Hydroxylation is directedOrganic compoundMolecular introductionhydroxylReaction.It can be prepared by hydroxylation reactionalcoholsAndPhenolschemical compound.
It can be prepared by hydroxylationalcoholsAndPhenolschemical compound.These two types of substancesFine chemical industryIt is widely used in productionsynthetic resin, variousauxiliary, dyes, pesticidessurface active agent , spices and food additives, etc.In addition, alkylphenol ether, diaryl ether, aromatic primary amine, diaryl secondary amine and many other compounds containingfunctional groupImportant intermediates and products.[1]
Hydroxylation method
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There are many ways to introduce hydroxyl groups into compound molecules, includingreduction、Mark up、replace、oxidation、hydrolysis、condensationandrearrangementAnd other types of chemical reactions.For example, reducing fatty acids and their esters or otherOxygenates(such as aldehyde or ketone) reduction, and aromatics andethylene oxideCondensation to alcohol is an important method to synthesize alcohol compounds in industrial production.[1]
Direct hydroxylation of benzene to phenol
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There are mainly the following methods: (1) Benzene reacts with nitrous oxide;(2) Direct oxidation of benzene with molecular oxygen;(3) Benzene is directly oxidized with hydrogen peroxide.Although there are many studies, there are still some shortcomings, such as NtwoWhen O is used as oxidant, the reaction temperature is high and the cost is too high;With Otwo(Air), as an oxidant, is cheap and easy to obtain, and has cost advantage. Gas phase molecular oxygen oxidizes liquid phase benzene, and the reaction temperature is not high, but the yield and selectivity of the reaction are poor;With HtwoOtwoAs an oxidant, it is easy to reach under laboratory conditionstwo）The yield and selectivity of phenol as oxidant are relatively high, so HtwoOtwoAs an oxidant, the direct hydroxylation of benzene to phenol was studied.
1. Preparation of catalyst
There are many kinds of catalysts used in this experiment. Under laboratory conditions, the yield can reach more than 20% and the selectivity of phenol can reach more than 90%.This experiment usesSolid catalyst, select appropriate carrier, load a certain amount of active components, and use the impregnation method or public impregnation method to prepare.
2. Experimental operation steps
（1）A magnetic stirrerAdd 1mL benzene, 3mL hydrogen peroxide, 20mL acetonitrile and 0.25g catalyst (cms; GAC (Blank) - 450 ℃ respectively) into the two neck bottle of the reflux condenser tube;GAC (Fe) - 450 ℃) reacts at 70 ℃ for 5 hours, and samples once after 2 hours;(2) Stop reaction after 5 hours, sample, dilute to constant volume, useHigh performance liquid chromatographytesting.[1]
Steroid biotransformation hydroxylation
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There are many types of reactions involved in biotransformation, such as hydrogenation, dehydrogenation, ammoniation, deamination, phthalidation, lightening, despinning, hydrolysis, condensation, epoxidation, and phthalamidation;Halogenation, cooling, dehydration, methylation, phosphorylation, glycosyl transfer reaction, and disproportionation, isomerization, racemization of substrate molecules.Biotransformation has been successfully applied toSteroidEspecially the hydroxylation of steroids.The first hydroxylation reaction used in industrial production was the conversion of progesterone by Rhizopus niger to produce Ⅱ α hydroxy derivatives.In this paper, the research progress of hydroxylation in bioconversion of steroids is reviewed.[2]
Hydroxylation mechanism
Isotope tracerThe experimental research shows that the hydroxyl group converted to the steroid compound directly replaces the hydrogen position on the steroid carbon frame, and there is no change in the stereo configuration during the replacement process, nor is it completed through the formation of an olefin intermediate, that is, the stereo configuration (α or β configuration) of the hydroxyl group replacement is determined by the original space position of the hydrogen atom.The oxygen for hydroxylation does not come from the hydroxyl group (- OH) in water, but from the oxygen in air.This point theoretically explains the reason why industrial transformation of steroids with Rhizopus niger requires sufficient oxygen supply.Hoyam used pregnastero-3,20-dione on C11 and C12 sites replaced by H3 as a substrate to transform with Rhizopus niger. The results showed that the enzymatic hydroxylation of steroids was the direct substitution of hydrogen on the hydroxylation site.[2]
Effect of substrate solubility
In the process of bioconversion of steroid compounds, due to the poor solubility of steroid substrate, low mass transfer efficiency of culture medium, feedback inhibition of substrate products and whole cellBiocatalysisDue to many by-products, the transformation ability of strains and the transformation efficiency of steroids are still low, which is the main bottleneck for the industrialization of steroid biotransformation technology.
China isSteroidThe main producing countries of raw materials and preparations, with an annual output value of nearly 10 billion yuan, 70% of which are exported, andCorticosteroidsThe production scale of raw materials has ranked first in the world.DiosgeninThe gradual depletion of the "" has led to the rise in the cost of raw materials and the lack of international competitiveness of low-end synthetic products, which has brought a serious crisis to China's steroid drug industry.Therefore, efforts should be made to develop new steroid raw material resources and study green processes with high yield, low cost and little environmental pollution.
Steroid raw materials includePhytosterol, including β - sitosterol, stigmasterol, rape sterol, etc. They mainly come from legumes or oil refining leftovers.They have the parent core structure of steroids, so turning them into treasure can effectively solve the environmental pollution problem caused by hydrolysis of zingiber officinale.
Other sterol raw materials, such as those found in yeast and fungiErgosterol, also known asErgosterolIt is an important pharmaceutical and chemical raw material, which can be used in the production of hydrocortisone, progesterone and other drugs.
Because of the solubility of raw materialsSteroidTherefore, finding new and effective steroid drug precursor materials is still the main research direction of steroid biotransformation in the future.[2]
Studies on steroid hydroxylase
As early as 1981, Ghosh et al. first studied the Ⅱ α hydroxylation of progesterone by the cell-free extract of Aspergillusochraceus, and conducted a preliminary study on the Ⅱ α hydroxylase.The research shows that this enzyme is an inducible enzyme, which mainly exists in the supernatant of mitochondria after centrifugation of cell-free extract. Further centrifugation of this supernatant can obtain microsome and microsome rear supernatant. Both of them can not be hydroxylated when they exist alone, while the microsome part is added with NaIOfourIt is suggested that hydroxylase may be a multi enzyme systemhemoglobinSome of them are in microsomes, and the post microsome supernatant may contain the non hemoglobin part of the hydroxylase system.The in vitro hydroxylation activity of the enzyme was stimulated by cyanide, metorapone,Cytochrome P450It is further confirmed that microbial hydroxylation is mediated by cytochrome P450.[2]
