CN111072743B - Synthetic method of loteprednol etabonate intermediate - Google Patents
Synthetic method of loteprednol etabonate intermediate Download PDFInfo
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- CN111072743B CN111072743B CN201811214772.XA CN201811214772A CN111072743B CN 111072743 B CN111072743 B CN 111072743B CN 201811214772 A CN201811214772 A CN 201811214772A CN 111072743 B CN111072743 B CN 111072743B
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Abstract
The invention provides a preparation method of an loteprednol etabonate intermediate, which takes cheap and easily-obtained 11 alpha-hydroxy-ADD as a starting material and obtains 17 beta carboxylic acid (a compound VII) through dehydration, Grignard, hydrolysis, oxidation, hydroxyl bromination and reduction. The invention has the advantages of easily obtained starting materials, high yield, good purity and stable process.
Description
Technical Field
The invention relates to a preparation method of a steroid drug intermediate, in particular to a preparation method of a loteprednol etabonate intermediate.
Background
Loteprednol Etabonate (LE) is a steroid drug used for treating ocular inflammation, and can be used for treating corticosteroid-sensitive inflammation such as eyelid and bulbar conjunctivitis, uveitis, inflammation of cornea and anterior segment of eye, and also for treating postoperative inflammation after various ocular surgeries. Loteprednol etabonate can also be prepared into a compound preparation with tobramycin. Loteprednol etabonate suspension eye drops were first developed by the U.S. Pharmos Corp company and first approved to be marketed in the U.S. in 1997 and marketed in china in 2011.
The synthesis process of the loteprednol etabonate raw material medicament takes 17 beta carboxylic acid as an important intermediate. The synthesis methods of 17 beta carboxylic acid reported in the literature at present all use prednisolone as a raw material. The 21-position of prednisolone is hydroxyl structure, so that prednisolone needs oxidation reaction to obtain 17 beta carboxylic acid. This synthesis method has the disadvantage of excessive raw material costs.
Disclosure of Invention
The invention aims to provide a novel preparation method of 17 beta carboxylic acid with low raw material cost.
The technical scheme of the invention is as follows: a process for preparing the intermediate of loteprednol etabonate from 11 alpha-hydroxy-ADD (compound I) through dewatering, Grignard reaction, hydrolysis, oxidizing, bromohydric reaction and reduction includes such steps as
(1) And (3) dehydration reaction: reacting the compound I with a dehydrating agent in an organic solvent to obtain a compound II;
(2) and (3) performing a Grignard reaction: reacting the compound II with dimethyl isopropoxy silane methyl magnesium chloride in an organic solvent to obtain a compound III;
(3) and (3) hydrolysis reaction: reacting the compound III with a hydrogen peroxide solution in an organic solvent in the presence of an alkaline reagent and a complexing agent to obtain a compound IV;
(4) and (3) oxidation reaction: adding the compound IV into an organic solvent, and reacting with a chromic acid solution to obtain a compound V;
(5) and (3) carrying out hydroxyl bromine reaction: adding the compound V into an organic solvent, and reacting with a bromination reagent in the presence of an acidic catalyst to obtain a compound VI;
(6) reduction reaction: and reacting the compound VI with a reducing agent in an organic solvent to obtain a compound VII.
In the preparation method of the loteprednol etabonate intermediate, the organic solvent in the dehydration reaction is selected from one or more of dichloromethane, chloroform, tetrahydrofuran and methyl tetrahydrofuran, and dichloromethane is preferred.
In the preparation method of the loteprednol etabonate intermediate, the dehydrating agent in the dehydration reaction is selected from one or more of phosphoric acid and phosphorus pentoxide; phosphoric acid is preferred;
according to the preparation method of the loteprednol etabonate intermediate, the temperature of the Grignard reaction is selected from-10-20 ℃, and preferably 0-5 ℃.
The preparation method of the loteprednol etabonate intermediate comprises the following steps that the Grignard reaction organic solvent comprises one or more of tetrahydrofuran, methyltetrahydrofuran and diethyl ether, and the volume/weight ratio of the organic solvent to the compound II is 5-20 ml/g;
according to the preparation method of the loteprednol etabonate intermediate, the molar ratio of dimethyl isopropoxysilane methyl magnesium chloride subjected to Grignard reaction to a compound II is 1.0-2.0: 1.
According to the preparation method of the loteprednol etabonate intermediate, the reaction temperature of hydrolysis reaction is 10-30 ℃; preferably 20 to 30 ℃.
In the preparation method of the loteprednol etabonate intermediate, the concentration of hydrogen peroxide in the hydrolysis reaction is 10-50%, preferably 30%.
In the preparation method of the loteprednol etabonate intermediate, an organic solvent for hydrolysis reaction is selected from THF, 2-methyltetrahydrofuran, acetonitrile, dichloromethane and methanol, and is mixed and dissolved; the volume/weight ratio of the hydrogen peroxide solution to the compound III is 1-3: 1 ml/g.
The preparation method of the loteprednol etabonate intermediate is characterized in that an alkaline reagent for hydrolysis reaction is selected from KHCO3，NaHCO3，K2CO3One or two of them.
The preparation method of the loteprednol etabonate intermediate is characterized in that a complexing agent for hydrolysis reaction is selected from one or two of KF and NaF.
In the preparation method of the loteprednol etabonate intermediate, the organic solvent for the oxidation reaction comprises ketones with the carbon atom number less than 6, preferably acetone.
The preparation method of the loteprednol etabonate intermediate comprises the following steps of (1) preparing a mixture of chromic acid and a compound IV in an oxidation reaction, wherein the volume/weight ratio of the chromic acid to the compound IV is 20-40: 1 ml/g.
The preparation method of the loteprednol etabonate intermediate has the oxidation reaction temperature of-10-35 ℃, and preferably-5 ℃.
The preparation method of the loteprednol etabonate intermediate comprises the following steps of: the acidic catalyst is selected from one or more of organic acid or inorganic acid, and the brominating agent is selected from one or more of dibromocyanoacetamide, dibromocyanopropionamide, dibromohydantoin, N-bromoacetamide, N-bromophthalic acid diamide or N-bromosuccinimide.
The preparation method of the loteprednol etabonate intermediate comprises the following steps of: the acidic catalyst is selected from one or more of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, formic acid or acetic acid; the brominating reagent is N-bromosuccinimide.
In the preparation method of the loteprednol etabonate intermediate, the organic solvent for the hydroxyl bromination reaction comprises ketones with the carbon atom number less than 6, preferably acetone; the volume/weight ratio of the organic solvent to the compound V is 2-4: 1 ml/g.
According to the preparation method of the loteprednol etabonate intermediate, the weight ratio of a bromination reagent for hydroxyl bromination to a compound IV is 0.4-1: 1.
The preparation method of the loteprednol etabonate intermediate is characterized in that the organic solvent for the reduction reaction comprises fatty alcohol with the carbon atom number less than 6, preferably ethanol.
The preparation method of the loteprednol etabonate intermediate is characterized in that the reducing agent is selected from one or more of divalent chromium salt, trivalent chromium salt, tributyltin hydride, iron powder, zinc powder, nickel powder and tin powder; preferably: the reducing agent is trivalent chromium salt and zinc powder.
The preparation method of the loteprednol etabonate intermediate comprises the following steps of (1-3): 1.
according to the preparation method of the loteprednol etabonate intermediate, the temperature of the dehydration reaction is selected from 0-60 ℃, the temperature of the bromine hydroxyl reaction is selected from-20-30 ℃, and the temperature of the reduction reaction is selected from 0-40 ℃.
The invention has the advantages and positive effects that: the invention takes cheap and easily obtained 11 alpha-hydroxy-ADD as a starting material, and 17 beta carboxylic acid (compound VII) is obtained through dehydration, Grignard, hydrolysis, oxidation, hydroxyl bromination and reduction. The invention has the advantages of easily obtained starting materials, high yield, good purity and stable process.
Detailed Description
The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
Example 1: synthesis of Compound II
Examples 1 to 1
Under the protection of nitrogen, 15g of 11 alpha hydroxy-ADD (compound I), 100ml of dichloromethane and 2ml of acetic anhydride are added into a reaction bottle, 10ml of phosphoric acid is dripped into the reaction bottle at the temperature of 0-5 ℃, the reaction bottle is kept warm and stirred for 5 hours, then the reaction bottle is diluted into 10% sodium bicarbonate aqueous solution for neutralization, the stirring is carried out for 30 minutes, and the reaction bottle is filtered and dried to obtain 13.6g of yellow solid, the molar yield is 96.5%, and the HPLC purity is 93%.
Examples 1 to 2
Adding 100ml of tetrahydrofuran and 5g of phosphorus pentoxide into a reaction bottle under the protection of nitrogen, controlling the temperature to be 0-5 ℃, adding 15g of 11 alpha-hydroxy-ADD (compound I), keeping the temperature, stirring for 5 hours, diluting to 10% sodium bicarbonate water solution, neutralizing, stirring for 30 minutes, filtering, and drying to obtain 13.1g of compound II, wherein the molar yield is 92.9%, and the HPLC purity is 95%.
Example 2: synthesis of Compound III
Example 2-1
Preparation of dimethylisopropoxysilane methylmagnesium chloride: under the protection of nitrogen, a small amount of THF solution of dimethyl isopropoxy chloromethylsilane is added into a dry reaction bottle, 2.4g of magnesium chips and 2 drops of 1, 2-dibromoethane are added, 100ml of THF solution containing 17ml of dimethyl isopropoxy chloromethylsilane is added after bubbles are generated, and the temperature is kept at 50-60 ℃ for reaction for 1 hour for later use.
Adding 10g of compound II and 100ml of tetrahydrofuran into a reaction bottle under the protection of nitrogen, cooling to 0-5 ℃, dropping 50ml of dimethyl isopropoxy silane methyl magnesium chloride, stirring, controlling the temperature to be 0-10 ℃, reacting for 1 hour, cooling the reaction liquid to-5-0 ℃ after the reaction is completed, and adding 10% of NH4Quenching with Cl 10ml, stirring for 10 min, adding ethyl acetate, separating the organic phase, washing with water, concentrating the organic phase under reduced pressure, adding ethyl acetate to the residue, stirring, filtering and drying to obtain 13.1g of compound III, the molar yield being 89.2% and the HPLC purity being 95%.
Examples 2 to 2
Preparation of dimethylisopropoxysilane methyl magnesium chloride: under the protection of nitrogen, a small amount of THF solution of dimethyl isopropoxy chloromethylsilane is added into a dry reaction bottle, 2.4g of magnesium chips and 2 drops of 1, 2-dibromoethane are added, 100ml of THF solution containing 17ml of dimethyl isopropoxy chloromethylsilane is added after bubbles are generated, and the temperature is kept at 50-60 ℃ for 1 hour of reaction for later use.
Adding 10g of compound II and 100ml of methyltetrahydrofuran into a reaction bottle under the protection of nitrogen, cooling to-5-0 ℃, dripping 70ml of dimethyl isopropoxy silane methyl magnesium chloride, stirring, controlling the temperature to be 0-5 ℃, reacting for 1 hour, cooling the reaction liquid to-5-0 ℃ after the reaction is completed, and adding 10% NH4Quenching with Cl 15ml, stirring for 10 min, adding ethyl acetate, separating the organic phase, washing with water, concentrating the organic phase under reduced pressure, adding ethyl acetate to the residue, stirring, filtering and drying to obtain 13.5g of compound III, with a molar yield of 91.9% and a HPLC purity of 96%.
Example 3: synthesis of Compound IV
Example 3-1
Under the protection of nitrogen, 10g of compound III and 100ml of tetrahydrofuran are added into a reaction bottle, stirred and added with 0.25g KHCO3And 0.3g of KF, stirring for half an hour at 10 ℃, then adding 40% hydrogen peroxide solution, continuing to react for 4 hours at 10 ℃, after the reaction is completed, adding 10% sodium thiosulfate solution for quenching, stirring for 10 minutes, adding ethyl acetate, separating out an organic phase, washing with water, concentrating the organic phase under reduced pressure, adding ethyl acetate into a residue, stirring, filtering, and drying to obtain 6.9g of a compound IV, wherein the molar yield is 90.9%, and the HPLC purity is 92%.
Examples 3 to 2
Under the protection of nitrogen, 10g of compound III and 100ml of tetrahydrofuran are added into a reaction bottle, stirred and added with 0.20g of NaHCO3And 0.3g of KF, stirring for half an hour at 25 ℃, then adding 30% hydrogen peroxide solution, continuing to react for 5 hours at 25 ℃, after the reaction is completed, adding 10% sodium thiosulfate solution for quenching, stirring for 10 minutes, adding ethyl acetate, separating an organic phase, washing with water, concentrating the organic phase under reduced pressure, adding ethyl acetate into a residue, stirring, filtering, and drying to obtain 7.0g of a compound IV, wherein the molar yield is 92.3%, and the HPLC purity is 94%.
Example 4: synthesis of Compound V
Example 4-1
And (3) preparing a chromic acid solution, namely dissolving 12g of chromium trioxide into 40 ml of water, dropwise adding 10ml of sulfuric acid at the temperature of 0-10 ℃, and stirring for 30 minutes at 25 ℃ after dropwise adding is finished, so as to be used for later use.
Adding 5g of compound IV into acetone, controlling the temperature to be 0-5 ℃, slowly dropwise adding 10ml of chromic acid solution, raising the temperature to 25 ℃ for reaction after the dropwise adding is finished, diluting the mixture into water after the reaction is finished, filtering, washing with water, and drying to obtain 5.1g of compound V, wherein the molar yield is 97.6%, and the HPLC purity is 96%.
Example 4 to 2
And (3) preparing a chromic acid solution, namely dissolving 12g of chromium trioxide into 40 ml of water, dropwise adding 10ml of sulfuric acid at the temperature of 0-10 ℃, and stirring for 30 minutes at 22 ℃ after dropwise adding is finished, so as to be used for later use.
Adding 5g of compound IV into acetone, controlling the temperature to be-5-0 ℃, slowly dropwise adding 15ml of chromic acid solution, raising the temperature to 22 ℃ for reaction after the dropwise adding is finished, diluting the mixture into water after the reaction is finished, filtering, washing with water, and drying to obtain 5g of compound V, wherein the molar yield is 95.7%, and the HPLC purity is 94%.
Example 5: synthesis of Compound VI
Example 5-1
Adding 10g of compound V and 300ml of butanone into a reaction bottle under the protection of nitrogen, stirring, cooling to 0-5 ℃, and dropwise adding a hydrochloric acid solution. After dropping, 5g N-bromosuccinimide was added in 5 portions, each at 20 minute intervals. After the addition, the temperature is controlled to be 10-20 ℃ for heat preservation reaction for 2 hours. After the reaction was completed, acetic acid was added to neutralize, concentrate, filter, wash with water, and dry 11.1g of compound VI in 85.9% molar yield and 90% HPLC purity.
Examples 5 and 2
Under the protection of nitrogen, 10g of compound V and 300ml of acetone are added into a reaction bottle, stirred, cooled to 0-5 ℃, and 30ml of 1% perchloric acid is dripped. After dropping, 4.5g of N-bromoacetamide was added in 5 portions, each at 20 minute intervals. After the addition, the temperature is controlled to be-5-0 ℃ and the reaction is carried out for 3 hours. After the reaction was completed, acetic acid was added to neutralize, concentrate, filter, wash with water, and dry 11.7g of compound VI in 90.5% molar yield and 91% HPLC purity.
Example 6: synthesis of Compound VII
Example 6-1
Preparing a chromium reagent: 20g of chromium chloride, 20ml of ethanol, 20ml of distilled water and 2g of zinc powder are added into a reaction bottle, stirred at the temperature of 25 ℃, added with 10ml of hydrochloric acid and stirred for 30 minutes for later use.
Under the protection of nitrogen, adding 10g of compound VI and 200ml of ethanol into a reaction bottle, cooling to 10-15 ℃, adding a chromium reagent, controlling the temperature to 10-15 ℃, and carrying out heat preservation reaction for 40 minutes. After completion of the reaction, concentration, filtration, washing with water and drying gave 7.8g of compound VII in 95.6% molar yield and 96% HPLC purity.
Example 6 to 2
Preparing a chromium reagent: 20g of chromium chloride, 20ml of ethanol, 20ml of distilled water and 2g of zinc powder are added into a reaction bottle, stirred at the temperature of 25 ℃, added with 10ml of hydrochloric acid and stirred for 30 minutes for later use.
Adding 10g of compound VI and 200ml of ethanol into a reaction bottle under the protection of nitrogen, adding 1ml of thioglycollic acid, stirring, cooling to 10-15 ℃, adding a chromium reagent, controlling the temperature to 20-30 ℃, and carrying out heat preservation reaction for 30 minutes. After the reaction was completed, concentration, dilution, filtration, washing with water, and drying were carried out to obtain 8.0g of compound VII, with a molar yield of 98.0% and a HPLC purity of 97%.
Although one embodiment of the present invention has been described in detail, the description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.
Claims (21)
1. A preparation method of loteprednol etabonate intermediate is characterized by comprising the following steps: is prepared from 11 alpha-hydroxy-ADD (compound I) through dewatering, Grignard reaction, hydrolysis, oxidation, hydroxyl bromination and reduction, and comprises the following steps:
(1) and (3) dehydration reaction: reacting the compound I with a dehydrating agent in an organic solvent to obtain a compound II;
(2) and (3) performing a Grignard reaction: reacting the compound II with dimethyl isopropoxy silane methyl magnesium chloride in an organic solvent to obtain a compound III;
(3) and (3) hydrolysis reaction: reacting the compound III with a hydrogen peroxide solution in an organic solvent in the presence of an alkaline reagent and a complexing agent to obtain a compound IV;
(4) and (3) oxidation reaction: adding the compound IV into an organic solvent, and reacting with a chromic acid solution to obtain a compound V;
(5) and (3) carrying out hydroxyl bromine reaction: adding the compound V into an organic solvent, and reacting with a bromination reagent in the presence of an acidic catalyst to obtain a compound VI;
(6) reduction reaction: and reacting the compound VI with a reducing agent in an organic solvent to obtain a compound VII.
2. The method for preparing the loteprednol etabonate intermediate as claimed in claim 1, wherein: in the dehydration reaction, the dehydrating agent is selected from one or more of phosphoric acid and phosphorus pentoxide.
3. A process for the preparation of loteprednol etabonate intermediate as claimed in claim 1 or 2, wherein: the molar ratio of dimethyl isopropoxy silane methyl magnesium chloride and the compound II in the Grignard reaction is 1.0-2.0: 1.
4. The method for preparing a loteprednol etabonate intermediate as claimed in claim 3, wherein: the temperature of the Grignard reaction is selected from-10 to 20 ℃.
5. A process for the preparation of a loteprednol etabonate intermediate as claimed in any one of claims 1, 2 or 4, wherein: the alkaline agent for the hydrolysis reaction is selected from KHCO3，NaHCO3,K2CO3One or two of them, the complexing agent for hydrolysis reaction is selected from one or two of KF and NaF.
6. The method for preparing a loteprednol etabonate intermediate as claimed in claim 5, wherein: the concentration of hydrogen peroxide in the hydrolysis reaction is 10-50%, and the volume/weight ratio of hydrogen peroxide solution to the compound III is 1-3: 1 ml/g.
7. The process for the preparation of loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4 or 6, wherein: the volume/weight ratio of chromic acid to a compound IV in the oxidation reaction is 20-40: 1 ml/g.
8. The process for the preparation of loteprednol etabonate intermediate as claimed in claim 7, wherein: the acidic catalyst is selected from one or more of organic acid or inorganic acid, and the brominating agent is selected from one or more of dibromocyanoacetamide, dibromocyanopropionamide, dibromohydantoin, N-bromoacetamide, N-bromophthalic acid diamide or N-bromosuccinimide.
9. A process for the preparation of a loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4, 6 or 8, wherein: the weight ratio of a bromination reagent and a compound IV in the hydroxyl bromine reaction is 0.4-1: 1.
10. the process for the preparation of loteprednol etabonate intermediate as claimed in claim 9, wherein: the reducing agent is selected from one or more of divalent chromium salt, trivalent chromium salt, tributyltin hydride, iron powder, zinc powder, nickel powder and tin powder.
11. A process for the preparation of a loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4, 6, 8 or 10, wherein: the organic solvent in the dehydration reaction is one or more selected from dichloromethane, chloroform, tetrahydrofuran and methyl tetrahydrofuran.
12. The process of claim 11 wherein the intermediate of loteprednol etabonate is prepared by: the Grignard reaction organic solvent is one or more selected from tetrahydrofuran, methyltetrahydrofuran and diethyl ether, and the volume/weight ratio of the organic solvent to the compound II is 5-20 ml/g.
13. A process for the preparation of a loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4, 6, 8, 10 or 12, wherein: the organic solvent for hydrolysis reaction is selected from THF, 2-methyltetrahydrofuran, acetonitrile, dichloromethane and methanol mixed solution.
14. The process of claim 13, wherein the intermediate of loteprednol etabonate is prepared by: the reaction temperature of the hydrolysis reaction is 10-30 ℃.
15. A process for the preparation of a loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4, 6, 8, 10, 12 or 14, wherein: the organic solvent for the oxidation reaction is selected from ketones with less than 6 carbon atoms.
16. The process of claim 15 wherein the intermediate of loteprednol etabonate is prepared by: the oxidation reaction temperature is-10-35 ℃.
17. A process for the preparation of loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4, 6, 8, 10, 12, 14 or 16, wherein: in the bromine hydroxyl reaction: the acidic catalyst is selected from one or more of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, formic acid or acetic acid; the brominating reagent is N-bromosuccinimide.
18. The process for preparing a loteprednol etabonate intermediate as claimed in claim 17, wherein: the organic solvent for the hydroxyl bromide reaction is selected from ketones with carbon number less than 6; the volume/weight ratio of the organic solvent to the compound V is 2-4: 1 ml/g.
19. A process for the preparation of loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16 or 18, wherein: the organic solvent for the reduction reaction is selected from fatty alcohols with less than 6 carbon atoms.
20. The process of claim 19 wherein the intermediate of loteprednol etabonate is prepared by: the weight ratio of the reducing reaction reducing agent to the compound VI is 1-3: 1.
21. a process for the preparation of loteprednol etabonate intermediate as claimed in any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20, wherein: the temperature of the dehydration reaction is selected from 0-60 ℃, the temperature of the hydroxyl bromide reaction is selected from-20-30 ℃, and the temperature of the reduction reaction is selected from 0-40 ℃.
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| CN101397321A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of hydrocortisone and derivatives thereof |
| CN104311625A (en) * | 2014-11-06 | 2015-01-28 | 江西赣亮医药原料有限公司 | Preparation method for fluocinolone acetonide midbody |
| CN107619423A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of hydrocortisone |
| CN108659083A (en) * | 2017-03-31 | 2018-10-16 | 天津药业研究院有限公司 | A kind of synthetic method of Loteprednol etabonate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101397321A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of hydrocortisone and derivatives thereof |
| CN104311625A (en) * | 2014-11-06 | 2015-01-28 | 江西赣亮医药原料有限公司 | Preparation method for fluocinolone acetonide midbody |
| CN107619423A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of hydrocortisone |
| CN108659083A (en) * | 2017-03-31 | 2018-10-16 | 天津药业研究院有限公司 | A kind of synthetic method of Loteprednol etabonate |
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Address after: 300 457 days north of Xinye Jiujie Street and east of Xinhuan West Road, Dongli District Development Zone, Tianjin Applicant after: Tianjin Pharmaceutical Research Institute Co., Ltd Address before: 300 457 days north of Xinye Jiujie Street and east of Xinhuan West Road, Dongli District Development Zone, Tianjin Applicant before: TIANJIN PHARMACEUTICALS Group Corp. |
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