CN107163021B - 一种锅法制备2-噻吩乙醇磺酸酯的方法 - Google Patents
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- YOOFPKLWLZDAFY-UHFFFAOYSA-N sodium 2-thiophen-2-ylethanolate Chemical compound C1=CSC(=C1)CC[O-].[Na+] YOOFPKLWLZDAFY-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明公开了一种锅法制备2‑噻吩乙醇磺酸酯的方法，解决了现有技术中制备2‑噻吩乙醇时存在路线过程繁琐、成本较高、生成关键杂质3位异构体的问题。本发明包括：(1)在有机溶剂中，芳香金属化合物与环氧乙烷反应生成2‑芳香基取代的乙氧基金属化合物；(2)将2‑芳香基取代的乙氧基金属化合物直接与酰卤RZX’反应，得到2‑芳基乙醇磺酸酯；芳香金属化合物为ArM或者ArMX；乙氧基金属化合物为ArCH2CH2OM或ArCH2CH2OMX；Ar为芳香族取代基团，M为金属元素，X为卤族元素，R为C1～C4的烷基、取代的或者未取代的单环或者多环芳香族基团，Z为磺酰基或者羰基，X’为卤族元素。本发明具有反应条件简单，副反应少，不会产生关键3位杂质等优点。
Description
技术领域
本发明涉及一种2-噻吩乙醇磺酸酯的合成方法，具体涉及一种锅法制备2-噻吩乙醇磺酸酯的方法。
背景技术
2-噻吩乙醇磺酸酯是重要的医药中间体，通过它可合成氯吡格雷等重磅原料药。氯吡格雷由法国Sanofi公司研制，用于预防和治疗因血小板高聚引起的心、脑及其他动脉循环障碍疾病。
2-噻吩乙醇磺酸酯是合成氯吡格雷的关键中间体。关于2-噻吩乙醇磺酸酯的合成方法有很多文献报道，采取路线基本一致。
如美国专利US2007/225320,A1,(2007)：
但在制备2-噻吩乙醇时均采用格氏方法:
此方法需采用溴素；路线过程繁琐，采用昂贵的溴素，在制备2-噻吩乙醇会生成关键杂质3位异构体：3-噻吩乙醇，3-噻吩乙醇会在后面反应中生成3-噻吩乙醇磺酸酯从而影响产品质量。
发明内容
本发明所要解决的技术问题是：现有技术中制备2-噻吩乙醇时存在路线过程繁琐、成本较高、生成关键杂质3位异构体的问题，目的在于提供操作过程简单、绿色环保、成本低、副反应少、不会产生关键3位杂质的一种锅法制备2-噻吩乙醇磺酸酯的方法。
本发明通过下述技术方案实现：
一种锅法制备2-噻吩乙醇磺酸酯的方法，包括：
(1)在有机溶剂中，芳香金属化合物与环氧乙烷反应生成2-芳香基取代的乙氧基金属化合物；
(2)将2-芳香基取代的乙氧基金属化合物直接与酰卤RZX’反应，得到2-芳基乙醇磺酸酯；
上述芳香金属化合物为ArM或者ArMX；上述乙氧基金属化合物为ArCH2CH2OM或ArCH2CH2OMX。
进一步，所述芳香金属化合物的制备方法为：
在有机溶剂中，芳香族化合物与金属M反应生成芳香金属化合物。
本发明的化学反应式如下：
1)ArX or ArH+M→|ArMX|or|ArM|
2)[ArMX]or[ArM]+EO→[ArCH2CH2OM]or[ArCH2CH2OMX]
上述化合物中Ar为芳香族取代基团，M为元素周期表主族第一、二族金属元素，X为卤族元素，R为C1～C4的烷基、取代的或者未取代的单环或者多环芳香族基团，Z为磺酰基或者羰基，X’为卤族元素。
其中，所述芳香金属化合物为ArMX时，该ArMX为格氏试剂，通过格氏反应制备，具体反应方程式为：ArX+Mg＝ArMgX，其中，当ArX为2-氯噻吩时，即得到格氏试剂2-噻吩基氯化镁；芳基金属卤化物ArMX与EO(环氧乙烷)反应，得到2-芳基乙氧基金属卤化物ArCH2CH2OMX。当Ar＝2-噻吩基、X＝Cl(即2-氯噻吩)、M＝金属镁时，即得到2-(2-噻吩基)乙氧氯化镁。
所述的芳香金属化合物为ArM时，ArM可在电子转移试剂存在下，通过芳香烃ArH与碱金属反应制备，具体反应方程式为：ArH+M＝ArM，其中，当Ar为噻吩和其衍生物，M为金属钠时，得到2-噻吩钠。ArM与EO(环氧乙烷)在有机溶剂中反应得到2-芳基乙氧基金属化物ArCH2CH2OM。当Ar＝2-噻吩基、M＝金属钠时，即得到2-(2-噻吩基)乙氧基钠。
优选地，所述金属M、芳香族化合物、环氧乙烷、酰卤RZX’的摩尔比为1∶1～1.5∶1～1.1∶1～1.2。所述芳香族化合物与金属M反应时的温度为15～100℃，时间为1～48h。
进一步，所述有机溶剂为非质子溶剂。优选地，所述有机溶剂为正己烷，环己烷、芳香烃、四氢呋喃、2-甲基四氢呋喃或烷烃。更为优选地，所述有机溶剂选自甲苯、二甲苯、苯、四氢呋喃。
进一步，所述R选自甲基、苯基、苄基。
进一步，所述步骤(1)和步骤(2)中反应的温度均不高于15℃，反应的时间为0.5～3h。
本发明与现有技术相比，具有如下的优点和有益效果：
1、本发明所述方法操作过程简单，一锅即可合成2-噻吩乙醇磺酸酯；
2、本发明所述的方法不产生废水、废料，对环境友好，绿色环保；
3、本发明所述的方法选择性好，副反应少，不会产生关键3位杂质；
4、本发明所述的方法反应条件简单，后处理简单，绿色环保，产品质量高，生产成本低，适宜于工业化生产。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例，对本发明作进一步的详细说明，本发明的示意性实施方式及其说明仅用于解释本发明，并不作为对本发明的限定。
实施例1
一种锅法制备2-噻吩乙醇磺酸酯的方法，具体制备方法如下：
在1000ml三口烧瓶中，加入二甲苯100ml，油浴升温至内温40℃，将新鲜切割的金属钠23g分批加入反应瓶中，加毕，一次性加入噻吩109g，保温35—40℃搅拌反应5小时。撤走油浴，改用冰水降温至5℃，控温0—10℃缓慢滴加环氧乙烷46.2g,加毕，保温0—10℃反应1小时后，开始滴加185g苯磺酰氯，控制温度不操过15℃，加毕，保温反应1小时中控结束，过滤、浓缩，得2-噻吩乙醇苯磺酸酯252g,HPLC纯度96％。
实施例2
一种锅法制备2-噻吩乙醇磺酸酯的方法，具体制备方法如下：
在1000ml三口烧瓶中，加入甲苯100ml，油浴升温至内温40℃，将新鲜切割的金属钠23g分批加入反应瓶中，加毕，一次性加入噻吩126g，保温25—30℃搅拌反应4小时。撤走油浴，改用冰水降温至5℃，控温0—10℃缓慢滴加环氧乙烷46.2g,加毕，保温0—10℃反应1小时后，开始滴加126g甲基磺酰氯，控制温度不操过15℃，加毕，保温反应1小时中控结束，过滤、浓缩，得2-噻吩乙醇甲基磺酸酯190g,HPLC纯度95％。
以上所述的具体实施方式，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施方式而已，并不用于限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种一锅法制备2-噻吩乙醇磺酸酯的方法，其特征在于，具体制备方法为：
在1000ml三口烧瓶中，加入二甲苯100ml，油浴升温至内温40℃，将新鲜切割的金属钠23g分批加入反应瓶中，加毕，一次性加入噻吩109g，保温35-40℃搅拌反应5小时；撤走油浴，改用冰水降温至5℃，控温0-10℃缓慢滴加环氧乙烷46.2g，加毕，保温0-10℃反应1小时后，开始滴加185g苯磺酰氯，控制温度不操过15℃，加毕，保温反应1小时中控结束，过滤、浓缩，得2-噻吩乙醇苯磺酸酯。
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| Title |
|---|
| 《2-噻吩乙醇的合成技术及其在药物中的应用》;杨海玉等;《化学与黏合》;20071115(第6期);第436页 * |
| 《对甲苯磺酸-2-噻吩乙酯的工业化研究》;徐汉青;《广州化工》;20140423;第86页 * |
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