CN109970631A - 一种5-碘-2-吡啶乙酸的合成方法 - Google Patents
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- -1 iodo- 2- pyridylacetic acid Chemical compound 0.000 title claims abstract description 18
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 229940125904 compound 1 Drugs 0.000 claims abstract description 8
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940125782 compound 2 Drugs 0.000 claims abstract description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims abstract description 4
- 239000012312 sodium hydride Substances 0.000 claims abstract description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N anhydrous cyanoacetic acid Natural products OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 4
- 102000001332 SRC Human genes 0.000 abstract description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 239000000741 silica gel Substances 0.000 abstract description 3
- 229910002027 silica gel Inorganic materials 0.000 abstract description 3
- 108010087686 src-Family Kinases Proteins 0.000 abstract description 3
- BFNYNEMRWHFIMR-UHFFFAOYSA-N tert-butyl 2-cyanoacetate Chemical compound CC(C)(C)OC(=O)CC#N BFNYNEMRWHFIMR-UHFFFAOYSA-N 0.000 abstract description 3
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ATKULCGQSLCGEK-UHFFFAOYSA-N 2-(5-bromopyridin-2-yl)acetic acid Chemical compound OC(=O)CC1=CC=C(Br)C=N1 ATKULCGQSLCGEK-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940122924 Src inhibitor Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 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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- Pyridine Compounds (AREA)
Abstract
本发明涉及一种5‑碘‑2‑吡啶乙酸的合成方法。主要解决5‑碘‑2‑吡啶乙酸无法采用合硅胶色谱柱纯化制备的技术问题。本发明合成方法包括以下步骤：氰乙酸叔丁酯在二甲基亚砜溶液中，和氢化钠反应，生成的中间体和2‑溴‑5‑碘吡啶反应，生成化合物1；化合物1在盐酸溶液中，加热脱羧、氰基水解，生成目标化合物2；作为价格昂贵的医药中间体，5‑碘‑2‑吡啶乙酸在化学制药领域有广泛的应用前景，可用于合成KX2‑391，一种高选择性的Src激酶抑制剂。
Description
技术领域
本发明涉及到5-碘-2-吡啶乙酸（CAS：1234616-74-0）的合成方法。
背景技术
作为价格昂贵的医药中间体，5-碘-2-吡啶乙酸在化学制药领域有广泛的应用前景，可用于合成KX2-391，一种高选择性的Src激酶抑制剂。
KX2-391是一种非ATP竞争性Src抑制剂，也是第一种靶向Src激酶底物结合位点的抑制剂，最早报导于US Patent 7,300,931， 其合成方法如下：
5-溴-2-吡啶乙酸作为一种医药中间体，其合成方法和应用，已经以专利的形式报导出来，常见的合成方法是5-溴-2-碘吡啶和丙二酸脂反应，经过水解、脱羧得到；作为反应活性更大的5-碘-2-吡啶乙酸，因为其活性大，容易脱羧，不适合硅胶色谱柱纯化，无法用此方法合成。
发明内容
本发明的目的是提供一种5-碘-2-吡啶乙酸的合成方法，主要解决5-碘-2-吡啶乙酸无法采用合硅胶色谱柱纯化制备的技术问题。
本发明技术方案为：一种5-碘-2-吡啶乙酸的合成方法，其特征是包括以下步骤：第一步，氰乙酸叔丁酯在二甲基亚砜溶液中，和氢化钠反应，生成的中间体和2-溴-5-碘吡啶反应，生成化合物1；第二步，化合物1在盐酸溶液中，加热脱羧、氰基水解，生成目标化合物2。合成线路如下：
。
第一步反应125 ℃，反应时间为6小时；第二步反应在6 M盐酸中反应，反应温度为100℃，反应时间为3小时。反应后用2 M的氢氧化钠水溶液调pH = 9-10，进行萃取；再用2 M的盐酸盐调pH = 4进行抽滤干燥。
本发明的有益效果是：本发明首次报导了5-碘-2-吡啶乙酸的合成方法，化合物1经过脱羧、水解，即可得到高纯度的目标化合物2。本发明的反应线路独特，原料便宜，无需色谱柱纯化，适合于放大生产。
具体实施方式
步骤1：
向1 升三口烧瓶中加入二甲基亚砜 （500 mL），在室温时加入氢化钠 （60%，27.7 g，692 mmol），滴加氰乙酸叔丁酯（100.7 g，713 mmol），约1小时滴完，室温搅拌半小时，再加2-溴-5-碘吡啶（76.7 g，270 mmol），加热至125 ℃，反应6小时，停止加热，冷至室温后，搅拌下将反应液慢慢倒入氯化铵溶液中（150 g氯化铵溶于1.5 L水），析出固体，抽滤，水洗，将固体溶于约乙酸乙酯（2 L），饱和食盐水洗涤，有机相干燥，旋干，用乙酸乙酯和石油醚混合液（体积比1:10，200 mL）打浆，抽滤出固体，转入纸盘过夜晾干，得到黄色固体，目标化合物1（54 g，157 mmol， 58%）；
步骤2：
向1 升三口烧瓶中加入加入水（300 mL），浓盐酸（300 mL）和目标化合物1（54 g，157mmol），加热至100℃，反应3小时。黄色固体消失，反应液变为浅棕色。将反应液转至1升单口瓶，在70℃旋蒸至糊状，冷至室温，再加少量碎冰（100 g），在冰浴中，慢慢加2 M的氢氧化钠水溶液调pH = 9-10（约400 mL），用甲基叔丁基醚（200 mL）萃取两次，弃去有机相，水相抽滤后，用2 M的盐酸盐调pH = 4，析出土黄色固体，再搅拌10分钟后抽滤，用少量水洗，固体转入真空干燥箱，40 ℃真空干燥2小时，得土黄色固体，目标化合物2（30 g，114 mmol，73%）。1H NMR (400 MHz, DMSO-d6): 12.89 （s, 1 H）, 8.69 (d, J = 1.6 Hz, 1 H),8.10-8.08 (m, 1 H), 7.20 (d, J = 1.6 Hz, 1 H), 3.69 (s, 2 H)。
Claims (6)
1.一种5-碘-2-吡啶乙酸的合成方法, 其特征是：包括以下步骤：第一步，氰乙酸叔丁酯在二甲基亚砜溶液中，和氢化钠反应，生成的中间体和2-溴-5-碘吡啶反应，生成化合物1；第二步，化合物1在盐酸溶液中，加热脱羧、氰基水解，生成目标化合物2；合成线路如下：
。
2.根据权利要求1所述的一种5-碘-2-吡啶乙酸的合成方法， 其特征是：第一步反应温度125 ℃，反应时间为6小时。
3.根据权利要求1所述的一种5-碘-2-吡啶乙酸的合成方法， 其特征是：第二步在6 M盐酸中反应。
4.根据权利要求1所述的一种5-碘-2-吡啶乙酸的合成方法， 其特征是：第二步反应温度为100℃时，反应3小时。
5.根据权利要求4所述的一种5-碘-2-吡啶乙酸的合成方法， 其特征是：第二步反应后用2 M的氢氧化钠水溶液调pH = 9-10进行萃取。
6.根据权利要求5所述的一种5-碘-2-吡啶乙酸的合成方法， 其特征是：萃取后用2 M的盐酸调pH = 4进行抽滤干燥。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102939290A (zh) * | 2010-03-19 | 2013-02-20 | 辉瑞大药厂 | 2,3-二氢-1h-茚-1-基-2,7-二氮杂螺[3.6]壬烷衍生物及其作为生长激素释放肽受体的拮抗剂或反向激动剂的用途 |
| WO2015092610A1 (en) * | 2013-12-20 | 2015-06-25 | Pfizer Limited | N-acylpiperidine ether tropomyosin-related kinase inhibitors |
| CN108026045A (zh) * | 2015-05-15 | 2018-05-11 | 奥瑞基尼探索技术有限公司 | 用作RORγ调节剂的经过取代的四氢喹啉酮化合物 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102939290A (zh) * | 2010-03-19 | 2013-02-20 | 辉瑞大药厂 | 2,3-二氢-1h-茚-1-基-2,7-二氮杂螺[3.6]壬烷衍生物及其作为生长激素释放肽受体的拮抗剂或反向激动剂的用途 |
| WO2015092610A1 (en) * | 2013-12-20 | 2015-06-25 | Pfizer Limited | N-acylpiperidine ether tropomyosin-related kinase inhibitors |
| CN108026045A (zh) * | 2015-05-15 | 2018-05-11 | 奥瑞基尼探索技术有限公司 | 用作RORγ调节剂的经过取代的四氢喹啉酮化合物 |
Non-Patent Citations (1)
| Title |
|---|
| SUBOTA, ANDRII I. 等: "Scalable synthesis and properties of 7-methyl-4-azaindole", 《HETEROCYCLIC COMMUNICATIONS》 * |
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