CN107286083A - 一种2‑氯‑6‑溴‑3‑吡啶甲醛的合成方法 - Google Patents

一种2‑氯‑6‑溴‑3‑吡啶甲醛的合成方法 Download PDF

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CN107286083A
CN107286083A CN201710455280.9A CN201710455280A CN107286083A CN 107286083 A CN107286083 A CN 107286083A CN 201710455280 A CN201710455280 A CN 201710455280A CN 107286083 A CN107286083 A CN 107286083A
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徐红岩
马敬祥
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Kang (shanghai) New Medicine Research & Development Co Ltd
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • 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
    • C07D213/80—Acids; Esters in position 3
    • 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
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    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom

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Abstract

本发明涉及一种2‑氯‑6‑溴‑3‑吡啶甲醛的合成方法。主要解决现在未见其有效合成方法的技术问题。本发明合成方法包括以下步骤：2‑氯烟酸乙酯的氧化，得到化合物1；化合物1在乙腈中和三溴氧磷反应，生成化合物2；化合物2和二异丁基氢化铝反应，脂基被还原成羟基，生成化合物3；化合物3和戴斯‑马丁氧化剂反应，羟基被氧化成醛基，生成目标化合物4。作为医药中间体，2‑氯‑6‑溴‑3‑吡啶甲醛在制药行业中得到广泛应用。

Description

一种2-氯-6-溴-3-吡啶甲醛的合成方法
技术领域
本发明涉及到2-氯-6-溴-3-吡啶甲醛的合成。
背景技术
2-氯-6-溴-3-吡啶甲醛（CAS：1125410-08-3）作为医药中间体，在制药行业中得到广泛应用。但是迄今为止关于其合成方法未见公开报道。
发明内容
本发明的目的是提供一种2-氯-6-溴-3-吡啶甲醛的合成方法，主要解决现在未见其有效合成方法的技术问题。
本发明技术方案为：一种2-氯-6-溴-3-吡啶甲醛的合成方法，其特征是包括下步骤：第一步，2-氯烟酸乙酯在三氟乙酸中和过氧化氢反应，搅拌过夜，得到化合物1；第二步，化合物1在乙腈中和三溴氧磷反应，室温搅拌过夜，得到化合物2，产品在石油醚中重结晶纯化；第三步，在二氯甲烷中，化合物2和二异丁基氢化铝反应，脂基被还原成羟基，室温时盐酸溶液淬灭反应，生成化合物3，产品无需纯化，直接用于下一步反应；第四步，二氯甲烷作为溶剂，化合物3和戴斯-马丁氧化剂反应，室温搅拌过夜，羟基被氧化成醛基，生成化合物4，产物经过硅胶柱色谱分离。
合成线路如下：
。
第一步反应温度60-80℃，优选70℃；第三步反应时间为2-4小时，优选3小时，第三步反应温度-60--90℃，优选-75℃。
本发明的有益效果是：本发明合成方法设计的合成线路简单；在整个合成过程中，原料便宜，中间体和目标产物纯化简单。
具体实施方式
实施例1：
步骤1：
向三口烧瓶中加入2-氯烟酸乙酯 （50.0 g, 269.4 mmol）， 三氟乙酸 （500 mL）；在70℃中加入过氧化氢水溶液 （30%, 90 mL, 808.2 mmol）。 反应液70℃搅拌过夜。冷却至室温，减压蒸馏除去三氟乙酸，残留物用饱和碳酸氢钠溶液调pH至7-8，用水（60 mL）稀释。用乙酸乙酯（70 mL x 3）萃取，有机相合并，用饱和食盐水（70 mL）洗涤，硫酸钠干燥，过滤。滤液旋干，粗产物用硅胶柱色谱分离（石油醚：乙酸乙酯体积比 = 50:1），得到淡黄色固体，化合物1 （21.0 g, 104.2 mmol, 39%）。LC-MS (ESI): m/z 201.94 [M+H]+；
步骤2：
向三口烧瓶中加入化合物1 （21.0 g, 104.2 mmol），三溴氧磷 （35.0 g, 125.0mmol）和乙腈（400 mL）；反应液室温搅拌过夜。旋干得到粗产物，在石油醚（50 mL）中室温下重结晶得到白色固体，化合物2 （20.0 g, 76.0 mmol, 73%）。1H NMR (400 MHz, DMSO-d6):8.19 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H),1.32 (t, J = 6.8 Hz, 3H) ppm. LC-MS (ESI): m/z 263.93 [M+H]+；
步骤3：
向三口烧瓶中加入化合物2 （2.0 g, 7.6 mmol）和二氯甲烷（40 mL）；室温滴加二异丁基氢化铝甲苯溶液（1.5 M, 15 mL, 22.8 mmol），反应液-75℃搅拌3小时。反应液升至室温，加入1 N盐酸溶液（20 mL），二氯甲烷萃取（20 mL x 3）；有机相合并，用饱和食盐水（100mL）洗涤，硫酸钠干燥，过滤。 滤液旋干得到白色固体，化合物3（5.1 g, 38.6 mmol, 80%），产物直接用于下一步反应。LC-MS (ESI): m/z 221.82 [M+H]+.
步骤4：
向三口烧瓶中加入化合物3 （7.6 mmol, from last step）和二氯甲烷（46 mL）；加入戴斯-马丁氧化剂（8.8 g, 20.8 mmol），反应液室温搅拌过夜。溶剂旋干，粗产物用硅胶柱色谱分离（石油醚：乙酸乙酯体积比 = 30:1），得到白色固体，化合物4 （1.1 g, 5.0 mmol,79%）。1H NMR (400 MHz, CDCl3): 10.39 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.61(d, J = 8.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δc 188.2, 152.8, 146.3,139.5, 128.1, 127.9 ppm. GC-MS: m/z 219 [M]+。
实施例2：第一步反应温度60℃；第三步反应时间为4小时，第三步反应温度-60℃；其余同实施例1。
实施例3：第一步反应温度80℃；第三步反应时间为2小时，第三步反应温度-90℃；其余同实施例1。

Claims (5)

1.一种2-氯-6-溴-3-吡啶甲醛的合成方法, 其特征是包括以下步骤：第一步，2-氯烟酸乙酯在三氟乙酸中和过氧化氢反应，搅拌过夜，得到化合物1；第二步，化合物1在乙腈中和三溴氧磷反应，室温搅拌过夜，得到化合物2；第三步，化合物2和二异丁基氢化铝反应，脂基被还原成羟基，室温时盐酸溶液淬灭反应，生成化合物3；第四步，化合物3和戴斯-马丁氧化剂反应，室温搅拌过夜，羟基被氧化成醛基，生成化合物4；合成线路如下：
。
2.根据权利要求1所述的一种2-氯-6-溴-3-吡啶甲醛的合成方法， 其特征是第
一步反应温度为60-80℃。
3. 根据权利要求1所述的一种2-氯-6-溴-3-吡啶甲醛的合成方法， 其特征是第
三步在二氯甲烷中，-60--90℃反应2-4小时。
4. 根据权利要求1所述的一种2-氯-6-溴-3-吡啶甲醛的合成方法， 其特征是第
三步用1 N盐酸溶液。
5. 根据权利要求1所述的一种2-氯-6-溴-3-吡啶甲醛的合成方法， 其特征是第
四步在二氯甲烷中反应。
CN201710455280.9A 2017-06-16 2017-06-16 一种2‑氯‑6‑溴‑3‑吡啶甲醛的合成方法 Withdrawn CN107286083A (zh)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2010131030A1 (en) * 2009-05-14 2010-11-18 Pulmagen Therapeutics (Inflammation) Limited Pyridylurea derivatives and their therapeutic use
WO2010132999A1 (en) * 2009-05-21 2010-11-25 Chlorion Pharma, Inc. Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics
CN102199120A (zh) * 2011-04-01 2011-09-28 聊城大学 一种2,2'-联吡啶-4,4'-二甲酸的合成方法
WO2013111108A1 (en) * 2012-01-27 2013-08-01 Novartis Ag 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors
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Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010131030A1 (en) * 2009-05-14 2010-11-18 Pulmagen Therapeutics (Inflammation) Limited Pyridylurea derivatives and their therapeutic use
WO2010132999A1 (en) * 2009-05-21 2010-11-25 Chlorion Pharma, Inc. Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics
CN102199120A (zh) * 2011-04-01 2011-09-28 聊城大学 一种2,2'-联吡啶-4,4'-二甲酸的合成方法
WO2013111108A1 (en) * 2012-01-27 2013-08-01 Novartis Ag 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors
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