Studies On Synthesis And Quality Control Of Hymecromone

In order to solve the problems of synthesising hymecromone about low catalytic efficiency and pollution of the environment, which catalyzed by traditional liquid acid (concentrated sulfuric acid, etc.), we selected the type of solid super acid SO₄^2-/MxOy as the experimental object to increase the acidity of the solid super acid, to improve the catalytic performance and its catalytic life by adding metal oxide or improving the accelerating agent, and finally to set up a process for the highest acidic catalyst, the composite solid super acid and also to build hymecromone's green synthetic process with a high yield, meanwhile to establish the quality standards of hymecromone on this basis. The results obtained were as fllows:1.Preparation of the composite solid super acid SO₄^2-/ZrO₂-TiO₂ and its optimization process: The solid super acid SO₄^2-/ZrO₂-TiO₂, S2O82-/ZrO₂, SO₄^2-/ZrO₂ and SO₄^2-/TiO₂ were prepared by the methods of"precipitated- dipped"and"Sol-Gel", respectively, and then the acidity of solid super acid was uesed as an evaluation index through the Hammett indicators to optimize the preparation of modified composite solid super acid SO₄^2-/ZrO₂-TiO₂ by orthogonal experimental design. The results indicated that molar ratio of zirconyl chloride and tetra-n-butyl titanate 1:1, aging temperature 28℃, aging time 10 h, soaking concentration of sulphuric acid 1 mol/L, calcination temperature 600℃and calcination time 3 h. The acidity of the composite solid super acid SO₄^2-/ZrO₂-TiO₂, H0≤-13.75, was higher than that of the single component solid super acid SO₄^2-/ZrO₂ and SO₄^2-/TiO₂, H0≤-11.99, and S2O82-/ZrO₂, H0≤-12.70.2.Green synthesis of hymecromone and its optimization process: Being used the yield of hymecromone as an evaluation index, the catalytic efficiency of the solid super acid SO₄^2-/ZrO₂-TiO₂, S2O82-/ZrO₂, SO₄^2-/ZrO₂, SO₄^2-/TiO₂ and the solid acid phosphotungstic acid loaded on carbon were evlaluated through synthesising hymecromone of the one-step Pechmann reaction under the same conditions that were the mole ratio of resorcinol and ethyl acetoacetate 1:1 (resorcinol 0.1 mol), reaction temperature 150℃, catalyst dosage 0.8 g and reaction time 1.5 h. Then the process of synthesising hymecromone catalyzed by the composite solid super acid SO₄^2-/ZrO₂-TiO₂ was optimized via orthogonal experimental design, and also the yields of synthesisig hymecromone with scaling up to 10 and 20 times were examined. The results indicated that the highest yield of hymecromone catalyzed by the composite solid super acid SO₄^2-/ZrO₂-TiO₂ was 79.3%, comparing with the yields of hymecromone catalyzed by the catalysts SO₄^2-/ZrO₂ (57.1%), SO₄^2-/TiO₂ (65.1%), S2O82-/ZrO₂ (65.3%) and phosphotungstic acid loaded on carbon (45.3%) under the same conditions. The composite solid super acid SO₄^2-/ZrO₂-TiO₂ was the best catalyst for synthesising hymecromone. And the optimized conditions catalyzed by the composite modified solid super acid SO₄^2-/ZrO₂-TiO₂ were that the mole ratio of resorcinol and ethyl acetoacetate 1:1.5, catalyst dosage 0.7 g (resorcinol 0.1 mol), reaction temperature 150℃, reaction time 100 min and yield 90.2%. The yields of synthesising hymecromone with scaling up to 10 and 20 times were 91.1% and 90.6%, respectively, and the catalyst could be reused for several times. This process had the green synthesis characteristic and it was suitable for industrial production.3.Quality control and stability tests of crude drug of hymecromone: Referring to the methods in"Veterinary Pharmacopoeia of the People's Republic of China", the quality of the crude drug of hymecromone was detected, and its stabilities were investigated under the conditions of high temperature, high humidity, bright light, and by accelerating tests and being kept at room temperature. The results showed that the crude product of hymecromone was acicular crystals with off-white color, melting point 188～191℃, and it was soluble in dilute sodium hydroxide, insoluble in dilute acid and water, and sparingly soluble in methanol, ethanol and acetone. loss on drying 0.22%, ignited residue 0.03%, and heavy metal, chloridion and sulfate ion not more than 0.00066%, 0.002% and 0.02%, respectively. The content of the product samples detected by the UV method was built, wich the equation of standard curves was y=0.0998x+ 0.0610 (R2=0.9968) and the linear relations were good in the concentration range of 0～30μg/mL, and the mean content of hymecromone synthesized by this new process was 99.2%. The crude drug of hymecromone showed stable properties at high temperature, accelerating tests and being kept at room temperature, and it had hygroscopicity at high humidity and its content was lowered by 0.8% in bright light. Therefore, the crude drug of hymecromone should be kept and transported under dry condition and in a dark place.