CN109574868A - 一种四环素类及其差向异构体氘代内标物的制备方法 - Google Patents
一种四环素类及其差向异构体氘代内标物的制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/16—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of hydrazones
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
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- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
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- C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
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Abstract
本发明创造的一种四环素类及其差向异构体氘代内标物的制备方法经过环化、开环和还原三步反应得到脱甲基的伯胺中间体，最后再由氘代多聚甲醛经还原胺化后制得四环素类氘代内标试剂。与传统的通过发酵或全合成的方法制备稳定同位素标记的四环素类内标试剂相比，本发明中的方法具有步骤短，操作简便，收率高，成本低，质量好等诸多优点。所得产物纯度及原子氘代率均在98％以上。
Description
技术领域
本发明创造属于有机合成领域，具体涉及到四环素类抗生素中的金霉素、四环素和土霉素及其差向异构体等的氘代稳定同位素内标试剂的制备方法。
背景技术
四环素类抗生素是由放线菌产生的一类广谱抗生素，包括金霉、土霉素、四环素及半合成衍生物甲烯土霉素、强力霉素、二甲胺基四环素等，其结构均含并四苯基本骨架。广泛用于多种细菌及立克次氏体、衣原体、支原体等所致之感染。四环素类抗生素是兽医常用的广谱抗生素，广泛的用于动物疾病的预防和治疗，并常作为动物促生长剂使用。但这类药物在发挥药效的同时，对人体的胃、肠、肝脏和牙齿也有着较大的毒副作用，除此之外，此类药物还会造成二重感染、过敏反应及致畸作用。目前，在动物养殖过程中存在着滥用抗生素的现象，导致了动物性食品中的抗生素残留污染，直接影响了广大消费者的身体健康，并使得细菌的抗药性增加。
综上所述，在食品检测领域对于四环素类抗生素残留的检测具有着非常重要的意义，而稳定同位素标记化合物在利用高分辨质谱进行食品安全监测和检测中具有着前处理简单、重复性好、检出限低等优势。而目前的四环素类稳定同位素内标试剂生产的技术路线长，操作过程繁杂，成本高，这些都严重的制约着四环素类稳定同位素内标试剂的应用。因此研究和开发一种技术路线短，操作简便，收率高，成本低，质量好的四环素类内标物的生产方法具有着重要的经济价值和社会意义。
发明内容
本发明旨在提供一种四环素类及其差向异构体氘代内标物的制备方法，该方法设计合理，原料价廉易得，技术路线短，操作简便，收率高，成本低。本发明创造采用的技术方案主要包括以下步骤：
(一)环化反应制备中间体II
将四环素类化合物溶解于水和浓盐酸的混合溶剂中，室温搅拌下分批加入N-氯代丁二酰亚胺，加毕搅拌反应得中间体II；
(二)水合肼肼解开环得中间III
将步骤(一)制备的中间体II溶解于乙醇中，室温条件下滴加溶有水合肼的乙醇溶液，加毕室温搅拌反应得到中间III。
(三)还原后得中间IV
将步骤(二)制备的中间体III溶解于丙酮和水的混合溶液中，室温条件下分批加入连二亚硫酸钠，加毕搅拌反应得中间IV；
(四)还原胺化得终产物V和VI
将步骤(三)制备的中间体IV溶解于甲醇和醋酸的混合溶液中，加入氘代多聚甲醛，室温条件下分批加氘代氰基硼氢化钠，加毕搅拌反应过夜得终产物V和VI；
反应路线如下：
进一步，所述步骤(一)中需要加入1.2当量的浓盐酸和2.4当量的N-氯代丁二酰亚胺，N-氯代丁二酰亚胺加毕后搅拌反应30min；温度为25℃。
所述步骤(一)中需要加入酸可以是氢溴酸、浓硫酸等强质子酸，N-氯代丁二酰亚胺也可以是N-溴代丁二酰亚胺。
所述步骤(二)中，所用水合肼在1倍当量。25℃反应18h。
所述步骤(三)中，连二亚硫酸钠为5当量。25℃反应30min。
所述步骤(三)中，连二亚硫酸钠还原剂也可以是铁粉，锌粉、亚硝酸钠、氯化亚锡等还原剂，溶剂可以是甲醇、乙醇等试剂。
所述步骤(四)中，需要加入约20倍当量的醋酸做催化剂已利于反应较多的转化为四环素类D6化合物而非差向四环素类D6化合物。25℃反应15h。
所述步骤(四)中的还原剂也可以是硼氘化钠、硼氘化钾、醋酸硼氘化钠等还原试剂，溶剂可以为二氯甲烷，1,2-二氯乙烷，乙醇等。
所述步骤(四)中可以是加酸催化得四环素类氘代内标物，也可以不加酸催化主要得到差向四环素氘代内标试剂。
本方法的有益效果是：本方法技术路线短，且大量使用水为溶剂放应，大大减少了有机溶剂的用量。本方法在放应最后一步引入氘代官能团，既降低了制备风险，同时也保证了同位素的丰度。
具体实施方式
下面将结合具体实施实例来详细说明本发明创造。
实施例1
(1R,4aS,11R,11aS,12aR)-1,2,4a,5,7-五羟基-11-甲基-4,6-二氧代亚甲基-1,4,4a,6,11,11a,12,12a-八氢-1,11-环氧并四苯-3-甲酰胺(IIa)的制备：
将4.6克四环素(Ia)溶于含有1毫升的浓盐酸的250毫升水溶液中，25℃条件下分批加入3.5克的N-氯代丁二酰亚胺，加毕，25℃条件下搅拌反应30min；抽滤，滤饼用水洗涤，将滤饼溶于300毫升的甲基叔丁基醚中，用50毫升的水洗涤4遍。减压旋干溶剂后得产物3.2克淡黄色的固体直接用于下一步反应，产率74.4％。LCMS(ESI+)：m/z＝416[M+H]+。
实施例2
(4aS,5aS,6S,12aS,E)-4-肼基-3,6,10,12,12a-五羟基-6-甲基-1,11-二氧代亚甲基-1,4,4a,5,5a,6,11,12a-八氢并-2-甲酰胺(IIIa)的制备：
将3.2g(1R,4aS,11R,11aS,12aR)-1,2,4a,5,7-五羟基-11-甲基-4,6-二氧代亚甲基-1,4,4a,6,11,11a,12,12a-八氢-1,11-环氧并四苯-3-甲酰胺(IIa)溶于25毫升的95％的乙醇溶液中，25℃条件下将溶有0.46毫升的80％的水合肼的25毫升乙醇溶液慢慢滴加到反应混合物中。滴毕，保温反应18h。旋干溶剂后得3.3克红棕色的固体直接用于下一步反应。产率99.7％。LCMS(ESI+)：m/z＝430[M+H]+。
实施例3
(4aS,5aS,6S,12aS)-4-氨基-3,6,10,12,12a-五羟基-6-甲基-1,11-二氧代亚甲基-1,4,4a,5,5a,6,11,12a-八氢并-2-甲酰胺(IVa)的制备：
将3.3克(4aS,5aS,6S,12aS,E)-4-肼基-3,6,10,12,12a-五羟基-6-甲基-1,11-二氧代亚甲基-1,4,4a,5,5a,6,11,12a-八氢并-2-甲酰胺(IIIa)溶于130毫升的丙酮和100的水的混合溶液中，25℃条件下分批加入6.6克的连二亚硫酸钠，控制温度在30℃左右，加毕，25℃搅拌反应30min。反应结束后加入3克活性炭，搅拌10分钟后加硅藻土抽滤并用水和丙酮1/1的混合溶液洗涤。合并滤液，旋干丙酮后调PH在4-5，用乙酸乙酯洗涤水层后正丁醇萃取，无水硫酸钠干燥后抽滤旋干得粗产品1.3克。经粗产品溶于50毫升的N,N-二甲基甲酰胺中，室温条件下滴加18毫升的水并搅拌2h。析出红棕色的固体，抽滤得纯品0.9克。产率28.1％。LCMS(ESI+)：m/z＝417[M+H]+。
实施例4
四环素及其差向异构体D6(Va，VIa)的制备：
将100毫克的(4aS,5aS,6S,12aS)-4-氨基-3,6,10,12,12a-五羟基-6-甲基-1,11-二氧代亚甲基-1,4,4a,5,5a,6,11,12a-八氢并-2-甲酰胺(IVa)溶于10毫升的无水甲醇中，加入0.25毫升的醋酸，36毫克的氘代多聚甲醛和50毫克的氰基硼氘化钠，氮气保护条件下25℃反应15h。反应结束后直接用制备HPLC纯化分别得30毫克四环素D6和20毫克差向四环素D6，均为土黄色固体。总产率46.3％。LCMS(ESI+)：m/z＝451[M+H]+,Va：1H NMR(400MHz,MeOD)δ7.81(d,J＝8.0Hz,1H)，7.62(m,1H),6.78(d,J＝8.6Hz,1H),3.49(s,1H),3.35(s,1H),3.24-3.28(m,1H)2.85-2.90(m,1H),2.73(s,3H).VIa：1H NMR(400MHz,MeOD)δ7.81(d,J＝8.0Hz,1H)，7.62(m,1H),6.78(d,J＝8.6Hz,1H),3.47(d,J＝9.1Hz1H),3.23(s,1H),3.24-3.28(m,1H)2.81-2.89(m,1H),2.73(s,3H).
以上对本发明创造的一个实施例进行了详细说明，但所述内容仅为本发明创造的较佳实施例，不能被认为用于限定本发明创造的实施范围。凡依本发明创造申请范围所作的均等变化与改进等，均应仍归属于本发明创造的专利涵盖范围之内。
Claims (10)
1.四环素类及其差向异构体氘代内标物的制备方法，其特征在于，包括以下步骤：
(一)将四环素类化合物进行环化，得到中间体II；
(二)中间体II经水合肼肼解开环得中间体III；
(三)中间体III还原后得中间体IV；
(四)中间体IV经还原胺化得四环素类及其差向异构体D6目标化合物V和VI；
反应路线如下：
2.根据权利要求1所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，主要包括以下步骤：
(一)环化反应制备中间体II
将四环素类化合物溶解于水和强质子酸的混合溶剂中，室温搅拌下分批加入N-卤代丁二酰亚胺，加毕搅拌反应得中间体II；
(二)水合肼肼解开环得中间III
将步骤(一)制备的中间体II溶解于乙醇中，室温条件下滴加溶有水合肼的乙醇溶液，加毕室温搅拌反应得到中间III；
(三)还原后得中间IV
将步骤(二)制备的中间体III溶解于溶剂X中，室温条件下分批加入还原剂X，加毕搅拌反应得中间IV；
(四)还原胺化得终产物V和VI
将步骤(三)制备的中间体IV溶解于溶剂Y中，加入氘代多聚甲醛，室温条件下分批加入还原剂Y，加毕搅拌反应过夜得终产物V和VI。
3.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述步骤(一)中需要加入1.2当量的强质子酸和2.4当量的N-卤代丁二酰亚胺，N-卤代丁二酰亚胺加毕后搅拌反应30min，温度为25℃。
4.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述步骤(一)中强质子酸是浓盐酸、氢溴酸或浓硫酸，N-卤代丁二酰亚胺是N-氯代丁二酰亚胺或N-溴代丁二酰亚胺。
5.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述步骤(二)中，所用水合肼优选为1倍当量；25℃反应18h。
6.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述步骤(三)中，还原剂X为5当量；25℃反应30min。
7.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述步骤(三)中，还原剂X是连二亚硫酸钠、铁粉、锌粉、亚硝酸钠、或氯化亚锡，溶剂X是甲醇、乙醇、或丙酮和水的混合溶液。
8.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述步骤(四)中，还加入20倍当量的酸催化剂；25℃反应15h。
9.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述酸催化剂为醋酸。
10.根据权利要求2所述的四环素类及其差向异构体氘代内标物的制备方法，其特征在于，所述步骤(四)中的还原剂Y是氘代氰基硼氢化钠、硼氘化钠、硼氘化钾、或醋酸硼氘化钠，溶剂Y为甲醇、二氯甲烷、1,2-二氯乙烷、或乙醇。
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