CN102321136B - Preparation method for S-adenosine-L-methionine disulfate tosylate - Google Patents
Preparation method for S-adenosine-L-methionine disulfate tosylate Download PDFInfo
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Abstract
The invention discloses a preparation method for S-adenosine-L-methionine disulfate tosylate. The method comprises the following steps of: precipitating S-adenosine-L-methionine (SAM) which is prepared through thallus collection, cell disruption of an acid heat method, extraction, and separation and purification; adjusting and controlling proportion of sulfate radial to para-toluenesulfonic acid radical; and drying to prepare the high-purity SAM disulfate tosylate. The method has the advantages of simple technological line, high processing capacity, product recovery rate of up to 75-80 percent, proportion of active ingredients in a product of more than 90 percent, product purity of up to 96-98 percent, corresponding indexes meeting pharmacopoeial requirements, low production cost and capability of realizing industrial production.
Description
Technical field
The present invention relates to bionic biochemical separation field, more particularly, the present invention relates to a kind of preparation method of SAMe disulfate tosylate.
Background technology
SAMe (S-adenosyl-L-methionine; SAM; SAMe or AdoMet) be the sulfonyl compound of organic tetravalence sulphur form (metal sulfonium) of methionine(Met); be called as " active methionine "; be a kind of important Metabolic Intermediate being extensively present in organism, first nineteen fifty-two is found by Cantoni.SAM is two chiral materials, has 2 kinds of isomer: (R, S)-SAM and (S, S)-SAM, only have (S, S)-SAM has biological activity.In vivo, SAM is catalyzed and synthesized through SAM synthetic enzyme (S-adenosylmethionine synthetase) by METHIONINE (L-Met) and Triphosaden (ATP).The high energy sulfonium atom that contains a nucleophillic attack reaction that can activate adjacent carbons due to SAM, thereby there is transmethylase, turn sulfenyl, turn the effects such as aminopropyl.SAM has participated in more than 40 kind of biochemical reaction in body, synthetic closely related with protein, nucleic acid, neurotransmitter, phospholipid and VITAMIN, and connect the conversion of polyamines and gsh.In Europe, SAM has been widely used in the treatment of the diseases such as hepatopathy, dysthymia disorders, sacroiliitis as prescription drugs; In the U.S., a kind of healthcare products salable have been become.There are numerous hepatitis, sacroiliitis and patients with depression in China, and the demand of SAM also will constantly increase, and the prospect of marketing of product is wide.
SAM molecule, due to the existence of high energy sulfonium cation, shows extreme unstable.No matter be solution or drying regime, room temperature or higher than room temperature, under neutrality or alkaline condition, all can generate different degraded products.The inactivation reaction of SAM can carry out according to 3 kinds of different mechanism, topmost inactivation reaction is, by the carboxyl oxygen on amino acid chain, gamma carbon atom is carried out to nucleophillic attack in molecule, thereby cracking forms MTA (5 '-methylthioadenosine, MTA) and homoserine lactone (homoserine), lactone hydrolysis subsequently; Next is (R, S)-SAM that the spontaneous racemization of (S, S)-SAM is abiotic activity.In addition, SAM is hydrolyzed, and generates VITAMIN B4 (adenine) and S-pentose methionine(Met) (S-pentosylmethionine).
SAM vitriol and SAM hydrochloride are under dry, cold condition, and stability is still poor, therefore can only be used to general Biochemical Research.US3954726, US4028183 confirms that the stability of the disulfate tosylate of SAM improves a lot than simple SAM hydrochloride, vitriol, under 45 ℃ of drying conditionss, the former is basic not loss after 6 months, then both complete losses after 6 months; Therefore the SAM salt, using is clinically mainly SAM disulfate tosylate.There are at present many reports of preparing and improving stability by additive about the two salt of SAM.Although US3954726, US4057686 all can make the two salt of purer SAM, owing to needing the reactant that price is higher, are not suitable for suitability for industrialized production.Although EPA0141914 provides the two salt preparation methods of a kind of SAM of applicable suitability for industrialized production, the ethyl acetate organic solvent of its broken use is difficult for reclaiming, and need to be dried waste mycelia, avoids organic solvent volatilization residual on it.In addition, the processing power of resin is limited, and the amount of resin that same treatment amount needs is larger, and elutriant need to pass through another kind of plastic resin treatment, and to adsorb impurity wherein, step is complicated.The very environmental protection of crumbling method that EPA1091001 adopts, but it is strict to equipment requirements.Its resin of selecting has higher exchange capacity, but its removal of impurities is limited in one's ability, needs to select resin decolorization after wash-out.Its fragmentation of CN1907996 need to be used organic solvent, reclaims difficulty; Ion exchange process elution step is complicated, and water loss is large; Need to cross anion-exchange column decolouring concentrated; Elutriant product concentration is low, and the concentration after concentrated 12 times is similar to the unconcentrated concentration of this patent.
Yao Jinxiao, Deng people, " research of SAMe in hot water extraction yeast saccharomyces cerevisiae; biological processing; 2008; 6 (1); 74～77 ", adopt hot-water process directly to extract yeast saccharomyces cerevisiae intracellular product SAMe (SAM), and be optimized affecting the reaction conditions of SAM extracting, the optimum experimental condition drawing is: every 30g wet thallus adds hot water 100mL, sulfuric acid concentration 0.25mol/L, mixing speed 160r/min, 70～76 ℃ of temperature of reaction, reaction times 10min.Adopt the extract content of the method SAM to reach more than 90%.But SAM is a kind of thermolability material, when solution temperature is greater than 60 ℃, the degradation rate of SAM increases rapidly.When the reaction times surpasses 30min, SAM severely degrade, the extract content of SAM is reduced to below 50%.Especially along with treatment capacity increases, the degree of irregularity of being heated increases, and intensification and cooling rate reduce, and cause thalline to be degraded in a large number, and the extract content of SAM reduces, and causes larger SAM loss.Therefore, for reducing SAM degradation rate, reduce the loss of SAM, SAM leaching process requires strict control temperature of reaction and reaction times, and require system to there is higher intensification and cooling rate, higher to equipment and operational requirement, cost is higher, the method only limits to laboratory and uses, and is unsuitable for industrial application.
At present, need to develop technology of preparing a kind of applicable suitability for industrialized production, low-loss, low cost, high yield, highly purified SAM disulfate tosylate.
Summary of the invention
Technical problem to be solved by this invention is for above-mentioned the deficiencies in the prior art, and a kind of preparation method of SAMe disulfate tosylate is provided.The method is for the preparation of SAM disulfate tosylate, and treatment capacity is large, and purity is high, and yield is high, with low cost, and is suitable for suitability for industrialized production.
For this reason, the invention provides the preparation method of 1. 1 kinds of SAMe disulfate tosylates, comprising:
Steps A, collects thalline;
Step B, extracts SAM, makes SAM extraction liquid;
Step C, carries out ultrafiltration to SAM extraction liquid, makes SAM filtrate;
Step D, adopts ion exchange method to carry out ion exchange treatment to SAM filtrate, makes SAM elutriant;
Step e, carries out precipitation process to SAM elutriant, makes SAM precipitation;
Step F, preparation SAM disulfate tosylate solution;
Step G, dry SAM disulfate tosylate;
Wherein, step B adopts acid heat method to carry out fragmentation and extraction to the collected thalline of steps A, and temperature of reaction is 30～60 ℃, and the reaction times is controlled at 0.5～3h.The temperature of reaction of step B is preferably 45～55 ℃.
In one embodiment of the invention, in the fermenting process of preparation SAM, adopt yeast saccharomyces cerevisiae high density fermentation, by adding precursor METHIONINE, make resulting fermented liquid there is the higher thalline content that is rich in SAM.Steps A, under 4 ℃ of conditions, by fermented liquid centrifugal treating 10min, collects thalline with the rotating speed of 6000rpm.
According to the inventive method, in the reaction process of step B, the rotating speed of clarifixator is controlled at 300～10000rpm.Described in step B, acid is sulphuric acid soln, and its concentration is 0.1～0.5M, and consumption is 2～5L/kg wet thallus.Adopt cold water by the cooling of cytoclasis liquid, and under 4 ℃ of conditions, with 6000rpm rotating speed centrifugal treating 10min, collect supernatant liquor, obtain SAM extraction liquid, SAM extraction liquid yield is 85%～90%.
In one embodiment of the invention, step C adopts ultra-filtration membrane to carry out uf processing to SAM extraction liquid, to remove the impurity such as deproteinize.Described ultra-filtration membrane is that molecular weight cut-off is 6000～10000 ultra-filtration membrane.Seldom, SAM filtrate yields is greater than 98% in ultrafiltration step loss.
According to the inventive method, step D comprises spent ion exchange resin treatment S AM filtrate, makes SAM be adsorbed in ion exchange resin surface, then use deionized water wash-out impurity, use eluent wash-out SAM, wherein, described ion exchange resin is macropore weak-acid ion exchange resin again.The exchange capacity of described ion exchange resin is 90～120g SAM/L resin.
According to the inventive method, the NaOH by 15%～20% in ion exchange treatment process is controlled at 4～7 by pH.This ion exchange resin is few to impurity absorption amount, and removal of impurities process is simple.
In one embodiment of the invention, the input concentration of the filtrate of SAM described in step D is 4～10g/L, and input speed is 1～4BV/h (BV is column volume), and inlet amount is 12～22.5BV.The flow velocity of described deionized water is 1～4BV/h, and consumption is 4～6BV.Described eluent is sulphuric acid soln, and its concentration is 0.05～0.25M, and flow velocity is 1～4BV/h.In prepared elutriant, SAM concentration is 22～35g/L, and the SAM elutriant rate of recovery is 93～96%.
In another embodiment of the present invention, step e adds SAM elutriant to carry out precipitation process in the acetone that is equivalent to 6～10 times of effluent volumes, static ageing 24h, and elimination supernatant liquor, makes SAM precipitation.
According to the inventive method, step F adopts tosic acid/sulphuric acid soln by SAM resolution of precipitate, makes SAM disulfate tosylate solution, and wherein the ratio of SAM/ tosic acid/sulfuric acid is 1: 1: 1.5～1: 3: 3.The concentration of described tosic acid/sulphuric acid soln is 0.5M～2M.
In one embodiment of the invention, step G adopts lyophilize or boulton process, and SAM disulfate tosylate is dry, and making purity is the SAM disulfate tosylate of 96～98wt%, and product is white powder.
The present invention is under 30～60 ℃ of conditions, adopt acid heat method to carry out cytoclasis and SAM extraction, extraction process is less demanding to system intensification and cooling rate, thalline treatment capacity is large, cell crashing ratio and SAM extraction yield are high, and not containing residual organic solvent, the selected resin of the present invention has been realized the larger loading capacity of SAM and stronger absorption specificity in prepared extraction liquid.According to the proportioning of the contained SAM of the prepared elutriant of the inventive method and sulfate radical, tosic acid, can be regulated to the ratio that meets salify, and foreign matter content is few, SAM concentration is high, thereby can omit decolouring removal of impurities and enrichment step, greatly simplify sepn process.It is reusable after the acetone of precipitation use reclaims.Operational path of the present invention is simple, and treatment capacity is large, and product recovery rate is up to 75%～80%, in product, activeconstituents (S, S)-SAM proportion is greater than 90%, and product purity is up to 96～98%, corresponding index meets pharmacopeia requirement, and production cost is low, can realize suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, describe the present invention in detail, these embodiment only play illustrative effect, are not limited to range of application of the present invention.
Embodiment
Embodiment 1:
(1) in the fermenting process of preparation SAM, adopt yeast saccharomyces cerevisiae high density fermentation, by adding precursor METHIONINE, make resulting fermented liquid there is the higher thalline content that is rich in SAM.After fermentation ends, under 4 ℃ of conditions, with the rotating speed of 6000rpm, by 30L fermented liquid centrifugal treating 10min, obtain about 10kg wet thallus.
(2) get prepared wet thallus in 8kg step (1), add 24L50 ℃, 0.1M H
2sO
4solution, under 50 ℃ of conditions, homogenization treatment 1h, homogenizer rotating speed is 500rpm.After bacterial cell disruption, with cold water, lower the temperature, and under 4 ℃ of conditions, the rotating speed centrifugal treating 10min with 6000rpm removes bacterial chip, obtains SAM extraction liquid, its output, concentration and yield are in Table 1.
(3) adopt the ultra-filtration membrane that molecular weight cut-off is 10000 to carry out uf processing to the prepared SAM extraction liquid of step (2), remove protein-based impurity, make SAM filtrate.
(4) with 15% NaOH solution by the pH regulator to 5 of the prepared SAM filtrate of step (3), the ion exchange column that displacement pile volume is about 1.9L carries out ion exchange treatment, the exchange capacity of its resin is 110g/L resin, the input concentration of SAM is 7.2g/L, input speed is 1.5BV/h, and inlet amount is 15.3BV; Charging finishes the rear deionized water wash-out impurity with 6BV, and the flow velocity of deionized water is 4BV/h; Finally use the H of 0.15M
2sO
4solution is made the SAM that adsorb on eluent wash-out ion exchange resin surface, H
2sO
4the flow velocity of solution is 2BV/h, obtains SAM elutriant, and its output and concentration are in Table 1.
(5) add the acetone that is equivalent to 7 times of volumes of the prepared SAM elutriant of step (4) to carry out precipitation process to the prepared SAM elutriant of step (4), static ageing 24h, elimination supernatant liquor, collects SAM precipitation.
(6) adopt prepared SAM precipitation in tosic acid/sulphuric acid soln dissolving step (5) that concentration is 1M, make SAM disulfate tosylate solution, the ratio of its SAM/ tosic acid/sulfuric acid is 1: 1: 2.
(7) prepared concentrated SAM disulfate tosylate solution in step (6) is carried out to lyophilize, obtain white powder SAM disulfate tosylate, the total yield of its purity, output and SAM is in Table 1.
Embodiment 2:
Embodiment 2 is as different from Example 1:
(2) get prepared wet thallus in 1kg step (1), add 5L30 ℃, the H of 0.2M
2sO
4solution, under 30 ℃ of conditions, homogenization treatment 3h, homogenizer rotating speed is 300rpm, the results are shown in Table 1.
(3) adopt the ultra-filtration membrane that molecular weight cut-off is 6000 to carry out uf processing to the prepared SAM extraction liquid of step (2).
(4) with 20% NaOH solution by the pH regulator to 7 of the prepared SAM filtrate of step (3), the ion exchange column that displacement pile volume is about 0.3L carries out ion exchange treatment, the exchange capacity of its resin is 90g/L resin, the input concentration of SAM is 4.0g/L, input speed is 4.0BV/h, and inlet amount is 22.5BV; The consumption of deionized water is 5BV, and flow velocity is 1BV/h; The concentration of sulphuric acid soln is 0.05M, and flow velocity is 1BV/h, the results are shown in Table 1.
(5) add the acetone that is equivalent to 6 times of volumes of the prepared SAM elutriant of step (4) to carry out precipitation process to the prepared SAM elutriant of step (4).
(6) adopt prepared SAM precipitation in tosic acid/sulphuric acid soln dissolving step (5) that concentration is 0.5M, make SAM disulfate tosylate solution, the ratio of its SAM/ tosic acid/sulfuric acid is 1: 1: 1.5.
(7) prepared concentrated SAM disulfate tosylate solution in step (6) is carried out to vacuum-drying, the results are shown in Table 1.
Embodiment 3:
Embodiment 3 is as different from Example 1:
(2) get prepared wet thallus in 10kg step (1), add 20L60 ℃, the H of 0.5M
2sO
4solution, under 60 ℃ of conditions, homogenization treatment 0.5h, homogenizer rotating speed is 600rpm, the results are shown in Table 1.
(3) adopt the ultra-filtration membrane that molecular weight cut-off is 6000 to carry out uf processing to the prepared SAM extraction liquid of step (2).
(4) with 20% NaOH solution by the pH regulator to 4 of the prepared SAM filtrate of step (3), the ion exchange column that displacement pile volume is about 2.1L carries out ion exchange treatment, the exchange capacity of its resin is 120g/L resin, the input concentration of SAM is 10.0g/L, input speed is 1.0BV/h, and inlet amount is 12.0BV; The consumption of deionized water is 4BV, and flow velocity is 2BV/h; The concentration of sulphuric acid soln is 0.25M, and flow velocity is 4BV/h, the results are shown in Table 1.
(5) add the acetone that is equivalent to 8 times of volumes of the prepared SAM elutriant of step (4) to carry out precipitation process to the prepared SAM elutriant of step (4).
(6) adopt prepared SAM precipitation in tosic acid/sulphuric acid soln dissolving step (5) that concentration is 2.0M, make SAM disulfate tosylate solution, the ratio of its SAM/ tosic acid/sulfuric acid is 1: 3: 3.
(7) prepared concentrated SAM disulfate tosylate solution in step (6) is carried out to vacuum-drying, the results are shown in Table 1.
Embodiment 4:
Embodiment 4 is as different from Example 1:
(2) get prepared wet thallus in 5kg step (1), add 20L45 ℃, 0.2M H
2sO
4solution, under 45 ℃ of conditions, homogenization treatment 2h, homogenizer rotating speed is 500rpm.After bacterial cell disruption, with cold water, lower the temperature, and under 4 ℃ of conditions, the rotating speed centrifugal treating 10min with 6000rpm removes bacterial chip, the results are shown in Table 1.
(3) adopt the ultra-filtration membrane that molecular weight cut-off is 10000 to carry out uf processing to the prepared SAM extraction liquid of step (2), remove protein-based impurity, make SAM filtrate.
(4) with 20% NaOH solution by the pH regulator to 6 of the prepared SAM filtrate of step (3), the ion exchange column that displacement pile volume is about 1.3L carries out ion exchange treatment, the exchange capacity of its resin is 100g/L resin, the input concentration of SAM is 5.8g/L, input speed is 2BV/h, and inlet amount is 17.3BV; Charging finishes the rear deionized water wash-out impurity with 6BV, and the flow velocity of deionized water is 3BV/h; Finally use the H of 0.1M
2sO
4solution is made the SAM that adsorb on eluent wash-out ion exchange resin surface, H
2sO
4the flow velocity of solution is 1.5BV/h, the results are shown in Table 1.
(5) add the acetone that is equivalent to 6 times of volumes of the prepared SAM elutriant of step (4) to carry out precipitation process to the prepared SAM elutriant of step (4), static ageing 24h, elimination supernatant liquor, collects SAM precipitation.
(6) adopt prepared SAM precipitation in tosic acid/sulphuric acid soln dissolving step (5) that concentration is 1M, make SAM disulfate tosylate solution, the ratio of its SAM/ tosic acid/sulfuric acid is 1: 2: 2.
(7) prepared concentrated SAM disulfate tosylate solution in step (6) is carried out to lyophilize, the results are shown in Table 1.
Embodiment 5:
(2) get prepared wet thallus in 7kg step (1), add 17L55 ℃, 0.3M H
2sO
4solution, under 55 ℃ of conditions, homogenization treatment 1h, homogenizer rotating speed is 400rpm.After bacterial cell disruption, with cold water, lower the temperature, and under 4 ℃ of conditions, the rotating speed centrifugal treating 10min with 6000rpm removes bacterial chip, the results are shown in Table 1.
(3) adopt the ultra-filtration membrane that molecular weight cut-off is 6000 to carry out uf processing to the prepared SAM extraction liquid of step (2), remove protein-based impurity, make SAM filtrate.
(4) with 15% NaOH solution by the pH regulator to 5 of the prepared SAM filtrate of step (3), the ion exchange column that displacement pile volume is about 1.6L carries out ion exchange treatment, the exchange capacity of its resin is 112g/L resin, the input concentration of SAM is 8.5g/L, input speed is 2.5BV/h, and inlet amount is 13.2BV; Charging finishes the rear deionized water wash-out impurity with 5BV, and the flow velocity of deionized water is 3BV/h; Finally use the H of 0.2M
2sO
4solution is made the SAM that adsorb on eluent wash-out ion exchange resin surface, H
2sO
4the flow velocity of solution is 2.5BV/h, the results are shown in Table 1.
(5) add the acetone that is equivalent to 7 times of volumes of the prepared SAM elutriant of step (4) to carry out precipitation process to the prepared SAM elutriant of step (4), static ageing 24h, elimination supernatant liquor, collects SAM precipitation.
(6) adopt prepared SAM precipitation in tosic acid/sulphuric acid soln dissolving step (5) that concentration is 1.5M, make SAM disulfate tosylate solution, the ratio of its SAM/ tosic acid/sulfuric acid is 1: 2: 3.
(7) prepared concentrated SAM disulfate tosylate solution in step (6) is carried out to lyophilize, the results are shown in Table 1.
Comparative example 1:
Comparative example 1 is as different from Example 1:
(2) get prepared wet thallus in 1kg step (1), adopt 500ml, 50% the ethyl acetate aqueous solution to process 40min, add again the 0.4mol/L sulphuric acid soln of 2BV (1000ml) to process 90min, then thalline is carried out to fragmentation and centrifugal treating.Other reaction conditionss are identical with embodiment 1, the results are shown in Table 1.The SAM disulfate tosylate product of extraction liquid preparation proportioning identical with embodiment 1, equal in quality and the purity being obtained with comparative example 1 step (2), the used in amounts of same resin increases 50wt%.
From above-described embodiment and comparative example and table 1, can find out, according to the inventive method, carry out cytoclasis and SAM extraction, owing to not using ethyl acetate class organic solvent in process, in the SAM extraction liquid obtaining, there is no residual organic solvent, in ion exchange process, do not exist organic solvent for the detrimentally affect of diffusion, resin has larger loading capacity and stronger absorption specificity to target product SAM, the processed in units amount of resin and resin utilization ratio all improve a lot thus, yield and the purity of target product also improve a lot, and preparation cost reduces.
Comparative example 2:
Comparative example 2 is as different from Example 1:
(2) get prepared wet thallus in 1kg step (1), adopt 3L70 ℃, 0.1M H
2sO
4solution, under 70 ℃ of conditions, homogenization treatment 30min, other reaction conditionss are identical with embodiment 1, the results are shown in Table 1.
From above-described embodiment and comparative example and table 1, can find out, under 70 ℃ of conditions, extract SAM, because treatment capacity is larger, thalline is heated inhomogeneous, system intensification and cooling are rapid not, even if the reaction times is 30min, also can cause a large amount of SAM degradeds, thereby reduce SAM extraction liquid yield, and finally reduce the total yield of SAM; According to the inventive method, extract SAM, because temperature of reaction is lower, thalline is heated more even, less demanding to system intensification and cooling rate, can not cause the degraded of SAM, even if the reaction times extends to 3h, treatment capacity increases to 10kg, still can obtain higher cell crashing ratio and SAM extraction yield, thereby obtain higher SAM total yield.
Table 1
Claims (7)
1. a preparation method for SAMe disulfate tosylate, comprising:
Steps A, collects thalline;
Step B, extracts SAM, makes SAM extraction liquid;
Step C, carries out ultrafiltration to SAM extraction liquid, makes SAM filtrate;
Step D, adopts ion exchange method to carry out ion exchange treatment to SAM filtrate, makes SAM elutriant;
Step e, carries out precipitation process to SAM elutriant, makes SAM precipitation;
Step F, preparation SAM disulfate tosylate solution;
Step G, dry SAM disulfate tosylate;
Wherein, step B adopts acid heat method to carry out fragmentation and extraction to the collected thalline of steps A, and temperature of reaction is 45～55 ℃, and the reaction times is controlled at 0.5～3h;
Step e adds SAM elutriant to carry out precipitation process in the acetone that is equivalent to 6～10 times of SAM effluent volumes;
Described in step B, acid is sulphuric acid soln, and its concentration is 0.1～0.5M, and consumption is 2～5L/kg wet thallus;
Step D comprises spent ion exchange resin treatment S AM filtrate, makes SAM be adsorbed in ion exchange resin surface, then uses deionized water wash-out impurity, then uses eluent wash-out SAM, and wherein, described ion exchange resin is macropore weak-acid ion exchange resin.
2. method according to claim 1, is characterized in that: the exchange capacity of described ion exchange resin is 90～120g SAM/L resin.
3. method according to claim 1, is characterized in that: the input concentration of the filtrate of SAM described in step D is 4～10g/L, and input speed is 1～4BV/h, and inlet amount is 12～22.5BV.
4. method according to claim 1, is characterized in that: the flow velocity of deionized water described in step D is 1～4BV/h, and consumption is 4～6BV.
5. method according to claim 1, is characterized in that: eluent described in step D is sulphuric acid soln, and its concentration is 0.05～0.25M, and flow velocity is 1～4BV/h.
6. method according to claim 1, is characterized in that: step F adopts tosic acid/sulphuric acid soln by SAM resolution of precipitate, makes SAM disulfate tosylate solution, and wherein the ratio of SAM/ tosic acid/sulfuric acid is 1:1:1.5～1:3:3.
7. method according to claim 6, is characterized in that: the concentration of described tosic acid/sulphuric acid soln is 0.5M～2M.
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