- Method for preparing high-purity fluocinolone acetonide
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The invention belongs to the technical field of preparation of steroid hormones and particularly relates to a method for preparing high-purity fluocinolone acetonide. The method comprises the steps ofmixing fluocinolone acetonide with a mixed solution, and carrying out a hydrolysis reaction, thereby obtaining the high-purity fluocinolone acetonide, wherein the mixed solution is a mixed solution of sulfite and a strong base. According to the method, an ester group of 21-position is hydrolyzed by employing a system of the strong base and the sulfite, by adding the sulfite, the reaction can be carried out at the temperature of 0 DEG C to 30 DEG C, and loci of the reaction are subjected to in-situ protection, so that the problem of deterioration of the product during hydrolysis can be excellently avoided, the product can fully meet the requirements of EP9.0 through only simple refining, the purity of the obtained product is remarkably higher than that in the prior art, and the purity andyield of a crude product are greatly improved.
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Paragraph 0016-0027
(2020/02/18)
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- Synthesis method and application of 9-fluorosteroid compound
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The invention provides a synthesis method and application of a 9-fluorosteroid compound, and relates to the technical field of chemical synthesis. The synthesis method of the 9-fluorosteroid compoundcomprises the following step: reacting a compound II in an ionic liquid containing hydrogen fluoride salt to obtain a 9-fluorosteroid compound III. According to the synthesis method of the 9-fluorosteroid compound, the ionic liquid containing the hydrogen fluoride salt is used as a fluorinating agent to replace a traditional hydrogen fluoride aqueous solution, volatilization of hydrogen fluoride gas is avoided, corrosivity is small, toxicity is greatly reduced, reaction conditions are mild, reaction can be completed at the room temperature, operability is high, the safety coefficient is high,and production applicability is improved. The synthesis method of the 9-fluorosteroid compound is used for preparing corticosteroid drugs, highly toxic chemical reagents are not used in the synthesisroute, the operability is high, the safety coefficient is high, and the production applicability is improved.
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Paragraph 0143-0144; 0149-0150
(2021/01/15)
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- Improved synthesis of fluocinolone acetonide and process research of 6α,9α-fluorination
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An efficient and improved synthetic route of fluocinolone acetonide with combination of bio-fermentation was developed from 21-acetyloxy-17α-hydroxy-4,9(11)-diene-3,20-dione (1a). Process of the 6α and 9α fluorination steps was studied, and it was observe
- Tang, Jie,Zeng, Chunling,Xie, Longyong,Wang, Jinghua,Tian, Mi,Guo, Cancheng
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supporting information
p. 110 - 112
(2018/01/26)
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- NOVEL PROCESS FOR PREPARATION OF CORTICOSTEROIDS
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The present invention discloses a process for the preparation of pregnadiene derivatives having formula I, their stereoisomer and intermediate thereof. Formula I wherein each substituent is independently, R1 and R2 is hydrogen or C1 –C8straight, branched alkyl chain, saturated or unsaturated cycloalkyl; R3 is hydrogen or wherein R5 represents C1-C8 straight, branched alkyl chain or cycloalkyl; R4 is hydrogen or halogen; R6 is hydrogen or halogen;
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Page/Page column 18; 21
(2018/03/25)
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- Preparation method of high-purity fluocinolone acetonide
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The invention provides a preparation method of high-purity fluocinolone acetonide. The preparation method comprises the following steps: (1) performing hydrolysis reaction on 11 beta-hydroxyl-16 alpha,17-[(1-methyl ethylidene)-bis (oxygen)]-21-(acetoxy)-6 alpha,9-difluorobenzene-1,4-diene-3,20-diketone; (2) refining a 11 beta-hydroxyl-16 alpha,17-[(1-methyl ethylidene)-bis (oxygen)]-6 alpha,9-difluorobenzene-1,4-diene-3,20-diketone crude product to obtain a 11 beta-hydroxyl-16 alpha,17-[(1-methyl ethylidene)-bis (oxygen)]-6 alpha,9-difluorobenzene-1,4-diene-3,20-diketone I crystal; (3) refining the 11 beta-hydroxyl-16 alpha,17-[(1-methyl ethylidene)-bis (oxygen)]-6 alpha,9-difluorobenzene-1,4-diene-3,20-diketone I crystal to obtain a fluocinolone acetonide finished product.
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Paragraph 0085; 0090; 0095; 0100; 0105; 0110; 0115; 0120
(2018/07/30)
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- A preparation method of fluocinonide (by machine translation)
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The present invention provides a new preparation of the synthetic route of the Fluocinonide, raw material of the more cheap and easy to obtain, after the hydroxylation reaction raw material, and then carry on the five-membered ring double bond of selective oxidation, then oxidation of the double-hydroxyl protection, then ring oxidation six-membered ring double bond, fluorinated after ring opening to remove the carbonyl protecting group [...] easily product. The reaction process is easy to operate, the various steps in the production rate is comparatively high, the higher the purity of the product is obtained also, effectively prevent the formation of by-products, and reducing the production cost, and is favorable for industrial production. (by machine translation)
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Paragraph 0032; 0048; 0049; 0050
(2018/03/24)
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- Investigation of solvolysis kinetics of new synthesized fluocinolone acetonide C-21 esters-an in vitro model for prodrug activation
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In this study the solvolysis of newly synthesized fluocinolone acetonide C-21 esters was analysed in comparison with fluocinonide during a 24-hour period of time. The solvolysis was performed in an ethanol-water (90:10 v/v) mixture using the excess of NaHCO3. The solvolytic mixtures of each investigated ester have been assayed by a RPHPLC method using isocratic elution with methanol-water (75:25 v/v); flow rate 1 mL/min; detection at 238 nm; temperature 25 °C. Solvolytic rate constants were calculated from the obtained data. Geometry optimizations and charges calculations were carried out by Gaussian W03 software. A good correlation (R = 0.9924) was obtained between solvolytic rate constants and the polarity of the C-O2 bond of those esters. The established relation between solvolytic rate constant (K) and lipophilicity (cLogP) with experimental anti-inflammatory activity could be indicative for topical corticosteroid prodrug activation.
- Markovic, Bojan D.,Dobricic, Vladimir D.,Vladimirov, Sote M.,Cudina, Olivera A.,Savic, Vladimir M.,Karljikovic-Rajic, Katarina D.
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scheme or table
p. 2658 - 2671
(2011/05/08)
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- Challenges and difficulties in synthesis of tritium labeled fluocinolone acetonide
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Tritium labeled fluocinolone acetonide was synthesized through five-step procedure. Many challenges and difficulties were encountered in the synthesis, especially in the regeneration of 1,2 double bond from reaction of oxidative de-hydrogenation of tritium labeled 4-ene analog. Selenium oxide oxidative de-hydrogenation of 11,21-dihydroxy un-protected 4-ene fluocinolone acetonide analog gave a complex product mixture. The reaction gave a clean unlabeled intermediate after protection of 21-hydroxy group by acetylation, but the same procedure failed to give desired tritium labeled intermediate due to fast tritium-hydrogen exchange reaction. The de-hydrogenation proceeded well with DDQ in refluxing benzene for unlabeled intermediate, but no reaction at all for the tritium labeled one. Benzeneseleninic anhydride/toluene refluxed with tritium labeled 4-ene analog was found to be the best de-hydrogenation reaction conditions after exploring suitable conditions. Detailed examination of the de-hydrogenation product, 1,4-diene analog by radio-HPLC, HPLC-MS, proton and tritium NMR found that not only had the de-hydrogenation taken place, but also 11-hydroxy group was oxidized to ketone at the same time. This problem was resolved by acetylation protection of both 11,21-dihydoxy groups. De-protection of tritium labeled 11,21-diacetyl 1,4-diene intermediate in K2CO 3/CH3OH/H2O gave expected final product, [1,2-3H]fluocinolone acetonide with a specific activity of 36.8 Ci/mmol (radiochemical purity: 97%) after purification. Copyright
- Zhong, Desong,Lewin, Anita H.
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scheme or table
p. 260 - 265
(2011/05/06)
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- An application of second-order UV-derivative spectrophotometry for study of solvolysis of a novel fluocinolone acetonide ester
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A novel topical corticosteroid FA-21-PhP, 2-phenoxypropionate ester of fluocinolone acetonide, has been synthesized in order to investigate the possibility of decreasing systemic side effects. In this study model system for in vitro solvolytic reaction of FA-21-PhP has been analyzed in ethanol/water (90:10, v/v) with excess of sodium hydrogen carbonate. The selected conditions have been used as in vitro model for activation of corticosteroid C-21 ester prodrug. The second-order derivative spectrophotometric method (DS) using zero-crossing technique was developed for monitoring ternary mixture of solvolysis. Fluocinolone acetonide (FA) as a solvolyte was determined in the mixture in the concentration range 0.062-0.312 mM using amplitude 2D274.96. Experimentally determined LOD value was 0.0295 mM. The accuracy of proposed DS method was confirmed with HPLC referent method. Peak area of parent ester FA-21-PhP was used for solvolysis monitoring to ensure the initial stage of changes. Linear relationship in HPLC assay for parent ester was obtained in the concentration range 0.054-0.54 mM, with experimentally determined LOD value of 0.0041 mM. Investigated solvolytic reaction in the presence of excess of NaHCO3 proceeded via a pseudo-first-order kinetic with significant correlation coefficients 0.9891 and 0.9997 for DS and HPLC, respectively. The values of solvolysis rate constant calculated according to DS and HPLC methods are in good accordance 0.038 and 0.043 h-1, respectively.
- Markovic, Bojan,Vladimirov, Sote,Cudina, Olivera,Savic, Vladimir,Karljikovic-Rajic, Katarina
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experimental part
p. 930 - 935
(2010/04/01)
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- Preparation of high specific activity tritium labeled 6α,9,-difluoro- 11 β,21-dihydroxy- 16α,17-[(1-methylethylidene)bis(oxy)]pregna- 1,4-diene-3,20-one, fluocinolone acetonide
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Fluocinolone acetonide was tritiated by selective reduction of the 1,2-double bond of the O-protected analog under tritium, followed by re-establishment of the 1,2-double bond and deprotection. Protection of both hydroxyl functionalities was required. The product was obtained with specific activity 36.8Ci/mmol. Copyright
- Zhong,Lewin, Anita H.
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body text
p. 103 - 109
(2009/10/24)
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- Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
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Methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.
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- Composition for the topical treatment of poison ivy and other forms of contact dermatitis
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Composition for topical administration comprising (a) a corticosteroid, and (b) a drying agent.
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- Pharmaceutical composition
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This invention relates to a topical, anti-inflammatory, pharmaceutical composition which comprises (a) a pharmaceutically acceptable solvent, e.g. propylene glycol and water, and (b) at least two corticosteroids chosen from those represented by formulas A through K defined hereinafter, each corticosteroid dissolved in said solvent at a concentration equal to the saturation solubility for each steroid. Other suitable pharmaceutical formulation additives may be added to prepare the desired type of formulation, e.g. cream, ointment, lotion, or gel. The invention includes a process for preparing the compositions and a method for treating inflamed skin conditions using the novel compositions.
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