摘要
流感是由流感病毒引起的急性呼吸道传染病,其发病率居传染病首位。流感病毒神经氨酸酶抑制剂是一类新型的抗流感病毒药物。“达菲”是目前开发的特异性最高、活性最好的流感病毒NA抑制剂,也是治疗流感最有效的药物。本文以(?)-莽草酸为原料不对称全合成了流感NA抑制剂新药“达菲”;根据构效关系、生物电子等排原理设计了新型苯甲酸类流感病毒NA抑制剂,并基于2-氨基噻唑的合成基础设计新化合物的合成路线,制备了目标化合物。
1. NA抑制剂“达菲”的不对称全合成
以来源丰富的(?)-莽草酸为原料,经乙酯化、缩酮交换、甲磺酰化、还原性开环,环氧闭环和开环,氮丙啶形成和开环,酰化,盐酸成盐,叔丁胺消除,二烯丙基催化转移和磷酸酸化共13步反应全合成了“达菲”,关键性中间体和“达菲”经~1HNMR确证。“达菲”[α]D =-39.0°(c = 1,H2O,25℃)。
酯化反应用固体光气代替毒性较大的二氯亚砜催化,使用方便,减少了污染。甲磺酰化反应中严格控制三乙胺滴加速度,后处理采用过滤的方法除去不溶物代替离心分离,二氯亚砜作催化剂为58.3 %(3步总收率),固体光气作催化剂为55.6 %(3步总收率)。该中间体比旋光度[α]D =-89.5°(c = 1,CH3OH,25℃);与3-戊酮缩酮交换中改用二氯甲烷和3-戊酮1∶1匹配使用,代替了原工艺单独使用3-戊酮,消耗降低,反应可操作性强,收率77.4 %;还原性开环反应中采用Et3SiH/TiCl4复合物开环,避免了价格贵的三甲基甲硅烷基三氟甲基磺酸酯(TMSOTf)的使用,同时用二氯甲烷与四氯化钛匹配加料克服了四氯化钛易水解的问题;二烯丙胺基的消除采用了醋酸钯催化转移法。
整条路线方法新颖、反应条件温和,所用试剂安全性好,成本适中,具有很好的可行性和操作性。
2. 2-氨基噻唑类化合物的合成
α-溴代芳基烷基酮与硫脲投料摩尔比1∶1,在乙醇或乙酸乙酯中环合,再经氨水中和得2-氨基噻唑类化合物。共合成了13种2-氨基-4-芳基噻唑类化合物,其中4种为未见报道的新化合物。校正了已报道的2-氨基-4-(6-甲氧基-2-萘基)噻唑(m.p. 220～221℃,文献值m.p. 162℃)和2-氨基-4-(2,4-二氯-5-氟苯基)噻唑(m.p. 186～188℃,文献值m.p. 169℃)的熔程数据;目标化合物物经1HNMR、IR和MS确证。
3.苯并咪唑噻唑类新化合物的合成
对氨基苯甲酸乙酯为原料,经乙酸酐酰化、混酸硝化、氢化还原得取代苯胺,其和苯甲酰氯、硫氰酸铵一锅反应,再经氨水/甲醇水解合成了N-取代苯基硫脲,N-取代苯基硫脲与α-溴代芳基烷基酮环合、氨水中和得18种2-甲基-1-(4-芳基噻唑-2-基)-苯并咪唑-6-甲酸乙酯类新化合物;酯类化合物经氢氧化钠水解得10种2-甲基-1-(4-芳基噻唑-2-基)-苯并咪唑-6-甲酸类新化合物。
N-取代苯基硫脲中间体的制备乙酸酐酰化收率97.6 %;混酸硝化收率91.3 %;还原反应采用催化氢化法,无水乙醇作溶剂,5 %钯-炭催化,收率84.0 %。还原得到的苯胺与苯甲酰氯、硫氰酸铵一锅反应反应制得N-苯甲酰基取代硫脲,反应转化率高,收率94.3 %,毒性中间体苯甲酰基异硫氰酸酯残留量很少。N-苯甲酰基取代硫脲用氨水/甲醇(1∶1)水解制备N-取代苯基硫脲,收率87.8 %。
α-溴代芳基烷基酮中间体的制备讨论了溴化酮、吡啶氢溴酸盐过溴化物(PPB)及5,5-二甲基-1,3-二溴海因(DBDMH)作溴化剂的适用性。溴化酮选择性好、操作简便,具有普遍适用性;PPB溴化反应条件温和,但毒性大,所得产物难纯化、熔程偏低;DBDMHα-溴化方法新颖,对于间硝基苯乙酮和对乙基苯乙酮α-溴代效果好,适用性还有待研究。制备了20种α-溴代芳基烷基酮中间体。
环合与中和反应基于2-氨基噻唑合成方法,N-取代苯基硫脲与α-溴代芳基烷基酮环合,一锅形成苯并咪唑环和噻唑环,并经氨水中和得到18种2-甲基-1-(4-芳基噻唑-2-基)-苯并咪唑-6-甲酸乙酯类新化合物,结构经1HNMR、IR等确证。反应条件温和、操作简单,方法新颖。
水解反应2-甲基-1-(4-芳基噻唑-2-基)-苯并咪唑-6-甲酸乙酯类新化合物经碱性水解可得苯并咪唑噻唑羧酸类化合物。对于噻唑环4-位苯环上为非羟基取代时,均以丙酮作溶剂,底物与氢氧化钠摩尔比1∶5进行水解,收率较高;对于噻唑环4-位苯环上有羟基取代时,直接以底物与氢氧化钠摩尔比1∶8进行水解,收率偏低。当噻唑环4-位连有分子量较大基团时,难水解。
单晶X-射线衍射分析
15.HBr的单晶X-射线衍射分析进一步确定了化合物结构,并由单晶分析可知:分子中三个环不共面,氢溴酸与2-氨基噻唑类化合物成盐位置为噻唑环上的氮原子,分子中存在N-H...O,N-H...Br,O-H...Br氢键。
化合物28经单晶X-射线衍射确定了结构,与设计的化合物结构一致。苯并咪唑环中的苯环与咪唑环不共平面,二面角为1.24(70)°;噻唑环的最小直角平面(C12-N3)与C3/C4/C5/C6/C7/C8母体苯环的二面角为9.57(55)°;C15/C16/C17/ C18/C19/C20苯环最小直角平面(C15-C20)与C3/C4/C5/C6/C7/C8母体苯环的二面角为12.11(53)°;C15/C16/C17/C18/ C19/ C20苯环最小直角平面(C15-C20)与噻唑环的二面角为3.62(47)°,分子经由C-H...O氢键连接,晶体结构由普遍存在的范德华力进一步稳定。
生物活性研究
对合成的10种2-甲基-1-(4-芳基噻唑-2-基)-苯并咪唑-6-甲酸类新化合物分别进行抗流感甲型病毒活性测试和抗金黄色葡萄球细菌活性测试,测试结果均不理想,但对于今后该模型的调整修饰仍有启发。
对合成的2-甲基-1-(4-芳基噻唑-2-基)-苯并咪唑-6-甲酸乙酯类新化合物进行农业杀菌活性测试,取得了满意的结果。化合物31对油菜菌核病菌(500 mg/L)抑制率为56.1 %;33 (500 mg/L)对小麦白粉病菌抑制率达95 %;化合物35对辣椒疫霉病菌(25 mg/L)的抑制率为61.9 %,对油菜菌核病菌(500 mg/L)抑制率高达97.2 %。化合物42 (25 mg/L)对小麦赤霉病菌抑制率为55.1%。其它化合物在测试条件下对水稻稻瘟病菌,黄瓜灰霉病菌和水稻纹枯病菌杀菌活性较弱或无杀菌活性。基于此活性研究可探讨其构效关系,并对该类化合物进行进一步的开发,有望得到有应用价值的新农药。
Influenza, caused by influenza viruses, is the most serious respiratory disease in terms of morbidity. Influenza virus neuraminidase inhibitors are a new class of anti- -influenza drugs. The research work in this thesis mainly includes the asymmetric total synthesis of“Tamiflu”, the design of a new style benzoic acid derivatives as influenza neuraminidase inhibitors based on the structure-activity relationship and the bioisosterism, and the synthesis of the designed compounds based on the synthetic methods of 2-amino-thiazole compounds.
1. Total synthesis of“tamiflu”as an influenza NA inhibitor
The target“tamiflu”can be prepared from (-)-shikimic acid via esterification, transketalization, mesylation, reductive opening ring, forming epoxide and opening epoxide, forming aziridine and opening aziridine, acetylation, hydrochloric salt formation, cleavage of the tert-butyl acetamide, deallylation and phosphate salt formation, total 13-step reaction. The structure of the key intermediates and“tamiflu”were confirmed by 1HNMR, The power rotation([α]D) of“tamiflu”is -39.0°(c = 1, water, 25°C).
Especially, in esterification, thionyl chloride(SOCl2) was replaced by solid phosgene(BTC) as a catalyst which is easy to use, less toxic and pollution. In mesylation, the rate of dropping triethylamine was strictly controlled, and filter replacing centrifugal separation was used to remove the insoluble substance in post-processing. The three-step total yield was calculated, 58.3 % for SOCl2, 55.6 % for BTC. The power rotation([α]D) of the third intermediate is -89.5°(c = 1,methanol,25℃). Dichloro methane (CH2Cl2) was used as solvent in transketalization replacing excessive 3-pentanone, reducing the cost and simplifying the operation. The purification of product was implemented on a silica gel chromatography with yield of 77.4 %. The dropping of TiCl4 was matched with CH2Cl2 in reductive opening ring to avoid the hydrolysis of TiCl4. Deallylation can be realized by transferring allyl group to NDMBA with a palladium-catalyzed.
The reaction conditions of whole route are mild. The reagents used are safety. In addition, the cost is moderate. Consequently, the process has good feasibility and optimization space.
2. The synthesis of 2-amino-4-aryl thiazole compounds
Thiourea andα-bromo alkylaryl ketone (molar ratio 1:1) can be cyclized in ethanol or ethyl acetate and neutralized by ammonia to obtain nine kinds of 2-amino thiazole compounds which have been reported. Especially, we corrected the melting point of 2-amino-4-(6-methoxy-2-naphthyl)thiazole(220～221℃, 162℃in the literature) and 2-amino-4-(2,4-dichloro-5-fluoro phenyl)thiazole(186～188℃,169℃in the literature). In addition, four kinds of new compounds were prepared. The structures were confirmed by 1HNMR, IR or MS.
3. The design and synthesis of new benzimidazole thiazole compounds
Firstly, N-substituted phenyl thiourea as an important intermediate was prepared from ethyl 4-aminobenzoate via acetylation, nitration, hydrogenation reduction, N-substituted phenyl N’-benzamide thiourea formation and ammonia/methanol hydrolysis. Then N-substituted phenyl thiourea occurred cyclization withα-bromo alkylaryl ketone and neutralized by ammonia based on 2-aminothiazole synthesis, eighteen kinds of new ethyl 2-methyl-1-(4-arylthiazol-2-yl)-benzoimidazole-6- carboxylate compounds were obtained , the esters were hydrolysised by sodium hydroxide to yield ten kinds of new 2-methyl-1-(4-arylthiazol-2-yl)-benzoimidazole-6- carboxylic acid compounds.
Preparation of N-substituted phenyl thiourea: The yield of acylation and nitration was 97.6 % and 91.3 %, respectively. The yield of hydrogenation reduction was 84.0 % with anhydrous ethanol as solvent and 5 % palladium-carbon as catalyst. The intermediate obtained by hydrogenation reduction reacted with benzoyl chloride and ammonium thiocyanate to yield N-benzoyl-substituted thiourea with high conversion rate, little residue of toxic intermediates benzoyl isothiocyanate and the yield of up to 94.3 %. The yield of hydrolysis using ammonia/methanol (1:1) was 87.8 %.
Preparation ofα-bromo alkylaryl ketone: The applicability of cupric bromide, pyridine perbromide hydrobromide (PPB) and 1,3-dibromo 5,5-dimethyl hydantoin (DBDMH) as bromination regents were discussed. Cupric bromide has universal applicability with good selectivity and simple operation. The reactive condition for PPB is mild, but with high toxicity and low purity. DBDMH,as a new bromination regent forα-bromo, has good effect for 3-nitro-acetophenone and 4-ethyl- acetophenone. Certainly, further investigation on its applicability is necessary. A total of twenty kinds ofα-bromo aryl alkyl ketones were prepared as intermediates.
Cyclization and neutralization: N-substituted phenyl thiourea occurred cyclization withα-bromo alkylaryl ketone and neutralized by ammonia based on 2-aminothiazole synthesis, eighteen kinds of new ethyl 2-methyl-1-(4-arylthiazol-2-yl)-benzoimidazole -6-carboxylate compounds were obtained . The structure of new compounds were 1HNMR, IR or MS.
Hydrolysis of esters: New benzimidazole thiazole esters compounds can be hydrolysised by 1 mol/L sodium hydroxide to obtain ten kinds of new 2-methyl-1-(4-arylthiazol-2-yl)-benzoimidazole-6-carboxylic acid compounds. The esters without hydroxy phenyl on 4-thiazole ring can be hydrolysised with higher yield under the condition of acetone as solvent and the molar ratio of 5:1 for sodium hydroxide and the esters. The esters which have hydroxy phenyl on 4-thiazole ring can be hydrolysised only using sodium hydroxide with the molar ratio of 8:1 for sodium hydroxide and the esters. However, it provided relatively lower yield. The esters which have larger molecular weight group on the phenyl of 4-thiazole ring were hardly hydrolysised.
4. X-ray analysis of single crystals
The single crystals X-ray analysis of 15.HBr made sure the compound structure again, gave the information of three rings in molecule was not coplanar, and hydrobromic acid and“N”atom on the thiazole ring formed salt.The structure has intermolecular hydrogen bonds of N-H...O,N-H...Br,O-H...Br.
The single crystals of the compound of 28 suitable for X-ray analysis were obtained by slow evaporation from saturated ethanolic solution at room temperature. The benzene ring and imidazole ring in the benzimidazole ring is not coplanar, and thiazole ring is also not coplanar with other rings. The structure has no evident hydrogen bond because of no donor hydrogen-bond donor elements. Crystal structure was stabled by the van der Waals force.
5. Biological activity research
The research of anti-influenza virus activity and anti-staphylococcus aureus bacterial activity of new benzimidazole thiazole acids compounds showed no obvious effect for ten kinds of new benzimidazole thiazole carboxylic acid compounds. But it is still helpful for the modified model in the future.
The preliminary bioassays of new benzimidazole thiazole ester compounds indicated that compound 33 showed good fungicidal activity againt Blumeria graminis with 95% inhibition rate; 35 exhibited 61.9 % inhibition rate against Phytophythora capsici at 25 mg/L. compound 35 showed excellent fungicidal activity againt Sclerotonia sclerotiorums with 97.2% inhibition rate at 500 mg/L. and compounds 42 exhibited 55.1% inhibition rate against Gibberella zeae. It holds great promise to develop new pesticides.
引文
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