CN102660611A - Method for preparing ademetionine 1,4-butanedisulfonate - Google Patents
Method for preparing ademetionine 1,4-butanedisulfonate Download PDFInfo
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- CN102660611A CN102660611A CN2012101268390A CN201210126839A CN102660611A CN 102660611 A CN102660611 A CN 102660611A CN 2012101268390 A CN2012101268390 A CN 2012101268390A CN 201210126839 A CN201210126839 A CN 201210126839A CN 102660611 A CN102660611 A CN 102660611A
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Abstract
The invention discloses a method for preparing ademetionine 1,4-butanedisulfonate. By means of the method, the problem that products prepared by the existing method are unstable in quality, low in product purity and deep in color is solved, and the method includes: (1) fermenting through saccharomyces cerevisiae, directly using fermentation liquor or centrifuging and filtering the fermentation liquor to obtain thallus for use, (2) stirring and mixing EA aqueous solution and the thallus, or stirring or mixing sulfuric acid and the fermentation liquor, filtering the mixed liquor, adding carbonate for neutralizing, and centrifuging and filtering, (3) enabling supernate to pass through an H+ type ion exchange column, washing through acetic acid, washing through purified water, eluting ademetionine through 1,4-butanedisulfonate, and starting collecting the eluent liquor when pH is lower than 3.5, (4) enabling the eluent liquor to pass through a polymeric adsorbent column, performing butting washing through 1,4-butanedisulfonate, and collecting effluent when the pH is smaller than 4.0, (5) filtering and then concentrating the effluent to obtain concentrated liquor, and (6) adjusting the proportion of 1,4-butanedisulfonate to ademetionine to be (1.63-1.66):1.
Description
Technical field:
The preparation method of the present invention and 1,4-fourth disulfonic acid ademetionine is relevant, and especially stable with preparation quality, the method for 1,4-fourth disulfonic acid ademetionine that color and luster is low is relevant.
Background technology:
1; (S-Adenosyl-L-methionnine 1,4-butanedisulfonate) is S-ademetionine (S-adenosyl-L-methionine, SAM to 4-fourth disulfonic acid ademetionine; SAMe) 1; 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate is used to treat illness such as dysthymia disorders, sacroiliitis, liver dysfunction clinically, is applicable to before the liver cirrhosis and intrahepatic cholestasis due to the liver cirrhosis; Be applicable to Gestation period intrahepatic cholestasis.
Its chemical name: (+)-5
,-[(R*)-[(R*)-3-amino-3-carboxylic propyl group) the first sulfo group]-5
,-Desoxyadenosine, 1,4-butane stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate.Its molecular structure is following:
The ademetionine preparation technology of bibliographical information roughly is divided into following three kinds: 1) chemical synthesis: with S-adenosyl homocysteine and methyl donor (CH3I) synthesizing adenosine methionine.Because productive rate is lower, and the steric configuration non-selectivity of product, seldom use.2) Enzymatic transformation method: utilize adenomethionine synthase (adenosyl transferase) catalytic substrate L-methionine(Met) and ATP to generate ademetionine.3) microbe fermentation method: utilize certain micro-organisms (especially saccharomycetic bacterial strains) when in containing the substratum of a certain amount of L-methionine(Met), growing; In cell, can accumulate the characteristics of the ademetionine of higher concentration, through the fermentative prepn ademetionine.Based on cost consideration, the main at present producing adenosine through zymotechnics methionine(Met) that adopts, method realizes industriallization basically, the difficult point of this product is that separation and purification obtains steady quality, 1,4-fourth disulfonic acid ademetionine that color and luster is low.
Chinese patent CN200510019206.x, U.S. Pat P4,990,606, USP5,128,249 have all illustrated separation and purification and salify (comprising 1, the 4-fourth stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate) technology of SAM with European patent EP 0,162,323.The basic line of these patents is: the material that contains ademetionine (SAM) is handled the filtrating that obtains containing SAM through organic solvent and acid solution, through ultrafiltration membrance filter, crosses ion exchange column; Wash with acetic acid; Then with 1,4-fourth disulfonic acid eluant solution, purification on adsorbent resins; A series of processes such as reverse osmosis membrane concentrates, spraying drying or solvent crystal finally obtain the multi-form salt of ademetionine.U.S. Pat P4 wherein, 1,4-fourth disulfonic acid is 1.5:1 with the ratio of ademetionine in 990,606, USP5,128,249 products that obtain with European patent EP 0,162,323, the insufficient strength of acid in this product influences the stability of product.These patents place ultrafiltration membrance filter before the extraction, because ferment filtrate contains a large amount of high molecular weight proteins and cell debris, are unfavorable for ultrafiltration; Simultaneously, before carrying out product purification, also to carry out operations such as IX, decolouring, can in product, bring materials such as thermal source into, too early carry out ultrafiltration and have little significance.The unstable product quality that the method for describing according to these patents obtains, isomer proportion and related substance do not reach the drug quality requirement, and perhaps color and luster is yellow partially.
Summary of the invention:
It is reasonable to the purpose of this invention is to provide a kind of technical process, and sepn process is simple, constant product quality, the preparation method of 1,4-fourth disulfonic acid ademetionine of lighter color.
The present invention is achieved in that
The preparation method of the present invention's 1,4-fourth disulfonic acid ademetionine comprises:
(1) with yeast saccharomyces cerevisiae aerobic fermentation 24-72 hours in fermentor tank; Add L-methionine(Met) in the fermenting process; Fermented liquid directly is used for the thalline use that subsequent step perhaps must contain fermented liquid centrifuging ademetionine, perhaps must contains the mixed solution of ademetionine through the Enzymatic transformation method
(2) V/V concentration 40-60%EA aqueous solution and the thalline with 0.3--0.6 times of thalline volume mixed 25-50 minutes; The V/V concentration of perhaps using 1-1.5 times of fermentating liquid volumes is that 1.5-2.5 sulfuric acid and fermented liquid or mixed solution mixed 2.5-3.5 hours, will mix liquid and filter with whizzer, in filtrating, adds V/W concentration 10-20% carbonate and neutralizes; By pH4.0-5.0 o'clock; With neutralizer centrifuging, get supernatant
(3) supernatant is crossed H
+The type ion exchange column, pH4.0-5.0,0.3-0.6 times of column volume of flow; Using concentration is that the acetic acid of 0.1-0.2mol/L washs to the liquid fluid and is less than or equal to pH3.0, washs to effluent pH4.0-5.0 with purified water again, and using concentration is 1 of 0.1-0.2mol/L; 4-fourth disulfonic acid wash-out ademetionine; Flow velocity 0.3-0.6 volume/hour, pH＜3.5 begin to collect elutriant
(4) elutriant is crossed adsorption resin column, 0.3-0.6 times of column volume of flow/hour, after upper prop finished, use concentration was that 1.0-2.0 column volumes are washed on 1,4-fourth disulfonic acid top of 10-20mol/L, behind pH＜4.0, collects effluent,
(5) effluent is concentrated through reverse osmosis membrane behind ultrafiltration membrance filter again, perhaps with effluent after reverse osmosis membrane concentrates again through ultrafiltration membrance filter, liquid concentrator, temperature is 0-30 ℃,
(6) through in liquid concentrator, adding 1,4-fourth disulfonic acid, adjusting 1,4-fourth disulfonic acid is 1.63-1.66: 1 with the ratio of ademetionine,
The neutralizer centrifugal rotational speed is not less than 6000rpm in the step (2).
Carbonate described in the step (2) is inorganic carbonate or organic bases carbonate.
H in the step (3)
+The type ion exchange column is a weak-acid ion exchange resin, and the adsorption resin column in the step (4) is the low-pole polymeric adsorbent, and the ultra-filtration membrane molecular weight cut-off is 1000-15000 in the step (5).
Key step of the present invention comprise the material that contains ademetionine (SAM) handle through organic solvent and acid solution the filtrating that obtains containing SAM ion exchange column, with the acetic acid washing, then with 1; 4-fourth disulfonic acid eluant solution, purification on adsorbent resins is passed through ultrafiltration membrance filter again; Reverse osmosis membrane concentrates, regulates liquid concentrator 1; 4-fourth disulfonic acid concentration, a series of processes such as spraying drying finally obtain 1; 4-fourth disulfonic acid ademetionine product (ratio of 1,4-fourth disulfonic acid and ademetionine is that 1.63:1 is between the 1.66:1).
Through the process step of adjustment traditional preparation process method, treat just to carry out ultrafiltration membrance filter after the separation and purification completion, reverse osmosis concentration, spraying drying can obtain superior in quality product.Ultrafiltration step is placed on after the separation purifying technique, not only helps operation, and before refining, carry out ultrafiltration, can go out macromole impurity effectively up hill and dale, avoid product to deepen at storage and transport process color and luster; A large amount of high molecular weight proteins in the ferment filtrate and cell debris are then removed through high speed centrifugation (being higher than 6000rpm).Simultaneously, improve the ratio of 1,4-fourth disulfonic acid in the product, be more conducive to product and stablize.Sepn process of the present invention is simple, and product purity is high, steady quality, and lighter color is fit to suitability for industrialized production.
Embodiment:
Embodiment 1:
Adopt yeast saccharomyces cerevisiae
Saccharomyces cerevisiaeCPCC340488 (buy in Sichuan Industrial Institute of Antibiotics microbial strains preservation center, this bacterial classification is open to be sold society) aerobic fermentation in general fermentor tank is added L-methionine(Met) in the middle of the process, and fermented liquid is through the centrifugal thalline that obtains.
Yeast saccharomyces cerevisiae
Saccharomyces cerevisiaeSubstratum that CPCC340488 is concrete and culture condition:
Medium component and prescription (table 1)
Culture condition (table 2)
Yeast saccharomyces cerevisiae
Saccharomyces cerevisiaeCPCC340488 aerobic fermentation 71 hours in general fermentor tank is added L-methionine(Met) in the middle of the process, and fermented liquid is through the centrifugal thalline that obtains.Contain 45mg/g ademetionine (SAM) in the thalline.
After mixing 25～50 minutes with 60%EA (v/v) aqueous solution of 2L and 5 kilograms of thalline, add above-mentioned mixed solution with 7.5L 3% (v/v) sulfuric acid, stir 4 hours then after, centrifugal with whizzer, deposition is pushed up with 2.0 L purified water and is washed merging filtrate.In filtrating, slowly adding concentration is 20% KHCO
3(v/w), and constantly stir, when pH4.5, centrifugal then (7500rpm) goes deposition to keep supernatant.
Ion exchange column (DK110, H will filtrate
+Type, 10L), pH is controlled at 4.5, and flow control is at 0.6 times of column volume/hour be advisable.Acetic acid with 0.12mol/L washs to effluent pH3.0 then, wash to effluent pH5.0 with purified water again, with 1,4-fourth disulfonic acid wash-out SAM of 0.12mol/L, flow rate control 0.3 volume/hour, pH begins to collect the about 15L of elutriant less than 3.5.
Elutriant cross purification column (HZ845,10L), flow control 0.5 times of column volume/hour about, after upper prop finishes, wash 8L with 1,4-fourth disulfonic acid of 20mmol/L top, after pH is lower than 4.0, collect all effluent.
Elutriant ultra-filtration membrane (CUT-OFF 5000) filters.Reverse osmosis membrane (PA membrane) concentrates, and this process liquid concentrator temperature is no more than 30 ℃, and the phegma outlet is immersed in the solution.Liquid concentrator contains SAM totally 196 grams.Through adding 0.3～0.5mol/L1 to liquid concentrator, it is 175 grams that 4-fourth disulfonic acid is regulated its content.
The liquid concentrator bullion filters through the 0.2m ceramic filtration membrane, and spray-dired input speed is controlled at 0.5L/h～5L/h; EAT is adjusted in 150～170 ℃, and air outlet temperature is controlled at 85～95 ℃.Finally obtain 348 grams, 1,4-fourth disulfonic acid ademetionine, content is 98.9%, and maximum related substance methylthioadenosine is 0.33%.These article of getting 0.9g adds water 5ml and makes dissolving, and the solution clarification is colourless.
Embodiment 2:
Adopt yeast saccharomyces cerevisiae
Saccharomyces cerevisiaeCPCC340488 aerobic fermentation 69 hours in general fermentor tank is added L-methionine(Met) in the middle of the process, and fermented liquid is through the centrifugal thalline that obtains.Contain 51mg/g ademetionine (SAM) in the thalline.
After mixing 25～50 minutes with 60%EA (v/v) aqueous solution of 25L and 75 kilograms of thalline, add above-mentioned mixed solution with 100L 3% perchloric acid (v/v), stir 3 hours then after, centrifugal with whizzer, deposition is pushed up with the 20L purified water and is washed merging filtrate.In filtrating, slowly add 20% KHCO
3(v/w), and constantly stir, when pH4.5, centrifugal then (7500rpm) goes deposition to keep supernatant.
Ion exchange column (D152, H will filtrate
+Type, 150L), pH is controlled at 4.5, and flow control is at 0.5 times of column volume/hour be advisable.Acetic acid with 0.10mol/L washs to effluent pH2.8 then, wash to effluent pH5.0 with purified water again, with 1,4-fourth disulfonic acid wash-out SAM of 0.10mol/L, flow rate control 0.55 column volume/hour, pH begins to collect the about 170L of elutriant less than 3.5.
Elutriant cross purification column (HZ801,150L), flow control 0.52 times of column volume/hour about, after upper prop finishes, wash 140L with 1,4-fourth disulfonic acid of 20mmol/L top, after pH is lower than 4.0, collect all effluent.
Elutriant ultra-filtration membrane (CUT-OFF 5000) filters.Reverse osmosis membrane (PA membrane) concentrates, and this process liquid concentrator temperature is no more than 30 ℃, and the phegma outlet is immersed in the solution.Liquid concentrator contains totally 3.1 kilograms of SAM.Through adding 0.3～0.5mol/L1 to liquid concentrator, it is 2.6 kilograms that 4-fourth disulfonic acid is regulated its content.
The liquid concentrator bullion filters through the 0.2m ceramic filtration membrane, and spray-dired input speed is controlled at 0.5L/h～5L/h; EAT is adjusted in 150～170 ℃, and air outlet temperature is controlled at 85～95 ℃.Finally obtain 5.5 kilograms of 1,4-fourth disulfonic acid ademetionines, content is 99.1%, and maximum related substance methylthioadenosine is 0.25%.These article of getting 0.9g adds water 5ml and makes dissolving, and the solution clarification is colourless.
Embodiment 3:
Utilize adenomethionine synthase (yeast saccharomyces cerevisiae
Saccharomyces cerevisiaeThe thalline that the CPCC340488 seed culture was collected after 24 hours, 500 grams) containing 20mM sal epsom, catalytic substrate L-methionine(Met) (20Mm) and ATP (20mM) generate ademetionine in the solution of pH6.0.Contain 5.3mg/ml ademetionine (SAM) in the reaction solution.
12L 2% sulfuric acid (v/v) adds the above-mentioned mixed solution of 8L reaction solution, stir 3 hours then after, centrifugal with whizzer.In filtrating, slowly add 20% NaHCO
3(v/w), and constantly stir, when pH4.5, centrifugal then (7500rpm) goes deposition to keep supernatant.
Ion exchange column (HZD-2, H will filtrate
+Type, 15L), pH is controlled at 4.5, and flow control is at 0.5 times of column volume/hour be advisable.Acetic acid with 0.10mol/L washs to effluent pH3.0 then, wash to effluent pH5.0 with purified water again, with 1,4-fourth disulfonic acid wash-out SAM of 0.1mol/L, flow rate control 0.50 volume/hour, pH begins to collect the about 15L of elutriant less than 3.5.
Elutriant cross purification column (HZ803,15L), flow control 0.40 times of column volume/hour about, after upper prop finishes, wash 1.3L with 1,4-fourth disulfonic acid of 20mmol/L top, after pH is lower than 4.0, collect all effluent.
Elutriant concentrates through reverse osmosis membrane (PA membrane), and this process liquid concentrator temperature is no more than 30 ℃, and the phegma outlet is immersed in the solution.Liquid concentrator ultra-filtration membrane (CUT-OFF 10000) filters.Filtrating contains SAM totally 33.2 grams.Through add its content of 0.3～0.5mol/L, 1,4-fourth disulfonic acid adjusting to liquid concentrator is 29.1 grams.
The liquid concentrator bullion filters through the 0.2m ceramic filtration membrane, and spray-dired input speed is controlled at 0.5L/h～5L/h; EAT is adjusted in 150～170 ℃, and air outlet temperature is controlled at 85～95 ℃.Finally obtain 58.0 grams, 1,4-fourth disulfonic acid ademetionine, content is 98.7%, and maximum related substance methylthioadenosine is 0.45%.These article of getting 0.9g adds water 5ml and makes dissolving, and the solution clarification is colourless.
The resin that the present invention uses is purchased Shanghai Hua Zhen company, filters and concentrates the membrane element that adopts and purchase U.S. GE company.
Claims (4)
1.1 the preparation method of 4-fourth disulfonic acid ademetionine comprises:
(1) with yeast saccharomyces cerevisiae aerobic fermentation 24-72 hours in fermentor tank; Add L-methionine(Met) in the fermenting process; Fermented liquid directly is used for the thalline use that subsequent step perhaps must contain fermented liquid centrifuging ademetionine, perhaps must contains the mixed solution of ademetionine through the Enzymatic transformation method
(2) V/V concentration 40-60%EA aqueous solution and the thalline with 0.3--0.6 times of thalline volume mixed 25-50 minutes; The V/V concentration of perhaps using 1-1.5 times of fermentating liquid volumes is that 1.5-2.5 sulfuric acid and fermented liquid or mixed solution mixed 2.5-3.5 hours, will mix liquid and filter with whizzer, in filtrating, adds V/W concentration 10-20% carbonate and neutralizes; By pH4.0-5.0 o'clock; With neutralizer centrifuging, get supernatant
(3) supernatant is crossed H
+The type ion exchange column, pH4.0-5.0,0.3-0.6 times of column volume of flow; Using concentration is that the acetic acid of 0.1-0.2mmol/L washs to the liquid fluid and is less than or equal to pH3.0, washs to effluent pH4.0-5.0 with purified water again, and using concentration is 1 of 0.1-0.2mol/L; 4-fourth disulfonic acid wash-out ademetionine; Flow velocity 0.3-0.6 volume/hour, pH＜3.5 begin to collect elutriant
(4) elutriant is crossed adsorption resin column, 0.3-0.6 times of column volume of flow/hour, after upper prop finished, use concentration was that 1.0-2.0 column volumes are washed on 1,4-fourth disulfonic acid top of 10-20mmol/L, behind pH＜4.0, collects effluent,
(5) effluent is concentrated through reverse osmosis membrane behind ultrafiltration membrance filter again, perhaps with effluent after reverse osmosis membrane concentrates again through ultrafiltration membrance filter, liquid concentrator, temperature is 0-30 ℃,
(6) through in liquid concentrator, adding 1,4-fourth disulfonic acid, adjusting 1,4-fourth disulfonic acid is 1.63-1.66: 1 with the ratio of ademetionine.
2. method according to claim 1 is characterized in that the neutralizer centrifugal rotational speed is not less than 6000rpm in the step (2).
3. method according to claim 1 and 2 is characterized in that carbonate described in the step (2) is inorganic carbonate or organic bases carbonate.
4. method according to claim 1 and 2 is characterized in that the H in the step (3)
+The type ion exchange column is a weak-acid ion exchange resin, and the adsorption resin column in the step (4) is the low-pole polymeric adsorbent, and the ultra-filtration membrane molecular weight cut-off is 1000-15000 in the step (5).
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103265595A (en) * | 2013-05-21 | 2013-08-28 | 南京基准生物科技有限公司 | Method for extracting S-adenosylmethionine from brewing yeast fermentation broth |
| CN104418928A (en) * | 2013-08-27 | 2015-03-18 | 上海医药工业研究院 | Preparation method of 1, 4-succinic acid adenosine methionine |
| CN109456377A (en) * | 2018-12-17 | 2019-03-12 | 山东金城生物药业有限公司 | Preparation method of ademetionine salt |
| CN113444757A (en) * | 2021-06-23 | 2021-09-28 | 贵州卡本嘉泰生物科技产业发展有限公司 | Preparation method of 1, 4-butanedisulfonic acid adenosine methionine |
| CN116023419A (en) * | 2023-01-13 | 2023-04-28 | 山东金城生物药业有限公司 | Preparation method of high-purity butanedisulfonic acid ademetionine |
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| US4990606A (en) * | 1984-05-16 | 1991-02-05 | Bioresearch S.P.A. | Stable sulpho-adenosyl-L-methionine (SAMe) salts, particularly suitable for parenteral use |
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| US4990606A (en) * | 1984-05-16 | 1991-02-05 | Bioresearch S.P.A. | Stable sulpho-adenosyl-L-methionine (SAMe) salts, particularly suitable for parenteral use |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103265595A (en) * | 2013-05-21 | 2013-08-28 | 南京基准生物科技有限公司 | Method for extracting S-adenosylmethionine from brewing yeast fermentation broth |
| CN103265595B (en) * | 2013-05-21 | 2015-12-23 | 南京基准生物科技有限公司 | The method of S-adenosylmethionine is extracted in a kind of fermentation by saccharomyces cerevisiae liquid |
| CN104418928A (en) * | 2013-08-27 | 2015-03-18 | 上海医药工业研究院 | Preparation method of 1, 4-succinic acid adenosine methionine |
| CN104418928B (en) * | 2013-08-27 | 2017-03-29 | 上海医药工业研究院 | A kind of preparation method of 1,4 fourth disulfonic acid ademetionine |
| CN109456377A (en) * | 2018-12-17 | 2019-03-12 | 山东金城生物药业有限公司 | Preparation method of ademetionine salt |
| CN113444757A (en) * | 2021-06-23 | 2021-09-28 | 贵州卡本嘉泰生物科技产业发展有限公司 | Preparation method of 1, 4-butanedisulfonic acid adenosine methionine |
| CN116023419A (en) * | 2023-01-13 | 2023-04-28 | 山东金城生物药业有限公司 | Preparation method of high-purity butanedisulfonic acid ademetionine |
| CN116023419B (en) * | 2023-01-13 | 2024-01-16 | 山东金城生物药业有限公司 | Preparation method of high-purity butanedisulfonic acid ademetionine |
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Application publication date: 20120912 |