CN101056857B - 异烟酸衍生物的制备方法 - Google Patents
异烟酸衍生物的制备方法 Download PDFInfo
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Classifications
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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
- C07D213/60—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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种用于制备式Ia或Ib的化合物及其药物上可接受的加成盐的方法，其中，R为低级烷基。式Ia或Ib的化合物是用于制备作为腺苷A2a受体拮抗剂或亲代谢性谷氨酸盐受体拮抗剂的药物活性的化合物的有价值中间产物。它们的重要性在于调节细胞代谢的多个方面和调整不同中枢神经系统活动。
Description
本发明涉及一种用于制备式Ia或Ib的化合物及其药物上可接受的加成盐的方法，
其中，
R为低级烷基。
式Ia或Ib的化合物是用于制备作为腺苷A2a受体拮抗剂(adenosineA2a receptor antagonist)或代谢型谷氨酸盐受体2拮抗剂(metabotropicGlutamate receptor 2 antagonist)的药物活性的化合物的有价值中间产物。它们的重要性在于调节细胞代谢的多个方面和调节不同中枢神经系统活动(WO 01/97786、WO 03/043636和WO 02/083665)。
本发明的目的是提供一种用于由廉价初始化合物制备式Ia或Ib的异烟酸衍生物的新方法。
令人吃惊地，该目的通过如图1中所示的方法得以实现。
图1
该新方法的优点在于：其相对于本领域的已知方法(R.Johnson，T.Lovet and T.Stevens，Journal of the Chemical Society 796，1970；J.Bardhan，Journal of the Chemical Society 2223，1929；J.LoCicero and R.Johnson，Journal of the American Chemical Society，74，2094-7；1952)是简单、廉价和有效的。
该新方法包括步骤：
a)用锂二乙基酰胺将式II的化合物锂化(lithiating)为式III的锂化化合物；
b)将式III的化合物与DMF反应以制得式IV的化合物；
c)用O3和H2O2将式IV的化合物氧化以制得式Ia的化合物；
d)如果期望的话，用式ROH的醇将式Ia的化合物酯化以制得式Ib的化合物；
其中，R如上所定义。
术语“低级烷基”表示含有1～6个碳原子的饱和直链或支化烷基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、2-丁基、叔丁基等。优选的低级烷基为具有1～4个碳原子的基团。更优选的低级烷基为甲基。
术语“药物上可接受的酸加成盐”包含与无机和有机酸的盐，例如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲烷-磺酸、对-甲苯磺酸等。
步骤a)
步骤a)包括用锂化试剂如锂二乙基酰胺将式II的2，4-二甲基-吡啶锂化为式III的锂化化合物。
通常，该反应在有机溶剂中进行，例如醚、烃或THF，优选THF。
该反应温度通常范围为-70℃～0℃，优选为-70℃～-50℃。
该反应时间通常为0.5～3小时，优选1小时。
步骤b)
步骤b)包括将式III的化合物与DMF反应以制备式IV的化合物。
通常，该反应在式III的化合物的有机溶液中进行，并且加入DMF。
该反应温度通常范围为-70℃～0℃，优选为-60℃～-40℃。
该反应通常在0.5～3小时后结束，优选1小时。
步骤a)和b)的一般原理描述于J.Ragan，B.Jones，C.Meltz和J.Teixeira，Synthesis，483(4)2002中。
步骤c)
步骤c)包括用O3和H2O2将式IV的化合物氧化以制得式Ia的化合物。
步骤c的反应通常在有机溶剂中进行，例如有机酸、醇、氯代烃或酯，含有少量的水，如1～10％，优选含有5％水的乙酸。包含水避免了反应混合物中危险的过氧化物的聚积，特别是在质子溶剂存在时。该臭氧分解在0℃～50℃、优选15℃～20℃的温度范围下进行通常0.5～3小时、优选1小时。
将该反应混合物用H2O2进一步氧化，通常时间范围为0.5～3小时。
在不存在其它酸时，使用H2O2的氧化过程需要加热到30～100℃的温度范围，优选50℃。
在存在其它酸时，例如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、甲烷-磺酸、对-甲苯磺酸，优选盐酸、硫酸或甲酸，随后地使用H2O2的氧化过程可以在室温下实现。可以从臭氧分解反应开始或者之后加入H2O2。由此，通过同时提供水的存在和用于从开始的第二阶段的附加氧化剂的H2O2水溶液(优选地大约1当量，也构成～5％含水量)代替添加的水。
步骤d)
步骤d)包括用式ROH的醇将式Ia的化合物酯化以制得式Ib的化合物
使用式ROH的醇的酯化以制得式Ib的化合物通常在醇(例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、2-丁醇或叔丁醇，优选甲醇)中在无机酸或产生无机酸的物质原位地(例如SOCl2)进行。
该反应温度主要取决于所使用的醇的沸点，通常范围为60℃～150℃。
该反应时间通常在1～24小时之后结束，优选1小时。
下列实施例将详细地阐述本发明，而非限定本发明。
实施例1
二甲基-[2-(2-甲基-吡啶-4基)-乙烯基]-胺的制备
将11.05g 2，4-二甲基吡啶(0.1mol)溶解于50ml THF中。将该溶液冷却并搅拌，保持温度在-70～50℃之间。在0.25小时之内加入81.25ml nBuLi(0.13mol)。将暗红色溶液再搅拌0.5小时，随后将15.14ml二乙胺(0.145mol)一次加入，形成橙色悬浮液。0.5小时之后，加入15.5ml DMF(0.2mol)。将该棕红色溶液搅拌1小时，随后用50ml 50％饱和氯化铵水溶液淬灭。在加热到室温之后，用叔丁基甲基醚(TBME)(3×100ml)萃取反应混合物，并且将混合的有机相用50ml H2O洗涤、在Na2SO4之上干燥、过滤和在减压(45℃/450-20mbar)下浓缩，获得直接用于下一步骤的充分纯(气液色谱法(GLC)98面积％)的橙红色油状物(14.8g，91％)。
实施例2
i)2-甲基-异烟酸的制备(无其它酸，50℃)
将1.63g二甲基-[2-(2-甲基-吡啶-4基)-乙烯基]-胺(10mmol)溶解于含有1ml水的19ml乙酸中。往保持和在约15-20℃下搅拌的红色溶液中通O3(～85mmol/小时)1小时。该反应温和地放热，外观从橙色(10分钟)变为黄色溶液(15分钟)，随后由黄色(20分钟)变为白色悬浮液(30分钟)。用氩气将过量臭氧清除，直到过氧化物试验基本上为负。将1.02ml30％H2O2水溶液(10mmol)一次加入，并且将获得的黄色悬浮液在50℃下搅拌2小时，期间形成白色悬浮液。借助甲苯，在减压(45℃/100-50mbar)下除去含水的乙酸溶剂。将白色残余物在25ml叔丁基甲基醚(TBME)中在40℃下随后在室温下简短地蒸煮30分钟。将产物过滤、用TBME洗涤和在45℃/25mbar下干燥2小时：1.17g(85％)浅褐色(biege)晶体(GLC 98面积％，作为三甲基甲硅烷基酯)。
1H-NMR：(400MHz，D6DMSO)：δ＝2.54(s，3H)，7.59(dd，1H)，7.70(s，1H)，8.60(dd，1H)
ii)2-甲基-异烟酸的制备(其它酸，室温)
依据i)进行反应过程。在用氩气吹扫之后，将1.16ml 98％甲酸水溶液(30mmol)和1.02ml 30％H2O2水溶液(10mmol)一次加入，并且将该悬浮液在室温下搅拌3小时。借助甲苯在减压(45℃/80-20mbar)下除去溶剂。将残余物在25ml叔丁基甲基醚(TBME)中在40℃下随后在室温下简短地蒸煮30分钟。将产物过滤、用TBME洗涤和在45℃/25mbar下干燥2小时：1.17g浅橙色晶体(GLC 99面积％，作为三甲基甲硅烷基酯)。
iii)2-甲基-异烟酸.H2SO4的制备
依据i)在1当量30％H2O2水溶液的存在下进行臭氧分解过程(2mmol量级)。在用氩气吹扫之后，将0.12ml浓H2SO4(2.1mmol)一次加入，且将该黄色悬浮液在室温下搅拌1小时。借助甲苯在减压(45℃/80-20mbar)下除去溶剂。将残余物在5ml THF中在50℃下随后在室温下简短地蒸煮30分钟。将产物过滤、用THF洗涤和在45℃/20mbar下干燥1小时：0.43g(92％)浅黄色晶体(HPLC 82面积％，作为三甲基甲硅烷基酯)。
iv)2-甲基-异烟酸.HCl的制备
依据iii)在2mmol量级上进行反应过程。在用氩气吹扫之后，将1.1ml37％HCl水溶液(2当量)一次加入，且将该悬浮液在室温下搅拌1小时。借助甲苯在减压(45℃/80-20mbar)下除去溶剂。将残余物在5ml THF中在50℃下随后在室温下简短地蒸煮30分钟。将产物过滤、用THF洗涤和在45℃/20mbar下干燥1小时：0.33g(94％)粉色晶体(HPLC 88面积％，GLC 98面积％，作为三甲基甲硅烷基酯)。
1H-NMR：(400MHz，D6DMSO)：δ＝2.77(s，3H)，8.03(dd，1H)，8017(s，1H)，8.83(dd，1H)
实施例3
2-甲基-异烟酸甲酯的制备
依据实施例2iv)在10mmol量级上进行反应过程，但是在最初的臭氧分解步骤之后加入37％HCl水溶液(2当量)和30％H2O2水溶液(1当量)。将粗制产物在10ml MeOH中吸收，将悬浮液冷却到约5℃和小心地加入1.62ml亚硫酰氯(SOCl2)(22mmol)。将反应混合物在65℃下加热1小时，期间黄色悬浮液转化为橙色溶液。在减压(45℃/200-20mbar)下除去溶剂，并且将残余物在20ml乙酸乙酯(EtOAc)和20ml饱和NaHCO3水溶液之间分配。将水相分离并用EtOAc(2×20ml)萃取。将混合的有机相用20ml饱和NaHCO3水溶液洗涤，在Na2SO4之上干燥，过滤和在减压(45℃/150-20mbar)下浓缩，获得橙红色油状物(1.19g，79％，GLC 100面积％)。
1H-NMR：(400MHz，CDCl3)：δ＝2.63(s，3H)，3.95(s，3H)，7.63(dd，1H)，7.71(s，1H)，8.65(dd，1H)
MS：151.0(M+)
Claims (15)
1.一种用于制备式Ia或Ib的化合物及其药物上可接受的加成盐的方法，
其中
R为低级烷基，其中低级烷基表示含有1～6个碳原子的饱和直链或支化烷基；
该方法包括以下步骤：
a)用锂化试剂将式II的化合物锂化为式III的锂化化合物，
b)将式III的化合物与DMF反应以制得式IV的化合物，
c)用O3和H2O2将式IV的化合物氧化以制得式Ia的化合物；
d)如果期望的话，用式ROH的醇将式Ia的化合物酯化以制得式Ib的化合物；
其中，R如上所定义。
2.权利要求1的方法，其特征在于R为甲基。
3.权利要求1的方法，其特征在于锂化试剂为锂二乙基酰胺。
4.权利要求1的方法，其特征在于步骤a)在-70℃～0℃的温度下在有机溶剂中进行。
5.权利要求4的方法，其特征在于步骤a)中的有机溶剂为THF，温度为-70℃～-50℃。
6.权利要求1的方法，其特征在于步骤b)包括在-70℃～0℃的温度下将式III的化合物与DMF反应。
7.权利要求6的方法，其特征在于温度为-60℃～-40℃。
8.权利要求1的方法，其特征在于，在步骤c)中将0℃～50℃的温度下在含有1～10％水的有机溶剂中进行臭氧分解。
9.权利要求8的方法，其特征在于有机溶剂为乙酸，含水量为5％，温度为15℃～20℃。
10.权利要求1的方法，其特征在于，在步骤c)中，在30℃～100℃的温度下在不存在其它酸的情况下采用H2O2进行氧化。
11.权利要求10的方法，其特征在于温度为50℃。
12.权利要求1的方法，其特征在于，在步骤c)中，在室温下在存在其它酸的情况下采用H2O2进行氧化。
13.权利要求12的方法，其特征在于其它酸为盐酸、硫酸或甲酸。
14.权利要求1的方法，其特征在于步骤d)在60℃～150℃的温度下在无机酸或产生无机酸的物质的存在下在醇中进行。
15.权利要求14的方法，其特征在于所述醇为甲醇，所述产生无机酸的物质为SOCl2。
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| CN103848783B (zh) * | 2014-01-14 | 2016-05-04 | 红太阳集团有限公司 | 一种一步氧化合成2-氯烟酸的方法 |
| CN110452165B (zh) * | 2018-05-07 | 2020-09-25 | 新发药业有限公司 | 一种2-甲基吡啶-4-甲酸的制备方法 |
| CN113845502A (zh) * | 2021-11-29 | 2021-12-28 | 山东诚创蓝海医药科技有限公司 | 一种3-（苄氧基）-4-氧代-4h-吡喃-2-羧酸的制备方法 |
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| US4471957A (en) * | 1979-12-03 | 1984-09-18 | Baltimore Therapeutic Equipment Company | Method and apparatus for rehabilitation of damaged limbs |
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| CA2586931A1 (en) | 2006-05-11 |
| EP1812392B1 (en) | 2008-07-09 |
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| ATE400557T1 (de) | 2008-07-15 |
| US20060100440A1 (en) | 2006-05-11 |
| ES2309814T3 (es) | 2008-12-16 |
| CN101056857A (zh) | 2007-10-17 |
| JP4633123B2 (ja) | 2011-02-16 |
| DE602005008095D1 (de) | 2008-08-21 |
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| US7459563B2 (en) | 2008-12-02 |
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