CN1045993A - A kind of preparation method of sodium salt for rifainycin S - Google Patents
A kind of preparation method of sodium salt for rifainycin S Download PDFInfo
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- CN1045993A CN1045993A CN 89101893 CN89101893A CN1045993A CN 1045993 A CN1045993 A CN 1045993A CN 89101893 CN89101893 CN 89101893 CN 89101893 A CN89101893 A CN 89101893A CN 1045993 A CN1045993 A CN 1045993A
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- rifamycin
- rifainycin
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Abstract
The invention discloses a kind of preparation method of the mould rope S of the sharp good fortune of starting raw material sodium salt of semi-synthetic rifomycins antibacterials, comprising steps such as spawn culture, fermentation, filtering fermentation liquor, butylacetate extraction, oxidation, washings, washing back liquid is that 10-50 ℃, pH are controlled under 8.5-10.5 the condition and are carried out to reactant salt with sodium hydroxide in temperature, makes sodium salt for rifainycin S.Overcome in the prior art defectives such as on the low side because of the purity of the sodium salt for rifainycin S that causes through enrichment step, that yield is relatively poor, improved the quality and the output of product.
Description
The present invention relates to the preparation method of the starting raw material sodium salt for rifainycin S of semi-synthetic rifomycins antibacterials, particularly from the Rifamycin Sodium fermented liquid, extract the method for sodium salt for rifainycin S.
Since nineteen fifty-seven Italy Lepetit company found rifamycinoid antibiotics from the nutrient solution of the S.me diterranei of streptomycete family after, antimicrobial spectrum and lower antibiotic concentration were subjected to generally noting owing to it has more widely.Rifamycin Sodium entered clinical trial in 1962, and Rifamycin Sodium resisting gram-positive bacteria and tuberculosis efficiently divides the limb bacterium, but after the oral administration, it is not high to exist blood middle concentration, drain fast, shortcomings such as weak curative effect.For obtain oral absorption good, in blood, can keep higher concentration enduringly, drain the high Ryfamycin derivative of slow curative effect, Rifamycin Sodium has been carried out structure of modification, its emphasis is at C
3Position and C
4Transform on the position, produced a series of new Ryfamycin derivatives, as rifomycin antitubercular agent Rifampin (Rifapicin), Rifordin (Rifandin), rifapentine (Rifapentine) etc.These medicine production technologies are as follows usually: 1, seed fermentation, by strain fermentation to obtain the Rifamycin Sodium fermented liquid.2, extraction and salify extract the form of the Rifamycin Sodium in the fermented liquid with sodium salt for rifainycin S.3, semi-synthetic, be starting raw material with sodium salt for rifainycin S, obtain various rifamycinoid antibioticses through synthesizing.Therefore, sodium salt for rifainycin S is the starting raw material of synthetic various rifamycin drugs.
In the prior art, to pass through following steps as mentioning producing of sodium salt for rifainycin S among United States Patent (USP) u, s, p3884763, day clear 54-110391 of disclosure special permission communique, the Rifamycin Sodium that is obtained fermenting is with solvent extraction, extracting solution oxygenant oxidation, make the Rifamycin Sodium in the extracting solution be oxidized to rifamycin-S, then, the solvent that will contain rifamycin-S is concentrated into proper volume, adds NaOH solution again and carries out salify crystallization generation sodium salt for rifainycin S.Reaction equation is as follows:
The preparation method of present domestic sodium salt for rifainycin S, publish in " national bulk drug technology compilation " as State Pharmaceutical Administration's publication in 1980, to pass through following steps: spawn culture, seed tank culture, ferment tank, the fermented liquid that contains Rifamycin Sodium filters through plate-and-frame filter press, the liquid solvent extraction of filter back, extracting solution carries out oxidation with oxygenant, make the Rifamycin Sodium in the extracting solution be oxidized to rifamycin-S, through washing, extracting solution enters thin film concentrator and carries out high temperature (100 ℃), vacuum (pressure is the 160mm mercury column), thin film concentration, make the solvent that contains rifamycin-S be concentrated into an amount of volume (be about original volume 1/6), add sodium hydroxide then and crystallize into reactant salt, after the crystal separation, drying obtains sodium salt for rifainycin S.Need pass through enrichment step owing to contain the extracting solution of rifamycin-S in this technology, therefore exist following problem: 1, rifamycin-S (1.4-dideoxy-1.4-dihydro-1.4-dioxo rifomycin) is a big heterogeneous ring compound, have a lot of unstable groups on the structure, high temperature is totally unfavorable to it.When concentrating, because of direct use steam, the pipe surface temperature of the film standpipe of thin film concentrator can reach 100 ℃, and the part rifamycin-S depends on tube wall and flows through and be damaged.2, Rifamycin Sodium is through biosynthetic, in the fermented liquid that the spawn culture fermentation generates, Rifamycin Sodium only accounts for 0.4%(weight), contain a lot of impurity in the fermented liquid, as the mycelium and the protein-based impurity that ferment and generate, and fermention medium residuals.Fermented liquid is after solvent extraction, oxygenant oxidation, also brought partly impurity such as lipotropy mycelium and protein in the extract into, concentrate through the high-temperature steam film under vacuum again, the concentration of impurity increases in the extract, therefore, the sodium salt for rifainycin S impurity that crystallization goes out from this concentrated extract is more, and purity is on the low side.3, because will carry out vacuum decompression concentrates, to the sealing requirements height of equipment, often, leakage reduces in the production because of causing vacuum tightness, influence product production and quality.In addition, the film standpipe caliber of thin film concentrator is thinner, when extracting solution is concentrated into when denseer, often makes line clogging and influences production.
The objective of the invention is to provide a kind of preparation method of starting raw material sodium salt for rifainycin S of semi-synthetic rifomycins antibacterials, it has avoided concentrating owing to the high-temperature steam film under vacuum destruction of the rifamycin-S that causes, overcome the more and purity defective on the low side of impurity in the sodium salt for rifainycin S that crystallization goes out the extract after concentrating, solved because of thickening equipment and leaked and concentrate the problem that the film standpipe stops up influences product production and quality.
Fig. 1 is a process flow sheet of the present invention.
Its each part title is as follows: the fermented liquid 1 that contains Rifamycin Sodium, the ferment filtrate 2 that contains Rifamycin Sodium, the butylacetate extracting solution 3 that contains Rifamycin Sodium, the butylacetate oxidation liquid 4 that contains rifamycin-S, the butylacetate that contains rifamycin-S is washed back liquid 5, sodium salt for rifainycin S crystallization 6, butylacetate mother liquor 7.
With reference to accompanying drawing, the present invention realizes like this, through bacterial classification cultivation, seed tank culture, ferment tank, generation contains the zymotic fluid 1 of Rifamycin Sodium, and zymotic fluid is removed partly mycelia and culture medium residue through Filter Press, the ferment filtrate that contains Rifamycin Sodium 2 that obtains clarifying, ferment filtrate extracts with butyl acetate solvent, and the PH of feed liquid is controlled at 2.5-3.5, obtains containing the butyl acetate extract 3 of Rifamycin Sodium. Isolated butyl acetate extract 3 is used Fecl3Solution carries out oxidation, Fecl3Addition and extract in contain the Rifamycin Sodium scale ratio be: 0.8: 1-1: 1(weight), Rifamycin Sodium is oxidized to rifamycin-S, obtains containing the butyl acetate oxidation solution 4 of rifamycin-S. Branch vibration layer, oxidation solution 4 usefulness PH equal 2.5 sour water and wash for the first time, use then 1%(weight) NaHco3Second, third time of aqueous solution washing is the 4th washing of 2.5 sour water with PH again, and the butyl acetate that obtains containing rifamycin-S is washed rear liquid 5. Constantly stir down, after the above-mentioned butyl acetate that contains rifamycin-S is washed, in the liquid, add 2-4%(weight) NaHCO3The aqueous solution, addition are to wash the long-pending 20-60% of rear liquid, then, are normal pressure at pressure, and temperature is 10-50 ℃, and optimal reaction temperature is 30-40 ℃, under constantly stirring, add NaOH solution and carry out salt-forming reaction, control The PH of feed liquid is 8.5-10.5, and best pH value is 9.5-10.5, continue to stir 3-4 hour, static after, obtain after filtration sodium salt for rifainycin S crystallization 6, crystal separates with centrifuge, drying namely obtains sodium salt for rifainycin S. The front operation that enters isolated butyl acetate mother liquor contains in the butyl acetate extract of Rifamycin Sodium and recycles.
The present invention washes back liquid without concentrated direct salify with the butylacetate that contains rifamycin-S of gained, and partly rifamycin-S is destroyed by high temperature can, and therefore, the yield of sodium salt for rifainycin S will be improved.
Sodium salt for rifainycin S yield=(rifamycin-S sodium dry product weight * rifamycin-S sodium is tired)/(fermentating liquid volume * fermentation titer * 0.9) * 100%
(weight yield of tiring)
In the formula: fermentating liquid volume is for after fermentation puts jar, the static volume that records during to the basic non-foam in upper strata, and 0.9 is the foam coefficient.
According to experimental result, technology of the present invention is than the prior art with enrichment step, and the yield of sodium salt for rifainycin S can improve 5%-6%.
The present invention washes the direct salify of back liquid from the rifamycin-S butylacetate, therefore, it is low to wash in the liquid of back foreign matter contents such as mycelium and protein, the purity of the sodium salt for rifainycin S that crystallization goes out is higher by the measuring method in two ones of in 1985 versions of the Pharmacopoeia of the People's Republic of China, and the biological value (main quality index) of the sodium salt for rifainycin S of the present invention's preparation can improve 40u/mg than prior art.
Because the butyl acetate solvent among the present invention can recycle, the butyl acetate solvent quantity that the per kilogram sodium salt for rifainycin S is consumed descends, and has saved production cost.Owing to do not re-use thin film concentrator, eliminated because of the film riser tube and stopped up and the vacuum tightness reduction influences the output of product and the problem of quality, reduce production unit, shortened man-hour, reduced energy consumption.
The present invention is further illustrated below in conjunction with example.
Example one
It is 2484ml that the butylacetate that contains rifamycin-S is washed back liquid 350ml(fermentating liquid volume, and fermented liquid is tired and is 4160u/ml), under normal temperature, normal pressure, add 2%(weight) NaHCO
3Aqueous solution 175ml, it is 31 ℃ in temperature then, constantly stir down, add 30%(weight) NaOH solution, the PH of control feed liquid is 8.5, continue to stir 3 hours, obtain the sodium salt for rifainycin S crystallization, obtain sodium salt for rifainycin S dry product 10 grams through separation, drying, through estimation of biological potency, tire and be that 834u/mg, sodium salt for rifainycin S yield are 89.68%.
Case of comparative examples one
It is 2484ml that the butylacetate that contains rifamycin-S is washed back liquid 350ml(fermentating liquid volume, fermented liquid is tired and is 4160u/ml), become 100ml butylacetate concentrated solution through high-temperature steam (100 ℃) vacuum (pressure is the 40mm mercury column) thin film concentration, after the cooling, at normal temperatures and pressures, add 2%(weight) NaHCO
3Aqueous solution 50ml, in temperature is 31 ℃, constantly stir down, adding 30%(weight) NaOH solution, control feed liquid PH was 8.5, generated the sodium salt for rifainycin S crystallization through 3 hours, obtain sodium salt for rifainycin S dry product 10 grams through separation, drying, through estimation of biological potency, tiring is that 756u/mg, sodium salt for rifainycin S yield are 81.29%.
Example two
It is 3080ml that the butylacetate that contains rifamycin-S is washed back liquid 350ml(fermentating liquid volume, and fermented liquid is tired and is 4410u/ml), under normal temperature, normal pressure, add 3%(weight) NaHCO
3Aqueous solution 175ml, it is 10 ℃ in temperature then, constantly stir down, add 30%(weight) NaOH solution, control feed liquid PH is 9.5, continue to stir 3 hours, obtain the sodium salt for rifainycin S crystallization, obtain sodium salt for rifainycin S dry product 13.4 grams through separation, drying, through estimation of biological potency, tire and be that 785u/mg, sodium salt for rifainycin S yield are 86.07%.
Case of comparative examples two
It is 2431ml that the butylacetate that contains rifamycin-S is washed back liquid 350ml(fermentating liquid volume, fermented liquid is tired and is 5000u/ml), become 80ml butylacetate concentrated solution through high-temperature steam (100 ℃) vacuum (pressure is the 40mm mercury column) thin film concentration, after the cooling, at normal temperatures and pressures, add 3%(weight) NaHCO
3Aqueous solution 40ml, in temperature is 10 ℃, constantly stir down, add 30%(weight) NaOH solution, control feed liquid PH is 9.5, continues to stir the crystallization of 3 hours generation sodium salt for rifainycin S, through separation, dry that sodium salt for rifainycin S dry product 13 restrains, through estimation of biological potency, tiring is that 719u/mg, sodium salt for rifainycin S yield are 85.48%.
Example three
It is 2516ml that the butylacetate that contains rifamycin-S is washed back liquid 350ml(fermentating liquid volume, and fermented liquid is tired and is 4289u/ml), under normal temperature, normal pressure, add 4%(weight) NaHCO
3Aqueous solution 175ml, it is 50 ℃ in temperature then, constantly stir down, add 30%(weight) NaOH solution, control feed liquid PH is 10.5, continue to stir 3 hours, obtain the sodium salt for rifainycin S crystallization, obtain sodium salt for rifainycin S dry product 11.4 grams through separation, drying, through estimation of biological potency, tire and be that 763u/mg, sodium salt for rifainycin S yield are 89.60%.
Case of comparative examples three
It is 2516ml that the butylacetate that contains rifamycin-S is washed back liquid 350ml(fermentating liquid volume, fermented liquid is tired and is 4289u/ml), become 70ml butylacetate concentrated solution through high-temperature steam (100 ℃) vacuum (pressure is the 40mm mercury column) thin film concentration, after the cooling, at normal temperatures and pressures, add 4%(weight) NaHCO
3Aqueous solution 35ml, in temperature is 50 ℃, constantly stir down, add 30%(weight) NaOH solution, control feed liquid PH is 10.5, continues to stir the crystallization of 3 hours generation sodium salt for rifainycin S, obtain sodium salt for rifainycin S dry product 12.7 grams through separation, drying, through estimation of biological potency, tiring is that 656u/mg, sodium salt for rifainycin S yield are 85.80%.
Example four
It is 25000 l that the butylacetate that contains rifamycin-S is washed back liquid 3250 l(fermentating liquid volumes, and fermented liquid is tired and is 5236u/ml), under normal temperature, normal pressure, add 3%(weight) NaHCO
3The aqueous solution 1625 l, it is 40 ℃ in temperature then, constantly stir down, add 30%(weight) NaOH solution, control feed liquid PH is 10.5, continue to stir 3 hours, obtain the sodium salt for rifainycin S crystallization, obtain 126 kilograms of sodium salt for rifainycin S dry products through separation, drying, through estimation of biological potency, tire and be that 798u/mg, sodium salt for rifainycin S yield are 89.60%.
Example five
It is 25000 l that the butylacetate that contains rifamycin-S is washed back liquid 3150 l(fermentating liquid volumes, and fermented liquid is tired and is 5242u/ml), under normal temperature, normal pressure, add 3%(weight) NaHCO
3The aqueous solution 1575 l, it is 30 ℃ in temperature then, constantly stir down, add 30%(weight) NaOH solution, control feed liquid PH is 9.5, continue to stir 3 hours, obtain the sodium salt for rifainycin S crystallization, obtain 125 kilograms of sodium salt for rifainycin S dry products through separation, drying, through estimation of biological potency, tire and be that 800u/mg, sodium salt for rifainycin S yield are 84.78%.
Claims (3)
1, a kind of preparation method with following structural formula sodium salt for rifainycin S,
Comprising spawn culture, fermentation, filtering fermentation liquor, it is characterized in that:
A, the ferment filtrate that contains Rifamycin Sodium extract with butyl acetate solvent, and the PH of feed liquid is controlled at 2.5-3.5, obtains containing the butylacetate extracting solution of Rifamycin Sodium;
B, isolated butylacetate extracting solution Fecl
3Solution carries out oxidation, Fecl
3Add-on and extracting solution in contain the Rifamycin Sodium scale ratio be 0.8: 1-1: 1 (weight), Rifamycin Sodium is oxidized to rifamycin-S, obtain containing the butylacetate oxidation liquid of rifamycin-S;
C, branch vibration layer, oxidation liquid PH are that 2.5 sour water washs for the first time, use 1% (weight) NaHCO then
3Second, third time of aqueous solution washing is the 4th washing of 2.5 sour water with PH again, and the butylacetate that obtains containing rifamycin-S is washed back liquid;
D, the continuous stirring are down washed in the liquid of back at the above-mentioned butylacetate that contains rifamycin-S, add 2-4% (weight) NaHCO
3The aqueous solution, add-on are to wash the long-pending 20-60% of back liquid, then, are normal pressure at pressure, temperature is 10-50 ℃, constantly stirs down, adds NaOH solution and is carried out to reactant salt, the pH value of control feed liquid is 8.5-10.5, continues to stir 3-4 hour, obtains the sodium salt for rifainycin S crystallization.
2, a kind of method for preparing sodium salt for rifainycin S as claimed in claim 1, the butylacetate that it is characterized in that containing rifamycin-S is washed in the liquid of back, when adding NaOH solution was carried out to reactant salt, the best pH value of feed liquid was 9.5-10.5, and optimal reaction temperature is 30-40 ℃.
3, a kind of method for preparing sodium salt for rifainycin S as claimed in claim 1 or 2 is characterized in that isolated mother liquor can enter in the butylacetate extracting solution that contains Rifamycin Sodium after the salt-forming reaction to recycle.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 89101893 CN1045993A (en) | 1989-03-28 | 1989-03-28 | A kind of preparation method of sodium salt for rifainycin S |
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| CN 89101893 CN1045993A (en) | 1989-03-28 | 1989-03-28 | A kind of preparation method of sodium salt for rifainycin S |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1037015C (en) * | 1992-09-01 | 1998-01-14 | 太原工业大学 | Impregnation treatment of graphite anode for chlor-alkali industry |
| CN102140102A (en) * | 2010-11-25 | 2011-08-03 | 河北欣港药业有限公司 | Production method for directly extracting rifamycin S from fermentation filtrate |
| CN102703541A (en) * | 2012-05-31 | 2012-10-03 | 河南省南街村（集团）有限公司 | Feeding method for improving rifamycin SV fermentation yield |
| CN102942574A (en) * | 2012-11-29 | 2013-02-27 | 蒋德刚 | Novel process for producing rifamycin S |
| CN107686490A (en) * | 2017-10-25 | 2018-02-13 | 陈磊 | A kind of method for extracting rifamycin B |
-
1989
- 1989-03-28 CN CN 89101893 patent/CN1045993A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1037015C (en) * | 1992-09-01 | 1998-01-14 | 太原工业大学 | Impregnation treatment of graphite anode for chlor-alkali industry |
| CN102140102A (en) * | 2010-11-25 | 2011-08-03 | 河北欣港药业有限公司 | Production method for directly extracting rifamycin S from fermentation filtrate |
| CN102703541A (en) * | 2012-05-31 | 2012-10-03 | 河南省南街村（集团）有限公司 | Feeding method for improving rifamycin SV fermentation yield |
| CN102942574A (en) * | 2012-11-29 | 2013-02-27 | 蒋德刚 | Novel process for producing rifamycin S |
| CN102942574B (en) * | 2012-11-29 | 2015-06-03 | 郑州民众制药有限公司 | Novel process for producing rifamycin S |
| CN107686490A (en) * | 2017-10-25 | 2018-02-13 | 陈磊 | A kind of method for extracting rifamycin B |
| CN107686490B (en) * | 2017-10-25 | 2020-02-07 | 南京久安源环保科技有限公司 | Method for extracting rifamycin B |
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