- An unusual dienone-phenol rearrangement product formed during the synthesis of mometasone furoate (Sch 32088).
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The structure of an unusual dienone-phenol rearrangement product 4 obtained during the synthesis of mometasone furoate (Sch 32088) was assigned on the basis of NMR and x-ray crystallographic data. The mechanism of formation is discussed.
- Draper,Puar,Vater,McPhail
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- Preparation method of mometasone furoate
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The invention relates to the technical field of chemical pharmacy, in particular to a preparation method of mometasone furoate. The preparation method comprises the following steps: carrying out a cyanohydrination reaction on a compound I to obtain a compound II, carrying out an alkylation reaction on the compound II to obtain a compound III, carrying out an intramolecular substitution reaction on the compound III to obtain a compound IV, carrying out a furfurylation reaction on the compound IV to obtain a compound V, and finally carrying out a chlorohydroxyl reaction on the compound V to obtain mometasone furoate. The mometasone furoate is obtained by adopting the compound I through the cyanohydrination reaction, the alkylation reaction, the intramolecular substitution reaction, the furfurylation reaction and the chlorohydroxyl reaction, the quality and the yield of the obtained mometasone furoate have obvious competitiveness, the quality yield is high, the purity is high, the purity reaches 99.20% or above, and the content of any impurity is smaller than 0.10%. The preparation method of mometasone furoate provided by the invention adopts the easily prepared compound I as the raw material, and is low in cost, green and environment-friendly.
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- Preparation process of mometasone furoate
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The invention relates to a chemical synthesis method of steroid drugs, in particular to a process for synthesizing mometasone furoate by a one-step method. The preparation method is characterized by comprising the following steps: mixing a compound shown in a formula 1 with liquid chloralkane, adding 4-dimethylaminopyridine under the protection of nitrogen, dropwise adding methylsulfonyl chloride at a temperature of below 5 DEG C, carrying out a stirring reaction to achieve 21-site sulfonation after dropwise adding, heating, refluxing, adding alkali, adding furfuryl chloride at a temperature of below 30 DEG C, carrying out heat preservation reaction at normal temperature, adding acetic acid and hydrochloric acid at a temperature below 25 DEG C, carrying out a 9-11-site epoxy ring-opening reaction at normal temperature, adding water after the ring-opening reaction is completed, extracting, carrying out alkali washing and water washing on an organic phase reaction solution to be neutral, layering, concentrating an organic phase, flushing with methanol/n-hexane to form crystals, and filtering to obtain mometasone furoate. According to the invention, the method effectively overcomes the defects of long original process route, complex reaction system, long consumed time and the like; and the invention provides a simpler synthesis process, which greatly shortens the synthesis route, does not need to separate and purify the compounds shown in the formulas 2 and 3, can reduce the solvent consumption and the drying time, is beneficial to energy conservation and emission reduction, and reduces the production cost.
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Paragraph 0012
(2021/06/26)
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- One-pot technology for synthesizing mometasone furoate (by machine translation)
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The method comprises the following steps S1: adding the compound 8 DM into an organic solvent, adding a chlorination reagent, wherein the organic solvent is an alkyl halide with a carbon number of less 6, and the chlorination reagent is a sulfonyl chloride reagent. S2: Addition of a catalyst, dropping furfuryl chloride, adding an acid solution, combining the chloroalkane layer, cooling down to 5 °C or less dropwise addition of a catalyst, and the catalyst was an organic base type reaction temperature -20 °C to 20 °C. The reaction is ended. S3: The chloroalkane layer is added with mixed liquid of concentrated hydrochloric acid and glacial acetic acid, and static layering is carried out to obtain the target product mometasone furoate. The whole reaction process is completed in one system, the quality and yield of the whole reaction process are 99.5% or more, the HPLC content of the product is less than 0.10%, and the yield 115% or more. (by machine translation)
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Paragraph 0022; 0024; 0028; 0029; 0033; 0034; 0038; 0039-004
(2020/12/31)
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- Steroid 21-hydroxyl chlorination or bromination method
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The invention discloses a steroid 21-hydroxyl chlorination or bromination method. A compound shown as formula A is adopted as the start material, and in the presence of SO2, reaction with a chlorination or bromination reagent is carried out to prepare a compound shown as formula B. The method provided by the invention has the characteristics of mild process conditions, environmental friendliness,easily available reagents, easy operation, low cost and high yield, and is suitable for industrial mass production.
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Paragraph 0054-0056
(2019/01/24)
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- Preparation method of mometasone furoate
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The invention provides a preparation method of mometasone furoate. The method includes: 1) chlorination reaction: in the presence of SO2, reacting a compound 1 with a chlorination reagent to generatea compound 2, wherein the chlorination reagent is selected from one or more of acetyl chloride, propionyl chloride, benzoyl chloride, lithium chloride, carbon tetrachloride, chlorosuccinimide and dichloro dimethylhydantoin; 2) furoylaction reaction: reacting the compound 2 with furoyl chloride to obtain a compound 3; and 3) ring-opening reaction: in the presence of hydrochloric acid, subjecting the compound 3 to ring-opening reaction so as to obtain mometasone furoate. The invention has the beneficial effects that: the steroid 21-hydroxyl chlorination method has the advantages of mild reactionconditions, environmental friendliness, easy operation, low cost and high yield. The new technology adopted by the invention has greater industrialization value, can effectively control side reactions and improve the reaction yield and quality. The process design does not involve high-risk reaction, and is easy to realize industrialization; high-pollution reaction does not exist, and the environmental protection treatment pressure is alleviated.
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Paragraph 0057-0063
(2019/01/24)
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- Method for preparing mometasone furoate
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The invention provides a method for preparing mometasone furoate avoiding introducing potential genotoxic impurities. According to the method, the condition is mild, and the molar yield of the whole route can be over 80 percent.
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Paragraph 0039; 0040; 0043; 0044
(2019/01/20)
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- Method for synthesizing mometasone furoate or monohydrate of mometasone furoate
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The invention belongs to a synthesizing method for medicine, and particularly relates to a method for synthesizing mometasone furoate or a monohydrate of the mometasone furoate. The method includes the steps that 8-DM serving as a first compound is used as an initial material, and the first compound and paratoluensulfonyl chloride are subjected to a sulfonylation reaction to generate a second compound; the second compound is not subjected to after-treatment and is subjected to a chlorination reaction with RCl (R is Li, Na, K and Et3N) to generate a third compound; the third compound is not subjected to after-treatment, a part of organic alkali is replenished, and the mixture and furoyl chloride are subjected to an esterification reaction to generate a fourth compound; the fourth compound is not subjected to after-treatment, acid adjustment is carried out, a large quantity of chlorine elements existing in a reaction system are used for a ring-opening reaction, and the mometasone furoate or the mometasone-furoate monohydrate is obtained. The method is simple in technology, mild in reaction condition, high in yield, low in cost, high in quality and raw-auxiliary-material using rate, free of genetic toxicity impurity generation and suitable for industrial production.
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Paragraph 0048-0053
(2017/05/05)
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- Method for synthesizing mometasone furoate
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The invention belongs to synthetic methods of medicines, and in particular relates to a method for synthesizing mometasone furoate. According to the method, chlorination is carried out to obtain a compound 2 while an esterification reaction is carried out between a compound 1 and furoyl chloride, and ring opening operation is carried out on the compound 2 in the presence of hydrochloric acid to generate mometasone furoate. According to the method, the defects of long process route, complex reaction system, long consumed time and the like of the original process are effectively overcome. The method provided by the invention is simple in process, mild in reaction condition, high in yield, low in cost, high in quality, and low-price and easily-available in raw and auxiliary materials, and is suitable for industrial production.
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Paragraph 0019
(2016/10/31)
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- 8DM derivative, and method for synthesizing mometasone furoate from 8DM derivative
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The invention relates to a 8DM derivative, and a method for synthesizing mometasone furoate from the 8DM derivative. The method comprises the following steps: carrying out an esterification reaction on a compound 1 and furoyl chloride to generate a compound 2 which is the 8DM derivative, and simultaneously carrying out a ring opening reaction and a 21th position chlorination reaction on the compound 2 in the presence of concentrated hydrochloric acid to generate a compound 3 which is mometasone furoate. The disadvantages of long route, complex reaction system and long time of original technologies are effectively solved in the invention. The method has the advantages of simple process, mild reaction conditions, high yield, low cost, high quality, cheap and easily available raw and auxiliary materials, and suitableness for industrial production.
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Paragraph 0021; 0053; 0054; 0055
(2016/10/10)
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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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- Unusual hydroxy-γ-sultone byproducts of steroid 21- methanesulfonylation. An efficient synthesis of mometasone 17-furoate (Sch 32088)
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An efficient two stage synthesis of the steroid anti-inflammatory agent mometasone 17-furoate (Sch 32088) 4 from 17α,21-dihydroxy-16α-methyl- 9β,11β-oxidopregna-1,4-diene-3,20-dione 6 is described and the structures of unusual δ-hydroxy-γ-sultone byproducts of 4-dimethylaminopyridine catalyzed methanesulfonylation of 21-hydroxy-20-ketosteroids are deduced.
- Draper, Richard W.,Bin, Hu,McPhail, Andrew T.,Puar, Mohindar S.,Vater, Eugene J.,Weber, Lois
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p. 3355 - 3364
(2007/10/03)
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- An unusual rearrangement product formed during production of mometasone furoate (Sch 32088)
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The structure of an unusual rearrangement product obtained during the production of mometasone furoate (Sch 32088) was assigned on the basis of NMR and X-ray crystallography data. - Keywords: mometasone furoate; rearrangement product; mechanism; NMR data; X-ray
- Puar, M. S.,Thompson, P. A.,Ruggeri, M.,Beiner, D.,McPhail, A. T.
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p. 612 - 614
(2007/10/02)
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- 17-Heteroaroyl Esters of Corticosteroids. 2. 11β-Hydroxy Series
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The preparation and topical antiinflammatory potencies of a series of 17-furoyl and -thenoyl esters of 9α-fluoro-11β-hydroxy-16-methyl and 9α-chloro-11β-hydroxy-16-methyl corticosteroids are described.The 17α-esters were introduced to the 9α-fluoro 11-ketones or the appropriate Δ9(11) compounds by direct acylation with the appropriate heteroaryl carbonyl chloride in the presence of 4-(dimethylamino)pyridine.Functionalization of the C ring was completed by standard methods.The most extensively studied heterocyclic acyl group was 2-furoyl, but 3-furoyl and 2- and 3-thienoyl derivatives were also investigated.Antiinflammatory potencies were measured in mice by a 5-day modification of the Tonelli croton oil ear assay.The most potent topical antiinflammatory agents were 1e, dexamethasone 17-(2'-furoate)-21-propionate, and 2c, the 21-chloro 17-(2'-furoate) in the 9α-chloro series, both being 6 times as potent as betamethasone 17-valerate.Several other 9α-chloro-11β-hydroxy-17-heteroaryl carboxylates (2a, 2b, 2d and 2g) were at least 4 times as potent as betamethasone 17-valerate.Evaluation of 2c in the clinic confirmed that the compound is a potent topical antiinflammatory agent in humans.
- Shapiro, Elliot L.,Gentles, Margaret J.,Tiberi, Robert L.,Popper, Thomas L.,Berkenkopf, Joseph,et al.
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p. 1581 - 1588
(2007/10/02)
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