CN105294546B - 一种吡啶化合物及其制备方法 - Google Patents
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- 229940125904 compound 1 Drugs 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- ONHMWUXYIFULDO-UHFFFAOYSA-N 4-bromo-2-chloropyridine Chemical class ClC1=CC(Br)=CC=N1 ONHMWUXYIFULDO-UHFFFAOYSA-N 0.000 claims description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
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- 229910052794 bromium Inorganic materials 0.000 abstract 1
- UIOXUDJRTRINKJ-UHFFFAOYSA-N cyclobutane pyridine Chemical compound C1CCC1.C1=CC=NC=C1 UIOXUDJRTRINKJ-UHFFFAOYSA-N 0.000 abstract 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
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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
- C07D213/61—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及一种吡啶化合物及其制备方法，该化合物为4‑溴‑2‑环丁烷吡啶，以环丁烷甲酸为起始原料，通过4步反应合成；是制备激酶抑制剂的重要的中间体，在预防和治疗癌症方面具有广泛的应用前景；其制备方法原料便宜易得，合成方法简单，是一种合成吡啶化合物的全新方法，适合规模化工业生产的需要。
Description
技术领域
本发明涉及化合物生产领域，尤其是一种吡啶化合物及其制备方法。
背景技术
吡啶化合物是制备激酶抑制剂的重要的中间体，是预防和治疗癌症药物的关键组成部分(1)Preparation of thiazole compounds as phosphatidylinositol 3-kinaseinhibitors for the treatment of diseases，PCT Int.Appl.(2010),WO 2010029082A1；(2)Preparation of substituted urea derivatives,especially 1-thiazol-2-ylamino carbonyl pyrrolidine-2-carboxamides,as phosphatidylinositol 3-kinaseinhibitors，U.S.Pat.Appl.Publ.(2009),US 20090163469)。用该化合物做母体能进一步进行合成更为复杂的衍生物，为更广泛地研究该类化合物性质提供条件。
发明内容
本发明所要解决的技术问题在于提供一种吡啶化合物。
本发明所要解决的另一技术问题在于提供上述吡啶化合物的制备方法。
为解决上述技术问题，本发明的技术方案是：
一种吡啶化合物，4-溴-2-环丁烷吡啶，其结构式为(Ⅰ)所示，
优选的，上述吡啶化合物，4-溴-2-环丁烷吡啶的核磁共振氢谱数据为1.930-1.903(m，1H)，2.113-2.041(m,1H),2.385-2.299(m,4H),3.674-3.630(t,1H),7.284-7.266(q,1H),7.346-7.343(d,1H),8.386-8.372(d,1H)。
上述吡啶化合物的制备方法，以环丁烷甲酸为起始原料，通过4步反应合成目标化合物，具体步骤如下：
(1)环丁烷甲酸(SM)与叔丁醇生成化合物1环丁烷甲酸叔丁脂；
(2)化合物1环丁烷甲酸叔丁脂与2-氯-4-溴吡啶在六甲基二硅基胺基锂(LiHMDS)作用下进行亲核取代反应得到化合物2A和化合物2B的混合物；
(3)在三氟乙酸(TFA)下对上述步骤(2)的产物(化合物2A和化合物2B的混合物)进行水解反应得到相应的羧酸化合物，生成化合物3A和化合物3B的混合物；
(4)对步骤(3)中的产物(化合物3A和化合物3B的混合物)进行高温脱羧，得到化合物4A和化合物4B的混合物；
(5)利用制备高压液相色谱(P-HPLC)对步骤(4)中的产物(化合物4A和化合物4B的混合物)进行分离，得到目标化合物5；其中，
上述吡啶化合物的制备方法中的中间产物化合物2A，其结构式为(Ⅱ)所示，
上述吡啶化合物的制备方法中的中间产物化合物3A，其结构式为(Ⅲ)所示，
上述吡啶化合物的制备方法的具体反应方程式如下：
本发明的有益效果是：
上述吡啶化合物4-溴-2-环丁烷吡啶是制备激酶抑制剂的重要的中间体，在预防和治疗癌症方面具有广泛的应用前景；其制备方法原料便宜易得，合成方法简单，是一种合成吡啶化合物的全新方法，适合规模化工业生产的需要。
附图说明
图1为4-溴-2-环丁烷吡啶的HNMR谱图。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施方式对本发明所述技术方案作进一步的详细说明。
实施例1
4-溴-2-环丁烷吡啶的制备方法，具体步骤如下：
(1)将30g环丁烷甲酸，32g叔丁醇，7.5g 4-二甲氨基吡啶(DMAP)溶于二氯甲烷(300ml)中，降温至0-10℃；将二环己基碳二亚胺(DCC)溶于200ml二氯甲烷中，然后于0-10℃滴加至上述溶液中，半小时滴完，充分搅拌16小时；将生成的白色不溶物过滤除去，滤液分别用1.5N的盐酸(200ml*2)，水(200ml)和NaHCO3溶液(200ml*2)洗，收集有机层液体(400ml)，将上述有机相通过100-200目硅胶柱子过滤，过柱所得溶液先用水泵于35℃减压除去大部分溶剂，再用油泵在35℃下减压浓缩5-10分钟，得化合物1，34g，产率72.6％。
(2)将33g化合物1和24g 2-氯-4-溴吡啶溶于350ml无水甲苯后，氩气保护下降温至5-10℃；将300ml六甲基二硅基胺基锂(LiHMDS)慢慢滴加至上述溶液中，大约半小时滴完，温度控制在5-10℃；升温至室温,反应20小时，大部分原料反应后，用饱和氯化铵溶液(500ml)淬灭,然后分出有机层,干燥浓缩得化合物2A和化合物2B的混合物粗品50g；过柱纯化(PE：EA＝100：1出杂质，PE：EA＝80：1出产品)，得化合物2A和化合物2B的混合物20g，淡黄色油状物。TLC信息：原料Rf＝0.7，产品Rf＝0.6，展开剂：PE：EA＝10：1。
(3)将15g化合物2A和化合物2B的混合物溶于100ml二氯甲烷，滴加60ml三氟乙酸(TFA)，控制温度为小于30℃；2.5分钟滴毕，室温搅拌2.5小时，反应完毕，浓缩除去溶剂，然后将浓缩物溶于甲苯(100ml)，5％碳酸钠溶液(75ml*2)洗涤，有机层干燥浓缩得化合物3A和化合物3B的混合物。TLC信息：原料Rf＝0.8，产品Rf＝0.25，展开剂：PE：EA＝5：1；测得化合物3A和化合物3B的混合物粗品12克，棕色油状物。
(4)将12g化合物3A和化合物3B的混合物溶于150ml甲苯，升温至90℃反应，1小时后化合物3A和化合物3B反应完全后，浓缩得化合物4A和化合物4B的混合物粗品，TLC上为一个点；该粗品用制备高压液相色谱分离(乙腈+水+甲酸(体积比80:18:2))，得纯品化合物51.3g。TLC信息：原料Rf＝0.25，产品Rf＝0.80，展开剂：PE：EA(石油醚：乙酸乙酯)＝5：1；化合物4A和化合物4B的混合物粗品分离得纯品化合物5(化合物4A)1.3克，无色油状物，三步总计产率为12％。如图1所示，4-溴-2-环丁烷吡啶的HNMR谱图(CDCl3)，其氢谱数据为：1.930-1.903(m，1H)，2.113-2.041(m,1H),2.385-2.299(m,4H),3.674-3.630(t,1H),7.284-7.266(q,1H),7.346-7.343(d,1H),8.386-8.372(d,1H)。
上述具体反应方程式如下：
应用试验例
用小鼠做抗肿瘤实验，20只小鼠采用《中国普通外科杂志》第16卷第7期657-658页所述方法建立肝癌动物模型，将实施例1所得化合物4-溴-2-环丁烷吡啶100mg溶于50ml注射用水中并进行瘤内注射，每只1ml，每天一次，用药疗程为5天，试验结果显示，平均抑瘤率为85％。
上述参照具体实施方式对该一种吡啶化合物及其制备方法进行的详细描述，是说明性的而不是限定性的，可按照所限定范围列举出若干个实施例，因此在不脱离本发明总体构思下的变化和修改，应属本发明的保护范围之内。
Claims (1)
1.一种吡啶化合物的制备方法，所述吡啶化合物为4-溴-2-环丁烷吡啶，其结构式为(Ⅰ)所示，
其特征在于：
以环丁烷甲酸为起始原料，通过4步反应合成目标化合物，具体步骤如下：
(1)环丁烷甲酸与叔丁醇生成化合物1环丁烷甲酸叔丁酯；
(2)化合物1环丁烷甲酸叔丁酯与2-氯-4-溴吡啶在六甲基二硅基胺基锂作用下进行亲核取代反应得到化合物2A和化合物2B的混合物；
(3)在三氟乙酸下对上述步骤(2)的产物-化合物2A和化合物2B的混合物进行水解反应得到相应的羧酸化合物，生成化合物3A和化合物3B的混合物；
(4)对步骤(3)中的产物-化合物3A和化合物3B的混合物进行高温脱羧，得到化合物4A和化合物4B的混合物；
(5)利用制备高压液相色谱对步骤(4)中的产物-化合物4A和化合物4B的混合物进行分离，得到目标化合物5；其中，
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| US5374726A (en) * | 1992-03-03 | 1994-12-20 | Degraw; Joseph I. | Process for preparing 10-deazaaminopterins and 5,10-and 8,10-dideazaaminopterins from pteroic dicarboxylic acid diesters |
| CN102149711A (zh) * | 2008-09-10 | 2011-08-10 | 诺瓦提斯公司 | 有机化合物 |
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| US5374726A (en) * | 1992-03-03 | 1994-12-20 | Degraw; Joseph I. | Process for preparing 10-deazaaminopterins and 5,10-and 8,10-dideazaaminopterins from pteroic dicarboxylic acid diesters |
| CN102149711A (zh) * | 2008-09-10 | 2011-08-10 | 诺瓦提斯公司 | 有机化合物 |
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