CN110105374A - A kind of phenylacetyl -7-ADCA method for crystallising that granularity is controllable with brilliant habit - Google Patents
A kind of phenylacetyl -7-ADCA method for crystallising that granularity is controllable with brilliant habit Download PDFInfo
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- CN110105374A CN110105374A CN201910517514.7A CN201910517514A CN110105374A CN 110105374 A CN110105374 A CN 110105374A CN 201910517514 A CN201910517514 A CN 201910517514A CN 110105374 A CN110105374 A CN 110105374A
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- phenylacetyl
- adca
- granularity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of phenylacetyl -7-ADCA method for crystallising that granularity is controllable with brilliant habit, the following steps are included: phenylacetyl -7-ADCA crude product is added in ammonium hydroxide, it is uniformly mixed, filtering, obtains phenylacetyl -7-ADCA solution；Under 5-30 DEG C, the stirring condition of 90-180r/min, hydrochloric acid is added in Xiang Suoshu phenylacetyl -7-ADCA solution, adjusts pH to 1.5-3.0, and growing the grain 1-5h obtains phenylacetyl -7-ADCA.The preparation method of phenylacetyl -7-ADCA provided by the invention, for the purity of phenylacetyl -7-ADCA obtained up to 99.7%, brilliant practise is that length is rodlike or needle-shaped, has many advantages, such as that brilliant habit is complete, purity is high, good fluidity, is not easy to coalesce, has broad application prospects.
Description
Technical field
The present invention relates to the controllable phenylacetyl -7- of medication chemistry production technical field more particularly to a kind of granularity and brilliant habit
The method for crystallising of amido-3-deacetoxy cefaeicosanoic acid.
Background technique
Cephalosporin analog antibiotic is widely used in the treatment of bacterium infection due to spectrum and hypotoxicity.7- amino -3- is de-
Important intermediate of the acetoxyl group cephalosporanic acid (7-ADCA) as semi-synthetic cephalosporin analog antibiotic, demand gradually increase, and
7-ADCA is mainly to be obtained by phenylacetyl -7-ADCA deacylation base.Traditional phenylacetyl -7-ADCA synthetic method is with penicillin
G sulfoxide is raw material, using chemical method esterification, resets ring expansion, hydrolysis, Basic fluxing raction, obtains the water containing phenylacetyl -7-ADCA salt
Solution.Due to containing the organic impurities for being largely difficult to remove in the technique in the aqueous solution of phenylacetyl -7-ADCA salt, therefore need to be to benzene
Acetyl -7-ADCA just can be applied in subsequent synthesis technology after carrying out crystallization treatment.Current existing phenylacetyl -7-
The product granularity that the crystallization purifications of ADCA obtain is less than normal, uneven, and has coalescence, and the purity of product can reach
81.7%, purity is lower, and the active pharmaceutical ingredient so as to cause the cephalosporin analog antibiotic of subsequent technique synthesis reduces, related substance
Content increases, and does not meet the requirement of pharmaceutical purity.Therefore, seek high-content, high-purity phenylacetyl -7-ADCA preparation side
Method, so that the cephalo drug that high quality is made is the important directions that researcher explores.
Summary of the invention
It is on the lower side, uneven for product granularity made from existing phenylacetyl -7-ADCA crystallization purifying technique, and have coalescence,
And the problem of product purity is low, the present invention provide a kind of deacetylated oxygen of phenylacetyl -7- amino -3- that granularity is controllable with brilliant habit
The method for crystallising of base cephalosporanic acid.
In order to solve the above technical problems, present invention provide the technical scheme that
A kind of phenylacetyl -7-ADCA method for crystallising that granularity is controllable with brilliant habit, it is described
It is long rodlike or acicular crystal that crystalline substance, which is practised, and the preparation method comprises the following steps:
Step 1: phenylacetyl -7-ADCA crude product is added in ammonium hydroxide, it is uniformly mixed, mistake
Filter, obtains phenylacetyl -7-ADCA solution；
Step 2: under the stirring condition of 90-180r/min, Xiang Suoshu phenylacetyl -7- amino -3- is deacetylated in 5-30 DEG C
Hydrochloric acid is added in oxygroup cephalosporanic acid solution, adjusts pH to 1.5-3.0, growing the grain 1-5h, obtains the phenylacetyl -7- amino -3- and takes off second
Acyloxy cephalosporanic acid.
Compared with the existing technology, granularity provided by the invention and crystalline substance practise controllable phenylacetyl -7- amino -3- desacetoxy
The method for crystallising of cephalosporanic acid, using ammonium hydroxide-dilute hydrochloric acid as recrystallisation solvent, the ammonium chloride that is generated in crystallization process and residual
The impurity such as the ammonium hydroxide, the dilute hydrochloric acid that stay can be decomposed voluntarily in product heat drying and volatilize product system, be reduced due to crystallization
The impurity that solvent introduces, reduces the generation of crystallization process impurity to greatest extent；Condition by controlling crystallization process obtains
Crystalline substance habit is complete, the length without coalescence is rodlike or acicular crystal.The method for crystallising of phenylacetyl -7-ADCA provided by the invention is made
Phenylacetyl -7-ADCA purity up to 99.7%, the main granularity of phenylacetyl -7-ADCA is 85-95 μm, and size distribution presents single
Peak distribution, and the brilliant of the phenylacetyl -7-ADCA being prepared is practised to be long rodlike or needle-shaped, crystalline substance practises complete, no agglomeration phenomena.With this
Phenylacetyl-the 7-ADCA of preparation process preparation can make as subsequent 7-ADCA or the raw material of the cephalosporins in downstream
The impurity of 7-ADCA and cephalosporins is aqueous to be substantially reduced, and the competitiveness of product in market is helped to improve, and reduces medicine
Toxic side effect of the object to user.
Preferably, in step 1, the phenylacetyl -7-ADCA crude product and the ammonium hydroxide
Mass ratio be 1-5:100.
It is furthermore preferred that in step 1, the phenylacetyl -7-ADCA crude product and the ammonia
The mass ratio of water is 3.02:100.
The mass ratio of phenylacetyl -7-ADCA and ammonium hydroxide is too low, and product yield is caused to reduce；Mass ratio is excessively high, although can be with
The yield of product is improved, but the degree of supersaturation in system is not easily controlled in the range of being conducive to crystal at one and well grow,
And it is also easy to produce impurity inclusion in phenylacetyl -7-ADCA crystal, it is unfavorable for the raising of product purity.Phenylacetyl -7-ADCA is dense
Height is spent, it is too fast to also result in crystalline rate, and plane of crystal adheres to fine microcrystalline, causes product granularity uneven, coalesces
Phenomenon, and the crystalline substance habit obtained is imperfect.
Preferably, the mass concentration of the ammonium hydroxide is 0.25-3%.
It is furthermore preferred that the mass concentration of the ammonium hydroxide is 1%.
Preferred ammonia concn advantageously ensures that the abundant precipitation of crystal under the premise of reducing production cost.
Preferably, it in step 1, is filtered using miillpore filter, the aperture of the miillpore filter is 0.22-0.45 μ
m。
It is furthermore preferred that the miillpore filter is 0.45 μm of mixing filter membrane in step 1.
It can be filtered using organic filter membrane or mixing filter membrane in the present invention, preferably 0.45 μm mixing filter membrane, preferably
Filter membrane can the insoluble impurities as much as possible by phenylacetyl -7-ADCA crude product remove, reduce to the greatest extent in crystallization process
The appearance of impurity inclusion problem.
Preferably, in step 2, phenylacetyl -7- amino -3- desacetoxy is added by the way of being added dropwise in the hydrochloric acid
In cephalosporanic acid solution, drop rate 0.1-0.5mL/min.
It is furthermore preferred that the drop rate of the hydrochloric acid is 0.3mL/min.
Preferably, the concentration of the hydrochloric acid is 0.25-1.25mol/L.
It is furthermore preferred that the concentration of the hydrochloric acid is 0.5mol/L.
Concentration of hydrochloric acid is excessively high or hydrochloric acid drop rate is too fast, will lead to system pH decline it is too fast, local degree of supersaturation is excessively high,
Larger so as to cause crystallization process motive force, crystal nucleation and crystal growth are too fast, cause impurity inclusion phenomenon, reduce product
Purity；Meanwhile also will cause the increase of nucleation amount, cause crystal to be easy to reunite together, moreover, because nucleation rate is greater than crystal
Growth rate, therefore, the granularity of gained crystal are smaller, and particle diameter distribution is uneven.Preferred concentration of hydrochloric acid and drop rate, can
Primary nucleation phenomenon caused by avoiding local degree of supersaturation excessively high, so that brilliant practise well-grown, and particle diameter distribution Relatively centralized.
Preferably, in step 2, mixing speed 120r/min.
Mixing speed is too small, is easy to appear local supersaturation, and part is caused to break out nucleation, has dead zone to have crystal heavy
Product, is unfavorable for crystal uniform growth；Mixing speed is too fast, can smash crystal, and the brilliant habit of appearance is imperfect, and fine grain is caused to occur,
Cause Granularity Distribution uneven, coalesces.
Preferably, in step 2, pH to 2.1 is adjusted.
Preferably, in step 2, crystallization temperature is 20 DEG C.
Preferably, in step 2, rearing crystal time 4h.
Preferred crystallization temperature and rearing crystal time give crystal sufficient ageing time, so that phenylacetyl -7- ADCA crystalline substance is practised
Completely, crystal particle diameter is big and uniform, is conducive to subsequent filter, reduces filtration time, improves production efficiency.
Detailed description of the invention
Fig. 1 is the microscope photo of phenylacetyl -7-ADCA prepared by embodiment 1；
Fig. 2 is the grain size distribution of phenylacetyl -7-ADCA prepared by embodiment 1；
Fig. 3 is X-ray diffraction (XRD) map of phenylacetyl -7-ADCA prepared by embodiment 1；
Fig. 4 is the microscope photo of the phenylacetyl -7-ADCA prepared in comparative example 1.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1
A kind of phenylacetyl -7-ADCA method for crystallising that granularity is controllable with brilliant habit:
It is placed in a beaker Step 1: weighing 3.02g phenylacetyl -7-ADCA crude product fully dried, mass fraction is added
For 1% dilute ammonia solution 100g, stirring and dissolving is removed insoluble impurity, is obtained benzene second using 0.45 μm of mixing membrane filtration
Acyl -7-ADCA solution；
Step 2: phenylacetyl -7-ADCA the solution is transferred in jacketed crystallizer, agitating device is opened, control turns
Speed is 120r/min, opens constant temperature water bath apparatus, and controlling crystalline environment temperature in jacketed crystallizer is 20 DEG C, with 0.3mL/min
Drop rate the dilute hydrochloric acid solution of 0.5mol/L is added dropwise in phenylacetyl -7-ADCA solution, detection architecture pH be 2.1 when
Stopping that dilute hydrochloric acid solution is added dropwise, starts growing the grain, rearing crystal time 4h filters after growing the grain, is placed in a vacuum drying oven drying,
Obtain phenylacetyl -7-ADCA product.
The microscope photo for the phenylacetyl -7-ADCA product that the present embodiment is prepared is as shown in Figure 1, can from figure
Out, the brilliant habit for the phenylacetyl -7-ADCA that the present invention is prepared is rodlike for length, and crystalline substance is practised completely, and without coalescence.
The partial size of the present embodiment products obtained therefrom is measured by 3000 Malvern ParticleSizer of Mastersizer, and grain size distribution is such as
Shown in Fig. 2, size distribution is in Unimodal Distribution, and main partial size is 93.5 μm.
Product purity is measured by 1220 Agilent high performance liquid chromatograph of Agilent, and measurement result shows that its purity is
99.7%.
The XRD spectrum for the phenylacetyl -7-ADCA product that the present embodiment is prepared is as shown in Figure 3.
Embodiment 2
A kind of phenylacetyl -7-ADCA method for crystallising that granularity is controllable with brilliant habit:
It is placed in a beaker Step 1: weighing 1g phenylacetyl -7-ADCA crude product fully dried, mass fraction, which is added, is
0.25% dilute ammonia solution 100g, stirring and dissolving remove insoluble impurity using 0.45 μm of organic membrane filtration, obtain benzene second
Acyl -7-ADCA solution；
Step 2: phenylacetyl -7-ADCA the solution is transferred in jacketed crystallizer, agitating device is opened, control turns
Speed is 90r/min, opens constant temperature water bath apparatus, and controlling crystalline environment temperature in jacketed crystallizer is 5 DEG C, with 0.1mL/min's
The dilute hydrochloric acid solution of 0.25mol/L is added dropwise in phenylacetyl -7-ADCA solution by drop rate, and detection architecture pH stops when being 3.0
It is only added dropwise dilute hydrochloric acid solution, starts growing the grain, rearing crystal time 1h is filtered after growing the grain, is placed in a vacuum drying oven drying, obtains
Phenylacetyl -7-ADCA product.
The partial size of the present embodiment products obtained therefrom is measured by 3000 Malvern ParticleSizer of Mastersizer, and size distribution is in single
Peak distribution, main partial size are 89.1 μm.
Product purity is measured by 1220 Agilent high performance liquid chromatograph of Agilent, and measurement result shows that its purity is
98.9%.
Embodiment 3
A kind of phenylacetyl -7-ADCA method for crystallising that granularity is controllable with brilliant habit:
It is placed in a beaker Step 1: weighing 5g phenylacetyl -7-ADCA crude product fully dried, mass fraction, which is added, is
3% dilute ammonia solution 100g, stirring and dissolving are removed insoluble impurity, are obtained phenylacetyl-using 0.22 μm of mixing membrane filtration
7-ADCA solution；
Step 2: phenylacetyl -7-ADCA the solution is transferred in jacketed crystallizer, agitating device is opened, control turns
Speed is 180r/min, opens constant temperature water bath apparatus, and controlling crystalline environment temperature in jacketed crystallizer is 30 DEG C, with 0.5mL/min
Drop rate the dilute hydrochloric acid solution of 1.25mol/L is added dropwise in phenylacetyl -7-ADCA solution, detection architecture pH be 1.5 when
Stopping that dilute hydrochloric acid solution is added dropwise, starts growing the grain, rearing crystal time 5h filters after growing the grain, is placed in a vacuum drying oven drying,
Obtain phenylacetyl -7-ADCA product.
The partial size of the present embodiment products obtained therefrom is measured by 3000 Malvern ParticleSizer of Mastersizer, and size distribution is in single
Peak distribution, main partial size are 92.8 μm.
Product purity is measured by 1220 Agilent high performance liquid chromatograph of Agilent, and measurement result shows that its purity is
99.1%.
Comparative example 1
A kind of method for crystallising of phenylacetyl -7-ADCA:
It is placed in a beaker Step 1: weighing 3.02g phenylacetyl -7-ADCA crude product fully dried, mass fraction is added
For 1% ammonium bicarbonate aqueous solution 100g, stirring and dissolving is removed insoluble impurity, is obtained benzene using 0.45 μm of mixing membrane filtration
Acetyl -7-ADCA solution；
Step 2: phenylacetyl -7-ADCA the solution is transferred in jacketed crystallizer, agitating device is opened, control turns
Speed is 120r/min, opens constant temperature water bath apparatus, and controlling crystalline environment temperature in jacketed crystallizer is 20 DEG C, with 0.3mL/min
Drop rate by mass fraction be 20% dilution heat of sulfuric acid be added dropwise in phenylacetyl -7-ADCA solution, detection architecture pH is
Stop that dilute hydrochloric acid solution is added dropwise when 2.1, start growing the grain, rearing crystal time 4h is filtered after growing the grain, is placed in a vacuum drying oven
It is dry, obtain phenylacetyl -7- ADCA product.
The microscope photo for the phenylacetyl -7-ADCA product that this comparative example is prepared is as shown in Figure 1, can from figure
Out, the partial size for the phenylacetyl -7-ADCA product that the above method is prepared is partially small and uneven, there is coalescence.
The partial size of this comparative example products obtained therefrom is measured by 3000 Malvern ParticleSizer of Mastersizer, and size distribution is in single
Peak distribution, main partial size are 63.5 μm.
Product purity is measured by 1220 Agilent high performance liquid chromatograph of Agilent, and measurement result shows that its purity is
81.7%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modification, equivalent replacement or improvement etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of granularity and crystalline substance practise controllable phenylacetyl -7-ADCA method for crystallising, feature
It is, comprising the following steps:
Step 1: phenylacetyl -7-ADCA crude product is added in ammonium hydroxide, it is uniformly mixed, filtering,
Obtain phenylacetyl -7-ADCA solution；
Step 2: in 5-30 DEG C, under the stirring condition of 90-180r/min, Xiang Suoshu phenylacetyl -7- amino -3- desacetoxy
Hydrochloric acid is added in cephalosporanic acid solution, adjusts pH to 1.5-3.0, growing the grain 1-5h, obtains the deacetylated oxygen of the phenylacetyl -7- amino -3-
Base cephalosporanic acid.
2. granularity as described in claim 1 and crystalline substance practise controllable phenylacetyl -7-ADCA knot
Crystal method, which is characterized in that in step 1, the phenylacetyl -7-ADCA crude product and the ammonia
The mass ratio of water is 1-5:100.
3. granularity as claimed in claim 2 and crystalline substance practise controllable phenylacetyl -7-ADCA knot
Crystal method, which is characterized in that in step 1, the phenylacetyl -7-ADCA crude product and the ammonia
The mass ratio of water is 3.02:100.
4. granularity as described in any one of claims 1-3 and crystalline substance practise controllable phenylacetyl -7- amino -3- desacetoxy cephalo
The method for crystallising of alkanoic acid, which is characterized in that the mass concentration of the ammonium hydroxide is 0.25-3%.
5. granularity as claimed in claim 4 and crystalline substance practise controllable phenylacetyl -7-ADCA knot
Crystal method, which is characterized in that the mass concentration of the ammonium hydroxide is 1%.
6. granularity as described in claim 1 and crystalline substance practise controllable phenylacetyl -7-ADCA knot
Crystal method, which is characterized in that in step 1, be filtered using miillpore filter, the aperture of the miillpore filter is 0.22-0.45
μm。
7. granularity as described in claim 1 and crystalline substance practise controllable phenylacetyl -7-ADCA knot
Crystal method, which is characterized in that in step 2, the deacetylated oxygen of phenylacetyl -7- amino -3- is added by the way of being added dropwise in the hydrochloric acid
In base cephalosporanic acid solution, drop rate 0.1-0.5mL/min.
8. granularity as claimed in claim 7 and crystalline substance practise controllable phenylacetyl -7-ADCA knot
Crystal method, which is characterized in that the drop rate of the hydrochloric acid is 0.3mL/min.
9. granularity as claimed in claim 7 or 8 and crystalline substance practise controllable phenylacetyl -7-ADCA
Method for crystallising, which is characterized in that the concentration of the hydrochloric acid be 0.25-1.25mol/L.
10. granularity as described in claim 1 and crystalline substance practise controllable phenylacetyl -7-ADCA
Method for crystallising, which is characterized in that in step 2, temperature is 20 DEG C；And/or mixing speed is 120r/min；And/or adjust pH to
2.1；And/or rearing crystal time is 4h.
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| CN201910517514.7A CN110105374B (en) | 2019-06-14 | 2019-06-14 | Crystallization method of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid with controllable granularity and crystal habit |
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| CN201910517514.7A CN110105374B (en) | 2019-06-14 | 2019-06-14 | Crystallization method of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid with controllable granularity and crystal habit |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526928A (en) * | 2019-09-17 | 2019-12-03 | 河北科技大学 | A kind of refining methd of 7-aminodesacetoxycephalosporanic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6442489A (en) * | 1987-08-11 | 1989-02-14 | Yoshitomi Pharmaceutical | Method for crystallization and purification of 7-acylamidodeacetoxycephalosporanic acid |
| WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
-
2019
- 2019-06-14 CN CN201910517514.7A patent/CN110105374B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6442489A (en) * | 1987-08-11 | 1989-02-14 | Yoshitomi Pharmaceutical | Method for crystallization and purification of 7-acylamidodeacetoxycephalosporanic acid |
| WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526928A (en) * | 2019-09-17 | 2019-12-03 | 河北科技大学 | A kind of refining methd of 7-aminodesacetoxycephalosporanic acid |
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