CN1355795A - 噻唑烷的制备方法 - Google Patents

噻唑烷的制备方法 Download PDF

Info

Publication number
CN1355795A
CN1355795A CN00808725A CN00808725A CN1355795A CN 1355795 A CN1355795 A CN 1355795A CN 00808725 A CN00808725 A CN 00808725A CN 00808725 A CN00808725 A CN 00808725A CN 1355795 A CN1355795 A CN 1355795A
Authority
CN
China
Prior art keywords
thiazolidine
salt
formula
reaction
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.)
Granted
Application number
CN00808725A
Other languages
English (en)
Other versions
CN1169799C (zh
Inventor
汉斯-乌尔里希·德穆特
苏珊·科鲁伯
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.)
Prosidion Ltd
Original Assignee
Probiodrug AG
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 Probiodrug AG filed Critical Probiodrug AG
Publication of CN1355795A publication Critical patent/CN1355795A/zh
Application granted granted Critical
Publication of CN1169799C publication Critical patent/CN1169799C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

制备噻唑烷碱及其盐的方法,其特征在于,使式(I)的六亚甲基四胺与式(II)的半胱胺或其盐反应,其中X(－)代表酸基,并优选为卤离子或硫酸根。

Description

噻唑烷的制备方法
本发明涉及制备噻唑烷碱及其盐的方法，该方法简单而且在技术上易于操作。
噻唑烷可用作合成氨基酰基-和肽基-thiazolidides的中间产物，后者作为酶抑制剂具有诊断和治疗价值(H.-U.DEMUTH，J.EnzymeInhibition 3，249(1990))。
因为氨基酰基thiazolidides特别适合于调节哺乳动物的血糖水平，成本低而且可工业应用的制备这些化合物以及它们的母体化合物的方法在医药、制药和经济方面都是令人感兴趣的(参见DE 19 616 486)。
已知噻唑烷和噻唑烷衍生物可如下制得：在水溶液中使醛与硫酸氨基乙酯或者氨基乙基卤及硫化钠回流，其中输入过量的能量，时间为几个小时。产率约为理论值的60％(参见US 4 584 407)。
本发明的目的是提供一种制备噻唑烷碱或其盐的方法，其中不需要输入过量的能量。
本发明现提供制备噻唑烷碱及其盐的方法，其特征在于，使式(I)的六亚甲基四胺与式(II)的半胱胺或其盐反应
Figure A0080872500051
其中X(-)代表酸残基，并优选为卤离子或者硫酸根。
非常令人惊奇地发现，上述方法以非常高的纯度和产率形成游离碱噻唑烷及其盐，而且在反应期间不需要施加过量的热量。这使得本发明的方法具有成本和技术上的优势，特别是作为制备噻唑烷的工业方法(参见EP 0 054 409)。
在本发明中，反应例如在极性溶剂中进行，如醇。优选的溶剂是甲醇和/或乙醇。
本发明的方法在工业制备噻唑烷时还具有经济和技术方面的优势，六亚甲基四胺可作为噻唑烷副产物的药物用途，这是因为其是药物学上可以接受的：许多年来，已使用该物质作为尿消毒剂和食品防腐剂(参见Mutschler，Arzneimittelwirkungen，第572页以及随后页，Stuttgart：Wissenschaftliche Verlagsges.(1986))。
优选的是，使用氨作为初始物和/或在反应期间添加。通过这种方法，可在单个步骤中进行至游离碱的合成(参见S.Ratrner，H.T.Clarke，J.Am.Chem.Soc.59，200-206(1937))，使得可省略复杂而且昂贵的额外反应步骤。
本发明的方法可设计成用于实验室和商业规模，例如如下进行：一次性或者分批将六亚甲基四胺添加在优选半胱胺盐的甲醇溶液中，该半胱胺盐可为固体形式或者溶解在溶剂中。在室温下搅拌该混合物几个小时，或者在约30-35℃的温度下搅拌。如果需要，所述添加步骤可按照相反的顺序进行。
本发明的方法并不需要象其他方法那样在惰性气体环境中进行(参见EP 0 695 744)。
根据本发明的方法制得的噻唑烷可用作制备药物活性物质的起始物。以下将参考实施例来描述本发明。
实施例
在30-35℃将1.358kg(12mol)作为起始物的半胱胺盐酸盐溶解在1.8 L甲醇中形成溶液，然后在30-35℃的反应温度下分两批添加291.59g(2.08mol)六亚甲基四胺。在添加第一批六亚甲基四胺后，观察到明显的放热反应(约45℃)，并形成紫色，然后冷却反应混合物。开始形成氯化铵粗沉淀物。当放热反应停止(约1.5小时)后，添加第二批六亚甲基四胺。在反应物中添加氨至饱和，然后添加700ml的叔丁基甲基醚。
定量沉淀的氯化铵可作为反应进程的指示剂。真空过滤氯化铵，并用反应溶液洗涤滤饼。在溶液中加入30ml的氨基乙基乙醇胺作为Sumpfbildner。蒸馏纯制噻唑烷，bp：60-70℃，8-10mbar。得到非常纯的物质，产率为88-93％。1H NMR(200MHz，D2O)δ(ppm)＝2.80-2.83(t，3J＝6.45Hz，2H，NCH2CH2)，3.04-3.19(t，3J＝6.45Hz，2H，CH2CH2S)，4.05(s，2H，NCH2S)13C NMR(100.5MHz，DMSO-d6)δ(ppm)＝30.69(s，NCH2CH2)，47.31(s，CH2CH2S)，47.95(s，NCH2S)MS(MALDI-TOF)89(M+H)EA：C3H7NS理论：C＝40.44％       实测：C＝40.27％
                 H＝7.91％              H＝8.02％
                 N＝15.72％             N＝15.90％
                 S＝35.91％             S＝35.73％

Claims (7)

1、制备噻唑烷碱及其盐的方法，其特征在于，使式(I)的六亚甲基四胺
Figure A0080872500021
与式(II)的半胱胺或其盐反应其中X(-)代表酸残基。
2、如权利要求1所述的方法，其特征在于X(-)是卤离子或者硫酸根。
3、如前述权利要求之一所述的方法，其特征在于反应是在极性溶剂中进行的。
4、如权利要求3所述的方法，其特征在于所述溶剂是醇。
5、如权利要求3或4所述的方法，其特征在于所述溶剂是甲醇或乙醇。
6、如权利要求3或4所述的方法，其特征在于在反应之前或者反应期间添加氨。
7、如前述权利要求之一所述的方法，其特征在于分离铵盐和/或蒸馏产物。
CNB008087253A 1999-06-10 2000-04-11 噻唑烷的制备方法 Expired - Fee Related CN1169799C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19926233.0 1999-06-10
DE19926233A DE19926233C1 (de) 1999-06-10 1999-06-10 Verfahren zur Herstellung von Thiazolidin

Publications (2)

Publication Number Publication Date
CN1355795A true CN1355795A (zh) 2002-06-26
CN1169799C CN1169799C (zh) 2004-10-06

Family

ID=7910641

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB008087253A Expired - Fee Related CN1169799C (zh) 1999-06-10 2000-04-11 噻唑烷的制备方法

Country Status (18)

Country Link
US (1) US6559314B2 (zh)
EP (1) EP1185520B1 (zh)
JP (1) JP3803292B2 (zh)
KR (1) KR100467898B1 (zh)
CN (1) CN1169799C (zh)
AT (1) ATE261946T1 (zh)
AU (1) AU758605B2 (zh)
BR (1) BR0011445A (zh)
CA (1) CA2373834C (zh)
DE (2) DE19926233C1 (zh)
DK (1) DK1185520T3 (zh)
ES (1) ES2215045T3 (zh)
HK (1) HK1042483B (zh)
MX (1) MXPA01012237A (zh)
NZ (1) NZ515561A (zh)
PT (1) PT1185520E (zh)
RU (1) RU2218336C2 (zh)
WO (1) WO2000076986A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104910128A (zh) * 2015-06-02 2015-09-16 安徽兴东化工有限公司 一种2,2-二甲基四氢噻唑的制备方法

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR200000815T2 (tr) * 1997-09-29 2000-12-21 Point Therapeutics Inc. In vitro hematopoietik hücrelerin stimulasyonu.
US6979697B1 (en) * 1998-08-21 2005-12-27 Point Therapeutics, Inc. Regulation of substrate activity
US6890904B1 (en) * 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
EP1608317B1 (en) 2003-03-25 2012-09-26 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7579357B2 (en) * 2003-08-13 2009-08-25 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP2007505121A (ja) 2003-09-08 2007-03-08 武田薬品工業株式会社 ジペプチジルぺプチダーゼ阻害剤
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CN102127057A (zh) 2004-03-15 2011-07-20 武田药品工业株式会社 二肽基肽酶抑制剂
EP1753730A1 (en) * 2004-06-04 2007-02-21 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2006019965A2 (en) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
CN101087756B (zh) * 2004-07-23 2011-04-06 纽阿达有限责任公司 肽酶抑制剂
US20060063719A1 (en) * 2004-09-21 2006-03-23 Point Therapeutics, Inc. Methods for treating diabetes
JP2008524331A (ja) 2004-12-21 2008-07-10 武田薬品工業株式会社 ジペプチジルペプチダーゼ阻害剤
WO2007033266A2 (en) * 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors for treating diabetis
PE20070622A1 (es) * 2005-09-14 2007-08-22 Takeda Pharmaceutical Administracion de inhibidores de dipeptidil peptidasa
ZA200802857B (en) 2005-09-14 2009-09-30 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for treating diabetes
TW200745080A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of tartrate salt of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile and methods of use therefor
TW200745079A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
KR101368988B1 (ko) 2005-09-16 2014-02-28 다케다 야쿠힌 고교 가부시키가이샤 디펩티딜 펩티다제 억제제
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8460362B2 (en) * 2006-07-20 2013-06-11 Orbusneich Medical, Inc. Bioabsorbable polymeric medical device
AR062760A1 (es) * 2006-09-13 2008-12-03 Takeda Pharmaceutical Administracion de inhibidores de dipeptidilpetidasa
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2961377A (en) 1957-08-05 1960-11-22 Us Vitamin Pharm Corp Oral anti-diabetic compositions and methods
US3594377A (en) * 1967-11-07 1971-07-20 Uniroyal Inc Condensation products of n - (3 -thiazolidinylmethyl) - nitrogen base compounds
DE2009743A1 (de) 1970-03-03 1971-09-16 Farbenfabriken Bayer Ag, 5090 Leverkusen Substituierte Biguanide mit antihyperglykämischer Wirkung
US3960949A (en) 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
CH590857A5 (en) * 1973-05-30 1977-08-31 Givaudan & Cie Sa Substd. thiazolidine odourants flavourants - having a wide aroma spectrum and usable in small concns.
CH602612A5 (zh) 1974-10-11 1978-07-31 Hoffmann La Roche
ATE15668T1 (de) * 1980-12-12 1985-10-15 Fine Organics Ltd Verfahren zur herstellung von thiazolidinderivaten.
US4935493A (en) 1987-10-06 1990-06-19 E. I. Du Pont De Nemours And Company Protease inhibitors
JPH01272570A (ja) * 1988-04-26 1989-10-31 Nippon Shokubai Kagaku Kogyo Co Ltd ４−メチル−５−［（２−アミノエチル）−チオメチル］−イミダゾールの製法
US5433955A (en) 1989-01-23 1995-07-18 Akzo N.V. Site specific in vivo activation of therapeutic drugs
JPH04334357A (ja) 1991-05-02 1992-11-20 Fujirebio Inc 酵素阻害作用を有するアシル誘導体
WO1993008259A2 (en) 1991-10-22 1993-04-29 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type iv
IL106998A0 (en) 1992-09-17 1993-12-28 Univ Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
FR2696740B1 (fr) 1992-10-13 1994-12-30 Dospharma Sa Dérivés prodrogués de la diméthylbiguanide et applications comme médicaments.
WO1995011689A1 (en) 1993-10-29 1995-05-04 Trustees Of Tufts College Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells
IL111785A0 (en) 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
US5543396A (en) 1994-04-28 1996-08-06 Georgia Tech Research Corp. Proline phosphonate derivatives
DE4427569A1 (de) * 1994-08-04 1996-02-08 Bayer Ag Verfahren zur Herstellung von Cyanimino-1,3-thiazolidin
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5614379A (en) 1995-04-26 1997-03-25 Eli Lilly And Company Process for preparing anti-obesity protein
DE19616486C5 (de) 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Verfahren zur Senkung des Blutglukosespiegels in Säugern
EP0914123A4 (en) 1996-05-29 2000-10-11 Prototek Inc THALIDOMIDE PRODUCTS AND METHODS OF USING SAID PRODUCTS AS T CELL MODIFIERS
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
AR016751A1 (es) 1996-11-22 2001-08-01 Athena Neurosciences Inc Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo
WO2000001849A1 (en) 1998-07-02 2000-01-13 Invitro Diagnostics, Inc. Methods, compositions and apparatus for making nucleic acid molecules having a selected affinity to a target molecule
AU3960400A (en) 1999-03-05 2000-09-28 Molteni L. E C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. Use of metformin in the preparation of pharmaceutical compositions capable of inhibiting the enzyme dipeptidyl peptidase iv
AU2001233622A1 (en) 2000-02-25 2001-09-03 Novo-Nordisk A/S Inhibition of beta cell degeneration

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104910128A (zh) * 2015-06-02 2015-09-16 安徽兴东化工有限公司 一种2,2-二甲基四氢噻唑的制备方法

Also Published As

Publication number Publication date
DE50005699D1 (de) 2004-04-22
CA2373834A1 (en) 2000-12-21
US20020082427A1 (en) 2002-06-27
US6559314B2 (en) 2003-05-06
BR0011445A (pt) 2002-03-19
AU4399600A (en) 2001-01-02
MXPA01012237A (es) 2002-08-12
PT1185520E (pt) 2004-08-31
WO2000076986A1 (de) 2000-12-21
CA2373834C (en) 2005-11-08
KR20020022688A (ko) 2002-03-27
KR100467898B1 (ko) 2005-02-21
DK1185520T3 (da) 2004-06-28
ATE261946T1 (de) 2004-04-15
CN1169799C (zh) 2004-10-06
DE19926233C1 (de) 2000-10-19
AU758605B2 (en) 2003-03-27
JP3803292B2 (ja) 2006-08-02
EP1185520A1 (de) 2002-03-13
JP2003502319A (ja) 2003-01-21
ES2215045T3 (es) 2004-10-01
HK1042483A1 (en) 2002-08-16
EP1185520B1 (de) 2004-03-17
NZ515561A (en) 2003-06-30
RU2218336C2 (ru) 2003-12-10
HK1042483B (zh) 2004-09-10

Similar Documents

Publication Publication Date Title
CN1169799C (zh) 噻唑烷的制备方法
RU2550202C2 (ru) Способ синтеза эрготионеина и его аналогов
CN101412732B (zh) 三水合3-氨基丙基胺乙基硫代磷酸高纯稳定晶体及其制备方法
CN101426795B (zh) 制备多佐胺的方法
CN112225761A (zh) 一种嘧啶并三氮唑及其合成方法
CN113735751B (zh) 一种制备芳基异硫脲的方法
CN108358928A (zh) 一种(6s)-5-甲基四氢叶酸钙的制备方法
CN112480106B (zh) 一种马来酸阿伐曲泊帕杂质的制备方法
CN101851181B (zh) 一种1-位取代牛磺酸的制备方法
CN114634428A (zh) 6-苯胺基/对甲苯胺基-2-萘磺酸的微波条件制备方法
JP2018104312A (ja) イミダゾピロロキノリン塩及びその製造方法、並びに、医薬品、化粧品及び食品
CN113214043A (zh) 一种高效制备氘代碘甲烷的方法及其应用
CN115611899B (zh) 一种l-5-甲基四氢蝶酸的制备方法
CN104725470B (zh) 一种他替瑞林新晶型及其制备方法与应用
EP2599772B1 (en) Manufacturing method for aminoalkyl thiosulfuric acid compound
CN100534989C (zh) (rs)-苯并二噁烷-2-甲酸的拆分方法
SU1447820A1 (ru) Способ получени (S)-2-N-(N @ -бензилпролил)-аминобензофенонов
CN106278898B (zh) 一种肽缩合试剂3’,5’-双三氟甲基联苯-3,5-二乙酸亚碘酰苯及其制备方法
TWI549935B (zh) Long alkyl tetrazole organic complex 3 -MN-16Bn, a precursor thereof and a process for its preparation
JP2022074008A (ja) トレプロスチニル一水和物結晶およびその製造方法
CN117658963A (zh) 一种维生素c衍生物的非对映异构体及其制备和应用
CN117865832A (zh) L-谷氨酸-α-叔丁酯的合成方法
EP2051963B1 (en) Process for resolving chiral piperidine alcohol and process for synthesis of pyrazolo [1,5-a]pyrimidine derivatives using same
KR20220125856A (ko) 신규한 오르트산염 중간체를 이용한 카르니틴 오르트산염의 제조방법
CN112724143A (zh) 一种由3-甲基黄嘌呤甲基化制备可可碱的方法

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: PROLON STILON CO., LTD.

Free format text: FORMER OWNER: QIANTI BIOLOGY MEDICINE STOCK CO., LTD.

Effective date: 20050325

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20050325

Address after: oxford

Patentee after: Prosidion Ltd.

Address before: Harley

Patentee before: Probildrug AG

C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20041006

Termination date: 20130411