CN103819384A - Preparation method of glycopyrronium bromide - Google Patents

Preparation method of glycopyrronium bromide Download PDF

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CN103819384A
CN103819384A CN 201310643664 CN201310643664A CN103819384A CN 103819384 A CN103819384 A CN 103819384A CN 201310643664 CN201310643664 CN 201310643664 CN 201310643664 A CN201310643664 A CN 201310643664A CN 103819384 A CN103819384 A CN 103819384A
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glycopyrrolate
reaction
step
hydrogen
δ
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CN 201310643664
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李庆
岳峰
黄健鹏
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广东嘉博制药有限公司
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12Oxygen or sulfur atoms

Abstract

The invention discloses a preparation method of glycopyrronium bromide, which comprises the following steps that 1) a dimethylformamide solution dissolved with a-cyclopentyl mandelic acid is pretreated via an excessive CDI (carbonyldiimidazole) condensing agent; 1-methyl-3-pyrrolidinol is added; ester exchange reaction is performed; the reaction is terminated via purified water; an intermediate is obtained; 2) the intermediate is extracted via an organic solvent and then washed via the purified water; 3) the intermediate after Step 2) and methyl bromide perform quaterisation in a polar solvent; suction filtration is performed; a crude glycopyrronium bromide product is obtained; and 4) the crude glycopyrronium bromide product is added to an organic solution for recrystallization; and a finished glycopyrronium bromide product is obtained. The method has the characteristics of simple and convenient production operation, low production cost, high production efficiency, excellent product quality, low pollution, high safety and the like; and the obtained product meets a drug quality standard and a clinical application requirement.

Description

一种格隆溴铵的制备方法 A method of preparing glycopyrrolate

技术领域 FIELD

[0001] 本发明涉及医药合成技术领域,具体涉及一种改良的格隆溴铵的制备方法。 [0001] The present invention relates to the field of pharmaceutical synthesis techniques, particularly directed to an improved method for preparing glycopyrrolate.

背景技术 Background technique

[0002] 格隆溴铵(Glycopyrronium Bromide)是一种季铵类抗毒蕈碱型胆碱药物,由美国SH10N0GI INC公司研究开发,并于1982年在美国上市。 [0002] glycopyrrolate (Glycopyrronium Bromide) is a quaternary ammonium anti-muscarinic cholinergic drugs, by the United States SH10N0GI INC research and development company, and in 1982 in the United States. 该药物自上市以来先后被制成片剂、注射剂等剂型,适用于十二指肠溃疡、慢性胃炎、胃炎分泌过多以及麻醉手术腺体分泌管理的临床治疗。 Since the drug has been listed as tablets, injections and the like formulation for duodenal ulcer, chronic gastritis, gastritis hypersecretion clinical anesthesia and management of glandular secretion. 同时,临床研究表明,格隆溴铵是比常用抗胆碱药物阿托品安全性更高,抑制腺体分泌作用更强的抗胆碱药物。 Meanwhile, clinical studies showed that glycopyrrolate is higher than conventional anticholinergic atropine safety, inhibition of glandular secretion stronger anticholinergic drugs.

[0003] 近年来,随着国内医药事业的持续发展,临床医生对于格隆溴铵的临床优势愈发关注,国内对于格隆溴铵的临床需求也日益凸显,因此,具有易操作、污染小、产率高且药性安全等特点的格隆溴铵的制备方法已成为人们的研究对象,且该种方法的研究有利于促进格隆溴铵的工业化生产,能满足市场及人们的需求。 [0003] In recent years, with the continued development of the domestic pharmaceutical industry, clinical advantages for clinicians glycopyrrolate increasingly concerned that domestic demand for clinical glycopyrrolate has become increasingly prominent, therefore, it is easy to operate, less pollution , preparation of glycopyrrolate high yield and potency of safety features has become the object of study, and study the ways in favor of the promotion of industrial production glycopyrrolate, can meet the market and people's needs.

[0004] 现格隆溴铵的制备方法主要有以下几种: [0004] A method is now glycopyrrolate are the following:

一、美国专利US 2956062或US 2009005577中公布的格隆溴铵的制备方法,该方法的具体合成路线如下: A preparation method of U.S. Patent Publication US 2956062 or in US 2009005577 glycopyrrolate, specific synthesis route for the method are as follows:

Figure CN103819384AD00031

该方法以a-环戊基扁桃酸为起始原料,先进行酯化反应生成a-环戊基扁桃酸甲酯,再在正庚烷溶剂中,采用金属钠或氢化钠作为碱,与1-甲基-3-吡咯烷醇进行酯交换反应,得中间体产物,经纯化后,在乙酸乙酯溶剂中与溴甲烷进行季铵化反应,制得格隆溴铵粗品,再经丁酮和乙酸乙酯混合溶剂重结晶,制得精制品格隆溴铵。 The method a- cyclopentyl-mandelic acid as a starting material, the esterification reaction to a- cyclopentyl mandelate, then in n-heptane solvent using metallic sodium or sodium hydride as a base, with 1 - methyl-3-pyrrolidinol transesterification reaction, yielding intermediate product purified, the quaternization reaction with ethyl bromide in a solvent to prepare a crude glycopyrronium bromide, methyl ethyl ketone, and then by a mixed solvent of ethyl acetate and recrystallized to obtain the purified product glycopyrrolate. 由于方法中酯交换反应需用到金属钠或氢化钠,属于易燃易爆物,容易造成安全隐患。 Since the method required the transesterification reaction to metallic sodium or sodium hydride, it is flammable and explosive material, likely to cause safety problems. 同时该方法所得的中间体易引起可逆性的外源性精神疾病,纯化时,操作要求高、安全风险大,不利于工业化生产。 While the resulting intermediates can lead to reversible exogenous mental illness, when purified, high operating requirements, large security risk is not suitable for industrial production.

[0005] 二、常德市洞庭制药厂发表在医药工业杂志上(医药工业,3,1974,p8~10)的格隆溴铵的制备方法,该方法的具体合成路线如下: [0005] Second, Changde City Dongting pharmaceutical published in the Journal of Pharmaceuticals (the pharmaceutical industry, 3,1974, p8 ~ 10) Preparation of glycopyrrolate, specific synthesis route for the method are as follows:

Figure CN103819384AD00041

该方法以苯乙烯为起始原料,经高锰酸钾氧化、甲醇及硫酸做酸催化剂酯化、环戊二烯与溴甲烷格式试剂取代、催化剂活性镍及氢气还原、1-甲基-3-吡咯烷醇和金属钠酯交换,最后通过季铵化反应制得粗品格隆溴铵。 In this method the styrene starting material, the potassium permanganate oxidation, methanol and sulfuric acid as an acid catalyst for the esterification, a substituted cyclopentadiene with a Grignard reagent methyl bromide, hydrogen reduction and catalytic activity of nickel, 1-methyl-3- pyrrolidinol transesterification and metallic sodium, and finally by a quaternization reaction of crude glycopyrronium bromide. 但该方法不仅反应步骤多、产率低,同时也未解决制备过程中使用金属钠带来的安全隐患问题,因此不适宜格隆溴铵的工业化生产。 However, this method is not only multi-step reaction, low yields, but also safety problems unresolved during preparation using sodium metal brought glycopyrrolate therefore unsuitable for industrial production. 尽管,随后该厂在1979年(文献医药工业,3,1979,pl(Tl2)对此合成路线进行了改良,但此次改良只是以苯乙酮酸甲酯替代苯乙烯为起始原料,其它后续反应并未进行革新,故合成中缺陷依然明显。 Although the plant is then carried out in 1979 (Document pharmaceutical industry, 3,1979, pl (Tl2) was modified for this synthetic route, but only to the improvement of acetophenone as a starting material methyl styrene Alternatively, other No subsequent reaction for innovation, it is still evident defects synthesis.

发明内容 SUMMARY

[0006] 本发明的目的在于提出一种格隆溴铵的制备方法,该方法具有生产操作简便、生产成本低廉、生产效率高、产品质量优良、污染小和安全性高等特点。 [0006] The object of the present invention is to provide a method for preparing glycopyrrolate, the production method is simple operation, low production costs, high production efficiency, product quality, low pollution and high security features.

[0007] 为了解决现有技术问题,本发明通过以下技术方案实现: [0007] In order to solve the prior art problems, the present invention is achieved by the following technical solution:

一种格隆溴铵的制备方法,该方法包括以下步骤: Preparing one kind of glycopyrronium bromide, the method comprising the steps of:

1)先采用过量的CDI缩合剂对溶解有a-环戊基扁桃酸的二甲基甲酰胺溶液进行预处理,加入1-甲基-3-吡咯烷醇后进行酯交换反应,然后采用纯化水终止反应,得到中间体; 1) to use an excess of condensing agent to CDI-dimethylformamide was dissolved a- cyclopentyl mandelic acid pretreatment, was added after the transesterification 1- methyl-3-pyrrolidinol, is then purified using The reaction was quenched with water, to give an intermediate;

2)采用有机溶剂对中间体进行萃取,再用纯化水洗涤; 2) an organic solvent for intermediate was extracted, washed with purified water;

3)将经步骤2)之后的中间体与溴甲烷在极性溶剂中进行季铵化反应,抽滤后得到格隆漠按粗广品; 3) carried by the intermediate with methyl bromide after step 2) in a polar solvent in the quaternization reaction, the desert by suction filtration to give crude glycopyrronium wide product;

4)将格隆溴铵粗产品加入至有机溶液中进行重结晶,得到格隆溴铵成品。 4) The crude product of glycopyrrolate was added to the organic solution and recrystallization, to give the finished glycopyrrolate.

[0008] 经步骤4)所得的格隆溴铵成品为富集(3R,2S)和(3S,2R)的外消旋体格隆溴铵。 [0008] Step 4 over) the resulting finished glycopyrrolate is enriched (3R, 2S) and (3S, 2R) racemic glycopyrrolate. [0009] 步骤I)中所述的中间体为α-环戊基-α-苯基-α-羟基乙酸-N-甲基-吡咯烷酯。 [0009] Step I) in the intermediate is α- cyclopentyl -α- phenyl -α- methyl glycolate -N- - pyrrolidine ester.

[0010] 步骤I)中所述预处理的温度为18~40°C,时间为0.5~2.0h。 [0010] Step I) in the pretreatment temperature of 18 ~ 40 ° C, time 0.5 ~ 2.0h.

[0011] 步骤I)中所述酯交换反应的反应温度为18~150°C,反应时间为l~72h。 The reaction temperature is [0011] Step I) in the transesterification reaction is 18 ~ 150 ° C, the reaction time is l ~ 72h.

[0012] 步骤2)中所述季铵化反应的反应温度为-2(T0°C,反应时间为f 5h。 The reaction temperature [0012] Step 2) the quaternization reaction is -2 (T0 ° C, the reaction time is f 5h.

[0013] 步骤2)中所述的有机溶剂为甲苯、叔丁基甲醚、异丙醇、正丙醇和丁酮中的任一种或几种的组合。 [0013] Step 2) in the organic solvent is any combination of toluene, t-butyl methyl ether, isopropanol, n-propanol and methyl ethyl ketone or several of.

[0014] 步骤3)中所述的极性溶剂为丙醇或酮。 [0014] Step 3) in said polar solvent is alcohol or ketone.

[0015] 步骤4)中所述的有机溶剂为甲醇、丙醇和酮中的任一种或几种的组合。 [0015] Step 4) in the organic solvent is a combination of any one or more of methanol, propanol, and ketones.

[0016] 本发明对格隆溴铵合成路线中酯交换反应进行了优化,实现了起始原料a_环戊基扁桃酸和1-甲基-3-吡咯烷醇的一步酯交换反应,代替了多步反应,简化了工艺流程,提高了生产效率;同时,本发明还避免了使用易燃易爆的金属或低分子烃类物质,有效弥补了格隆溴铵生产过程中的安全性缺陷,降低了生产成本;此外,本发明所得产品的纯度好,产品质量高,符合药品质量标准,满足临床应用需求。 [0016] The present invention of glycopyrrolate in Scheme transesterification reaction were optimized to achieve a starting material exchange reaction mandelic a_ cyclopentyl and methyl-3-pyrrolidinol esters step, instead of a multi-step reaction, simplifies the process, improve production efficiency; the same time, the present invention also avoids the low molecular weight hydrocarbon material or metal used explosive, the security flaw effectively compensate glycopyrrolate production process reduced production cost; in addition, the purity of the resulting product of the present invention, high quality products, meet drug quality standards, to meet the requirements of clinical application.

具体实施方式 detailed description

[0017] 本发明揭示了一种格隆溴铵的制备方法,该方法包括以下步骤: 1)先采用过量的CDI缩合剂对溶解有a-环戊基扁桃酸的二甲基甲酰胺溶液进行预处理,预处理的温度为18~4(TC,时间为0.5^2.0h ;然后加入1-甲基_3_吡咯烷醇后进行酯交换反应,酯交换反应的反应温度为18~150°C,反应时间为l~72h ;再采用纯化水终止反应,得到中间体,中间体为α-环戊基-α-苯基-α-羟基乙酸-N-甲基-吡咯烷酯; [0017] The present invention discloses a method for preparing glycopyrrolate, the method comprising the steps of: 1) first with an excess of condensing agent of CDI were dissolved in dimethylformamide with a solution of a- cyclopentyl mandelic acid is pretreatment, pretreatment temperature of 18 ~ 4 (TC, time is 0.5 ^ 2.0h; _3_ then added 1-methyl ester exchange reaction pyrrolidinol, the reaction temperature of the transesterification reaction is 18 ~ 150 ° C, the reaction time is l ~ 72h; then using purified water to terminate the reaction, to give the intermediate, α- intermediate is cyclopentyl -α- phenyl -α- methyl glycolate -N- - pyrrolidine ester;

2)采用有机溶剂对中间体进行萃取,所述有机溶剂为甲苯、叔丁基甲醚、异丙醇、正丙醇或丁酮,所提及的有机溶剂可以单独一种使用,也可多种组合使用,所述萃取法为本领域技术人员所熟知的技术,再用纯化水洗涤; 2) organic solvent extraction of the intermediates, the organic solvent is toluene, tert-butyl methyl ether, isopropanol, n-propanol or methyl ethyl ketone, it may be mentioned organic solvents used alone, may be a variety of combinations in use, the extraction method is well known to those skilled in the art, washed with purified water;

3)将经步骤2)之后的中间体与溴甲烷在极性溶剂中进行季铵化反应,季铵化反应的反应温度为-2(T0°C,反应时间为f5h,所述的极性溶剂为丙醇或酮,再进行抽滤,得到格隆漠按粗广品; 3) The following intermediate with methyl bromide by step 2) quaternization reaction in a polar solvent, the reaction temperature of the quaternization reaction is -2 (T0 ° C, the reaction time is F5H, a polar solvent propanol, or a ketone, and then subjected to suction filtration to obtain a crude glycopyrronium wide by desert product;

4)将格隆溴铵粗产品加入至有机溶液中进行重结晶,得到格隆溴铵成品,所得的格隆溴铵为富集(3R,2S)和(3S,2R)的外消旋体格隆溴铵;所述有机溶剂为甲醇、丙醇和酮中的任一种或几种的组合。 4) The crude product of glycopyrrolate was added to the organic solution and recrystallization, to give the finished glycopyrrolate, resulting glycopyrrolate is enriched (3R, 2S) and (3S, 2R) racemic physique Long bromide; the organic solvent is a combination of any one or more of methanol, propanol, and ketones.

[0018] 上述提及的⑶I缩合剂为N,N' -羰基二咪唑,可促进酯交换反应,能更好的得到中间体为α -环戊基-α -苯基-α -羟基乙酸_Ν_甲基-吡咯烷酯。 [0018] The above-mentioned condensing agent is ⑶I N, N '- carbonyl diimidazole, can promote the transesterification reaction intermediate is better to give α - cyclopentyl -α - phenyl -α - glycolic acid _ Ν_ methyl - pyrrolidine ester.

[0019] 本发明对格隆溴铵合成路线中酯交换反应进行了优化,实现了起始原料a_环戊基扁桃酸和1-甲基-3-吡咯烷醇的一步酯交换反应,代替了多步反应,简化了工艺流程,提高了生产效率;同时,本发明还避免了使用易燃易爆的金属或低分子烃类物质,有效弥补了格隆溴铵生产过程中的安全性缺陷,降低了生产成本;此外,本发明所得产品的纯度好,产品质量高,符合药品质量标准,满足临床应用需求。 [0019] The present invention of glycopyrrolate in Scheme transesterification reaction were optimized to achieve a starting material exchange reaction mandelic a_ cyclopentyl and methyl-3-pyrrolidinol esters step, instead of a multi-step reaction, simplifies the process, improve production efficiency; the same time, the present invention also avoids the low molecular weight hydrocarbon material or metal used explosive, the security flaw effectively compensate glycopyrrolate production process reduced production cost; in addition, the purity of the resulting product of the present invention, high quality products, meet drug quality standards, to meet the requirements of clinical application.

[0020] 为了本领域技术人员的理解,以下通过具体实施例对本发明作进一步详细的描述。 [0020] In order understood by those skilled in the art, the following specific embodiments will be further detailed description of the present invention. [0021] 实施例1 [0021] Example 1

一种格隆溴铵的制备方法,该方法包括以下步骤: Preparing one kind of glycopyrronium bromide, the method comprising the steps of:

1)将150g的a-环戊基扁桃酸溶解于Ikg的二甲基甲酰胺(DMF)中,溶解后置于5L干燥反应瓶中,加入135g的N,N' -羰基二咪唑,于18°C下进行搅拌2.0h ;然后加入85g的1-甲基-3-吡咯烷醇,在Ih内加热至60°C,维持搅拌18h,冷却,加入Ikg纯化水终止反应,得中间体a-环戊基-a-苯基-a-羟基乙酸-N-甲基-吡咯烷酯; 1) 150g of the a- cyclopentyl Ikg mandelic acid was dissolved in dimethyl formamide (DMF), the dried and dissolved 5L reaction flask was placed, was added 135g of N, N '- carbonyl diimidazole, in 18 carried out with stirring 2.0H ° C; followed by the addition of 85g methyl-3-pyrrolidinol, was heated to 60 ° C in Ih is, maintaining the stirring for 18 h, cooled, purified water was added to terminate the reaction Ikg, yielding intermediate a- cyclopentyl glycolate -a- -a- -N- phenyl-methyl - pyrrolidine ester;

2)加入Ikg甲苯,对步骤1)反应所得的中间体进行萃取,然后采用纯化水洗涤3次; 2) Ikg toluene was added, step 1) obtained reaction intermediate was extracted and then washed three times with purified water;

3)采用旋蒸减压浓缩对经步骤2)处理后的中间体进行浓缩,浓缩至浓度为50%的甲苯溶液,加入600g正丙醇稀释,将稀释后的溶液冷却至(TC;加入85g的溴甲烷,在0°C条件下搅拌2h后,继续搅拌并加热升温至60°C,停止反应;冷却至室温后,抽滤,滤饼干燥,得到123g格隆漠按粗品; 3) concentrated under reduced pressure using rotary evaporator after intermediate) by treatment step 2 was concentrated to a concentration of 50% solution in toluene, diluted with 600g of n-propanol was added, the solution was cooled diluted to (the TC; was added 85g methyl bromide, stirred at 0 ° C under conditions after 2h, stirring and continued heating to 60 ° C, the reaction was stopped; after cooling to room temperature, filtered off with suction, the filter cake was dried to give 123g crude glycopyrronium by desert;

4)将全部粗品加入1.23kg重量百分比为0.l%wt的正丙醇进行重结晶,得到115g高纯度的格隆溴铵。 4) The entire crude product was added 1.23kg weight percentage of 0.l% wt n-propanol recrystallized glycopyrrolate to give 115g of high purity. 收率为84%,经HPLC检验,其纯度>99.0%。 The yield was 84%, tested by HPLC, purity> 99.0%. 对产物进行元素分析、核磁分析以及质谱分析,均表明本发明方法制备的产物为格隆溴铵成品。 The product was elemental analysis, NMR analysis and mass spectrometric analysis show that the product prepared by the process of the present invention is a finished glycopyrrolate.

[0022] 实施例2 [0022] Example 2

一种格隆溴铵的制备方法,该方法包括以下步骤: Preparing one kind of glycopyrronium bromide, the method comprising the steps of:

1)将600g的a-环戊基扁桃酸溶解于4kg的二甲基甲酰胺(DMF)中,溶解后置于20L干燥反应瓶中,加入540g的N,N' -羰基二咪唑,于室温下进行搅拌1.0h ;然后加入340g的1-甲基-3-吡咯烷醇,于室温下持续搅拌72h,冷却,加入4kg纯化水终止反应,得中间体a-环戊基-a-苯基-a-羟基乙酸-N-甲基-吡咯烷酯; 1) 600g of a- cyclopentyl 4kg mandelic acid was dissolved in dimethyl formamide (DMF), the dried and dissolved was placed 20L reaction flask was added 540g of N, N '- carbonyl diimidazole, at room temperature under stirring 1.0H; was then added 340g of 1-methyl-3-pyrrolidinol, stirring was continued at room temperature for 72h, was cooled, was added 4kg of purified water to terminate the reaction, yielding intermediate -a- phenyl-cyclopentyl-a- -a- glycolate -N- methyl - pyrrolidine ester;

2)加入4kg叔丁基甲醚,对步骤I)反应所得的中间体进行萃取,采用纯化水洗涤3次; 2) tert-butyl methyl ether was added 4kg of step I) the obtained reaction intermediate was extracted, washed three times with purified water;

3)采用旋蒸减压浓缩对经步骤2)处理后的中间体进行浓缩,浓缩至浓度为50%的甲苯溶液,然后加入2.4kg正丙醇稀释,将稀释后的溶液置于_20°C条件下;加入340g的溴甲烷,在-20°C条件下搅拌2h后,继续搅拌并加热升温至60°C,停止反应;冷却至室温后,抽滤,滤饼干燥,得到521g格隆溴铵粗品; 3) concentrated under reduced pressure using rotary evaporator after intermediate) by treatment step 2 was concentrated to a concentration of 50% solution in toluene, 2.4kg diluted with n-propanol was then added, the diluted solution was placed _20 ° under conditions of C; 340g of methyl bromide was added, stirred at -20 ° C condition after 2h, and stirring was continued heating to 60 ° C, the reaction was stopped; after cooling to room temperature, filtered off with suction, the filter cake was dried to give 521g glycopyrrolate The crude ammonium;

4)将全部粗品加入1.23kg重量百分比为0.l%wt的正丙醇进行重结晶,得到505g高纯度的格隆溴铵成品。 4) The entire crude product was added 1.23kg weight percentage of 0.l% wt n-propanol and recrystallized, to give 505g of high purity finished glycopyrrolate. 产率为92%,经HPLC检验,其纯度>99.0%。 The yield was 92%, tested by HPLC, purity> 99.0%. 对产物进行元素分析、核磁分析以及质谱分析,均表明本发明方法制备的产物为格隆溴铵成品。 The product was elemental analysis, NMR analysis and mass spectrometric analysis show that the product prepared by the process of the present invention is a finished glycopyrrolate.

[0023] 实施例3 [0023] Example 3

一种格隆溴铵的制备方法,该方法包括以下步骤: Preparing one kind of glycopyrronium bromide, the method comprising the steps of:

1)将600g的a-环戊基扁桃酸溶解于4kg的二甲基甲酰胺(DMF)中,溶解后置于20L干燥反应瓶中,加入540g的N,N' -羰基二咪唑,于40°C下进行搅拌0.5h ;然后加入340g的1-甲基-3-吡咯烷醇,于150°C下持续搅拌lh,冷却,加入4kg纯化水终止反应,得中间体a-环戊基-a-苯基-a-羟基乙酸-N-甲基-吡咯烷酯; 1) 600g of a- cyclopentyl 4kg mandelic acid was dissolved in dimethyl formamide (DMF), the dried and dissolved was placed 20L reaction flask was added 540g of N, N '- carbonyl diimidazole, in 40 It was stirred at ° C for 0.5H; was then added 340g of 1-methyl-3-pyrrolidinol, stirring was continued at 150 ° C lh, was cooled, was added 4kg of purified water to terminate the reaction, yielding intermediate a- cyclopentyl - phenyl a- -a- glycolate -N- methyl - pyrrolidine ester;

2)加入4kg叔丁基甲醚,对步骤I)反应所得的中间体进行萃取,采用纯化水洗涤3次; 2) tert-butyl methyl ether was added 4kg of step I) the obtained reaction intermediate was extracted, washed three times with purified water;

3)采用旋蒸减压浓缩对经步骤2)处理后的中间体进行浓缩,浓缩至浓度为50%的甲苯溶液,然后加入2.4kg正丙醇稀释,将稀释后的溶液置于-10°C条件下;加入340g的溴甲烷,在-10°C条件下搅拌5h后,继续搅拌并加热升温至60°C,停止反应;冷却至室温后,抽滤,滤饼干燥,得到513g格隆溴铵粗品;4)将全部粗品加入1.23kg重量百分比为0.l%wt的正丙醇进行重结晶,得到486g高纯度的格隆溴铵成品。 3) concentrated under reduced pressure using rotary evaporator after intermediate) by treatment step 2 was concentrated to a concentration of 50% solution in toluene, 2.4kg diluted with n-propanol was then added, the diluted solution was placed in -10 ° under conditions of C; 340g of methyl bromide was added, stirred at -10 ° C condition after 5h, stirring and continued heating to 60 ° C, the reaction was stopped; after cooling to room temperature, filtered off with suction, the filter cake was dried to give 513g glycopyrrolate the crude ammonium; 4) the entire crude product was added 1.23kg weight percentage of 0.l% wt n-propanol was recrystallized to give 486g of high purity finished glycopyrrolate. 产率为91%%,经HPLC检验,其纯度>99.0%。 The yield was 91 %%, tested by HPLC, purity> 99.0%.

[0024] 对实施例1~3所得的格隆溴铵成品进行元素分析、核磁分析以及质谱分析,分析结果如下所示: [0024] The finished product obtained in Example glycopyrrolate embodiment 1 to 3, elemental analysis, NMR analysis and mass spectrometry analysis results as follows:

元素分析: Elemental analysis:

采用中国药品生物制品检定所提供的格隆溴铵结构确证对照品作为对照品。 Glycopyrrolate structure using China Pharmaceutical and Biological Products confirmation reference provided as the reference. 所得结果如表1所示: The obtained results are shown in Table 1:

Figure CN103819384AD00071

表1:元素分析结果。 Table 1: Results of elemental analysis.

[0025] 结构确证磁谱分析: [0025] Magnetic spectral analysis confirmed the structure:

1H-NMR谱图解析 1H-NMR spectrum of analytical

根据COSY谱及重水交换谱,结合HMQC谱、HMBC谱和DEPT谱,可对格隆溴铵样品的IH谱进行归属: The COSY spectrum and exchanges with D₂O spectra, combined spectra of HMQC, HMBC and DEPT spectra spectrum, the spectrum can be attributed to the IH glycopyrrolate sample:

H谱显示有16组氢,由低场到高场氢的积分比例分别为2:2:1:1:1:1:1:1:1:3:3:1:1:1:6: 2,与格隆溴铵的结构相符。 H-NMR spectrum showed a 16 group of hydrogen, the low field to high field hydrogen integral ratio are 2: 2: 1: 1: 1: 1: 1: 1: 1: 3: 3: 1: 1: 1: 6: 2, and glycopyrrolate consistent structure.

[0026] δ 7.60处氢为一组二重峰,质子数为2 ;C0SY谱显示,该处氢与δ 7.36氢、δ 7.27氢相关;归属为14,14'位苯环芳氢。 [0026] δ 7.60 hydrogen at a set doublet, number of protons is 2; C0SY spectrum shows, where the hydrogen and hydrogen δ 7.36, δ 7.27 correlation hydrogen; assigned as 14, 14 'of the phenyl ring aromatic hydrogen.

[0027] δ 7.36处氢为一组双二重峰,质子数为2 ;C0SY谱显示,该处氢与δ 7.60氢14,14'相关;归属为15,15'位苯环芳氢。 [0027] δ 7.36 hydrogen at a set of double doublet, number of protons is 2; C0SY spectrum shows, where δ 7.60 hydrogen to hydrogen 14, 14 'associated; assigned as 15, 15' of the phenyl ring aromatic hydrogen.

[0028] δ 7.27处氢为一组二重峰,质子数为I ;C0SY谱显示,该处氢与δ 7.60氢14,14' [0028] δ 7.27 hydrogen at a set doublet, number of protons is I; C0SY spectrum shows, where δ 7.60 hydrogen to hydrogen 14, 14 '

相关;归属为16位苯环芳氢。 Related; 16 attributed to the aromatic benzene ring hydrogen.

[0029] δ 5.85处氢为一组单峰,质子数为I ;经重水交换后,该峰基本消失;应为活泼氢,归属为17为羟基氢。 [0029] δ 5.85 hydrogen at a set singlet, protons of I; heavy water by the exchange, this peak disappeared; active hydrogen should, 17 attributed to hydrogen is a hydroxyl group.

[0030] δ 5.38处氢为一组多重峰,质子数为I ;C0SY谱显示,该处氢与δ3.92氢相关;归属为3位次甲基氢。 [0030] δ 5.38 hydrogen at a set multiplet, proton number I; C0SY spectrum shows, where the hydrogen associated with the δ3.92 hydrogen; 3 ranking attributed to the methyl hydrogen.

[0031] δ 3.92、δ 3.64处氢分别为一组双二重峰,质子数均为I ;C0SY谱显示,这两组氢相关;HMQC谱和DEPT谱显示,这两组氢与同一仲碳相关;归属为2位亚甲基上的两个氢2b和2a。 [0031] δ 3.92, δ 3.64 hydrogen respectively at a set of double doublet, protons are I; C0SY spectrum shows these two sets of hydrogen-related; and DEPT spectra show HMQC spectrum, which hydrogen sets the same to a secondary carbon Related; 2b attributed to two hydrogens on the methylene group 2 and 2a.

[0032] δ 3.74、δ 3.57处氢分别为一组多重峰,质子数均为I ;C0SY谱显示,这两组氢相关;HMQC谱和DEPT谱显示,这两组氢与同一仲碳相关;归属为5位亚甲基上的两个氢5b和5a。 [0032] δ 3.74, δ 3.57 hydrogen at a set of multiple peaks, respectively, number of protons are I; C0SY spectrum shows these two sets of correlation hydrogen; and DEPT spectra show HMQC spectrum, which hydrogen sets relating to the same secondary carbon; 5 is home on the two methylene hydrogen 5b and 5a.

[0033] δ 3.22处氢为一组单峰,质子数为3;归属为I 0-)位甲基氢。 [0033] δ 3.22 hydrogen at a set singlet, 3 protons; attributed to I 0-) Methyl hydrogen.

[0034] δ 3.13处氢为一组单峰,质子数为I ;归属为I'(I)位甲基氢。 [0034] δ 3.13 hydrogen at a set singlet, protons of I; home as I '(I) Methyl hydrogen.

[0035] δ 2.92处氢为一组多重峰,质子数为I ;归属为8位次甲基氢。 [0035] δ 2.92 hydrogen at a set multiplet, proton number I; 8 ranking attributed to methyl hydrogen.

[0036] δ 2.66、δ 2.08处氢分别为一组多重峰,质子数均为I ;C0SY谱显示,这两组氢相关;HMQC谱和DEPT谱显示,这两组氢与同一仲碳相关;归属为4位亚甲基上的两个氢4b和4a . [0036] δ 2.66, δ 2.08 hydrogen at a set of multiple peaks, respectively, number of protons are I; C0SY spectrum shows these two sets of correlation hydrogen; and DEPT spectra show HMQC spectrum, which hydrogen sets relating to the same secondary carbon; attributed to the four two hydrogen 4b and 4a on the methylene group.

[0037] δ 1.6"?.2处氢为一组多重锋,质子数为8 ;归属为9、10、11、12位上的亚甲基氢。 [0037] δ 1.6 "at a set of multiple two hydrogen Feng, 8 protons;?. 9, 10, a home position of the methylene hydrogen.

[0038] 13C-NMR 谱图解析 [0038] 13C-NMR spectrum of analytical

格隆溴铵分子结构中有19个碳,其中14和14'、15和15'、9和12、10和11为对称碳,而本品的13C谱显示共有15组碳峰,而本品显示有17组碳峰,这是由于样品中可能存在旋光异构体,旋光异构体9和12、10和11位化学位移差异引起的,这与格隆溴铵分子结构相符。 Glycopyrrolate molecular structure 19 carbons, wherein 14 and 14 ', 15 and 15', 12, 10 and 9 and 11 is asymmetric carbon, and 13C spectra of this product displayed a total of 15 carbon peak group, and the product group showed 17 carbon peak, which is present in the sample due to the optical isomers, 9, and 12, 10 and 11 chemical shift difference due to optical isomers, consistent with the molecular structure of glycopyrrolate. 根据DEPT谱、HMQC谱及HMBC谱,解析如下: The DEPT spectrum, HMQC and HMBC spectra spectrum, interpreted as follows:

DEPT谱显示含有2组伯碳峰,这与格隆溴铵分子结构相符。 DEPT spectrum showed groups containing 2 primary carbon peak, which is consistent with the molecular structure of glycopyrrolate. 其中δ 52.54的伯碳峰,在HMQC谱中与δ 3.22氢1 0-)相关,归属为1 (1')位甲基碳;HMBC谱显示,该碳峰与δ 3.13氢1'(1)、δ 3.57氢5a、δ 3.92氢2b远程相关,证实归属正确。 Wherein the primary carbon peak of δ 52.54, HMQC correlation spectrum with hydrogen 10- δ 3.22), home 1 (1 ') - methyl carbon; HMBC spectrum revealed that the carbon peaks δ 3.13 hydrogen and 1' (1) , δ 3.57 hydrogen 5a, δ 3.92 hydrogen 2b associated remote, the home confirmed correct.

[0039] δ 52.01的伯碳峰,在HMQC谱中与δ 3.13氢1'(1)相关,归属为1'(1)位甲基碳;HMBC 谱显不,该碳峰与δ 3.22 氢1 (1,)、δ 3.64 氢2b、δ 3.57 氢5a、δ 3.92 氢2b 远程相关,证实归属正确。 Primary carbon peak [0039] δ 52.01, and '(1), attributed to the 1' and HMQC spectrum δ 3.13 hydrogen 1 (1) Methyl carbons; HMBC spectrum is not significant, the carbon peak δ 3.22 hydrogen 1 (1,), δ 3.64 hydrogen 2b, δ 3.57 hydrogen 5a, δ 3.92 hydrogen 2b associated remote, the home confirmed correct.

[0040] DEPT谱显示有7组仲碳峰存在,这与格隆溴铵分子结构相符。 [0040] DEPT spectrum showed the presence of seven groups of secondary carbon peak, which is consistent with the molecular structure of glycopyrrolate. 其中δ 69.18的一组仲碳峰,在HMQC谱中与δ3.92氢2b、δ 3.64氢2a同时相关,归属为2位亚甲基碳;HMBC谱显示,该碳峰与δ 3.22 氢1 0-)、δ 3.13 氢1' (1 )、δ 3.57 氢5a、δ 2.66 氢4b、δ 3.74氢5b远程相关,证实归属正确。 Wherein a set of secondary carbon peak of δ 69.18, 2a in the HMQC spectrum associated with simultaneously hydrogen δ3.92 2b, δ 3.64 hydrogen, attributed to two methylene carbon; HMBC spectrum shows the carbon peak δ 3.22 hydrogen 10 -), δ 3.13 hydrogen 1 '(1), δ 3.57 hydrogen 5a, δ 2.66 hydrogen 4b, δ 3.74 hydrogen 5b remote coherency, the correct attribution was confirmed.

[0041] δ 63.82的一组仲碳峰,在HMQC谱中与δ 3.74氢5b、δ 3.57氢5a同时相关,归属为5位亚甲基碳;HMBC谱显示,该碳峰与δ 3.22氢1 (1')、δ3.13氢1' (1)、δ3.57氢5a、δ 2.08 4a、δ 2.66 氧4b、δ 5.38 氧3、δ 3.64 2a、δ 3.92 2b 远程相关,证实归 A set of secondary carbon peak [0041] δ 63.82 in HMQC spectrum, δ 3.57 hydrogen simultaneously related 5a δ 3.74 hydrogen 5b, attributed to the methylene carbon 5; HMBC spectrum shows the carbon peak δ 3.22 hydrogen 1 (1 '), δ3.13 hydrogen 1' (1), δ3.57 hydrogen 5a, δ 2.08 4a, δ 2.66 oxygen 4b, δ 5.38 oxygen 3, δ 3.64 2a, δ 3.92 2b remotely related, normalized confirmed

属正确。 Is a right.

[0042] δ 29.62的一组仲碳峰,在HMQC谱中与δ 2.66氢4b、δ 2.08氢4a同时相关,归属为4位亚甲基碳;HMBC谱显示,该碳峰与δ 3.57氢5a、δ 3.64氢2a、远程相关,证实归属正确。 A set of secondary carbon peak [0042] δ 29.62 a, δ 2.66 hydrogen 4b, δ 2.08 hydrogen 4a HMQC correlation spectrum simultaneously with, attributed to the methylene carbon 4; HMBC spectrum shows the carbon peak δ 3.57 hydrogen 5a , δ 3.64 hydrogen 2a, relevant distance, the correct attribution was confirmed.

[0043] δ 26.55,25.54的仲碳峰分别归属为分子中存在的旋光异构体的10位、11位甲基碳。 Secondary carbon peak [0043] δ 26.55,25.54 were attributed to the molecule, optical isomers present in 10, 11 methyl carbons.

[0044] δ 26.01、δ 25.95的仲碳峰分别归属为分子中存在的旋光异构体的9位、12位甲基碳。 [0044] δ 26.01, a secondary carbon peak δ 25.95 were attributed to the molecule in the presence of optical isomers of 9, 12 methyl carbons.

[0045] DEPT谱显示有5组叔碳峰存在,与格隆溴铵分子结构相符。 [0045] DEPT spectrum showed a peak with a tertiary carbon group 5 exists, consistent with the molecular structure of glycopyrrolate. 其中δ 127.92的叔碳峰,在HMQC谱中与δ7.36氢15、15'相关,归属为15、15'位次甲基碳。 Wherein the tertiary carbon of the δ 127.92 peak, in HMQC spectrum 'related to the home 15, 15' and 15, 15 ranking δ7.36 hydrogen methyl carbon.

[0046] δ 127.21叔碳峰,在HMQC谱上与δ 7.27氢16相关,归属为16位次甲基碳;HMBC谱显示,该碳峰与3 7.60氢14、14'远程相关,证实归属正确。 [0046] δ 127.21 peak tertiary carbon, HMQC correlation spectrum of the δ 7.27 hydrogen 16, 16 ranking attributed to the methyl carbon; HMBC spectrum revealed that the carbon hydrogen peak 3 7.60 14, 14 'associated remote confirm correct attribution .

[0047] δ 125.60的叔碳峰,在HMQC谱中与δ 7.60氢14、14'相关,归属为14、14'位次甲基碳;HMBC谱显示,该碳峰与δ 7.27氢16远程相关,证实归属正确。 Tertiary carbon peak [0047] δ 125.60 in HMQC spectrum 'related to the home 14, 14' and 14, 14 rank δ 7.60 hydrogen methyl carbon; HMBC spectrum shows the carbon peak δ 7.27 hydrogen associated remote 16 , confirming ownership right.

[0048] δ 72.64的叔碳峰,在HMQC谱上与δ 5.38氢3相关,归属为3位次甲基碳;HMBC谱显不,该碳峰与δ 2.08氢4a、δ 2.66氢4b、δ 3.64氢2a、δ 3.74氢5b远程相关,证实归属正确。 Tertiary carbon peak [0048] δ 72.64 in the HMQC spectrum associated with hydrogen 3 δ 5.38, attributed to the methyl carbon rank 3; HMBC spectrum is not significant, the carbon peak δ 2.08 hydrogen 4a, δ 2.66 hydrogen 4b, δ hydrogen 3.64 2a, δ 3.74 hydrogen 5b remote coherency, the correct attribution was confirmed.

[0049] δ 46.58的叔碳峰,在HMQC谱中与δ 2.92氢8相关,归属为8位次甲基碳;HMBC谱显不,该碳峰与δ 5.85氢17、δ 1.21氢、δ 1.61氢远程相关,证实归属正确。 Tertiary carbon peak [0049] δ 46.58 in HMQC spectrum associated with the δ 2.92 hydrogen 8, 8 ranking attributed to the methyl carbon; HMBC spectrum is not significant, the carbon peak δ 5.85 hydrogen 17, δ 1.21 hydrogen, δ 1.61 hydrogen remotely related, confirming ownership right.

[0050] DEPT谱显示有3组季碳峰存在,与格隆溴铵分子结构相符。 [0050] DEPT spectrum showed the presence of three groups of quaternary carbon peak, consistent with the molecular structure of glycopyrrolate. 其中δ 173.37的季碳峰,在HMBC谱中显示与δ 5.85氢17、δ 5.38氢3远程相关,归属为6位羰基碳。 Wherein the quaternary carbons δ 173.37 peak, with the display 17 in the δ 5.85 hydrogen HMBC spectrum, δ 5.38 hydrogen remotely related 3, 6 attributed to the carbonyl carbon.

[0051] δ 142.07的季碳峰,在HMBC谱中显示与δ 5.85氢17、δ 7.36氢15,15'远程相关,归属为13位季碳。 Quaternary carbon peak [0051] δ 142.07, showing the HMBC spectrum δ 5.85 hydrogen and 17, δ 7.36 hydrogen 15, 15 'remote coherency, 13 attributed to a quaternary carbon.

[0052] δ 79.20 的季碳峰,在HMBC 谱中显示与δ 7.60 氢14,14,、δ 5.85 氢17、δ 1.21 [0052] δ 79.20 quaternary carbon peak showing the δ 7.60 hydrogen 14,14,, δ 5.85 hydrogen 17, δ 1.21 in the HMBC spectrum

氢远程相关,归属为7位季碳。 Hydrogen remotely related, belonging to seven quaternary carbon.

[0053] MS:m/z (Μ+) 318 (100% ),与格隆溴铵碱基分子量一致,符合格隆溴铵结构。 [0053] MS: m / z (Μ +) 318 (100%), and glycopyrrolate base molecular weight and consistent with the structure of glycopyrrolate.

[0054] 由此可知,本发明所制得的格隆溴铵成品为富集(3R,2S)和(3S,2R)的外消旋体格隆溴铵,且产品质量优良,符合药品质量标准,满足临床应用需求。 [0054] It can be seen, the present invention is prepared glycopyrrolate is finished enriched (3R, 2S) racemic glycopyrrolate and (3S, 2R), and product quality, meet drug quality standards to meet the needs of clinical applications.

[0055] 上述实施例中提到的内容并非是对本发明的限定,在不脱离本发明的发明构思的前提下,任何显而易见的替换均在本发明的保护范围之内。 SUMMARY [0055] The above-mentioned embodiments are not limiting the present invention, without departing from the inventive concept of the present invention is the premise of any obvious alternative are within the scope of the present invention.

Claims (9)

  1. 1.一种格隆溴铵的制备方法,该方法包括以下步骤: 1)先采用过量的CDI缩合剂对溶解有a-环戊基扁桃酸的二甲基甲酰胺溶液进行预处理,加入1-甲基-3-吡咯烷醇后进行酯交换反应,然后采用纯化水终止反应,得到中间体; 2)采用有机溶剂对中间体进行萃取,再用纯化水洗涤; 3)将经步骤2)之后的的中间体与溴甲烷在极性溶剂中进行季铵化反应,抽滤后得到格隆漠按粗广品; 4)将格隆溴铵粗产品加入有机溶液中进行重结晶,得到格隆溴铵成品。 1. A method for preparing glycopyrrolate, the method comprising the steps of: 1) first with an excess of condensing agent of CDI were dissolved in dimethylformamide with a solution of a- cyclopentyl mandelic acid pretreatment, was added 1 - methyl-3-pyrrolidinol after transesterification reaction, and then the reaction was terminated using purified water, to give an intermediate; 2) of the intermediate organic solvent was extracted, then purified by washing with water; 3) via the step 2) after the intermediate with methyl bromide in a polar solvent in the quaternization reaction, the desert by suction filtration to give crude glycopyrronium wide product; 4) the crude product was added glycopyrrolate organic solution was recrystallized to give glycopyrrolate bromide finished.
  2. 2.根据权利要求1所述的格隆溴铵的制备方法,其特征在于:经步骤4)所得的格隆溴铵成品为富集(3R,2S)和(3S,2R)的外消旋体格隆溴铵。 The production method of claim 1 glycopyrrolate claim, wherein: after step 4) the resulting finished glycopyrrolate is enriched (3R, 2S) and (3S, 2R) racemic glycopyrrolate body.
  3. 3.根据权利要求2所述的格隆溴铵的制备方法,其特征在于:步骤I)中所述的中间体为a-环戊基-α -苯基-α -羟基乙酸_Ν_甲基-吡咯烷酯。 3. The method of glycopyrrolate prepared according to claim 2, wherein: in step I) the intermediates a- cyclopentyl -α - phenyl -α - hydroxy carboxylic acid _Ν_ group - pyrrolidine ester.
  4. 4.根据权利要求3所述的格隆溴铵的制备方法,其特征在于:步骤I)中所述预处理的温度为18~40°C,时间为0.5~2.0h。 4. The method of glycopyrrolate prepared according to claim 3, wherein: in step I) the pretreatment temperature of 18 ~ 40 ° C, time 0.5 ~ 2.0h.
  5. 5.根据权利要求4所述的格隆溴铵的制备方法,其特征在于:步骤I)中所述酯交换反应的反应温度为18~150°C,反应时间为l~72h。 The production method of the glycopyrrolate claimed in claim 4, wherein: in step I) the ester exchange reaction is a reaction temperature 18 ~ 150 ° C, the reaction time is l ~ 72h.
  6. 6.根据权利要求5所述的格隆溴铵的制备方法,其特征在于:步骤2)中所述季铵化反应的反应温度为-2(T(TC, 反应时间为l~5h。 6. The method of glycopyrrolate prepared according to claim 5, wherein: the reaction temperature in step 2) the quaternization reaction is -2 (T (TC, the reaction time is l ~ 5h.
  7. 7.根据权利要求1飞中任一项所述的格隆溴铵的制备方法,其特征在于:步骤2)中所述的有机溶剂为甲苯、叔丁基甲醚、异丙醇、正丙醇和丁酮中的任一种或几种的组合。 The production method of glycopyrrolate fly in claim any one of claims 1, wherein: in step 2) in the organic solvent is toluene, tert-butyl methyl ether, isopropanol, n-propanol and butoxy any combination of one or more ketones.
  8. 8.根据权利要求1飞中任一项所述的格隆溴铵的制备方法,其特征在于:步骤3)中所述的极性溶剂为丙醇或酮。 8. A method of preparing a flying glycopyrrolate according to any one of the preceding claims, characterized in that: in step 3) said polar solvent is alcohol or ketone.
  9. 9.根据权利要求1飞中任一项所述的格隆溴铵的制备方法,其特征在于:步骤4)中所述的有机溶剂为甲醇、丙醇和酮中的任一种或几种的组合。 9. A method of preparing a flying glycopyrrolate according to any one of the preceding claims, characterized in that: in step 4) according to any one of organic solvent is methanol, propanol, and ketones or several of combination.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102388021A (en) * 2009-04-09 2012-03-21 诺瓦提斯公司 Process for preparing pyrrolidinium salts
CN102627595A (en) * 2012-03-09 2012-08-08 徐奎 Method for preparation of glycopyrronium bromide
CN103159659A (en) * 2011-12-19 2013-06-19 沈阳药科大学 Preparation method of muscarinic receptor antagonist glycopyrronium bromide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102388021A (en) * 2009-04-09 2012-03-21 诺瓦提斯公司 Process for preparing pyrrolidinium salts
CN103159659A (en) * 2011-12-19 2013-06-19 沈阳药科大学 Preparation method of muscarinic receptor antagonist glycopyrronium bromide
CN102627595A (en) * 2012-03-09 2012-08-08 徐奎 Method for preparation of glycopyrronium bromide

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