CN103467349B - Method utilizing methyl sodium sulfate offscum to synthesize S-methyl-iso-thiourea sulfate - Google Patents
Method utilizing methyl sodium sulfate offscum to synthesize S-methyl-iso-thiourea sulfate Download PDFInfo
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Abstract
The invention discloses a method utilizing methyl sodium sulfate offscum to synthesize S-methyl-iso-thiourea sulfate. Methyl sodium sulfate offscum and thiourea are taken as fundamental raw materials, water is taken as the solvent, and reflux reaction is performed under the neutrality condition to obtain the S-methyl-iso-thiourea sulfate, of which the reaction formula is 2(H2N)2C=S + 2CH3OSO3Na react to generate (HN=C(SCH3)NH2)2,H2SO4+Na2SO4. The methyl sodium sulfate offscum, a by-product with the content of larger than or equal to 90%, obtained through producing hemiacetal or vitamin B1, and thiourea are taken as initial raw materials, water is taken as the solvent, and reaction is performed under the neutrality condition to prepare the end product. The method has the characteristics of high reaction speed, low demand on reaction conditions, good product quality, high product yield and the like; water replaces an organic solvent, and the methyl sodium sulfate offscum replaces a highly toxic product (methyl sulfate) to serve as a methylate raw material, so that not only is the advantage of low cost is achieved, but also the difficult pollution problem of the methyl sodium sulfate offscum is solved; only methanol is taken as a crystallization solvent and is recyclable for repeated use in the production process; waste water and other offscums are not produced in the production process, so that comprehensive utilization of the methyl sodium sulfate offscum and green production are realized.
Description
Technical field
The invention belongs to fine chemistry industry and field of Environment Protection, relate to the synthetic technology of meticulous medicine intermediate, particularly relate to a kind of technology utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea.
Background technology
S-methyl-isourea is the important intermediate of organic synthesis, for the production of cancer therapy drug (as 5-fluor-uracil, methyl-GAG and hydroxyguanidine sulfate) in medicine industry, and depressor Vatensol etc.; Pesticide industry is for the production of fungicide carbendazim, F-1991 and sterilant pririmiphos_methyl etc.; Also be the intermediate preparing guanethidine monosulfate and prednisolone sodium phosphate.
The U.S. patent Nos Preparation for producing creatine or creatine monohy drate(USA of the application such as Li hua, 6326513) a kind of method utilizing sarkosine, sodium sarcosinate or sarkosine potassium and the reaction of S-methyl-isourea to produce creatine is disclosed in, with water or water and ORGANIC SOLVENT MIXTURES for solvent, 15-140 DEG C, react under pH7-13, product is purified through alkaline complex compound, and average yield reaches 71.15%.The method advantage is that S-methyl-isourea can produce the harmful side product such as ammonia and cyanogen unlike cyanamide, and the creatine therefore prepared by the method is not containing harmful material.Yao Fang etc. [reference 1] had done improvement to this technique afterwards, in the creatine yield of sodium sarcosinate close to 96%.
[reference 1], Yao Fang, Xu Tianyou, Xu Wensong. creatine new synthetic process [J]. chemical reaction engineering and technique, 2003,19(2): 150-154,
Gabexate mesilate is a kind of inhibitor of non-peptide proteinoid enzyme, within 1978, gone on the market in Japan by little Ye drugmaker, it can suppress trypsinase, kallikrein, Tryptase, the activity of the proteolytic enzyme such as zymoplasm, thus the pathology preventing that these enzymes cause, for acute mild (edema type) pancreatitic treatment, also can be used for the assisting therapy of Acute haemorrhagic-necrotizing pancreatitis.6-aminocaprolc acid and S-methyl-isourea react, acidified 6-guanidine radicals hexanoic acid hydrochloride, with obtained through sulfur oxychloride condensation by ethyl p-hydroxybenzoate 4,4 '-(thionyl dioxy base) dibenzoic acid diethyl ester reacts to obtain gabexate hydrochloride, then reacts to obtain gabexate mesilate with methylsulfonic acid.
The Li Lu of Institute of Radiation Medicine, Academy of Military Medical Sciences, PLA etc. disclose the one synthetic method of-methyl-isothiourea salt " the dextrorotation S-(2-aminopropyl) " in national inventing patent CN200410029932.5, comprise the following steps: 2-bromine propylamine salt is split obtained dextrorotation 2-bromine propylamine Ltartaric acid through Ltartaric acid, then product is obtained by reacting with S-methylthiourea after changing gained dextrorotation 2-bromine propylamine Ltartaric acid into dextrorotation 2-bromine propylamine halogen hydracid salt, this invention is simple and easy to do, split process is simple, resolved product purifying is easy, carry out condensation reaction after fractionation again to obtain product and be the higher dextrorotation-S-of purity (2-aminopropyl)-methyl-isothiourea product salt.
Current S-Methyl Isourea Sulfate synthetic method has five kinds:
(1) take haloalkane as methylating reagent, carry out reaction in organic solvent with thiocarbamide and generate target product: Japanese Patent JP60184062, academic journal Journal of Organic Chemistry, 1999, 64 (22): 8080-8083 and Bioorganic & Medicinal Chemistry Letters, 2007, in 17 (24): 6853-6859, all report methyl iodide reacts generation S-methyl-isourea as methylating reagent and thiocarbamide in ethanolic soln, there is again document European Journal of MedicinalChemistry, 2010, 46 (1): 265-274 report methyl chloride prepare S-methyl-isothiourea hydrochloride as methylating reagent reaction (taking ethanol as reaction solvent).But there is larger defect using methyl halide as methylating reagent, as methyl iodide is expensive, methyl chloride is gas, increases to reaction and control difficulty, make to be not easy to industrialization and produce.
(2) aqueous hydrochloric acid of thiocarbamide and alcohol thermal response altogether: thiocarbamide is when thermal response prepares S-methyl-isothiourea to the aqueous hydrochloric acid of alcohol altogether, more owing to generating by product in reaction, cause the shortcomings such as product yield is low and of poor quality, thus can not realize industrialization and produce.
(3) thiocarbamide and methyl-sulfate react and generate halogeno salt and S-methyl-isourea respectively: produce at present and generally adopt methyl-sulfate to produce S-Methyl Isourea Sulfate as methylating reagent, as document Chinese Chemical Letters, 2011,22 (11): 1277-1280 and Japanese Patent JP2011148719 etc. report the method using methyl-sulfate to prepare S-methyl-isourea as methylating reagent.Sun Xiaohong, Zeng Zhenfang, Liu Yuanfa etc. are report in document " creatinol replaces synthesis and the biological activity that pyrrole determines hydrochlorate ", and methyl-sulfate and thiocarbamide are with mol ratio for 0.67, and 110 ~ 120 DEG C of back flow reaction 4h, obtain S-methyl-isourea, yield 92.0%; The Kang Ruhong of Hebei Normal University etc. are at " chemical reagent " (1994,16 (6): 373; 380) published on " Phase transfer catalyzed synthesis of S-melhylisothiourea salts ", they are phase-transfer catalyst with the triethyl benzyl ammonia chloride of 0.0013mol, the thiocarbamide of 0.1mol and the methyl-sulfate of 0.055mol are in 6.5ml water, back flow reaction 1.5h at 110 DEG C, the yield of S-methyl-isourea can reach 94%, and fusing point is 234-236 DEG C.The synthetic method being raw material with sulfuric acid and methyl-sulfate is commonly used to present industrialization and produces, but in this production line, it is excessive that the feed ratio of methyl-sulfate all needs, be generally the 1.1-1.4 of theoretical amount doubly, cause the waste of starting material methyl-sulfate, because methyl-sulfate is highly toxic product, huge potential safety hazard is brought to environment and workman.
(4) with O, O-dimethyl phosphorous acid as methylating reagent: document Justus Liebigs Annalen derChemie, 1967,703:31-3 report, prepare S-methyl-isourea with O, O-dimethyl phosphorous acid as methylating reagent.But this route product yield is lower, and containing more phosphoric in waste water, easily causes body eutrophication, be difficult to meet industrialization demand.
(5) to disclose a kind of synthetic method of S-methyl-isothiourea salt in the Chinese invention patent CN201210096827.8 of application such as the synthetic route that cyanamide and thiomethyl alcohol are raw material: Yan Feng and Wu Zhihong of Shandong Chambroad Holding Co., Ltd. and Yellow River Delta Jingbo Chemical Research Institute Co., Ltd. etc., this invention with cyanamide and thiomethyl alcohol for raw material, synthesize S-methyl-isothiourea acetate in acid condition, then replace with strong acid and obtain required S-methyl-isourea.This patented method not only operation steps is simple, reaction time is short, transformation efficiency is high, and energy consumption is low, and required equipment is simple, be applicable to industrial-scale production, the S-methyl-isothiourea salts contg adopting this invention to produce, more than 99%, can meet the technical requirements of market to S-methyl-isothiourea salt, but the price of starting material cyanamide is high, cause its production cost too high, product does not have the market competitiveness.
Methyl sodium sulphate is the sodium salt of methyl-hydrogen-sulfate monomethyl-sulfate, it is the Main By product that VITMAIN B1 and hemiacetal are produced, methyl sodium sulphate waste residue is all dispose as solid waste for a long time, and disposal costs is high, methyl sodium sulphate is all temporarily deposited by a lot of enterprise, conservative estimation, the current domestic methyl sodium sulphate amount of having, more than 100,000 tons, therefore needs to develop new methyl sodium sulphate comprehensive utilization technique.
Methyl sodium sulphate can be used as methylating reagent for the preparation of Nitromethane 99Min., but because product yield is low, poor product quality (color and luster is brown color and zero pour is high) and by-product sodium sulfate contains the shortcomings such as Sodium Nitrite.For the integrated application of methyl sodium sulphate, there is report for the production of to MSM toluene and dimethyl thioether.
Hu Xinhe in nineteen ninety-five disclose on " Zhejiang chemical industry " magazine a kind of based on methyl sodium sulphate and Tosyl chloride raw material production to the method for MSM toluene, tosic acid sodium salt and methyl sodium sulphate are 7.4-7.8 at pH, temperature is back flow reaction 36h at 98-102 DEG C, add decolorizing with activated carbon, be cooled to room temperature to filter, wash and drain, dry at 65 DEG C must to MSM toluene finished product, yield reaches 92%, but containing a large amount of tertiary sodium phosphate, sodium-chlor and sodium bicarbonate in its sodium sulfate byproduct, a large amount of saliferous high concentrated organic wastewater can be produced simultaneously.
The Meng Juying of Dongbei Pharmaceutical General Factory etc. publish paper " utilizing methyl sodium sulphate waste residue to prepare dimethyl thioether " on " chemical industry environmental protection ", taking a certain amount of methyl sodium sulphate is dissolved in a certain amount of water, be stirred to CL, static layering, joins lower floor's methylsulfuric acid sodium solution and appropriate sodium sulphite and stirs with in the synthetic reaction device stirred.Electrically heated thermostat water bath is transferred to 100 DEG C, carries out building-up reactions at ambient pressure.Reactant distills, and gained cut icy salt solution cools, and tail gas sodium hydroxide solution absorbs.Vinasse carries out recrystallization after filtering, and filter through secondary crystal and obtain byproduct sulfite, filtrate goes biochemical treatment after neutralization reaction, and product recovery rate is 83.59%.It is simple that this method has technique, the advantage of technical feasibility and stable operation, but can produce the shortcoming such as foul gas and treating high-concentration saline organic wastewater in production process.
Summary of the invention
The technical problem to be solved in the present invention is to provide the methyl sodium sulphate waste residue that utilizes that a kind of cost is low, product yield is high and synthesizes the method for S-methyl-isourea.
In order to solve the problems of the technologies described above, the invention provides a kind of method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea, the method is raw material based on methyl sodium sulphate waste residue and thiocarbamide, take water as solvent, the obtained S-methyl-isourea of reaction in neutral conditions, reaction formula is as follows:
2(H
2N)
2C=S+2CH
3OSO
3Na→(HN=C(SCH
3)NH
2)
2·H
2SO
4+Na
2SO
4。
As the improvement utilizing methyl sodium sulphate waste residue to synthesize the method for S-methyl-isourea of the present invention, comprise the following steps:
1), in reaction vessel, after water and thiocarbamide being mixed according to the mass ratio of 1:0.5 ~ 1, heating (75 ~ 85 DEG C) is stirred, until thiocarbamide all dissolves; Obtain thiourea solution;
2) in the thiourea solution of step 1) gained, add the methyl sodium sulphate waste residue of (can be and slowly add) solid state, heat up (being 105 ~ 115 DEG C), react 1 ~ 3 hour under reflux state, thiocarbamide: the mol ratio of methyl sodium sulphate (pure substance) is 1:1 ~ 1.5;
3), by step 2) the reaction mass liquid of gained is cooled to 35 ~ 45 DEG C (being preferably 40 DEG C), and control mixing speed at 50 ~ 100 revs/min, add methyl alcohol and carry out crystallization, the add-on of methyl alcohol is 1 ~ 3 times of the volume of water in step 1);
4), by step 3) gained material carry out solid-liquid separation by whizzer, controlling water content≤3%(in the solid materials (mixture for S-methyl-isourea and sodium sulfate) of centrifugal rear gained is quality %);
5), in another reaction vessel under agitation condition, in methyl alcohol, add sodium hydroxide; After naturally cooling to room temperature, obtain methanolic sodium hydroxide solution; The mass volume ratio of described sodium hydroxide and methyl alcohol is that 1g:3.5 ~ 4.5ml(is preferably 4ml);
6) be, the feed ratio of 1:0.8 ~ 1.2 according to the mol ratio of the sodium hydroxide in step 5) and the thiocarbamide in step 1), the solid materials (mixture for S-methyl-isourea and sodium sulfate) of the centrifugal gained of step 4) is added, in 5 ~ 20 DEG C (being preferably 10 ~ 20 DEG C) reaction 1.5 ~ 2.5 hours under agitation condition in the methanolic sodium hydroxide solution of step 5) gained;
7), by the reacting rear material of step 6) gained carry out suction filtration by negative pressure of vacuum (-0.098MPa), obtain filtrate and filter cake respectively;
After described filter cake methanol wash, oven dry, obtain the sodium sulfate as byproduct;
8), under ice bath (0 ~ 5 DEG C), under the condition of stirring at low speed (rotating speed controls as 50-60 rev/min), in the filtrate of step 7) suction filtration gained, the vitriol oil is dripped until in neutrality; A large amount of white crystal can be separated out in dropping vitriol oil process;
The described vitriol oil refers to the sulfuric acid of mass concentration 98%;
9), by the gains of step 8) carry out vacuum filtration, obtain filtrate and the crystal as filter cake, described crystal methanol wash, then carries out vacuum-drying in 70 ~ 90 DEG C, obtains S-methyl-isourea.
As the further improvements in methods utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea of the present invention, the present invention also comprises: reclaim methyl alcohol by rectifying after the liquid of step 4) solid-liquid separation gained and the filtrate of step 9) gained merge, methyl alcohol after rectifying carries out recovery, aqueous phase (importantly water wherein also has the methyl sodium sulphate of minute quantity and S-methyl-isourea) does not need just can directly return step 1) alternative steps 1 through disposing) in water (consumption is the same with the consumption of water).
As the further improvements in methods utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea of the present invention, step 2) in the methyl sodium sulphate waste residue of solid state be the waste residue as by product producing hemiacetal or VITMAIN B1 gained, methylsulfuric acid sodium content >=90%(quality % in described waste residue).
As the further improvements in methods utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea of the present invention, water in step 1): the mass ratio of thiocarbamide is 1:1.
As the further improvements in methods utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea of the present invention, step 2) in react 2 hours at reflux, thiocarbamide: the mol ratio of methyl sodium sulphate (pure substance) is 1:1.1.
As the further improvements in methods utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea of the present invention, in described step 3), the add-on of methyl alcohol is 2 times or 3 times of the volume of water in step 1).
As the further improvements in methods utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea of the present invention, in described step 6), be the feed ratio of 1:1 according to the mol ratio of the thiocarbamide in sodium hydroxide in step 5) and step 1), the solid materials (mixture of S-methyl-isourea and sodium sulfate) of the centrifugal gained of step 4) is added, in 20 DEG C of reactions 2 hours under agitation condition in the methanolic sodium hydroxide solution of step 5) gained.
Remarks illustrate:
1), in the present invention, room temperature refers to 10 ~ 25 DEG C.
2), in the present invention, not doing the stirring that clear and definite rotating speed limits is conventional alr mode, and rotating speed is generally 100 ~ 300 revs/min.
In the present invention, the poorly soluble opposite sex in methyl alcohol according to S-methyl-isourea and S-methyl-isothiourea, add appropriate sodium hydroxide and the reaction of S-methyl-isourea, the S-methyl-isothiourea of free state is dissolved in methanol phase, and sodium sulfate crystal is insoluble to methyl alcohol, realize the separation between sodium sulfate and S-methyl-isourea.
In the present invention, also utilize the solvability of S-methyl-isourea in methyl alcohol, suction filtration institute filtrate is dripped the vitriol oil under (0-5 DEG C) under ice bath until solution is in neutral, S-methyl-isothiourea is converted to form crystallization from methyl alcohol of vitriol.
In sum, the invention provides a kind of synthetic method preparing S-Methyl Isourea Sulfate, the method, to produce the methyl sodium sulphate waste residue of by-product content >=90% of hemiacetal or VITMAIN B1 and thiocarbamide for starting raw material, take water as solvent, the obtained finished product of reaction in neutral conditions.This processing method have be swift in response and reaction conditions requirement low; Good product quality and product yield high; With water to replace organic solvent, replace highly toxic product methyl-sulfate for the raw material that methylates with methyl sodium sulphate waste residue, not only there is the advantage that cost is low, a pollution difficult problem for methyl sodium sulphate waste residue can also be solved; Sodium sulfate byproduct quality is good; Only use methyl alcohol in whole production process as recrystallisation solvent and recyclablely to apply mechanically; Produce without waste water and other waste residue in production process, really achieve comprehensive utilization and the green production of methyl sodium sulphate.
Embodiment
Below in conjunction with specific embodiment, invention is described further, but not as the restriction to invention, allly all belongs to integral part of the present invention based on technology of the present invention.
Starting material of the present invention:
Methyl alcohol, technical grade, commercially available;
Thiocarbamide, technical grade, commercially available;
Methyl sodium sulphate waste residue, produce the by product of hemiacetal, the content of methyl sodium sulphate is 92.3%(quality %), Zhejiang pelagic organism science and technology group;
The vitriol oil (mass concentration is the sulfuric acid of 98%), technical grade, commercially available;
Solid sodium hydroxide, technical grade, commercially available.
Embodiment 1, a kind of method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea, carry out following steps successively:
1), in a 1000ml tri-mouthfuls of reaction flasks water 152ml is added, thiocarbamide 152g(2mol), be warming up to 80 DEG C and stir until thiocarbamide all dissolves; Obtain thiourea solution.
2) the methyl sodium sulphate waste residue 319g(methyl sodium sulphate 2.2mol of (adding complete in about 10 ~ 20 minutes) solid state, in the thiourea solution of step 1) gained is slowly added), be warming up to 105 ~ 115 DEG C, make its back flow reaction 2h.
3), by step 2) reacting rear material of gained is cooled to 40 DEG C (now reacting rear material does not solidify), controls mixing speed at 50-100 rev/min, slowly add 304ml methyl alcohol and carry out crystallization.
4), by the gained material after step 3) crystallization carry out solid-liquid separation by whizzer, after centrifugal, obtain solid materials (mixture of S-Methyl Isourea Sulfate and sodium sulfate) 400g;
After testing, the water content of above-mentioned solid materials is about 2.8%(quality %).
5), in another 1000ml tri-mouthfuls of reaction flasks add methyl alcohol 300ml, (be such as divided into 4 batches) under stirring in batches and add sodium hydroxide 80g(2mol), question response heat release returns to room temperature, obtains methanolic sodium hydroxide solution, for subsequent use.
6), in the methanolic sodium hydroxide solution of step 5) gained, add the whole 400g solid materials (mixture for S-Methyl Isourea Sulfate and sodium sulfate) of step 4) gained, control temperature is at 10 ~ 20 DEG C of stirring reaction 2h.
7), by the reacting rear material of step 6) gained carry out suction filtration by negative pressure of vacuum (-0.098MPa), filter cake 400ml methyl alcohol washs at twice, and obtain 275g white sodium sulfate crystal after oven dry, content (purity) is 98.8%(quality %);
8), the filtrate of step 7) suction filtration gained under ice bath (0-5 DEG C) with vitriol oil titration (dripping and controlling mixing speed in vitriol oil process is 50 revs/min), until stop in neutrality dripping the vitriol oil, drip in vitriol oil process and can separate out a large amount of white crystal;
9), the gains of step 8) are carried out vacuum filtration, obtain filtrate and the crystal as filter cake, crystal 200ml methyl alcohol washs at twice, vacuum-drying at 80 DEG C, obtain product S-methyl-isourea 220g, content is 99.3%(quality %), be pure white crystal, fusing point 242-243 DEG C, product yield 79.1% (in starting raw material thiocarbamide).
10) methyl alcohol is reclaimed by rectifying after, the liquid of step 4) solid-liquid separation gained and step 9) suction filtration gained filtrate being merged, methyl alcohol after rectifying carries out recovery, aqueous phase does not need to replace water (that is, the consumption of aqueous phase is with the consumption of water) to recycle through disposing directly to return in step 1).
Embodiment 2, a kind of method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea, carry out following steps successively:
1), in a 1000ml tri-mouthfuls of reaction flasks water 304ml is added, thiocarbamide 152g(2mol), be warming up to 80 DEG C and stir until thiocarbamide all dissolves; Obtain thiourea solution.
2), in the thiourea solution of step 1) gained, the methyl sodium sulphate waste residue 436g(methyl sodium sulphate 3mol of solid state is slowly added), be warming up to 105 ~ 115 DEG C, make its back flow reaction 2h.
3), by step 2) the reaction mass liquid of gained is cooled to 40 DEG C (now reactant feed liquid is not solidified), controls mixing speed at 50-100 rev/min, slowly add 608ml methyl alcohol and carry out crystallization.
4), by the gained material after step 3) crystallization carry out solid-liquid separation by whizzer, after centrifugal, obtain solid materials (mixture of S-Methyl Isourea Sulfate and sodium sulfate) 405g;
After testing, the water content of above-mentioned solid materials is about 2.8%(quality %).
5), in another 1000ml tri-mouthfuls of reaction flasks add methyl alcohol 300ml, add sodium hydroxide 80g under stirring in batches, question response heat release obtains methanolic sodium hydroxide solution after returning to room temperature; For subsequent use.
6), in the methanolic sodium hydroxide solution of step 5) gained, add the whole 405g solid materials (mixture for S-Methyl Isourea Sulfate and sodium sulfate) of step 4) gained, temperature controls at 10 ~ 20 DEG C of stirring reaction 2h.
7), by the reacting rear material of step 6) gained carry out suction filtration by negative pressure of vacuum, obtain filtrate and filter cake respectively;
Filter cake 400ml methyl alcohol washs at twice, and filter cake obtains 278g sodium sulfate after drying, and product content (purity) is 98.1%.
8), the filtrate of step 7) suction filtration gained under ice bath (0-5 DEG C) with vitriol oil titration (dripping mixing speed in vitriol oil process is 50 revs/min), stop dripping the vitriol oil until solution is neutrality, drip in vitriol oil process and can separate out a large amount of white crystal.
9), by the gains of step 8) carry out vacuum filtration, obtain filtrate and the crystal as filter cake; Crystal 200ml methyl alcohol washs at twice, 80 DEG C of vacuum-dryings, obtains product S-methyl-isourea 222g, and content is 98.1%, is pure white crystal, fusing point 240-242 DEG C, product yield 79.9% (in starting raw material thiocarbamide).
10) methyl alcohol is reclaimed by rectifying after, the filtrate of the liquid of step 4) solid-liquid separation gained and step 9) suction filtration gained being merged, methyl alcohol after rectifying carries out recovery, and aqueous phase does not need directly to return step 1) alternative steps 1 through disposing) in water recycle.
Embodiment 3, a kind of method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea, carry out following steps successively:
1), in a 1000ml tri-mouthfuls of reaction flasks water 152ml is added, thiocarbamide 152g(2mol), be warming up to 80 DEG C and stir until thiocarbamide all dissolves; Obtain thiourea solution.
2), in the thiourea solution of step 1) gained, the methyl sodium sulphate waste residue 290g(methyl sodium sulphate 2mol of solid state is added), be warming up to 105 ~ 115 DEG C, make its back flow reaction 2h.
3), by step 2) the reaction mass liquid of gained is cooled to 40 DEG C (now, reaction mass does not solidify), controls mixing speed at 50-100 rev/min, slowly add 304ml methyl alcohol and carry out crystallization.
4), by the gained material after step 3) crystallization carry out solid-liquid separation by whizzer, after centrifugal, obtain solid materials (mixture of S-Methyl Isourea Sulfate and sodium sulfate) 380g;
After testing, the water content of above-mentioned solid materials is about 2.8%(quality %).
5), in another 1000ml tri-mouthfuls of reaction flasks add methyl alcohol 300ml, add sodium hydroxide 80g under stirring, question response heat release returns to room temperature in batches, obtains methanolic sodium hydroxide solution; For subsequent use.
6), in the methanolic sodium hydroxide solution of step 5) gained, add whole 380g solid materials (mixture of S-Methyl Isourea Sulfate and sodium sulfate) of step 4) gained, temperature controls stirring reaction 2h below 20 DEG C.
7), by the reacting rear material of step 6) gained carry out suction filtration by negative pressure of vacuum, obtain filtrate and filter cake respectively;
Filter cake 400ml methyl alcohol washs at twice, and filter cake obtains 266g sodium sulfate after drying, and product content is 98.6%.
8), the filtrate of step 7) gained under ice bath (0-5 DEG C) with vitriol oil titration (dripping mixing speed in vitriol oil process is 50 revs/min), stop dripping the vitriol oil until solution is neutrality, drip in vitriol oil process and can separate out a large amount of white crystal.
9), step 8) gained material is carried out vacuum filtration, obtain filtrate and the crystal as filter cake, crystal 150ml methyl alcohol washs at twice, 80 DEG C of vacuum-dryings, obtain product S-methyl-isourea 201g, content is 99.0%, is pure white crystal, fusing point 241-243 DEG C, product yield 72.3% (in starting raw material thiocarbamide).
10) methyl alcohol is reclaimed by rectifying after, the liquid of step 4) solid-liquid separation gained and step 9) suction filtration gained filtrate being merged, methyl alcohol after rectifying carries out recovery, and aqueous phase does not need directly to return step 1) alternative steps 1 through disposing) in water recycle.
Comparative example 1
The method that " the organic synthesis topical reference book " 264 pages (press of Beijing Institute of Technology publishes in January, 1992) that reference Fan Nengting writes describes, 152g (2mol) thiocarbamide is added in three mouthfuls of reaction flasks of 2000ml, add 70ml water, stir, add 138g(1.1mol) methyl-sulfate, immediately flask is linked one band trap long reflux exchanger on.Reaction is allowed automatically to carry out, when reaction accelerates, in bottle during aerification, logical water quench.After initial vigorous reaction, reflux mixture 1h, after reaction terminates, is cooled to room temperature, adds 95% ethanol of 200ml, suction filtration after mixing.Filter cake, with 95% washing with alcohol (2*100ml), dries in atmosphere, obtains the S-methyl-isourea of 182g.Mother liquor is through concentrated, and cooling, add 95% ethanol of 120ml, obtain second batch product, weight is 41g.Secondary obtains S-methyl-isourea 223g altogether, product yield 80.2% (in starting raw material thiocarbamide), and content is 98.8%, is pure white crystal, fusing point 240-243 DEG C.
Comparative example 2
According to Kang Ruhong of Hebei Normal University etc. at " chemical reagent " (1994,16 (6): 373; 380) method of " Phase transfer catalyzed synthesis of S-melhylisothiourea salts " has been published on, be phase-transfer catalyst with the triethyl benzyl ammonia chloride of 0.0013mol, the thiocarbamide of 0.1mol and the methyl sodium sulphate of 0.055mol are in 6.5ml water, back flow reaction 1.5h at 110 DEG C, final S-methyl-isourea 8.9g, yield is only 63.9%, and content is 97.3%, and fusing point is 228-232 DEG C.
Comparative example 3
With reference to the method described by PCT patent WO2007/074391, at an outfit agitator, hot plate, water-bath, in the round-bottomed flask of condenser, adds attached salt solution 77ml, thiocarbamide (100g, 1.3137mol) at 25-30 DEG C.Stir and add methyl-sulfate (90.64g, 0.7186mol), having spent for some time at leisure, improve temperature to 80 DEG C and keep several minutes, improving temperature further, maintaining reaction 5h at a reflux temperature.Cooling reaction mass, to 25-35 DEG C, adds Virahol 133ml, stirs 60 minutes.With 73.5ml mixing, washing filter cake (100mL Virahol: 47ml water), dry cake at 70-75 DEG C, obtains 144g sample, and content is 97.8%, and yield is 78.9%, fusing point 240-243 DEG C.
Comparative example 4
S-methyl-isothiourea salt synthetic method disclosed in the Chinese invention patent CN201210096827.8 of the applications such as Yan Feng and Wu Zhihong of reference Shandong Chambroad Holding Co., Ltd. and Yellow River Delta Jingbo Chemical Research Institute Co., Ltd., mixes the glacial acetic acid of 42g cyanamide crystal and 57.5ml; At-5 DEG C, in the mixing solutions of above-mentioned cyanamide and acetic acid, pass into methyl mercaptan gas, react 5 hours; To step 2) add 50% sulphuric acid soln of 196g in solution, temperature rises to 20 DEG C, stirring reaction, obtains the solution of S-methyl-isourea and acetic acid; Step 3) gained solution is cooled to 0 DEG C of crystallization, filters, filter cake is with dry after 20ml methanol wash, and obtain the S-methyl-isourea of 94.2g, content is 98.3%, and yield is 67.6%.Obtain the high concentrated organic wastewater that 120ml contains sulfuric acid and acetic acid, due to containing sulfuric acid and water, this waste water can not be applied mechanically, and therefore needs to carry out biotreatment, pollutes quite serious simultaneously.
Comparative example 5,
Make the step 5) of embodiment 1 into following content:
5), in another 1000ml tri-mouthfuls of reaction flasks add methyl alcohol 300ml, (be such as divided into 4 batches) under stirring in batches and add sodium hydroxide 60g, question response heat release returns to room temperature, obtains methanolic sodium hydroxide solution, for subsequent use.
All the other are all equal to embodiment 1.
Finally, obtain product S-methyl-isourea 172g, content is 99.2%, is pure white crystal, fusing point 242-243 DEG C, product yield 61.9% (in starting raw material thiocarbamide).
And as in the sodium sulfate of byproduct due to containing a large amount of S-methyl-isoureas, therefore purity is lower.
Comparative example 6
Make the step 8) of embodiment 1 into following content:
8), the filtrate of step 7) suction filtration gained under ice bath (0-5 DEG C) with vitriol oil titration (dripping and controlling mixing speed in vitriol oil process is 50 revs/min), until stop dripping the vitriol oil when solution is in acid (pH is 3), drip in vitriol oil process and can separate out a large amount of white crystal; Then partial crystals is had to be dissolved again.
All the other are all equal to embodiment 1.
Finally, obtain product S-methyl-isourea 198g, content is 99.3%, is pure white crystal, fusing point 242-243 DEG C, product yield 71.2% (in starting raw material thiocarbamide).
Finally, it is also to be noted that what enumerate above is only several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be had.All distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Claims (7)
1. utilize methyl sodium sulphate waste residue to synthesize the method for S-methyl-isourea, it is characterized in that: raw material based on methyl sodium sulphate waste residue and thiocarbamide, take water as solvent, and back flow reaction obtains in neutral conditions; Reaction formula is as follows:
2(H
2N)
2C＝S+2CH
3OSO
3Na→(HN＝C(SCH
3)NH
2)
2·H
2SO
4+Na
2SO
4；
Comprise the following steps:
1), in reaction vessel, after water and thiocarbamide being mixed according to the mass ratio of 1:0.5 ~ 1, heated and stirred, until thiocarbamide all dissolves; Obtain thiourea solution;
2), toward step 1) add the methyl sodium sulphate waste residue of solid state in the thiourea solution of gained, heat up, react 1 ~ 3 hour under reflux state, thiocarbamide: the mol ratio of methyl sodium sulphate is 1:1 ~ 1.5;
3), by step 2) the reaction mass liquid of gained is cooled to 35 ~ 45 DEG C, control mixing speed at 50 ~ 100 revs/min, add methyl alcohol and carry out crystallization, the add-on of methyl alcohol is step 1) in 1 ~ 3 times of volume of water;
4), by step 3) gained material carries out solid-liquid separation by whizzer, and control water content≤3% in the solid materials of centrifugal rear gained, this % is quality %;
5), in another reaction vessel under agitation condition, in methyl alcohol, add sodium hydroxide; After naturally cooling to room temperature, obtain methanolic sodium hydroxide solution; The mass volume ratio of described sodium hydroxide and methyl alcohol is 1g:3.5 ~ 4.5ml;
6), according to step 5) in sodium hydroxide and step 1) in the mol ratio of thiocarbamide be the feed ratio of 1:0.8 ~ 1.2, to step 5) add step 4 in the methanolic sodium hydroxide solution of gained) solid materials of centrifugal gained, in 5 ~ 20 DEG C of reactions 1.5 ~ 2.5 hours under agitation condition;
7), by step 6) reacting rear material of gained carries out suction filtration by the negative pressure of vacuum of-0.098Mpa, respectively filtrate and filter cake;
After described filter cake methanol wash, oven dry, obtain the sodium sulfate as byproduct;
8), under ice bath, under the condition of stirring at low speed, to step 7) drip the vitriol oil until in neutrality in the filtrate of suction filtration gained; A large amount of white crystal can be separated out in dropping vitriol oil process;
The described vitriol oil refers to the sulfuric acid of mass concentration 98%;
9), by step 8) gains carry out vacuum filtration, obtain filtrate and the crystal as filter cake, described crystal methanol wash, then carries out vacuum-drying in 70 ~ 90 DEG C, obtains S-methyl-isourea.
2. the method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea according to claim 1, is characterized in that:
Step 4) liquid of solid-liquid separation gained and step 9) filtrate of gained reclaims methyl alcohol by rectifying after merging, methyl alcohol after rectifying carries out recovery, aqueous phase do not need through disposal just directly can return step 1) alternative steps 1) and in water.
3. the method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea according to claim 2, it is characterized in that: described step 2) in the methyl sodium sulphate waste residue of solid state be the waste residue as by product producing hemiacetal or VITMAIN B1 gained, methylsulfuric acid sodium content >=90% in described waste residue, this % is quality %.
4. the method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea according to claim 3, is characterized in that: described step 1) middle water: the mass ratio of thiocarbamide is 1:1.
5. the method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea according to claim 4, is characterized in that: described step 2) in react 2 hours at reflux, thiocarbamide: the mol ratio of methyl sodium sulphate is 1:1.1.
6. the method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea according to claim 5, is characterized in that: described step 3) in the add-on of methyl alcohol be step 1) in 2 times or 3 times of volume of water.
7. the method utilizing methyl sodium sulphate waste residue to synthesize S-methyl-isourea according to claim 6, it is characterized in that: described step 6) in, according to step 5) in sodium hydroxide and step 1) in the mol ratio of thiocarbamide be the feed ratio of 1:1, to step 5) add step 4 in the methanolic sodium hydroxide solution of gained) solid materials of centrifugal gained, in 20 DEG C of reactions 2 hours under agitation condition.
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|---|---|---|---|---|
| CN1752071A (en) * | 2005-10-26 | 2006-03-29 | 东北制药总厂 | Method of preparing dimethyl thioether using methyl sodium sulphate |
| WO2007074391A2 (en) * | 2005-12-28 | 2007-07-05 | Bakulesh Mafatlal Khamar | Preparation of a key intermediate in the synthesis of rosuvastatin |
| CN102633701A (en) * | 2012-04-05 | 2012-08-15 | 山东京博控股股份有限公司 | Synthesis method of S-methyl isothiourea salt |
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|---|---|---|---|---|
| CN1752071A (en) * | 2005-10-26 | 2006-03-29 | 东北制药总厂 | Method of preparing dimethyl thioether using methyl sodium sulphate |
| WO2007074391A2 (en) * | 2005-12-28 | 2007-07-05 | Bakulesh Mafatlal Khamar | Preparation of a key intermediate in the synthesis of rosuvastatin |
| CN102633701A (en) * | 2012-04-05 | 2012-08-15 | 山东京博控股股份有限公司 | Synthesis method of S-methyl isothiourea salt |
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| 康汝洪,马志博,刘俊玲.相转移催化合成S-甲基异硫脲盐.《化学试剂》.1994,第16卷(第06期), * |
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