布林佐胺重要中间体及其类似物的合成
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摘要
以来源丰富的单糖为原料,合成和修饰具有生物活性的糖类化合物是糖化学研究的重要领域之一。本论文着眼于现代合成化学对原子经济和环境友好的发展要求,针对现有某些糖类药物或其先导化合物难以满足生物化学、药理学和临床研究的需要,主要对稀有庚酮糖和糖苷化合物进行了化学合成和方法学研究。
天然稀有庚酮糖的合成上研究了三种方法：(1)对2,3；5,6-二-O-异丙叉-D-甘露呋喃糖的C-2上引入羟甲基侧链,再脱异丙叉保护后得到2-C-羟甲基-D-甘露糖,钼酸催化下,C-2上的羟甲基迁移到C-1上、醛糖转变为酮糖,实现了钼酸催化碳链重排合成D-葡萄庚酮糖,总产率37%；(2)以2,3,4,5,6-五-O-苄基-D-甘露糖为原料,通过Wittig反应增长碳链得苄基保护的甘露庚糖烯,进而在KMnO4/HOAc体系中对烯键的选择性氧化得到羟基半缩酮结构中间体,最后脱保护、酸性水解得到D-甘露庚酮糖,四步产率39%,纯度>99%；(3)使用CH2I2/n-BuLi体系对糖酸内酯的酯羰基进行碘甲基化加成,并通过碱性水解等步骤,制得葡萄庚酮糖、甘露庚酮糖和半乳庚酮糖的苄基化衍生物,加成、水解两步产率35%。以上三种方法丰富和发展了稀有庚酮糖的合成方法,具有条件温和,试剂易得的优点,有着重要的理论意义和一定的应用前景。
在本课题组对四-O-苄基-Valiolone成功合成的基础上,初步研究了Valielone、Validone的苄基化衍生物的化学合成(产率分别为95%和20%),还制备了Valiolone(四步产率36%)、Valielone(产率90%)的甘露糖构型的类似物,为此类糖苷酶抑制剂类药物的先导化合物提供实验基础。
具有生物活性的糖苷合成上包括两方面研究：(1)以四-O-乙酰基-α-溴代葡萄糖、半乳糖为糖基给体,对中药丹皮酚及其在生物体内的代谢中间体2,4-二羟基苯乙酮进行了糖苷化修饰,立体专一性的合成了β-构型的糖苷化产物,糖苷化产率30-73%；(2)以游离单糖为原料,通过炔丙苷化(产率50-90%)、碘代(产率75-92%)等两步反应,制备了7种具有抗菌活性的新型1’-碘代炔丙基糖苷。选取4种合成的碘代炔丙基糖苷化合物对引起农作物疾病的几种常见真菌进行了抑菌活性测试,发现均有一定的抗菌效果,为此类低毒、环保型农药的研究提供了思路。
Brinzolamide, as a new topical carbonic anhydrase inhibitors, is currently the drug of first choice for treatment of glaucoma, and has high selectivity, affinity, and good security. The synthesis of important intermediate of brinzolamide and its analogues was studied in this thesis, and then reactive conditions of some steps were optimized.
Starting from thiophene, we compared some factors such as material cost, operational feasibility and industrialization, and prepared (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno-[3,2-e]-1,2-thiazine-1,1-dioxide by 6 steps including chlorination, C-acylation, etherification, sulfamation, carbonyl a-hydrogen bromination and asymmetric reduction-cyclization. The total yield was 21%, ee>97%.
The process of bromination of 3-acetyl-5-chloro-2-thiophenesulfonamide was improved, by using 1,3-dibromo-5,5-dimethylhydantoin, copper bromide, N-bromosuccinimide, hydrobromic acid, and liquid bromine as brominating agents instead of pyridinium bromide perbromide. After comparison, it was found that 1,3-dibromo-5,5-dimethylhydantoin has good effect, and the reactive conditions were optimized by orthogonal experiment. The optimium conditions were determined as follows:reactive temperature is 40℃, mole ratio of 3-acetyl-5-chloro-2-thiophenesulfonamide to 1,3-dibromo-5,5-dimet-hylhydantoin is 1:1.4, and time is 5 hours. The novel synthesis increased the yield to 75%, and reduced cost and pollution.
Five analogues were synthesized via N-alkylated reaction to (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno-[3,2-e]-1,2-thiazine-1,1-dioxide, and then two kinds of sulfa compounds were prepared by sulfamated reaction to parts of above-mentioned N-alkylated products.
天然稀有庚酮糖的合成上研究了三种方法：(1)对2,3；5,6-二-O-异丙叉-D-甘露呋喃糖的C-2上引入羟甲基侧链,再脱异丙叉保护后得到2-C-羟甲基-D-甘露糖,钼酸催化下,C-2上的羟甲基迁移到C-1上、醛糖转变为酮糖,实现了钼酸催化碳链重排合成D-葡萄庚酮糖,总产率37%；(2)以2,3,4,5,6-五-O-苄基-D-甘露糖为原料,通过Wittig反应增长碳链得苄基保护的甘露庚糖烯,进而在KMnO4/HOAc体系中对烯键的选择性氧化得到羟基半缩酮结构中间体,最后脱保护、酸性水解得到D-甘露庚酮糖,四步产率39%,纯度>99%；(3)使用CH2I2/n-BuLi体系对糖酸内酯的酯羰基进行碘甲基化加成,并通过碱性水解等步骤,制得葡萄庚酮糖、甘露庚酮糖和半乳庚酮糖的苄基化衍生物,加成、水解两步产率35%。以上三种方法丰富和发展了稀有庚酮糖的合成方法,具有条件温和,试剂易得的优点,有着重要的理论意义和一定的应用前景。
在本课题组对四-O-苄基-Valiolone成功合成的基础上,初步研究了Valielone、Validone的苄基化衍生物的化学合成(产率分别为95%和20%),还制备了Valiolone(四步产率36%)、Valielone(产率90%)的甘露糖构型的类似物,为此类糖苷酶抑制剂类药物的先导化合物提供实验基础。
具有生物活性的糖苷合成上包括两方面研究：(1)以四-O-乙酰基-α-溴代葡萄糖、半乳糖为糖基给体,对中药丹皮酚及其在生物体内的代谢中间体2,4-二羟基苯乙酮进行了糖苷化修饰,立体专一性的合成了β-构型的糖苷化产物,糖苷化产率30-73%；(2)以游离单糖为原料,通过炔丙苷化(产率50-90%)、碘代(产率75-92%)等两步反应,制备了7种具有抗菌活性的新型1’-碘代炔丙基糖苷。选取4种合成的碘代炔丙基糖苷化合物对引起农作物疾病的几种常见真菌进行了抑菌活性测试,发现均有一定的抗菌效果,为此类低毒、环保型农药的研究提供了思路。
Brinzolamide, as a new topical carbonic anhydrase inhibitors, is currently the drug of first choice for treatment of glaucoma, and has high selectivity, affinity, and good security. The synthesis of important intermediate of brinzolamide and its analogues was studied in this thesis, and then reactive conditions of some steps were optimized.
Starting from thiophene, we compared some factors such as material cost, operational feasibility and industrialization, and prepared (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno-[3,2-e]-1,2-thiazine-1,1-dioxide by 6 steps including chlorination, C-acylation, etherification, sulfamation, carbonyl a-hydrogen bromination and asymmetric reduction-cyclization. The total yield was 21%, ee>97%.
The process of bromination of 3-acetyl-5-chloro-2-thiophenesulfonamide was improved, by using 1,3-dibromo-5,5-dimethylhydantoin, copper bromide, N-bromosuccinimide, hydrobromic acid, and liquid bromine as brominating agents instead of pyridinium bromide perbromide. After comparison, it was found that 1,3-dibromo-5,5-dimethylhydantoin has good effect, and the reactive conditions were optimized by orthogonal experiment. The optimium conditions were determined as follows:reactive temperature is 40℃, mole ratio of 3-acetyl-5-chloro-2-thiophenesulfonamide to 1,3-dibromo-5,5-dimet-hylhydantoin is 1:1.4, and time is 5 hours. The novel synthesis increased the yield to 75%, and reduced cost and pollution.
Five analogues were synthesized via N-alkylated reaction to (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno-[3,2-e]-1,2-thiazine-1,1-dioxide, and then two kinds of sulfa compounds were prepared by sulfamated reaction to parts of above-mentioned N-alkylated products.
引文
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