CN101066969A - 喹胺醇的制备方法 - Google Patents
喹胺醇的制备方法 Download PDFInfo
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Abstract
本发明为喹胺醇的制备方法,涉及化学合成领域,尤其是喹噁啉类化合物的合成,喹胺醇是一种效果好的抗菌促生产的兽药,但存在较大的毒副作用,单纯地改变侧链已不能满足需要,本发明为克服这一问题用乙酰甲喹为原料,通过Claisen-Schmidt反应在乙二胺碱性条件下乙酰甲喹的α-氢原子与呋喃甲醛的羰基发生缩合反应,并失水得α、β不饱和酮,通过这一新的合成路线可得到抗菌活性强,促生产作用高,毒性低的喹胺醇晶体。
Description
技术领域
本发明涉及有机化合物的化学合成领域,尤其是喹噁啉类化合物的合成。
背景技术
自1965年黎巴嫩贝鲁特(Beirut)的Haddalin和Issidorides发表Beirut反应第一篇文章以来,已有上百种应用该反应合成的专利问世和合成不下一千种新的N,N-二氮杂奈-1,4二氧化物(喹噁啉)类化合物。事实上,根据Beirut反应合成的多种喹噁啉化合物质的取代衍生物如:痢立清(Catbadox)、喹乙醇(Olaquindox)、乙酰甲喹等作为抗菌及促生长剂应用于畜牧兽医及养殖业中,已取得了巨大的经济与社会效益。但此类化合物存在较大的毒副作用,单纯地改变其侧链已不能满足需要,因为结果往往是毒性降低,其效果也大大下降。
为此必须寻找一种具有抗菌活性与促生长作用高,但毒性远低于同类药物的有发展潜力的喹噁啉类的药物饲料添加剂新品种。
发明内容
本发明的目的为提供一种抗菌活性与促生长作用强,但毒性低的喹胺醇的制备方法。
喹胺醇是以乙酰甲喹为原料,通过Claisen-schmidt反应在二乙胺碱性条件下乙酰甲喹的∝一氢原子与呋喃甲醛的羰基发生缩合反应,并失水得∝,β不饱和酮。合成路线为:
工艺步骤如下:
(1)将18.3g邻硝基苯胺和0.42g四丁基溴化铵溶于70g甲苯中,加入25.3g的50%氢氧化钠水溶液,在15-20℃下搅拌,滴入127g次氯酸钠水溶液,然后在15-20℃下继续搅拌,分去水相,得苯并呋咱-1-氧化物的甲苯溶液,在真空下蒸去甲苯,得17.4g的苯并呋咱-1-氧化物。
(2)将16.2g的苯并呋咱-1-氧化物和13.5g的乙酰丙酮溶于30ml的三乙胺中,让该溶液在室温下静置,收集沉淀,干燥后可得2-乙酰基-2甲基喹噁啉-1,4二氧化物。
将5g的2-乙酰基-2甲基喹噁啉-1,4二氧化物溶于10g的呋喃甲醛中,加热至溶解,放在冰水混合物中冷却至20-35℃,缓慢倒入4ml二乙胺,颜色逐渐变为褐色,到入水中,继续搅拌,有沉淀析出,抽滤,得到粗产品,乙醇重结晶得到喹胺醇的纯品。
本发明的化合物呈黄色固体粉末状,用谱学鉴定的方法对该物质进行化学结构测试。
谱学鉴定:
1、红外光谱(IR):仪器采用Nicolet NEXUS 670 FT-IR仪器,IR(KBr)cm-1:3500-2846,3103,1668,1604,1546,1316,1335,1271,758;
2、质谱(NS):仪器型号:ZAB-HS,FAB-MS显示有[M]+296;
3、核磁共振(NMR)仪器采用INOVA-400MHz超导核磁共振仪,1HNMR(CDCL3)δppm:8.61(1H,d,J=8.4Hz,H-5),8.55(1H,d,J=8.4Hz,H-8),7.85(2H,m,H-6,H-7),7.53(1H,H-16),7.34(1H,d,J=15.6Hz,H-13),6.96(1H,d,J=15.6Hz,H-12),6.75(1H,d,J=3.6Hz,H-18),6.49(1H,d,J=2.0,3.6Hz,H-17),2.53(3H,s,3-CH3);13CNMR(CDCL3)δppm;185.2,150.4,146.4,139.9,139.1,137.8,136.9,132.7,132.5,131.4,121.9,120.2,120.1,118.5,113.2,14.2;根据FAB-MS数据,结合核磁共振(NMR)谱数据可确定该化合物分子式为C16H12N2O4,分子量为296;根据HMQC归属碳上的质子信号,根据HMBC归属碳氢远程相关,COSY显示5、8上的质子与6、7位的质子有远程偶合关系,12位和13位上的质子有远程偶俣关系,17位和16,18位上的质子有远程偶合关系;
以上数据及分析结果可确定该化合物为喹胺醇。
表1:化合物的1HNMR(400MHz)和13CNMR(100MHz)数据及gHMBC相互关系(δ,ppm,TMS,CDCl3)
NO | δh | δc | DEPT | gHMBC correlations |
23567891011121314161718CH3 | 8.61(1H,d,J=8.4Hz)7.85(H,m,H-6)7.85(H,m,H-7)8.55(1H,d,J=8.4Hz)6.96(1H,d,J=15.6Hz,)7.34(1H,d,J=15.6Hz)7.53(1H,H-16)6.49(1H,d,J=2.0,3.6Hz)6.75(1H,d,J=3.6Hz)2.53(3H,s,3-CH3) | 139.9139.1120.2131.4132.5120.1137.8136.9185.2121.9132.5150.4146.4113.2118.514.2 | CCCHCHCHCHCCCCHCHCCHCHCHCH3 | H-12,H-CH3H-CH3H-6,H-7H-8H-5H-6.H-7H-5,H-7H-6,H-8H-12,H-13H-13H-18H-12,H-13,H-16,H-17,H-18H-17,H-18H-16,H-18H-13,H-16,H-17C-2,C-3 |
根据以上测试得出以下分子结构,
经查阅资料,在我们研究之前,国内外均无此类结构的药物饲料添加剂,虽有相同的母环结构,但侧链不同,因此本发明在分子结构方面是一种创新。
合成反应的产率60-90%,得到喹胺醇结晶纯度达98%以上。
由于消费理念和人们对自我健康的关注,对合成抗生素的评价变得十分重要,为评价和推广使用喹胺醇,也为食品卫生方面提供一个理论依据,对喹胺醇作了促生长试验、毒性试验和药物残留分析。
一增重效果及促进蛋白同化作用研究
1.几种合成抗生素添加剂促生长作用的比较
1.1试鸡分组 2003年8月7日从华陇种鸡场进1日龄安卡红羽雏鸡400只,根据随机分组,雌雄各半的原则分为5组,组间初始体重差异不显著,组内又分为4个重复,分别接受空白对照,喹乙醇(50ppm),喹胺醇(50ppm),喹胺醇(100ppm),喹烯酮(50ppm)五个处理。
1.2饲养 从1日龄开始饲喂自行配制的全价饲料和实验用药物添加剂,自由采食,自由饮水。每天记录采食量,每周称体重和剩余料量,并按饲养手册进行免疫。
1.3结论 饲喂42日龄后,经统计得出喹乙醇组比对照组日增重提高3.5%,采食量提高5.4%;喹胺醇(50ppm)组比对照组日增重提高8.3%,采食量提高7.2%;喹烯酮(50ppm)组比对照组日增重提高8.00%,采食量提高7.29%。喹胺醇(100ppm)组到42日龄时和对照组比差异不显著。喹胺醇(50ppm)和喹烯酮(50ppm)组相比增重效果和采食量差异不显著。
2.喹胺醇不同浓度梯度之间增重效果及促蛋白合成比较
2.1分组及饲养2003年9月28日从华陇种鸡场进1日龄安卡红羽雏鸡200只,饲喂一周后,根据随机分组,雌雄各半的原则分为4组,分组后经检验体重差异不显著,且每组又分为4个重复。4组分别接受空白对照,喹胺醇(50ppm),喹胺醇(75ppm),喹胺醇(100ppm),4个处理。饲养全程未加其他抗生素,饲养方法和第一批实验相同。每天记录投料量,每周称试鸡体重和余料量。饲养实验到11月24日结束,共56天。
2.2结论 经统计添加50ppm喹胺醇采食量和日增重分别比对照组提高7.28%和8.93%;75ppm喹胺醇组比对照组采食量和日增重提高4.4%和4.97%;而100ppm喹胺醇组和对照组比稍有提高,但差异不显著。因此,在鸡的日粮中添加50ppm喹胺醇增重效果比较理想。
二喹胺醇在鸡体内的药物残留分析
1检测波长 喹胺醇有紫外吸收值,在紫外-可见分光光度计上检测到3个最高吸收峰的波长334nm,254nm,228nm,经高效液相检测334nm波长比较理想。
2流动相 流动相选择范围比较大,改变流动相的种类和比例时,都会对柱效,分离效果产生大的影响。因此,我们在选择流动相时做了大量工作,根据极性和溶解性选择了乙腈,甲醇和水做流动相,乙腈和甲醇保留时间为3.16分,乙腈和水为7.32分,于是流动相定为水和乙腈。经检测喹胺醇在该流动相中100ng-800ng在线性范围内。
3制样 准确称取2g组织,加入4ml乙腈在FSH-2上匀浆5分钟,准确匀取相当于1g组织的匀浆于10ml具塞离心管内,加入1ml饱和硫酸铵振荡20分,离心15分钟。
吸出上清液加磷酸二氢钾溶液,加提取液3ml震荡20分钟,离心15分钟,吸出有机相,余液重复抽提一次,合并有机相,静置过夜,第二天吸出上层有机相,在40℃-50℃水浴上氮气缓慢吹干,-20℃保存待测.测定时用1ml流动相溶解,吸取100μl注入高效液相进行测定。
4标准曲线的制作
4.1.配制标准液 准确称取10mg喹胺醇纯品,用流动相溶解于100ml容量瓶内,作为第一贮备液,吸取第一贮备液1ml,用流动相定容于25ml棕色容量瓶内,浓度为4000ng/ml,作为第二贮备液。吸取第二贮备液0.625ml,1ml,1.5ml,2ml,2.5ml,3ml,4ml,5ml,浓度分别为100ng/ml,160ng/ml,240ng/ml,320ng/ml,400ng/ml,480ng/ml,640ng/ml,800ng/ml。
4.2.称取空白组织2g,按制样方法处理,测定时加入配好的各浓度标准液1ml,HPLC测定,由峰面积和浓度作标准曲线。
5.回收率的测定
5.1药品的配制 准确称取10mg喹胺醇纯品,用乙腈溶解于100ml容量瓶内,作为第一贮备液,吸取第一贮备液1ml,用乙腈定容于25ml棕色容量瓶内,浓度为4000ng/ml,作为第二贮备液。吸取第二贮备液0.625ml,2ml,4ml,5ml,浓度分别为100ng/ml,320ng/ml,640ng/ml,800ng/ml。
5.2称取空白组织2g,加入2ml配好的各浓度的标准液,匀浆5分钟,再加2ml乙腈混合均匀,准确匀取相当于1g组织的匀浆,以下同制样方法。上机测定后,由标准曲线计算出浓度,再计算回收率。
6.试验动物分组及采样 用第一批实验中的空白对照鸡32只,随机分为8组,每组4只,观察一周,鸡只健康。于10月3日晚上20时用胶囊给药法,给药50ppm,每隔12小时给药一次,共给药6次。采样时间依次为2,6,12,18,24,36,48,72小时,在最后一次给药后2小时,剖杀,取肌肉,肝脏,肾脏装于白色自封袋内,-20℃冰箱中待测。
样品测定 按照制样程序进行,之后经HPLC测定结果
采样时间(h) | 肌肉(ng/ml) | 肝脏(ng/ml) | 肾脏(ng/ml) |
26121824 | 589.91323.28169.82104.71ND | 723.27374.15179.80113.88ND | 786.80244.56193.39121.9448ND |
喹胺醇在肌肉,肝脏,肾脏中的消除时间为37.57,38.06,39.31小时,因此停药期定为2天。
喹胺醇对肉仔鸡亚急性毒性试验研究:
选用222只艾维茵雏鸡,分为2期,分别进行亚急性饲喂试验。第一期4组,每组25只鸡,第一组为空白对照组,第2-4组每千克饲料中分别添加喹胺醇100mg、150mg及300mg;第二期分为4组,每组18只鸡,第一组为空白对照组,第2-4组每千克饲料中分别添加喹胺醇250mg、500mg及1000mg。第一期在20d、30d、40d测定各组鸡血清中的尿素N(BUN)、肌酐(Cr)、谷丙转氨酶(ALT)、谷草转氨酶(AST)的指数;第二期在第10d、20d、30d分别测定脏器系数及血清BUN、Cr、ALT、AST指数。ALT、AST、BUN、Cr、检测指标显示,饲料中添加喹胺醇50-1000ppm均与空白对照组无显著差异(p>0.05);病理组织学检测显示,饲料中添加喹胺醇50-150ppm对机体心脏、肝脏、肾脏、肺脏和消化系统组织结构均无明显可见影响;脏器系数检测显示,饲料中添加250-1000ppm喹胺醇与空白对照组无显著差异(p>0.05),但在喂喹胺醇10d时肾脏、30d时法氏囊出现显著性差异(p>0.05与(p<0.01)。
作为药物饲料添加剂的良好新品种,试验采用小白鼠,LD50为9000mg/kg、肉仔鸡LD50为4949.94mg/kg。它对大肠杆菌、沙门氏菌等有明显的抑菌效果;对雏鸡白痢、仔猪黄痢的预防效果高于喹乙醇15-20%,可明显提高仔猪增重与饲料利用率,减少腹泻病的发生。
喹胺醇属喹噁啉类衍生物,一方面具有广谱的抗菌效果,尤其对大肠杆菌、沙门氏杆菌等革兰氏阴性菌所致的消化道疾病具有良好的效果,从而提高生长速度。另一方面能影响动物体内代谢(特别是内分泌系统)促进蛋白同化作用,增加机体蛋白合成,提高饲料中能量的利用效果改善饲料转化率,提高氮的生物学价值,使更多的氮储存于体内呈现促生长和多产瘦肉的作用,与喹乙醇,卡巴氧、西吖氧相比,无致病,致畸,致癌性作用。
本发明喹胺醇的制备方法具有以下有益效果:
通过此制备方法可得到抗菌活性与促生长作用高,毒性低的喹胺醇晶体。
具体实施方式
现通过下述实施例对本发明技术方案作进一步说明。
喹胺醇的化学合成工艺为:
(1)将18.3g(0.133mol)邻硝基苯胺和0.42g(0.0013mol)四丁基溴化铵溶于70g甲苯中,加入25.3g(0.266mol)的50%氢氧化钠水溶液,在15-20℃下搅拌,慢慢滴入127g(0.185mol)次氯酸钠水溶液(有效氯含量为5.2%),然后在15-20℃下继续搅拌3小时,分去水相,得苯并呋咱-1-氧化物的甲苯溶液,在真空下蒸去甲苯,得17.4g的苯并呋咱-1-氧化物;
(2)将16.2g的苯并呋咱-1-氧化物和13.5g的乙酰丙酮溶于30ml的三乙胺中,让该溶液在室温下静置18小时,收集沉淀,干燥后可得16g的2-乙酰基-2甲基喹噁啉-1,4二氧化物,经甲醇重结晶得纯品;
(3)将5g的2-乙酰基甲基喹噁啉-1,4二氧化物溶于10g的呋喃甲醛中,加热至50-80℃溶解,放在冰水混合物中冷却至20-35℃,缓慢倒入4ml二乙胺,颜色逐渐变为褐色,到入水中,继续搅拌,有沉淀析出,抽滤,得到粗产品,乙醇重结晶得到喹胺醇的纯品。
Claims (1)
1、喹胺醇的制备方法,其特征为:
(1)将18.3g邻硝基苯胺和0.42g四丁基溴化铵溶于70g甲苯中,加入25.3g的50%氢氧化钠水溶液,在15-20℃下搅拌,滴入127g次氯酸钠水溶液,然后在15-20℃下继续搅拌,分去水相,得苯并呋咱-1-氧化物的甲苯溶液,在真空下蒸去甲苯,得17.4g的苯并呋咱-1-氧化物,
(2)将16.2g的苯并呋咱-1-氧化物和13.5g的乙酰丙酮溶于30ml的三乙胺中,让该溶液在室温下静置,收集沉淀,干燥后可得2-乙酰基-2甲基喹噁啉-1,4二氧化物,
(3)将5g的2-乙酰基-2甲基喹噁啉-1,4二氧化物溶于10g的呋喃甲醛中,加热至溶解,放在冰水混合物中冷却至20-35℃,缓慢倒入4ml二乙胺,颜色逐渐变为褐色,到入水中,继续搅拌,有沉淀析出,抽滤,得到粗产品,乙醇重结晶得到喹胺醇的纯品。
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CN103172621A (zh) * | 2013-03-15 | 2013-06-26 | 广东省天宝生物制药有限公司 | 一种改进的喹胺醇的制备方法 |
CN104841399A (zh) * | 2015-05-06 | 2015-08-19 | 华中农业大学 | 一种喹噁啉-2-甲醛-1,4-二氧-亲和基质的制备方法及应用 |
CN105732525A (zh) * | 2016-03-24 | 2016-07-06 | 中国农业大学烟台研究院 | 一种3-甲基-2-乙酰苯腙喹喔啉1,4-二氧物的制备方法 |
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CN104841399A (zh) * | 2015-05-06 | 2015-08-19 | 华中农业大学 | 一种喹噁啉-2-甲醛-1,4-二氧-亲和基质的制备方法及应用 |
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CN108426996A (zh) * | 2017-02-15 | 2018-08-21 | 江苏美正生物科技有限公司 | 一种3-甲基喹噁啉-2-羧酸残留的快速检测试剂盒及其制备方法和应用 |
CN108426996B (zh) * | 2017-02-15 | 2020-09-15 | 江苏美正生物科技有限公司 | 一种3-甲基喹噁啉-2-羧酸残留的快速检测试剂盒及其制备方法和应用 |
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