CN104725402B - A kind of method of 6 aminopenicillanic acid continuous crystallization - Google Patents
A kind of method of 6 aminopenicillanic acid continuous crystallization Download PDFInfo
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- CN104725402B CN104725402B CN201510127394.1A CN201510127394A CN104725402B CN 104725402 B CN104725402 B CN 104725402B CN 201510127394 A CN201510127394 A CN 201510127394A CN 104725402 B CN104725402 B CN 104725402B
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- amino
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- penicillanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/42—Compounds with a free primary amino radical attached in position 6
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of method of 6 aminopenicillanic acid continuous crystallization, it is related to the technical field of medicine intermediate synthesis, method of the method using continuous crystallization, overcome the big defect of prior art intermittent split-phase method for crystallising products obtained therefrom quality differences between batches, the homogeneity of product greatly improved, also applied Automated condtrol simultaneously, improve production efficiency, saved the energy.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of preparation method of medicine intermediate, and in particular to a kind of 6- ammonia
The method of base penicillanic acid continuous crystallization.
Background technology
6-amino-penicillanic acid, abbreviation 6-APA, structure are as follows：
6-APA can introduce different side chains, obtain the antibiotic of different drug effects, be production semi-synthetic penicillins antibiotic
Ammonia benzyl sodium and the important intermediate of Amoxicillin.
The conventional preparation techniques of 6-APA are with penicillin fermentation liquid as initiation material, extract split-phase through twice, are contained
The degreaser of penicillanic acid, cracks through PA ase, obtains the lysate containing 6-APA, is subsequently adding salt acid extraction point
Phase, adds ammoniacal liquor crystallization to obtain 6-APA in water phase.This interim split-phase, the operation of crystallization are intermittent, can cause product
Quality is unstable, differences between batches are larger, and intermittent operation cannot realize Automated condtrol, needs to expend substantial amounts of manpower,
Increase manufacturing enterprise's cost.
Content of the invention
It is an object of the invention to provide a kind of method of 6-amino-penicillanic acid continuous crystallization, the method is by serialization
Extract and separate, it is achieved that the continuous crystallization of 6-APA, reduces the differences between batches of product, and production efficiency greatly improved, and reduces
Production cost.
In order to realize purpose of the present invention, technical scheme below is inventor provided.
A kind of method of 6-amino-penicillanic acid continuous crystallization, including following operating procedure：
A. the lysate containing 6-APA and butanol are mixed, obtains mixed solution；
B. 5-10 DEG C of temperature control, stirs, in the at the uniform velocity lasting addition reaction vessel of the mixed solution that step a is obtained, while
It is 0-0.5 that aqueous hydrochloric acid solution is added the pH value for controlling reactant liquor in reaction vessel；
C., when the liquid level of reactant liquor in step b rises to setting height, knot is passed through by the uniform velocity lasting for lower floor's reactant liquor
In brilliant container, it is passed through at the uniform velocity lasting for upper strata reactant liquor in retracting device, while keeping the constant liquid level of reactant liquor in setting
Highly；
D. it is 4.0-4.5 to add the pH value that ammoniacal liquor controls solution in crystallisation vessel while lower floor's reactant liquor is passed through, and obtains
Arrive crystallization solution；
E., when the liquid level of crystallization solution rises to setting height, it is passed through at the uniform velocity lasting for crystallization solution in filter
Filtered, obtained filter cake, while the constant liquid level of crystallization solution is kept in setting height；
F. the filter cake that step e is obtained is washed, dries, that is, obtain the mould clearly alkanoic acid of 6- amino.
The method of above-mentioned 6-amino-penicillanic acid continuous crystallization, in lysate described in step a, the content of 6-APA is 22-
28%.
Lysate described in step a is 5 with the volume ratio of butanol:1.
Flow velocity described in step b during mixed solution addition reaction vessel is per 100 liters of reaction vessel 24-36L/min.
Stirring described in step b is located at the 1/2-2/3 of reactant liquor liquid level using the bottom of paddle.
60-80% of the setting height described in step c for reaction vessel height.
The concentration of aqueous hydrochloric acid solution described in step b is 20%.
The concentration of ammoniacal liquor described in step d is 20%.
Filter described in step e is preferably many sets, is passed through the crystallization solution of same volume, respectively in every sets filtering device
Carry out filter operation, it is ensured that crystallization solution being capable of filters.
It is acetone to wash the solvent for using described in step e.
The temperature dried described in step f is 40-50 DEG C, and the dry time is 40-60min.
The method of the invention is suitable for for the lysate containing 6-APA that conventional method is obtained.
The method of continuous crystallization provided by the present invention, in step a after the addition of the lysate containing 6-APA hydrochloric acid immediately
It is layered, butanol organic phase of the upper strata for phenylacetic acid, lower floor is the water phase containing 6-APA, stirring in the process is located at anti-
The middle and upper part of container is answered, while under conditions of limiting lysate addition speed, limiting liquid level, upper organic phase is persistently led
Go out and conventionally recycled accordingly, lower floor's water is mutually persistently derived and enters crystallisation vessel, both ensure that acidifying is anti-
That answered is fully carried out, and does not interfere with being sufficiently separated for organic phase and water phase again, and during stable reaction conditions, be product matter
Good basis determined by the stable pad of amount；The process of crystallization by control liquid level, it is ensured that crystallization time constant, so as to
It is obtained in that the homogeneous product of quality；Filtration step can according to actual needs using one or more sets filters, crystallization solution
Continual can be passed through in filter, reduce because intermittent operation causes the fluctuation of product quality.Whole process is operated continuously,
Thus Automated condtrol, the more accurately key operation such as control material flow velocity, valve opening time can be adopted, it is to avoid people
For operating the error for causing.
The advantage of the method for 6-amino-penicillanic acid continuous crystallization of the present invention is：
1st, continuous mass production can be realized, operation is reduced, operating efficiency is improved, is reduced production cost, is manufacturing enterprise
Create objective economic benefit.
2nd, the realization of continuous prodution, overcomes the caused unstable product quality of traditional batch production, differences between batches
Big problem, the homogeneity of product are more preferable.
3rd, the realization of continuous prodution so that Automated condtrol is applied, further ensure that the homogeneous of product quality
Property.
4th, the realization of continuous prodution, effectively reduces the generation of odd powder, reduces and reclaims the money for causing because of odd powder
Source wastes.
Specific embodiment
Content of the present invention is described in further detail with reference to specific embodiment.
Embodiment 1
Retort volume is 100L, the setting height of liquid level for retort height 60% in retort, and paddle is most
Bottom is located at and sets at the 2/3 of liquid level.
Crystallization tank volume is 100L, the setting height of liquid level for crystallizing tank height 60% in crystallizing tank.
Filter is five sets.
A. lysate that 6-APA contents are 22% is passed through in pipe-line mixer so that the flow velocity of 20L/min is at the uniform velocity lasting,
At the same time butanol is passed through in pipe-line mixer so that the flow velocity of 4L/min is at the uniform velocity lasting, the two mixing obtains mixed solution；
B. 10 DEG C of retort temperature control, open stirring, by the mixed solution in pipe-line mixer with the flow velocity of 24L/min at the uniform velocity
Lasting is passed through in retort, while it is 0 that 20% aqueous hydrochloric acid solution is added the pH value for automatically controlling reactant liquor in retort；
C. when the liquid level of reactant liquor in retort rises to setting height, by lower floor's reactant liquor with the speed of 28L/min
At the uniform velocity lasting is passed through in crystallizing tank, upper strata reactant liquor is passed through in recycling can so that the speed of 6L/min is at the uniform velocity lasting, entirely
Process controls the constant liquid level of reactant liquor all the time in setting height；
D. crystallizing tank opens stirring, and lower floor's reactant liquor adds the pH value that 20% ammoniacal liquor controls solution while being passed through be 4.0,
Obtain crystallization solution；
E. when the liquid level of crystallization solution rises to setting height, crystallization solution is at the uniform velocity lasting with the speed of 31L/min
Be passed through in filter, per the crystallization solution for being passed through 825L in sets filtering device, five sets filtering devices are continual to be entered successively
OK, vacuum filtration, obtains filter cake, and in crystallizing tank, the constant liquid level of crystallization solution is in setting height；
F. obtain five filter cakes are washed in three times with proper amount of acetone respectively, is subsequently done under the conditions of 40-50 DEG C
Dry 40min, obtains five batches of 6-amino-penicillanic acids, weighs 101.2kg, 101.2kg, 101.1kg, 101.0kg, 101.3kg respectively,
Average yield 91.03%.
Embodiment 2
Retort volume is 100L, sets the height of liquid level in retort as the 80% of retort height, and paddle is most
Bottom is located at and sets at the 1/2 of liquid level.
Crystallization tank volume is 100L, the setting height of liquid level for crystallizing tank height 80% in crystallizing tank.
Filter is three sets.
A. lysate that 6-APA contents are 28% is passed through in pipe-line mixer so that the flow velocity of 30L/min is at the uniform velocity lasting,
At the same time butanol is passed through in pipe-line mixer so that the flow velocity of 6L/min is at the uniform velocity lasting, the two mixing obtains mixed solution；
B. 5 DEG C of retort temperature control, open stirring, by the mixed solution in pipe-line mixer with the flow velocity of 36L/min at the uniform velocity
Lasting is passed through in retort, while it is 0.5 that 20% aqueous hydrochloric acid solution is added the pH value for controlling reactant liquor in retort；
C. when the liquid level of reactant liquor in retort rises to setting height, by lower floor's reactant liquor with the speed of 46L/min
At the uniform velocity lasting is passed through in crystallizing tank, and upper strata reactant liquor is passed through in recycling can so that 9L/min is at the uniform velocity lasting, and whole process begins
The constant liquid level of control reactant liquor is in setting height eventually；
D. crystallizing tank opens stirring, and lower floor's reactant liquor adds the pH value that 20% ammoniacal liquor controls solution while being passed through be 4.0,
Obtain crystallization solution；
E. when the liquid level of crystallization solution in crystallizing tank rises to setting height, by crystallization solution with the speed of 49L/min
At the uniform velocity lasting is passed through in filter, is passed through the crystallization solution of 795L in every sets filtering device, and three sets filtering devices are uninterrupted
Carry out successively, vacuum filtration obtains filter cake, and in crystallizing tank, the constant liquid level of crystallization solution is in setting height；
F. three filter cakes that step e is obtained are washed in three times with proper amount of acetone respectively, subsequently in 40-50 DEG C of condition
Under dry 60min, obtain three batches of 6-amino-penicillanic acids, respectively weigh 126.2kg, 125.9kg, 126.1kg, average yield
92.47%.
Embodiment 3
The 6-amino-penicillanic acid that inventor is obtained to embodiment 1-2 has carried out quality testing, as a result such as table 1,2 institute of table
Show.
Table 1
| Sample | Content | Single miscellaneous | Always miscellaneous | Color level | Moisture |
| Embodiment 1-1 | 99.5% | 0.21% | 0.53% | 2# | 0.3% |
| Embodiment 1-2 | 99.4% | 0.32% | 0.54% | 2# | 0.3% |
| Embodiment 1-3 | 99.3% | 0.31% | 0.51% | 2# | 0.2% |
| Embodiment 1-4 | 99.5% | 0.24% | 0.49% | 2# | 0.2% |
| Embodiment 1-5 | 99.2% | 0.23% | 0.55% | 2# | 0.3% |
Table 2
| Sample | Content | Single miscellaneous | Always miscellaneous | Color level | Moisture |
| Embodiment 2-1 | 99.5% | 0.23% | 0.58% | 2# | 0.2% |
| Embodiment 2-2 | 99.5% | 0.30% | 0.60% | 2# | 0.2% |
| Embodiment 2-3 | 99.3% | 0.24% | 0.62% | 2# | 0.2% |
Embodiment 4
The 6-amino-penicillanic acid that inventor is obtained to embodiment 1-2 has carried out study on the stability, as a result such as table 3,4 institute of table
Show.
Experiment condition：Temperature 45 C, humidity 60%, accelerate 4 hours.
Table 3
| Sample | Content | Single miscellaneous | Always miscellaneous | Color level | Moisture |
| Embodiment 1-1 | 99.2% | 0.29% | 0.67% | 3# | 0.4% |
| Embodiment 1-2 | 99.2% | 0.42% | 0.69% | 3# | 0.3% |
| Embodiment 1-3 | 99.1% | 0.38% | 0.66% | 2# | 0.3% |
| Embodiment 1-4 | 99.2% | 0.34% | 0.63% | 3# | 0.3% |
| Embodiment 1-5 | 99.1% | 0.33% | 0.68% | 2# | 0.4% |
Table 4
| Sample | Content | Single miscellaneous | Always miscellaneous | Color level | Moisture |
| Embodiment 2-1 | 99.5% | 0.34% | 0.58% | 3# | 0.3% |
| Embodiment 2-2 | 99.5% | 0.39% | 0.59% | 3# | 0.3% |
| Embodiment 2-3 | 99.3% | 0.31% | 0.61% | 3# | 0.3% |
Claims (10)
1. a kind of method of 6-amino-penicillanic acid continuous crystallization, it is characterised in that including following operating procedure：
A. the lysate containing 6-APA and butanol are mixed, obtains mixed solution；
B. 5-10 DEG C of temperature control, stirring, in the at the uniform velocity lasting addition reaction vessel of the mixed solution that step a is obtained, while by salt
It is 0-0.5 that aqueous acid adds the pH value for controlling reactant liquor in reaction vessel；
C., when the liquid level of reactant liquor in step b rises to setting height, the at the uniform velocity lasting crystallization that is passed through of lower floor's reactant liquor is held
In device, it is passed through at the uniform velocity lasting for upper strata reactant liquor in retracting device, while keeping the constant liquid level of reactant liquor in setting height；
D. it is 4.0-4.5 to add the pH value that ammoniacal liquor controls solution in crystallisation vessel while lower floor's reactant liquor is passed through, and is tied
Brilliant solution；
E., when the liquid level of crystallization solution rises to setting height, crystallization solution at the uniform velocity lasting being passed through in filter is carried out
Filter, obtain filter cake, while the constant liquid level of crystallization solution is kept in setting height；
F. the filter cake that step e is obtained is washed, dries, that is, obtain the mould clearly alkanoic acid of 6- amino.
2. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step a
In the lysate, the content of 6-APA is 22-28%.
3. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step a
The lysate is 5 with the volume ratio of butanol:1.
4. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step b
Flow velocity during the mixed solution addition reaction vessel is per 100 liters of reaction vessel 24-36L/min.
5. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step b
The stirring is located at the 1/2-2/3 of reactant liquor liquid level using the bottom of paddle.
6. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step c
60-80% of the setting height for reaction vessel height.
7. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step b
The concentration of the aqueous hydrochloric acid solution is 20%.
8. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step d
The concentration of the ammoniacal liquor is 20%.
9. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step e
The filter is many sets, is passed through the crystallization solution of same volume, carries out filter operation respectively in every sets filtering device.
10. a kind of method of 6-amino-penicillanic acid continuous crystallization according to claim 1, it is characterised in that step f
The solvent for using that washs is acetone.
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| CN105693747B (en) * | 2016-03-07 | 2018-02-06 | 内蒙古常盛制药有限公司 | A kind of 6 APA is without the dry technology of solvent washing |
| CN108218893B (en) * | 2017-12-18 | 2021-02-23 | 伊犁川宁生物技术有限公司 | Method for recovering 6-APA from 6-APA crystallization mother liquor |
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| EP0950660A1 (en) * | 1998-03-20 | 1999-10-20 | Gist-Brocades B.V. | A process for recovery of 6-aminopenicillanic acid from a mother liquor |
| CN101735243A (en) * | 2008-11-11 | 2010-06-16 | 华北制药股份有限公司 | Process for preparing straight-through 6-aminopenicillanic acid |
| CN102925526B (en) * | 2012-11-23 | 2014-10-15 | 华北制药河北华民药业有限责任公司 | Preparation method for 6-amino penicillanic acid |
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Effective date of registration: 20180730 Address after: 010000 Inner Mongolia Togtoh Industrial Park, Hohhot, the Inner Mongolia Autonomous Region Patentee after: INNER MONGOLIA CHANGSHENG PHARMACEUTICAL CO., LTD. Address before: 050000 47, Feng Shou Road, Shijiazhuang, Hebei Patentee before: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group |
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