CN1771229A - 制备吡啶基和嘧啶基单氟化的β-酮酯的方法 - Google Patents
制备吡啶基和嘧啶基单氟化的β-酮酯的方法 Download PDFInfo
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- CN1771229A CN1771229A CN200480009687.XA CN200480009687A CN1771229A CN 1771229 A CN1771229 A CN 1771229A CN 200480009687 A CN200480009687 A CN 200480009687A CN 1771229 A CN1771229 A CN 1771229A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
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Abstract
本发明涉及制备通式(I)的吡啶基和嘧啶基单氟化的β-酮酯的方法,其中:R1代表吡啶环或嘧啶环,这些环可任选地被C3-6环烷基、C1-4烷基、C1-4烷氧基、苄基或卤原子取代;R2代表氢原子、C1-6烷基或卤原子;R3代表C1-6烷基;通过用氟与通式(II)的化合物反应,其中R1、R2和R3的定义如上述。本发明还涉及通式(I)的吡啶基和嘧啶基单氟化的β-酮酯。
Description
技术领域
本发明涉及制备吡啶基和嘧啶基单氟化的β-酮酯的方法,该β-酮酯可用作药物化合物的中间体。
发明内容
因此,本发明的目的是提供制备下式(I)的吡啶基和嘧啶基单氟化的β-酮酯的方法:
其中:R1代表吡啶环或嘧啶环,这些环可任选地被C3-6环烷基、C1-4烷基、C1-4烷氧基、苄基或卤原子取代;
R2代表氢原子、C1-6烷基或卤原子;以及
R3代表C1-6烷基;通过下式(II)化合物与氟气反应
其中R1、R2和R3与上述定义相同。
本发明的另一个目的是提供通式(I)的化合物,其中R1、R2和R3与上述定义相同,前提是通式(I)化合物不是2-氟-3-氧代-3-吡啶-4-基丙酸乙酯。
通式(I)化合物可包含一个或多个不对称碳原子。因此它们可以对映体或非对映体的形式存在。这些对映体和非对映体以及它们的混合物,包括外消旋混合物,构成本发明的一部分。
通式(I)化合物可以游离碱的形式或以酸加成盐的形式提供,它们也构成本发明的一部分。这些盐可按本领域公知的方法制备。
通式(I)化合物可用作中间体,制备如PCT/EP02/11127和PCT/EP02/11128所述的药物化合物。
按照本发明,下列的术语具有以下的含义:
-吡啶环代表2,3或4-吡啶基;
-嘧啶环代表2,4或5-嘧啶基;
-卤原子相应于氯、溴或碘原子;
-C1-6烷基代表有1-6个碳原子的直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、1,1-二甲基丙基、正己基、异己基等;
-C3-6环烷基代表有3-6个碳原子的环烷基。例子如下:环丙基、甲基环丙基、环丁基,
-烷氧基相应于0-烷基,其中烷基如上定义。
按照本发明的另一个目的,实施本发明方法来制备通式(I)的化合物,其中:
R1代表3或4-吡啶基,更优选4-吡啶基;或4-或5-嘧啶基,更优选4-嘧啶基,这些环任选地被C1-2烷基取代,和/或
R2代表氢原子或C1-3烷基;和/或
R3代表C1-3烷基;
更优选制备通式(I)的化合物,其中:
R1代表未取代的4-吡啶基或4-嘧啶基;和/或
R2代表氢原子;和/或
R3代表甲基。
按照本发明的又一个目的,实施本发明方法制备通式(I)的化合物:
-2-氟-3-氧代-3-吡啶-4-基丙酸乙酯,和
-2-氟-3-氧代-3-嘧啶-4-基丙酸乙酯。
按照本发明,氟化方法可按以下流程1进行:
流程1:
在流程1中,起始化合物(II)和反应试剂,除非另外指明,可以购买或在文献中已有叙述,或者可按照文献方法或本领域已知的方法制备。
例如,通式(II)化合物可按照PCT/EP02/11127和PCT/EP02/11128所述的方法制备。
按照流程1,通式(II)化合物(其中R1、R2和R3如通式(I)化合物的定义)可用氟气在一种或多种酸的存在下进行氟化。这些酸最好选自甲酸、三氟乙酸、硫酸、三氟甲烷磺酸和氢氟酸。该反应可在惰性溶剂(如乙腈或氯仿)中进行,或者不使用溶剂。优选该反应在氢氟酸存在下不用任何溶剂进行。
用于本发明的氟气优选用惰性气体如氮气或氦气稀释。氟在惰性气体中的浓度在1-50体积%,优选在2-25体积%,更优选5-15体积%的范围。氟对化合物(II)的比例取决于实验条件。摩尔比的范围在例如0.5-2,更优选0.7-1.5(氟:化合物(II))的范围。
反应可在以下的温度范围内进行:-78℃到50℃,优选-50℃到0℃,更优选-25℃到-7℃。
通式(I)化合物可按照本领域公知的方法分离和提纯。例如,当使用氢氟酸时,过量的酸可通过蒸发除去。可中和过量的酸,然后提取和蒸馏。
本发明的进一步的目的是提供通式(I)的化合物(其中R1、R2和R3如上述定义),前提是通式(I)的化合物不是2-氟-3-氧代-3-吡啶-4-基丙酸乙酯。更具体地,通式(I)的化合物是2-氟-3-氧代-3-嘧啶-4-基丙酸乙酯。这些化合物可用作中间体,制备在PCT/EP02/11127和PCT/EP02/11128中叙述的药物化合物如GSK3β抑制剂。
以下实施例叙述本发明方法。这些实施例不是限制性的,只是用来说明本发明。
具体实施方式
实施例1:2-氟-3-氧代-3-吡啶-4-基丙酸乙酯
1.1.程序A
冷却下将3-氧代-3-吡啶-4-基丙酸乙酯(49.13g,0.25moles)加入到无水氟化氢(AHF)(440g)中。在-20℃冰浴中使在氮气中的氟(10%)(67升,0.28moles,1.12当量)在325分钟过程中通过混合物。AHF大部分通过真空蒸发除去。反应获得褐色半固体。将粗混合物加到饱和碳酸钠溶液(800ml)中,如果需要,可加入更多的固体碳酸钠。用二氯甲烷(4×500ml)提取溶液。提取物合并,干燥(MgSO4)。在减压下除去溶剂得到褐色的油(45g)。
气体色谱显示90%的2-氟-3-氧代-3-吡啶-4-基丙酸乙酯。
1.2.程序B
冷却并搅拌下将3-氧代-3-吡啶-4-基丙酸乙酯(340.1g,1.76moles)加入到无水氟化氢(AHF)(7.0kg)中。在冷却到-9℃的混合物中搅拌通过氮气中的氟(10%)(420升,1.75moles,1.0当量),为时130分钟。从反应器取出样品,处理,然后分析,表明起始材料已完全转化。
蒸发除去AHF。得到的液体(613g)转移到容器中。容器用饱和碳酸钠溶液洗涤。这些洗涤液用来中和剩下的产物。粗产物再蒸发到氮气中过夜,使得60g的HF被蒸发出来。产物混合物用碳酸钠和水中和。加入更多的水使得体积达到9升。用二氯甲烷(5×2升已够)分步提取混合物。合并提取物,干燥(MgSO4,除去溶剂,得到褐色液体(218.5g)。
气体色谱分析显示88%的2-氟-3-氧代-3-吡啶-4-基丙酸乙酯。
1.3.粗产物的蒸馏
合并2-氟-3-氧代-3-吡啶-4-基丙酸乙酯(397.6g,含一些溶剂),并在真空下蒸馏(蒸馏头温度125℃,0.12mbar-0.4mbar)。回收的产物重量为258.4g。
气体色谱分析显示83%的2-氟-3-氧代-3-吡啶-4-基丙酸乙酯。放置时混合物开始结晶。
实施例2:2-氟-3-氧代-3-嘧啶-4-基丙酸乙酯
冷却下将3-氧代-3-嘧啶-4-基丙酸乙酯(9.98g,0.051moles)加入到无水氟化氢(AHF)(130g)中。在-20℃冰浴中使在氮气中的氟(10%)(19升,0.079moles,1.54当量)在1.5小时过程中通过混合物。样品分析表明反应已经完成(处理后的样品的气体色谱表明72%的2-氟-3-氧代-3-嘧啶-4-基丙酸乙酯),氟化在此时停止。AHF大部分通过真空蒸发除去。反应获得褐色固体(13.9g)。冷却下加入水接着加入碳酸钠中和。用二氯甲烷(3×250ml)提取溶液。提取物合并,干燥(MgSO4)。减压除去溶剂,得到褐色的油(3.35g)。
按照实施例1.3所述的方法,回收最终产物。
Claims (9)
2.如权利要求1所述的方法,其特征在于,反应在一种或多种酸存在下进行,所述酸选自甲酸、三氟乙酸、硫酸、三氟甲烷磺酸和氢氟酸。
3.如权利要求1或2所述的方法,其特征在于,在不存在任何溶剂的条件下进行反应。
4.如权利要求1或2所述的方法,其特征在于,反应在惰性溶剂乙腈或氯仿存在下进行。
5.如权利要求2或3所述的方法,其特征在于,反应在氢氟酸存在和无任何溶剂的条件下进行。
6.如上述权利要求中任一项所述的方法,其特征在于,进行反应以制备化合物(I),其中:
R1代表3或4-吡啶基或4-或5-嘧啶基,这些环可任选地被C1-2烷基取代;
R2代表氢原子或C1-3烷基;以及
R3代表C1-3烷基。
7.如上述权利要求中任一项所述的方法,其特征在于,进行反应以制备以下化合物(I):
2-氟-3-氧代-3-吡啶-4-基丙酸乙酯,或
2-氟-3-氧代-3-嘧啶-4-基丙酸乙酯。
8.如权利要求1所述的通式(I)化合物,其特征在于,前提是化合物(I)不是2-氟-3-氧代-3-吡啶-4-基丙酸乙酯。
9.如权利要求1所述的通式(I)化合物,其特征在于,该化合物是2-氟-3-氧代-3-嘧啶-4-基丙酸乙酯。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP03290568A EP1454900A1 (en) | 2003-03-07 | 2003-03-07 | Process for the preparation of pyridinyl and pyrimidinyl mono-fluorinated beta keto-esters |
EP03290568.9 | 2003-03-07 |
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CN1771229A true CN1771229A (zh) | 2006-05-10 |
CN100398518C CN100398518C (zh) | 2008-07-02 |
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CNB200480009687XA Expired - Fee Related CN100398518C (zh) | 2003-03-07 | 2004-03-05 | 制备吡啶基和嘧啶基单氟化的β-酮酯的方法 |
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US (1) | US7135569B2 (zh) |
EP (2) | EP1454900A1 (zh) |
JP (1) | JP4805809B2 (zh) |
CN (1) | CN100398518C (zh) |
AT (1) | ATE353877T1 (zh) |
DE (1) | DE602004004767T2 (zh) |
ES (1) | ES2281786T3 (zh) |
RU (1) | RU2330844C2 (zh) |
WO (1) | WO2004078725A1 (zh) |
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EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
WO2007025177A2 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
EP2377530A3 (en) | 2005-10-21 | 2012-06-20 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
US20070112017A1 (en) | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
EP2377531A2 (en) | 2006-05-09 | 2011-10-19 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
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EP0996606B1 (en) * | 1997-07-18 | 2002-01-16 | F2 Chemicals Ltd. | Catalysed fluorination of carbonyl compounds |
US6455728B1 (en) * | 1999-11-01 | 2002-09-24 | Air Products And Chemicals, Inc. | Direct fluorination process for preparing high purity 2-fluoro-1,3-dicarbonyl compounds using oxygen as a radical scavenger |
SI1430057T1 (sl) * | 2001-09-21 | 2006-02-28 | Sanofi Aventis | Substituirani 2-piridinil-6,7,8,9-tetrahidropirimido -(1,2-a)pirimidin-4-onski in 7-piridinil-2,3-dihidroimidazo -(1,2-a)pirimidin-5(1H)onski derivati |
EP1295884A1 (en) * | 2001-09-21 | 2003-03-26 | Sanofi-Synthelabo | 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]Pyrimidin-4-one and 7-Pyrimidinyl-2,3-Dihydroimidazo[1,2-a]Pyrimidin-5(1H)one derivatives |
EP1295885A1 (en) * | 2001-09-21 | 2003-03-26 | Sanofi-Synthelabo | Substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido(1,2-a)pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo(1,2-a)pyrimidin-5(1H)one derivatives |
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2003
- 2003-03-07 EP EP03290568A patent/EP1454900A1/en not_active Withdrawn
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- 2004-03-05 AT AT04717645T patent/ATE353877T1/de not_active IP Right Cessation
- 2004-03-05 JP JP2006504814A patent/JP4805809B2/ja not_active Expired - Fee Related
- 2004-03-05 CN CNB200480009687XA patent/CN100398518C/zh not_active Expired - Fee Related
- 2004-03-05 RU RU2005131007/04A patent/RU2330844C2/ru not_active IP Right Cessation
- 2004-03-05 WO PCT/EP2004/003052 patent/WO2004078725A1/en active Search and Examination
- 2004-03-05 EP EP04717645A patent/EP1603876B1/en not_active Expired - Lifetime
- 2004-03-05 DE DE602004004767T patent/DE602004004767T2/de not_active Expired - Lifetime
- 2004-03-05 ES ES04717645T patent/ES2281786T3/es not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
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US20060058526A1 (en) | 2006-03-16 |
WO2004078725A1 (en) | 2004-09-16 |
JP2006519815A (ja) | 2006-08-31 |
DE602004004767D1 (de) | 2007-03-29 |
ES2281786T3 (es) | 2007-10-01 |
ATE353877T1 (de) | 2007-03-15 |
EP1603876A1 (en) | 2005-12-14 |
RU2005131007A (ru) | 2006-06-27 |
DE602004004767T2 (de) | 2007-12-06 |
EP1454900A1 (en) | 2004-09-08 |
EP1603876B1 (en) | 2007-02-14 |
JP4805809B2 (ja) | 2011-11-02 |
RU2330844C2 (ru) | 2008-08-10 |
CN100398518C (zh) | 2008-07-02 |
US7135569B2 (en) | 2006-11-14 |
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