- Preparation method of metoproprazine intermediate
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The invention belongs to the technical field of preparation of metopromazine intermediates, and particularly relates to a preparation method of a metopromazine intermediate. The method comprises the following steps: (1) taking 2-nitro-4-methylsulfonylthiophenol as a raw material, and carrying out a hydrogenation reduction reaction to obtain 2-amino-4-methylsulfonylthiophenol; and (2) carrying outa C-N/C-S coupling reaction between the 2-amino-4-methylsulfonylthiophenol and o-dichlorobenzene or o-difluorobenzene to generate 2-methylsulfonyl-10H-phenothiazine. In the step (2), ferric salt is used as a catalyst, and N, N, N', N'-tetramethyl-1, 8-naphthalene diamine is used as a ligand. The conditions of the method are mild; and by the use of o-dichlorobenzene or o-difluorobenzene, the cost is low and the method is efficient and environmentally-friendly. Ferric salt is used as a catalyst, so that the problem of heavy metal residues in the drug intermediate is solved, and the catalyst costis reduced.
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Paragraph 0042-0087
(2020/05/02)
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- New process for preparing metopimazine
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The invention discloses a new process for preparing metopimazine. The new process comprises the following steps: in a reactor, using o-fluorothiophenol and 1-chloro-4-(methylsulphonyl)-2-nitrobenzeneas raw materials to react in acetone to obtain 2-(2-fluorophenyl thio)-5-(methylsulfonyl) nitrobenzene; then adding ethanol and ferric chloride for a heating reaction to generate 2-(2-fluorophenyl thio)-5-(methylsulfonyl) aniline; adding dimethyl sulfoxide, adding NaH, heating for reaction, cooling to a room temperature, adding water, and stirring to prepare 2-methylsulfonyl-10H-phenothiazine; then adding 10-acetyl-2-methylsulfoxide-10H phenothiazine and potassium hydroxide to react to prepare 10-acetyl-2-methylsulfonyl-(5-sulfoxide)-10H phenothiazine; adding acetone, carrying out concentration and extraction to obtain a methylene chloride solution of 10-acetyl-2-methylsulfonyl-10H phenothiazine; adding piperidine-4-formamide after the temperature is lowered; adding sodium borohydride acetate; carrying out reaction and filtration; and pulping filter cakes to obtain metopimazine. According to the new process provided by the invention, the final yield is greatly improved by optimizing the reaction route and reaction conditions, and the product purity reaches 99.3% or higher.
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- Synthesis and biological properties of aryl methyl sulfones
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A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 μM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 μM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.
- Navarro, Lorena,Rosell, Gloria,Sánchez, Silvia,Boixareu, Núria,Pors, Klaus,Pouplana, Ramon,Campanera, Josep M.,Pujol, M. Dolors
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p. 4113 - 4126
(2018/07/06)
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- Preparation method of 2-(methyl sulphonyl)-10H-phenothiazine
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The invention relates to a preparation method of 2-(methyl sulphonyl)-10H-phenothiazine and belongs to the technical field of medical intermediate preparation. According to the method, parachlorobenzenesulfonyl chloride and sodium salt of 2-bromothiophenol are taken as starting materials, two novel intermediates M1 and M3 not reported are involved, ideal schemes different from related references are explored in all experimental procedures, and particularly the cyclization process for synthesis of the final product 2-(methyl sulphonyl)-10H-phenothiazine completely breaks through various restrictions in literatures. The method has the advantages that the whole process is simple in step, convenient to operate, mild in reaction condition and easy to control, product yield in all the steps is high and the like, thereby being suitable for industrial production and having high value in use and social and economic benefits.
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