CN103274976A - Refining method of tiamulin fumarate - Google Patents
Refining method of tiamulin fumarate Download PDFInfo
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- CN103274976A CN103274976A CN2013102655747A CN201310265574A CN103274976A CN 103274976 A CN103274976 A CN 103274976A CN 2013102655747 A CN2013102655747 A CN 2013102655747A CN 201310265574 A CN201310265574 A CN 201310265574A CN 103274976 A CN103274976 A CN 103274976A
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- tiamulin
- fumaric acid
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Abstract
The invention relates to a refining method of tiamulin fumarate, which comprises the process steps that tiamulin alkali, methanol and fumarate are subjected to a neutralization salification reaction and then centrifugal separation; an obtained crude product is added to 4-methyl-2-pentanone; the temperature is preserved for 90-110min in a 40-60 DEG C stirring state; the temperature is rapidly reduced between -20 and-10 DEG C; the temperature is preserved for 90-110min; the centrifugal separation is performed again; an obtained quality product is put into a two-cone rotary vacuum drier; drying is performed until the material moisture is less than or equal to 0.5%; and then sieving and subpackaging are performed. The method simplifies a production process of domestic conventional tiamulin fumarate refining, and adopts MIBK (Methyl Isobutyl Ketone) (4-methyl-2-pentanone) to replace butyl acetate or acetone, so that the consumption of an organic solvent is reduced; the safety coefficient is increased; potential safety hazards are reduced; the production cycle is shortened; the crystallization quality and the yield are improved and increased; the energy consumption is reduced; the production efficiency is improved; and the method has a certain development prospect.
Description
Technical field
The invention belongs to field of biological pharmacy, particularly relate to a kind of process for purification of fumaric acid tiamulin.
Background technology
Fumaric acid tiamulin (Tiamulin fumarate) is after producing pleuromutilin by fermentation, pass through again semi-synthetic, a kind of diterpenoids (pluromulin) microbiotic of the final preparation of salify.It is by suppressing the synthetic bacteriostatic action that plays of microorganism rrna interoceptive protein.This product has germicidal action under high density, germicidal action is the strongest in pH8.5 ~ 9.0 environment.Tiamulin is the pleuromulins microbiotic of first animal specific, in the prospect that has a very wide range of applications aspect veterinary drug industry and the livestock and poultry disease control and prevention.
At present, the refining fumaric acid tiamulin technological process of production of domestic production enterprise be in and salify, bipyramid drying, refining backflow, centrifuge dripping, bipyramid drying, be pulverized and mixed and packing, the subject matter that this technology exists is:
Used three kinds of organic solvents in the 1 conventional refining fumaric acid tiamulin technology, namely be neutralized into and used methyl alcohol, MIBK(4-methyl-2 pentanone in the salt technology), use N-BUTYL ACETATE or acetone in the refining reflux technique.Acetone or the N-BUTYL ACETATE consumption in refining reflux technique is big, produces irritating smell in the acetone use, easily diffusion; Use vinyl acetic monomer in the fumaric acid tiamulin crystallisation process, crystallization time is long, and impurity-eliminating effect is poor, contain fumaric acid tiamulin in the crystalline mother solution, influence crystallization yield, caking phenomenon appears in fumaric acid tiamulin easily after the bipyramid drying, needs to carry out packing after pulverizing, sieving.
2 refining fumaric acid tiamulin process cycles are long, and labour intensity is big.
There is security risk in the use of 3 above-mentioned organic solvents, and the potential safety hazard that exists in the production process is more, and safety coefficient is low.
4 yields are lower, and energy consumption is big, and production cost is higher.
Summary of the invention
The object of the invention is to overcome the defective of above-mentioned prior art, and a kind of effective raising crystalline quality and yield are provided, and shortens the production cycle, cuts down the consumption of energy and the process for purification of the fumaric acid tiamulin of labour intensity.
The technical scheme of taking for achieving the above object is as follows:
A kind of process for purification of fumaric acid tiamulin, it is characterized in that its processing step is: at first Tiamulin alkali and methyl alcohol, fumaric acid are neutralized into reactant salt, centrifugation then, the gained crude product joins in the 4-methyl-2 pentanone, under 40～60 ℃ of whipped states, be incubated 90～110min, be cooled to-20～-10 ℃ afterwards rapidly, insulation 90～110min, recentrifuge separates, the gained elaboration drops into DoubletaperedVacuumdrier, be dried to sieve behind material moisture≤0.5%, packing gets final product.
In above-mentioned and salification process be: methyl alcohol and fumaric acid are joined in the Tiamulin alkali successively, at 30～50 ℃ of following temperature reaction 80～100min, after when being cooled to-20～-10 ℃ rapidly, insulation 100～120min; Above-mentioned Tiamulin alkali, methyl alcohol and fumaric acid calculate according to the ratio of 1:4.0～6.0:0.4～0.6, and its unit is W/V/W.
The crystalline mother solution clarification that above-mentioned centrifugation is discharged is bright, does not have visual solid.
The consumption of above-mentioned 4-methyl-2 pentanone calculates according to the ratio of Tiamulin alkali: 4-methyl-2 pentanone=1:10～15, and its unit is W/V.
Control DoubletaperedVacuumdrier rotating in the above-mentioned drying process, 50～100 ℃ of temperature, vacuum tightness be-0.01～-0.10MPa.
With conventional refining fumaric acid tiamulin production of raw medicine technology contrast, advantage of the present invention mainly contains:
1 former technology organic solvent has used 3 kinds, and organic solvent has only methyl alcohol and MIBK in the novel process, and adopts MIBK to replace acetone and N-BUTYL ACETATE, has improved crystalline quality and yield, improves safety coefficient, reduces potential safety hazard.
2 bipyramid drying plants reduce 1 time to be used, and stops using disintegrating apparatus, cuts down the consumption of energy.
3 production cycles shortened 20h at least, had reduced labour intensity.
The crystallization effect of 4 fumaric acid tiamulins in MIBK is better than ethyl acetate, is convenient to centrifuge dripping, and good separating effect, TMF content in the mother liquor is very low, and TMF elaboration drying is not lumpd, the mixing of can directly sieving, be convenient to packing, improved the working efficiency of mixed powder, packing.
The yield of 5 products improves, and has reduced energy consumption, and production cost descends about 50 yuan on the basis of former technology.
Embodiment
With example the present invention is described below, is it should be understood that example is for explanation the present invention rather than limitation of the present invention.Scope of the present invention and core content are determined according to claims.
Embodiment 1
Get TM(Tiamulin alkali) 100kg, Me (methyl alcohol) 400L, FA(fumaric acid 40kg adds Me earlier, adds FA again, 30～31 ℃ of insulation reaction 80min, when insulation finishes to be cooled to-10 ℃ rapidly, insulation 100min.Use whizzer to carry out solid-liquid separation, the crystalline mother solution clarification of discharging is bright, does not have visual solid, obtains TMF (fumaric acid tiamulin) crude product 142.4kg.Weighing MIBK (4-methyl-2 pentanone) 1000L is heated to 40～41 ℃, adds the TMF crude product, starts and stirs, and rotating speed is controlled at 10r/min, insulation 90min.Insulation finishes back cooling rapidly, when cooling the temperature to-10 ℃, and insulation 140min.Start whizzer, carry out solid-liquid separation, the crystalline mother solution of discharging should be clarified bright, does not have visual solid.Obtain TMF elaboration 137.6kg after separating end.The TMF elaboration is dropped into DoubletaperedVacuumdrier, open drying machine, regulate making it can rotating.The double-cone dryer temperature is risen to 50 ℃, and control vacuum tightness is-0.01MPa dry 15h.After testing, moisture is 0.42%.Dry end obtains TMF elaboration 136.8kg.TMF elaboration dry powder is sieved, drop into full-automatic mixing machine, packing obtains TMF bulk drug 135.9kg, and mass yield is 97.1%, and the production time spent is 23.8h.
Embodiment 2
Get TM100kg, Me500L, FA50kg adds Me earlier, adds FA again, 40～41 ℃ of insulation reaction 90min, when insulation finishes to be cooled to-15 ℃ rapidly, insulation 110min.Use whizzer to carry out solid-liquid separation, the crystalline mother solution clarification of discharging is bright, does not have visual solid, obtains TMF crude product 153.2kg.Weighing MIBK1200L is heated to 50～51 ℃, adds the TMF crude product, starts and stirs, and rotating speed is controlled at 15r/min, insulation 100min.Insulation finishes back cooling rapidly, when cooling the temperature to-15 ℃, and insulation 150min.Start whizzer, carry out solid-liquid separation, the crystalline mother solution of discharging should be clarified bright, does not have visual solid.Obtain TMF elaboration 147.5kg after separating end.The TMF elaboration is dropped into DoubletaperedVacuumdrier, open drying machine, regulate making it can rotating.The double-cone dryer temperature is risen to 75 ℃, and control vacuum tightness is-0.05MPa dry 10h.After testing, moisture is 0.37%.Dry end obtains TMF elaboration 147.2kg.TMF elaboration dry powder is sieved, drop into full-automatic mixing machine, packing obtains TMF bulk drug 147.0kg, and mass yield is 98.0%, and the production time spent is 19.3h.
Embodiment 3
Get TM100kg, Me600L, FA60kg adds Me earlier, adds FA again, 49～50 ℃ of insulation reaction 100min, when insulation finishes to be cooled to-20 ℃ rapidly, insulation 120min.Use whizzer to carry out solid-liquid separation, the crystalline mother solution clarification of discharging is bright, does not have visual solid, obtains TMF crude product 163.1kg.Weighing MIBK1500L is heated to 59～60 ℃, adds the TMF crude product, starts and stirs, and rotating speed is controlled at 20r/min, insulation 110min.Insulation finishes back cooling rapidly, when cooling the temperature to-20 ℃, and insulation 160min.Start whizzer, carry out solid-liquid separation, the crystalline mother solution of discharging should be clarified bright, does not have visual solid.Obtain TMF elaboration 157.3kg after separating end.The TMF elaboration is dropped into DoubletaperedVacuumdrier, open drying machine, regulate making it can rotating.The double-cone dryer temperature is risen to 75 ℃, and control vacuum tightness is-0.05MPa dry 7h.After testing, moisture is 0.31%.Dry end obtains TMF elaboration 156.8kg.TMF elaboration dry powder is sieved, drop into full-automatic mixing machine, packing obtains TMF bulk drug 156.5kg, and mass yield is 97.8%, and producing the time spent is 16.7 h.
The comparative example
Get TM100kg, Me500L, FA50kg adds Me earlier, adds FA again, 40～41 ℃ of insulation reaction 90min.When insulation finishes to be cooled to-15 ℃ rapidly, insulation 110min.Start whizzer, carry out solid-liquid separation, the crystalline mother solution clarification of discharging is bright, does not have visual solid, obtains TMF crude product 153.2kg.The TMF crude product is dropped into DoubletaperedVacuumdrier, open drying machine, regulate making it can rotating.The double-cone dryer temperature is risen to 70 ℃, and control vacuum tightness is-0.05 MPa, dry 11h.Obtain dry TMF crude product 149.1kg.Weighing N-BUTYL ACETATE 1200L is heated to 50～51 ℃, adds the TMF crude product, starts and stirs, and rotating speed is controlled at 15r/min, insulation 100min.Insulation finishes back cooling rapidly, when cooling the temperature to-15 ℃, and insulation 150min.Start whizzer, carry out solid-liquid separation, the crystalline mother solution of discharging should be clarified bright, does not have visual solid.Obtain TMF elaboration 144.1kg after separating end.The TMF elaboration is dropped into DoubletaperedVacuumdrier, open drying machine, regulate making it can rotating.The double-cone dryer temperature is risen to 70 ℃, and control vacuum tightness is-0.05MPa dry 11h.After testing, moisture is 0.40%.Dry end obtains TMF elaboration 143.8kg.TMF elaboration dry powder powder is dropped into full-automatic pulverizer, and by complete mechanical flow process, the powder after the pulverizing enters mixing machine automatically to be mixed, and carries out packing then and obtains TMF bulk drug 142.9kg, and mass yield is 95.3%, and the production cycle is 33.4h.
Claims (5)
1. the process for purification of a fumaric acid tiamulin, it is characterized in that its processing step is: at first Tiamulin alkali and methyl alcohol, fumaric acid are neutralized into reactant salt, centrifugation then, the gained crude product joins in the 4-methyl-2 pentanone, under 40～60 ℃ of whipped states, be incubated 90～110min, be cooled to-20～-10 ℃ afterwards rapidly, insulation 90～110min, recentrifuge separates, the gained elaboration drops into DoubletaperedVacuumdrier, be dried to sieve behind material moisture≤0.5%, packing gets final product.
2. according to the process for purification of the described fumaric acid tiamulin of claim 1, it is characterized in that above-mentioned in and salification process be: methyl alcohol and fumaric acid are joined in the Tiamulin alkali successively, temperature reaction 80～100min under 30～50 ℃, after when being cooled to-20～-10 ℃ rapidly, insulation 100～120min; Above-mentioned Tiamulin alkali, methyl alcohol and fumaric acid calculate according to the ratio of 1:4.0～6.0:0.4～0.6, and its unit is W/V/W.
3. according to the process for purification of the described fumaric acid tiamulin of claim 1, it is characterized in that the crystalline mother solution clarification that above-mentioned centrifugation discharges is bright, there is not visual solid.
4. according to the process for purification of the described fumaric acid tiamulin of claim 1, it is characterized in that the consumption of above-mentioned 4-methyl-2 pentanone calculates according to the ratio of Tiamulin alkali: 4-methyl-2 pentanone=1:10～15, its unit is W/V.
5. according to the process for purification of the described fumaric acid tiamulin of claim 1, it is characterized in that control DoubletaperedVacuumdrier rotating in the above-mentioned drying process, 50～100 ℃ of temperature, vacuum tightness be-0.01～-0.10MPa.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103884797A (en) * | 2014-04-14 | 2014-06-25 | 宁夏泰瑞制药股份有限公司 | Method for detecting residual solvent 4-methyl-2-pentanone in tiamulin fumarate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070499A (en) * | 2010-12-01 | 2011-05-25 | 安徽省皖北药业股份有限公司 | Refining method of tiamulin hydrogen fumarate |
| CN102875432A (en) * | 2012-10-18 | 2013-01-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of high-yield tiamulinfumarate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070499A (en) * | 2010-12-01 | 2011-05-25 | 安徽省皖北药业股份有限公司 | Refining method of tiamulin hydrogen fumarate |
| CN102875432A (en) * | 2012-10-18 | 2013-01-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of high-yield tiamulinfumarate |
Non-Patent Citations (2)
| Title |
|---|
| 崔剑: "截短侧耳素与Tiamulin", 《国外医药.抗生素分册》, no. 6, 31 December 1983 (1983-12-31), pages 491 - 500 * |
| 王其合: "延胡索酸泰妙菌素成盐结晶工艺优化", 《中国兽药杂志》, vol. 42, no. 11, 31 December 2008 (2008-12-31) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103884797A (en) * | 2014-04-14 | 2014-06-25 | 宁夏泰瑞制药股份有限公司 | Method for detecting residual solvent 4-methyl-2-pentanone in tiamulin fumarate |
| CN103884797B (en) * | 2014-04-14 | 2015-12-09 | 宁夏泰瑞制药股份有限公司 | The detection method of residual solvent 4-methyl-2 pentanone in fumaric acid tiamulin |
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Application publication date: 20130904 |