CN104803845A - Synthetic method of medicinal citrate - Google Patents

Synthetic method of medicinal citrate Download PDF

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Publication number
CN104803845A
CN104803845A CN201410511185.2A CN201410511185A CN104803845A CN 104803845 A CN104803845 A CN 104803845A CN 201410511185 A CN201410511185 A CN 201410511185A CN 104803845 A CN104803845 A CN 104803845A
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heteropolyacid
reaction
citric acid
citrate
catalyzer
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CN104803845B (en
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帅放文
章家伟
王向峰
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Hunan Er Kang Pharmaceutical Co Ltd
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Hunan Er Kang Pharmaceutical Co Ltd
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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
    • 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
    • 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
    • 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
    • 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
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)

Abstract

The invention discloses a synthetic method of medicinal citrate, specifically a method for preparing a citric acid mixed ester finished product by steps of preparing a mesoporous molecular sieve-supported hetropolyacid catalyst by an in situ synthesis method, catalyzing a reaction between citric acid and ethanol and n-butanol to synthesize a citric acid mixed ester crude product and refining and purifying. The method has advantages as follows: reaction condition is mild; reaction time is short; and the catalyst can be recovered and reused. The method is suitable for industrial production. In addition, esterification rate of the product is high. According to the mixed ester, advantages of two citrates are combined and insufficiencies of a single citrate product are compensated. The mixed ester has more excellent performance than a single citrate.

Description

A kind of synthetic method of medicinal citrate
Technical field
The invention belongs to organic synthesis field, relate to a kind of synthetic method of citrate, be specifically related to a kind of method of mesoporous molecular sieve carried heteropoly acid catalysis synthesizing citric acid ester.
Background technology
Citric acid ester plasticizer is the environment-friendlyplasticizer plasticizer that a kind of non-petroleum feedstocks is produced, and in the developed country such as American-European-Japanese, achieves industrialization already to it.And China is as the second largest producing country of citric acid, domesticly also start a small amount of suitability for industrialized production in last century end, and come into the market the beginning of this century.
Citric acid ester plasticizer is considered to substitute environment-friendlyplasticizer plasticizer ideal in phthalic ester plasticizer, its not only nontoxic, without specific peculiar smell, and having extraordinary plastification to PVC, speedup effect is suitable with DOP, DINP, almost can substitute DOP by 1:1.But because its price is relatively high, be mainly used in non-toxic and safe at present and require high field.Such as, the U.S., Europe have allowed citric acid ester plasticizer product as package plastics of food processing film, plastic children toy processing, medicine parcel and medicine equipment manufacture etc. and human body close contact, and require the softening agent of higher plastic prod.
Two principal items of citric acid ester type are: (Triethyl Citrate, has another name called citric acid triethyl ester to triethyl citrate, and molecular formula is C 12h 20o 7), and tributyl citrate (Tributyl Citrate, has another name called tributyl citrate, and molecular formula is C 18h 32o 7).
Be colourless, slightly lemon fragrance transparent liquid under triethyl citrate normal temperature, in water, solubleness is 6.5g/100ml(25 oc), be dissolved in most of organic solvent, be insoluble in oils.Good consistency is had with most of Mierocrystalline cellulose, polyvinyl chloride and chlorinated rubber etc.And tributyl citrate is the high boiling point oily liquids of colorless and odorless at normal temperatures, dissolves each other with most organic solvent, be slightly soluble in water.With resin compatibles such as polyvinyl chloride, polystyrene, vinyl chloride-vinyl acetate copolymer, nitrocellulose, ethyl cellulose, polyvinyl butyral acetals.Citric acid ester plasticizer is as a kind of non-toxic plastic softening agent, can be widely used among daily necessities, food, medical packaging, makeup etc., have that plasticizing efficiency is high, volatility is little, be easily biodegradable, do not grow the advantages such as mould, and winter hardiness, photostabilization and have excellent water-resistance, thus extensively concerned.
U.S. food and Drug Administration (FDA) approved citric acid ester type as non-toxic plasticizer, for food product pack, medical apparatus, the aspect such as toy for children and personal hygiene article.In medicament manufactures, triethyl citrate and tributyl citrate are then generally used for the plasticity of pharmaceutical preparation coating material.In dressing, relate to the formulations such as capsule, tablet, pilule granule, object is for taste masking or quick-release and enteric prescription.In addition, citric acid ester type also directly can be used as foodstuff additive, plays the effect of flavoring, solubilising or tensio-active agent.
Industrially, the preparation method of triethyl citrate and tributyl citrate be all by citric acid and ethanol or propyl carbinol under corresponding catalyst existent condition, by controlling temperature of reaction and reaction times, esterification and corresponding work in-process, obtain purer esters product finally by purifying.Traditional esterification uses the vitriol oil to make catalyzer, although good catalytic activity, but the vitriol oil has strongly-acid and strong oxidizing property, large to the corrodibility of equipment, require high, easily there is side reaction simultaneously, as organism by vitriol oil charing, ethanol self-condensation becomes ether etc., cause the yield of product low, and cause product quality problem: product purity is low, color and luster is poor, easy acidifying, validity period are short.
The appearance of the policy corresponding to country of the development along with national economy, the demand of non-toxic plastic grows with each passing day, also more and more stricter to the requirement of softening agent.Again because China's citric acid output occupies the second in the world, therefore existing increasing researcher carries out Exploration & stu dy to the synthetic method of citrate in recent years, its emphasis point is selection and the existence form of catalyzer, be intended to improve processing condition, make it lower to equipment requirements, condition milder, reacts more controlled.
CN102079704A discloses a kind of preparation method of triethyl citrate, wherein by adding the vitriol oil or benzene sulfonic acid sodium salt carries out back flow reaction as catalyzer, utilize sodium hydroxide titration determination reaction end using phenolphthalein as indicator, then obtain triethyl citrate sterling through aftertreatment and purifying.Although the method by strictly controlling reaction end, can reduce unnecessary side reaction, prevent from reacting insufficient or the waste of quality product that overlong time causes and cost.But adopt the vitriol oil to make catalyzer, still have that selectivity is lower, by product is more, product yield is undesirable, large to equipment corrosion, three-protection design requires high inferior position.
CN102659591A discloses a kind of method that continuous catalysis prepares triethyl citrate, easily run off for catalyzer in such scheme, the problems such as aftertreatment technology is complicated, propose the production using fixed bed continuous catalytic reaction device to carry out triethyl citrate, the lewis acidic styrene type cation exchange resin of working load is as catalyzer, be loaded in series connection fixed bed, reactant enters from reactor head, through intermediate catalytic layer, esterification is there is under heat-retaining condition, reaction product is discharged from reactor bottom, and enter among gas-liquid separation device, unreacted ethanol is discharged on gas-liquid separation device top, triethyl citrate crude product is discharged in bottom, through refining to obtain sterling.But because catalyst cupport is on resin, not easily carry out cleaning and regenerating to resin, easy cooperating microorganisms, thus cannot ensure that the microbial limit of product and other quality regulation can fulfilling medicinal requirements.
CN1762969A discloses a kind of method of mesoporous material catalytic citric acid tri-n-butyl, the HAl-MCM-41 mesopore molecular sieve adopted in patent has following shortcoming: 1. acid sites is ammonium nitrate roasting gained, do not form chemical bonding with carrier, easily run off in the reaction; 2. ammonium nitrate roasting gained active centre is H +, strength of acid is less, and citric acid transformation efficiency is lower.
CN201010535730.3 discloses a kind of Catalysts and its preparation method for the synthesis of tributyl citrate, the strongly-acid mesoporous material that described catalyzer is prepared with hydrothermal synthesis method is for carrier, with the mode chemical bonding acidic ion liquid of finishing on mesoporous material carrier, mesoporous material is mesoporous silicon, mesoporous zirconium or mesoporous titanium, and acidic ion liquid is the ionic liquid containing phosphate radical or sulfate radical.Use this catalyzer citric acid transformation efficiency 90 ~ 99%.
CN200610024372.3 discloses a kind of method that tributyl citrate is prepared in heterogeneous catalysis, it be in Lipase absobed process with carbon back sulfonic acid for catalyzer, the preparation process of carbon back sulfonic acid adds in 10 ~ 15g C 9 fraction of cracking by the vitriol oil of 8 ~ 15ml, 200 ~ 250 oc carries out reacting by heating 3 ~ 5h, then adds boiling water and carries out backflow and stir 2 ~ 4h, suction filtration, 130 ~ 150 DEG C of bakings oc does, and obtains carbon back sulfonic acid.
There is building-up process complexity in above-mentioned prior art, long reaction time, the restricted height of reaction conditions, the shortcoming that catalyzer cost is high, quality product controllability is lower, is not too suitable for suitability for industrialized production.In addition, also there is not yet the patented method simultaneously using two kinds of different alcohols and citric acid to carry out esterification at present to report.
The class condensation oxygen acid that heteropolyacid consists of oxygen atom ligand bridging by certain structure heteroatoms (as P, Si, Fe, Co etc.) and polyatom (as Mo, W, V, Nb, Ta etc.), there is very high catalytic activity, be a kind of protonic acid of even intensity, and have redox ability.Heteropolyacid of a great variety, by changing the composition of heteropolyanion, anti-lotus positively charged ion and crystal water or organic molecule, can go out different heteropolyacids by design and synthesis.The structure type of conventional heteropolyacid is A type (structure with Keggin), and general formula can be expressed as H nxM 12o 40, wherein include again the tertiary structure of polyacid, primary structure refers to polyanionic structure, can represent component and the number of polyacid, and the skeleton structure of combination between them.The secondary structure of polyacid refers to that polyanionic and gegenion combine the crystalline structure of polyacid and the salt thereof obtained.The tertiary structure of polyacid refer to polyanionic, gegenion and crystal water three part form, can be expressed as follows.
Generally, heteropolyacid good stability, catalytic effect is excellent, and environmentally safe, be the coming green catalyst of a class, can be used for alkylating aromatic hydrocarbon and dealkylation, esterification, dehydration/combination reaction, redox reaction and open loop, condensation, addition and etherification reaction etc.Reporting in document with silicotungstic acid is catalyzer synthesizing citric acid tri-n-butyl, and optimum experimental condition is: citric acid 2.1g, propyl carbinol 55mL, silicotungstic acid 0.3g, and temperature of reaction is 145 oc, the reaction times is 2.5h, and esterification yield can reach 98.3%, and product purity can reach more than 98%.It is the reaction of catalyst synthesizing citric acid tri-n-butyl that Liu Chuntao etc. have studied with Keggin type phospho-wolframic acid and silicotungstic acid.To experiment condition as raw material ratio, catalyst levels, esterification time, temperature of reaction etc. are explored, proposing best enzymatic synthesis condition is: the condition that heteropolyacid 0.2 g, citric acid 3.0 g, acid alcohol mol ratio are 1:3.4, the reaction times is 3 h, temperature of reaction is 145 ~ 150 DEG C, esterification yield can reach 97.04%.
Very high catalytic activity and selectivity is had to citrate by the known heteropolyacid catalyst of above-mentioned document.But, less (the < 10m of heteropolyacid specific surface area 2/ g), catalytic activity can not give full play to, heteropolyacid large usage quantity, and still exists in homogeneous reaction and reclaim the problem such as difficulty, contaminate environment, limits heteropolyacid applying in the industrial production to a certain extent.Therefore, ensureing that under the prerequisite that its catalytic effect does not reduce, seek a kind of consumption less, the existence form of recoverable is particularly important.
At present, prior art adopts multiple different methods by loaded by heteropoly acid on carrier, and make it immobilized, the carrier adopted mainly contains the porous materials such as gac, ion exchange resin, metal oxide and molecular sieve.Certainly, catalyzer also can only be attracted in molecular sieve with Intermolecular Forces, but this reactive force is extremely weak compared with covalent linkage, easily causes catalyzer De contamination and runs off.But be carrier loaded heteropolyacid with metal oxide, the alkalescence of carrier itself is comparatively large to the Structural Disintegration of heteropolyacid, and the increase rate of specific surface area is limited; And ion exchange resin easy swelling inactivation in the solution.Although gac has higher specific surface area and the pH stability of relative broad range as carrier, catalytic activity is good, and it exists the problem of more serious heteropolyacid active substance solution-off.
Therefore, people begin one's study molecular sieve carried heteropolyacid.Molecular sieve is the porous medium that a class has special construction, and it is made up of a series of irregular duct or cage.Due to special structure, determine it and there is special property, especially molecular sieve is as the excellent properties shown during heteropolyacid carrier, pass through load, not only increase the specific surface area of heteropolyacid, thermostability, and its catalytic activity and reusability have also been obtained improvement, solve current Problems existing in heteropolyacid industrial applications.At present, report in domestic and foreign literature that the molecular sieve carrier being used for carried heteropoly acid mainly contains MCM series, SBA-15, Y type and HMS molecular sieve etc.And the carrying method usually adopted has pickling process, backflow absorption method, sol-gel method, hydro-thermal decentralization method and in-situ synthesis.As bibliographical information adopts pickling process to prepare SBA-15 load phosphorus heteropoly tungstic acid catalyzer, and be applied to the synthesis of triethyl citrate, investigate the factor of impact reaction.Result shows, back flow reaction 3h, and catalyst levels is 1.0% of raw materials quality, and when acid alcohol mol ratio is 1:4, triethyl citrate yield is more than 90%.Ou Zhiyi etc. have studied Sol-gel immobilization catalysis of phosphotungstic acid citric acid and propyl carbinol synthesizing citric acid tri-n-butyl, at the ratio 1:4 of acid alcohol amount of substance, and catalyst levels 2.5%, reaction times 3.5h, temperature of reaction 140 ~ 145 oc, productive rate is greater than 95%, and catalyzer reuses 7 times, and productive rate still reaches more than 87%.
In fact, because the interaction between heteropolyacid and carrier surface belongs to acid-base reaction substantially, so along with the difference of carrier surface alcohol acid base strength and heteropolyacid intensity, both interactional results form strength of acid active body firmly different with load, have influence on carried heteropoly acid catalyst activity in the reaction and solution-off amount.But the alcohol acid base strength of mesopore molecular sieve is wayward is also difficult to adjustment, therefore by changing the molecular composition of heteropolyacid or modifying, to regulate strength of acid and the redox property of heteropolyacid through atoms metal.
In sum, the problems such as the solution-off that the catalyst levels still existed for carried heteropoly acid is comparatively large and comparatively serious, the present invention, on a large amount of exploitative experiment bases, creatively uses PdCl 2modification is carried out to heteropolyacid, has achieved and non-obvious beneficial effect, successfully solve the major issue that above-mentioned carried heteropoly acid exists at present.
Summary of the invention
In order to overcome the defect that above-mentioned prior art exists, the invention discloses a kind of synthetic method of medicinal citrate, particularly one prepares mesoporous molecular sieve carried heteropolyacid catalyst by in-situ synthesis, there is esterification in catalytic citric acid and ethanol and propyl carbinol simultaneously, synthesizing citric acid ester crude product, then the method for citrate sterling is obtained through polishing purification.
Therefore, the invention discloses one and utilize mesoporous molecular sieve carried heteropolyacid catalyst, the esterification of catalytic citric acid and alcohol mixture, prepare the method for the pharmaceutical grade citric acid mixed ester of nontoxic green, comprising:
A, obtain mesoporous molecular sieve carried heteropolyacid catalyst by in-situ synthesis;
B, by citric acid, ethanol, propyl carbinol and catalyzer according to the mixing of certain ratio, take propyl carbinol as water entrainer, be incubated back flow reaction 4 hours at a certain temperature;
After c, reaction terminate, filter and washing and recycling catalyzer, crude product is after distillation removing excess ethyl alcohol and propyl carbinol, and through activated carbon decolorizing adsorption-edulcoration, underpressure distillation obtains citrate sterling again.
Wherein, the in-situ synthesis described in step a prepares mesoporous molecular sieve carried heteropolyacid catalyst, is first
Template is dissolved in acidic medium to obtain template solution, again by the heteropolyacid solution of tetraethoxy and palladium modification and template solution hybrid reaction, obtain through crystallization, washing, filtration, drying, roasting.
Further, in step a, in reaction, used catalyst is obtained by tetraethoxy, template P123 and heteropolyacid, the mass ratio that feeds intake be 1:0.2 ~ 0.4:0.13 ~ 0.56.
Further, in step a, use catalyzer to be obtained by tetraethoxy, P123 and heteropolyacid in reaction, the mass ratio that feeds intake is 1:0.3:0.39.
Further, in step a, described template is P123, and the heteropolyacid of palladium modification is selected from the phosphorus heteropoly tungstic acid of palladium modification, silicotungstic heteropolyacid, phosphato-molybdic heteropolyacid, silicon-molybdenum heteropoly acid, phosphorus tungsten heteropolyacid and silicon tungsten heteropolyacid, is preferably the silicotungstic heteropolyacid Pd-H of palladium modification 4siW 12o 40.
Further, in step a, the heteropolyacid of palladium modification can obtain by the following method: take a certain amount of heteropolyacid, after dissolving with distilled water, then mix 2 hours with PdCl2 solution equal-volume, then at 120 DEG C dry 6 hours, roasting 2 hours at 250 DEG C again, to obtain final product.
Further, in step a, heteropolyacid and PdCl 2mass ratio be 50 ~ 150:1.
Further, in step b, the mass ratio that feeds intake of catalyzer, citric acid and ethanol, propyl carbinol alcohol mixture is catalyzer: citric acid: ethanol, propyl carbinol mixture=1:150 ~ 300:150 ~ 450.
Further, in step b, the mass ratio that feeds intake of the water entrainer propyl carbinol added and citric acid is 0.5 ~ 1:1.
Further, the reaction times is preferably 4 hours, adopts the mode of temperature programming to carry out reacting by heating, temperature
Gradient is 70 oc(1h) → 85 oc(1h) → 100 oc(1h) → 80 oc.
Further, above-mentioned preparation method can implement by following a kind of concrete scheme:
A. the preparation of catalyzer
1, after taking the dissolving of a certain amount of heteropolyacid distilled water, then with PdCl 2solution equal-volume mixing 2
Hour, then 120 odrying 6 hours under C, then 250 oroasting 2 hours under C, i.e. the heteropolyacid of obtained palladium modification;
2, a certain amount of template P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving,
30 ~ 50 ounder C, the tetraethoxy of certain volume and heteropolyacid solution are slowly dropwise added P123 solution respectively, continue constant temperature and stir 3-5h; Then 80 ocrystallization 36 hours are left standstill under C; After taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature, 500 oc roasting for some time obtains the heteropolyacid catalyst be carried on SBA-15 of fabricated in situ.
B. the synthesis of citrate
Take citric acid, ethanol and propyl carbinol, according to certain mass than dropping in reaction unit, adding solid supported heteropolyacid catalyst, take propyl carbinol as water entrainer, reacts 4 hours under temperature programming condition.After reaction terminates, filter, reclaim catalyzer, with alcohol flushing 2 ~ 3 times, a large amount of alcohol of pressure reducing and steaming, repeatedly washs residuum with 10% sodium bicarbonate aqueous solution, divides a sub-cloud water layer to obtain citric acid mixed ester crude product.In crude product, add the gac of crude product weight 1%, filter, filtrate, in 120 DEG C of underpressure distillation, obtains water white citrate sterling.
Mesoporous molecular sieve carried heteropolyacid catalyst of the present invention, the citrate made has higher esterification yield and purity.The kind of heteropolyacid used and modifying method thereof, consumption and be all through with the mode of loading of mesopore molecular sieve that great many of experiments finally determines.
Beneficial effect of the present invention is:
1. use triblock copolymer (P123) as template, molecular sieve synthesising mesoporous with tetraethyl orthosilicate,
Effectively expand Si-OH quantity in the aperture of mesopore molecular sieve and hole, for commercial silica gel and the mesopore molecular sieve that synthesizes with cetyl trimethylammonium bromide and tetraethyl orthosilicate, improve charge capacity and catalytic efficiency, decrease the loss of catalyzer; Adopt above-mentioned mesoporous molecular sieve carried heteropolyacid again, by load, not only can improve the specific surface area of heteropolyacid, thermostability, and its catalytic activity and reusability thereof also improve.
2. adopt palladium to carry out modification to heteropolyacid, not only can affect the acidity of heteropolyacid to a certain extent, make to mix
The combination of polyacid and mesopore molecular sieve is more tight, makes heteropolyacid not easily solution-off, and through the heteropolyacid of palladium modification, be compared to normal load type heteropolyacid catalyst, its consumption significantly reduces, and catalytic activity is stronger, and catalytic efficiency is higher.
3. prior art adopts the method for fractional steps to synthesize this catalyzer, i.e. first synthesising mesoporous molecular sieve, then by loaded by heteropoly acid
On it, this load functioning efficiency is low, and in heteropolyacid molecular sieve pores more difficult to get access, easily causes waste and the loss of heteropolyacid.In the present invention program, adopt " in-situ synthesis ", after triblock copolymer is first dissolved, again tetraethyl orthosilicate and heteropolyacid solution are added simultaneously, make the formation of mesopore molecular sieve and the bonding load of heteropolyacid carry out simultaneously, make heteropolyacid all can carry out useful load in the surface and hole of molecular sieve, greatly improve load efficiency, thus significantly improve catalytic efficiency.
4. there is esterification with ethanol and propyl carbinol and citric acid simultaneously, three end positions at citric acid can be synthesized
Carboxyl generates the citric acid mixed ester that there is different alcohol and replace.This mixed ester not only can the respective advantage of both combining citric acid triethyl and tributyl citrate, and compensate for the deficiency existed each other.
5. reacted by ramped heating schedule, ethanol, propyl carbinol and citric acid can be made to react as far as possible fully, effectively improve the esterification yield of product.
Embodiment
Following examples, for further illustrating the present invention, not do further restriction to the present invention.Should be appreciated that those skilled in the art are on the basis fully understanding the present invention program, can make appropriate amendment after being enlightened to the parameter of scheme, these amendments are also in protection scope of the present invention.
The method of the catalyzer for the synthesis of citrate described in preparation, step is:
The first step, after taking the dissolving of a certain amount of heteropolyacid distilled water, then with PdCl 2solution equal-volume
Mix 2 hours, then 120 odrying 6 hours under C, then 250 oroasting 2 hours under C, i.e. the heteropolyacid of obtained palladium modification, wherein heteropolyacid and PdCl 2mass ratio be 100:1;
Second step, after a certain amount of template P123 is fully dissolved, 30 ~ 50 ounder C, by certain volume just
Tetraethyl silicate and heteropolyacid solution slowly dropwise add P123 solution respectively, after continuing back flow reaction for some time, leave standstill crystallization, washing, filtration, drying, then 500 oc roasting for some time obtains the heteropolyacid catalyst be carried on SBA-15 of fabricated in situ.
The acid number of product and the transformation efficiency (esterification yield) of citric acid are obtained by following formulae discovery:
Y=（1-k/k 0）×100%；
K 0the acid number reacting forward and backward system is respectively with k;
Acid number k=40 × 10 -3× V × C/m;
V and C is respectively volume and the concentration of NaOH.
Embodiment 1:
2g P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 40 ounder C, by 10ml
Tetraethoxy and the Pd-H of 1.3g 4siW 12o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 5h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 oc roasting for some time obtains finished catalyst.
Embodiment 2:
10g P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 40 ounder C, by the tetraethoxy of 50ml and the Pd-H of 6.5g 3pW 12o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 5h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 onamely C roasting for some time obtains finished catalyst.
Embodiment 3:
30g P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 40 ounder C, by the tetraethoxy of 50ml and the Pd-H of 39g 3pM o12o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 4h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 onamely C roasting for some time obtains finished catalyst.
Embodiment 4:
100g P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 40 ounder C, by the tetraethoxy of 330ml and the Pd-H of 185g 4siM o12o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 4h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 onamely C roasting for some time obtains finished catalyst.
Embodiment 5:
300g P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 30 ounder C, by the tetraethoxy of 300ml and the Pd-H of 390g 3pW 6m o6o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 5h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 onamely C roasting for some time obtains finished catalyst.
Embodiment 6:
300g P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 50 ounder C, by the tetraethoxy of 300ml and the Pd-H of 390g 4siW 6m o6o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 3h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 onamely C roasting for some time obtains finished catalyst.
Embodiment 7:
1kg P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 40 ounder C, by the tetraethoxy of 2.5L and the Pd-H of 1.4kg 4siW 12o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 4h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 onamely C roasting for some time obtains finished catalyst.
Embodiment 8:
2kg P123 being dissolved in concentration is in the hydrochloric acid of 2mol/L, after fully dissolving, and 50 ounder C, by the tetraethoxy of 2L and the Pd-H of 5.6kg 4siW 12o 40solution slowly dropwise adds P123 solution respectively, continues constant temperature and stirs 5h.Then 80 ocrystallization 36 hours are left standstill under C, after taking-up, product washing is extremely neutral, filter to obtain solid, dry under room temperature.Finally, 500 onamely C roasting for some time obtains finished catalyst.
Embodiment 9-18:
M in mass ratio catalyzer: m citric acid: m ethanol, propyl carbinolthe ratio of=1:150 ~ 300:150 ~ 450, Citric Acid, usp, Anhydrous Powder, catalyzer, ethanol and propyl carbinol are added simultaneously the reactor of band water trap, adopt temperature-programmed mode, if thermograde is insulation reaction 1h at 70 DEG C, then at 85 DEG C, reaction 1h is continued, react 1h at being warming up to 100 DEG C again, finally treat that temperature drops to 80 DEG C, stopped reaction after reaction 1h.After reaction terminates, filter, reclaim catalyzer, with alcohol flushing 2 ~ 3 times, a large amount of alcohol of pressure reducing and steaming, repeatedly washs residuum with 10% sodium bicarbonate aqueous solution, divides a sub-cloud water layer to obtain citrate crude product.In crude product, add the gac of about crude product weight 1%, filter, filtrate, in 120 DEG C of underpressure distillation, obtains water white citrate sterling.
Embodiment 19-embodiment 25
Except for the following differences, other are identical with embodiment 11.

Claims (10)

1. a synthetic method for medicinal citrate, is characterized in that comprising the following steps:
A, obtain mesoporous molecular sieve carried heteropolyacid catalyst by in-situ synthesis;
B, by citric acid, ethanol, propyl carbinol and catalyzer according to certain ratio mixing, take propyl carbinol as water entrainer, back flow reaction for some time under temperature programming condition;
After c, reaction terminate, filter and washing and recycling catalyzer, crude product is after distillation removing excess ethyl alcohol and propyl carbinol, and through activated carbon decolorizing adsorption-edulcoration, underpressure distillation obtains citrate sterling again;
Described mesoporous molecular sieve carried heteropolyacid catalyst first template P123 is dissolved in acidic medium to obtain template solution, again by the heteropolyacid solution of tetraethoxy and palladium modification and P123 solution hybrid reaction, obtain through crystallization, washing, filtration, drying, roasting.
2. according to method described in claim 1, it is characterized in that, in reaction, used catalyst is obtained by tetraethoxy, P123 and heteropolyacid, and the mass ratio that feeds intake is 1:0.2 ~ 0.4:0.13 ~ 0.56.
3. according to method described in claim 2, it is characterized in that, in reaction, used catalyst is obtained by tetraethoxy, P123 and heteropolyacid, and the mass ratio that feeds intake is 1:0.3:0.39.
4. method according to claim 1, is characterized in that, described heteropolyacid can be the phosphorus heteropoly tungstic acid of palladium modification, silicotungstic heteropolyacid, phosphato-molybdic heteropolyacid, silicon-molybdenum heteropoly acid, phosphorus tungsten heteropolyacid and silicon tungsten heteropolyacid.
5. method according to claim 4, it is characterized in that, described heteropolyacid is Pd-H 4siW 12o 40.
6. according to the method described in claim 1, it is characterized in that, the heteropolyacid of described palladium modification is prepared by the following method: take a certain amount of heteropolyacid, after dissolving with distilled water, then with PdCl 2solution equal-volume mixes 2 hours, then 120 oClower dry 6 hours, then roasting 2 hours at 250 DEG C, to obtain final product.
7. method according to claim 6, is characterized in that, heteropolyacid and PdCl 2mass ratio be 50 ~ 150:1.
8. method according to claim 1, it is characterized in that, the mass ratio that feeds intake of described catalyzer, citric acid, alcohol mixture is catalyzer: citric acid: alcohol mixture=1:150 ~ 300:150 ~ 450.
9. method according to claim 1, it is characterized in that, the mass ratio that feeds intake of the water entrainer propyl carbinol added and citric acid is 0.5 ~ 1:1.
10. method according to claim 1, it is characterized in that, the reaction times is preferably 4 hours, and adopt the mode of temperature programming to carry out reacting by heating, thermograde is 70 oc(1h) → 85 oc(1h) → 100 oc(1h) → 80 oc.
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