CN117326992A - 一种氨苯砜的合成方法 - Google Patents
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Abstract
本发明公开了一种氨苯砜的合成方法,属于氨苯砜合成技术领域,过程包括:向反应釜中加入二氯甲烷和乙酰苯胺,搅拌下分批加入无水三氯化铝和氯化亚砜,搅拌反应结束后,分批倒入水中,搅拌,过滤得到中间体1;中间体1与乙酸、钨酸钠、双氧水在控温搅拌反应结束后,加入到水中搅拌,过滤得到中间体2;中间体2在碱性条件下水解得到固体溶解在盐酸中,用活性炭脱色,中和后得粗品,用醇溶剂结晶得到氨苯砜,有关物质小于0.1%。
Description
技术领域
本发明涉及氨苯砜合成技术领域,更具体地说是涉及一种氨苯砜的合成方法。
背景技术
氨苯砜,化学名为4,4-二氨基二苯砜,结构与磺胺药近似。它既可用作环氧树脂固化中的硬化剂也可用作人或动物细菌感染的治疗剂,自1963年起被食品与药品管理局批注为抗生素。关于其在人类医学中的用途,氨苯砜事实上是一种用于麻风病治疗初期的有效抗生素,也用作疱疹状皮痒的抑制剂。
1945年Hans Heymann和Louis F.Fieser发表了由氯苯经浓硫酸缩合后得到氯苯砜,再用氨基代氯得到氨苯砜。针对结构中砜的合成开发出傅克反应法、硫醚氧化法等。针对结构中氨基,开发出硝基还原法、氨基脱保护法等。这些合成方法中,最具代表性的主要有2个:高压取代氯法和常压氨基脱保护法。高压法的弊端就是对反应条件要求高,需要40kg压力。常压法的优势是对设备要求低,不足之处是起始物料乙酰苯胺比氯苯贵。随着对化工产业管制越来越严,高压设备越来越难以获批,因此,常压法能显现出一定的优势。
因此,如何提供一种氨苯砜的合成方法是本领域技术人员亟需解决的问题。
发明内容
有鉴于此,本发明提供了一种氨苯砜的合成方法。
为了实现上述目的,本发明采用如下技术方案:
一种氨苯砜的合成方法,过程包括:
1)向反应釜1中加入二氯甲烷和乙酰苯胺,搅拌下分批加入无水三氯化铝和氯化亚砜,搅拌,分批倒入水中,搅拌,过滤,洗涤,滤干,鼓风干燥,得到中间体1;其中,乙酰苯胺:无水三氯化铝:氯化亚砜的摩尔比例为1:1.5~3:0.40~0.70,优选比例为1:2:0.55;该过程得到中间体1。
反应式为:
2)向反应釜2中加入中间体1、乙酸、钨酸钠、双氧水,室温机械搅拌,缓慢升温到90℃,保持30~60min,待反应温度降到约50℃,将反应体系加入到水中,搅拌,过滤得到中间体2;其中,中间体1:钨酸钠:双氧水摩尔比为1:0.01~0.1:2.0~3.0,优选比例为1:0.026:2.24。
反应式为:
3)向反应釜3中加入多元醇、水、氢氧化钠,混合后,加入中间体2,加热搅拌至澄清后,停止加热,降温析晶,过滤得到固体;其中,中间体2:氢氧化钠摩尔比为1:2~10,优选为1:4.17;
4)将固体加入到反应釜4中,加入1.5倍水、浓盐酸,待固体溶解澄清后,加入活性炭,搅拌,过滤,洗涤,合并滤液,搅拌下调节碱性,过滤,纯水洗涤,滤干、得粗品,提纯,得到氨苯砜。
反应式为
优选地,步骤1)中,乙酰苯胺:无水三氯化铝:氯化亚砜摩尔比为1:1.5~3:0.40~0.70,优选比例为1:2:0.55;。
优选地,步骤2)中,控温过程分为二个阶段,室温搅拌和升温搅拌。室温搅拌时间为30~60min,升温搅拌时间为2小时达到90℃,并在90℃保持30~60min。
优选地,步骤3)中,中间体2:氢氧化钠摩尔比为1:2~10,优选为1:4.17;多元醇为乙醇、丙醇、异丙醇,优选为乙醇。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1制备氨苯砜
合成路线总体为:
步骤一
在1L茄型瓶中加入360ml二氯甲烷,121.5g乙酰苯胺,搅拌下分批加入无水三氯化铝120g,然后加入氯化亚砜36ml,再加入无水三氯化铝120g。搅拌9小时后,分批倒入2.5升水中,搅拌,过滤,水洗涤,滤干,55℃鼓风干燥,得到中间体1,122.3g,收率43.0%,含量86.45%(面积归一化法),本步骤是形成双苯环过程,反应效率最高只能到50%,目前是43.0%,相当于86%收率;
步骤二:
在1L三口瓶中加入中间体1,122.3g,4.5倍乙酸550ml(也可以是4倍,只要搅拌功率够大),钨酸钠3.0克,双氧水98ml,室温机械搅拌30min。然后油浴到50℃,待油浴达到50℃,再升温到90℃,保持30min,油浴温度会短时间冲到96℃左右,无影响。待油浴温度降到50℃左右,加入到550*4=2200ml水中,搅拌,过滤,水洗涤,滤干,55℃烘干,得到中间体2,102.2g,收率79.5%,含量96.08%(面积归一化法)。
步骤三:
在1L茄型瓶中加入290ml乙醇,290ml水,氢氧化钠(102.2/2=51.1g),配好后,加入中间体2,102.2g,水浴75℃,大约30分钟澄清,待澄清后,搅拌1小时,移去水浴,室温搅拌,结晶。过滤,水洗得到固体,转移到烧杯中,加入(1.5倍)153ml水,浓盐酸约75ml,使固体溶解澄清后,加入活性炭10.2g,搅拌10min,过滤,滤饼用少量10%盐酸洗涤,合并滤液,搅拌下用氨水调节碱性,得到大量固体。过滤,纯水洗涤,滤干,烘干得到氨苯砜粗品59.7g。粗品的纯度通常是只有一个杂质大于0.1%。粗品加3倍甲醇,2倍水,即180ml甲醇,120ml水于65℃打浆1小时,待室温过滤后得到53.6g固体,再用倍甲醇,即268ml甲醇重结晶得到氨苯砜36.2g,本步骤收率47.4%,含量大于99.9%(面积归一化法),有关物质<0.1%,达到药品申报要求。
对比例1
称取1克中间体1,分别用甲醇、乙醇、二氯甲烷、DMF、四氢呋喃、乙腈、1,4-二氧六环各20ml,加热溶解,微溶。在乙酸中能溶。
对比例2
在1L三口瓶中加入中间体1,122.3g,4.5倍乙酸550ml(也可以是4倍,只要搅拌功率够大),钨酸钠3.0克,双氧水98ml,室温机械搅拌30min。然后油浴到50℃,保持6h,加入到550*4=2200ml水中,搅拌,过滤,水洗涤,滤干,55℃烘干,得到中间体2,107.1g,收率87.6%,含量81.35%(面积归一化法)。
本说明书中各个实施例采用递进的方式描述,每个实施例重点说明的都是与其他实施例的不同之处,各个实施例之间相同相似部分互相参见即可。
对所公开的实施例的上述说明,使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (3)
1.一种氨苯砜的合成方法,其特征在于,过程包括:
1)向反应釜1中加入二氯甲烷和乙酰苯胺,搅拌下分批加入无水三氯化铝和氯化亚砜,搅拌反应,分批倒入水中,搅拌,过滤得到中间体1;其中,乙酰苯胺:无水三氯化铝:氯化亚砜摩尔比为1:1.5~3:0.40~0.70,优选比例为1:2:0.55;
2)中间体1在乙酸中与钨酸钠、双氧水,控温搅拌结束后,加入到水中,搅拌,得到中间体2;其中,中间体1:钨酸钠:双氧水摩尔比为1:0.01~0.1:2.0~3.0,优选比例为1:0.026:2.24;
3)中间体2与醇、水、氢氧化钠,加热水解得到固体;其中,中间体2、氢氧化钠摩尔比为:1:2~10,优选为1:4.17;
4)将固体加入到反应釜中,加入1.5倍水、浓盐酸,待固体溶解澄清后,加入活性炭脱色得到滤液调节碱性,过滤,得粗品,经醇溶剂结晶,得到氨苯砜。
2.根据权利要求2所述的一种氨苯砜的合成方法,其特征在于,步骤2)中,控温过程分为二个阶段,室温搅拌和升温搅拌。室温搅拌时间为30~60min,升温搅拌时间为2小时达到90℃,并在90℃保持30~60min。
3.根据权利要求3所述的一种氨苯砜的合成方法,其特征在于,步骤3)中,醇为乙醇、丙醇、异丙醇,优选为乙醇。
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