CN117586335A - Method for removing characteristic genotoxic impurities in deflazacort bulk drug - Google Patents
Method for removing characteristic genotoxic impurities in deflazacort bulk drug Download PDFInfo
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- CN117586335A CN117586335A CN202311592460.3A CN202311592460A CN117586335A CN 117586335 A CN117586335 A CN 117586335A CN 202311592460 A CN202311592460 A CN 202311592460A CN 117586335 A CN117586335 A CN 117586335A
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- deflazacort
- genotoxic impurities
- characteristic
- genotoxic
- mixed solution
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- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 title claims abstract description 54
- 229960001145 deflazacort Drugs 0.000 title claims abstract description 53
- 239000012535 impurity Substances 0.000 title claims abstract description 53
- 231100000024 genotoxic Toxicity 0.000 title claims abstract description 52
- 230000001738 genotoxic effect Effects 0.000 title claims abstract description 52
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 33
- 229940079593 drug Drugs 0.000 title claims abstract description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000011259 mixed solution Substances 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 12
- 239000006184 cosolvent Substances 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000005760 Difenoconazole Substances 0.000 claims description 5
- BQYJATMQXGBDHF-UHFFFAOYSA-N difenoconazole Chemical compound O1C(C)COC1(C=1C(=CC(OC=2C=CC(Cl)=CC=2)=CC=1)Cl)CN1N=CN=C1 BQYJATMQXGBDHF-UHFFFAOYSA-N 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 229960004544 cortisone Drugs 0.000 claims 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000012043 crude product Substances 0.000 abstract description 4
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 238000007599 discharging Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000005086 pumping Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 208000037088 Chromosome Breakage Diseases 0.000 description 1
- 230000009946 DNA mutation Effects 0.000 description 1
- 238000012270 DNA recombination Methods 0.000 description 1
- 206010013453 Disseminated tuberculosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 201000006836 Miliary Tuberculosis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000005886 chromosome breakage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0057—Nitrogen and oxygen
- C07J71/0068—Nitrogen and oxygen at position 16(17)
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, and belongs to the technical field of drug synthesis. The method for removing the characteristic genotoxic impurities in the deflazacort bulk drug comprises the following steps: adding the crude product of the deflazacort and acetic acid into the mixed solution, stirring and dissolving at 50-55 ℃, then dripping water, and cooling to obtain purified deflazacort; the mixed solution is obtained by mixing methanol, acetone and a cosolvent. The removal method can effectively remove the residual genotoxic impurities in the deflazacort.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for removing characteristic genotoxic impurities in a deflazacort bulk drug.
Background
Defucort (defzacor) is a third generation glucocorticoid, is an important medicine for treating primary adrenocortical hypofunction, skin diseases, rheumatism, explosive tuberculosis, disseminated tuberculosis and other diseases, has the daily requirement of 200t at home and abroad, has an anti-inflammatory effect far higher than that of prednisolone, hydrocortisone and the like, and is widely used for treating inflammation and immune diseases after successful research and development in the 80 th century. Recently, the FDA in the united states officially approved it as a DMD (duchenne muscular dystrophy) alleviating hormonal medication with obvious success. The deflazacort CAS number is: 14484-47-0, the molecular formula is: c (C) 25 H 31 NO 6 The molecular weight is: 383.48, the structural formula of which is shown below:
the finished product of deflazacort obtained by the existing synthesis method (shown in the following figure) contains a certain content of genotoxic impurities, wherein the genotoxic impurities are substances capable of causing DNA mutation, chromosome breakage or DNA recombination, and the substances can also cause human tumor.
The genotoxic impurities are mainly derived from starting materials, intermediates, reagents and reaction byproducts in the synthesis process of the bulk drug. In addition, drugs may also degrade during synthesis, storage or formulation to produce genotoxic impurities. In recent years, with the gradual perfection of the regulations of genotoxic impurities, the regulatory requirements of the departments such as the U.S. Food and Drug Administration (FDA) and the european pharmaceutical administration (EMEA) on genotoxic impurities are increasing. If the control of genotoxic impurities in the medicine is improper, the clinical hidden trouble can be caused, and the time of new medicine to be marketed can be influenced, so that the removal of the genotoxic impurities is very important.
The content of genotoxic impurities in the registering and reporting process of the deflazacort crude drug is strictly controlled, and the existing refining scheme has equivalent genotoxic impurity residues, so that the risk of the deflazacort crude drug is increased; there is a need in the art for a method for removing such specific genotoxic impurities that achieves effective removal of such genotoxic impurities remaining in the current chemical synthesis process of deflazacort, provides deflazacort of high purity, and increases the safety of pharmaceuticals.
The structural formula of the genotoxic impurity of deflazacort is as follows:
disclosure of Invention
The invention aims to overcome the technical defects, and provides a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which solves the technical problem of how to effectively remove residual genotoxic impurities in deflazacort in the prior art.
In order to achieve the technical aim, the technical scheme of the invention provides a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding the deflocculant and the acetic acid into the mixed solution, stirring and dissolving the solution at 50-55 ℃, then dripping water, and cooling to obtain the purified deflocculant; the mixed solution is obtained by mixing methanol, acetone and a cosolvent.
In some embodiments, the mass ratio of the methanol to the acetone in the mixed solution is 2 (1-1.5).
In some embodiments, the mass ratio of the methanol to the cosolvent in the mixed liquor is 1 (1-1.5).
In some embodiments, the mass ratio of the deflazacort to the water is 1 (5-6).
In some embodiments, the time required to complete the water addition is 0.5-1h.
In some embodiments, the mass ratio of the deflazacort to the acetic acid is 1 (0.1-0.2).
In some embodiments, the co-solvent is dichloromethane.
In some embodiments, cooling to 0-5 ℃ yields the purified deflazacort.
In some embodiments, further comprising adding purified dif-cort and acetic acid to the mixture for further purification.
Compared with the prior art, the invention has the beneficial effects that: in the mixed solution, the dissolution of the difoliate is realized under the combined action of methanol, acetone and a cosolvent, the generation of genotoxic impurities can be restrained by acetic acid, firstly, the solution is stirred at 50-55 ℃, then water is added dropwise to reduce the solubility so that the difoliate is slowly separated out, and the impurities are remained in the solvent, so that the residual genotoxic impurities in the difoliate are effectively removed.
Drawings
FIG. 1 is a carbon spectrum of the purified Defucort of example 1 of the present invention.
FIG. 2 is a hydrogen spectrum of the purified Defucort of example 1 of the present invention.
Detailed Description
In the following description reference is made to "some embodiments," "this embodiment," and examples, etc., which describe a subset of all possible embodiments, but it is to be understood that "some embodiments" can be the same subset or different subsets of all possible embodiments and can be combined with one another without conflict.
If a similar description of "first/second" appears in the application document, the following description is added, in which the terms "first/second/third" are merely distinguishing between similar objects and not representing a particular ordering of the objects, it being understood that the "first/second/third" may be interchanged with a particular order or precedence, where allowed, so that the embodiments described herein can be implemented in an order other than that illustrated or described herein.
The term "and/or" in this embodiment is merely an association relationship describing an associated object, and indicates that three relationships may exist, for example, object a and/or object B may indicate: there are three cases where object a alone exists, object a and object B together, and object B alone exists.
The specific embodiment provides a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding the crude product of the difenoconazole and acetic acid into the mixed solution, stirring and dissolving at 50-55 ℃, then dripping water for 0.5-1h to finish dripping water, and then cooling to 0-5 ℃ to obtain the purified difenoconazole; the mixed solution is obtained by mixing methanol, acetone and a cosolvent; the mass ratio of the methanol to the acetone is 2 (1-1.5); the mass ratio of the methanol to the cosolvent is 1 (1-1.5); the mass ratio of the crude product of the dif-cort to the water is 1 (5-6); the mass ratio of the crude dif-cort product to the acetic acid is 1 (0.1-0.2); the cosolvent is dichloromethane.
To further purify the deflazacort, in some embodiments, further comprising adding the purified deflazacort and acetic acid to the mixture for further purification.
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
The embodiment provides a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding 1g of deflazacort and 0.1g of acetic acid into the mixed solution, stirring and dissolving at 50-55 ℃, then dripping 5g of water, finishing dripping of water after 0.5h, cooling to 0-5 ℃ to obtain a purified deflazacort filter cake, filtering, washing with a small amount of water, pumping, discharging and drying; the mixture was obtained by mixing 2g of methanol, 1g of acetone and 2g of methylene chloride. In this example, the yield of deflazacort was 98.8% and the content of genotoxic impurities was reduced from 379.07ppm to 30.24ppm.
Figures 1 and 2 are the carbon and hydrogen spectra, respectively, of the purified deflazacort.
Example 2
The embodiment provides a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding 1g of the crude dif-cort product and 0.1g of acetic acid into the mixed solution, stirring and dissolving at 50-55 ℃, then dripping 6g of water, finishing dripping of water after 1h, cooling to 0-5 ℃ to obtain a purified dif-cort filter cake, filtering, washing with a small amount of water, pumping, discharging and drying; the mixture was obtained by mixing 2g of methanol, 1.5g of acetone and 3g of methylene chloride.
In this example, the yield of deflazacort was 98.3% and the content of genotoxic impurities was reduced from 379.07ppm to 33.38ppm.
Example 3
The embodiment provides a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding 1g of the crude difoliate product and 0.2g of acetic acid into the mixed solution, stirring and dissolving at 50-55 ℃, then dripping 5.5g of water, finishing dripping of water after 1h, cooling to 0-5 ℃ to obtain a purified difoliate filter cake, filtering, washing with a small amount of water, pumping, discharging and drying; the mixture was obtained by mixing 2g of methanol, 1.2g of acetone and 2.5g of methylene chloride.
In this example, the yield of deflazacort was 97.9% and the content of genotoxic impurities was reduced from 379.07ppm to 35.43ppm.
Example 4
The embodiment also provides a method for removing characteristic genotoxic impurities in the deflazacort bulk drug, which comprises the following steps:
the filter cake obtained in example 1 was purified once more according to the removal method of example 1 and the dosage ratios of the respective substances.
In this example, the yield of deflazacort was 88.9% and the content of genotoxic impurities was reduced from 30.24ppm to 6.04ppm.
Example 5
The embodiment also provides a method for removing characteristic genotoxic impurities in the deflazacort bulk drug, which comprises the following steps:
the filter cake obtained in example 2 was purified once more according to the removal method of example 2 and the dosage ratios of the respective substances.
In this example, the yield of deflazacort was 88.9% and the content of genotoxic impurities was reduced from 33.38ppm to 7.28ppm.
Example 6
The embodiment also provides a method for removing characteristic genotoxic impurities in the deflazacort bulk drug, which comprises the following steps:
the filter cake obtained in example 3 was purified once more according to the removal method of example 3 and the dosage ratios of the respective substances.
In this example, the yield of deflazacort was 88.9% and the content of genotoxic impurities was reduced from 35.43ppm to 8.17ppm.
Comparative example 1
The comparative example proposes a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding 1g of the crude product of the difoliate and 0.1g of acetic acid into the mixed solution, stirring and dissolving at 50-55 ℃, then cooling to 0-5 ℃ to obtain purified difoliate, filtering, washing with a small amount of water, pumping, and discharging; the mixed solution consists of 2g of methanol, 1.2g of acetone and 2.5g of acetone
And mixing dichloromethane to obtain the product.
In this comparative example, the yield of deflazacort was 71.3% and the content of genotoxic impurities was changed from 379.07ppm to 302.61ppm.
Comparative example 2
The comparative example proposes a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding 1g of the crude difoliate into the mixed solution, stirring and clearing at 50-55 ℃, then dropwise adding 5g of water, finishing the dropwise adding of water after 0.5h, cooling to 0-5 ℃ to obtain purified difoliate, filtering, washing with a small amount of water, pumping, and discharging; the mixture was obtained by mixing 2g of methanol, 1.2g of acetone and 2.5g of methylene chloride.
In this comparative example, the yield of deflazacort was 97.2% and the content of genotoxic impurities was changed from 379.07ppm to 252.61ppm.
Comparative example 3
The comparative example proposes a method for removing characteristic genotoxic impurities in a deflazacort bulk drug, which comprises the following steps:
adding 1g of the crude difoliate and 0.1g of acetic acid into the mixed solution, stirring and dissolving at 50-55 ℃, then dripping water for 0.5-1h to finish dripping water, cooling to 0-5 ℃ to obtain purified difoliate, filtering, washing with a small amount of water, pumping, and discharging; the mixture was obtained by mixing 2g of methanol and 3.7g of methylene chloride.
In this comparative example, the yield of deflazacort was 85.3% and the content of genotoxic impurities was reduced from 379.07ppm to 251.52ppm.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any other corresponding changes and modifications made in accordance with the technical idea of the present invention shall be included in the scope of the claims of the present invention.
Claims (9)
1. The method for removing the characteristic genotoxic impurities in the deflazacort bulk drug is characterized by comprising the following steps of:
adding the deflocculant and the acetic acid into the mixed solution, stirring and dissolving the solution at 50-55 ℃, then dripping water, and cooling to obtain the purified deflocculant; the mixed solution is obtained by mixing methanol, acetone and a cosolvent.
2. The method for removing a characteristic genotoxic impurity in a deflazacort crude drug according to claim 1, wherein the mass ratio of methanol to acetone in the mixed solution is 2 (1-1.5).
3. The method for removing characteristic genotoxic impurities in a drug substance of difenoconazole according to claim 1, wherein the mass ratio of methanol to cosolvent in said mixed solution is 1 (1-1.5).
4. The method for removing characteristic genotoxic impurities in a crude drug of deflazacort according to claim 1, wherein the mass ratio of deflazacort to water is 1 (5-6).
5. The method for removing a characteristic genotoxic impurity in a crude drug of difenoconazole according to claim 4, wherein the time required for completing the water drop addition is 0.5-1h.
6. The method for removing characteristic genotoxic impurities in a crude drug of dif-cortisone according to claim 1, wherein the mass ratio of dif-cortisone to acetic acid is 1 (0.1-0.2).
7. The method for removing characteristic genotoxic impurities in a crude drug of difenoconazole according to claim 1, wherein said cosolvent is dichloromethane.
8. The method for removing characteristic genotoxic impurities in a crude drug of deflazacort according to claim 1, wherein the purified deflazacort is obtained by cooling to 0-5 ℃.
9. The method for removing characteristic genotoxic impurities in a crude drug of deflazacort according to claim 1, further comprising adding purified deflazacort and acetic acid to the mixed solution for further purification.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102942613A (en) * | 2012-09-21 | 2013-02-27 | 天津狄克特科技有限公司 | Method for preparing anti-inflammatory and anti-allergic drug deflazacort |
CN106008660A (en) * | 2016-06-20 | 2016-10-12 | 湖南科瑞生物制药股份有限公司 | Method for preparing deflazacort |
CN106397532A (en) * | 2016-08-30 | 2017-02-15 | 江西宇能制药有限公司 | Preparation method of deflazacort |
CN107459549A (en) * | 2017-08-24 | 2017-12-12 | 岳阳环宇药业有限公司 | A kind of deflazacort fast reaction technique and production system |
CN108484714A (en) * | 2018-03-13 | 2018-09-04 | 岳阳环宇药业有限公司 | The preparation process of deflazacort |
-
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- 2023-11-27 CN CN202311592460.3A patent/CN117586335A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102942613A (en) * | 2012-09-21 | 2013-02-27 | 天津狄克特科技有限公司 | Method for preparing anti-inflammatory and anti-allergic drug deflazacort |
CN106008660A (en) * | 2016-06-20 | 2016-10-12 | 湖南科瑞生物制药股份有限公司 | Method for preparing deflazacort |
CN106397532A (en) * | 2016-08-30 | 2017-02-15 | 江西宇能制药有限公司 | Preparation method of deflazacort |
CN107459549A (en) * | 2017-08-24 | 2017-12-12 | 岳阳环宇药业有限公司 | A kind of deflazacort fast reaction technique and production system |
CN108484714A (en) * | 2018-03-13 | 2018-09-04 | 岳阳环宇药业有限公司 | The preparation process of deflazacort |
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