CN1642916A - 制备n1-(2'-吡啶基)-1,2-丙烷二胺氨基磺酸的方法以及它在合成生物活性哌嗪中的用途 - Google Patents
制备n1-(2'-吡啶基)-1,2-丙烷二胺氨基磺酸的方法以及它在合成生物活性哌嗪中的用途 Download PDFInfo
- Publication number
- CN1642916A CN1642916A CNA038058421A CN03805842A CN1642916A CN 1642916 A CN1642916 A CN 1642916A CN A038058421 A CNA038058421 A CN A038058421A CN 03805842 A CN03805842 A CN 03805842A CN 1642916 A CN1642916 A CN 1642916A
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- compound formula
- aroyl
- aryl
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/04—Heterocyclic 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
- C07D213/60—Heterocyclic 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/04—Heterocyclic 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
- C07D213/60—Heterocyclic 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/04—Heterocyclic 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
- C07D213/60—Heterocyclic 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及制备N1- (2′-吡啶基)-1,2-烷烃二胺氨基磺酸式(II)的方法,包括将化合物式(I)和NH2R’反应,其中R和R’的定义见说明书。本发明还涉及化合物式(II)及其旋光异构体,化合物式(II)是制备手性哌嗪衍生物的中间体,后者对于5-HT1A受体有活性。
Description
发明的领域
本发明涉及制备N-芳基哌嗪及其中间体方法的领域。
发明的背景
式A的哌嗪:
其中R是低级烷基,Ar是未取代或取代的芳基或杂芳基,以及Q是氢,CO-(低级)烷基,CO-环烷基或CO-芳基,和*是手性中心,是潜在的5HT1A受体结合剂。U.S.专利No.6,127,357教导这种哌嗪衍生物用于治疗中枢神经系统(CNS)疾病。这种哌嗪对映体对5HT1A受体有不同的结合能力,因此它们的潜在能力,选择性及代谢效果是不同的。WO 9703982教导这种哌嗪的某些对映体显示改进的5HT1A结合亲和性和生物利用率,因此需要开发另一种制备这种旋光优选的哌嗪的有效、容易操作、廉价和安全的方法。
WO 9533725教导了使用对映体纯的2-(5-甲基-2,2-二氧-1,2,3-氧杂噻唑烷-3-基)吡啶烷基化相应的1-芳基-哌嗪合成某些手性哌嗪式A的方法。WO 9533725还教导了使用1-芳基哌嗪的氨基磺酸酯的亲核开环反应和使用各种伯胺或仲胺的开环反应(参见L.T.Boulton,J.Chem.Soc.,Perkin Trans.1,1999,1421-1429)。
WO 97/37655和Cignarella等人(Farmaco Ed.Sci.;31;1976;194,196)讨论了N1-(2’吡啶基)-1,2-丙烷二胺的制备方法和反应。
发明的概述
本发明涉及制备N1-(2′-吡啶基)-1,2-烷烃二胺氨基磺酸式II的方法,包括将化合物式I和NH2R’反应:
其中R选自C1-C3烷基,R′是H,C1-C6烷基,C3-C7环烷基,C2-C7酰基,C5-C10芳基C6-C11芳酰基,(C3-C7)环烷基(C1-C6)烷基,二-(C3-C7)环烷基-(C1-C6)烷基,(C5-C10)芳基(C1-C6)烷基,和二-(C5-C10)芳基-(C1-C6)烷基。本发明还包括化合物式II及其旋光异构体。
本发明的方法包括一个或多个以下反应步骤:
化合物式II可以氢化将R′转化为H(假如R’不表示H时),然后使用酸水解形成化合物式III。
无论其中R′=H的化合物式II或者是化合物式III都可以和化合物式IV反应形成化合物式V:
其中Ar是二氢苯并二氧杂环己烯基或苯并二氧杂环己烯基,或者是用直到三个独立地选自卤素,甲氧基,卤代甲基,二卤代甲基,三卤代甲基中的取代基任意取代的苯基,L是合适的基团如卤素(特别是氯或溴),甲苯磺酸酯,甲磺酸酯或p-溴苯基-磺酰基氧基。
化合物式V可以在碱存在下使用选自芳酰基氯,芳酰基溴和芳酰基酸酐的芳酰基化合物处理,形成化合物式VI:
其中芳基表示用直到三个独立地选自以下基团取代的C6-C12芳基:卤素原子,烷基,烷氧基,烷氧基羰基,硝基,氨基,烷基氨基,二烷基氨基,卤代烷基,二卤代烷基,三卤代烷基,氰基和酰胺基取代基,它们每个不多于6个碳原子。
本发明的目的是提供用于制备N-芳基哌嗪的新的中间体化合物式II。
本发明另一目的是提供用于制备N-芳基哌嗪及其中间体的新的方法。
本发明另一目的是提供制备化合物式II的新的方法。
在考虑到本文提供的本发明的详细说明和随后的权利要求书以后,本发明的其它目的和优点对于本领域的技术人员是明显的。
发明的详细说明
本发明的优选实施方案是使用N1-(2’-吡啶基)-1,2-丙烷二胺氨基磺酸制备N-芳基哌嗪的新的方法,特别是使用其中芳基是4-氰基苯基的式VI制备N-芳基哌嗪的方法。本发明的另一优选实施方案是制备N1-(2’-吡啶基)-1,2-丙烷二胺氨基磺酸(用于制备N-芳基哌嗪的新的,容易游离的固体中间体)及新的衍生物(也用于制备N-芳基哌嗪)的方法。
本发明方法的某些化合物含有一个不对称碳原子,形成化合物的对映体形式。应该理解本发明所述的对映体包括外消旋混合物。具有碱性氨原子的化合物能够和许多不同的酸形成络合物(质子酸或非质子酸)。本发明还包括和无机或有机酸通过加成反应形成的可接受的盐的形式,无机酸例如是盐酸(HCl),氢溴酸(HBr),氢碘酸(HI),硫酸,磷酸,硝酸是可用的;有机酸例如乙酸,丙酸,柠檬酸,马来酸,苹果酸,酒石酸,邻苯二甲酸,琥珀酸,甲磺酸,甲苯磺酸,萘磺酸,樟脑磺酸,苯磺酸是可用的。
在本发明的一个优选实施方案中,其中Ar是二氢苯并二氧杂环己烯基的化合物式IV通过苯胺的二烷基化制备,反应在过量氯乙醇存在下进行,随后将得到的羟基部分转化为合适的离去基团,例如Cl,Br,甲磺酸酯或甲苯磺酸酯:
另外其中Ar是二氢苯并二氧杂环己烯基的化合物式IV可以通过使用卤代乙酸烷基酯的苯胺的二烷基化反应,随后还原制备。
在本发明的优选实施方案中,其中R=CH3的式I化合物使用氨开环,同时发生立体中心的转化,得到N1-(2’-吡啶基)-1,2-丙烷二胺氨基磺酸,是很容易分离的固体。在另一实施方案中,氨基磺酸酯式I用胺例如苄基胺或二苯甲基胺开环,得到相应的氨基磺酸,得到的化合物能够在加氢条件下进行氢化反应,得到氨基磺酸,该实施方案说明如下:
其中R’是二苯甲基或苄基。
本发明的另一优选方面是N1-(2’-吡啶基)-1,2-丙烷二胺氨基磺酸能够和二甲磺酸酯偶合,形成哌嗪:
其中*表示不对称碳立体中心。
氨基磺酸部分在和二甲磺酸酯偶合步骤中作为保护基形成哌嗪,在全部合成序列中哌嗪化合物的手性保持不变。
本发明提供使用N1-(2’-吡啶基)-1,2-丙烷二胺氨基磺酸的方法,后者用于合成旋光活性的N,N’-二取代哌嗪,反应一步完成,是立体选择的,并且以简便的方式进行。旋光活性的N.N′-二取代哌嗪具有作为5-HT1A(5-羟色案)受体拮抗剂的活性。
在化合物式IV中,L可以是任何合适的离去基团,本领域的技术人员很容易确定的那些基团在实施本发明中是合适的,合适的离去基团的实例包括氯,溴,甲磺酸酯,甲苯磺酸酯,和P-溴苯基磺酰基氧基。
在本发明反应中当需要有酸、碱或溶剂存在时,任何本领域公知的合适的酸、碱或溶剂均可以使用,本领域的技术人员很容易确定合适的溶剂、酸及碱用于实施本发明。
以下实施例用于说明本发明的实施方案,但是不构成对本发明范围的限制。个别步骤的试剂和溶剂仅仅是为了说明本发明的方法被给出,可以使用本领域公知的其它试剂和溶剂代替。
实施例1:使用二苯甲基胺将氨基磺酸酯开环
往氨基磺酸酯式I(R=甲基)(8.0g,37mmol)的乙腈(64mL)溶液中加入氨基二苯基甲烷(8.1g,44mmol),于室温在氩气保护下搅拌反应混合物2天,然后温热到55℃ 8小时,过滤得到的悬浮液,用Et2O(40mL)洗涤,空气干燥得到12g(82%)上述化合物式VII,为灰白色固体。
Rr=0.31(10∶1 CHCl3∶CH3OH);
1H NMR(DMSO)δ9.77(bs,1H,OH),7.15-8.0(m,13H),6.7-6.8(m,1H),5.81(bs,1H,NH),4.1-4.3(m,2H),3.4(m,2H),1.3(d,J=4.8Hz,2H);
13C NMR(DMSO)δ155.2,146.5,137.4,136.4,129.4,129.3,129.2,129.0,128.8,128.1,127.8,127.7,127.5,127.5,126.3,116.0,114.8,62.4,57.3,53.2,50.1,14.4;IR(KBr):υmax 3432,3057,3010,2931,2836,2663,2508,2330,1599,1565,1500,1474,1433cm-1;
CHN(计算值)C 63.48 H 5.79 N 10.57,CHN(测定值)C 63.38 H 5.74 N 10.52;MP=203.5-208℃。
实施例2:氢化为氨基磺酸
二苯甲基保护的氨基磺酸式VII(5.0g,12mmol),10%Pd/C(2.1g)在EtOH(100mL)中的混合物于室温在氢气球保护下进行搅拌,2天以后通过硅藻土床过滤反应混合物,使用热EtOH(100mL)洗涤,真空浓缩得到1.98g(72%)化合物式VIII,为灰白色固体。
1H NMR(DMSO)δ8.17(d,J=3Hz,1H),7.5-7.9(m,5H),6.82(t,J=4.5Hz,1H),4.03(dd,J=10.8Hz,3.6Hz,1H),3.94(dd,J=10.8Hz,5.7Hz,1H),3.4-3.6(m,1H)1.18(d,J=5.1Hz,3H);13CNMR(DMSO)δ156.1,146.8,136.9,115.7,114.6,50.1,47.9,16.7;IR(KBr):υmax3426,3137,3073,2980,2518,1629,1588,1520,1465,1432,1366,1286,1234,1197,1146,1117,1063,1042cm-1;CHN(计算值)C 41.6 H 5.62 N 18.2,CHN(测定值)C 41.1 H 5.49 N 17.7;MP=175.5-179℃
实施例3:使用氨将氨基磺酸酯开环
氨基磺酸酯式I(R=甲基)(22g,0.11mol)和2N氨的EtOH溶液(216mL,0.432mol)的混合物于室温在氮气气氛下搅拌2天,将混合物浓缩到原来体积的1/4,过滤混合物,用Et2O(50mL)洗涤,空气干燥得到17g(72%)氨基磺酸式VIII,为灰白色固体。
实施例4:氨基磺酸的水解
氨基磺酸式VIII(0.97g,4.2mmol)于3N HCl(10mL)中的溶液于室温搅拌18小时,然后将反应混合物用6N NaOH(5mL)碱化到pH13-14,用Et2O(3×40mL)萃取,合并的有机相用Na2SO4干燥,过滤,真空浓缩得0.49g(78%)N1-(2’-吡啶基)-1,2-丙烷二胺,为黄色油状物。
1H NMR(CD3OD)δ7.8-8.0(m,2H),7.3-7.6(m,2H),6.5-6.7(m,2H),3.0-3.4(m,3H)。
实施例5:氨基磺酸和二甲磺酸酯的偶合
往二甲磺酸酯式X(30.5g,84mmol)的无水DMF(240mL)溶液中加入氨基磺酸VIII(16.2g,70mmol),碳酸钾(31.0g,224mmol)溴化锂(12.8g,147mmol),于氮气保护下在油浴中将反应混合物加热到80-83℃ 18小时,冷却到室温然后倒入3N HCl(400mL)和CHCl3(200mL)的混合物中,室温搅拌混合物1小时,然后分离两相,水层用CHCl3(2×75mL)洗涤,除去极性较小的杂质。使用5N NaOH(250mL)碱化到约pH14,碱性的水层用CHCl3(3×150mL)萃取,合并的有机相用Na2SO4干燥,过滤,真空浓缩得到23g(92%)化合物式XI,为棕色浆状物。
实施例6:形成哌嗪化合物
往二甲基磺酸酯式X(57mg,0.14mmol)的无水乙腈(1mL)溶液中加入氨基吡啶(20mg,0.13mmol),碳酸钾(52mg,0.38mmol)和溴化锂(26mg,0.30mmol),于氮气保护下将反应混合物加热到回馏15小时,冷却到室温,通过硅藻土垫过滤,将硅藻土用乙腈洗涤,合并的有机层用Na2SO4干燥,过滤,真空浓缩得到52g(105%)哌嗪XI,为黄色油状物(92%面积%GC/MS)。
实施例7:形成哌嗪二盐酸盐
往哌嗪XI(23g,65mmol)中加入1M HCl/EtOH(125mL,125mmol)溶液,真空浓缩该混合物,再溶解到CH3OH(25mL)中,慢慢加入Et2O(15mL),室温放置18小时以后得到灰白色固体,将固体过滤,用冷EtOH(5mL)洗涤,空气干燥得到4.6g化合物XI的二盐酸盐为灰白色固体。放置母液5天以后得到更多的固体,过滤,用冷EtOH(5mL)洗涤,空气干燥得到另外的3.7g化合物XI的二盐酸盐,为灰白色固体。
实施例8:哌嗪化合物的酰基化
往碳酸钾(3.4g,24.6mmol)的H2O(5mL)溶液中加入实施例7制备的二盐酸盐(3.0g,7.0mmol),然后加入EtOAc(17mL),混合物于冰浴中0-5℃搅拌15分钟,然后慢慢加入EtOAc(3.5mL)中的4-氰基苯甲酰基氯(1.3g,7.9mmol),1小时以后TLC分析指出还有少量原料,再加入4-氰基苯甲酰基氯(100mg,0.60mmol),1小时以后加入H2O(10mL)。分离两相,有机层用饱和NaCl溶液(10mL),H2O(10mL)萃取,水层用EtOAc(2×10mL)反萃取,合并的有机层用Na2SO4干燥,过滤和真空浓缩,得到3.0g(88%)化合物式XII,为黄色泡沫状物。
实施例9:苯并二噁烷苯胺烷基化形成二酯
苯并二噁烷苯胺(3.0g,20mmol),溴代乙酸乙酯(7.5mL,68mmol),Hunig′s碱(12.5mL,72mmol)和NaI(0.3g,2.0mmol)在甲苯(30mL)中的混合物加热到回馏,23小时以后将混合物冷却到室温,加入水(25mL),两相分离,水层用甲苯(25mL)萃取,合并的有机层用Na2SO4干燥,过滤,真空浓缩得到6.5g(100%)二酯,为棕色油状物。
1H NMR(CDCl3)δ6.70(t,J=8.1Hz,1H),6.3-6.6(m,2H),4.1-4.3(m,12H),1.2-1.3(m,6H)。
实施例10:苯并二噁烷二酯还原为二醇
二酯(24g,74.3mmol)在THF(240mL)中的混合物冷却到0-5℃,然后于维持反应温度10℃以下慢慢加入LAH垫衬(9.9g,260mmol),加入LAH以后移去冷却浴,于室温继续搅拌过夜,搅拌18小时以后反应混合物于冰/IPA浴中冷却到0±5℃,往反应混合物中慢慢加入水(10mL),再加入15%氢氧化钠水溶液(10mL)和水(30mL),将得到的混合物搅拌30分钟,过滤,固体用THF(100ML)洗涤,真空浓缩滤液得到14.5g(81%)二醇式IV(98面积%(LC-MS)纯度),为黏稠澄清油状物。
1H NMR(CDCl3)δ6.88-6.70(m,3H),4.34-4.22(m,4H),3.54(t,J=7.6Hz,4H),3.18(t,J=7.5Hz,4H).
实施例11:苯并二噁烷苯胺烷基化为二醇
苯并二噁烷苯胺和2-氯乙醇(210mL,3.1mol)及Hunigs碱(105mL,0.6mol)的混合物加热到120℃,12.5小时以后停止加热,将反应混合物冷却到室温,加入乙酸乙酯(300mL),溶液用于稀盐水洗涤(1×250mL),然后再用盐水(2×75mL)洗涤,合并全部水层,用K2CO3调整到pH 7,溶液用乙酸乙酯(2×100mL)反洗,合并全部有机相,用2N HCl(3×150mL)萃取,得到的水溶液用固体K2CO3中和到pH7,用乙酸乙酯(3×100mL)萃取,有机相用MgSO4干燥,浓缩和用甲苯(2×50mL)驱赶除去残留的氯乙醇,得到39.6g(80%)粗产品,为暗色油状物,94面积%(LC-MS)纯度。
1H NMR(CDCl3)δ6.88-6.70(m,3H),4.34-4.22(m,4H),3.54(t,J=7.5Hz,4H),3.18(t,J=7.5Hz,4H).
对于本领域的技术人员来说,本发明的各种变化是不需要解释的,本发明不限于本文所述的实施方案,而包括随后的权利要求书和等同物范围中的所有主题。
Claims (15)
1.制备N1-(2′-吡啶基)-1,2-烷烃二胺氨基磺酸式II的方法,包括将化合物式I和NH2R’反应:
其中R选自C1-C3烷基,R′是H,C1-C6烷基,C3-C7环烷基,C2-C7酰基,C5-C10芳基C6-C11芳酰基,(C3-C7)环烷基(C1-C6)烷基,二-(C3-C7)环烷基-(C1-C6)烷基,(C5-C10)芳基(C1-C6)烷基,和二-(C5-C10)芳基-(C1-C6)烷基。
2.按照权利要求1的方法,其中R是甲基。
4.按照权利要求3的方法,还包括化合物式III和化合物式IV反应形成化合物式V
其中Ar是二氢苯并二氧杂环己烯基或苯并二氧杂环己烯基,或者是用直到三个独立地选自卤素,甲氧基,卤代甲基,二卤代甲基,三卤代甲基中的取代基任意取代的苯基,L是合适的离去基团。
6.按照权利要求1的方法,还包括化合物式II和化合物式IV反应形成化合物式V
其中Ar是二氢苯并二氧杂环己烯基或苯并二氧杂环己烯基,或者是用直到三个独立地选自卤素,甲氧基,卤代甲基,二卤代甲基,三卤代甲基中的取代基任意取代的苯基,L是合适的离去基团。
7.按照权利要求6的方法,还包括化合物式V在碱存在下使用选自芳酰基氯,芳酰基溴和芳酰基酸酐的芳酰基化合物处理,形成化合物式VI:
其中芳基表示用直到三个独立地选自以下基团取代的C6-C12芳基:卤素原子,烷基,烷氧基,烷氧基羰基,硝基,氨基,烷基氨基,二烷基氨基,卤代烷基,二卤代烷基,三卤代烷基,氰基和酰胺基取代基,它们每个不多于6个碳原子。
8.按照权利要求7的方法,其中芳基是4-氰基苯基。
10.按照权利要求9的方法,还包括化合物式III和化合物式IV反应形成化合物式V
其中Ar是二氢苯并二氧杂环己烯基或苯并二氧杂环己烯基,或者是用直到三个独立地选自卤素,甲氧基,卤代甲基,二卤代甲基,三卤代甲基中的取代基任意取代的苯基,L是合适的离去基团。
11.按照权利要求10的方法,还包括在碱存在下使用选自芳酰基氯,芳酰基溴和芳酰基酸酐的芳酰基化合物处理化合物式V,形成化合物式VI:
其中芳基表示用直到三个独立地选自以下基团取代的C6-C12芳基:卤素原子,烷基,烷氧基,烷氧基羰基,硝基,氨基,烷基氨基,二烷基氨基,卤代烷基,二卤代烷基,三卤代烷基,氰基和酰胺基取代基,它们每个不多于6个碳原子。
12.化合物式II和化合物式IV反应形成化合物式V的方法
其中Ar是二氢苯并二氧杂环己烯基或苯并二氧杂环己烯基,或者是用直到三个独立地选自卤素,甲氧基,卤代甲基,二卤代甲基,三卤代甲基中的取代基任意取代的苯基,L是合适的离去基团。
13.按照权利要求12的方法,还包括在碱存在下使用选自芳酰基氯,芳酰基溴和芳酰基酸酐的芳酰基化合物处理化合物式V,形成化合物式VI:
其中芳基表示用直到三个独立地选自以下基团取代的C6-C12芳基:卤素原子,烷基,烷氧基,烷氧基羰基,硝基,氨基,烷基氨基,二烷基氨基,卤代烷基,二卤代烷基,三卤代烷基,氰基和酰胺基取代基,它们每个不多于6个碳原子。
15.按照权利要求14的化合物,其中R′选自H,苄基和二苯甲基。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36345702P | 2002-03-12 | 2002-03-12 | |
US60/363,457 | 2002-03-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1642916A true CN1642916A (zh) | 2005-07-20 |
CN100341854C CN100341854C (zh) | 2007-10-10 |
Family
ID=28041771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB038058421A Expired - Fee Related CN100341854C (zh) | 2002-03-12 | 2003-03-10 | 制备n1-(2’-吡啶基)-1,2-丙烷二胺氨基磺酸的方法及其用于合成生物活性哌嗪 |
Country Status (27)
Country | Link |
---|---|
US (1) | US6784294B2 (zh) |
EP (2) | EP1483243B1 (zh) |
JP (1) | JP4397693B2 (zh) |
KR (1) | KR20040091720A (zh) |
CN (1) | CN100341854C (zh) |
AR (1) | AR038932A1 (zh) |
AT (2) | ATE449073T1 (zh) |
AU (1) | AU2003220122A1 (zh) |
BR (1) | BR0308315A (zh) |
CA (1) | CA2477886A1 (zh) |
CY (1) | CY1106677T1 (zh) |
DE (2) | DE60330199D1 (zh) |
DK (1) | DK1483243T3 (zh) |
EC (1) | ECSP045291A (zh) |
ES (2) | ES2334836T3 (zh) |
HK (1) | HK1068618A1 (zh) |
IL (1) | IL163829A0 (zh) |
MX (1) | MXPA04008731A (zh) |
NO (1) | NO20044049L (zh) |
NZ (1) | NZ535170A (zh) |
PT (1) | PT1483243E (zh) |
RU (1) | RU2314294C2 (zh) |
SI (1) | SI1483243T1 (zh) |
TW (1) | TWI288642B (zh) |
UA (1) | UA80272C2 (zh) |
WO (1) | WO2003078396A1 (zh) |
ZA (1) | ZA200408213B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060223824A1 (en) * | 2000-11-28 | 2006-10-05 | Wyeth | Serotonergic agents |
CA2453837C (en) * | 2001-07-20 | 2011-10-04 | Psychogenics, Inc. | Treatment for attention-deficit hyperactivity disorder using eltoprazine and related compounds |
JP4397693B2 (ja) | 2002-03-12 | 2010-01-13 | ワイス | N1−(2’−ピリジル)−1,2−アルカンジアミンスルファミン酸の合成および生物学的に活性なピペラジンの合成におけるその使用 |
US7361773B2 (en) * | 2002-03-12 | 2008-04-22 | Wyeth | Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines |
WO2003078420A2 (en) * | 2002-03-12 | 2003-09-25 | Wyeth | Process for making chiral 1,4-disubstituted piperazines |
US20070099931A1 (en) * | 2004-03-19 | 2007-05-03 | Wyeth | Pharmaceutical dosage forms and compositions |
PA8626301A1 (es) * | 2004-03-19 | 2006-12-07 | Wyeth Wyeth | Proceso para preparar derivados de n-aril-piperazina |
US20050215561A1 (en) * | 2004-03-19 | 2005-09-29 | Krishnendu Ghosh | Pharmaceutical dosage forms and compositions |
AU2006218845A1 (en) * | 2005-03-01 | 2006-09-08 | Wyeth | Crystalline and amorphous 4-cyano-N{(2R)-2-(4-(2,3-dihydro-benzo(1,4)dioxin-5-yl)-piperazin-1-yl)-propyl}-N-pyridin-2-yl-benzamide hydrochloride |
AU2011225122B8 (en) * | 2010-03-12 | 2013-12-12 | Nippon Soda Co., Ltd. | Compound containing pyridine ring and method for producing halogenated picoline derivative and tetrazolyloxime derivative |
EP2602248A1 (en) | 2011-12-05 | 2013-06-12 | University Of Leicester | Novel pyrrole compounds |
GB201310126D0 (en) * | 2013-06-06 | 2013-07-24 | Univ Leicester | Novel pyrrole derivatives |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3586794T2 (de) | 1984-12-21 | 1993-05-27 | Duphar Int Res | Arzneimittel mit psychotroper wirkung. |
JPH01125357A (ja) | 1987-11-06 | 1989-05-17 | Dainippon Pharmaceut Co Ltd | トリペプチドの誘導体 |
MX9201991A (es) * | 1991-05-02 | 1992-11-01 | Jonh Wyeth & Brother Limited | Derivados de piperazina y procedimiento para su preparacion. |
JP3077047B2 (ja) | 1993-04-16 | 2000-08-14 | 参天製薬株式会社 | 新規ピペラジン誘導体 |
EP0763024B1 (en) * | 1994-06-03 | 2002-08-14 | JOHN WYETH & BROTHER LIMITED | Processes and intermediates for the preparation of piperazine derivatives |
GB9411099D0 (en) | 1994-06-03 | 1994-07-27 | Wyeth John & Brother Ltd | Piperazine derivatives |
GB9514901D0 (en) * | 1995-07-20 | 1995-09-20 | American Home Prod | Piperazine derivatives |
CA2251017A1 (en) | 1996-04-10 | 1997-10-16 | Mark E. Duggan | .alpha.v.beta.3 antagonists |
MXPA04008729A (es) * | 2002-03-12 | 2005-07-13 | Wyeth Corp | Proceso para sintetizacion de piperazinas n-arilicas quirales. |
JP4397693B2 (ja) | 2002-03-12 | 2010-01-13 | ワイス | N1−(2’−ピリジル)−1,2−アルカンジアミンスルファミン酸の合成および生物学的に活性なピペラジンの合成におけるその使用 |
-
2003
- 2003-03-10 JP JP2003576402A patent/JP4397693B2/ja not_active Expired - Fee Related
- 2003-03-10 WO PCT/US2003/007228 patent/WO2003078396A1/en active IP Right Grant
- 2003-03-10 NZ NZ535170A patent/NZ535170A/xx unknown
- 2003-03-10 SI SI200330817T patent/SI1483243T1/sl unknown
- 2003-03-10 MX MXPA04008731A patent/MXPA04008731A/es active IP Right Grant
- 2003-03-10 BR BR0308315-2A patent/BR0308315A/pt not_active IP Right Cessation
- 2003-03-10 US US10/385,337 patent/US6784294B2/en not_active Expired - Fee Related
- 2003-03-10 KR KR10-2004-7014252A patent/KR20040091720A/ko active IP Right Grant
- 2003-03-10 AT AT07007755T patent/ATE449073T1/de not_active IP Right Cessation
- 2003-03-10 DE DE60330199T patent/DE60330199D1/de not_active Expired - Lifetime
- 2003-03-10 CN CNB038058421A patent/CN100341854C/zh not_active Expired - Fee Related
- 2003-03-10 CA CA002477886A patent/CA2477886A1/en not_active Abandoned
- 2003-03-10 DK DK03716415T patent/DK1483243T3/da active
- 2003-03-10 AU AU2003220122A patent/AU2003220122A1/en not_active Abandoned
- 2003-03-10 DE DE60313301T patent/DE60313301T2/de not_active Expired - Lifetime
- 2003-03-10 EP EP03716415A patent/EP1483243B1/en not_active Expired - Lifetime
- 2003-03-10 EP EP07007755A patent/EP1801103B1/en not_active Expired - Lifetime
- 2003-03-10 IL IL16382903A patent/IL163829A0/xx unknown
- 2003-03-10 ES ES07007755T patent/ES2334836T3/es not_active Expired - Lifetime
- 2003-03-10 ES ES03716415T patent/ES2283762T3/es not_active Expired - Lifetime
- 2003-03-10 RU RU2004130314/04A patent/RU2314294C2/ru not_active IP Right Cessation
- 2003-03-10 AT AT03716415T patent/ATE360002T1/de not_active IP Right Cessation
- 2003-03-10 PT PT03716415T patent/PT1483243E/pt unknown
- 2003-03-10 TW TW092105099A patent/TWI288642B/zh not_active IP Right Cessation
- 2003-03-11 AR ARP030100833A patent/AR038932A1/es unknown
- 2003-10-03 UA UA20041008214A patent/UA80272C2/uk unknown
-
2004
- 2004-09-10 EC EC2004005291A patent/ECSP045291A/es unknown
- 2004-09-24 NO NO20044049A patent/NO20044049L/no not_active Application Discontinuation
- 2004-10-11 ZA ZA200408213A patent/ZA200408213B/en unknown
-
2005
- 2005-02-02 HK HK05100856A patent/HK1068618A1/xx not_active IP Right Cessation
-
2007
- 2007-06-26 CY CY20071100843T patent/CY1106677T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100341854C (zh) | 制备n1-(2’-吡啶基)-1,2-丙烷二胺氨基磺酸的方法及其用于合成生物活性哌嗪 | |
US6743920B2 (en) | Process for imidazo[4,5-c]pyridin-4-amines | |
CN1114594C (zh) | 具有d4受体选择性的哌嗪衍生物 | |
EP0693478B1 (en) | Quinoline compounds | |
SK27196A3 (en) | Bicyclic aromatic compounds as therapeutic agents | |
TW201302723A (zh) | 白三烯素生成之苯并二噁烷抑制劑 | |
KR20080021134A (ko) | 5-ht1a 수용체의 피페라진-피페리딘 길항제 및 효능제 | |
KR20110036069A (ko) | 5,6,7,8-테트라히드로-이미다조[1,5-a]피라진 화합물 | |
CN101948437A (zh) | 一种盐酸苯达莫司汀的精制方法 | |
CN101268076A (zh) | 二氮杂䓬并喹啉、其合成和中间体 | |
CN1304388C (zh) | 合成手性n-芳基哌嗪的方法 | |
JPS63156763A (ja) | 塩基性置換フェニルアセトニトリル及びカルシウム拮抗作用を有する心血管系疾患の治療剤 | |
JPWO2020132014A5 (zh) | ||
JP2007529553A (ja) | N−アリール−ピペラジン誘導体を調製する方法 | |
JPS63225356A (ja) | ジヒドロピリジン誘導体 | |
WO2006123767A1 (ja) | 不斉四置換炭素原子含有化合物の製法 | |
RU2282615C2 (ru) | Способ получения индан-1,3-дикарбоновой кислоты | |
CN102249982A (zh) | 新型截短侧耳素类化合物、其药物组合物及其制备方法和用途 | |
KR20160149561A (ko) | 5-ht7 수용체에 작용하는 바이페닐 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 약학조성물 | |
RU2795581C2 (ru) | Синтез замещенных конденсированных с гетероциклом гаммакарболинов | |
JP2001512491A (ja) | 1−(イソキノリン−1−イル)−4−(1−フェニメチル)ピペラジン;ドーパミン受容体サブタイプ特異的リガンド | |
CN116082259B (zh) | 氨基甲酸酯基或氨甲酰基取代的5-ht2b拮抗剂 | |
JP2007531775A (ja) | 高増殖状態の処置のためのキノロンカルボン酸誘導体 | |
CN106176709B (zh) | 治疗结核病用药物组合物及其制备方法 | |
JP2002504125A (ja) | ドーパミンd▲下4▼リガンドとしての2−アミノアルキルアミノキノリン |
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 | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071010 Termination date: 20100310 |