Study On Synthesis Of Pharmaceutical Intermediate Coenzyme Q₀ And Muti-Substituted Pyrimidines

Coenzyme Qo (2,3-dimethoxyl -5-methyl-1,4-benzoquinone) is an important transferring-hydrogen carrier of biologic respiratory chain, and also used widely in pharmaceutical synthesis as intermediate of multifunctional pharmaceutical coenzyme Q10.A better technology for the synthesis of coenzyme Qo with an overall yield of 47.3% is developed via dibromination, methoxylation, hydroxy methylation and oxidation from cheap and easily available β-methyl phenol. The route have some merits as following: cheap and available material, short steps, mild reaction conditions and simple operation.The better technology conditions for the preparation of 2,6-dibromo-4-methylphenol from p-methylphenol are as follows: the solvent is water; the ratio of p-methylphenol to bromine is 1:2.2 (molar ratio); reaction time is 1 hour in the room temperature. Its yield is 98.0% with the purity of 97.2% .2,6-dimetoxy-4-methylphenol is prepared better with the yield of 93.4% and the purity of 95.4% as follows: the catalyst is cuprous chloride; reaction temperature is 110℃; reaction time is 2 hours; the ratio of 2,6-dibromo-4-methylphenol to sodium methoxide and cuprous chloride is 1:6:0.17 (molar ratio). Cheap cuprous chloride instead of cuprous cyanide or cuprous iodide and the recovery of N,N- Dimethyl Formamide make the cost lower.After many experiments, we have obtained a better technology for preparation of 3,4,5-trimethoxy toluene. The better reaction conditions of the technology as following: the ratio of 2,6-dimetoxy-4-methylphenol to potassium hydroxide, dimethyl sulfate and polyethleneglycol is 1:0.76:1.28:0.15 (quality ratio); Reaction temperature is 90℃; Reaction time is 2 hours. Its yield is 89.2% with the purity of 98.4%. It makes the operation simply and reaction velocity accelerated that potassium hydroxide and dimethyl sulfate are added once.By quadrature experiment the better reaction conditions in which coenzyme Q0 is synthesizes are as follows: the ratio of 3,4,5-trimethoxy toluene to ammoniumpersulfate and concentrated sulfuric acid is 1:0.36:0.24 (quality ratio); reaction temperature is 30癈; reaction time is 1 hour. Its field is 57.9% with the purity of 99.3%.Multi-substituted pyrimidines are applied widely in synthesis of pesticides and medicines. The relation between their chemical structure and biological activity is depended on affect of substituents in different position of pyrimidin ring. Three 2-sulfhydylmethyl-4-hydroxypyrimidines ( I1~ I3) and nine 2,4,5,6-pyrimidines ( I4-I12) are synthesised with the yield of 65.4-95.1% from a series of P -dione compounds and amidine salts via closing ring, bromination and chlorination. It increases yield and reduces costs that compounds I 1~ I3 are obtained with S-methyl isothiourea sulfate, sodium methoxide and β-dione compounds instead of pyrimidines and iodomethane or dimethyl sulfate. Among them synthetic methods of compounds I 5, I 6and I n aren't reported in the literature and compounds I 8, I9 and I 12 are new compounds. The structure of them is confirmed by IR> MS.