- Magic Bullet! Rebamipide, a Superior Anti-ulcer and Ophthalmic Drug and Its Large-Scale Synthesis in a Single Organic Solvent via Process Intensification Using Krapcho Decarboxylation
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Rebamipide (1) is a superior drug compared to existing drugs for use in healing of peptic ulcers, gastrointestinal bleeding, and dyspepsia. It is also useful as an ophthalmic drug for the treatment of dry eye syndrome. Process intensification for its synthesis was achieved by (i) averting uncontrollable frothing using Krapcho decarboxylation instead of conventional acid hydrolysis, where uncontrollable frothing became chaotic, (ii) minimizing organic waste generation by using a single organic solvent, and (iii) avoiding anti-foaming agents (n-octanol, acetophenone) and acetic acid. With these trifling modifications, the overall yield of active pharmaceutical ingredient (API) was ≥83% with excellent purity (≥99.89%), and the process meets the metrics of "green" chemistry with an E-factor = 11.5. The developed hassle-free commercial process is viable for multi-kilogram synthesis of Rebamipide (1) as the key step, Krapcho decarboxylation is safe to run at 130-140 °C in DMSO, and it was proved to be effective by differential scanning calorimetry thermal screening studies. The characterization data of intermediates, process-related impurities, and API are reported. The carryover and process-related impurities were controlled efficiently. The present work can enhance the scope and worldwide adoptability of Rebamipide (1), which is currently limited to Asian countries.
- Babu, Prashanth Kumar,Bodireddy, Mohan Reddy,Puttaraju, Reshma Choudlu,Vagare, Dnyaneshwar,Nimmakayala, Raghu,Surineni, Naresh,Gajula, Madhusudana Rao,Kumar, Pramod
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Read Online
- Preparation method of rebamipide bulk drug
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The invention discloses a preparation method of a rebamipide bulk drug. The preparation method comprises the following steps: 1, preparing a crude product of the rebamipide bulk drug: preparing the crude product of the rebamipide bulk drug by utilizing a compound III and 4-chlorobenzoyl chloride; and 2, purifying the rebamipide bulk drug. The compound III is prepared from a compound II, deionized water and concentrated hydrochloric acid, the compound II is prepared from a compound I, glacial acetic acid and concentrated hydrochloric acid, and the compound I is prepared from diethyl acetamidomalonate and 4-bromomethylquinolone. A process control method is utilized, impurities in the synthesized compound I, impurities in the synthesized compound II and impurities in the synthesized compound III are respectively subjected to impurity removal and purification by a common purification method, and the purity of the rebamipide bulk drug is improved in combination with a method for crystallizing and purifying the crude product of the rebamipide bulk drug.
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- New process for synthesizing rebamipide
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The invention discloses a novel process for synthesizing rebamipide. The novel process comprises the following steps: adopting glycine methyl ester as a starting raw material, then performing amidation and chlorination to obtain chloroimide intermediate, enabling the chloroimide intermediate to react with bromomethylquinolone, and hydrolyzing to obtain the rebamipide. The novel process has the advantages that the starting raw material is low in price and easy to obtain, the reaction yield is high, the industrialization is easy to realize and the like.
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Paragraph 0013; 0029; 0036-0037; 0038; 0045-0046
(2020/12/30)
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- Green and efficient preparation method of rebamipide
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The invention belongs to the technical field of medical synthesis and in particular relates to a green and efficient preparation method of rebamipide. The synthesis method provided by the invention has a green and simple route and the price of raw materials is low, so that industrial production is easy to realize. The invention further discloses a novel method for preparing aniline from benzoic acid.
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- A synthesis process of fluorinated
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The present invention discloses a process for synthesizing a fluorinated, the specific synthetic process are as follows: ammonia added in a reaction vessel, then drip to the wherein the dripped into the 4 - chlorobenzene chloride, to obtain 4 - chlorobenzene formyl ammonia; format after the reaction will be carried out with the formic acid reaction product 1; the product 1, to carry out addition reaction product 2; then the product 2 with chloro after 4 - chlorobenzene formyl ammonia reaction to obtain the product 3; the product 3 added in a reaction vessel, then adding the mass fraction is 60% sulfuric acid solution, heating to 80 °C stirring reaction 3 h, to obtain the product 2 - (4 - chlorophenyl formamido) - 3 - [2 (1 H) - quinolinone - 4] propionic acid. In the process of synthesis of the present invention through the form reaction, nucleophilic addition and the substitution reaction preparation, the production cost is low, and a high yield of product, synthetic condition is simple, can be suitable for large-scale production.
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- Process for synthesizing rebamipide
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The invention provides a process for synthesizing rebamipide. The process comprises the following steps: taking aminomalonic acid diethyl ester and 4-chlorobenzoyl chloride as raw material substrates so as to prepare an intermediate 4-chlorobenzoyl diethyl aminomalonate; reacting with 4-bromomethylcarbostyril so as to obtain 2-(4-chlorobenzhylamino)-2-ethoxycarbonyl-3-[2(1H)-quinolinone-4-yl] ethyl propionate; and finally, heating and refluxing in a sodium alcoholate solution, concentrating, and re-crystallizing, thereby obtaining the final product. The rebamipide prepared by the process disclosed by the method is high in yield, and the purity can reach 99.2%.
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Paragraph 0028; 0029; 0030
(2017/08/28)
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- COMPOUND, COMPOSITION AND USES THEREOF
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The disclosures herein provide compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII or its pharmaceutical acceptable compositions and salts, as well as polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These compositions or salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of stomach and esophageal problems or its associated complications.
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Paragraph 00169
(2017/03/28)
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- A preparation method of a fluorinated
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The invention discloses a preparation method of high-purity rebamipide. During synthesis process of a rebamipide crude product, the rebamipide crude product is precipitated out, in the form of a rebamipide salt solid, directly from a reaction solution. Thus, effective separation of impurities from a product is realized. A rebamipide salt crude product has good quality and high purity. Without further refining, dissociating is carried out directly by an acid-alkali method so as to obtain a high-purity rebamipide finished product. By the above method to obtain rebamipide, operational steps and refining frequency are minimized, and production efficiency is raised remarkably. In addition, a solvent used is cheap and easily available, and it is beneficial to realize industrial production.
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Paragraph 0005; 0016-0024
(2017/10/12)
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- IMPROVED PROCESS FOR PREPARING REBAMIPIDE
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The invention provides an improved process for preparing rebamipide that is useful as a medicament, which makes it possible to prepare rebamipide with high purity and high yield. The invention is an improved process for preparing rebamipide of the formula (1), comprising subjecting a carbostyril amino acid compound of the formula (5) or a salt thereof containing a compound of the formula (11) as an impurity to a reduction treatment in the presence of hydrogen and a catalyst in a basic aqueous solution, thereby selectively reducing the impurity compound (11) to transform into the carbostyril amino acid compound (5); and then acylating the compound (5) in a basic aqueous solution to give rebamipide (1).
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Page/Page column 11-12
(2010/11/08)
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- PROCESS FOR PRODUCTION OF CARBOSTYRIL COMPOUND
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Disclosed is an improved process which can produce a carbostyril compound of the formula (1) or a salt thereof, which is useful as a pharmaceutical agent, more safely with higher efficiency. An improved process for producing a carbostyril compound comprising the steps of adding a high boiling solvent to a compound of the formula (4) and refluxing the resulting mixture under heating in hydrochloric acid to produce a compound of the formula (5) safely and acylating the compound of the formula (5) to produce a carbostyril compound of the formula (1).
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Page/Page column 11
(2008/06/13)
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- Process for preparing 2-(4-chlorobenzolamino)-3[ (1h)-quinolinon-4-yl] propionic acid
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The invention relates to a novel method for preparing 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid, also known as Rebamipide represented by the formula I and useful for treatment of peptic ulcer from alkyl 2-(4-chlorobenzoylamino)-2-alkoxycarbonyl-3-[2(1H)-quinolinon-4-yl]propionate represented by the formula II in the presence of a base solution for hydrolysis and decarboxylation to remove a carboxyl group.
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- Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (Rebamipide)
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The enantiomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid [(±)-1, rebamipide, OPC-12759], a new antiulcer agent that enhances mucosal resistance, were synthesized from optically active α-amino acid derivatives of 2(1H)-quinolinone. The key intermediates, α-amino acid derivatives, were prepared by asymmetric synthesis and optical resolution. The (±)-1 was ahout 1.7 times as potent as the (-)-isomer in antiulcer activity against ethanol-induced gastric ulcers.
- Otsubo,Morita,Uchida,Yamasaki,Kanbe,Shimizu
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p. 2906 - 2909
(2007/10/02)
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