CN112194788B - 一种水溶性氟苯尼考及其制备方法 - Google Patents

一种水溶性氟苯尼考及其制备方法 Download PDF

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CN112194788B
CN112194788B CN202010967680.XA CN202010967680A CN112194788B CN 112194788 B CN112194788 B CN 112194788B CN 202010967680 A CN202010967680 A CN 202010967680A CN 112194788 B CN112194788 B CN 112194788B
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florfenicol
water
formula
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史兰香
张宝华
陈东
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Hebei Goldman Sachs Pharmaceutical Co ltd
Shijiazhuang University
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Abstract

本发明公开了一种水溶性氟苯尼考。本发明在氟苯尼考结构中引入了聚乙二醇基团，合成了结构新颖的氟苯尼考且其具有好的水溶性。该类化合物具有抗菌作用，能应用于抗菌药物的制备。本发明公开了其制法。

Description

一种水溶性氟苯尼考及其制备方法
技术领域
本发明涉及水溶性氟苯尼考，及其在制药中的应用，属于医药技术领域。
背景技术
氟苯尼考是一种广谱抗生素，主要用于猪、牛、羊、鱼和禽类感染性疾病的治疗。氟苯尼考主要是通过口服或胃肠外给药，但它的水溶性极低，临床使用通常希望药物在水中的溶解度≥300mg/mL，因此，提高其在水中的溶解度是必须攻克的技术问题。用聚乙二醇修饰药物来改善药物的理化性质和生物学性能是常用的手段。聚乙二醇修饰药物一方面能极大地提高药物的水溶解性，另一方面，聚乙二醇及其结合的水分子在药物表面能形成了一个类似于屏蔽层的东西，减少了药物酶解的可能，使得药物不能被肾快速的清除，提高了药物生物利用度。本发明用聚乙二醇修饰氟苯尼考，极大地提高了氟苯尼考在水中的溶解性能。
发明内容
本发明的目的在于提供一种水溶性氟苯尼考，其具有抗菌作用和良好的水溶性。
本发明的另一目的在于提供所述水溶性氟苯尼考的制备方法。
本发明的再一目的在于提供所述水溶性氟苯尼考的用途。
以下对本发明进行详细描述。
本发明提供的水溶性氟苯尼考，如式I、式II所示：
Figure GDA0002821010340000011
本发明还提供了所述水溶性氟苯尼考的制备方法：
Figure GDA0002821010340000021
本发明的水溶性氟苯尼考具有良好的水溶性和抗菌作用。
通过以下实施例进一步举例说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
附图说明：
图1是指式I和式II化合物在猪体内转化为氟苯尼考的情况。
具体实施方式
实施例1
中间体的制备
将20g干燥的PEG4000或MeOPEG4000溶于100mL无水二氯甲烷中，加入50mL吡啶和6g TsCl，室温反应30h，有机层分别用10％NaHCO3溶液和饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，得MeOPEG-对甲苯磺酸酯或PEG-双对甲苯磺酸酯粗品。
将19g MeOPEG-对甲苯磺酸酯或PEG-双对甲苯磺酸酯粗品与250mL浓氨水加入高压釜中，140℃反应6h，冷至室温，加入同体积的二氯甲烷,搅拌，再加入同体积的1mol/L的NaOH，继续搅拌2h，分层，水洗至中性，制得MeOPEGNH2或NH2PEGNH2，收率分别为85.0％和84.3％。
实施例2
式I化合物的制备
将4.012g MeOPEGNH2和303mg三乙胺溶于10mL无水DMF中，冷至0℃，滴入356.1mg固体光气与5mL无水DMF的溶液，保温反应1h，继续滴加358.2mg氟苯尼考与5mL无水DMF的溶液，反应2h后，升至室温搅拌过夜。减压蒸除DMF得式I化合物粗品。将粗品用3mL乙酸乙酯/甲醇(体积比2:1)混合溶剂溶解,采用干法装柱以甲醇作洗脱剂进行柱色谱分离,得式I化合物,收率50％。1H NMR(300MHz,DMSO-d6)δ:8.91(s,1H,NH),7.89(d,J＝8.5Hz,2H,ArH),7.63(d,J＝8.5Hz,2H,ArH),6.43(s,1H,CHCl2),6.01(dd,J＝8.5,3.2Hz,CHOCO),4.63-4.30(m,3H,CHN,CH2F),3.63-3.42(m,364H,PEG),3.29(s,3H,CH3O),3.19(s,3H,SO2CH3)；13CNMR(75MHz,DMSO-d6)δ:171.1,163.8,143.6,136.3,130.4,130.1,128.3,128.2,82.7,81.0,72.5,71.4-69.5(PEG),66.1,43.3,26.0.IR(KBr,cm-1)3402(N-H),2887(PEG CH2),1735(C＝O),1600(Ar),1468(PEG CH2),1280(C-O-C)。.
实施例3
式II的制备
用3.997g NH2PEGNH2代替4.012g MeOPEGNH2，用606mg三乙胺代替303mg三乙胺，其它操作与实施例2相同，制得式II化合物,收率57％。1H NMR(300MHz,DMSO-d6)δ:8.90(s,2H,NH),7.91(d,J＝8.5Hz,4H,ArH),7.65(d,J＝8.5Hz,4H,ArH),6.45(s,2H,CHCl2),6.02(dd,J＝8.5,3.2Hz,2H,CHOCO),4.63-4.30(m,6H,CHN,CH2F),3.70-3.44(m,364H,PEG),3.20(s,6H,SO2CH3)。13C NMR(75MHz,DMSO-d6)δ:171.3(2C),165.0(2C),143.6(2C),136.3(2C),130.4(2C),130.1(2C),128.3(2C),128.2(2C),82.7(2C),81.0(2C),72.5(2C),71.4-69.5(PEG),66.1(2C),43.5(2C).IR(KBr,cm-1)3402(N-H),2885(PEG CH2),1739(C＝O),1606(Ar),1468(PEG CH2),1280(C-O-C)。
实施例4
式I和式II化合物在水中溶解性测定
取一定量的式I或式II化合物分别连续等份的加入水中,持续加入直到溶液因粘度增大出现搅拌困难为止。取已知体积的溶液，用已知体积的水稀释，用HPLC法(C18柱3.9x150nm，流动相H2O/CH3CN(73:27)，波长224nm，流速1.0mL/min)测定氟苯尼考最初含量，计算式I、式II化合物的溶解度。结果显示，式I和式II的溶解度均大于500mg/mL，完全能满足临床要求(临床要求溶解度≥300mg/mL)。比氟苯尼考原药溶解度(1.3mg/mL)提高384倍。
实施例5
式I和式II化合物在猪体内转化为氟苯尼考情况：将式I和式II化合物分别溶于水中，使浓度500mg/mL，将该溶液分别静脉注入3头体重10-16kg健康猪的体内，式I、式II化合物注射剂量分别为55.1mg/Kg和30mg/Kg(折合为氟苯尼考等效剂量5mg/Kg)，给药后不同时间点采集血液，HPLC测定血浆中氟苯尼考浓度(图1)。结果显示，血浆中氟苯尼考浓度迅速增加，说明式I、式II化合物在猪体内能很好地转化成氟苯尼考。

Claims (1)

1.一种水溶性氟苯尼考的制备方法，其特征在于：包括以下步骤：
Figure DEST_PATH_IMAGE001
。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101289416A (zh) * 2008-03-03 2008-10-22 西南大学 体内速释的高水溶性氟苯尼考前药
CN101530619A (zh) * 2009-04-16 2009-09-16 山东大学 一种水溶性聚乙二醇化羟基喜树碱衍生物的制备方法
CN102321239A (zh) * 2011-05-30 2012-01-18 河北科技大学 水溶性二苯乙烯类化合物前药的制备方法
CN103721263A (zh) * 2014-01-08 2014-04-16 王玉万 含抗菌药物/聚乙二醇载药微粒的油质注射剂
CN108586726A (zh) * 2018-06-27 2018-09-28 湖南华腾制药有限公司 一种peg化姜黄素衍生物及其在抗肿瘤药物中的应用
CN110078729A (zh) * 2019-06-11 2019-08-02 石家庄学院 一种水溶性氟苯尼考前药及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8084643B2 (en) * 2006-12-13 2011-12-27 Intervet Inc. Water-soluble prodrugs of florfenicol and its analogs

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101289416A (zh) * 2008-03-03 2008-10-22 西南大学 体内速释的高水溶性氟苯尼考前药
CN101530619A (zh) * 2009-04-16 2009-09-16 山东大学 一种水溶性聚乙二醇化羟基喜树碱衍生物的制备方法
CN102321239A (zh) * 2011-05-30 2012-01-18 河北科技大学 水溶性二苯乙烯类化合物前药的制备方法
CN103721263A (zh) * 2014-01-08 2014-04-16 王玉万 含抗菌药物/聚乙二醇载药微粒的油质注射剂
CN108586726A (zh) * 2018-06-27 2018-09-28 湖南华腾制药有限公司 一种peg化姜黄素衍生物及其在抗肿瘤药物中的应用
CN110078729A (zh) * 2019-06-11 2019-08-02 石家庄学院 一种水溶性氟苯尼考前药及其制备方法

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