CN104803845B - A kind of synthetic method of medicinal citrate - Google Patents
A kind of synthetic method of medicinal citrate Download PDFInfo
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- CN104803845B CN104803845B CN201410511185.2A CN201410511185A CN104803845B CN 104803845 B CN104803845 B CN 104803845B CN 201410511185 A CN201410511185 A CN 201410511185A CN 104803845 B CN104803845 B CN 104803845B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/1608—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes the ligands containing silicon
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/49—Esterification or transesterification
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a kind of synthetic method of medicinal citrate, particularly one kind prepares mesoporous molecular sieve carried heteropolyacid catalyst by in-situ synthesis, catalytic citric acid and ethanol, n-butanol reaction synthesize a kind of citric acid mixed ester crude product, then the method for citric acid mixed ester finished product are obtained through polishing purification.This method reaction condition is gentle, and the reaction time is short, and the repeatable recovery of catalyst uses, and is adapted to industrialized production.In addition, product esterification yield is high, mixed ester compensate for the deficiency of single citrate product while two kinds of citrate advantages are combined, more excellent compared to single citric acid ester type performance.
Description
Technical field
The invention belongs to organic synthesis field, is related to a kind of synthetic method of citrate, and in particular to a kind of mesoporous molecular
The method that sieve carried heteropoly acid catalyzes and synthesizes citrate.
Background technology
Citric acid ester plasticizer is a kind of environment-friendlyplasticizer plasticizer of non-petroleum feedstocks production, in American-European-Japanese flourishing state of grade
Family, realizes industrialization to it already.And China has also started few as the second largest producing country of citric acid, the country in last century end
Industrialized production is measured, and enters market in the beginning of this century.
Citric acid ester plasticizer is considered as that can substitute environmental protection ideal in phthalic ester plasticizer
Type plasticizer, it is not only nontoxic, without specific peculiar smell, and has extraordinary plasticization to PVC, speedup effect and DOP, DINP
Quite, almost can be with 1:1 substitutes DOP.But because its price is of a relatively high, it is currently used primarily in the neck that non-toxic and safe requires high
Domain.For example, the U.S., Europe have allowed for citric acid ester plasticizer product as package plastics of food processing film, plastics
Virgin toy processing, medicine parcel and medicine equipment manufacture etc. and human body close contact, and require the plasticising of higher plastic product
Agent.
Two principal items of citric acid ester type are：Triethyl citrate（Triethyl Citrate, also known as citric acid three
Ethyl ester, molecular formula C12H20O7）, and ATBC（Tributyl Citrate, also known as tributyl citrate, molecular formula
For C18H32O7）.
It is colourless, slightly lemon fragrance transparency liquid under triethyl citrate normal temperature, solubility is 6.5g/ in water
100ml（25oC）, most of organic solvents are dissolved in, are insoluble in oils.With most of celluloses, polyvinyl chloride and chlorinated rubber etc.
There is good compatibility.It is organic molten with majority and ATBC is the higher boiling oily liquids of colorless and odorless at normal temperatures
Agent is dissolved each other, and is slightly soluble in water.With polyvinyl chloride, polystyrene, vinyl chloride-vinyl acetate copolymer, nitrocellulose, ethyl cellulose
The resins such as element, polyvinyl butyral resin are compatible.Citric acid ester plasticizer can be widely used for as a kind of non-toxic plastic plasticizer
Among commodity, food, medical packaging, cosmetics etc., there is plasticizing efficiency height, volatility is small, is easily biodegradable, does not grow
The advantages that mould, and cold resistance, light resistance and have excellent water-resistance, thus it is wide concerned.
U.S.'s food and Drug Administration（FDA）Approved citric acid ester type is as nontoxic plasticizer, for food
Packaging, medical apparatus, toy for children and personal hygiene article etc..In medicament manufacture, triethyl citrate and citric acid
Tributyl is then generally used for the plasticity of pharmaceutical preparation coating material.It is related to capsule, tablet, pilule granule in terms of coating
Etc. formulation, it is therefore an objective to for taste masking or quick-release and enteric prescription.In addition, citric acid ester type can also be directly used as food addition
Agent, play a part of flavoring, solubilising or surfactant.
Industrially, the preparation method of triethyl citrate and ATBC is by citric acid and ethanol or positive fourth
Alcohol, by controlling reaction temperature and reaction time, is esterified under the conditions of existing for corresponding catalyst and obtains corresponding semi-finished product, most
Afterwards purer esters product is obtained by purifying.Traditional esterification makees catalyst using the concentrated sulfuric acid, although catalytic effect compared with
It is good, but the concentrated sulfuric acid has highly acid and strong oxidizing property, it is big to the corrosivity of equipment, require high, while side reaction easily occurs, such as
Organic matter is carbonized by the concentrated sulfuric acid, ethanol self-condensation into ether etc., cause the yield of product low, and cause product quality problem：
Product purity is low, color and luster is poor, it is easy acidifying, the term of validity it is short.
With the appearance of the corresponding policy of the development of national economy and country, the demand of non-toxic plastic is growing day by day, to plasticising
The requirement of agent is also more and more stricter.Again because China's lemon acid yield occupies the second in the world, thus it is existing in recent years more and more
Researcher the synthetic method of citrate is explored and studied, its emphasis point is the selection and presence of catalyst
Form, it is intended to improve process conditions, be allowed to lower to equipment requirement, condition milder, react more controllable.
CN102079704A discloses a kind of preparation method of triethyl citrate, wherein by adding the concentrated sulfuric acid or benzene
Sodium sulfonate carries out back flow reaction as catalyst, and reaction end is determined using phenolphthalein as indicator and using sodium hydroxide titration,
Post-treated again and purifying obtains triethyl citrate sterling.Although this method is by strictly controlling reaction end, it is possible to reduce
Unnecessary side reaction, the waste of product quality and cost caused by preventing from reacting insufficient or overlong time.But use dense
Sulphur acid as catalyst, however it remains selectivity is relatively low, accessory substance is more, and product yield is undesirable, at, the three wastes big to equipment corrosion
Reason requires high inferior position.
CN102659591A discloses a kind of method that continuous catalysis prepares triethyl citrate, for being urged in such scheme
Agent is easy to run off, the problems such as aftertreatment technology complexity, it is proposed that uses fixed bed continuous catalytic reaction device to carry out citric acid three
The production of ethyl ester, using the styrene type cation exchange resin of supported Lewis acid as catalyst, it is loaded into series connection and fixes
In bed, reactant enters from reactor head, and by intermediate catalytic layer, esterification, reaction production occur under heat-retaining condition
Thing is discharged from reactor bottom, and is entered among gas-liquid separation device, and unreacted ethanol is discharged on gas-liquid separation device top, under
Portion discharges triethyl citrate crude product, through being refining to obtain sterling.But because catalyst is carried on resin, it is not easy to carry out clearly resin
Clean and regeneration, easy cooperating microorganisms, thus can not ensure that the microbial limit of product and other quality regulations disclosure satisfy that medicine
With requiring.
CN1762969A discloses a kind of method of mesoporous material catalytic citric acid tributyl, the HAl- used in patent
MCM-41 mesopore molecular sieves have a disadvantage that：1. acid centre is ammonium nitrate roasting gained, chemical bond is not formed with carrier
Bonding, is easily lost in the reaction；2. ammonium nitrate roasting gained activated centre is H+, acid strength is smaller, citric acid conversion ratio compared with
It is low.
CN201010535730.3 discloses a kind of catalyst for synthesizing citric acid tributyl and preparation method thereof, institute
Highly acid mesoporous material that catalyst is prepared using hydrothermal synthesis method is stated as carrier, with the side of surface modification on mesoporous material carrier
Formula is chemically bonded acidic ion liquid, and mesoporous material is mesoporous silicon, mesoporous zirconium or mesoporous titanium, and acidic ion liquid is to contain phosphorus
The ionic liquid of acid group or sulfate radical.Use the catalyst citric acid conversion ratio 90~99%.
CN200610024372.3 discloses a kind of method that heterogeneous catalysis prepares ATBC, and it is closed in ester
The preparation process of carbon-based sulfonic acid, it is that the 8~15ml concentrated sulfuric acid is added into 10~15g during using carbon-based sulfonic acid as catalyst
In C 9 fraction of cracking, 200~250oC carries out 3~5h of heating response, and then addition boiling water carries out backflow and stirs 2~4h, filters,
130~150 DEG C of bakingsoC is done, and obtains carbon-based sulfonic acid.
It is above-mentioned in the prior art there is building-up process is complicated, reaction time length, the restricted height of reaction condition, catalyst into
The shortcomings that this height, relatively low product quality controllability, it is poorly suited for industrialized production.In addition, at present also there is not yet make simultaneously
The patented method that esterification is carried out with two kinds of different alcohols and citric acid is reported.
Heteropoly acid is by hetero atom（Such as P, Si, Fe, Co）And polyatom（Such as Mo, W, V, Nb, Ta）By certain knot
A kind of condensation oxyacid that structure is made up of oxygen atom ligand bridging, has very high catalytic activity, is a kind of even intensity
Bronsted acid, and have redox ability.The species of heteropoly acid is various, by changing heteropolyanion, anti-lotus cation and knot
The composition of brilliant water or organic molecule, can design and synthesize different heteropoly acids.The structure type of conventional heteropoly acid is A types
（Structure with Keggin）, formula is represented by HnXM12O40, wherein include the tertiary structure of polyacid again, primary structure refer to it is more it is cloudy from
The structure of son, can represent the component and number of polyacid, and between them combination skeleton structure.The two level of polyacid
Structure refers to that polyanionic combines the crystal structure of obtained polyacid and its salt with gegenion.The tertiary structure of polyacid refers to more
Anion, gegenion and crystallization water three parts form, and can represent as follows.
Generally, heteropoly acid stability is good, and catalytic effect is excellent, and environmentally safe, is a kind of promising
Green catalyst, available for alkylating aromatic hydrocarbon and dealkylation, esterification, dehydration/combination reaction, redox reaction
And open loop, condensation, addition and etherification reaction etc..Reported in document using silico-tungstic acid as catalyst synthesizing citric acid tributyl,
Optimum experimental condition is：Citric acid 2.1g, n-butanol 55mL, silico-tungstic acid 0.3g, reaction temperature 145oC, reaction time is
2.5h, esterification yield is up to 98.3%, and product purity is up to more than 98%.Liu Chuntao etc. have studied with Keggin types phosphotungstic acid and silicon
Wolframic acid is the reaction of catalyst synthesizing citric acid tributyl.During to experiment condition such as raw material ratio, catalyst amount, esterification
Between, reaction temperature etc. explored, propose that optimal enzymatic synthesis condition is：The g of heteropoly acid 0.2, the g of citric acid 3.0, acid alcohol mole
Than for 1:3.4th, the condition that the reaction time is 3 h, reaction temperature is 145 ~ 150 DEG C, esterification yield can reach 97.04%.
Understand that heteropolyacid catalyst has very high catalytic activity and selectivity to citrate by above-mentioned document.But
Heteropoly acid specific surface area is smaller（＜ 10m2/g）, catalytic activity can not give full play to, and heteropoly acid dosage is larger, and is being contrary
The problems such as difficult recovery, pollution environment are still suffered from answering, limits the popularization of heteropoly acid in the industrial production to a certain extent
Using.Therefore, on the premise of ensureing that its catalytic effect do not reduce, seek that a kind of dosage is less, the presence shape of recoverable
Formula is particularly important.
At present, prior art uses a variety of distinct methods that on carrier, loaded by heteropoly acid is allowed into immobilized, used
The main porous material such as active charcoal, ion exchange resin, metal oxide and molecular sieve of carrier.Certainly, catalyst can also
Only it is attracted to intermolecular force in molecular sieve, but this active force is extremely weak compared with covalent bond, easily causes to urge
Agent De contamination and be lost in.But using metal oxide as carrier loaded heteropoly acid, knot of the alkalescence of carrier to heteropoly acid in itself
Structure destruction is larger, and the increase rate of specific surface area is limited；And easily swelling inactivates ion exchange resin in the solution.Activated carbon
Although as pH stability of the carrier with higher specific surface area and relative broad range, catalytic activity is good, its exist compared with
The problem of serious heteropoly acid active material solution-off.
Therefore, people begin one's study molecular sieve carried heteropoly acid.Molecular sieve is a kind of porous media with special construction,
It is made up of a series of irregular ducts or cage.Due to special structure, determine that it has special nature, especially divide
The excellent properties shown when son sieve is as heteropoly acid carrier, by load, specific surface area, the heat for not only increasing heteropoly acid are steady
It is qualitative, and its catalytic activity and reusability are also improved, and solve and presently, there are in heteropoly acid industrial applications
The problem of.At present, report that the molecular sieve carrier for carried heteropoly acid mainly has MCM series, SBA-15, Y in domestic and foreign literature
Type and HMS molecular sieves etc..And the carrying method of generally use has infusion process, backflow absorption method, sol-gel process, hydro-thermal decentralization
Method and in-situ synthesis.Phosphorus heteropoly tungstic acid catalyzer is loaded as document report is prepared for SBA-15 using infusion process, and is applied to
The synthesis of triethyl citrate, the factor for influenceing reaction is investigated.As a result show, back flow reaction 3h, catalyst amount is raw material
The 1.0% of quality, acid alcohol mol ratio are 1:When 4, triethyl citrate yield is more than 90%.Ou Zhiyi etc. have studied Sol-gel
Immobilization catalysis of phosphotungstic acid citric acid and n-butanol synthesizing citric acid tributyl, in the ratio between amount of acid alcohol material 1:4, catalyst is used
Amount 2.5%, reaction time 3.5h, reaction temperature 140 ~ 145oC, yield are more than 95%, and catalyst is reused 7 times, and yield still reaches
More than 87%.
In fact, because the interaction between heteropoly acid and carrier surface substantially belongs to acid-base reaction, so with
The difference of carrier surface hydroxyl Acid-Base strengths and heteropoly acid intensity, the result that both interact form acid strength and load jail
Gu different active bodies, have influence on the activity and solution-off amount of carried heteropoly acid catalyst in the reaction.However, mesopore molecular sieve
Hydroxyl Acid-Base strengths it is whard to control be also difficult to adjust, therefore can repair by changing the molecular composition of heteropoly acid or through metallic atom
Decorations, to adjust the acid strength of heteropoly acid and redox property.
In summary, larger and more serious solution-off of the catalyst amount that is still had for carried heteropoly acid etc.
Problem, the present invention is on the basis of substantial amounts of exploitative experiment, creatively using PdCl2Heteropoly acid is modified, obtained
And non-obvious beneficial effect, successfully solve the major issue that above-mentioned carried heteropoly acid presently, there are.
The content of the invention
The defects of in order to overcome above-mentioned prior art to exist, the invention discloses a kind of synthesis side of medicinal citrate
Method, it is particularly a kind of that mesoporous molecular sieve carried heteropolyacid catalyst, catalytic citric acid and ethanol are prepared by in-situ synthesis
Occur esterification simultaneously with n-butanol, synthesizing citric acid ester crude product, then the method for obtaining through polishing purification citrate sterling.
Therefore, the invention discloses one kind to utilize mesoporous molecular sieve carried heteropolyacid catalyst, and catalytic citric acid is with mixing
The esterification of alcohol, the method for preparing nontoxic green pharmaceutical grade citric acid mixed ester, including：
A, mesoporous molecular sieve carried heteropolyacid catalyst is made by in-situ synthesis；
B, citric acid, ethanol, n-butanol and catalyst are mixed according to certain ratio, using n-butanol as water entrainer,
Back flow reaction 4 hours are incubated under certain temperature；
C, after reaction terminates, filtering and washing recovery catalyst, crude product is after being distilled off excess ethyl alcohol and n-butanol, warp
Activated carbon decolorizing adsorption-edulcoration, citrate sterling is evaporated under reduced pressure to again.
Wherein, the in-situ synthesis described in step a prepares mesoporous molecular sieve carried heteropolyacid catalyst, is first
Template is dissolved in acid medium template solution, the heteropoly acid solution for being again modified tetraethyl orthosilicate and palladium is made
With template solution hybrid reaction, crystallized, washing, filtering, dry, roasting are made.
Further, in step a, used catalyst is made by tetraethyl orthosilicate, template P123 and heteropoly acid in reaction,
The mass ratio that feeds intake for 1：0.2~0.4：0.13~0.56.
Further, the use of catalyst it is made by tetraethyl orthosilicate, P123 and heteropoly acid in reaction, feed intake matter in step a
Amount is than being 1:0.3:0.39.
Further, in step a, the template is P123, the heteropoly acid that palladium is modified be selected from the phosphorus heteropoly tungstic acid that palladium is modified,
The silicon that silicotungstic heteropolyacid, phosphato-molybdic heteropolyacid, silicon-molybdenum heteropoly acid, phosphorus tungsten heteropoly acid and silicon tungsten heteropoly acid, preferably palladium are modified
Heteropoly tungstic acid Pd-H4SiW12O40。
Further, in step a, the heteropoly acid that palladium is modified can obtain by the following method：A certain amount of heteropoly acid is weighed,
After being dissolved with distilled water, then mix with PdCl2 solution 2 hours, then dried 6 hours at 120 DEG C in equal volume, then 250
It is calcined 2 hours, produces at DEG C.
Further, in step a, heteropoly acid and PdCl2Mass ratio be 50 ~ 150:1.
Further, in step b, catalyst, citric acid and ethanol, the mass ratio that feeds intake of n-butanol mixed alcohol are catalyst：
Citric acid：Ethanol, n-butanol mixture=1:150~300:150~450.
Further, in step b, the water entrainer n-butanol of addition and the mass ratio that feeds intake of citric acid are 0.5 ~ 1：1.
Further, the reaction time is preferably 4 hours, and heating response, temperature are carried out by the way of temperature programming
Gradient is 70oC（1h）→85oC（1h）→100oC（1h）→80oC。
Further, above-mentioned preparation method can be implemented by a kind of following concrete scheme：
A. the preparation of catalyst
1st, weigh after a certain amount of heteropoly acid dissolves with distilled water, then with PdCl2Solution mixing 2 in equal volume
Hour, then 120oDried 6 hours under C, then 250oIt is calcined under C 2 hours, that is, the heteropoly acid that palladium is modified is made；
2nd, a certain amount of template P123 is dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving,
30~50oUnder C, the tetraethyl orthosilicate of certain volume and heteropoly acid solution are slowly added dropwise P123 solution respectively,
Continue constant temperature stirring 3-5h；Then 80o36 hours are stood still for crystals under C；Product is washed to neutrality after taking-up, filtering to consolidate
Body, dry at room temperature, 500oC roasting a period of times obtain the heteropolyacid catalyst being carried on SBA-15 of fabricated in situ.
B. the synthesis of citrate
Citric acid, ethanol and n-butanol are weighed, according to certain mass than in input reaction unit, it is miscellaneous more to add solid supported
Acid catalyst, using n-butanol as water entrainer, reacted 4 hours under the conditions of temperature programming.After reaction terminates, filtering, catalyst is reclaimed,
With alcohol flushing 2 ~ 3 times, decompression boils off a large amount of alcohol, repeatedly washs residue with 10% sodium bicarbonate aqueous solution, divide sub-cloud water
Layer obtains citric acid mixed ester crude product.The activated carbon of crude product weight 1%, filtering are added into crude product, filtrate is evaporated under reduced pressure in 120 DEG C,
Obtain the citrate sterling of water white transparency.
Mesoporous molecular sieve carried heteropolyacid catalyst of the present invention, manufactured citrate have higher esterification yield
And purity.The species and its method of modifying of heteropoly acid used, dosage and its be through excessive with the mode of loading of mesopore molecular sieve
Amount experiment finally determines.
The beneficial effects of the present invention are：
1. use triblock copolymer（P123）As template, and the synthesising mesoporous molecular sieve of tetraethyl orthosilicate,
Si-OH quantity in the aperture and hole of mesopore molecular sieve is effectively expanded, relative to commercial silica gel and with hexadecane
For the mesopore molecular sieve that base trimethylammonium bromide synthesizes with tetraethyl orthosilicate, load capacity and catalytic efficiency are improved, is reduced
The loss of catalyst；Above-mentioned mesoporous molecular sieve carried heteropoly acid is used again, by loading, can not only improve the ratio of heteropoly acid
Surface area, heat endurance, and its catalytic activity and its reusability are also improved.
2. being modified using palladium to heteropoly acid, the acidity of heteropoly acid can be not only influenceed to a certain extent, is made miscellaneous
The combination of polyacid and mesopore molecular sieve is even closer, heteropoly acid is not easy solution-off, and by the miscellaneous more of palladium modification
Acid, normal load type heteropolyacid catalyst is compared to, its dosage is greatly decreased, and catalytic activity is stronger, and catalytic efficiency is higher.
3. prior art synthesizes the catalyst using the method for fractional steps, i.e. first synthesising mesoporous molecular sieve, then by loaded by heteropoly acid
Thereon, this load effect efficiency is low, and in heteropoly acid molecular sieve pores more difficult to get access, easily causes heteropoly acid
Waste and be lost in.In the present invention program, using " in-situ synthesis ", after triblock copolymer is first dissolved, then by positive silicic acid
Tetra-ethyl ester and heteropoly acid solution add simultaneously, make the formation of mesopore molecular sieve load while carry out with being bonded for heteropoly acid so that
Heteropoly acid can carry out pay(useful) load in the surface of molecular sieve and hole, greatly improve load efficiency, so as to significantly improve
Catalytic efficiency.
4. esterification occurs simultaneously with citric acid with ethanol and n-butanol, can synthesize in three ends position of citric acid
Citric acid mixed ester of the generation with the substitution of different alcohol on carboxyl.This mixed ester not only can be with combining citric acid three
The respective advantage of both ethyl ester and ATBC, and compensate for existing deficiency each other.
5. being reacted by ramped heating schedule, ethanol, n-butanol and citric acid can be made fully to occur as far as possible anti-
Answer, effectively improve the esterification yield of product.
Embodiment
Following examples not do further restriction to further illustrate the present invention to the present invention.It should be appreciated that this
Art personnel can do to the parameter of scheme on the basis of the present invention program is fully understood, after being enlightened and repair in right amount
Change, these modifications are also in protection scope of the present invention.
The method for preparing the described catalyst for synthesizing citric acid ester, step are：
The first step, weigh after a certain amount of heteropoly acid dissolves with distilled water, then with PdCl2Solution is isometric
Mixing 2 hours, then 120oDried 6 hours under C, then 250oIt is calcined under C 2 hours, that is, the miscellaneous of palladium modification is made
Polyacid, wherein heteropoly acid and PdCl2Mass ratio be 100:1；
Second step, after a certain amount of template P123 is fully dissolved, 30 ~ 50oUnder C, by certain volume just
Silester and heteropoly acid solution are slowly added dropwise P123 solution respectively, after continuing back flow reaction for a period of time,
Stand still for crystals, wash, filtering, drying, then 500oIt is miscellaneous on SBA-15 that C roasting a period of times obtain being carried on for fabricated in situ
More acid catalysts.
The acid number of product and the conversion ratio of citric acid（Esterification yield）Calculated and obtained by below equation：
Y=（1-k/k0）×100%；
K0The acid number of forward and backward system is respectively reacted with k；
Acid number k=40 × 10-3×V×C/m；
V and C is respectively NaOH volume and concentration.
Embodiment 1：
2g P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, 40oUnder C, by 10ml
Tetraethyl orthosilicate and 1.3g Pd-H4SiW12O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature
Stir 5h.Then 80o36 hours are stood still for crystals under C, washs product to neutrality after taking-up, solid is filtered to obtain, does at room temperature
It is dry.Finally, 500oC roasting a period of times obtain finished catalyst.
Embodiment 2：
10g P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, 40oUnder C, by 50ml positive silicic acid
The Pd-H of ethyl ester and 6.5g3PW12O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature stirring 5h.Then 80oC
Under stand still for crystals 36 hours, product is washed to neutrality after taking-up, solid is filtered to obtain, dries at room temperature.Finally, 500oC is roasted
Burn and produce finished catalyst for a period of time.
Embodiment 3：
30g P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, 40oUnder C, by 50ml positive silicic acid
The Pd-H of ethyl ester and 39g3PMo12O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature stirring 4h.Then 80oC
Under stand still for crystals 36 hours, product is washed to neutrality after taking-up, solid is filtered to obtain, dries at room temperature.Finally, 500oC is roasted
Burn and produce finished catalyst for a period of time.
Embodiment 4：
100g P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, 40oUnder C, by 330ml positive silicon
The Pd-H of acetoacetic ester and 185g4SiMo12O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature stirring 4h.Then exist
80o36 hours are stood still for crystals under C, washs product to neutrality after taking-up, solid is filtered to obtain, dries at room temperature.Finally, 500oC
Roasting a period of time produces finished catalyst.
Embodiment 5：
300g P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, 30oUnder C, by 300ml positive silicon
The Pd-H of acetoacetic ester and 390g3PW6Mo6O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature stirring 5h.Then exist
80o36 hours are stood still for crystals under C, washs product to neutrality after taking-up, solid is filtered to obtain, dries at room temperature.Finally, 500oC
Roasting a period of time produces finished catalyst.
Embodiment 6：
300g P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, 50oUnder C, by 300ml positive silicon
The Pd-H of acetoacetic ester and 390g4SiW6Mo6O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature stirring 3h.Then exist
80o36 hours are stood still for crystals under C, washs product to neutrality after taking-up, solid is filtered to obtain, dries at room temperature.Finally, 500oC
Roasting a period of time produces finished catalyst.
Embodiment 7：
1kg P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, 40oUnder C, by 2.5L positive silicic acid
The Pd-H of ethyl ester and 1.4kg4SiW12O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature stirring 4h.Then exist
80o36 hours are stood still for crystals under C, washs product to neutrality after taking-up, solid is filtered to obtain, dries at room temperature.Finally, 500oC
Roasting a period of time produces finished catalyst.
Embodiment 8：
2kg P123 are dissolved in the hydrochloric acid that concentration is 2mol/L, after abundant dissolving, at 50 DEG C, by 2L positive silicic acid second
The Pd-H of ester and 5.6kg4SiW12O40Solution is slowly added dropwise P123 solution respectively, continues constant temperature stirring 5h.Then at 80 DEG C
Under stand still for crystals 36 hours, product is washed to neutrality after taking-up, solid is filtered to obtain, dries at room temperature.Finally, in 500 DEG C of roastings
Burn and produce finished catalyst for a period of time.
Embodiment 9-18：
M in mass ratioCatalyst：mCitric acid：mEthanol, n-butanol=1:150~300:150~450 ratio, by anhydrous citric acid, urge
Agent, ethanol and n-butanol add the reactor with water knockout drum simultaneously, use temperature-programmed mode, if thermograde is at 70 DEG C
Insulation reaction 1h, then continue to react 1h at 85 DEG C, then be warming up at 100 DEG C and react 1h, finally treat that temperature drops to 80 DEG C, instead
Stop reaction after answering 1h.After reaction terminates, filtering, catalyst is reclaimed, with alcohol flushing 2~3 times, decompression boils off a large amount of alcohol, uses
10% sodium bicarbonate aqueous solution repeatedly washs residue, divides sub-cloud water layer to obtain citrate crude product.Added into crude product about thick
The activated carbon of product weight 1%, filtering, filtrate obtain the citrate sterling of water white transparency in 120 DEG C of vacuum distillations.
Embodiment 19- embodiments 25
Except for the following differences, other are identical with embodiment 11.
Claims (7)
1. a kind of synthetic method of medicinal citrate, it is characterised in that comprise the following steps：
A, mesoporous molecular sieve carried heteropolyacid catalyst is made by in-situ synthesis；
B, citric acid, ethanol, n-butanol and catalyst are mixed according to certain ratio, using n-butanol as water entrainer, in program
Back flow reaction is for a period of time under Elevated Temperature Conditions；
C, after reaction terminates, filtering and washing recovery catalyst, crude product is after being distilled off excess ethyl alcohol and n-butanol, through activity
Carbon decoloring adsorption-edulcoration, citrate sterling is evaporated under reduced pressure to again；
The mesoporous molecular sieve carried heteropolyacid catalyst is template P123 first to be dissolved in into acid medium template solution is made,
The heteropoly acid solution and P123 solution hybrid reactions for being again modified tetraethyl orthosilicate and palladium, crystallized, washing, filtering, dry, roasting
Fire；It is described to prepare mesoporous molecular sieve carried heteropolyacid catalyst specific method and be：A certain amount of template P123 is dissolved in dense
Spend in the hydrochloric acid for 2mol/L, after abundant dissolving, at 30~50 DEG C, the tetraethyl orthosilicate of certain volume and palladium are modified miscellaneous
More acid solutions are slowly added dropwise P123 solution respectively, continue constant temperature stirring 3-5h；Then 36 hours are stood still for crystals at 80 DEG C；
Product is washed to neutrality after taking-up, solid is filtered to obtain, dries at room temperature, fabricated in situ is obtained in 500 DEG C of roasting a period of times
The heteropolyacid catalyst being carried on mesopore molecular sieve；
Described catalyst, citric acid, ethanol, the mass ratio that feeds intake of n-butanol mixed alcohol are catalyst：Citric acid：Ethanol, just
Butanol mixture=1:150~300:150~450；
The reaction time of esterification is 4 hours, and heating response is carried out by the way of temperature programming, and thermograde is 70 DEG C, is protected
Temperature reaction 1h → 85 DEG C, insulation reaction 1h → 100 DEG C, insulation reaction 1h → 80 DEG C, insulation reaction 1h；
Used catalyst is that the heteropoly acid being modified by tetraethyl orthosilicate, P123 and palladium is made in reaction, and the mass ratio that feeds intake is 1：0.2
~0.4：0.13~0.56.
2. according to the method for claim 1, it is characterised in that used catalyst is by tetraethyl orthosilicate, P123 in reaction
The heteropoly acid being modified with palladium is made, and the mass ratio that feeds intake is 1:0.3:0.39.
3. according to the method for claim 1, it is characterised in that it is miscellaneous that the heteropoly acid that the palladium is modified is selected from the phosphorus tungsten that palladium is modified
Polyacid, silicotungstic heteropolyacid, phosphato-molybdic heteropolyacid, silicon-molybdenum heteropoly acid, phosphorus tungsten heteropoly acid and silicon tungsten heteropoly acid.
4. according to the method for claim 3, it is characterised in that the heteropoly acid that the palladium is modified is Pd-H4SiW12O40。
5. according to the method described in claim 1, it is characterised in that the heteropoly acid that the palladium is modified is prepared by the following method：
Weigh a certain amount of heteropoly acid, after being dissolved with distilled water, then with PdCl2Solution mixes 2 hours in equal volume, then at 120 DEG C
Lower drying 6 hours, then be calcined 2 hours at 250 DEG C, produce.
6. according to the method for claim 5, it is characterised in that heteropoly acid and PdCl2Mass ratio be 50~150:1.
7. according to the method for claim 1, it is characterised in that the water entrainer n-butanol of addition and the quality that feeds intake of citric acid
Than for 0.5~1：1.
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