CN104045602A - Improved method for preparing tetrazole for valsartan - Google Patents

Improved method for preparing tetrazole for valsartan Download PDF

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CN104045602A
CN104045602A CN 201410307545 CN201410307545A CN104045602A CN 104045602 A CN104045602 A CN 104045602A CN 201410307545 CN201410307545 CN 201410307545 CN 201410307545 A CN201410307545 A CN 201410307545A CN 104045602 A CN104045602 A CN 104045602A
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compound
valsartan
step
iii
intermediate
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CN 201410307545
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朱晓仁
陕年平
张文灵
王鹏
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浙江华海药业股份有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D257/00Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04Five-membered rings

Abstract

The invention provides an improved method for preparing tetrazole from valsartan. The method comprises the following steps: (1) carrying out a thermal reaction between a compound I and valeryl chloride in an organic solvent in the presence of an acid-binding agent, thereby obtaining an oily compound II; (2) dissolving the compound II obtained in the step (1) in a strongly polar aprotic solvent, adding a certain amount of sodium azide and zinc chloride anhydrous, and reacting in the presence of a catalyst to obtain a solution of a compound III. The method is simple and convenient to operate, and has the advantages that the reaction conditions are relatively mild, the production cost is relatively low, impurities can be better controlled, and the requirement of later valsartan production for a high-quality intermediate can be met.

Description

一种缬沙坦成四氮唑的改进方法 To an improved method of valsartan tetrazole

技术领域 FIELD

[0001] 本发明涉及一种缬沙坦成四氮唑的改进方法。 [0001] The present invention relates to an improved process for valsartan tetrazolium.

[0002] 发明背景 [0002] Background of the Invention

[0003] 缬沙坦其化学名为(S)-N-戊酰基-Ν-[[2'-(1Η-5-四氮唑-基)[1,1'_联苯]-4 基]甲基]缬氨酸,结构式如下所示: [0003] Valsartan and its chemical name (S) -N- pentanoyl -Ν - [[2 '- (1Η-5- tetrazol - yl) [1,1'_ biphenyl] -4-yl] methyl] valine, structural formula shown below:

[0004] [0004]

缬沙坦结构式 Valsartan structural formula

[0005]纟颜沙坦由瑞士Novartis公司开发,是Novartis在抗血压药物领域投下的重磅炸弹,目前缬沙坦在美国的专利已经到期,缬沙坦仿制药迎来了一轮高峰,制剂对API的需求量不断放大。 [0005] Si Yan Chastain developed by the Swiss company Novartis, Novartis is dropped in the field of blockbuster antihypertensive drugs, currently in the United States valsartan patent has expired, generic valsartan ushered in a peak, the demand for API formulation continued to enlarge. 目前关于缬沙坦的报道文献专利有很多,有关缬沙坦合成路线的报道多大几十条,其中依据成四氮唑的方式不同主要分为两类: Currently on valsartan patent literature reports there are many dozens of reports about how much valsartan synthesis route, which according to the way into tetrazolium different divided into two categories:

[0006] 第一类路线是以2 ' -氰基-4-溴甲基联苯与叠氮根盐合成四氮唑环,例如以L-缬氨酸为起始物料经酯化,再与2' -氰基-4-溴甲基联苯进行缩合反应,再经戊酰化、成四氮唑生成缬沙坦,而其中成四氮唑步骤是缬沙坦合成路线的关键步骤,有文献报道以三丁基叠氮化锡为成四氮唑关键物料(W02009125416、US20090203921),另有文献报道以叠氮酸的金属盐为成四氮唑关键物料,具体以(S)-N-戊酰基-N-[[2'_氰基联苯]-4基]甲基]缬氨酯、叠氮钠、金属卤化物、在130°C左右反应30小时成四氮唑(CN101270096)。 [0006] The first route is 2 '- cyano-4-bromomethyl-biphenyl and azide salts synthesized tetrazolium ring, for example, as a starting material L- valine by esterification, and then 2 '- cyano-4-bromomethyl-biphenyl-condensation reaction, and then by pivaloylation, to generate tetrazolium valsartan, of which the tetrazolium to step is a key step in the synthetic route of valsartan with reported a three tributyltin azide as a key material to tetrazolium (W02009125416, US20090203921), are reported in the literature and another metal salt of hydrazoic acid into a tetrazolium critical material, in particular (S) -N- pentanoyl -N - [[2'_ cyano-biphenyl] -4-yl] methyl]-valine ester, sodium azide, a metal halide, at 130 ° C to about 30 hours tetrazolium (CN101270096). 前者用到了剧毒的金属锡,致使后处理锡残留难以控制。 The former uses a highly toxic metallic tin, tin residues after treatment resulting in difficult to control. 后者反应时间偏长,转化率不高,反应温度偏闻,杂质较难控制。 The latter reaction time is rather long, the conversion rate is not high, the reaction temperature is partial smell, difficult to control impurities.

[0007] 第二类路线是以2'-(N'_三苯甲基)四氮唑基-4-溴甲基联苯(BBTT)经过脱保护基,形成四氮唑环。 [0007] The second type of line is 2 '- (N'_ triphenylmethyl) tetrazol-yl-4-bromomethyl-biphenyl (BBTT) after deprotection, a tetrazolium ring is formed. 具体包括L-缬氨酰胺为原料,经缩合、戊酰化、脱保护基生成缬沙坦,该路线规避了成四氮唑环所用到的苛刻条件,但是该路线操作相对路线一更复杂,而且缩合步骤用到价格昂贵的BBTT,脱保护工序还要用到昂贵的Pd/C,(EP1849777、CN101045712) 增加了生产成本。 Comprises L- valinamide was synthesized by condensation, pivaloylation, valsartan deprotection generated, the route to avoid the harsh conditions of the tetrazolium ring used, but a route opposite the route operation more complex, used in the condensation step and expensive BBTT, deprotection step have to use expensive Pd / C, (EP1849777, CN101045712) increases production costs.

[0008] 本发明主要对路线一成四氮唑工序进行改进,以2'-氰基-4-溴甲基联苯、叠氮钠和金属卤化物为成四氮唑关键物料,针对文献报道中存在的缺点(转化率不高、反应时间长、反应温度高、杂质较难控制)。 [0008] The present invention of course a step to improve the tetrazolium to 2'-cyano-4-bromomethyl-biphenyl, sodium azide and a metal halide into a tetrazolium critical material, reported in the literature for disadvantages present (the conversion rate is not high, long reaction times, the reaction temperature is high, difficult to control impurities). 通过选用特定反应溶剂,加入特定的催化剂,对成四氮唑条件进行优化。 By selecting specific reaction solvent, adding a specific catalyst for the tetrazolium to optimize conditions.

发明内容 SUMMARY

[0009] 本发明的目的是改进合成缬沙坦方法,改进后的工艺适合工业化生产,反应温度低,安全节能,反应时间短,提高了产能,杂质易于控制,产品质量好。 [0009] The object of the present invention to improve the method of synthesis of valsartan, the improved process suitable for industrial production, the reaction temperature is low, energy security, short reaction time, improve productivity, easy to control impurities, good quality.

[0010] 更具体而言,本发明提供了一种缬沙坦中间体化合物III的改进方法,包括以下步骤: [0010] More specifically, the present invention provides an intermediate compound III valsartan improved method, comprising the steps of:

[0011] (1)化合物I在缚酸剂存在的条件下,在有机溶剂中与正戊酰氯保温反应得到油状物化合物II; [0011] (1) Compound I in the presence of an acid-binding agent, in an organic solvent n-valeryl chloride and the reaction incubated to give oil compound II;

[0012] (2)将上步制得的化合物II溶于强极性非质子溶剂当中,加入一定量的叠氮钠和无水氯化锌,在催化剂存在的条件下得到化合物III溶液。 [0012] (2) The compound obtained above Step II was dissolved in aprotic polar solvents, a certain amount of anhydrous zinc chloride and sodium azide, to give a solution of compound III in the presence of a catalyst. 所述R为-CH3,-C2H 5或 The R is -CH3, -C2H 5, or

[0013] [0013]

[0014] 步骤(1)所述缚酸剂为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾中的一种或两种。 [0014] Step (1) of the acid binding agent is one or both of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.

[0015] 步骤(1)所述缚酸剂与化合物I摩尔比为2 : 1〜3 : 1。 [0015] Step (1) the acid-binding agent and molar ratio of the compound I is 2: 1~3: 1.

[0016] 步骤(1)所述有机溶剂为甲苯、二甲苯、二氯甲烷,优选为甲苯。 The [0016] Step (1) the organic solvent is toluene, xylene, methylene chloride, preferably toluene.

[0017] 步骤⑴所述保温温度为20〜30°C。 [0017] Step ⑴ the incubation temperature is 20~30 ° C.

[0018] 步骤2)具体过程为将上步制得的化合物II溶于强极性非质子溶剂当中,加入一定量的叠氮钠和无水氯化锌,搅拌均匀,再加入催化剂,加热反应一段时间,中间过程控制。 [0018] Step 2) on the specific process steps compound II obtained is dissolved in polar aprotic solvents, a certain amount of anhydrous zinc chloride and sodium azide, stir, then add the catalyst, the reaction was heated period of time, the process control center. 反应结束后,料液冷却至室温。 After completion of the reaction, the material was cooled to room temperature. 加入提取溶剂、水、淬灭剂进行淬灭,调酸、分层、洗涤,得化合物III溶液。 Added to the extraction solvent, water, quenched quencher, of acid, stratification, and washed to give a solution of compound III.

[0019] 步骤⑵所述强极性非质子溶剂为DMF(N,N- 二甲基甲酰胺)、DMA(N,N_ 二甲基乙酰胺)、DMS0 ( 二甲基亚砜)中的一种。 [0019] Step ⑵ said polar aprotic solvent is a DMF (N, N- dimethylformamide), DMA (N, N_-dimethylacetamide), DMSO (dimethyl sulfoxide) in species. 优选为DMF。 Preferably DMF.

[0020] 步骤(2)所述强极性非质子溶剂质量用量为化合物II质量的2〜3倍。 [0020] Step (2) the mass of strongly polar aprotic solvent in an amount of 2 to 3 times the mass of the compound II.

[0021] 步骤(2)所述叠氮钠与化合物II摩尔比1. 5 : 1〜2 : 1。 [0021] Step (2) of the stack molar ratio of II with a compound of nitrogen, sodium 1.5: 1 to 2: 1.

[0022] 步骤(2)所述无水氯化锌用量与叠氮钠质量用量相等。 [0022] Step (2) is equal to the amount of anhydrous zinc chloride and sodium azide mass amount.

[0023] 步骤(2)所述催化剂为季铵盐包括:甲基三辛基氯化铵、苄基三乙基氯化铵、四丁基硫酸氢铵;或为金属齒化物包括氯化锂、氯化铝、溴化锂、溴化铝,优选为甲基三辛基氯化铵、四丁基硫酸氢铵、氯化锂。 [0023] Step (2) the catalyst is a quaternary ammonium salt comprising: methyltrioctylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate; or a metal compound include lithium chloride teeth , aluminum chloride, lithium bromide, aluminum bromide, preferably methyl trioctyl ammonium chloride, tetrabutylammonium hydrogen sulfate, lithium chloride.

[0024] 步骤⑵所述催化剂用量为化合物II质量的2%〜10%。 [0024] Step ⑵ the catalyst in an amount of 2% ~ 10% by mass of Compound II.

[0025] 步骤⑵所述成四氮唑反应温度为80〜135°C,优选为80〜100°C。 [0025] Step ⑵ into the tetrazolium reaction temperature is 80~135 ° C, preferably 80~100 ° C.

[0026] 步骤(2)所述成四氮唑反应时间为8〜35小时,优选为8〜15小时。 [0026] Step (2) into the tetrazolium reaction time 8~35 hours, preferably 8~15 hours.

[0027] 步骤⑵所述提取溶剂为甲基叔丁基醚、二异丙醚、苯甲醚、甲苯、优选为甲基叔丁基醚。 [0027] Step ⑵ the extraction solvent is a methyl t-butyl ether, diisopropyl ether, anisole, toluene, preferably methyl tert-butyl ether.

[0028] 步骤(2)所述淬灭剂为亚硝酸钠、次氯酸钠。 [0028] Step (2) the quencher is sodium nitrite, sodium hypochlorite.

[0029] 本发明提供合成方法操作简便,使用催化剂能缩短反应时间、降低反应温度,有利于产能提升和杂质控制。 [0029] The present invention provides a synthetic method is simple, the reaction time can be shortened using a catalyst, lowering the reaction temperature, is conducive to production capacity and control of impurities. 上四氮唑工序完成后增加淬灭步骤,有利于降低生产危险系数、减少对员工的健康危害。 Tetrazolium process after the completion of the quenching step increase, help reduce production risk factor, reduce health hazards for employees.

具体实施方式 detailed description

[0030] 以下实施例对本发明技术作具体阐述,但本发明的内容不限于此: [0030] The following examples set forth techniques of the present invention is specifically, but the present invention is not limited thereto:

[0031] 实施例1 :化合物II的制备 Preparation of compound II: Example 1 [0031] Embodiment

[0032] 向500ml四口瓶中加入30g化合物I (R = _CH3)和100ml甲苯,加入17. 7g碳酸钠(与化合物II摩尔比为2 : 1)和80ml水搅拌溶清,降温至20°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制。 [0032] 30g of the compound I (R = _CH3) 100ml of toluene and 500ml 4-neck flask, 17. 7g of sodium carbonate was added (molar ratio of compound II is 2: 1) and 80ml water stirred clear solution was cooled to 20 ° C, holding dropwise 12g n-pentyl chloride and 40ml of toluene mixture, the addition was complete the mixture was stirred for 2 hours, the intermediate process control. 反应结束,分去水层,160ml 水洗涤有机相,蒸干溶剂,得化合物II,收率:98.0%,纯度(HPLC) :99.2%,单杂(HPLC): 0. 11%,总杂(HPLC) :0. 7%o The reaction end, layer of water, the organic phase was washed with 160ml water, the solvent was evaporated to dryness to afford compound II, yield: 98.0%, purity (HPLC): 99.2%, single hetero (HPLC): 0. 11%, of the total hetero ( HPLC):. 0 7% o

[0033] 实施例2 :化合物II的制备 Preparation of compound II: Example 2 [0033] Embodiment

[0034] 向500ml四口瓶中加入30g化合物I(R = _C2H5)和100ml甲苯,加入17. 7g碳酸钠(与化合物II摩尔比为2 : 1)和80ml水搅拌溶清,降温至20°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制。 [0034] 30g of the compound I (R = _C2H5) 100ml of toluene and 500ml 4-neck flask, 17. 7g of sodium carbonate was added (molar ratio of compound II is 2: 1) and 80ml water stirred clear solution was cooled to 20 ° C, holding dropwise 12g n-pentyl chloride and 40ml of toluene mixture, the addition was complete the mixture was stirred for 2 hours, the intermediate process control. 反应结束,分去水层,160ml 水洗涤有机相,蒸干溶剂,得化合物II,收率:97. 5%,纯度(HPLC) :98.9%,单杂(HPLC): 0. 15%,总杂(HPLC) :1. 0%o The reaction end, layer of water, the organic phase was washed with 160ml water, the solvent was evaporated to dryness to afford compound II, yield: 975%, purity (HPLC): 98.9%, single hetero (HPLC): 0. 15%, total hetero (HPLC):. 1 0% o

[0035] 实施例3 :化合物II的制备 Preparation of compound II: Example 3 [0035] Embodiment

[0036] 向500ml四口瓶中加入30g化合物I [0036] 30g of Compound I was added to a 500ml four neck flask

和100ml甲苯,加入17. 7g 碳酸钠(与化合物II摩尔比为2 : 1)和80ml水搅拌溶清,降温至20°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制。 And 100ml of toluene was added 17. 7g of sodium carbonate (molar ratio of compound II is 2: 1) and stirred clear solution and 80ml water, cooled to 20 ° C, 12g insulation dropwise n-pentyl chloride and 40ml of toluene mixture, dropwise addition the mixture was stirred for 2 hours, the intermediate process control. 反应结束,分去水层,160ml水洗涤有机相,蒸干溶剂,得化合物II,收率:97.0%,纯度(HPLC) :98. 4%,单杂(HPLC) :0. 16%,总杂(HPLC) :1. 5%0 The reaction end, layer of water, the organic phase was washed with 160ml water, the solvent was evaporated to dryness to afford compound II, yield: 97.0%, purity (HPLC):. 98 4%, single hetero (HPLC):. 0 16%, of the total hetero (HPLC):. 1 5% 0

[0037] 实施例4 :化合物II的制备 Preparation of compound II: Example 4 [0037] Embodiment

[0038] 向500ml四口瓶中加入30g化合物I (R = _CH3)和100ml甲苯,加入23. lg碳酸钾(与化合物II摩尔比为2 : 1)和60ml水搅拌溶清,降温至20°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制。 [0038] 30g of the compound I (R = _CH3) 100ml of toluene and 500ml 4-neck flask, was added 23. lg of potassium carbonate (molar ratio of compound II is 2: 1) and 60ml water stirred clear solution was cooled to 20 ° C, holding dropwise 12g n-pentyl chloride and 40ml of toluene mixture, the addition was complete the mixture was stirred for 2 hours, the intermediate process control. 反应结束,分去水层,120ml 水洗涤有机相,蒸干溶剂,得化合物II,收率:98.4%,纯度(HPLC) :99.6%,单杂(HPLC): 0. 08%,总杂(HPLC) :0. 3%o The reaction end, layer of water, the organic phase was washed with 120ml water, the solvent was evaporated to dryness to afford compound II, yield: 98.4%, purity (HPLC): 99.6%, single hetero (HPLC): 0. 08%, of the total hetero ( HPLC):. 0 3% o

[0039] 实施例5 :化合物II的制备 Preparation of compound II: 5 cases of [0039] Embodiment

[0040] 向500ml四口瓶中加入30g化合物I (R = _CH3)和100ml甲苯,加入26. 6g碳酸钠(与化合物II摩尔比为3 : 1)和80ml水搅拌溶清,降温至20°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制。 [0040] 30g of the compound I (R = _CH3) 100ml of toluene and 500ml 4-neck flask, 26. 6g of sodium carbonate was added (molar ratio of compound II is 3: 1) and stirred clear solution and 80ml water, cooled to 20 ° C, holding dropwise 12g n-pentyl chloride and 40ml of toluene mixture, the addition was complete the mixture was stirred for 2 hours, the intermediate process control. 反应结束,分去水层,160ml 水洗涤有机相,蒸干溶剂,得化合物II,收率:98.0%,纯度(HPLC) :99.4%,单杂(HPLC): 0. 10%,总杂(HPLC) :0. 5%o The reaction end, layer of water, the organic phase was washed with 160ml water, the solvent was evaporated to dryness to afford compound II, yield: 98.0%, purity (HPLC): 99.4%, single hetero (HPLC): 0. 10%, of the total hetero ( HPLC):. 0 5% o

[0041] 实施例6 :化合物II的制备 Preparation of compound II: Example 6 [0041] Embodiment

[0042] 向500ml四口瓶中加入30g化合物I (R = _CH3)和100ml甲苯,加入17. 7g碳酸钠(与化合物II摩尔比为2 : 1)和80ml水搅拌,降温至30°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制。 [0042] A 500ml 4-neck flask was added 30g Compound I (R = _CH3) and 100ml of toluene was added 17. 7g of sodium carbonate (molar ratio of compound II is 2: 1) and 80ml of water was stirred, cooled to 30 ° C, 12g insulation dropwise n-pentyl chloride and 40ml of toluene mixture, the addition was complete the mixture was stirred for 2 hours, the intermediate process control. 反应结束,分去水层,160ml 水洗涤有机相,蒸干溶剂,得化合物II,收率:98. 4%,纯度(HPLC) :99.5%,单杂(HPLC): 0. 11%,总杂(HPLC) :0. 5%o The reaction end, layer of water, the organic phase was washed with 160ml water, the solvent was evaporated to dryness to afford compound II, yield: 984%, purity (HPLC): 99.5%, single hetero (HPLC): 0. 11%, total hetero (HPLC):. 0 5% o

[0043] 实施例7 :化合物II的制备 7 [0043] Example 2: Preparation of Compound II

[0044] 向500ml四口瓶中加入30g化合物I (R = _CH3)和100ml 二甲苯,加入17. 7g碳酸钠(与化合物II摩尔比为2 : 1)和80ml水搅拌,降温至30°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制,未反应完全,继续搅拌反应2小时,反应结束,分去水层,160ml水洗涤有机相,蒸干溶剂,得化合物II,收率:98. 2%,纯度(HPLC) :98.5%,单杂(HPLC) :0. 18%,总杂(HPLC) :1. 4% " [0044] A 500ml 4-neck flask was added 30g compound I (R = _CH3) and 100ml of xylene, 17. 7g of sodium carbonate was added (molar ratio of compound II is 2: 1) and 80ml of water was stirred, cooled to 30 ° C , 12g insulation dropwise n-pentyl chloride and 40ml of toluene mixture, the addition was complete the mixture was stirred for 2 hours, the intermediate process control, no reaction was complete, stirring was continued for 2 hours, the reaction was completed, to the water layer, the organic phase was washed with water 160ml solvent was evaporated to afford compound II, yield: 982%, purity (HPLC): 98.5%, single hetero (HPLC):. 0 18%, of the total heteroatoms (HPLC):. 1 4% "

[0045] 实施例8 :化合物II的制备 Preparation of compound II: Example 8 [0045] Embodiment

[0046] 向500ml四口瓶中加入30g化合物I (R = _CH3)和100ml 二氯甲烷,加入17. 7g碳酸钠(与化合物II摩尔比为2 : 1)和80ml水搅拌,降温至30°C,保温滴加12g正戊酰氯和40ml甲苯混合液,滴加完毕,保温搅拌2小时,中间过程控制,未反应完全,继续搅拌反应4小时,反应结束,分去水层,160ml水洗涤有机相,蒸干溶剂,得化合物II,收率:95. 4%,纯度(HPLC) :98.0%,单杂(HPLC) :0. 18%,总杂(HPLC) :1. 9%0 [0046] A 500ml 4-neck flask 30g compound I (R = _CH3) and 100ml of dichloromethane was added, 17. 7g of sodium carbonate was added (molar ratio of compound II is 2: 1) and 80ml of water was stirred, cooled to 30 ° C, holding dropwise 12g n-pentyl chloride and 40ml of toluene mixture, the addition was complete the mixture was stirred for 2 hours, the intermediate process control, no reaction was complete, stirring was continued for 4 hours, the reaction was completed, to the water layer, the organic was washed with water 160ml phase, the solvent was evaporated to dryness to afford compound II, yield: 954%, purity (HPLC): 98.0%, single hetero (HPLC):. 0 18%, of the total heteroatoms (HPLC):. 1 9% 0

[0047] 实施例9 :化合物III的制备 Preparation of compound III: Example 9 [0047] Embodiment

[0048] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0048] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:13小时,化合物III纯度(HPLC): 98.1%,化合物II 残留(HPLC) :1.6%,单杂(HPLC) :0. 11%0 Reaction time: 13 hours, Compound III Purity (HPLC): 98.1%, residual Compound II (HPLC): 1.6%, mono hetero (HPLC):. 0 11% 0

[0049] 实施例10 :化合物III的制备 Preparation of compound III: Example 10 [0049] Embodiment

[0050] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和99gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0050] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 99gDMF, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:15小时,化合物III纯度(HPLC): 97. 5%,化合物II 残留(HPLC) :2.3%,单杂(HPLC) :0. 10%。 Reaction time: 15 hours, Compound III Purity (HPLC): 97. 5%, the residual compound II (HPLC): 2.3%, mono hetero (HPLC):. 0 10%.

[0051] 实施例11 :化合物III的制备 Preparation of compound III: Example 11 [0051] Embodiment

[0052] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMA,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0052] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMA, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:14小时,化合物III纯度(HPLC): 98. 0%,化合物II 残留(HPLC) :1.6%,单杂(HPLC) :0. 11%0 Reaction time: 14 hours, Compound III Purity (HPLC): 98. 0%, the residual compound II (HPLC): 1.6%, mono hetero (HPLC):. 0 11% 0

[0053] 实施例12 :化合物III的制备 Preparation of compound III: Example 12 [0053] Embodiment

[0054] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMS0,加入8g 叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0054] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMS0, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:11小时,化合物III纯度(HPLC) :98. 3%,化合物II 残留(HPLC) :1.4%,单杂(HPLC) :0. 10%。 Reaction time: 11 hours, Compound III Purity (HPLC):. 98 3%, residual Compound II (HPLC): 1.4%, mono hetero (HPLC):. 0 10%.

[0055] 实施例13 :化合物III的制备 Preparation of compound III: Example 13 [0055] Embodiment

[0056] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入10. 6g 叠氮钠和10. 6g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0056] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, 10. 6g of sodium azide was added, and 10. 6g of anhydrous zinc chloride, uniformly stirring, was added 0. 66g methyl trioctyl ammonium chloride, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:12小时,化合物III纯度(HPLC) :98. 9%,化合物II 残留(HPLC) :1.0%,单杂(HPLC) :0. 07%" Reaction time: 12 hours, Compound III Purity (HPLC):. 98 9%, the residual compound II (HPLC): 1.0%, mono hetero (HPLC):. 0 07% "

[0057] 实施例14 :化合物III的制备 14 [0057] Example 2: Preparation of Compound III

[0058] 向500ml四口瓶中加入按实例2制备的化合物II (约33g)和66gDMF,加入10. 6g 叠氮钠和10. 6g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0058] A 500ml 4-neck flask was added compound II prepared in Example 2 (about 33g) and 66gDMF, 10. 6g of sodium azide was added, and 10. 6g of anhydrous zinc chloride, uniformly stirring, was added 0. 66g methyl trioctyl ammonium chloride, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:12小时,化合物III纯度(HPLC) : 98. 8%,化合物II 残留(HPLC) : 1.1%,单杂(HPLC) :0. 07%" Reaction time: 12 hours, Compound III Purity (HPLC): 98. 8%, residual Compound II (HPLC): 1.1%, mono hetero (HPLC):. 0 07% "

[0059] 实施例15 :化合物III的制备 Preparation of compound III: Example 15 [0059] Embodiment

[0060] 向500ml四口瓶中加入按实例3制备的化合物II (约33g)和66gDMF,加入10. 6g 叠氮钠和10. 6g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0060] A 500ml 4-neck flask was added compound II prepared in Example 3 (about 33g) and 66gDMF, 10. 6g of sodium azide was added, and 10. 6g of anhydrous zinc chloride, stir, added 0. 66g methyl trioctyl ammonium chloride, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:12小时,化合物III纯度(HPLC) :98. 5%,化合物II 残留(HPLC) :1.3%,单杂(HPLC) :0. 08%" Reaction time: 12 hours, Compound III Purity (HPLC):. 98 5%, residual Compound II (HPLC): 1.3%, mono hetero (HPLC):. 0 08% "

[0061 ] 实施例16 :化合物III的制备 16 [0061] Example 2: Preparation of Compound III

[0062] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入3. 3g甲基三辛基氯化铵,升温至80°C,搅拌反应,中间过程控制。 [0062] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, and sodium azide was added 8g 8g of anhydrous zinc chloride, uniformly stirring, was added 3. 3g methyltrioctylammonium chloride ammonium, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:9小时,化合物III纯度(HPLC): 98. 3%,化合物II 残留(HPLC) :1.5%,单杂(HPLC) :0. 09%。 Reaction time: 9 hours, Compound III Purity (HPLC): 98. 3%, residual Compound II (HPLC): 1.5%, mono hetero (HPLC):. 0 09%.

[0063] 实施例17 :化合物III的制备 Preparation of compound III: Example 17 [0063] Embodiment

[0064] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g四丁基硫酸氢铵,升温至80°C,搅拌反应,中间过程控制。 [0064] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, and sodium azide was added 8g 8g of anhydrous zinc chloride, uniformly stirred, and 0. 66g of ammonium hydroxide was added tetrabutylammonium heated to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:14小时,化合物III纯度(HPLC): 97. 8%,化合物II 残留(HPLC) :1.8%,单杂(HPLC) :0. 10%. Reaction time: 14 hours, Compound III Purity (HPLC): 97. 8%, residual Compound II (HPLC): 1.8%, mono hetero (HPLC):. 0 10%.

[0065] 实施例18 :化合物III的制备 Preparation of compound III: Example 18 [0065] Embodiment

[0066] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g氯化锂,升温至80°C,搅拌反应,中间过程控制。 [0066] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, sodium azide was added 8g 8g of anhydrous zinc chloride and stirred uniformly, added 0. 66g of lithium chloride, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:12小时,化合物III纯度(HPLC) :97. 5%, 化合物II 残留(HPLC) :1.8%,单杂(HPLC) :0. 12%. Reaction time: 12 hours, Compound III Purity (HPLC):. 97 5%, residual Compound II (HPLC): 1.8%, mono hetero (HPLC):. 0 12%.

[0067] 实施例19 :化合物III的制备 Preparation of compound III: Example 19 [0067] Embodiment

[0068] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g 叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至100°C,搅拌反应,中间过程控制。 [0068] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 100 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:10小时,化合物III纯度(HPLC) :98. 6%,化合物II 残留(HPLC) :1.2%,单杂(HPLC) :0. 12%" Reaction time: 10 hours, Compound III Purity (HPLC):. 98 6%, residual Compound II (HPLC): 1.2%, mono hetero (HPLC):. 0 12% "

[0069] 实施例20 :化合物III的制备 Preparation of compound III: Example 20 [0069] Embodiment

[0070] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至120°C,搅拌反应,中间过程控制。 [0070] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium hydroxide, heated to 120 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:9小时,化合物III纯度(HPLC): 98. 4%,化合物II 残留(HPLC) :0. 7%,单杂(HPLC) :0. 15%。 Reaction time: 9 hours, Compound III Purity (HPLC): 98. 4%, residual Compound II (HPLC):. 0 7%, single hetero (HPLC):. 0 15%.

[0071] 实施例21 :化合物III的制备 Preparation of compound III: Example 21 [0071] Embodiment

[0072] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至135°C,搅拌反应,中间过程控制。 [0072] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 135 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:8小时,化合物III纯度(HPLC): 97. 8%,化合物II 残留(HPLC) :0.6%,单杂(HPLC) :0. 19%. Reaction time: 8 hours, Compound III Purity (HPLC): 97. 8%, residual Compound II (HPLC): 0.6%, mono hetero (HPLC):. 0 19%.

[0073] 实施例22 :化合物III的制备 Preparation of compound III: Example 22 [0073] Embodiment

[0074] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应, 中间过程控制。 [0074] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂二异丙醚、水和8g亚硝酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added diisopropyl ether extraction solvent, 8g of sodium nitrite and water quenched, of acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:13小时,化合物III纯度(HPLC): 98.0%,化合物II 残留(HPLC) :1.5%,单杂(HPLC) :0. 11%0 Reaction time: 13 hours, Compound III Purity (HPLC): 98.0%, residual Compound II (HPLC): 1.5%, mono hetero (HPLC):. 0 11% 0

[0075] 实施例23 :化合物III的制备 Preparation of compound III: [0075] Example 23

[0076] 向500ml四口瓶中加入按实例1制备的化合物II (约33g)和66gDMF,加入8g叠氮钠和8g无水氯化锌,搅拌均匀,加入0. 66g甲基三辛基氯化铵,升温至80°C,搅拌反应, 中间过程控制。 [0076] A 500ml 4-neck flask was added compound II prepared as in Example 1 (about 33g) and 66gDMF, 8g of sodium azide was added anhydrous zinc chloride and 8g uniformly stirred, was added 0. 66g methyltrioctylammonium chloride ammonium, warmed to 80 ° C, the reaction was stirred, the intermediate process control. 反应结束,降至室温,加入提取溶剂甲基叔丁基醚、水和8. 6g次氯酸钠淬灭、调酸。 End of the reaction, cooled to room temperature, was added methyl tert-butyl ether, water and quenched with sodium hypochlorite 8. 6g extracting solvent by an acid. 分去水层、洗涤有机相,得化合物III溶液。 Layer of water, the organic phase is washed, a solution of Compound III. 反应时间:13小时,化合物III纯度(HPLC) :98· 0%,化合物II 残留(HPLC) :1.6%,单杂(HPLC) :0. 12%" Reaction time: 13 hours, Compound III Purity (HPLC): 98 · 0%, the residual compound II (HPLC): 1.6%, mono hetero (HPLC):. 0 12% "

[0077] 实施例24 :缬沙坦的制备 Valsartan prepared: Example 24 [0077] Embodiment

[0078] 向500ml四口瓶中加入按实例13制备的化合物III溶液,降温至_5〜15°C,保温滴加碱液,碱解8〜15小时,中间过程控制,碱解反应结束,分去上层有机相,水相倒回反应瓶。 [0078] A 500ml 4-neck flask was added compound III solution prepared in Example 13, cooled to _5~15 ° C, was added dropwise insulation alkali, alkaline hydrolysis 8~15 hours, the intermediate control process, the alkaline hydrolysis reaction was completed, points to the upper organic phase, the aqueous phase rewind the reaction flask. 加入乙酸乙酯,反应液降温至-5〜10°C,保温调酸,调酸结束,分去下层水相。 Ethyl acetate was added, the reaction was cooled to -5~10 ° C, incubation of acid, of acid end, points to the lower aqueous phase. 有机相用水洗涤两次,干燥、浓缩。 The organic phase was washed twice with water, dried, and concentrated. 向浓缩液加入一定量乙酸乙酯,降温析晶、过滤、烘干。 To the concentrate was added ethyl acetate and a certain amount, cooling crystallization, filtration and drying. 得缬沙坦,纯度(HPLC) :99.88%,总杂:0· 11,单杂(HPLC) :0. 05%。 Have Valsartan, purity (HPLC): 99.88%, total heteroaryl: 0 · 11, single hetero (HPLC):. 0 05%.

[0079] [0079]

[0080] [0080]

Claims (12)

1. 一种缬沙坦中间体化合物III的改进方法,其特征在于包括以下步骤: (1)化合物I在缚酸剂存在的条件下,在有机溶剂中与正戊酰氯保温反应得到油状物化合物II; (2)将上步制得的化合物II溶于强极性非质子溶剂当中,加入一定量的叠氮钠和无水氯化锌,在催化剂存在的条件下得到化合物III溶液;其中R = CH3,C2H5或 An intermediate compound III valsartan improved method comprising the steps of: (1) Compound I in the presence of an acid-binding agent, n-pentyl chloride is reacted with insulation to give an oil compound in an organic solvent II; (2) the compound obtained above step II was dissolved in aprotic polar solvents, a certain amount of anhydrous zinc chloride and sodium azide, to give a solution of compound III in the presence of a catalyst; wherein R = CH3, C2H5 or
ο ο
2.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(1)中缚酸剂为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾中的一种或两种。 2. The intermediate compound III valsartan improved process according to claim 1, wherein the step (1) in the acid binding agent is potassium carbonate, sodium hydroxide, potassium hydroxide, in a species or both.
3.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(1)中有机溶剂为甲苯、二甲苯、二氯甲烷,优选为甲苯。 3. The compound of claim 1 valsartan intermediate III improved method of claim, wherein the step (1) in the organic solvent is toluene, xylene, methylene chloride, preferably toluene.
4.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(1)中保温温度为15〜35°C,优选20〜25°C。 4. A compound according to one of claim 1 valsartan intermediate III improved method of claim, wherein the step (1) incubation temperature is 15~35 ° C, preferably 20~25 ° C.
5.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中强极性非质子溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜中的一种, 优选为N,N-二甲基甲酰胺。 5. A compound according to one of the intermediate valsartan 1 III improved method as claimed in claim, wherein step (2) the polar aprotic solvent is N, N- dimethylformamide, N, N - dimethylacetamide, dimethyl sulfoxide one, preferably N, N- dimethylformamide.
6.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中强极性非质子溶剂质量用量为化合物II质量的2〜3倍。 6. A compound according to one of the intermediate valsartan 1 III improved method as claimed in claim, wherein step (2) the mass strongly polar aprotic solvent in an amount of 2 to 3 times the mass of the compound II.
7.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中叠氮钠与化合物II摩尔比为1. 5 : 1〜2 : 1。 7. A compound according to one of claim 1 valsartan intermediate III improved method of claim, wherein the step (2) with sodium azide in the molar ratio of compound II is 1.5: 1 to 2: 1.
8.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中无水氯化锌质量用量与叠氮钠质量用量相等。 An intermediate compound according valsartan 1 III improved method of claim, wherein the step (2) of anhydrous zinc chloride equal mass amounts of sodium azide and the amount of mass.
9.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中催化剂为季铵盐选自:甲基三辛基氯化铵、苄基三乙基氯化铵、四丁基硫酸氢铵;或为金属卤化物选自氯化锂、氯化铝、溴化锂、溴化铝,优选为甲基三辛基氯化铵、四丁基硫酸氢铵、氯化锂。 9. A compound according to one of the intermediate valsartan 1 III improved method as claimed in claim, wherein step (2) the catalyst is selected from quaternary ammonium salts: methyltrioctylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate; or a metal halide selected from lithium chloride, aluminum chloride, lithium bromide, aluminum bromide, preferably methyl trioctyl ammonium chloride, tetrabutylammonium hydrogen sulfate ammonium, lithium chloride.
10.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中催化剂质量用量为化合物II质量的2%〜10%。 10. An intermediate compound according valsartan 1 III improved method of claim, wherein the step of mass of the catalyst in an amount of 2% ~ 10% by mass of Compound II (2).
11.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中成四氮唑反应温度为80〜135°C,优选为80〜100°C。 11. A compound of claim 1 valsartan intermediate III in improved process according to claim, wherein the step (2) into the tetrazolium reaction temperature is 80~135 ° C, preferably 80~100 ° C .
12.根据权利要求1所述的一种缬沙坦中间体化合物III的改进方法,其特征在于步骤(2)中成四氮唑反应时间为8〜35小时,优选为8〜15小时。 12. An intermediate compound according valsartan 1 III improved method of claim, wherein the step (2) into the tetrazolium reaction time 8~35 hours, preferably 8~15 hours.
CN 201410307545 2014-06-28 2014-06-28 Improved method for preparing tetrazole for valsartan CN104045602A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20100132180A (en) * 2009-06-09 2010-12-17 일동제약주식회사 A novel process for the preparation of valsartan
CN102010381A (en) * 2009-09-05 2011-04-13 山东新时代药业有限公司 Improved preparation method of valsartan
CN102822151A (en) * 2010-04-07 2012-12-12 新梅斯托克公司 Improved process for preparing valsartan

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20100132180A (en) * 2009-06-09 2010-12-17 일동제약주식회사 A novel process for the preparation of valsartan
CN102010381A (en) * 2009-09-05 2011-04-13 山东新时代药业有限公司 Improved preparation method of valsartan
CN102822151A (en) * 2010-04-07 2012-12-12 新梅斯托克公司 Improved process for preparing valsartan

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