CN103819439B

CN103819439B - Hesperidin one pot synthesis prepares diosmetin

Info

Publication number: CN103819439B
Application number: CN201410042948.3A
Authority: CN
Inventors: 李玉山
Original assignee: 李玉山
Current assignee: Shaanxi Huifeng Pharmaceutical Co., Ltd.
Priority date: 2014-01-21
Filing date: 2014-01-21
Publication date: 2015-11-25
Anticipated expiration: 2034-01-21
Also published as: CN103819439A

Abstract

Hesperidin one pot synthesis prepares diosmetin, and this technology is through following steps: one pot reaction; Prepared by crude product; Prepared by fine work; Dry, pulverize, detect, mixing, packaging.To originally need two steps of two-step reaction synchronously to carry out in one step, and on reactor, automatic temperature control instrument will be installed, and avoid the rising of temperature in the past or decline by manual operation, greatly improving production efficiency; Especially the consumption of dehydrating agent only has 1 ~ 5% of traditional method, and production cost significantly reduces.The judgement of reaction end controls with high performance liquid phase, greatly improves the accuracy of reaction, avoids the acid hydrolysis of traditional method, and reaction conditions is gentle, and the time is short, and yield and purity are all higher, resources conservation, environmental friendliness.

Description

Hesperidin one pot synthesis prepares diosmetin

Technical field

The present invention relates to Hesperidin one pot synthesis and prepare diosmetin

Background technology

Diosmetin (Diosmetin) is a kind of flavonoid compound, yellow powder, molecular formula C ₁₆h ₁₂o ₆, molecular weight 300.26, fusing point 256 ~ 258 DEG C.Diosmetin has anti-oxidant, anti-infective, antishock and antimutagenic and anti-allergy characteristic effect, is widely used in functional foodstuff, makeup and future drugs.Have and suppress people CYP1A enzyme activity, suppress the carcinogenic activity of carcinogenic substance, as the antiviral for the treatment of HIV and other virus infection, the inhibitory preparation of map kinase, treats various inflammation, can diuresis, step-down, have moderate spasmolysis to unstriated muscle.Diosmetin can be extracted by the pericarp of lemon Citruslimon (L.) Burm, and production technique is primarily of operations such as extraction using alcohol, concentrated extraction, column chromatography, crystallizations, but output is very little, without suitability for industrialized production meaning.Prepare diosmetin by Hesperidin to be made up of two reactions, Hesperidin prepares diosmin, then obtains diosmetin by diosmin, or prepares Hesperitin by Hesperidin, then obtains diosmetin by Hesperitin.

At present, prepare diosmetin both at home and abroad and have two kinds of modes: natural extract and semi-synthetic.Semi-synthetic is directly prepared by Hesperitin one step or obtain diosmetin from Hesperidin through two-step reaction.Hesperidin prepares Hesperitin, then prepares diosmetin by Hesperitin, or Hesperidin prepares diosmin, then prepares diosmetin by diosmin.No matter being directly prepare from Hesperitin or prepare by Hesperidin, is that raw material all could will be prepared through two-step reaction according to Hesperidin, and the large usage quantity of iodine.Natural extract step is numerous and diverse, and yield is low.Take a broad view of domestic and foreign literature, Hesperidin prepares diosmin roughly three kinds of modes: bromine dehydrogenation; Iodine dehydrogenation; The dehydrogenation of NBS/ peroxidation toluoyl.1) yield of the people such as bromine water is reacted in two steps to Hesperidin dehydrogenation, HorowitzRobertM.GeatiliRuno report only has 56.2%, content 92.0%, and technique is loaded down with trivial details, complicated condition, and will use toxic reagent bromine water, and cost is high; Bromine gas is to Hesperidin dehydrogenation, and Yang Ailing recognizes bromine gas to Hesperidin dehydrogenation, yield 56%, and yield is low, and will use aceticanhydride, methylene dichloride, and reagent is more, operational difficulty.2) NBS/ peroxidation toluoyl is to Hesperidin dehydrogenation, complex process, is substantially divided into three steps: 1. parent nucleus acetylize is to protect all hydroxyls; 2. the generation of parent nucleus 2,3 double bonds is with oxygenant or bromizating agent process acetylize parent nucleus; 3. the removing with the above-mentioned product removal ethanoyl of the dilute alcohol solution process of alkali of parent nucleus ethanoyl.The people such as HorowitzRobertM.GeatiliRruno recognize NBS/ peroxidation toluoyl to Hesperidin dehydrogenation, and need special reagent, cost is higher, and yield is low, is all not suitable for suitability for industrialized production.3) iodine is to Hesperidin dehydrogenation, and adopt iodine/pyridine dehydrogenation, only have single step reaction, the people such as Zhang Sigui, Zhang Wei adopt iodine to Hesperidin dehydrogenation, and yield reaches 94%, and content is not quite clear.The people such as Feng Xuan adopt iodine dehydrogenation, and the yield only people such as 70%, Dan Yang adopts iodine/pyridine dehydrogenation, and yield is higher, but content is not quite clear.Luo Meng with bromine and iodine two kinds of yields only 58%, content 89%.Yield and content higher, but cost is higher, and mainly the consumption of iodine is too large, and the consumption how reducing iodine becomes the core of technology.The principal feature of traditional technology is that operational path is complicated, the production cycle is long, yield is low, cost is high.It is harsh that diosmin prepares diosmetin condition, and need specific installation, react for a long time under pressurized high-temperature, yield and purity are not high, and environmental pollution is large.

Diosmin at present with France and Spain be main grown place, the NBS/ peroxidation toluoyl generally adopted is to Hesperidin dehydrogenation.Product yield 56%, content 90%, processing condition: aceticanhydride is acetylation reagent and reagent, pyridine is as the catalyzer of acetylization reaction, feed ratio is m (Hesperidin): m (aceticanhydride): m (pyridine)=1: 7: 0.5, intensification stirring and dissolving, 123 ~ 125 DEG C of insulations are after 10 hours, reclaim aceticanhydride sticky until evaporate to dryness to material, be cooled to less than 70 DEG C, every part of Hesperidin adds 7.5 part 1, 2-ethylene dichloride dissolves, dissolve logical 0.3 part, bromine gas completely to stir 2.5 hours, methyl alcohol 4.5 parts is added after adding 3 parts of water washings, 5.5 parts, water, 0.95 part, sheet alkali, stir 35 minutes, hydrolysis temperature 50 DEG C, leave standstill 1 hour, separate ethylene dichloride, add acetic acid and adjust pH=7 crystallization, filter and both obtained diosmin product.The principal feature of traditional technology is that Technology is very complicated, the production cycle is long, yield is low, cost is high.In the synthesis technique of diosmin, the purity of its raw material Hesperidin abstraction and purification is the key factor ensureing synthesis diosmin content yield, and controlling reasonable operation condition, is the principal element affecting diosmin quality and yield.

The present invention adopts Hesperidin to be that raw material one pot synthesis prepares diosmetin, will originally the process simplification of two-step reaction be needed to be that single step reaction carries out, reaction conditions is gentle, time is short, yield and purity are all higher, the consumption of non-environmental-pollution problem, especially key reagents only has 1 ~ 5% of traditional technology, and production cost significantly reduces.Crude product preparation process is owing to containing a large amount of impurity in reaction enriched material, and used alkali extraction-acid precipitation in the past, the product yield obtained is low, color is reddish-brown, uses the precipitator method now, and yield is high, content is high, and color and luster is good, and quality prepared by crude product is related to the yield of product and the quality condition of fine work.With vinegar acid instead of HCl in fine work preparation, the product color obtained is better.Reacting tank body temperature controls between 90 ~ 110 DEG C, under agitation back flow reaction 5 ~ 16h, detects diosmetin reaction solution, Hesperidin residual quantity≤0.5% (area normalization method) in reactant in span of control, illustrate that reaction controlling is rationally effective, can constant product quality be ensured; Distillating recovering solvent under the condition of temperature 80 ± 2 DEG C, vacuum tightness-(0.06 ~ 0.08) Mpa, effectively can reduce the residual quantity of solvent in reactant, operate in span of control, obtain diosmetin crude product in span of control.Diosmetin wet product is transferred in drying machine, dry under the condition of temperature 80 ± 2 DEG C, all parameters all within span of control, diosmetin moisture content≤6.0%.Through to repeatedly to diosmetin detection statistics, average content is 98.68%, and average moisture average 4.96%, sulfated ash is less than 0.1%.From above result, the diosmetin process of producing product of diosmetin Workshop Production is in slave mode, controls result all in specialized range.

Summary of the invention

First one pot reaction: quantitative Hesperidin is dissolved in the solvent orange 2 A of metering, adds auxiliary material B, and C reacts at a certain temperature, high performance liquid phase controls reaction end, obtains diosmetin reaction solution.

Second crude product preparation: reaction solution is reddish-brown, and concentrating under reduced pressure obtains enriched material, adds purified water and fully stirs, press filtration, and filter cake adds pure water again and stirs into pasty state, precipitation, press filtration, and washing, obtains diosmetin crude product.

3rd fine work preparation: diosmetin crude product, with after dissolution with solvents, adds activated carbon decolorizing, filters, refining, obtains diosmetin fine work.

3rd fine work is dry: diosmetin wet product transferred in drying machine dry, weigh.

4th pulverizes, mixing, packaging: pulverized by dried spiceleaf art element pulverizer, has pulverized rear sampling and has detected, mixing, packaging.

Embodiment

In mode one: 500Kg reactor, add 300.0Kg solvent orange 2 A, slowly add Hesperidin 100.0kg, and then add auxiliary material B 1.0 ~ 3.0kg, auxiliary material C3.0 ~ 4.5kg is slowly heated to 90 ~ 100 DEG C under stirring, and reacts 5 ~ 16h at this temperature.Sample thief detects the content of diosmetin, stopped reaction after content of hesperidin is lower than 0.5%.Vacuum tightness be-(0.01 ~ 0.07) Mpa under recycling design, in residue, add 500 ~ 1000L purified water, slightly heat, filter after fully stirring into pasty state, obtain yellow filter cake, filter cake is added purified water again and stir into pasty state, precipitation, filters, and obtains the crude product that diosmetin is wet.Diosmetin crude product is dropped in treatment tank and adds 500 ~ 800L purified water, fully stir into pasty state, add 10% sodium hydroxide solution 50 ~ 100L, abundant stirring and dissolving, adds 1.5 ~ 2.5kg gac, is heated to 40 ~ 60 DEG C of insulation 30min, filter, filtrate is limpid yellowish brown, adjusts neutral postprecipitation 5 ~ 12h with Glacial acetic acid, press filtration, filter cake purified water 3 × 500L washs, and is filtered dry, and obtains the fine work that diosmetin is wet, transfer in DoubletaperedVacuumdrier, temperature 70 ± 5 DEG C of dryings.Pulverized by dried diosmetin pulverizer, pulverized rear sampling and detected, determine mixed batch batch, joined total mixed machine, mixing completes.Material is divided in polyethylene packaging bag, and sampling detects, and pricks sealing, overlaps the 2nd layer of packing bag, pricks sealing, outsourcing, and labeling is put in storage.

In mode two: 1000Kg reactor, add 600 ~ 700Kg solvent orange 2 A, Hesperidin 200kg is slowly added in reactor, abundant stirring and dissolving, and then add auxiliary material B 2.0 ~ 3.0kg, auxiliary material C6.5 ~ 8.5kg, abundant stirring, is slowly heated to 90 ~ 100 DEG C, reacts 1 ~ 10h at this temperature, extract reaction solution the content detecting diosmetin, content of hesperidin is lower than 0.5% rear stopped reaction.Vacuum tightness be-(0.01 ~ 0.06) Mpa under recycling design, obtain diosmetin concentrated solution, 800 ~ 1500L purified water is added in concentrated solution, abundant stirring 30min, filter, obtain yellow filter cake, filter cake is stirred into pasty state with 500 ~ 800L purified water, filter, obtain diosmetin crude product.Diosmetin crude product is dried, drops in treatment tank and add 1000 ~ 1500L methyl alcohol, reflux, abundant stirring and dissolving, adds 2.5 ~ 4.5kg gac insulation 30min, filters, filtrate is limpid yellowish brown, be evaporated to 200L, adjust pH5 ~ 6 post crystallization with Glacial acetic acid, centrifugal, filter cake 3 × 800L purified water is washed, obtain the fine work that diosmetin is wet, transfer in DoubletaperedVacuumdrier, temperature 60 ± 5 DEG C of dryings.Pulverized by dried diosmetin pulverizer, pulverized rear sampling and detected, determine mixed batch batch, joined total mixed machine, mixing completes.Material is divided in polyethylene packaging bag, and sampling detects, and pricks sealing, overlaps the 2nd layer of packing bag, pricks sealing, outsourcing, and labeling is put in storage.

Claims

1. Hesperidin one pot synthesis prepares a method for diosmetin, it is characterized in that, take Hesperidin as raw material, the method is successively through following steps:

(1) one pot synthesis reaction: Hesperidin adds auxiliary material B after dissolving in solvent orange 2 A, C reaction, obtains diosmetin reaction solution, and described solvent orange 2 A is one of in pyridine, Isosorbide-5-Nitrae-dioxacyclohexanes, dimethyl formamide, methane amide; Auxiliary material B is one of in iodine, bromine water; Auxiliary material C is one of in sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide; The mass ratio of Hesperidin and solvent orange 2 A is: 1: 4 ~ 1: 8; The mass ratio of Hesperidin and auxiliary material B is: 1: 0.01 ~ 1: 0.05; The mass ratio of Hesperidin and auxiliary material C is: 1: 0.03 ~ 1: 0.1; Temperature of reaction is 90 ~ 100 DEG C;

(2) crude product preparation: diosmetin reaction solution concentrating under reduced pressure, adds purified water and fully stir, filter, filter cake adds purified water again and stirs into pasty state, precipitation, filters, obtains the diosmetin crude product wet;

(3) fine work preparation: add solvent in dissolution kettle, add diosmetin crude product, stirring and dissolving, add activated carbon decolorizing under stirring, filters, and can obtain the wet fine work of diosmetin by filtrate;

(4) dry, pulverize, mixing, packaging: the fine work that diosmetin is wet is transferred in DoubletaperedVacuumdrier dry.

2. a kind of Hesperidin one pot synthesis as claimed in claim 1 prepares the method for diosmetin, it is characterized in that, in step (2), concentration of reaction solution proportion is 1.0 ~ 1.3, adds purified water and is settled out diosmetin, filters and obtains crude product.

3. a kind of Hesperidin one pot synthesis as claimed in claim 1 prepares the method for diosmetin, it is characterized in that, solvent one of to can be in 5 ~ 30% sodium hydroxide, 5 ~ 30% potassium hydroxide solutions, methyl alcohol, ethanol or acetone in step (3).

4. a kind of Hesperidin one pot synthesis as claimed in claim 1 prepares the method for diosmetin, it is characterized in that, in step (3), the acquisition of fine work can adopt alkali extraction-acid precipitation, and buck dissolves, add activated carbon decolorizing, cross elimination insolubles, obtain diosmetin alkali aqueous solution, regulate potential of hydrogen, precipitation, filter, washing, obtains the fine work diosmetin wet.

5. a kind of Hesperidin one pot synthesis as claimed in claim 1 prepares the method for diosmetin, it is characterized in that, in step (3), the acquisition of fine work adopts methyl alcohol, ethanol or acetone heating for dissolving after diosmetin crude product can being dried, and adds activated carbon decolorizing, crosses elimination insolubles, obtain diosmetin solution, concentrated, crystallization, centrifugal, washing, obtains the fine work diosmetin wet.