Synthesis Of Coenzyme Q

Coenzyme Q are valuable medicines, especially Coenzyme Q₁₀ , which can be used in treatment of cardiovascular and cerebrovascular and improvement of immunity. Coenzyme Q₁₀ has been widely applied in pharmaceutical and health care. The national demands in China are about 30 tons per year, and the price of material is $21,000,000 per ton, which is remarkable benefit. At present about 90% products of Coenzyme Q₁₀ in global market are provided from Nisshin Seifun and Kyowa Hakko Kogyo in Japan. Perfect synthetic routes have not been realized in China as yet. In order to break the technical and market monopolies, to find a appropriate synthetic routes in industrial scale is significant.In the dissertation, fistly, retro-synthetic analysis of Coenzyme Q is accomplished; Secondly, synthetic routes of ring , side chains and coupling between ring and side chains are designed; Thirdly,Effects of technical and reaction conditions are determined;Finally,some interesting reaction machanisms are studied.Protective groups of hydroxybenzene are attempt,for example methyl and THP. 2,3,4,5-tetramethoxytoluene can be synthesized by three routes as following:(l) from Coenzyme Q₀ by hydrogenation and methylation with an overall yield of 91.0 % and content of 99.5%;(2)from p-cresol by bromization, methoxylation and methylation with an overall yield of 65.5% and content of 88.1%;(3)from 3,4,5-trimethoxytoluene by bromization and methoxylation with an overall yield of 82.9% and content of 85.0%.5-methyl-2,3-dimethoxy-1,4-dihydroquinone-ditetrahydropyran ether can be obtained from Coenzyme Q₀ by hydrogenation and tetrahydropyranylation with an overall yield of 63.5% for the first time;6-bormo-5-methyl-2,3-dimethoxy-1,4 -dihydroquinone-ditetrahydropyranyl ether can be obtained from Coenzyme Q₀ by bromization, hydrogenation and tetrahydropyranylation with an overall yield of 32.8%.C₅ building block (E)-4-bromo-3-methyl-2-buten-1-ol acetate and (E)-4-sulfonyl -3-methyl-2-buten-1-THP ether can be obtained from 4-chloro-3-methyl-2-buten-1-olacetate(E/Z=4:l) with yields of 40.4% and 51.2% respectively ;Ci0 building block (2E, 6E)-2,6-dimethyl-8-acetoxy-octadienyl-l-ol can be obtained from geraniol acetate with a yield of 30.4% by using SeC^rt-BuOOH series oxidation systems. Geranyl-geraniol can be obtained stereo selectively with a yield of 10.7% by virtue of Cio building block; Decaprenyl bromide can be obtained through three routes as following: (l)from solanesol by bromization,alkylation,decarboxylation,normant reaction and allylic rearrangement with a yield of 55.3%,which is mixture of isomer (E/Z=4:l);(2)from solanesol by bromization,sulfonylation,coupling with C5 building block and desulfonylation with a yield of 37.8%;(3)from 4-chloro-3-methyl-2-buten-l-ol acetate(E/Z=4:l) by sulfonylation, saponification, tetrahydropyranylation, coupling with solanesyl bromide,desulfonylation and detetrahydropyranylation. coupling product can be obtained with a yield of 40.3%.The coupling between ring and side chains is realized by direct alkylation and elongation.Three methods of direct alkylation are accomplished:(l)Coenzyme Q9 and Q10 are obtained stereoselectively with yields of 17.7% and 14.9% respectively by virtue of allylic organotin reagent derived from solanesol and decaprenol;(2)Coenzyme Q10 is obtained by Friedel-Crafts reaction of isodecaprenol with dihydroCoenzyme Qo with a yield of 30.5%,E/Z=95:5;(3)Coenzyme Q2,Q4 and Q9 are obtained from 2, 3,4,5-tetramethoxyltoluene by bromization,preparation of grignard reagent,coupling with geranyl bromide,geranylgeranyl bormide and solanesol bromide respectively and oxidation with excellent regioselectivity and stereoselectivity. The yields of coupling reaction are 80%⁸5%,but the yield of oxidation are about 40%.To select a novel oxidative reagents or protective groups is expected.The key intermediate 6-(3-methyl-4-sulfonyl-2-butene)-2,3,4,5-tetramethoxyl toluene can be obtained by two routes as following:(l)by Friediel-Crafts reaction with a yield of 60.5%,E/Z=6:l when using BF3'OEt2, and a yield of 32.5%,E/Z=10:l when using ZnBr2;(2)by Cross-Coupling reaction with a yield of 35.0% with excellent regioselectivity and stereoselectivity. Coulpling reactions of 6-(3-methyl-4- sulfonyl -2-butene)-2,3,4,5-tetramethoxyltoluene with geranyl bromide and solanesol bromideare achieved with yields of 82.7% and 78.5% respectively. Products of coupling reaction are tried to find a good method of desulfonylation. When lithium-naphthalene reagent is used, the yield of desulfonylation is 65.0% with 2:1 ratios of target products and double-bond migration product.The mechanisms of desulfonylation are studied for the first time.Some supposes are raised:desulfonylation deals with resonance of free radical;double-bond migration is difficult to avoid completely; distributions of products respect on the structure, temperature and solvents.These suppose can be proved by experimental results.In the dissertation,62 chemical compounds are synthesized including 11 novel chemical compounds.Their structure are confirmed by NMR or MS.