CN112403514A - 一种用于制备嘧菌酯中间体的催化体系及嘧菌酯的制备方法 - Google Patents
一种用于制备嘧菌酯中间体的催化体系及嘧菌酯的制备方法 Download PDFInfo
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Abstract
本发明公开了一种制备嘧菌酯及其中间体的新催化体系:所述的新的催化体系为含四甲基的三级二胺类化合物和砜类的助溶剂组成的复合催化体系。本发明使用新的催化体系制备嘧菌酯及其中间体,操作简单、反应时间短、能耗低,适合大规模工业化生产。
Description
技术领域
本发明属于化工领域,涉及一种制备嘧菌酯及其中间体的催化体系,尤其涉及用此催化体系制备嘧菌酯及其中间体的方法。
背景技术
嘧菌酯是甲氧基丙烯酸酯类杀菌剂,化学名称为(E)-2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3-甲氧基丙烯酸甲酯。由于其抗菌谱广、高效、用量小,几乎对所有真菌病害如白粉病、稻瘟病、锈病、霜霉病等均有良好的活性,是目前全球应用最广的农用杀菌剂,广泛应用于作物的茎叶处理和种子处理。对其工艺研究不断有新的研究成果报道,尤其是关于其制备的催化剂,目前报道的催化剂主要有以下几类:
一、铜盐类催化剂
1992年5月29日,由帝国化学工业公司申请的原药专利中,首先化合物III转位得到化合物IV,再与水杨腈耦合得到化合物I,具体反应式如下:
制备化合物I时以DMF为溶剂,选用CuCl或CuI催化剂,化合物(IV)与水杨腈或其盐在95-100℃下反应得到化合物(I)。
该类催化剂为铜盐类催化剂,后处理困难,残留的催化剂影响产品品质,对环境造成污染,且价格昂贵,不易回收再利用。
二、杂氮二环烃及其衍生物类
第一种,含有乙桥键的杂氮二环烃及其衍生物类
WO01/72719A1公开了1,4-二氮杂二环[2.2.2]辛烷(常用商品名:DABCO)为催化剂制备嘧菌酯的一种方法,催化剂用量为底物的2-40%mol。2006年4月13日,专利CN101163682A名为用DABCO作催化剂制备嘧菌酯的方法和用于该方法的新型中间体,对DABCO用量进行降低进行了保护。这种方法是对WO9208703和EP0382375用铜盐做催化剂合成嘧菌酯方法的改进。具体路线如下所示:
CN104230821A公开了一种新的催化剂,1,4-二氮杂双环[2,2,2]辛烷-1-乙基溴化物。CN104725321A专利中提到了一类DABCO衍生物作为新的催化剂。CN107602480A公开了一种新型催化剂1-丙基三乙烯二胺溴化物,该发明采用叔胺与季铵结构双催化,提高反应的选择性。
第二种,含有甲桥键的氮杂二环类催化剂及其衍生物
CN109776428A报道了一种含有甲桥的杂氮二环类化合物或其盐、杂氮笼状化合物或其盐的催化剂,用于制备嘧菌酯及关键中间体。随着催化剂的不断地深入研究,其制备工艺及制造成本也随之增加,不适于工业化大生产。
发明内容
针对上述问题,本发明公开了一种新的催化体系,活性高、能耗低,易处理,成本较低,易于工业化。
本发明采用的技术方案为:
一种制备嘧菌酯中间体的复合催化体系,其为含四甲基的三级二胺类化合物和砜类的助溶剂中任意一种两两混合。
本发明技术方案的进一步改进在于:所述含四甲基的三级二胺类化合物包括四甲基乙二胺、四甲基丙二胺、N、N、N’N’-四甲基-1,4-丁二胺。
本发明技术方案的进一步改进在于:所述砜类的助溶剂包括二甲亚砜、环丁砜。
本发明技术方案的进一步改进在于:在缚酸剂和权利要求1-3任一项所述的制备嘧菌酯中间体的复合催化体系作用下,3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮在甲醇钠作用下与4,6-二氯嘧啶反应得到嘧菌酯中间体式III,中间体式III和与水杨腈在复合催化剂和缚酸剂作用下反应得到中间体式II,式II化合物在硫酸氢钾催化作用下脱除一分子甲醇得到嘧菌酯式I化合物,反应式如下所示:
本发明技术方案的进一步改进在于:所述的缚酸剂为碳酸钾,制备式III化合物的碳酸钾用量为底物摩尔数的0.1~1.2倍,制备式II化合物的碳酸钾用量为底物摩尔数的0.5~2倍。
本发明技术方案的进一步改进在于:式Ⅲ化合物制备过程中的反应温度为-20~30℃,式Ⅲ化合物合成式II化合物过程中的反应温度为80~110℃。
本发明技术方案的进一步改进在于:硫酸氢钾用量为底物摩尔数的2~5%,式II化合物合成式Ι化合物的反应温度为80~110℃。
本发明技术方案的进一步改进在于:制备式III化合物和式II化合物所用复合催化剂的量为底物摩尔数的0.1~50%的含四甲基的三级二胺类化合物和0.5~4倍助溶剂。
本发明技术方案的进一步改进在于:反应所用溶剂包括醋酸正丁酯、醋酸仲丁酯、甲苯和二甲苯。
由于采用了以上技术方案,本发明与现有技术相比具有如下优势:
本发明所用催化剂为复合催化体系,活性高,反应条件更温和,原料廉价易得,尤其是加入砜类的助溶剂后,反应选择性大大提高。3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮在甲醇钠作用下开环放热剧烈,需低温严格控制温度,避免产生二取代和4-氯-6-甲氧基嘧啶两个杂质,使用新的复合催化体系后,温度范围控制在30℃以下,可明显降低二取代产物和4-氯-6-甲氧基嘧啶两个副产物生成的比例,突破了传统零度以下持续的低温反应,大大节约了能耗,更适于工业化大生产。
具体实施方式
本发明公开了一种制备嘧菌酯及其中间体的复合催化体系,及应用此复合催化体系制备嘧菌酯及其中间体的方法。
一种制备嘧菌酯及其中间体的复合催化体系,为含四甲基的三级二胺类化合物和砜类的助溶剂组成的复合催化体系,含四甲基的三级二胺类化合物包括四甲基乙二胺、四甲基丙二胺、N、N、N’N’-四甲基1,4-丁二胺,砜类的助溶剂包括二甲亚砜、环丁砜。
实施例1
2-[6-氯嘧啶-4-基氧基]苯基-3,3-二甲氧基丙酸甲酯(式III)化合物的合成
氮气保护下,1L四口瓶中加入150g甲苯,13.4g(0.1mol)3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮,15.3g(0.104mol)4,6-二氯嘧啶、0.23g(0.002mol)四甲基乙二胺和10g二甲基亚砜混合催化剂,4.14g(0.035mol)碳酸钾,搅拌状态下,降温至-5℃,缓慢滴加19.5g(30%)液体甲醇钠,滴加完毕后缓慢升温至25℃保持2h,液相监测3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮<1%,加入50ml水,搅拌分液,上层有机相185.8g,含量16.58%,收率87.5%。
2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3,3-二甲氧基丙酸甲酯(式II)化合物的合成
上述有机相加入10.6g(0.089mol)水杨腈,12.08g(0.087mol)碳酸钾,0.25g(0.002mol)四甲基乙二胺和10g二甲基亚砜混合催化剂,搅拌升温至80℃,保温7h,HPLC监测,式II化合物<0.1%,将反应液降温至50~60℃,加入50ml水搅拌静置分液,得到的式II的有机相205.6g,含量18.5%,收率94.8%。
E-2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3-二甲氧基丙酸甲酯(式I)化合物的合成
上述式II化合物的有机相中加入0.36g(0.0026mol)硫酸氢钾,升温至回流保温3h,降温至50℃加入50ml水,搅拌分液,得到的有机相减压浓缩、重结晶得到嘧菌酯32.45g,含量98.1%,收率95.2%。
实施例2
2-[6-氯嘧啶-4-基氧基]苯基-3,3-二甲氧基丙酸甲酯(式III)化合物的合成
氮气保护下,1L四口瓶中加入150g甲苯,13.4g(0.1mol)3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮,15.3g(0.104mol)4,6-二氯嘧啶、0.39g(0.003mol)四甲基丙二胺和15g二甲基亚砜混合催化剂,4.14g(0.035mol)碳酸钾,搅拌状态下,降温至0℃,缓慢滴加19.5g(30%)液体甲醇钠,滴加完毕后缓慢升温至20℃保持2h,液相监测3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮<1%,加入50ml水,搅拌分液,上层有机相187.7g,含量16.61%,收率88.6%。
2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3,3-二甲氧基丙酸甲酯(式II)化合物的合成
上述有机相加入10.75g(0.09mol)水杨腈,9.77g(0.07mol)碳酸钾,0.34g(0.0026mol)四甲基丙二胺和15g二甲基亚砜混合催化剂,搅拌升温至95℃,保温5h,HPLC监测,式II化合物<0.1%,将反应液降温至50~60℃,加入50ml水搅拌静置分液,得到的式II的有机相201.4g,含量18.2%,收率95.0%。
E-2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3-二甲氧基丙酸甲酯(式I)化合物的合成
上述式II化合物的有机相中加入0.47g(0.0034mol)硫酸氢钾,升温至80℃保温6h,加入50ml水,搅拌分液,得到的有机相减压浓缩、重结晶得到嘧菌酯32.23g,含量98.3%,收率93.4%。
实施例3
2-[6-氯嘧啶-4-基氧基]苯基-3,3-二甲氧基丙酸甲酯(式III)化合物的合成
氮气保护下,1L四口瓶中加入150g甲苯,13.4g(0.1mol)3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮,15.3g(0.104mol)4,6-二氯嘧啶、0.65g(0.005mol)四甲基丙二胺和25g二甲基亚砜混合催化剂4.14g(0.035mol)碳酸钾,搅拌状态下,降温至0℃,缓慢滴加19.5g(30%)液体甲醇钠,滴加完毕后缓慢升温至25℃保持2h,液相监测3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮<1%,加入50ml水,搅拌分液,上层有机相187.8g,含量16.31%,收率87.1%。
2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3,3-二甲氧基丙酸甲酯(式II)化合物的合成
上述有机相加入10.56g(0.088mol)水杨腈,10.2g(0.074mol)碳酸钾,0.57g(0.0043mol)四甲基丙二胺和25g二甲基亚砜混合催化剂,搅拌升温至回流,保温2h,HPLC监测,式II化合物<0.1%,将反应液降温至50~60℃,加入50ml水搅拌静置分液,得到的式II的有机相198.2g,含量18.3%,收率95.6%。
E-2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3-二甲氧基丙酸甲酯(式I)化合物的合成
上述式II化合物的有机相中加入0.34g(0.0025mol)硫酸氢钾,升温至90℃保温5h,加入50ml水,搅拌分液,得到的有机相减压浓缩、重结晶得到嘧菌酯32.16g,含量98.5%,收率94.1%。
对比例(用DABCO做催化剂分别合成化合物III和II再转化为化合物I)
2-[6-氯嘧啶-4-基氧基]苯基-3,3-二甲氧基丙酸甲酯(式III)化合物的合成
氮气保护下,1L四口瓶中加入150g甲苯,13.4g(0.1mol)3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮,15.3g(0.104mol)4,6-二氯嘧啶、0.336g(0.003mol)三乙烯二胺,4.14g(0.035mol)碳酸钾,搅拌状态下,降温至-5℃,缓慢滴加19.5g(30%)液体甲醇钠,滴加完毕后15℃保温2h,液相监测3-(α-甲氧基)亚甲基苯并呋喃酮-2-(3H)-酮<1%,加入50ml水,搅拌分液,有机相浓缩得到式III的粗品38.5g,含量68.5%,收率75%。
2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3,3-二甲氧基丙酸甲酯(式II)化合物的合成
上述有机相加入10.7g(0.09mol)水杨腈,12.07g(0.087mol)碳酸钾,0.032g(0.003mol)三乙烯二胺,搅拌升温至回流,保温3h,HPLC监测,式II化合物<0.1%,将反应液降温至50~60℃,加入50ml水搅拌静置分液,得到的式II的有机相193.5g,含量14.2%,收率89.2%。
E-2-{2-[6-(2-氰基苯氧基)嘧啶-4-基氧基]苯基}-3-二甲氧基丙酸甲酯(式I)化合物的合成
上述式II化合物的有机相中加入0.36g(0.0026mol)硫酸氢钾,升温至回流保温3h,加入50ml水,搅拌分液,得到的有机相减压浓缩、重结晶得到嘧菌酯29.5g,含量98.0%,收率91.4%。
式III、II收率对比表:
式III收率(%) | 式II收率(%) | |
实施例1 | 87.5 | 94.8 |
实施例2 | 88.6 | 95.0 |
实施例3 | 87.1 | 95.6 |
对比例 | 75.0 | 89.2 |
如上表所示,从数据可看出,使用本发明选用新的催化体系后明显提高了式III反应收率,新的催化体系下不受低温反应条件的限制,可以更好控制二取代物和甲氧基氯嘧啶两个杂质的产生,提高反应的转化率。
以上详细描述了本发明的优选实施方式,但本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变形,这些变形均属于本发明的保护范围。
Claims (9)
1.一种制备嘧菌酯中间体的复合催化体系,其特征在于:其为含四甲基的三级二胺类化合物和砜类的助溶剂中任意一种两两混合。
2.根据权利要求1所述的一种制备嘧菌酯中间体的复合催化体系,其特征在于:所述含四甲基的三级二胺类化合物包括四甲基乙二胺、四甲基丙二胺、N、N、N’N’-四甲基-1,4-丁二胺。
3.根据权利要求1所述的一种制备嘧菌酯中间体的复合催化体系,其特征在于:所述砜类的助溶剂包括二甲亚砜、环丁砜。
5.根据权利要求4所述的一种制备嘧菌酯的方法,其特征在于:所述的缚酸剂为碳酸钾,制备式III化合物的碳酸钾用量为底物摩尔数的0.1~1.2倍,制备式II化合物的碳酸钾用量为底物摩尔数的0.5~2倍。
6.根据权利要求4所述的一种制备嘧菌酯的方法,其特征在于:式Ⅲ化合物制备过程中的反应温度为-20~30℃,式Ⅲ化合物合成式II化合物过程中的反应温度为80~110℃。
7.根据权利要求4所述的一种制备嘧菌酯的方法,其特征在于:硫酸氢钾用量为底物摩尔数的2~5%,式II化合物合成式Ι化合物的反应温度为80~110℃。
8.根据权利要求4所述的一种制备嘧菌酯的方法,其特征在于:制备式III化合物和式II化合物所用复合催化剂的量为底物摩尔数的0.1~50%的含四甲基的三级二胺类化合物和0.5~4倍助溶剂。
9.根据权利要求4所述的一种制备嘧菌酯的方法,其特征在于:反应所用溶剂包括醋酸正丁酯、醋酸仲丁酯、甲苯和二甲苯。
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