WO2006059781A1 - Improved process for preparing rebamipide - Google Patents
Improved process for preparing rebamipide Download PDFInfo
- Publication number
- WO2006059781A1 WO2006059781A1 PCT/JP2005/022412 JP2005022412W WO2006059781A1 WO 2006059781 A1 WO2006059781 A1 WO 2006059781A1 JP 2005022412 W JP2005022412 W JP 2005022412W WO 2006059781 A1 WO2006059781 A1 WO 2006059781A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- rebamipide
- carbostyril
- amino acid
- impurity
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/74—Iron group metals
- B01J23/755—Nickel
Definitions
- the invention relates to an improved process for preparing rebamipide that is useful as a medicament for treating gastric ulcer and the like, which makes it possible to prepare rebamipide with high purity and high yield.
- Rebamipide which means a carbostyril compound (chemical name: 2- (4-chlorobenzoylamino) -3- [2 (IH) -quinolon- 4-yl]propionic acid) of the following formula (1), is a medicament that has a potent effect on the treatment of gastric ulcer, acute gastritis, or gastric mucosa lesion affected in acute exacerbation of chronic gastritis.
- carbostyril compound chemical name: 2- (4-chlorobenzoylamino) -3- [2 (IH) -quinolon- 4-yl]propionic acid
- bromomethyl carbostyril (2) is reacted with diethylacetamide malonate (3) in the presence of a base such as sodium ethoxide to give carbostyril malonate compound (4) ; the compound (4) is hydrolyzed and decarboxylated in the presence of a mineral acid such as hydrochloric acid to prepare carbostyril amino acid compound (5) ; and then the compound (5) is acylated with 4-chlorobenzoyl chloride (6) to prepare the desired rebamipide of the formula (1) .
- bromomethyl carbostyril (2) can be prepared, for example, as shown in the following scheme 2: That is, acetoacetanilide (7) is brominated with bromine, N- bromosuccinimide, or the like to give a compound of the formula (8) ; and then the compound (8) is ring-closed with a condensing agent such as concentrated sulfuric acid to prepare the compound (2) .
- the product (2) contains 6- bromocarbostyril compound of the following formula (9) as an impurity, which is one of by-products produced from the above bromination.
- 6-bromocarbostyril compound (9) is reacted in the same behavior of the bromomethyl carbostyril (2), as shown in the following scheme 3, to give the corresponding 6-bromo compound of the formula (12) via the corresponding compounds of the formula (10) and formula (11), and thereby the impurity (12) is contained in the desired rebamipide
- the method of removing the contaminated impurity 6-bromocarbostyril compound (9) from the bromomethyl carbostyril (2) includes, for example, recrystallizing from various solvents and dispersing/washing with various solvents; however, such methods do not provide any sufficient effect of the removal. Also, for example, using N,N-dimethyl formamide, N,N-dimethyl acetamide, l-methyl-2- pyrrolidone and the like, a certain effect of the removal will be observed; however, in this case the bromomethyl carbostyril (2) will be lost a lot due to transference into the filtrate. Accordingly, such method is also not useful in fact.
- the present inventors have extensively studied which step in the procedure is effective to remove the contaminated impurity ⁇ -bromo compound, and have found that the desired rebamipide could be prepared with high purity and high yield by subjecting the carbostyril amino acid compound (5) containing the 6-bromocarbostyril amino acid compound (11) as an impurity to a reduction treatment just before converting compound (5) into the desired rebamipide by the acylation, thereby selectively reducing only the compound (11) to transform into the useful carbostyril amino acid compound (5) ; and then acylating the produced compound (5) . Based upon the new findings, the present invention has been completed.
- An object of the present invention is to provide an improved process for preparing rebamipide that is useful as a medicament, which makes it possible to prepare rebamipide with ease, high purity and high yield.
- the desired rebamipide (1) can be prepared by subjecting the carbostyril amino acid compound (5) or the salt thereof containing the 6-bromocarbostyril amino acid compound (11) as an impurity to a reduction treatment in the presence of hydrogen and a catalyst in a basic aqueous solution, thereby selectively reducing only the impurity compound (11) to transform into the carbostyril amino acid compound (5) ; and then acylating the carbostyril amino acid compound (5) with 4-chlorobenzoyl chloride in a basic aqueous solution.
- the method of the invention is shown in the following scheme 4.
- the process of the invention is not a conventional method of removing impurities such as recrystallization using a solvent, dispersing/washing, and column chromatography; but a purification method through reduction wherein the desired compound itself is not reduced, but the impurity contained in the desired compound is reduced to be transformed into the desired compound; and thereby the purity of the product is enhanced.
- the desired rebamipide can be prepared in higher yield.
- the example of a salt of the carbostyril amino acid compound (5) containing the 6-bromocarbostyril amino acid compound (H) as an impurity, used herein, includes a mineral acid salt such as hydrochloride, sulfate, hydrobromide and the like; and an alkali metal salt such as sodium salt, lithium salt and the like.
- a mineral acid salt such as hydrochloride, sulfate, hydrobromide and the like
- an alkali metal salt such as sodium salt, lithium salt and the like.
- water and a basic compound is added to the carbostyril amino acid compound
- the water added herein is generally about 5-50 parts by weight to 1 part by weight of the carbostyril amino acid compound (5) or a salt thereof containing the impurity.
- the examples of the basic compound which is added to basify the aqueous solution include, for example, a mineral basic compound such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and lithium carbonate, which is preferably added so that the pH of the aqueous solution may exhibit below 14.
- a mineral basic compound such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and lithium carbonate
- the carbostyril amino acid compound (5) containing the impurity is transformed into a metal salt thereof with, for example, sodium salt, potassium salt, and lithium salt, then it is not necessary to add an additional basic compound due to the basicity of the aqueous solution.
- the examples of the catalyst in the invention which is used to subject the impurity 6-bromocarbostyril amino acid compound (11) to the selective reduction include palladium catalysts and nickel catalysts, preferably Raney nickel catalyst.
- the amount of the used catalyst is generally about 0.01-0.50 parts, preferably about 0.02-0.20 parts by weight to 1 part by weight of the carbostyril amino acid compound (5) or a salt thereof containing the impurity.
- the reduction of the invention is carried out generally at atmospheric pressure to 10 atm, preferably at atmospheric pressure to 4 atm, and generally at 0-40 0 C, preferably at 10-30 0 C. This reduction will be effectively advanced if using stirring.
- the catalyst is removed off, a filtrated basic solution of the carbostyril amino acid compound (5) is reacted with 4-chlorobenzoyl chloride to give the desired rebamipide (1) .
- the above reaction can be easily carried out according to a conventional method, for example, via Schotten-Baumann reaction.
- the amount of 4-chlorobenzoyl chloride used in the above acylation is an equimolar, preferably an equimolar to 2 moles, to 1 mole of the carbostyril amino acid compound (5) .
- an additional basic compound for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like
- 4-chlorobenzoyl chloride itself or a solution of 4-chlorobenzoyl chloride in an organic solvent such as acetone, acetonitrile, and ethyl acetate is added, and the resulting reaction can be carried out at about -10 0 C to 100 0 C, preferably about 0 0 C to 36°C, for about 5 minutes to 15 hours.
- Example 1 Example 1
- the invention provides a highly effective purification method without loss of the desired compound, by converting the contaminated impurity 6-bromo compound, which is hardly removed by a conventional purification method, into the desired compound by selective reduction thereof and thereby the purity of the whole desired compound can be enhanced. Accordingly, the method of the invention might be advantageously used in the industrial process for preparing rebamipide to be used as a medicament in which higher purity is required.
- the desired compound can easily be produced on industrial scale by easy operation since water may be used as a solvent for the reduction and the reaction may be carried out under a mild condition for relatively short time. Furthermore, after completion of the reduction in the former step, the basic aqueous solution obtained by removing the catalyst can be used in the next acylation step without further treatment, and hence the invention will be so useful to produce the desired rebamipide with high yield on large scale.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006546720A JP3911008B2 (en) | 2004-12-01 | 2005-11-30 | Improved production of rebamipide |
US10/587,509 US7718805B2 (en) | 2004-12-01 | 2005-11-30 | Process for preparing rebamipide |
KR1020067015793A KR101098116B1 (en) | 2004-12-01 | 2005-11-30 | Improved process for preparing rebamipide |
IL177039A IL177039A (en) | 2004-12-01 | 2006-07-23 | Process for preparing rebamipide |
HK07106485.2A HK1099298A1 (en) | 2004-12-01 | 2007-06-15 | Improved process for preparing rebamipide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004-348425 | 2004-12-01 | ||
JP2004348425 | 2004-12-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006059781A1 true WO2006059781A1 (en) | 2006-06-08 |
Family
ID=35788485
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/022412 WO2006059781A1 (en) | 2004-12-01 | 2005-11-30 | Improved process for preparing rebamipide |
Country Status (7)
Country | Link |
---|---|
US (1) | US7718805B2 (en) |
JP (1) | JP3911008B2 (en) |
KR (1) | KR101098116B1 (en) |
CN (1) | CN100537541C (en) |
HK (1) | HK1099298A1 (en) |
IL (1) | IL177039A (en) |
WO (1) | WO2006059781A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101870674B (en) * | 2009-04-21 | 2012-04-18 | 陕西大生化学科技有限公司 | Improved preparation method of rebamipide intermediate |
WO2014003424A1 (en) * | 2012-06-26 | 2014-01-03 | 삼진제약 주식회사 | Novel rebamipide prodrug, method for producing same, and usage thereof |
WO2016108319A1 (en) * | 2015-01-02 | 2016-07-07 | 삼진제약 주식회사 | Novel rebamipide prodrug salt and use thereof |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101032600B1 (en) | 2008-08-11 | 2011-05-06 | 동우신테크 주식회사 | Process for preparing highly pure Rebamipide |
CN102174015B (en) * | 2011-03-07 | 2013-10-16 | 江西同和药业有限责任公司 | Refining method of rebamipide |
CN103113294B (en) * | 2013-03-11 | 2016-04-27 | 浙江远力健药业有限责任公司 | The synthetic method of rebamipide |
CN104262346B (en) * | 2014-09-17 | 2016-06-08 | 广东众生药业股份有限公司 | A kind of preparation method of bromfenac sodium dimer impurity |
KR20170094584A (en) * | 2016-02-11 | 2017-08-21 | 삼진제약주식회사 | Oral pharmaceutical composition for prevention or treatment of immune disease and metabolic disease comprising rebamipide prodrug |
CN113248429A (en) * | 2021-06-01 | 2021-08-13 | 千辉药业(安徽)有限责任公司 | Preparation method of rebamipide bulk drug |
CN115028579B (en) * | 2022-06-21 | 2023-07-18 | 福建海西新药创制股份有限公司 | Synthesis method of rebamipide bulk drug |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6019767A (en) * | 1983-07-11 | 1985-01-31 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4578381A (en) * | 1982-07-05 | 1986-03-25 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
JP2820739B2 (en) | 1989-10-28 | 1998-11-05 | 大塚製薬株式会社 | Method for producing carbostyril derivatives |
JP3145468B2 (en) | 1992-02-27 | 2001-03-12 | マニー株式会社 | Lower die mounting structure in caulking device |
KR100669823B1 (en) * | 2001-02-20 | 2007-01-17 | 경동제약 주식회사 | Process for Preparing 2-4-Chlorobenzoylamino-3-[21?- quinolinon-4-yl]propionic acid and intermediate thereof |
KR100766578B1 (en) | 2001-12-18 | 2007-10-11 | 동화약품공업주식회사 | A process for preparing rebamipide |
KR100520184B1 (en) | 2002-10-11 | 2005-10-10 | 한미약품 주식회사 | Improved method for the preparation of rebamipide |
-
2005
- 2005-11-30 JP JP2006546720A patent/JP3911008B2/en active Active
- 2005-11-30 CN CNB2005800057780A patent/CN100537541C/en not_active Expired - Fee Related
- 2005-11-30 WO PCT/JP2005/022412 patent/WO2006059781A1/en active Application Filing
- 2005-11-30 US US10/587,509 patent/US7718805B2/en not_active Expired - Fee Related
- 2005-11-30 KR KR1020067015793A patent/KR101098116B1/en active IP Right Grant
-
2006
- 2006-07-23 IL IL177039A patent/IL177039A/en not_active IP Right Cessation
-
2007
- 2007-06-15 HK HK07106485.2A patent/HK1099298A1/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6019767A (en) * | 1983-07-11 | 1985-01-31 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
Non-Patent Citations (3)
Title |
---|
MINORU UCHIDA ET AL.: "Studies on 2(1H)-quinolinone derivatives as gastric acid antiulcer active agents", CHEM. PHARM. BULL., vol. 33, no. 9, 1985, pages 3775 - 3786, XP001208323 * |
PATENT ABSTRACTS OF JAPAN vol. 009, no. 134 (C - 285) 8 June 1985 (1985-06-08) * |
R. G. CHUDGAR; K. N. TRIVEDI: "Studies in the synthesis of quinoline derivatives: Part I: Synthesis of bromoquinolines", J. INDIAN CHEM. SOC., vol. 46, no. 6, 1969, pages 537 - 540, XP009062194 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101870674B (en) * | 2009-04-21 | 2012-04-18 | 陕西大生化学科技有限公司 | Improved preparation method of rebamipide intermediate |
WO2014003424A1 (en) * | 2012-06-26 | 2014-01-03 | 삼진제약 주식회사 | Novel rebamipide prodrug, method for producing same, and usage thereof |
CN104662004A (en) * | 2012-06-26 | 2015-05-27 | 三进制药株式会社 | Novel rebamipide prodrug, method for producing same, and usage thereof |
EP2865669A4 (en) * | 2012-06-26 | 2015-12-02 | Samjin Pharm Co Ltd | Novel rebamipide prodrug, method for producing same, and usage thereof |
AU2013281442B2 (en) * | 2012-06-26 | 2016-09-15 | Astech. Co., Ltd. | Novel rebamipide prodrug, method for producing same, and usage thereof |
CN104662004B (en) * | 2012-06-26 | 2017-04-19 | 三进制药株式会社 | Novel rebamipide prodrug, method for producing same, and usage thereof |
US11420963B2 (en) | 2012-06-26 | 2022-08-23 | Samjin Pharmaceutical Co., Ltd. | Rebamipide prodrugs, preparation method and use thereof |
WO2016108319A1 (en) * | 2015-01-02 | 2016-07-07 | 삼진제약 주식회사 | Novel rebamipide prodrug salt and use thereof |
Also Published As
Publication number | Publication date |
---|---|
CN1922145A (en) | 2007-02-28 |
KR20070085057A (en) | 2007-08-27 |
JP2007503476A (en) | 2007-02-22 |
US20070249835A1 (en) | 2007-10-25 |
JP3911008B2 (en) | 2007-05-09 |
US7718805B2 (en) | 2010-05-18 |
CN100537541C (en) | 2009-09-09 |
IL177039A0 (en) | 2006-12-10 |
KR101098116B1 (en) | 2011-12-26 |
IL177039A (en) | 2011-03-31 |
HK1099298A1 (en) | 2007-08-10 |
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