (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044412A (en) * 2012-12-26 2013-04-17 华润赛科药业有限责任公司 Azilsartan polymorph and preparation method thereof
CN103360381A (en) * 2013-07-30 2013-10-23 山东新华制药股份有限公司 New crystal form of Azilsartan, and preparation method and application thereof
CN103408500A (en) * 2013-07-25 2013-11-27 上海博志研新药物技术有限公司 Preparation method for angiotensin II receptor blocker and key intermediate thereof
CN103880830A (en) * 2013-03-22 2014-06-25 江西同和药业有限责任公司 Novel synthesis method of azilsartan
CN104072490A (en) * 2013-03-28 2014-10-01 江苏柯菲平医药有限公司 Preparation method of azilsartan key intermediate
CN104119326A (en) * 2013-04-25 2014-10-29 正大天晴药业集团股份有限公司 Method for preparing azilsartan
CN104119279A (en) * 2014-05-30 2014-10-29 上海天慈生物谷生物工程有限公司 Novel method for preparing 2-ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl) xenyl-4-yl]methyl}-1H- benzimidazole-7-carboxylic acid
CN104230909A (en) * 2014-08-30 2014-12-24 中国人民解放军第二三○医院 Preparation method of azilsartan
CN104341408A (en) * 2013-08-02 2015-02-11 江苏柯菲平医药股份有限公司 Novel crystal form of azilsartan and preparation method thereof
CN104774196A (en) * 2014-01-09 2015-07-15 武汉朗来科技发展有限公司 Preparation method of benzimidazole derivative
CN104803998A (en) * 2015-03-26 2015-07-29 晋江市托美汀生物科技有限公司 Impurity content decreasing method
CN105237527A (en) * 2012-09-28 2016-01-13 武汉朗来科技发展有限公司 Benzimidazole derivative, and preparation method and pharmaceutical applications thereof
CN105622595A (en) * 2014-11-21 2016-06-01 重庆朗天制药有限公司 Novel preparation method of azilsartan medoxomil sylvite and its intermediate
CN108752328A (en) * 2018-07-27 2018-11-06 常州大学 A kind of method of easy synthesis Azilsartan
CN108947993A (en) * 2018-07-27 2018-12-07 常州大学 A kind of method that water phase Green efficiently synthesizes Azilsartan
CN108997252A (en) * 2018-07-27 2018-12-14 常州大学 A kind of green synthesis method of oxadiazole derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015134A1 (en) * 2004-07-28 2006-02-09 Dr. Reddy's Laboratories Ltd. Process for preparing candesartan cilexetil

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015134A1 (en) * 2004-07-28 2006-02-09 Dr. Reddy's Laboratories Ltd. Process for preparing candesartan cilexetil

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HORNG-CHIH HUANG ET AL.: "Synthesis and Structure-Activity Relationships of Nonpeptide, Potent Triazole-Based Angiotensin II Receptor Antagonists", 《J. MED. CHEM.》 *
KEIJI KUBO ET AL.: "Nonpeptide Angiotensin II Receptor Antagonists. Synthesis and Biological Activity of Benzimidazolecarboxylic Acids", 《J. MED. CHEM.》 *
束蓓艳等: "阿奇沙坦的合成", 《中国医药工业杂志》 *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105237527A (en) * 2012-09-28 2016-01-13 武汉朗来科技发展有限公司 Benzimidazole derivative, and preparation method and pharmaceutical applications thereof
CN103044412A (en) * 2012-12-26 2013-04-17 华润赛科药业有限责任公司 Azilsartan polymorph and preparation method thereof
CN103044412B (en) * 2012-12-26 2016-04-06 华润赛科药业有限责任公司 Polymorphic of a kind of Azilsartan and preparation method thereof
CN103880830B (en) * 2013-03-22 2017-01-18 江西同和药业股份有限公司 Synthesis method of azilsartan
CN103880830A (en) * 2013-03-22 2014-06-25 江西同和药业有限责任公司 Novel synthesis method of azilsartan
CN104072490A (en) * 2013-03-28 2014-10-01 江苏柯菲平医药有限公司 Preparation method of azilsartan key intermediate
CN104119326A (en) * 2013-04-25 2014-10-29 正大天晴药业集团股份有限公司 Method for preparing azilsartan
CN104119326B (en) * 2013-04-25 2017-04-26 正大天晴药业集团股份有限公司 Method for preparing azilsartan
CN103408500A (en) * 2013-07-25 2013-11-27 上海博志研新药物技术有限公司 Preparation method for angiotensin II receptor blocker and key intermediate thereof
CN103408500B (en) * 2013-07-25 2016-03-16 上海博志研新药物技术有限公司 The preparation method of a kind of Angiotensin Ⅱ receptor antagonist and key intermediate thereof
CN103360381A (en) * 2013-07-30 2013-10-23 山东新华制药股份有限公司 New crystal form of Azilsartan, and preparation method and application thereof
CN103360381B (en) * 2013-07-30 2015-10-28 山东新华制药股份有限公司 New crystal of Azilsartan and its preparation method and application
CN104341408A (en) * 2013-08-02 2015-02-11 江苏柯菲平医药股份有限公司 Novel crystal form of azilsartan and preparation method thereof
CN104774196B (en) * 2014-01-09 2017-11-10 武汉朗来科技发展有限公司 A kind of preparation method of benzimidizole derivatives
CN104774196A (en) * 2014-01-09 2015-07-15 武汉朗来科技发展有限公司 Preparation method of benzimidazole derivative
CN104119279A (en) * 2014-05-30 2014-10-29 上海天慈生物谷生物工程有限公司 Novel method for preparing 2-ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl) xenyl-4-yl]methyl}-1H- benzimidazole-7-carboxylic acid
CN104119279B (en) * 2014-05-30 2018-01-02 上海天慈生物谷生物工程有限公司 The method for preparing the carboxylic acid of 2 ethyoxyl 1 { [base of 2 ' (base of 5 carbonyl, 4,5 dihydro, 1,2,4 oxadiazole 3) xenyl 4] methyl } 1H benzimidazoles 7
CN104230909A (en) * 2014-08-30 2014-12-24 中国人民解放军第二三○医院 Preparation method of azilsartan
CN105622595A (en) * 2014-11-21 2016-06-01 重庆朗天制药有限公司 Novel preparation method of azilsartan medoxomil sylvite and its intermediate
CN104803998A (en) * 2015-03-26 2015-07-29 晋江市托美汀生物科技有限公司 Impurity content decreasing method
CN108752328A (en) * 2018-07-27 2018-11-06 常州大学 A kind of method of easy synthesis Azilsartan
CN108947993A (en) * 2018-07-27 2018-12-07 常州大学 A kind of method that water phase Green efficiently synthesizes Azilsartan
CN108997252A (en) * 2018-07-27 2018-12-14 常州大学 A kind of green synthesis method of oxadiazole derivatives

Also Published As

Publication number Publication date
CN102766138B (en) 2017-10-24

Similar Documents

Publication Publication Date Title
EP1477481B1 (en) Process for producing quinazolin-4-one derivative
PT98608A (en) Method for the preparation of bifenilcarbonitrills and imidazole and quinoline derivatives
WO2000043370A1 (en) Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament
JPH07165709A (en) Carboxamide and anilide and application thereof in drug
CN1268112A (en) Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives
CN101463013A (en) Preparation of erlotinid hydrochloride
ES2398934T3 (en) Production process of 1- (3- (2- (1-benzothiophene-5-yl) ethoxy) propyl) acetidinol or salts thereof
JPH1029962A (en) Chalcone derivative and medicine containing the same
CN102633713B (en) Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate
Barnes et al. The Metalation of Methoxynaphthalenes1
CN1182122C (en) Synthesis path of Timisatem
CN101903375B (en) Carboxyl- or hydroxyl-substituted benzimidazole derivatives
CN101528688B (en) Process for preparing indol- 5 -oxy- quinazoline derivatives and intermediates
CN102093194B (en) New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid
CN102066355A (en) Method for producing an intermediate product of dabigatran etexilate
JP2002521352A (en) Method for producing ortho-alkylated benzoic acid derivatives
CN101560396B (en) Method for synthesizing fluorine-containing antiform alkyl cyclohexyl biphenyl single liquid crystal
CN101959840A (en) Process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates
CN104610250A (en) 1,2,3-thiadiazole-5-formamidine compound containing three N-heterocycles and synthesis
CN101691359B (en) Method for synthesizing highly-pure bendamustine hydrochloride
CN101709036B (en) Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine
CN102180868A (en) Method for preparing anti-depression medicine vilazodone
CN101367763B (en) Synthesis process of 1-phenyl-3-methyl-5-pyrazolone
Anderson et al. Synthesis of 1-Diethylamino-5-aminohexane1
CN101056853B (en) Process for the production of isoindole derivatives

Legal Events

Date Code Title Description
C06 Publication
C10 Entry into substantive examination
TA01
CB03
GR01