CN109293587B - 氯法齐明及其中间体的制备方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
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- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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Abstract
本发明公开了以3‑氨基‑10‑(4‑氯苯基)‑2(4‑氯苯基亚胺)‑2‑10‑二氢吩嗪为原料于酸性条件下,在30~50℃下反应36~96小时得到2‑氨基‑4’‑氯二苯胺,其进行自身缩合反应,获得N,5‑双(4‑氯苯基)‑3‑亚氨基‑3,5‑二氢吩嗪‑2‑胺,再与异丙胺反应生成氯法齐明。采用本方法可以回收利用工业化过程中产生的大量废弃的3‑氨基‑10‑(4‑氯苯基)‑2(4‑氯苯基亚胺)‑2‑10‑二氢吩嗪,避免了原辅料的浪费,不仅可以大幅降低生产成本,还可以发展循环生产,起到节约资源及保护环境的目的。
Description
技术领域
本发明涉及氯法齐明及其中间体制备方法,属于医药技术领域。
背景技术
氯法齐明化学名称为10-(对-氯苯基)-2,10-二氢-3-(对-氯苯氨基)-2-异丙亚氨基吩嗪,其化学式如下:
氯法齐明用于治疗菌检阳性的各型麻风患者,能控制反复发作的麻风反应。对瘤型麻风和其他类型的麻风有一定的疗效,对砜类耐药的麻风病亦有效,常与利福平、乙硫异烟胺或丙硫异烟胺合并应用。另对结核、结节性红斑、痤疮、脓疮性皮肤病、类天疱疮、坏死性皮肤病等也有疗效。皮肤病如盘状红斑狼疮、坏疽性脓皮症、掌跖脓疱病等。
下式化合物3是氯法齐明氨基物,其是制备氯法齐明粗品的关键中间体,其在三氯化铁、盐酸体系中生成化合物4氯法齐明缩合物。化合物4与异丙胺进行亲核取代反应生成氯法齐明。
上述制备氯法齐明缩合物的方法不可避免的会生成杂质化合物2,其是氯法齐明缩合物的异构体。现有技术中鲜有文献提到如何处理氯法齐明缩合物异构体,在工业化生产过程中造成原辅料的浪费,为此亟待一种新的技术方案,以提高原辅料利用率,减少资源浪费和环境保护,最大限度降低生产成本,使其更有利于大规模工业生产。
发明内容
本发明提供一种化合物3氯法齐明氨基物的制备方法,其特征在于,包括以下步骤:以化合物2或其药用盐为原料,在酸存在下,经反应得化合物3,反应式如下:
所述的原料是指E构型的氯法齐明缩合物或其药学上可接受的盐。
因缩合物和其异构体性质相近,分离较难,而异构体和氯法齐明在溶剂中存在溶解度差异,因此选择将缩合物粗品直接投入下一步反应,在制备氯法齐明的时去杂,在母液中回收缩合物异构体。
所述反应在有机溶剂中或在无有机溶剂条件下发生;
当有溶剂参加反应时,所述有机溶剂选自醚、醇或它们的混合。其中,醚选自甲基叔丁基醚,四氢呋喃,二氧六环,异丙醚;醇选自甲醇,乙醇,异丙醇,正丁醇。所述氯法齐明缩合物异构体或其盐与有机溶剂的摩尔体积比为1:0.5~1:30,优选1:5~1:15。
所述酸是酸性水溶液,是选自盐酸,硫酸,三氟乙酸,乙酸,硝酸,磷酸的水溶液;优选硫酸、三氟乙酸和磷酸的水溶液。
上述酸性水溶液的浓度为2mol/L~5mol/L;
所述化合物2或其盐与酸的投料摩尔比为1:2~1:10。
所述反应的温度为20~70℃,优选30-50℃;反应的时间为24~96小时;优选36~96小时。
反应结束后先蒸馏反应液,调碱后萃取化合物3,对萃取液进行浓缩,得到残渣固体,对所述残渣固体进行重结晶即可获得化合物3。
本发明还提供一种氯法齐明的制备方法,其特征在于:以氯法齐明缩合物异构体为原料在酸存在下反应得到化合物3,化合物3进行缩合反应得到化合物4,化合物4继续与异丙胺反应得到氯法齐明。反应式如下:
所述的缩合反应是指化合物3进行两分子自身脱氢偶联反应。
与现有技术相比,本发明体系的技术优点体现在以下几个方面:
(1)本发明提供的技术方案采用的起始原料化合物2,是现有技术制备化合物4过程中的固废或杂质,是一种“变废为宝”的清洁生产技术方案,可以大幅提高现有技术制备氯法齐明原辅料利用率,节约资源及保护环境,不但可以降低成本,亦可以使氯法齐明的生产可循环化。
(2)本发明提供的技术方案是以化合物2为起始原料,采用简单的反应条件即可制备获得化合物3,无需使用制备色谱或层析柱分离,相较于现有技术制备化合物3的方案具有合成线路步骤短(只需一步即可同时获得化合物3),收率高,成本低,更易于规模化工业生产的优势。
具体实施方式
下方实施例进一步说明本发明。这些实施例说明根据本发明制备氯法齐明中间体及氯法齐明的优选备选方案,它们专用于说明目的,不在任何方面限制本发明的范围。
实施例1
3-氨基-10-(4-氯苯基)-2(4-氯苯基亚胺)-2-10-二氢吩嗪的制备
向烧瓶中加入80g 2-氨基-4’-氯二苯胺、500ml甲醇、500ml 30%三氯化铁溶液,升温至60-70℃反应3-4小时,反应结束后降温至0℃过滤得滤饼,烘干,得到氯法齐明缩合物粗品(化合物4,其包含约20%的化合物2)。将烘干后的滤饼加入到烧瓶中,加入50g异丙胺、500ml二氧六环,回流反应12-14小时,反应结束,将反应液浓缩至干,向烧瓶中加入500ml甲醇和50ml二氯甲烷的混合溶液回流打浆2小时,0℃析晶2小时,过滤,得滤饼,即是氯法齐明粗品(化合物1)61g,收率70.4%,纯度99.0%。将过滤所得母液浓缩至干,加入50ml甲醇回流,降温析晶,过滤、烘干,得到12g标题化合物即化合物2,收率15.0%,纯度92.5%。
实施例2
2-氨基-4’-氯二苯胺的制备
取氯法齐明缩合物异构体30g、加入150ml 5mol/L硫酸、150ml甲醇、150ml二氧六环,升温至40℃,反应72小时,将反应浓缩至无液体流出,加入150ml甲苯,用饱和碳酸钠调至中性,分层,水相用150ml甲苯继续萃取一遍,合并甲苯层,浓缩有机相至剩余约150ml甲苯,升温至80℃,保温搅拌1h,降温析晶,室温保温搅拌,过滤,得27.0g 2-氨基-4’-氯二苯胺。收率88.8%,纯度98.5%
实施例3
2-氨基-4’-氯二苯胺的制备
取氯法齐明缩合物异构体30g、加入300ml 5mol/L三氟乙酸、300ml甲醇,升温至30℃,反48小时,将反应浓缩至无液体流出,加入150ml甲苯,用饱和碳酸钠调至中性,分层,水相用150ml甲苯继续萃取一遍,合并甲苯层,浓缩有机相至剩余约150ml甲苯,升温至80℃,保温搅拌1h,降温析晶,室温保温搅拌,过滤,得24g 2-氨基-4’-氯二苯胺,收率78.9%,纯度95.2%。
实施例4
2-氨基-4’-氯二苯胺的制备
取氯法齐明缩合物异构体30g、加入300ml 3mol/L硫酸,升温至40℃,反36小时,将反应浓缩至无液体流出,加入150ml甲苯,用饱和碳酸钠调至中性,分层,水相用150ml甲苯继续萃取一遍,合并甲苯层,浓缩有机相至剩余约150ml甲苯,升温至50℃,保温搅拌1h,降温析晶,室温保温搅拌,过滤,得21g 2-氨基-4’-氯二苯胺,收率69.0%,纯度96.3%。
实施例5
10-(对-氯苯基)-2,10-二氢-3-(对-氯苯氨基)-2-异丙亚氨基吩嗪的制备
取氯法齐明缩合物异构体30g、加入60ml 2mol/L盐酸、60ml二氧六环,升温至50℃,反应96小时,将反应浓缩至无液体流出,加入150ml甲苯,用饱和碳酸钠调至中性,分层,水相用150ml甲苯继续萃取一遍,合并甲苯层,浓缩有机相至剩余约150ml甲苯,升温至80℃,保温搅拌1h,降温析晶,室温保温搅拌,过滤,得25g 2-氨基-4’-氯二苯胺。将该产物在氯化铁催化下自身脱氢偶联成氯法齐明缩合物,并与异丙胺反应生成氯法齐明18.9g,收率57.6%,纯度93.1%。
Claims (23)
2.根据权利要求1所述的制备方法,其特征在于,所述的化合物2来源于制备氯法齐明的母液。
3.根据权利要求1所述的制备方法,所述反应在有机溶剂中或在无有机溶剂条件下发生。
4.根据权利要求3所述的制备方法,所述化合物2或其盐与有机溶剂摩尔体积比为1:5~1:15。
5.根据权利要求3所述的制备方法,所述有机溶剂选自醚、醇或它们的混合。
6.根据权利要求5所述的制备方法,其中,所述醚选自甲基叔丁基醚,四氢呋喃,二氧六环,异丙醚;醇选自甲醇,乙醇,异丙醇,正丁醇。
7.根据权利要求1所述的制备方法,所述酸性水溶液是选自盐酸、硫酸、三氟乙酸、乙酸、硝酸或磷酸的水溶液。
8.根据权利要求7所述的制备方法,所述酸性水溶液是选自硫酸、三氟乙酸或磷酸的水溶液。
9.根据权利要求1或7所述的制备方法,其特征在于,所述酸性水溶液的浓度为2mol/L~5mol/L。
10.根据权利要求1所述的制备方法,其特征在于,所述化合物2或其盐与酸的投料摩尔比为1:2~1:10。
11.根据权利要求1所述的制备方法,其特征在于,反应的温度为30~50℃。
12.根据权利要求1所述的制备方法,其特征在于,反应的时间为36~96小时。
14.根据权利要求13所述的制备方法,其特征在于,所述的化合物2来源于制备氯法齐明的母液。
15.根据权利要求13所述的制备方法,所述化合物2制备化合物3的反应在有机溶剂中或在无有机溶剂条件下发生。
16.根据权利要求15所述的制备方法,所述化合物2或其盐与有机溶剂摩尔体积比为1:5~1:15。
17.根据权利要求15所述的制备方法,所述有机溶剂选自醚、醇或它们的混合。
18.根据权利要求17所述的制备方法,其中,所述醚选自甲基叔丁基醚,四氢呋喃,二氧六环,异丙醚;醇选自甲醇,乙醇,异丙醇,正丁醇。
19.根据权利要求13所述的制备方法,所述酸性水溶液是选自盐酸、硫酸、三氟乙酸、乙酸、硝酸或磷酸的水溶液。
20.根据权利要求13或19所述的制备方法,其特征在于,所述酸性水溶液的浓度为2mol/L~5mol/L。
21.根据权利要求13所述的制备方法,其特征在于,所述化合物2或其盐与酸的投料摩尔比为1:2~1:10。
22.根据权利要求13所述的制备方法,其特征在于,所述化合物2制备化合物3的反应的温度为30~50℃。
23.根据权利要求13所述的制备方法,其特征在于,所述化合物2制备化合物3的反应的时间为36~96小时。
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