CN113121550B - 一种7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备方法 - Google Patents
一种7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备方法 Download PDFInfo
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Abstract
本发明涉及有机化合物的合成技术领域,具体公开了一种普拉洛芬降解杂质7‑乙氧羰基‑5H‑苯并吡喃[2,3‑b]吡啶‑5‑酮的合成方法。该方法以5H‑苯并吡喃[2,3‑b]吡啶等为原料,经乙酰化、氧化等反应,制备得到7‑乙氧羰基‑5H‑苯并吡喃[2,3‑b]吡啶‑5‑酮。本发明反应条件温和,操作简单,收率高,所得产物纯度较高。
Description
技术领域
本发明属于制药技术领域,具体涉及一种普拉洛芬降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备方法。
背景技术
普拉洛芬[(RS)-2-(10-氢-9-噁-1-氮杂蒽-6-基)丙酸]是丙酸类非类固醇抗炎药物,其作用机制为主要抑制环氧合酶(COX)活性,阻断二十碳四烯酸衍生物的合成,抑制前列腺素的合成,缓解炎症反应,属于非甾体类抗炎药的一种。普拉洛芬滴眼液滴眼后30分钟,药物能较好流入并分布到多数眼组织,其中以结膜、角膜浓度最高,其次为巩膜、眼肌、房水、虹膜和睫状体。它的消炎作用强于阿司匹林和布洛芬等。主要用于外眼及眼前部的对症治疗(眼睑炎、结膜炎、角膜炎、巩膜炎、浅层巩膜炎、虹膜睫状体炎)。其结构如下:
普拉洛芬可能因氧化、脱羧、再氧化而产生降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮。其具体过程如下:
杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的结构式如下式Ⅳ:
该降解杂质在国内外市场上均没有销售,而对普拉洛芬原料药和相关制剂进行质量分析时需要杂质作为对照品。因此,进行7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备方法研究具重要的意义。
发明内容
本发明的目的在于提供了一种普拉洛芬降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的合成方法。
针对现有技术中的空白,本申请人对7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备方法进行了大量探索研究后发现:以5H-苯并吡喃[2,3-b]吡啶为原料,三氯化铝为催化剂,在硝基苯和二氯甲烷体系中,与乙酰氯发生乙酰化反应,制备得中间体7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶,中间体再经氧化反应制备得目标产物,其具体过程如下:
为了实现上述目的,本发明的一种普拉洛芬降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的合成方法具体步骤如下:
(1)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的制备方法,依次包括如下步骤:
A、将无水三氯化铝、溶剂二氯甲烷加入到反应容器中;
B、然后向反应容器中加入5H-苯并吡喃[2,3-b]吡啶的二氯甲烷溶液;
C、再向反应容器中加入乙酰氯的硝基苯溶液,然后在10~30℃保温反应1~2h,再升温至40~50℃反应4~6h;
D、最后向其中加入冰水淬灭反应,再用二氯甲烷萃取后,水洗,蒸除其中的二氯甲烷,剩余物加入乙醇打浆,过滤,干燥得7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶
所述原料5H-苯并吡喃[2,3-b]吡啶、乙酰氯与无水三氯化铝的摩尔比为1:(1~2.5):(2~3.5),优选为1:(1~1.4):(2~2.8),最优选1:1.2:2.4;
所述硝基苯与无水三氯化铝的用量比为1ml:(2~5)g,优选1ml:2.4g。
(2)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备方法,依次包括如下步骤:
a.将高锰酸钾、水及二氯甲烷加入到反应容器中;
b.向反应容器中滴入7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的二氯甲烷溶液,然后再向其中滴加浓硫酸,再在室温下继续反应3~5h,反应完毕,加水,分层,水洗后有机层减压浓缩至干,加入无水乙醇打浆,抽滤,得到7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮
所述步骤(2)中7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶、高锰酸钾的摩尔比为1:(1.0~2.0),优选为1:(1.0~1.2),最优选1:1.0;
进一步的,所述步骤(1)的步骤A和B中二氯甲烷的总体积与步骤(1)中硝基苯的体积比为1:(8~12),优选1:10;
进一步的,所述步骤(a)和步骤(b)中二氯甲烷的总体积与步骤(a)水的体积比为1:10~1:20,优选1:17;
进一步的,所述高锰酸钾与水的比例为3.2g:(4-10)ml,优选为3.2g:5ml;
进一步的,所述7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮与浓硫酸用量比为4.5g:(1-5)ml,优选为4.5g:2ml。
进一步的,所述浓硫酸为98wt%的浓硫酸。
与现有技术相比,本发明的有益效果是:
(1)本发明通过5H-苯并吡喃[2,3-b]吡啶乙酰化反应生成中间体7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶,再经过氧化得目标产物7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮。反应路线短、反应条件温和、操作简单、所得产物纯度及收率高,可以作为普拉洛芬原料药和相关制剂中7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮杂质检测的对照品。
(2)本发明通过5H-苯并吡喃[2,3-b]吡啶乙酰化反应生成中间体7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶。反应条件温和、操作简单、所得产物纯度及收率高。
附图说明
图1是实施例1步骤(1)制备所得目标产物7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的质谱图;
图2是实施例1步骤(2)制备所得目标产物7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的核磁共振氢谱图;
图3是实施例1步骤(2)制备所得目标产物7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的质谱图。
具体实施例方式
以下通过具体的实施例结合附图来说明本发明的技术方案。这些实施例仅用于说明本发明,其不以任何方式限制本发明要求保护的范围。
实施例1一种普拉洛芬降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的合成方法,包括如下步骤:
(1)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的制备
将38.4g无水三氯化铝、96ml二氯甲烷加入到500ml反应瓶中,然后搅拌下向其中加入5H-苯并吡喃[2,3-b]吡啶的二氯甲烷溶液(22.0g 5H-苯并吡喃[2,3-b]吡啶溶解于66ml二氯甲烷中),加毕,再控温20℃,向其中加入乙酰氯的硝基苯溶液(11.3g乙酰氯溶解于16ml硝基苯中),加毕,保温20℃反应1h,再升温至40℃反应4h,加入200ml冰水淬灭反应,分别用200ml二氯甲烷萃取2次,再分别用200ml水洗涤3次,蒸除二氯甲烷后,向剩余物中加入30ml无水乙醇打浆1h后,过滤,50℃减压干燥5h,得7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶23.3g,质谱图如图1所示,收率86.1%,产物纯度为99.8%。
MS:[M+1]+=226.2。
(2)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备
在250ml反应瓶中加入高锰酸钾3.2g,搅拌下向其中加入5ml水及40ml二氯甲烷,然后缓慢向反应液中滴加7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的二氯甲烷的溶液(步骤(1)制备的4.5g 7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶溶解于45ml二氯甲烷中),滴毕后,向其中滴加2ml浓硫酸(浓度98wt%),于室温下搅拌3h反应完毕,加水30ml,分层,水洗后有机层减压浓缩至干,向剩余物中加入30ml无水乙醇打浆1h后,过滤,50℃减压干燥5h,得到7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮4.1g,步骤(2)的收率85.2%,产物纯度99.1%。其核磁共振氢谱图和质谱图如图2和图3所示,1H-NMR(CDCl3,400MHz)δ(ppm):2.7132(3H,s);7.4839~7.5148(1H,q);7.6720~7.6940(1H,d);8.3828~8.4126(1H,ddd);8.7139~8.7408(1H,dd);8.7751~8.7894(1H,dd);8.8453(1H,s);MS:[M+1]+=240.2。
实施例2一种普拉洛芬降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的合成方法,包括如下步骤:
(1)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的制备
将32.0g无水三氯化铝、52ml二氯甲烷加入到500ml反应瓶中,然后搅拌下向其中加入5H-苯并吡喃[2,3-b]吡啶的二氯甲烷溶液(22.0g 5H-苯并吡喃[2,3-b]吡啶溶解于36ml二氯甲烷中),加毕,再控温10℃,向其中加入乙酰氯的硝基苯溶液(9.4g乙酰氯溶解于11ml硝基苯中),加毕,保温10℃反应1h,再升温至40℃反应4h,加入200ml冰水淬灭反应,分别用200ml二氯甲烷萃取2次,再分别用200ml水洗涤3次,蒸除二氯甲烷,向剩余物中加入30ml无水乙醇打浆1h后,过滤,50℃减压干燥5h,得7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶21.8g,收率80.7%,产物纯度为98.5%。
(2)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备
在250ml反应瓶中加入高锰酸钾3.8g,搅拌下向其中加入7ml水及66ml二氯甲烷,然后缓慢向反应液中滴加7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的二氯甲烷的溶液(4.5g步骤(1)的7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶溶解于74ml二氯甲烷中),滴毕后,向其中滴加3ml浓硫酸(浓度98wt%),于室温下搅拌3h,反应完毕,加水30ml,分层,水洗后有机层减压浓缩至干,向剩余物中加入30ml无水乙醇打浆1h后,过滤,50℃减压干燥5h,得到7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮3.8g,步骤(2)收率79.4%,产物纯度98.2%。
实施例3一种普拉洛芬降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的合成方法,包括如下步骤:
(1)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的制备
将44.8g无水三氯化铝、160ml二氯甲烷加入到500ml反应瓶中,然后搅拌下向其中加入5H-苯并吡喃[2,3-b]吡啶的二氯甲烷溶液(22.0g 5H-苯并吡喃[2,3-b]吡啶溶解于110ml二氯甲烷中),加毕,再控温30℃,向其中加入乙酰氯的硝基苯溶液(13.2g乙酰氯溶解于22ml硝基苯中),加毕,保温30℃反应1h,再升温至40℃反应4h,加入200ml冰水淬灭反应,分别用200ml二氯甲烷萃取2次,再分别用200ml水洗涤3次,蒸除二氯甲烷,向剩余物中加入30ml无水乙醇打浆1h后,过滤,50℃减压干燥5h,得7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶22.3g,收率82.3%,产物纯度为97.1%。
(2)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备
在250ml反应瓶中加入高锰酸钾3.2g,搅拌下向其中加入4ml水及28ml二氯甲烷,然后缓慢向反应液中滴加7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的二氯甲烷的溶液(4.5g步骤(1)制备的7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶溶解于32ml二氯甲烷中),滴毕后,向其中滴加1ml浓硫酸(浓度98wt%),于室温下搅拌3h,反应完毕,加水30ml,分层,水洗后有机层减压浓缩至干,向剩余物中加入30ml无水乙醇打浆1h后,过滤,50℃减压干燥5h,得到7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮3.9g,步骤(2)收率81.5%,产物纯度98.6%。
Claims (3)
1.一种普拉洛芬降解杂质7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的合成方法,其特征在于,所述合成方法的具体步骤如下:
(1)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的制备,依次包括如下步骤:
A、将无水三氯化铝、溶剂二氯甲烷加入到反应容器中;
B、然后向反应容器中加入5H-苯并吡喃[2,3-b]吡啶的二氯甲烷溶液;
C、再向反应容器中加入乙酰氯的硝基苯溶液,然后在10~30℃保温反应1~2h,再升温至40~50℃反应4~6h;
D、最后向其中加入冰水淬灭反应,再用二氯甲烷萃取后,水洗,蒸除其中的二氯甲烷,剩余物加入乙醇打浆,过滤,干燥得7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶
所述原料5H-苯并吡喃[2,3-b]吡啶、乙酰氯与无水三氯化铝的摩尔比为1:(1~2.5):(2~3.5);
(2)7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮的制备方法,依次包括如下步骤:
a.将高锰酸钾、水及二氯甲烷加入到反应容器中;
b.向反应容器中滴入7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶的二氯甲烷溶液,然后再向其中滴加浓硫酸,再在室温下继续反应3~5h,反应完毕,加水,分层,水洗后有机层减压浓缩至干,加入无水乙醇打浆,抽滤,得到7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮
所述步骤(2)中7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶与高锰酸钾的摩尔比为1:(1.0~2.0);
所述步骤(1)的步骤A和B中二氯甲烷的总体积与步骤(1)中硝基苯的体积比为1:(8~12);
所述步骤(a)和步骤(b)中二氯甲烷的总体积与步骤(a)水的体积比为1:10~1:20;
所述步骤(1)中硝基苯与无水三氯化铝的用量比为1ml:(2~5)g。
2.根据权利要求1所述的合成方法,其特征在于,所述步骤(a)中高锰酸钾与水的比例为3.2g:(4-10)ml。
3.根据权利要求1所述的合成方法,其特征在于,所述步骤(b)中7-乙氧羰基-5H-苯并吡喃[2,3-b]吡啶-5-酮与浓硫酸的比例为4.5g:(1~5)ml。
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