CN102617476B - Method for synthesizing allantoin - Google Patents
Method for synthesizing allantoin Download PDFInfo
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- CN102617476B CN102617476B CN201210060965.0A CN201210060965A CN102617476B CN 102617476 B CN102617476 B CN 102617476B CN 201210060965 A CN201210060965 A CN 201210060965A CN 102617476 B CN102617476 B CN 102617476B
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Abstract
The invention relates to a method for synthesizing allantoin. The allantoin is synthesized by taking Bronsted acid ionic liquid as a catalyst and glyoxylic acid and urea as raw materials. A process is simple, raw materials are bulk chemical raw materials, yield is high, the method is easy to industrially popularize, the yield of allantoin is stable and can reach over 68 percent, and the acid ionic liquid used as the catalyst can be repeatedly used for more than 5 times; and the process is pollution-free and environment-friendly, and has a good ecological effect and social and economic benefits. Through assay determination, the content of the obtained allantoin product is in the range required by the United States Pharmacopeia (USP29), and other indexes of the obtained allantoin product also meet the USP 29.
Description
Technical field
The present invention relates to a kind of method of synthetic allantoin.
Background technology
Wallantoin (allantoin), chemical name is Allantio, belongs to imidazoles heterogeneous ring compound, conventionally has odorless, tasteless with the form of white crystal or crystalline form powder.
Wallantoin is extensively present in nature, in allantoic fluid, fetus urine, human body and mammiferous embryo and movement, also contains wallantoin in tobacco, wheat, beet.But natural wallantoin limited amount, extraction process complexity, productive rate is extremely low, so current commodity wallantoin mostly is synthetic.
Pharmaceutically, wallantoin is the medicine with multiple function, it both can directly use, also can do additive, wallantoin can be cured various tetter, as psoriatic, dermatitis, xerosis cutis etc., can promote the effect such as healing and analgesia rapidly of skin cells and tissue growth, promotion wound, skin or organized renewing true colours can be made, various ulcers can be treated.On daily-use chemical industry, wallantoin at home and abroad apply there is no so far stimulate, the report of photosensitive, anaphylaxis and other toxic side effect, can, directly as the additive (as cream frost, emulsion etc.) of the cosmetics of super quality and the additive (as toothpaste, shampoo, soap etc.) of other daily chemicals, there is the effects such as moisturizing, moisturizing, cutin softening and promotion cell regeneration.In addition, wallantoin is a plant growth regulators, and growth that can stimulating plant, is used micro-wallantoin, can make wheat, citrus, paddy rice, vegetables and soybean yield-increasing, and there is solid fruit, the effect such as accelerate the ripening.Wallantoin is again the requisite raw materials of fertilizer such as the various composite fertilizers of exploitation, micro-fertilizer, long-acting fertilizer or slow released fertilizer and rare-earth fertilizer, has important application in agricultural.Wallantoin has the cell proliferation of promoting digestion road simultaneously, strengthens Normocellular vigor, improves the effect of pipe intestinal digesting absorptive function, can make livestock and poultry pop epidemic disease produce resistibility simultaneously, is also a kind of good fodder additives.Due to the widespread use of wallantoin, demand increases year by year, and the wallantoin synthesis technique of studying a kind of efficient, high yield, environmental protection is significant.
At present, the synthetic method of wallantoin is that raw material is synthetic mainly with oxoethanoic acid and urea, but productive rate does not all exceed 70%.Li Guiyun, Ma Jiangquan disclose productive rate taking nitric acid, sulfuric acid nitration mixture as catalyzer synthetic allantoin as 59.3% in " wallantoin synthetic and characterize " (" Jiangsu Petrochemical Engineering College journal "), its raw material oxoethanoic acid is produced with nitric acid oxidation method, do not pass through purifying with regard to direct production wallantoin, product can be subject to the impact of the by product that residual oxalic dialdehyde and by product oxalic acid and multiple reaction produce and Quality Down.Lei Hong etc. disclose productive rate taking mineral acids such as sulfuric acid, hydrochloric acid and nitric acid as catalyzer synthetic allantoin between 52%～58% in " wallantoin production technique and Market Summary " (" the 21st technical conferences collection of thesis of nitrogen information cooperative groups in the whole nation "); China Patent Publication No. CN1528749A, in open day on September 15th, 2004, invention and created name is " novel allantoin synthesis process ", this application case discloses and has catalyzed and synthesized wallantoin yield with metal catalyst and only can reach 56%.In addition, the report taking solid acid as catalyzer synthetic allantoin is also of common occurrence, but productive rate is many below 60%, only history peak etc. in " novel allantoin synthesis process " (" detergents and cosmetic technique ") with phosphorus heteropoly tungstic acid [H
3pW
12o
40x H
2o] be catalyzer, productive rate can reach 68.6%, but amount of urea is too much; Pay firewood water chestnut etc. at " SO in 2007
4 2-/ TiO
2solid superacid as catalyst synthetic allantoin " in (" the 11st catalysis academic conference ") with SO
4 2-/ TiO
2to be that catalyst synthetic allantoin productive rate is the highest also only reach 57.35% to solid super-strong acid, and solid acid makes difficulty, and cost is high, is not suitable for suitability for industrialized production.In addition, China Patent Publication No. CN1765888A, open day on May 3rd, 2006, invention and created name is " a kind of synthesis technique of wallantoin ", this application case discloses with gel-type strongly acidic cation exchange resin or macroporous type storng-acid cation exchange resin can arrive 69.6% for catalyzing and synthesizing wallantoin yield, but catalyzer needs to process, and production cost is high.
The synthetic method of prior art wallantoin has: (1) uric acid potassium permanganate oxidation method, and this method application potassium permanganate is as oxygenant, and reaction belongs to strong oxidizing reaction, wayward, is not suitable for scale operation, and uric acid cost is high is difficult to obtain; (2) calcium glyoxylate dissolving with hydrochloric acid method, this method is carried out in two steps, first prepares calcium glyoxylate, then generates wallantoin with hcl acidifying and urea condensation, and this method needs strong acid and strong base in reaction process, not easy to operate, and productive rate is low, is not suitable for scale operation; (3) urea dichloro acetic acid heating method, this method one step generates wallantoin, but reaction needed methyl alcohol is as solvent, and need 40 DEG C～50 DEG C of heating, make reaction process have explosion hazard, and this reaction needed underpressure distillation, complicated operation, and productive rate is low, is not suitable for scale operation; (4) urea oxoethanoic acid condensation method, this method is the method that current wallantoin manufacturer generally adopts, this method is produced wallantoin by allantois and oxoethanoic acid one step condensation, apply traditional protonic acid and can obtain as catalyzer the productive rate that relative productive rate is higher as the mixing acid of the strong acid such as sulfuric acid, phosphoric acid, hydrochloric acid and different ratios protonic acid, and have simple to operate, raw material is easy to get, the advantage that productive rate is relatively high, but it is high that these routes also exist synthesis mother liquid acidity, the problem of three wastes difficult treatment.
Ionic liquid (Ionic Liquids) is the focus of studying in chemical field in recent years, is considered to and supercritical CO
2form three large green solvent and catalytic medias together with double water-phase, have broad application prospects.The present invention's application
acidic ion liquid is prepared wallantoin as catalyzer, this be for the first time taking ionic liquid as catalyzer prepares high yield, high-quality product, on the basis through constantly research and development, invented novel a, friendly process efficiently.
Summary of the invention
The object of the invention is to provide a kind of synthetic method of wallantoin.
The synthetic method of described wallantoin, with
acidic ion liquid is catalyzer, taking oxoethanoic acid and urea as raw material synthetic allantoin.
Specifically, the synthetic method of described wallantoin comprises: in reactor, add aqueous glyoxylic acid, urea and catalyzer, stir, heating; After reaction 4.0～24.0h, reaction mixture is cooled to room temperature (15 DEG C～25 DEG C), filters, wash, dry, obtain finished product; Filtrate and washing lotion merging collection and treatment are obtained to catalyzer, repeat catalysis next time.
The mass concentration of described aqueous glyoxylic acid is preferably 20%～80%, and more preferably the mass concentration of aqueous glyoxylic acid is 20%～60%; The mass concentration of better preferred aqueous glyoxylic acid is 40%～50%; Wherein, the oxalic dialdehyde in preferred aqueous glyoxylic acid and oxalic acid content (weight ratio) be not respectively higher than 1.0%, 3.0%.
Described Heating temperature is preferably 40 DEG C～80 DEG C, and more preferably Heating temperature is 60 DEG C～70 DEG C; Better preferred Heating temperature is 66 DEG C～68 DEG C.
The mol ratio of described oxoethanoic acid and urea is preferably 1: 2.0～and 1: 4.5, more preferably the mol ratio of oxoethanoic acid and urea is 1: 3.5～1: 4.5; The mol ratio of better preferred oxoethanoic acid and urea is 1: 3.8～1: 4.3; The mol ratio of best preferably oxoethanoic acid and urea is 1: 4.0～1: 4.3.
The mol ratio of described oxoethanoic acid and catalyzer is preferably 1: 0.2～and 1: 0.5, more preferably the mol ratio of oxoethanoic acid and catalyzer is 1: 0.3～1: 0.4;
Described washing is the water that filter cake is placed in to 2～4 times of weight, stirs (approximately 20～60min); Can wash repeatedly if desired;
The described reaction times is generally 4.0～24.0h, and the preferred reaction time is 5.0～12.0h, and more preferably the reaction times is 5.5～7.0h.
Described oven dry generally can be heating, drying (as baking oven), and temperature is 60 DEG C～150 DEG C, and preferably bake out temperature is 80 DEG C～110 DEG C, and best bake out temperature is 95 DEG C～105 DEG C.
Described catalyzer is
acidic ion liquid;
Described
acidic ion liquid is for taking imidazolyl or pyridyl or quaternary ammonium salt base as positively charged ion, with [HSO
4]
-, [H
2pO
4]
-, [EtOSO
3]
-, [(EtO)
2pO
2]
-, [CF
3cO
2]
-, [BF
6]
-, [PF
6]
-, [OTf]
-, [TsO]
-, [ClO
4]
-, Ac
-, NO
3 -or Cl
-deng the ionic liquid for negatively charged ion composition.
Described imidazolyl positively charged ion can be: [(CH
2)
3sO
3hMIM]
+, [(CH
2)
4sO
3hMIM]
+, [C
7mIM]
+, [BMIM]
+, [BMMIM]
+, [RMIM]
+, [MMIM]
+, [AMIM]
+, [EMIM]
+, [EMMIM]
+, [HMIM]
+, [PMIM]
+, [PMMIM]
+, [OMIM]
+, [EEIM]
+, [BEIM]
+, [AEIM]
+, [VMIM]
+, [C
5mIM]
+, [EOEIM]
+, [MOMIM]
+, [BzMIM]
+, [HOOCMIM]
+, [AOEMIM]
+, [AOMMIM]
+, or [1,2-Me-3-PIM]
+deng;
Described pyridyl positively charged ion can be: [(CH
2)
4sO
3hPy]
+, [(CH
2)
4sO
3hPy]
+, [BuPy]
+, [EtPy]
+, [HPy]
+or [OPy]
+deng;
Described quaternary ammonium salt base positively charged ion can be: [(CH
2)
4sO
3hEt
3n]
+, [(CH
2)
3sO
3hEt
3n]
+, [(n-C
3h
7) Me
3n]
+, [(n-C
6h
13) Et
3n]
+, [(n-C
8h
17) Et
3n]
+, [(n-C
8h
17) (C
4h
9)
3n]
+, [(MeOCH
2) Me
3n]
+, or [(n-C
4h
9) Me
3n]
+deng.
Described
acidic ion liquid can represent with following structural formula:
R=CH in formula (I)
3, C
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21, C
12h
25, C
14h
29, C
16h
33; X=HSO
4, H
2pO
4;
R=C in formula (II)
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21; X=HSO
4, H
2pO
4;
N=2 in formula (III); X=HSO
4, H
2pO
4;
N=2 in formula (IV); X=HSO
4, H
2pO
4;
R=CH in formula (V)
3, C
2h
5; X=HSO
4, H
2pO
4;
R=CH in formula (VI)
3, C
2h
5; X=HSO
4, H
2pO
4;
R=CH in formula (VII)
3, C
2h
5; X=HSO
4, H
2pO
4;
N=2 in formula (VIII); X=HSO
4, H
2pO
4;
N=3 in formula (IX), 4; X=HSO
4, H
2pO
4, CF
3cOO, OTf;
N=3 in formula (X); X=HSO
4, H
2pO
4;
In formula (XI), R=CH
3, C
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21, C
12h
25, C
14h
29, C
16h
33;
X＝BF
4，PF
6，EtOSO
3，(EtO)
2PO
2、CF
3CO
2，OTf、TsO，ClO
4，Ac，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=C in formula (XII)
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21;
X＝BF
4，PF
6，C
12SO
3，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
N=2 in formula (XIII);
X＝BF
4，PF
6，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
N=2 in formula (XIV);
X＝BF
4，PF
6，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (X V)
3, C
2h
5;
X＝BF
4，PF
6，OTf，TsO，NO
3；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (XVI)
3, C
2h
5;
X＝BF
4，PF
6，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (XVII)
3, C
2h
5; X=BF
4, PF
6, NO
3, Cl;
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=C in formula (XVIII)
2h
5, C
4h
9, C
6h
13, C
8h
17; X=HSO
4, H
2pO
4;
R=C in formula (XIX)
3h
7, C
4h
9; N=3,4; X=HSO
4, H
2pO
4;
R=C in formula (XX)
2h
5, C
4h
9, C
6h
13, C
8h
17;
X＝BF
4，PF
6，ClO
4，OTf，TsO，NO
3；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (XXI)
3, C
2h
5, C
3h
7, C
4h
9;
R
1＝CH
3，C
2H
5，C
3H
7，C
4H
9，C
6H
13，C
7H
7，C
8H
17，C
12H
25，C
16H
33，C
18H
35，
X＝HSO
4，H
2PO
4；
R=CH in formula (XXII)
3, C
2h
5, C
3h
7, C
4h
9;
n＝3，4；X＝HSO
4，H
2PO
4；
R=CH in formula (XXIII)
3, C
2h
5, C
3h
7, C
4h
9;
R
1＝H，CH
3，C
2H
5；n＝1，2；X＝HSO
4，H
2PO
4；
Described
acidic ionic liquid preparation:
In reactor, add glyoxaline compound or pyridine compounds and their or tertiary amine compounds and alkylate, stir, heating, reaction 8～24h, after reaction finishes, reaction mixture is cooled to room temperature (15 DEG C～25 DEG C), filters, washing, separate, be dried to constant weight and (as be placed in vacuum drying oven, 90 DEG C, 0.01Mpa), obtain dry intermediate; A certain amount of intermediate is dissolved, slowly drip a certain amount of protonic acid (as sulfuric acid or phosphoric acid etc.), heating, stirs, reaction 5～7h, after reaction finishes, reaction solution is evaporated away to unnecessary moisture (as used Rotary Evaporators), and the product obtaining is dried to constant weight and (as is placed in vacuum drying oven, 90 DEG C, 0.01Mpa), to obtain final product.
The mol ratio of described glyoxaline compound or pyridine compounds and their or tertiary amine compounds and alkylate is preferably 1: 0.80～and 1: 1.45, more preferably mol ratio is 1: 1.25.
Described glyoxaline compound or pyridine compounds and their or tertiary amine compounds are preferably 15～50 DEG C with the temperature of reacting of alkylate, and more preferably temperature is 40 DEG C.
Described glyoxaline compound or pyridine compounds and their or tertiary amine compounds are preferably 8～24h with the time of reacting of alkylate, and more preferably the time is 12h.
Described glyoxaline compound is imidazoles, N-Methylimidazole, 1,2 dimethylimidazole, N-ethyl imidazol(e), N-propyl imidazole, N-butyl imidazole, N-hexyl imidazoles, N-decyl imidazoles, N-octyl group imidazoles, N-dodecyl imidazoles, N-tetradecyl imidazoles or vinyl imidazole etc.;
Described pyridine compounds and their is pyridine or N-picoline etc.;
Described tertiary amine compounds is Trimethylamine 99, triethylamine, Tributylamine or tripropyl amine etc.;
Described alkylate is 1, 4-butane sultones, 1, 3-N-morpholinopropanesulfonic acid lactone, chloropropane, iodopropane, n-propyl bromide, chlorobutane, n-butyl bromide, bromooctane, chloroethyl ethyl ether, chloroethyl methyl ether, chloromethyl ethyl ether, chloromethyl methyl ether, methyl chloride, monobromethane, bromohexane, chlorohexane, monochloroethane, monobromethane, chloropentane, bromo pentane, heptyl bromide, chloroheptane, methyl iodide, iodoethane, butyl iodide, iodopentane, iodine heptane, iodo-octane, chlorinated dodecane, bromotetradecane, bromohexadecane, bromo-octadecane, vinylchlorid, benzyl chloride, chloroethanol, Mono Chloro Acetic Acid, bromoacetic acid, bromoethanol, chlorallylene, allyl bromide 98 or chloromethyl cyanide etc.
Described preparation
the solvent washing in acidic ion liquid process is preferably the organic solvent washings such as benzene, toluene, ethyl acetate or ether, and more preferably cleaning solvent is toluene;
The preferred water of described intermediate, hexanaphthene or methyl alcohol dissolve, then carry out next step reaction;
The amount of described dropping protonic acid (as sulfuric acid, phosphoric acid etc.) and the mol ratio of intermediate be preferably 1: 1.00～and 1: 1.10, more preferably mol ratio is 1: 1.01;
Described protonic acid (as sulfuric acid, phosphoric acid etc.) is preferably 60 DEG C～85 DEG C with the temperature of intermediate reaction, and more preferably temperature is 80 DEG C;
Described protonic acid (as sulfuric acid, phosphoric acid etc.) and the time of intermediate reaction are preferred 5.0～7.0h, and more preferably the reaction times is 6.0h;
The synthetic method of wallantoin of the present invention is the synthetic optimised process that conduct in-depth research and on the basis of many experiments obtain of applicant to wallantoin, with ionic liquid as catalyzer, have advantages of that traditional catalyst does not have, it has the high-density reaction active site of liquid acid and the non-volatility of solid acid simultaneously, acidity can exceed solid super-strong acid and can regulate as required, catalyzer easily separates with product, Heat stability is good, kind is many, there is adjustability of structure, and its physicochemical property depend on the zwitterion kind of application to a great extent, programmable green solvent and catalyzer truly, and ionic liquid has the potentiality that replace traditional industry catalyzer, its superiority more and more obtains people's attention.The method is compared with traditional synthetic method, and yield is improved, and this ionic liquid can be reused simultaneously, not only in environment protection, has accomplished zero emission, and has also greatly saved starting material on cost.The present invention uses ionic liquid for catalyzer first in the technique of synthetic allantoin, and technical process is simple, and raw material is large industrial chemicals, yield is high, is easy to industrialization promotion, wallantoin stable yield, yield can reach more than 68%, and catalyst ion liquid can be reused more than 5 times; And this technique is pollution-free, energy-saving and environment friendly, has good ecologic effect, preferably society and economic benefit.
The present invention couple
acid ion synthetic, is on forefathers' basis, to have carried out further groping, the proportioning raw materials of synthetic ionic liquid, process control have been carried out to further optimization, and has obtained stability and high efficiency
acid ion catalyzer.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.But do not limit the present invention with this.
Comparative example:
In reactor, add aqueous glyoxylic acid and urea, wherein, the mass concentration of aqueous glyoxylic acid is 45%, quality is 822g (5.0mol), stirs, then adds the urea of 1260g (21.0mol), the mol ratio of oxoethanoic acid and urea is 1: 4.2, reaction solution is heated to 68 DEG C, after reaction 6.5h, stops heating, be cooled to 15 DEG C, filtration obtains white solid, by 1L deionized water wash solid, washed twice, the white solid obtaining is wallantoin, taking-up is placed in 100 DEG C of oven for drying, the 471g that weighs, and calculating productive rate is 50.62%.
Embodiment 1
(1) preparation of ionic liquid:
By 850g 1,4-butane sultones is in the there-necked flask of 2L, at 25 DEG C, drip gradually 410gN-Methylimidazole, in 30min, dropwise, reaction solution is heated to 40 DEG C, stir 12h, filtration obtains white solid, is placed in 1.6L toluene and stirs 15min, suction filtration, by the crude product obtaining be placed in vacuum drying oven (90 DEG C, dry to constant weight under 0.01Mpa); Obtain intermediate 919g.Get above-mentioned obtained white powder solid 584g, add in the there-necked flask of 2L, add 1.1L dissolve with methanol, slowly drip sulfuric acid (massfraction 98%) 265g, after dropwising, temperature is remained on to 80 DEG C, reaction 6h, after reaction finishes, reaction solution is evaporated away to unnecessary moisture with Rotary Evaporators, the [(CH obtaining
2)
4sO
3hMIM] [HSO
4], be placed on (90 DEG C, 0.01Mpa, dries to constant weight) in vacuum drying oven, obtain 648g.Be this and react needed ionic-liquid catalyst A.
(2) wallantoin is synthetic:
In reactor, add aqueous glyoxylic acid, urea and a certain proportion of catalyst A, wherein, the mass concentration of aqueous glyoxylic acid is 45%, quality is 822g (5.0mol), stir, add again the urea of 1260g (21.0mol), the mol ratio of oxoethanoic acid and urea is 1: 4.2, when being heated to 50 DEG C, reaction solution stops heating, system insulation, adding catalyst A quality is 610g (2.0mol) (mol ratio of oxoethanoic acid and catalyzer is 1: 0.4), make system be warmed up to 68 DEG C, continue to stir, after reaction 6.5h, stop heating, be cooled to 15 DEG C, filtration obtains white solid, with 1L deionized water wash solid, wash three times (each 1L), merge washing lotion and filtrate, concentrated dewatering, be placed in vacuum drying oven inner drying for subsequent use, the white solid obtaining is wallantoin, taking-up is placed in 100 DEG C of oven for drying, 600g weighs, calculating productive rate is 75.95%, be labeled as first batch.
Embodiment 2
By embodiment 1 react the ionic liquid of collection dry after, add methyl alcohol 2.0L, reflux 2h, after backflow finishes, cooling, filter, obtain filtrate concentrated, separation of methanol (can get time use ready), obtain reusing the ionic liquid A1 of 1 time, add aqueous glyoxylic acid and urea, the mol ratio of oxoethanoic acid and urea is 1: 4.2, reaction solution is heated to 68 DEG C, reaction 6.5h, stop heating, be cooled to 15 DEG C, filtration obtains white solid, with 1L deionized water wash solid, wash three times (each 1L), merge washing lotion and filtrate, concentrated anhydrating, obtain reusable ionic liquid, be placed in vacuum drying oven inner drying for subsequent use, the white solid that reaction obtains is product wallantoin, taking-up is placed in 100 DEG C of oven for drying, weigh, calculating productive rate is 75.06%, be labeled as second batch.Can reuse three times according to this ionic liquid of this method, yield is respectively again: 74.68% (being labeled as the 3rd batch), 73.92% (being labeled as the 4th batch); 68.73% (being labeled as the 5th batch).
The wallantoin product that embodiment 1,2 is obtained is according to the methods analyst of American Pharmacopeia the 29th edition (USP29), and its result is as following table:
Embodiment 3
(1) preparation of ionic liquid:
By 850g 1,4-butane sultones is in the there-necked flask of 2L, at 25 DEG C, drip gradually 395g pyridine, in 30min, dropwise, reaction solution is heated to 40 DEG C, stir 12h, filtration obtains white solid, is placed in 1.6L toluene and stirs 15min, suction filtration, the crude product obtaining is placed in to vacuum drying oven (90 DEG C, dry to constant weight under 0.01Mpa) and obtains intermediate 896g; Get above-mentioned obtained white powder solid 578g, add in the there-necked flask of 2L, add 1.1L deionized water dissolving, slowly drip sulfuric acid (massfraction 98%) 265g, after dropwising, temperature is remained on to 80 DEG C, reaction 6h, after reaction finishes, reaction solution is evaporated away to unnecessary moisture with Rotary Evaporators, the [(CH obtaining
2)
4sO
3hPy] [HSO
4], be placed on (90 DEG C, 0.01Mpa, dries to constant weight) in vacuum drying oven, obtain 650g, be the ionic-liquid catalyst B of this reaction needed.
(2) wallantoin is synthetic:
Technological process is identical with embodiment 1, and catalyzer used is B, and the yield of wallantoin is 73.29%, and the analytical results that obtains product is as follows:
Embodiment 4
(1) preparation of ionic liquid:
By 850g 1,4-butane sultones is in the there-necked flask of 2L, at 25 DEG C, drip gradually 506g triethylamine, in 30min, dropwise, reaction solution is heated to 40 DEG C, stir 12h, filtration obtains white solid, is placed in 1.6L toluene and stirs 15min, suction filtration, the crude product obtaining is placed in to vacuum drying oven (90 DEG C, dry to constant weight under 0.01Mpa) and obtains intermediate 1074g; Get above-mentioned obtained white powder solid 637g, add in the there-necked flask of 2L, add 1.1L hexanaphthene to dissolve, slowly drip sulfuric acid (massfraction 98%) 265g, after dropwising, temperature is remained on to 80 DEG C, reaction 6h, after reaction finishes, reaction solution is evaporated away to unnecessary moisture with Rotary Evaporators, the [(CH obtaining
2)
4sO
3hEt
3n] [HSO
4], be placed on (90 DEG C, 0.01Mpa, dries to constant weight) in vacuum drying oven, obtain 710g, be the ionic-liquid catalyst C of this reaction needed.
(2) wallantoin is synthetic:
Technological process is identical with embodiment 1, and catalyzer used is C, and the yield of wallantoin is 72.03%, and the analytical results that obtains product is as follows:
Embodiment 5
(1) preparation of ionic liquid:
Method is identical with embodiment 1,3,4, Isosorbide-5-Nitrae-butane sultones, in the there-necked flask of 2L, is dripped respectively to N-Methylimidazole, pyridine, triethylamine at 25 DEG C gradually, in 30min, dropwise, reaction solution is heated to 40 DEG C, stirs 12h, filter and obtain white solid, be placed on and in toluene, stir 15min, suction filtration, is placed in vacuum drying oven (90 DEG C, dry to constant weight under 0.01Mpa) by the crude product obtaining and obtains intermediate; White powder solid obtained above a part is taken out and added in the there-necked flask of 2L, dissolve with methyl alcohol, water, hexanaphthene respectively, slowly drip phosphoric acid (massfraction 85%) 306g, after dropwising, temperature is remained on to 80 DEG C, reaction 6h, after reaction finishes, reaction solution is evaporated away to unnecessary solvent with Rotary Evaporators, obtain [(CH
2)
4sO
3hMIM] [H
2pO
4], [(CH
2)
4sO
3hPy] [H
2pO
4], [(CH
2)
4sO
3hEt
3n] [H
2pO
4], be placed on (90 DEG C, 0.01Mpa, dries to constant weight) in vacuum drying oven, be ionic-liquid catalyst D, E, the F of this reaction needed.
(2) wallantoin is synthetic:
Technological process is identical with embodiment 1, and catalyzer used is D, E, F, and the quality and the yield that obtain wallantoin are as shown in the table, and catalyzer also can be reused, and yield is basicly stable, qualified product.
| Catalyzer | Catalyzer D | Catalyzer E | Catalyzer F |
| Quality product (g) | ?573 | ?557 | ?555 |
| Yield (%) | ?72.53 | ?70.51 | ?70.25 |
Embodiment 6
(1) ionic liquid is synthetic
Method is as identical in embodiment 1, the catalyst A obtaining
(2) wallantoin is synthetic
In reactor, add aqueous glyoxylic acid, urea and a certain proportion of catalyzer, wherein, the mass concentration of aqueous glyoxylic acid is 20%, quality is 1850g (5.0mol), add again the urea of 1140g (19mol), the mol ratio of oxoethanoic acid and urea is 1: 3.8, when being heated to 50 DEG C, reaction solution stops heating, system insulation, adding catalyst A quality is 763g (2.5mol) (mol ratio of oxoethanoic acid and catalyzer is 1: 0.5), make system be warmed up to 55 DEG C, continue to stir, after reaction 24h, stop heating, be cooled to 15 DEG C, filtration obtains white solid, with 1L deionized water wash solid, wash three times (each 1L), the white solid obtaining is wallantoin, taking-up is placed in 105 DEG C of oven for drying, 561g weighs, calculating productive rate is 71.01%.
Embodiment 7
(1) ionic liquid is synthetic
Method is as identical in embodiment 6, the catalyzer D ([(CH obtaining
2)
4sO
3hMIM] [H
2pO
4]).
(2) wallantoin is synthetic
In reactor, add aqueous glyoxylic acid, urea and a certain proportion of catalyzer, wherein, the mass concentration of aqueous glyoxylic acid is 40%, quality is 925g (5.0mol), stir, add again the urea of 1350g (22.5mol), the mol ratio of oxoethanoic acid and urea is 1: 4.5, when being heated to 60 DEG C, reaction solution stops heating, system insulation, adding catalyzer D quality is 783g (2.5mol) (mol ratio of oxoethanoic acid and catalyzer is 1: 0.5), make system be warmed up to 80 DEG C, continue to stir, after reaction 24h, stop heating, be cooled to 15 DEG C, filtration obtains white solid, with 1L deionized water wash solid, wash three times (each 1L), the white solid obtaining is wallantoin, taking-up is placed in 105 DEG C of oven for drying, 557g weighs, calculating productive rate is 70.51%.
Claims (13)
1. a synthetic method for wallantoin, is characterized in that, with
acidic ion liquid is catalyzer, taking oxoethanoic acid and urea as raw material synthetic allantoin;
Described
acidic ion liquid be following any:
R=CH in formula I
3, C
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21, C
12h
25, C
14h
29, C
16h
33; X=HSO
4, H
2pO
4;
R=C in formula II
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21;
X＝HSO
4，H
2PO
4；
N=2 in formula III; X=HSO
4, H
2pO
4;
N=2 in formula IV; X=HSO
4, H
2pO
4;
R=CH in formula (V)
3, C
2h
5; X=HSO
4, H
2pO
4;
R=CH in formula VI
3, C
2h
5; X=HSO
4, H
2pO
4;
R=CH in formula (VII)
3, C
2h
5; X=HSO
4, H
2pO
4;
N=2 in formula (VIII); X=HSO
4, H
2pO
4;
N=3 in formula (IX), 4; X=HSO
4, H
2pO
4, CF
3cOO, OTf;
N=3 in formula (X); X=HSO
4, H
2pO
4;
In formula (XI), R=CH
3, C
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21, C
12h
25, C
14h
29, C
16h
33;
X＝BF
4，PF
6，EtOSO
3，(EtO)
2PO
2、CF
3CO
2，OTf、TsO，ClO
4，Ac，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=C in formula (XII)
2h
5, C
3h
7, C
4h
9, C
5h
11, C
6h
13, C
7h
15, C
8h
17, C
10h
21;
X＝BF
4，PF
6，C
12SO
3，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
N=2 in formula (X III);
X＝BF
4，PF
6，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
N=2 in formula (X IV);
X＝BF
4，PF
6，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (X V)
3, C
2h
5;
X＝BF
4，PF
6，OTf，TsO，NO
3；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (X VI)
3, C
2h
5;
X＝BF
4，PF
6，OTf，TsO，ClO
4，NO
3，Cl；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (X VII)
3, C
2h
5; X=BF
4, PF
6, NO
3, Cl;
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=C in formula (X VIII)
2h
5, C
4h
9, C
6h
13, C
8h
17; X=HSO
4, H
2pO
4;
N=3 in formula (X IX), 4; X=HSO
4, H
2pO
4;
R=C in formula (XX)
2h
5, C
4h
9, C
6h
13, C
8h
17;
X＝BF
4，PF
6，ClO
4，OTf，TsO，NO
3；
X
1＝H
2SO
4，H
3PO
4，HF，HAc，HNO
3，HCl，TsOH；
R=CH in formula (X XI)
3, C
2h
5, C
3h
7, C
4h
9;
R
1＝CH
3，C
2H
5，C
3H
7，C
4H
9，C
6H
13，C
7H
7，C
8H
17，C
12H
25，C
16H
33，C
18H
35，
X＝HSO
4，H
2PO
4；
R=CH in formula (X XII)
3, C
2h
5, C
3h
7, C
4h
9;
n＝3，4；X＝HSO
4，H
2PO
4；
R=CH in formula (XX III)
3, C
2h
5, C
3h
7, C
4h
9;
R
1＝H，CH
3，C
2H
5；n＝1，2；X＝HSO
4，H
2PO
4；
2. the synthetic method of wallantoin according to claim 1, is characterized in that, the synthetic method of described wallantoin comprises, in reactor, adds aqueous glyoxylic acid, urea and catalyzer, stirs heating; After reaction 4.0～24.0h, reaction mixture is cooled to room temperature, filters, wash, dry, obtain finished product; Filtrate and washing lotion merging collection and treatment are obtained to catalyzer, repeat catalysis next time.
3. the synthetic method of wallantoin according to claim 2, is characterized in that, the mass concentration of described aqueous glyoxylic acid is 20%～80%.
4. the synthetic method of wallantoin according to claim 2, is characterized in that, the mol ratio of described oxoethanoic acid and urea is 1:2.0～1:4.5.
5. the synthetic method of wallantoin according to claim 2, is characterized in that, the mol ratio of described oxoethanoic acid and catalyzer is 1:0.2～1:0.5.
6. the synthetic method of wallantoin according to claim 2, is characterized in that, described Heating temperature is 40 DEG C～80 DEG C.
7. the synthetic method of wallantoin according to claim 2, is characterized in that, the described reaction times is 4.0～24.0h.
8. according to the synthetic method of wallantoin described in claim 1～7 any one, it is characterized in that, described in
acidic ionic liquid preparation: add glyoxaline compound or pyridine compounds and their or tertiary amine compounds and alkylate in reactor, stir, heating, reaction 8～24h, after reaction finishes, reaction mixture is cooled to room temperature, filter, washing, separates, be dried to constant weight, obtain dry intermediate; Intermediate is dissolved, slowly drip protonic acid, heating, stirs, and reaction 5～7h, after reaction finishes, removes unnecessary moisture by reaction solution evaporation, and the product obtaining is dried to constant weight, to obtain final product.
9. the synthetic method of wallantoin according to claim 8, is characterized in that, the mol ratio of described glyoxaline compound or pyridine compounds and their or tertiary amine compounds and alkylate is 1:0.80～1:1.45.
10. the synthetic method of wallantoin according to claim 8, is characterized in that, the temperature of the reaction of described glyoxaline compound or pyridine compounds and their or tertiary amine compounds and alkylate is 15～50 DEG C; The time of the reaction of described glyoxaline compound or pyridine compounds and their or tertiary amine compounds and alkylate is 8～24h.
11. synthetic methods of wallantoin according to claim 8, it is characterized in that, described glyoxaline compound is imidazoles, N-Methylimidazole, 1,2 dimethylimidazole, N-ethyl imidazol(e), N-propyl imidazole, N-butyl imidazole, N-hexyl imidazoles, N-decyl imidazoles, N-octyl group imidazoles, N-dodecyl imidazoles, N-tetradecyl imidazoles or vinyl imidazole;
Described pyridine compounds and their is pyridine or N-picoline;
Described tertiary amine compounds is Trimethylamine 99, triethylamine, Tributylamine or tripropyl amine.
Described in 12. according to Claim 8 or 9～11 any one, the synthetic method of wallantoin, is characterized in that,
Described preparation
the solvent washing in acidic ion liquid process is benzene, toluene, ethyl acetate or ether.
Described in 13. according to Claim 8 or 9～11 any one, the synthetic method of wallantoin, is characterized in that,
The preferred water of described intermediate, hexanaphthene or methyl alcohol dissolve;
The described amount of dropping protonic acid and the mol ratio of intermediate are 1:1.00～1:1.10;
Described protonic acid and the temperature of intermediate reaction are 60 DEG C～85 DEG C;
Described protonic acid and the time of intermediate reaction are 5.0～7.0h.
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| CN103724273A (en) * | 2013-12-10 | 2014-04-16 | 芜湖华海生物工程有限公司 | Allantoin synthesis method |
| CN103724272A (en) * | 2013-12-10 | 2014-04-16 | 芜湖华海生物工程有限公司 | Allantoin synthesis method |
| CN103724274A (en) * | 2013-12-10 | 2014-04-16 | 芜湖华海生物工程有限公司 | Compound catalyst allantoin synthesis method |
| CN107721932A (en) * | 2017-11-09 | 2018-02-23 | 上海纳米技术及应用国家工程研究中心有限公司 | The method of purifying ampholytic ionic liquid presoma |
| CN109401814A (en) * | 2018-12-26 | 2019-03-01 | 诺泰生物科技(合肥)有限公司 | P t butylbenzoic acid alkanolamide class corrosion inhibitor and its synthetic method and the application in extraordinary oil |
| CN111848523A (en) * | 2020-08-04 | 2020-10-30 | 李金国 | A method for preparing allantoin for cosmetic |
| CN111808025A (en) * | 2020-08-04 | 2020-10-23 | 李金国 | Preparation method of allantoin for cosmetics |
| CN111848522A (en) * | 2020-08-04 | 2020-10-30 | 李金国 | A method for producing allantoin for cosmetic |
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| CN101347739A (en) * | 2007-07-16 | 2009-01-21 | 湖南大学 | Solid acid catalyst and reaction technique for synthesis of allantoin |
| CN102010372A (en) * | 2010-11-22 | 2011-04-13 | 天津市职业大学 | Method for synthesizing allantoin by catalysis of phosphorous acid |
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| CN101347739A (en) * | 2007-07-16 | 2009-01-21 | 湖南大学 | Solid acid catalyst and reaction technique for synthesis of allantoin |
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