CN1623987A - 托拉塞米的制备方法 - Google Patents

托拉塞米的制备方法 Download PDF

Info

Publication number
CN1623987A
CN1623987A CNA2004100787386A CN200410078738A CN1623987A CN 1623987 A CN1623987 A CN 1623987A CN A2004100787386 A CNA2004100787386 A CN A2004100787386A CN 200410078738 A CN200410078738 A CN 200410078738A CN 1623987 A CN1623987 A CN 1623987A
Authority
CN
China
Prior art keywords
chlorine
pyridine
sulphonamide
torasemide
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2004100787386A
Other languages
English (en)
Inventor
M·科尔多瓦
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of CN1623987A publication Critical patent/CN1623987A/zh
Pending legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/70Sulfur atoms
    • C07D213/71Sulfur atoms to which a second hetero atom is attached
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/74Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10Antioedematous agents; Diuretics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61Halogen atoms or nitro radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

本发明涉及新的合成托拉塞米的方法和新的合成托拉塞米合成用中间体(3-磺酰氯-4-氯)吡啶的方法。

Description

托拉塞米的制备方法
本申请是申请号为01806834.0母案的分案申请。该母案的申请日为2001年3月20日;发明名称为“新的制备托拉塞米中间体的方法”。
相关发明的互见条目
本申请要求了于2000年3月20日提出的临时申请60/190650和于2000年6月14日提出的临时申请60/211510的权益,二者均在此引入供参考。
技术领域
本发明涉及托拉塞米中间体(3-氨磺酰-4-氯)吡啶的新制备方法。本发明涉及托拉塞米的新制备方法。
背景技术
商标为DEMADEX的、具有以下化学结构的1-异丙基-3-[(4-间甲苯氨基-3-吡啶基)磺酰基]脲
已被美国食品与药品管理局认可用于治疗与充血性心力衰竭、肾病或肝病相关的高血压和浮肿。美国食品与药品管理局已认可该化合物的属名为托拉塞米(torsemide),不过该化合物在现有技术中也被称为“torasemide”。已发现是托拉塞米一种对于治疗与慢性肾衰竭有关的浮肿特别有效的强效利尿药。
托拉塞米、托拉塞米中间体和托拉塞米衍生物的合成阐述在以下参考文献中:Delarge,Ann.Pharm.Fr.31,467-474(1973);Delarge,Mem.Acad R.Med.Belg.47(3),131-210(1974);E.Koenigs等人,Chem.Ber.57,2080-2082(1924);L.Thunus,Ann.Pharm.Fr.33,487-494(1975);Kondo等人,Iyakuhin Kenkyu,25(9),734-50(1994);EP 618209;和US 2516025;6674794;4244950和Re.30633;此处参考引用所有这些文献。
托拉塞米中间体(3-氨磺酰-4-氯)吡啶、3-氨磺酰-4-(3’-甲基苯基)氨基吡啶和托拉塞米的制备方法阐述在下流程1中。
流程1
Figure A20041007873800041
4-羟基-3-吡啶磺酸               (3-磺酰氯-4-氯)吡啶             (3-氨磺酰-4-氯)吡啶
SAHPY                           SCCPY                           SAMCPY
I                               II                              III
(3-氨磺酰-4-氯)吡啶               3-氨磺酰-4-(3’-甲基苯基)          托拉塞米
                                  氨基吡啶
III                               IV                                  V
在用(3-磺酰氯-4-氯)吡啶制备(3-氨磺酰-4-氯)吡啶(SCCPY→SAMCPY)的已知方法中,反应在诸如丙酮或二噁烷的极性溶剂中进行,或在大大过量的氢氧化铵存在下在作为溶剂的熔融试剂中进行。通过这些已知的方法,将(3-磺酰氯-4-氯)吡啶(SCCPY)滴加到氢氧化铵水溶液中。将(3-磺酰氯-4-氯)吡啶滴加到过量氢氧化铵中的方法是为了使(3-磺酰氯-4-氯)吡啶与新形成的所需产物(3-氨磺酰-4-氯)吡啶(SAMCPY)之间的缩合降至最少。这种苛刻的反应条件迫使付出很大的努力来提纯所得产物,并产生与中和并处置大量浓缩的碱性溶液相关的环境废弃物处理问题。高碱性条件使得该方法需使用大量非常昂贵的碱。因此在这种条件下,(3-氨磺酰-4-氯)吡啶的产率低,约为50%,并被高百分比的杂质隔离,从而需要额外的提纯步骤。理想的是有一种方法来制备(3-氨磺酰-4-氯)吡啶,而不使(3-磺酰氯-4-氯)吡啶与(3-氨磺酰-4-氯)吡啶缩合。同样理想的是有一种方法来制备(3-氨磺酰-4-氯)吡啶,该方法能得到高产率和高纯度,适用于大规模的制造过程。
在由3-氨磺酰-4-(3’-甲基苯基)氨基吡啶制备托拉塞米的已知方法中,反应可在三乙胺和异丙基-异氰酸酯的存在下在二噁烷或二氯甲烷中进行。在这种条件下,托拉塞米的产率低,并被高百分比的杂质隔离,从而需要额外的提纯步骤。这些方法的产率低,可变性高,不适于大规模制造过程。因此理想的是有这样一种制备托拉塞米的方法,该方法能得到高产率和高纯度,且使用适用于大规模生产的溶剂。
发明内容
本发明涉及下式化合物的制备方法:
包括以下步骤:(a)将通式
的化合物加入到有机溶剂中;(b)加入约1.75~约2.25摩尔当量的氢氧化铵;和(c)分离出通式
的化合物,其中X1和X2独立的是氯、氟或溴。
在本发明优选实施方案中,X1和X2都是氯。
在本发明另一个优选实施方案中,有机溶剂选自叔丁基甲醚、甲苯、乙腈、甲基异丁酮、乙基甲基酮、丙酮、苯、二甲苯、乙醇和异丙醇。
在本发明另一个实施方案中,有机溶剂是叔丁基甲醚。
在本发明另一个实施方案中,氨是一种水溶液。
在本发明另一个实施方案中,将氨加入到步骤(a)的溶液中。
在本发明另一个实施方案中,以约1.75~约2.25摩尔当量的量加入氨。
本发明还涉及(3-氨磺酰-4-氯)吡啶的制备方法,包括以下步骤:(a)向有机溶剂中加入(3-磺酰氯-4-氯)吡啶;(b)加入氨;并分离出(3-氨磺酰-4-氯)吡啶。
在本发明的优选实施方案中,有机溶剂选自叔丁基甲醚、甲苯、乙腈、甲基异丁酮、乙基甲基酮、丙酮、苯、二甲苯、乙醇和异丙醇。在本发明另一个实施方案中,有机溶剂是叔丁基甲醚。在本发明另一个实施方案中,氨以水溶液的形式加入。在本发明另一个实施方案中,将氨加入步骤(a)的溶液中。在本发明另一个实施方案中,以约1.75~约2.25摩尔当量的量加入氨。
本发明还涉及托拉塞米的制备方法,包括以下步骤:在选自乙腈、甲苯、丙酮、乙酸乙酯和乙酸丁酯、及其混合物的溶剂中,在三乙胺存在下,使3-磺酰基酰胺-4(3’-甲基苯基)-氨基吡啶与异丙基异氰酸酯反应。在本发明的优选实施方案中,溶剂是丙酮。在本发明另一个优选实施方案中,溶剂是乙腈。
具体实施方式
本发明涉及托拉塞米中间体(3-氨磺酰-4-氯)吡啶的新制备方法。本发明的方法提供了比以前报导的方法有更高产率和更高纯度的(3-氨磺酰-4-氯)吡啶的合成方法。中间体(3-磺酰氯-4-氯)吡啶可用现有技术中的已知方法由4-羟基-3-吡啶磺酸制备,包括加拿大专利1051888和J.Med.Chem., 36,3211-3213,1993中公开的方法,此处参考引用这两篇文献的内容。
按照本发明的方法,将X1和X2各自独立地是氯、氟或溴的通式II’的化合物加入到合适的有机溶剂中(流程II)。优选地,X1和X2是氯。合适的有机溶剂包括乙腈、诸如叔丁基甲醚(MTBE)的醚、诸如乙醇和异丙醇的醇、诸如甲基-异丁酮(MIBK)、乙基甲基酮和丙酮的酮;和被取代或未被取代的芳族化合物,如苯和二甲苯。优选的溶剂是叔丁基甲醚。然后向混合物中加入可使混合物升温的氨。优选地,加入约2摩尔当量的氨。氨可以以气态氨或氢氧化铵的形式加入,更优选以氢氧化铵水溶液的形式加入。优选地,氢氧化铵以25%水溶液的形式加入。将溶液冷却到室温并搅拌,直到反应基本完成,如搅拌1到1.5小时,优选1小时。可通过监测pH值判断反应是否完成;当pH值停止下降并保持稳定时表示反应完成。通过加入氢氧化铵将溶液的pH值调节到约8±0.1,以诱发通式III’化合物的晶体沉淀。通过过滤该溶液然后干燥来分离出X1为氯、氟或溴的通式III’的化合物(流程II)。X1优选地是氯。
流程II
Figure A20041007873800071
I                                    II′                              III′
在本发明的实施方案中,将通式II的化合物(3-磺酰氯-4-氯)吡啶加入到有机溶剂中。合适的有机溶剂包括乙腈、诸如叔丁基甲醚(MTBE)的醚、诸如乙醇和异丙醇的醇、诸如甲基-异丁酮(MIBK)、乙基甲基酮和丙酮的酮;和被取代或未被取代的芳族化合物,如苯和二甲苯。优选的溶剂是叔丁基甲醚。然后向溶液中加入约1.75~约2.25摩尔当量的氨。优选地,加入约2.15摩尔当量的氨。氨可以气态氨或氢氧化铵的形式加入更优选地以氢氧化铵水溶液的形式加入。优选地以25%水溶液的形式加入氢氧化铵。加入氨可引起溶液温度上升。将溶液冷却到室温并搅拌,直到反应基本完成,如搅拌1到1.5小时,优选1小时。可通过监测pH值判断反应是否完成,当pH值停止下降并保持稳定时表示反应完成。通过加入氢氧化铵将溶液的pH值调节到约8±1,以诱发通式III的化合物(3-氨磺酰-4-氯)吡啶的晶体沉淀。通过过滤该溶液然后干燥来分离出通式III的化合物(3-氨磺酰-4-氯)吡啶。(3-氨磺酰-4-氯)吡啶以大约74%的高产率被分离出来。通过本发明的方法,(3-氨磺酰-4-氯)吡啶以意想不到的约93~约97%的高纯度被分离出来。
这样,该方法出乎意料地提供了一种用高浓度的(3-磺酰氯-4-氯)吡啶原料制备高纯度的(3-氨磺酰-4-氯)吡啶的方法。与已知方法比较,该方法出乎意料地产生了基本不含副产物的(3-氨磺酰-4-氯)吡啶,该副产物由原料与产物、即(3-磺酰氯-4-氯)吡啶与(3-氨磺酰-4-氯)吡啶的缩合反应产生,这在已知方法中可以观察到。
流程III
(3-磺酰氯-4-氯)吡啶            (3-氨磺酰-4-氯)吡啶
SCCPY                           SAMCPY
II                              III
因此该方法提供了适用于大规模反应的高产率和高纯度的新方法。高纯度还减少了对额外提纯步骤的需要。
本发明还涉及从3-氨磺酰-4-(3’-甲基苯基)氨基吡啶制备托拉塞米的新方法。3-氨磺酰-4-(3’-甲基苯基)氨基吡啶可用现有技术中的已知方法从(3-氨磺酰-4-氯)吡啶制备,包括US 3904636中公开的方法,此处参照引用该专利的内容。
按照本发明的方法,将通式IV的化合物3-氨磺酰4-(3’-甲基苯基)氨基吡啶加入到三乙胺(TEA)和有机溶剂中(流程IV)。合适的溶剂是乙腈、甲苯、丙酮、乙酸乙酯和乙酸丁酯、和它们的混合物。优选的溶剂是乙腈和丙酮。更优选的溶剂是乙腈。然后将异丙基异氰酸酯(IPIC)滴加到溶液中,并将溶液加热到约40℃。然后在约38~约42℃下搅拌所得的混合物直到所有反应物完全溶解,该搅拌约进行45~90分钟。然后将混合物冷却到室温并搅拌适当时间,约1.5到约2.5小时,优选约2小时。然后将混合物的pH值调节到约4.3±0.3,优选调节到4.3,并使温度升到约35℃。可用盐酸降低pH值。将混合物冷却到室温,然后过滤并清洗。对该湿的粗产品进行研磨,然后干燥形成粗托拉塞米。分离出的粗托拉塞米的产率约为81.5%。分离出的粗托拉塞米的纯度为约98~约99.9%,这比现有技术的已知方法有了实质性的改善。
流程IV
Figure A20041007873800091
3-氨磺酰-4-(3’-甲基苯基)                       托拉塞米
氨基吡啶
IV                                              V
实施例
本发明将在以下实施例中进一步解释。然而,不应认为本发明被其所限制。本领域普通技术人员应当了解如何改变所列举的制备方法以得到所需的结果
实施例1
(3-氨磺酰-4-氯)吡啶的合成
在一个装有磁力搅拌器、冷凝器、温度计和滴液漏斗的100ml三颈烧瓶中,将(3-磺酰氯-4-氯)吡啶(10g,1当量,46.7mmo1)在室温下悬浮在MTBE(30ml)中。以使温度上升到约22℃到约26℃的速率,将25%的氢氧化铵溶液(13.5ml,2.13当量)滴入悬浮液中,保持该温度直到加完所有的氢氧化铵。然后将悬浮液冷却到室温并搅拌1小时。通过滴入几滴25%的氢氧化铵溶液而将悬浮液的pH值调节到8±0.1。过滤悬浮液并用水(2×10ml)清洗,在40℃和1mm汞柱真空下干燥该湿产物(~8g)。以74.4%的产率分离出6.7g(3-氨磺酰-4-氯)吡啶。
实施例2
托拉塞米的合成
向装有机械搅拌器、温度计和冷凝器的100ml三颈烧瓶中加入乙腈(15ml)、3-氨磺酰-4-(3’-甲基苯基)氨基吡啶(5g)和三乙胺(TEA)(5.3ml)。在10分内钟滴加1.87ml异丙基异氰酸酯,在40±2℃下搅拌全部混合物以完全溶解。将混合物冷却到室温并再搅拌2小时。将混合物pH值调节到4.3同时将温度升到35℃左右。将混合物再冷却到室温,过滤并用乙腈∶水(1∶1)混合物(10ml)冲洗。在60℃、在乙腈∶水混合物(5∶1,13ml)研磨该湿的粗产物半小时,过滤并用乙腈∶水(5∶1)混合物(2×7ml)冲洗。然后在50℃和高真空(3mmHg)下将研磨过的产物干燥6小时,得到5.4g粗托拉塞米(81.5%粗产率)。
尽管此处阐述了本发明的部分优选实施方案,但本领域技术人员应当认识到,可以对所述实施方案进行改变和改进而不背离本发明的精神和范围。因此,本发明仅被限制在附属的权利要求和适用的法律规章所要求的范围内。

Claims (3)

1.托拉塞米的制备方法,包括以下步骤:在选自乙腈、甲苯、丙酮、乙酸乙酯和乙酸丁酯以及它们的混合物的溶剂中,在三乙胺存在下,使3-磺酰基酰胺-4(3’-甲基苯基)-氨基吡啶与异丙基异氰酸酯反应。
2.权利要求1的方法,其中溶剂是丙酮。
3.权利要求1的方法,其中溶剂是乙腈。
CNA2004100787386A 2000-03-20 2001-03-20 托拉塞米的制备方法 Pending CN1623987A (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US19065000P 2000-03-20 2000-03-20
US60/190650 2000-03-20
US21151000P 2000-06-14 2000-06-14
US60/211510 2000-06-14

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CNB018068340A Division CN1203059C (zh) 2000-03-20 2001-03-20 新的制备托拉塞米中间体的方法

Publications (1)

Publication Number Publication Date
CN1623987A true CN1623987A (zh) 2005-06-08

Family

ID=26886305

Family Applications (2)

Application Number Title Priority Date Filing Date
CNA2004100787386A Pending CN1623987A (zh) 2000-03-20 2001-03-20 托拉塞米的制备方法
CNB018068340A Expired - Fee Related CN1203059C (zh) 2000-03-20 2001-03-20 新的制备托拉塞米中间体的方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CNB018068340A Expired - Fee Related CN1203059C (zh) 2000-03-20 2001-03-20 新的制备托拉塞米中间体的方法

Country Status (15)

Country Link
US (2) US6635765B2 (zh)
EP (1) EP1284733A4 (zh)
JP (1) JP2003527425A (zh)
KR (1) KR20020081482A (zh)
CN (2) CN1623987A (zh)
AU (2) AU2001247592B2 (zh)
CA (1) CA2403382A1 (zh)
CZ (1) CZ20023395A3 (zh)
HR (1) HRP20020819A2 (zh)
HU (1) HUP0300241A3 (zh)
IL (1) IL151837A0 (zh)
NZ (1) NZ521852A (zh)
PL (1) PL370039A1 (zh)
SK (1) SK14802002A3 (zh)
WO (1) WO2001070226A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432532A (zh) * 2011-11-10 2012-05-02 天津市汉康医药生物技术有限公司 高纯度托拉塞米化合物
CN104370805A (zh) * 2013-08-13 2015-02-25 天津汉瑞药业有限公司 托拉塞米化合物
WO2020233289A1 (zh) * 2019-05-23 2020-11-26 上海勋和医药科技有限公司 托拉塞米磷酸酯类前药、其制备方法及组合物
CN115010659A (zh) * 2022-06-22 2022-09-06 南京正科医药股份有限公司 一种托拉塞米新杂质对照品及其制备方法
CN115417810A (zh) * 2022-09-22 2022-12-02 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003527319A (ja) * 1999-08-11 2003-09-16 テバ ファーマシューティカル インダストリーズ リミティド トルセミド多形体
IL149771A0 (en) * 2002-05-21 2002-11-10 Fintech Lab Ltd Process for preparation of torsemide
ITMI20022749A1 (it) * 2002-12-23 2004-06-24 Cosma S P A Nuovo procedimento per la sintesi della tosemide, in particolare della forma ii pura e stabile.
US7378527B2 (en) * 2004-03-16 2008-05-27 Daqing Che Process for the preparation of torsemide and related intermediates
DE102009005095A1 (de) * 2009-01-19 2010-07-22 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Verfahren zur Herstellung von Carbonitriden über Polykondensations- bzw. Sol-Gel-Verfahren unter Verwendung Wasserstoff-freier Isocyanate
SG10201913525QA (en) * 2015-10-29 2020-02-27 Aska Pharmaceutical Co Ltd Pyrimidine derivative
GB202102575D0 (en) 2021-02-23 2021-04-07 Teva Pharmaceutical Industries Ltd Fixed-dose pharmaceutical compositions

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2516025A (en) 1947-03-27 1950-07-18 Westinghouse Electric Corp Ground-relay transmission-line protection
BE758749A (fr) 1969-11-12 1971-05-10 Ciba Geigy Procede de preparation de nouveaux acides pyridine-sulfoniques
US3674794A (en) * 1970-03-18 1972-07-04 Ciba Geigy Corp Certain-3-pyridine-sulfonamide derivatives
US3787573A (en) 1970-03-18 1974-01-22 R Mizzoni Pyridine sulfonic acids as diuretics
US3824241A (en) 1970-08-26 1974-07-16 Ciba Geigy Corp Pyridinesulfonic acids
GB1368948A (en) 1970-11-11 1974-10-02 Manuf Prod Pharma Pyridine derivatives
US3904636A (en) 1971-11-09 1975-09-09 Christiaens Sa A 3-sulfonamido-4-phenyl aminopyridines and derivatives
ES436109A1 (es) 1974-04-04 1977-01-01 Christiaens Sa A Procedimiento para la preparacion de nuevos derivados de pi-ridina.
GB1477664A (en) * 1974-04-17 1977-06-22 Christiaens Sa A Pyridine derivatives
US4055650A (en) 1974-04-17 1977-10-25 A. Christiaens Societe Anonyme Certain 4-phenoxy(or phenylthio)-3-n-acylated-sulfonamido-pyridines
US4042693A (en) 1975-04-14 1977-08-16 A. Christiaens Societe Anonyme Derivatives of 1,2,4-thiadiazine
GB1593609A (en) 1978-01-31 1981-07-22 Christiaens Sa A Pyridine sulfonamides
DE3529529A1 (de) 1985-08-17 1987-02-19 Boehringer Mannheim Gmbh Verfahren zur herstellung einer stabilen modifikation von torasemid
DE3623620A1 (de) 1986-07-12 1988-01-21 Boehringer Mannheim Gmbh Spritzfertige, waessrige, alkalische injektionsloesungen von torasemid und verfahren zu ihrer herstellung
FR2703051B1 (fr) 1993-03-26 1995-04-28 Adir Nouvelles pyridothiadiazines, leurs procédés de préparation, et les compositions pharmaceutiques qui les contiennent.
US5914336A (en) 1998-06-02 1999-06-22 Boehringer Mannheim Gmbh Method of controlling the serum solubility of orally administered torasemide and composition relating thereto

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432532A (zh) * 2011-11-10 2012-05-02 天津市汉康医药生物技术有限公司 高纯度托拉塞米化合物
CN102432532B (zh) * 2011-11-10 2014-06-18 天津市汉康医药生物技术有限公司 高纯度托拉塞米化合物
CN104370805A (zh) * 2013-08-13 2015-02-25 天津汉瑞药业有限公司 托拉塞米化合物
WO2020233289A1 (zh) * 2019-05-23 2020-11-26 上海勋和医药科技有限公司 托拉塞米磷酸酯类前药、其制备方法及组合物
CN115010659A (zh) * 2022-06-22 2022-09-06 南京正科医药股份有限公司 一种托拉塞米新杂质对照品及其制备方法
CN115417810A (zh) * 2022-09-22 2022-12-02 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法
CN115417810B (zh) * 2022-09-22 2023-10-10 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法

Also Published As

Publication number Publication date
US20020019537A1 (en) 2002-02-14
HUP0300241A2 (hu) 2003-06-28
HUP0300241A3 (en) 2005-11-28
IL151837A0 (en) 2003-04-10
CN1203059C (zh) 2005-05-25
US20030212277A1 (en) 2003-11-13
JP2003527425A (ja) 2003-09-16
PL370039A1 (en) 2005-05-16
AU2001247592B2 (en) 2005-08-18
US6635765B2 (en) 2003-10-21
AU4759201A (en) 2001-10-03
US6670478B2 (en) 2003-12-30
KR20020081482A (ko) 2002-10-26
EP1284733A1 (en) 2003-02-26
CZ20023395A3 (cs) 2003-04-16
HRP20020819A2 (en) 2004-12-31
WO2001070226A1 (en) 2001-09-27
CA2403382A1 (en) 2001-09-27
CN1423558A (zh) 2003-06-11
NZ521852A (en) 2004-10-29
EP1284733A4 (en) 2003-07-16
SK14802002A3 (sk) 2003-05-02

Similar Documents

Publication Publication Date Title
CN1203059C (zh) 新的制备托拉塞米中间体的方法
CN1044246C (zh) 双环β-内酰胺/对羟苯甲酸酯复合物
CN102453023A (zh) 一种阿折地平生产工艺
CN110372708B (zh) 一种5H-苯并[c]咪唑并[1,2-a]氮杂环庚烯-6-羧酸类化合物的合成方法
CN1226295C (zh) 枸橼酸莫沙必利的制备方法
CN109516960B (zh) 一种盐酸乌拉地尔的制备方法
CN108947800B (zh) 一种(1s)-4,5-二甲氧基-1-(羰基氨基甲基)苯并环丁烷的合成方法
CN111285821A (zh) 一种连续制备非布司他的方法
CN1132817C (zh) 制备杂芳基甲酰胺和酯的方法
CN1023121C (zh) 鬼臼乙叉甙-2-二甲氨基化合物盐酸盐二水合物结晶的制备方法
CN1044463A (zh) 接续氧化取代的8-羟基喹啉而制备取代的吡啶-2,3-二羧酸的方法
CN1915974A (zh) 氨氯地平的拆分方法
CN111138354A (zh) 一种异烟肼的制备方法
JP2006193444A (ja) 4,4’−ジカルボキシ−2,2’−ビピリジンの製造法
CN111320622A (zh) 一种莫西沙星盐酸盐的合成方法
CN109705089A (zh) 化合物的纯化方法
CN100408577C (zh) 咪唑并(1,2-a)吡啶-3-乙酰胺类的制备方法
CN1082045C (zh) α-苯偶姻肟的合成方法
CN101037409B (zh) 制备n-取代的2-氰基吡咯烷的方法
CN102424651A (zh) 一种制备2,7-二乙酰氧基-9-芴酮和2,7-二羟基-9-芴酮的方法
CN110330454B (zh) 一种吡啶杂环偶氮苯的合成方法
CN101066943A (zh) 2,4-二氯-5-磺酰胺基苯甲酸的合成方法
CN1228340C (zh) 20(s)-喜树碱的纯化方法
CN105017287A (zh) 一种头霉素中间体的制备方法
JPH0140833B2 (zh)

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication