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Total Synthesis Of "Tamiflu" And The Synthesis, Characterization Of Thiazole Derivatives

Posted on:2008-11-04Degree:DoctorType:Dissertation
Country:ChinaCandidate:L M HeFull Text:PDF
GTID:1221360242465180Subject:Applied Chemistry
Abstract/Summary:PDF Full Text Request
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 inhibitorThe 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 compoundsThiourea 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 compoundsFirstly, 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 crystalsThe 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 researchThe 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.
Keywords/Search Tags:“Tamiflu”, Benzimidazole thiazoles, 2-Amino thiazole, Synthesis, Crystal structure, Biological activity
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