Ipratropium Bromide异丙托溴铵

合集下载

异丙托溴铵

异丙托溴铵

强持续至少21天,是气道高反应性的原因之一。
11.Global Initiative for Asthma. Global strategy for the diagnosis and management of asthma in children 5 years and younger.2006. 12.俞善昌等. 临床儿科杂志, 2008,26(3) :258.
8
病毒感染对M受体的影响及气道高反应性
M受体与气道高反应性相关

β、M受体是气道内存在的主要植物神经递质受体,介导体内交感、副交感神经递
质生物学效应,与气道高反应性关系密切
RSV感染使β受体亲和力下降,M受体密度增加、亲和力上升,两种受体系统之间 的平衡失调是引起气道高反应性的机制之一 RSV感染对M受体的长时间影响,可能是RSV感染后气道高反应性较长时间存在的原 因之一
5.Barnes PJ. Nat Rev Drug Discov, 2004; 3: 831-844. 6.Current Opinion in Pharmacology 2001;1:223-9
7
病毒感染对M受体的影响及气道高反应性
7.Kanazawa H. Current Opinion in Pulmonary Medicine, 2006; 12: 60-67.
4
病毒感染对M受体的影响及气道高反应性
儿童喘息性疾病与病毒感染 密切相关

呼吸道合胞病毒(RSV)是婴幼儿喘息的主要病因或诱因,由呼吸道合胞病毒(RSV)
引起者达50-80%。
鼻病毒(RV)所致毛细支气管炎后喘息和哮喘更常见。
其他喘息相关性病毒:腺病毒、肠道病毒、副流感病毒、人类偏肺病毒、博卡病毒等。

异丙托溴铵气雾剂Ipratropium-详细说明书与重点

异丙托溴铵气雾剂Ipratropium-详细说明书与重点

异丙托溴铵气雾剂Ipratropium英文名:Ipratropium Bromide Aerosol【成份】主要成份:每喷含(8γ)-3α-羟基-8-异丙基-1αH。

化学名称:(8r)-3α-羟基-8-异丙基-1αH,5αH-溴化托品(±)托品酸(=异丙托溴铵)-水合物。

化学结构式:分子式:C20H30BrNO3·H2O分子量:430.4【性状】本品在耐压容器中的药液为澄清无色液体,揿压阀门,药液即呈雾粒喷出。

【适应症】本品适用于预防和治疗与慢性阻塞性气道疾病相关的呼吸困难:慢性阻塞性支气管炎伴或不伴有肺气肿;轻到中度支气管哮喘。

【规格】139:4.86mg (以一水合异丙托溴铵计),每揿20μg (以异丙托溴铵计)【用法用量】用量:除非医生特别处方,下述剂量一般推荐用于成人和6岁以上儿童:预防和长期治疗:1-2揿,每日数次;平均每日剂量1-2揿,每天3-4次。

6岁以下儿童同样适用于上述剂量。

但对于该年龄人群至今尚无充分的用药经验,因此只能在医生监督下使用定量气雾剂。

如果患者需要逐渐增加剂量,则应确认是否需要其他合并治疗,同时每天总的剂量不得超过12揿。

重要说明:如果药物治疗不能产生明显的病情改善或导致患者病情恶化,应就诊以更改治疗计划。

若发生急性或迅速恶化的呼吸困难,应立即就诊。

可能需要额外增加肾上腺皮质激素,β-拟交感类药物或茶碱的治疗。

对于急性或迅速恶化的呼吸困难,应立即寻求医疗救护。

这样的病例中,应考虑250微克/2毫升吸入用溶液或500微克/2毫升吸入用溶液治疗。

用法:必须正确使用定量气雾器才能达到良好的治疗效果。

定量气雾剂只能用于吸入。

患者在吸入时最好坐下或站立。

初次使用定量气雾器前应先将气雾器活瓣揿动两次。

每次使用必须遵循以下的规则:1.除去防尘盖(见图1);2.深呼气;3.如图2所示手持定量气雾器,嘴唇合拢咬住喷嘴。

容器基底部箭头应指向上方而喷嘴指向下;4.尽量深吸气,同时用力按动气雾器的基底部,这样就释放一个定量。

普司乐异丙托溴铵吸入溶液

普司乐异丙托溴铵吸入溶液
现在学习的是第7页,共30页
支气管痉挛
• 外界致敏因素 • 刺激肥大细胞/嗜碱粒细胞释
放炎性介质
• 使支气管平滑肌发生突然收 缩
• 引起呼吸困难、咳嗽、缺氧 等症状
现在学习的是第8页,共30页
发生
高危人群
促发因素
慢性阻塞性肺病COPD
哮喘 Asthma
过敏性鼻炎 AR
上或下呼吸道
感染
现在分结合
药效基本结构:氨基乙醇酯
现在学习的是第12页,共30页
与受体附加结合
M胆碱受体拮抗剂
现在学习的是第13页,共30页
普司乐®的优势
➢ 药物直达呼吸道感染部位,局部药 物浓度高,药物沉积时间长;
➢ 起效迅速,疗效确切; ➢ 所用药物剂量小,明显减少药物毒
副作用; ➢ 雾化可同时吸入几种药物; ➢ 使用方便,不需要病人的配合,保
• 卖点:术前预防性吸入,术后维持,14d
现在学习的是第16页,共30页
普司乐® VS 爱全乐®
125例COPD患者 对照组:(雾化吸入)爱全乐®
实验组:(雾化吸入)普司乐®
普司乐®的治疗效果与爱全乐®相当,比治疗前同样具有显著治疗效果。
-杨顺志,梁日明,黄嫦敏;国产异丙托溴铵雾化吸入液治疗慢性阻塞性肺病的有效性和安全性观察 [J];广东医学院学报2013年2月第31卷第1期::38-39
➢ O:就诊患者增加,解痉用药多科室拓展
➢ T:复方制剂
现在学习的是第24页,共30页
低龄用法
现在学习的是第25页,共30页
现在学习的是第26页,共30页
雾化吸入 VS 气雾剂
➢ 气雾剂产品 异丙托溴铵气雾剂
噻托溴铵气雾剂
勃林格 北京海德润

爱全乐(异丙托溴铵气雾剂)说明书

爱全乐(异丙托溴铵气雾剂)说明书

爱全乐(异丙托溴铵气雾剂)说明书下面为大家介绍的西药是:爱全乐(异丙托溴铵气雾剂),一起来看看爱全乐(异丙托溴铵气雾剂)的详细说明书吧。

【药品名称】商品名称:爱全乐通用名称:异丙托溴铵气雾剂英文名称:IpratropiumBromideAerosol【主治疾病】慢性支气管炎支气管哮喘慢性阻塞性肺疾病【适应症】适用于慢性支气管炎、肺气肿、哮喘等慢性阻塞性肺疾玻作为支气管扩张剂用于慢性阻塞性肺部疾病引起的支气管痉挛的维持治疗,包括慢性支气管炎和肺气肿。

【用法用量】剂量应根据个体需要加以调整。

除非医生特别处方,以下为成人及学龄儿童推荐剂量:2喷/次,每日4次。

需要增加药物剂量者,一般每天的剂量不宜超过12喷。

如果药物治疗不能产生明显的病情改善或患者的状况恶化,应就诊以寻求新的治疗计划。

若发生急性呼吸困难或呼吸困难迅速恶化,应立即就诊。

爱全乐(Atrovent)雾化吸入液也可用于慢性阻塞性肺疾病急性发作时的治疗。

正确使用气雾剂才能获得满意疗效。

首次使用气雾剂前应先将气雾液摇匀,并将气雾器活瓣揿动一至二次。

每次使用前必须遵循以下规则:1.打开保护盖2.每次使用前摇匀(见图1)3.深呼气4.如图2所示,手持气雾器,嘴唇合拢咬住喷嘴,箭头和容器基底部应自下指向上方。

5.尽量深吸气,同时用力按动气雾器的基底部,这样就释放一喷。

屏住呼吸数秒,然后从口中移开气雾器喷嘴,缓慢呼气。

重复以上动作吸入第二喷。

6.重新盖上保护盖。

容器内部有压力,请勿用暴力打开容器,也不要将容器暴露于50℃以上温度的环境中。

由于容器不透明,所以不能看到药物是否用完,但振摇容器可显示是否还有剩余液体。

喷嘴应保持清洁,并可用温水清洗。

如用肥皂或清洁剂,喷嘴应用清水彻底冲洗干净。

【禁忌症】对大豆卵磷脂或有关的食品如大豆和花生过敏者禁用爱全乐(Atrovent)气雾剂。

这些患者可以使用不含大豆卵磷脂的爱全乐(Atrovent)的其它剂型如爱全乐(Atrovent)雾化吸入剂。

妊娠期哮喘药物治疗方案

妊娠期哮喘药物治疗方案

摘要:妊娠期哮喘是一种常见的孕期并发症,哮喘发作对孕妇和胎儿均有不良影响。

本文针对妊娠期哮喘的药物治疗方案进行探讨,旨在为临床医生提供参考。

一、引言妊娠期哮喘是一种在孕期发生的哮喘,其发病机制可能与孕妇的生理、内分泌、免疫等因素有关。

妊娠期哮喘发作不仅对孕妇的健康造成威胁,还可能影响胎儿的生长发育。

因此,合理选择药物进行治疗至关重要。

二、妊娠期哮喘药物治疗原则1. 早期诊断:孕妇在孕期出现呼吸困难、咳嗽、胸闷等症状时,应及时就诊,明确诊断。

2. 个体化治疗:根据孕妇的病情、体质、药物过敏史等因素,制定个体化治疗方案。

3. 长期治疗:妊娠期哮喘是一种慢性疾病,需要长期治疗,以控制病情。

4. 安全性:选择对孕妇和胎儿安全性高的药物。

5. 症状控制:以控制哮喘症状为目标,避免病情加重。

三、妊娠期哮喘药物治疗方案1. 吸入性皮质类固醇(ICS)吸入性皮质类固醇是治疗妊娠期哮喘的首选药物,具有以下优点:(1)局部作用:ICS主要作用于呼吸道,对全身副作用较小。

(2)安全性:研究证实,ICS对孕妇和胎儿的安全性较高。

(3)疗效显著:ICS可有效控制哮喘症状,减少发作次数。

常用ICS药物包括:(1)倍氯米松(Budesonide):倍氯米松是一种常用的ICS,适用于轻至中度妊娠期哮喘。

(2)氟替卡松(Fluticasone):氟替卡松也是一种常用的ICS,适用于轻至中度妊娠期哮喘。

(3)布地奈德(Budesonide):布地奈德是一种长效ICS,适用于中重度妊娠期哮喘。

2. 茶碱类药物茶碱类药物具有舒张支气管平滑肌、抗炎、抗过敏等作用,可用于治疗妊娠期哮喘。

但茶碱类药物对孕妇和胎儿的安全性存在争议,需谨慎使用。

常用茶碱类药物包括:(1)氨茶碱(Aminophylline):氨茶碱是一种常用的茶碱类药物,适用于轻至中度妊娠期哮喘。

(2)多索茶碱(Doxofylline):多索茶碱是一种长效茶碱类药物,适用于中重度妊娠期哮喘。

抗胆碱能药物的选择用法及注意事项

抗胆碱能药物的选择用法及注意事项

抗胆碱能药物的选择用法及注意事项抗胆碱能药物在临床上用于治疗呼吸系统疾病具有悠久的历史,此类药物通过与乙酰胆碱能毒蕈碱(M)受体激动剂竞争而发挥竞争性拮抗作用。

抗胆碱能药的叔铵类化合物如阿托品、东莨菪碱等自黏膜迅速吸收,全身分布,易通过血脑屏障,对周身组织的各型M受体均有阻断作用,使用后可引起一系列不良反应,如心率增快、口干、视力模糊、尿潴留和精神神经症状,特别是抑制呼吸道腺体分泌使痰液黏稠,并降低纤毛摆动频率,影响黏液纤毛清除功能而加重呼吸道阻塞,使其临床使用受到限制。

而季铵类化合物如异丙托品、氧托品等,其氨基基团上带有一正电荷,不易穿过细胞膜,故很少自黏膜吸收,亦不易透过血脑屏障,因此一般无中枢神经系统不良反应,当吸入给药时不但全身不良反应少见,且气道局部保持较高的药物浓度,作用维持更久。

【相关药物】1.异丙托溴铵(ipratropium bromide)异丙托溴铵又称溴化异丙托品,商品名爱全乐(Atrovent),由勃林格殷格翰公司生产,是目前临床上最常用的吸入型抗胆碱能药物。

本品对M1、M2、M3胆碱能受体无选择性,吸入后不易被气道黏膜吸收,可在气道内形成较高的药物浓度,故对气道平滑肌有一定的选择作用。

吸入后5分钟左右起效,30~90分钟作用达峰值,平喘作用维持4~6小时。

本品主要用于解除支气管哮喘、喘息性支气管炎和COPD患者的支气管痉挛。

其定量气雾吸入器(MDI)适用于慢性持续性哮喘和稳定期COPD的治疗,以及预防运动性哮喘和夜间哮喘。

药物溶液雾化吸入适用于中度至严重的哮喘急性发作和COPD急性加重期的治疗。

本品与β2受体激动剂或氨茶碱合用可增强疗效。

因本品起效较慢,如果采用吸入给药,应先吸入β2受体激动剂后,再吸入本品。

2.氧托溴铵(oxitropium bromide)氧托溴铵又称氧托品、溴乙东莨菪碱。

对M1、M2和M3三种亚型受体无选择性。

吸入后气道黏膜不易吸收,局部药物浓度高,故对气道平滑肌有选择性。

吸入用异丙托溴铵溶液

吸入用异丙托溴铵溶液

吸入用异丙托溴铵溶液【药品名称】通用名称:吸入用异丙托溴铵溶液英文名称:Ipratropium Bromide Solution for Inhalation【成份】(8r)-3α-羟基-8-异丙基-1αH,5αH-溴化托品(±)托品酸一水合物【适应症】1.作为支气管扩张剂用于慢性阻塞性肺部疾病引起的支气管痉挛的维持治疗,包括慢性支气管炎和肺气肿。

2.可与吸入性β受体激动剂合用于治疗慢性阻塞性肺部疾病包括慢性支气管炎和哮喘引起的急性支气管痉挛。

【用法用量】(20滴=约1ml;1滴=0.0125mg无水异丙托溴铵)剂量应按病人个体需要做适量调节;在治疗过程中病人应该在医疗监护之下。

除非另有医师处方,以下为推荐剂量:维持治疗:成人(包括老年人)以及12岁以上的青少年:2.0ml(40滴=0.5mg)每天3~4次6~12岁的儿童:由于此年龄组的用药资料有限,下述服药方法应在医生监护下进行。

1.0ml(20滴=0.25mg)每天3~4次6岁以下的儿童:由于此年龄组的用药资料有【不良反应】临床试验中最常见的非呼吸系统的不良反应为头痛、恶心和口干。

由于爱全乐(异丙托溴铵)肠道吸收较少,诸如心动过速、心悸、眼部调节障碍、胃肠动力障碍和尿潴留等抗胆碱能副作用少见并且可逆,但对已有尿道梗阻的病人其尿潴留危险性增高。

眼部副作用已做报道(见【注意事项】)。

和其它吸入性的支气管扩张剂一样,爱全乐可能引起咳嗽,局部刺激,极少情况下出现吸入刺激产生的支气管收缩。

变态反应如皮疹、舌、唇、和面部血管性水肿、荨麻疹、喉痉挛和过敏反应有报道。

【禁忌】已知对阿托品或其衍生物或本品任何其它成分有过敏反应者忌用。

【注意事项】本品含防腐剂氯化卞烷胺及稳定剂EDTA。

曾有报道一些患者在上述物质给药时引起支气管收缩。

有狭角性青光眼倾向、前列腺增生或膀胱颈部梗阻的患者应慎用爱全乐。

有囊性纤维化的病人更易于出现胃肠动力障碍。

使用本品后可能会立即出现过敏反应,极少病例报道出现荨麻疹、血管性水肿、皮疹、支气管痉挛和口咽部水肿及过敏反应等。

吸入用异丙托溴铵溶液说明书

吸入用异丙托溴铵溶液说明书

吸入用异丙托溴铵溶液以下内容仅供参考,请以药品包装盒中的说明书为准。

吸入用异丙托溴铵溶液说明书【说明书修订日期】核准日期:2006年10月27日修改日期:2009年05月27日修改日期:2010年09月29日修改日期:2013年05月17日【药品名称】吸入用异丙托溴铵溶液【英文名称】IpratropiumBromide Solution for Inhalation【汉语拼音】XiruyongYibingtuoxiu’an Rongye【成份】异丙托溴铵。

【性状】无色或几乎无色的澄清液体。

【适应症】爱全乐作为支气管扩张剂用于慢性阻塞性肺部疾病引起的支气管痉挛的维持治疗,包括慢性支气管炎和肺气肿。

爱全乐可与吸入性β受体激动剂合用于治疗慢性阻塞性肺部疾病包括慢性支气管炎和哮喘引起的急性支气管痉挛。

【规格】2毫升:500微克【用法用量】剂量:剂量应按病人个体需要做适量调节;在治疗过程中病人应该在医疗监护之下。

除非另有医师处方,以下为推荐剂量:维持治疗:成人(包括老人)和12岁以上青少年;每天3-4次,每次1个单剂量小瓶。

急性发作治疗:成人(包括老人)和12岁以上青少年:每次1个单剂量小瓶;病人病情稳定前可重复给药。

给药间隔可由医生决定。

爱全乐可与吸入性β受体激动剂联合使用。

单剂量小瓶中每1毫升雾化吸入液可用生理盐水稀释至终体积2-4毫升或者可以和Berotec雾化吸入液联合使用。

成人及12岁以上儿童日剂量超过2毫克应在医疗监护下给药。

无论急性期治疗或维持治疗,建议都不要超过推荐日剂量太多。

如果治疗后未产生病情显著的改善或病人情况更趋严重,必须寻求医生的建议以决定新的治疗方案。

发生急性或迅速恶化的呼吸困难时应立即咨询医生。

爱全乐雾化吸入液可使用市面上一般的雾化吸入器。

在有墙式给氧设施情况下,吸入液最好以每分钟6-8升的流速给予。

吸入用异丙托溴铵溶液(爱全乐)可以和祛痰剂盐酸氨溴索(沐舒坦)雾化吸入液、盐酸溴己新(Bisolvon)雾化吸入液和非诺特罗(Berotec)雾化吸入液共同吸入使用。

  1. 1、下载文档前请自行甄别文档内容的完整性,平台不提供额外的编辑、内容补充、找答案等附加服务。
  2. 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
  3. 3、如文档侵犯您的权益,请联系客服反馈,我们会尽快为您处理(人工客服工作时间:9:00-18:30)。

Ipratropium Bromide:Methods of Chemical and Biochemical Synthesis Heba H.Abdine,F.Belal and Abdullah A.Al-Badr Department of Pharmaceutical ChemistryCollege of PharmacyKing Saud UniversityP.O.Box2457Riyadh–11451Kingdom of Saudi Arabia85PROFILES OF DRUG SUBSTANCES,Copyrightß2003Elsevier Inc. EXCIPIENTS,AND RELATED All rights reserved METHODOLOGY–VOLUME30DOI:10.1016/S0099-5428(03)30004-886H.H.ABDINE,F.BELAL AND A.A.AL-BADRCONTENTS1.Introduction (87)2.Chemical Methods of Synthesis (87)2.1Partial synthesis (87)2.2Total synthesis of atropine and ipratropiumbromide (87)2.2.1Total synthesis of tropine (87)2.2.1.1Willstatter’s total synthesis oftropine (87)2.2.1.2Robinson’s total synthesis oftropine (89)2.2.1.3Willstatter’s second synthesis oftropine (89)2.2.1.4Elming synthesis of tropine (90)2.2.2Total synthesis of tropic acid (91)2.2.2.1Landenburg’s synthesis oftropic acid (91)2.2.2.2McKenzie and Wood’s synthesis oftropic acid (91)2.2.2.3Muller’s synthesis of tropic acid..922.2.2.4Chambon’s synthesisof tropic acid (92)2.2.2.5Blicke’s synthesis of tropic acid (92)2.3Synthesis of atropine and ipratropium bromide (93)2.4Synthesis of labeled atropine and labeledipratropium bromide (93)2.4.1Synthesis of labeled tropic acid (93)2.4.2Synthesis of labeled tropine (94)2.4.2.1Labeled at carbons6and7 (94)2.4.2.1.1Method one (94)2.4.2.1.2Method two (94)2.4.2.2Labeled at N-methyl carbon (94)2.4.2.3Labeled at carbon1or5 (95)3.Biosynthesis of Atropine (95)3.1Biosynthesis of tropine (95)3.2Biosynthesis of tropic acid (97)4.References (97)1.INTRODUCTIONIpratropium bromide is the quaternary ammonium compound obtained by treating atropine with isopropyl bromide.The synthesis of atropine,which is an ester prepared from tropic acid and tropine,was reported earlier in the profile of atropine [1].It is therefore appropriate to report all of the methods of chemical and biochemical synthesis,as these are also the synthetic routes used for the preparation of ipratropium bromide.2.CHEMICAL METHODS OF SYNTHESIS 2.1Partial synthesisAtropine (3)was synthesized by Landenburg [2]by heating tropine 1and tropic acid 2in the presence of hydrogenchloride.2.2Total synthesis of atropine and ipratropium bromideThe total synthesis of tropine and tropic acid,from which both atropine and ipratropium bromide are obtained by esterification (atropine),and subsequent quaternization with isopropyl bromide (ipratropium bromide)are described in the following sections.2.2.1Total synthesis of tropine2.2.1.1Willstatter’s total synthesis of tropine [3]Cycloheptanone (suberone,1)was reduced to cycloheptanol (suberol),which was treated with hydrogen iodide to give suberyl iodide (2).The treatment of suberyl iodide with potassium hydroxide in ethanol gave the cycloheptene (3).The latter compound was brominated to give 1,2-dibromocycloheptane (4),which was treated with dimethylamine to yield dimethylaminocyclohept-2-ene (5).This compound was then converted to cyclohepta-1,3-diene (6)by exhaustive pound (6)was IPRATROPIUM BROMIDE:METHODS OF SYNTHESIS 87brominated at the 1,4-positions to give 1,4-dibromocyclohept-2-ene (7).Elimination of two moles of hydrogen bromide from compound (7)was effected by quinoline to give cycloheptatriene (8).Compound (8)was treated with hydrogen bromide to give bromocyclohepta-3,5-diene (9),which was reacted with dimethylamine to give dimethylaminocyclohepta-2,4-diene (10).The latter compound was treated with sodium in ethanol,followed by bromination,to give 1,2-dibromo-5-dimethylaminocyclo-heptane (11).This compound was warmed in ether,causing intramole-cular alkylation to occur and yielding 2-bromotropane methobromide(12).Hydrogen bromide was eliminated from compound (12)by the action of an alkali to yield tropidine methobromide (13).This compound was transformed to tropidine methochloride (14)by the action of potassium iodide,followed by the action of silver pound(14)was then pyrolyzed to give tropidine (15).To an acetic acid solution of tropidine,hydrogen bromide was added to yield 3-bromotropane (16),which was hydrolyzed with 10%sulfuric acid at 200–210 C to give pseudotropine (17).This compound was then oxidized with chromium trioxide to give tropinone (18).This ketone was finally reduced with zinc and hydroiodic acid to tropine (19).88H.H.ABDINE,F.BELAL AND A.A.AL-BADR2.2.1.2Robinson’s total synthesis of tropine [4]Succinic dialdehyde (1)was condensed with methylamine (2)to give the condensate biscarbinolamine (3).This was in turn condensed with acetone (4)to give tropinone (5).Tropinone (5)was reduced with zinc and hydroiodic acid to yield tropine (6).The use of acetone dicarboxylate,or its ester,instead of acetone alone was found to improve the yield of tropine.Therefore,the condensation of succinodialdehyde (1)with methylamine (2)gives biscarbinolamine (3),which was then condensed with calcium acetonedicarboxylate (4)to afford the condensate (5).Compound (5)was warmed with hydrochloric acid to give tropinone (6)which was then reduced with zinc and hydroiodic acid to tropine (7).2.2.1.3Willstatter’s second synthesis of tropine [5]Succinyldiacetic ethyl ester (1)was condensed with methylamine (2)to give diethyl-N -methyl-pyrolediacetate (3).This compound was reduced to afford diethyl-N -methylpyrrolidine diacetate (4).The cis form of compound (4)was cyclized in the presence of sodium and p -cymene to give ethyltropinone-2-carboxylate (5).Hydrolysis of compound (5)with IPRATROPIUM BROMIDE:METHODS OF SYNTHESIS 8910%sulfuric acid gave tropinone-2-carboxylic acid (6).The latter compound was then heated to yield tropinone (7),which was reduced with zinc and hydroiodic acid to tropine (8).2.2.1.4Elming synthesis of tropine [6]Tropinone (5)and tropine (6)were synthesized using methylamine hydrochloride (4)and acetone dicarboxylic acid (3).Succindialdehyde (2)was generated in situ by action of the acid on 2,5-dimethoxytetrahy-drofuran (1),and finally reduction with zinc and hydroiodic acid yielded tropinone (6):90H.H.ABDINE,F.BELAL AND A.A.AL-BADR2.2.2Total synthesis of tropic acid2.2.2.1Landenburg’s synthesis of tropic acid [7]Acetophenone (1)was converted to a ,a -dichloroethylbenzene (2)by the action of phosphorous pound (2)was reacted with potassium cyanide and ethanol to give a -ethoxy-a -cyanoethylbenzene (3).This compound was then hydrolyzed with barium hydroxide solution to give atrolactic ethylether (4).The latter compound was heated with hydrogen chloride to yield atropic acid (5),and then converted to tropic acid (6).2.2.2.2McKenzie and Wood’s synthesis of tropic acid [8]Acetophenone (1)was converted to acetophenone cyanohydrin (2)by the action of potassium pound (2)was hydrolyzed to give atrolactic acid (3),which was heated under pressure to yield atropic acid(4).Atropic acid (4)was then treated with hydrogen chloride in ethereal solution to form b -chlorohydroatropic acid (5).Compound (5)was boiled with aqueous sodium carbonate to give tropic acid (6).IPRATROPIUM BROMIDE:METHODS OF SYNTHESIS 912.2.2.3Muller’s synthesis of tropic acid [9]Ethylphenyl acetate (1)was condensed with ethylformate to give ethyl-a -formylphenyl acetate (2).Compound (2)was reduced with aluminum amalgam to yield (DL )-tropic ester (3),which was then hydrolyzed to give tropic acid (4).2.2.2.4Chambon’s synthesis of tropic acid [10]Ethyl a -bromophenylacetate (1)was treated with zinc to give ethyl-a -zinc-bromophenylacetate (2).This compound was treated with formic acid to yield (DL )-tropic ethyl ester (3),and the hydrolysis of compound(3)yielded tropic acid (4).2.2.2.5Blicke’s synthesis of tropic acid [11]Phenylacetic acid (1)was boiled with isopropylmagnesium chloride in an ethereal solution to give compound (2).Treatment of the latter Grignard reagent (2)with formaldehyde yielded tropic acid (3).92H.H.ABDINE,F.BELAL AND A.A.AL-BADR2.3Synthesis of atropine and ipratropium bromideHeating of tropine (1)with tropic acid (2)in the presence of hydrogen chloride (the Fischer–Speier esterification)gives atropine (3).Quaternization of atropine (3)with isopropyl bromide yields ipratropium bromide (4).2.4Synthesis of labeled atropine and labeled ipratropium bromideLabeled atropine and labeled ipratropium bromide are synthesized from labeled tropine and/or labeled tropic acid to yield labeled or double labeled atropine.This compound is then quaternized with isopropyl bromide to give the labeled or double labeled ipratropiumbromide.2.4.1Synthesis of labeled tropic acidBenzylmagnesium chloride (1)was treated with 14CO 2,followed by magnesium chloride,to give the condensate (2).The addition of formaldehyde to condensate (2)gives the labeled tropic acid (3)[12].IPRATROPIUM BROMIDE:METHODS OF SYNTHESIS 932.4.2Synthesis of labeled tropine 2.4.2.1Labeled at carbons 6and 72.4.2.1.1Method one The synthesis of tropine-6,7-T (6),was achieved by the catalytic tritium addition to 2,5-dimethoxy-2,5-dihydrofuran (1)and following Robinson’s route to yield tropinone-6,7T (5)by subsequent reduction with hydrogen over Raney nickel [13].2.4.2.1.2Method two The use of arabinose-3,4-14C serves to yield 6,7-14C tropinone (3),and then eventually 6,7-14C tropine (4)[14].2.4.2.2Labeled at N-methyl carbonSynthesis of methyl-14C labeled tropine (5)was carried out from sodium cyanide (Na 14CN)via methylamine-14C (2)and based on Robinson’s route;methyl-14C tropinone (4)was obtained in 70%overall yield and 94H.H.ABDINE,F.BELAL AND A.A.AL-BADRtropine14C(5)in68%yield[15].2.4.2.3Labeled at carbon1or5Synthesis of1-14C tropine(4)can be obtained by starting with arabinose-5-14C(1),conversion into furan(2),and application of the Clauson–Kaas route to succindialdehyde.From here,one takes either1-or5-14C tropinone(3)on to either1-or5-14C tropine(4)[16].3.BIOSYNTHESIS OF ATROPINE3.1Biosynthesis of tropineOrnithine and related compounds(amino acids such as glutamic acid and proline)have been shown to be the precursors of the pyrrolidine ring system of tropine[17–22].Feeding[2-14C]-ornithine to Datura stramonium results in formation of radioactive hyoscyamine labeled only at the C–1 bridgehead carbon atom of tropine[23].Use of5-14C proline resulted in radioactive hyoscyamine labeled only the C–5position of tropine[21].[2-14C,d-15N]-ornithine has been reported to be incorporated into the tropine moiety of hyoscyamine,and the d-amino group of ornithine is anefficient precursor of the tropine nitrogen[21,23].The incorporation of glutamic acid and proline was considered to occur via ornithine[23]. Ornithine(1)was incorporated into tropine via d-N-methylornithine(2) [24–26],as[methyl-14C]-d-N-methyl-[2-14C]-ornithine was incorporated into hyoscyamine labeling at C-1,and the N-methyl pound (2)was decarboxylated to yield N-methylputrescine(4)[27,28]. Putrescine(3)has been shown to be a precursor of the tropine alkaloids [20,29–31].It was suggested[23]that putrescine(3)is converted by some enzymes in Datura plants to N-methylputrescine(4).Oxidation of the primary alcohol of(4)affords4-methylaminobutanol(5).This latter compound was cyclized to give N-methyl-Á1-pyrrolinium salt(6). Carbons2,3,and4of tropine are derived from acetate[32,33],and it was assumed that the acetate is incorporated via acetoacetic acid or some suitable activated derivative such as coenzyme A ester[23].Compound (6)was therefore condensed with acetoacetate to give hygrine-a-carboxylic acid(7).Decarboxylation of compound(7)afforded hygrine (8),which is an established precursor of tropine[33,34].Compound(8) was dehydrogenated to give dehydrohygrine(9).The latter compound was cyclized to yield tropinone(10).Stereospecific reduction of compound(10)yields tropine(11),and esterification of tropine(11) with tropic acid(12)gives atropine(14).3.2Biosynthesis of tropic acidTropic acid(15)is formed by the intramolecular rearrangement of phenylalanine(14)[35].Compounds which are metabolically related to phenylalanine,such as phenylpyruvic acid,are also reported to be incorporated into tropic acid[36,37].Tropine(11)is then esterified with tropic acid(15)to give atropine(16).Andfinally atropine(16)is quaternized with isopropyl bromide to give ipratropium bromide(17).4.REFERENCES1. A.A.Al-Badr and F.J.Muhtadi,‘‘Atropine’’,in AnalyticalProfiles of Drug Substances,Volume14,K.Florey,ed.,pp.325–389(1985).2. ndenburg,Ber.,12,946(1879);Ann.,217,74(1883).3.R.Willsta tter,Ber.,29,936(1896);Ber.,31,1537(1898);Ber.,34,129,3163(1901);Ann.,317,204,267,307(1901);Ann.,326,1,23(1903).4.R.Robinson,J.Chem.Soc.,111,762(1917).5.R.Willsta tter and A.Pfannenstiel,Ann.,422,1(1921);R.Willsta tter and M.B.Bommer,Ann.,422,15(1921).6.Elming et al.(1958),through I.L.Finar Organic ChemistryVolume2,5th edn.,Longmans,London,p.726(1975).7. ndenburg and L.Ru gheimer,Ber.,13,2041(1880);Ber.,22,2590(1889).8. A.McKenzie and J.K.Wood,J.Chem.Soc.,115,828(1919).9. E.Mu ller,Ber.,51,252(1918).10.M.M.Chambon,Compt.Rendu,186,1630(1928).11.Blicke et al.(1952),through I.L.Finar Organic ChemistryVolume2,5th edn.,Longmans,London,p.722(1975).12.G.Fodor,in The Alkaloids,Chemistry and Physiology,R.H.F.Manske,ed.,Volume XIII,Academic Press,New York,p.351(1971).13.W.Hespe,W.J.F.Klopper,and W.T.Nauta,Rec.Trav.Chim.,84,476(1965).14.G.C.Schmidt,T.E.Eling,and J.M.McOwen J.Pharm.Sci.,57,443(1968).15.G.Werner,H.L.Schmidt,and E.Kassner,Ann.,644,109(1961).16.G.C.Schmidt,T.E.Eling,J.M.McOwen,and J.C.Drach,J.Pharm.Sci.,56,1453(1967).17. E.Leete,J.Am.Chem.Soc.,84,55(1962).18. E.Leete,Tetrahedron Lett.,1619(1964).19. E.Leete,L.Marion,and I.D.Spenser,Can.J.Chem.,32,1116(1954).20.H.W.Liebisch,H.Ramin,and J.Schoffinius,Z.Naturforsch,20b,1183(1965).21.H.W.Liebisch and H.R.Schutte,Z.Pflanzenphysiol.,57,434(1967).22.N.Herbert,Phytochem.,20,2064(1981).23. E.Leete,Planta Medica,36,97(1979).24. A.Ahmad and E.Leete,Phytochem.,9,2345(1970).25. F.E.Baralle and E.G.Gros,m.,721,(1969).26. F.E.Baralle and E.G.Gros,Anales Asoc.Quim.Argentina,58,299(1970).27.H.W.Liebisch,W.Maier,and H.R.Schutte,Tetrahedron Lett.,4079(1966).28.H.W.Liebisch,A.S.Radwan,and H.R.Schutte,Ann.,721,163(1969).29.J.Kaczkowski and L.Marion,Can.J.Chem.,41,2651(1963).30. E.Leete and M.C.L.Louden,Chem.and Ind.(London),1725(1963).31.H.W.Liebisch,H.R.Schutte,and K.Mothes,Ann.,668,139(1963).32.J.Kaczkowski,H.R.Schutte,and K.Mothes,Biochem.Biophys.Acta,46,588(1961).33.H.W.Liebisch,K.Peisker,A.S.Radwan,and H.R.Schutte,Z.Pflanzepphysiol.,67,1(1972).34. D.G.O’Donovan and M.F.Keogh,J.Chem.Soc.C,223(1969).35. E.Leete,N.Kowanko,and R.A.Newmark.J.Am.Chem.Soc.97,6826(1975).36.W.C.Evans and J.G.Woolley,Phytochem.15,287(1976).37. E.Leete and E.P.Kirven,Phytochem.13,1501(1974).。

相关文档
最新文档