WO2006051079A1 - Process for preparing itopride hydrochloride - Google Patents
Process for preparing itopride hydrochloride Download PDFInfo
- Publication number
- WO2006051079A1 WO2006051079A1 PCT/EP2005/055839 EP2005055839W WO2006051079A1 WO 2006051079 A1 WO2006051079 A1 WO 2006051079A1 EP 2005055839 W EP2005055839 W EP 2005055839W WO 2006051079 A1 WO2006051079 A1 WO 2006051079A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dimethylaminoethoxy
- itopride
- hydrochloride
- benzylamine
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 0 C*CCOc1ccc(C*c(cc2)cc(OC)c2OC)cc1 Chemical compound C*CCOc1ccc(C*c(cc2)cc(OC)c2OC)cc1 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
Definitions
- the present invention relates to a process for preparing itopride hydrochloride.
- Itopride hydrochloride characterized by the following formula
- This process has a drawback caused by the use, in the reducing step of the oxime to the corresponding amine, of hydrogen, in other words a highly explosive gas and moreover at high pressure (50 kg/cm 2 ) for which expensive equipment (autoclaves and hydrogen lines) must be used.
- the process of the present invention differs mainly for the use in reducing step of 4-(2-dimethylaminoethoxy)-benzaldoxime to 4-(2- dimethylaminoethoxy)-benzylamine of powdered Zinc as reducing agent.
- e) salifying itopride with hydrochloric acid to obtain itopride hydrochloride is characterized in that in the reducing step (c) of 4-(2-dimethylaminoethoxy)- benzaldoxime hydrochloride to 4-(2-dimethylaminoethoxy)-benzylamine powdered Zinc is used as reducing agent.
- the reducing reaction is preferably carried out in an acidic aqueous solution of an organic acid, preferably concentrated acetic acid, more preferably 80% in weight. According to a particularly preferred solution, the reducing reaction (c) is carried out directly on the reaction mixture obtained from step (b) and not on the previously isolated benzaldoxime.
- EP306827 where the reducing reaction is carried out on the previously isolated benzaldoxime.
- 4-(2-dimethylaminoethoxy)-benzylamine obtained from reducing reaction (c) is salified with hydrochloric acid to obtain the corresponding dihydrochloride salt.
- the benzylamine is isolated from the impurities and by-products obtained in the reducing reaction, to obtain an HPLC purity higher than 98%.
- the itopride in step (d) is obtained with high purity; therefore, not only is it no longer necessary to purify it through crystallization prior to salification, but wet itopride separated by means of simple centrifugation of the reaction mixture obtained from step (d) of the process of the invention, is actually used as starting reactant during salification step (c).
- Another preferred embodiment of the process forming the subject of the present invention is based on the fact that in the salification reaction of itopride, to obtain the corresponding itopride hydrochloride, concentrated aqueous hydrochloric acid (37%) in an alcohol solvent, preferably sec-butanol, is used instead of gaseous hydrochloric acid dissolved in an alcohol solvent.
- an alcohol solvent preferably sec-butanol
- a further subject of the present invention is a salification process of itopride with hydrochloric acid characterized in that concentrated aqueous hydrochloric acid is used in an alcohol solution, in which the alcohol is preferably sec-butanol.
- Step (a) is preferably carried out in phase transfer in the presence of a catalyst consisting of a quaternary ammonium salt.
- step (a) a mixture of ethyl acetate, toluene and water is used as the solvent and the quaternary ammonium salt is tetrabutylammonium bromide.
- EXAMPLE 1 Preparation of 4-(2-dimethylaminoethoxy)benzaldehyde 17.5 kg of 2-dimethylaminoethylchloride hydrochloride, 75 kg of deionized water and 2.50 kg of toluene are charged into a batch, 17.5 kg of 30% sodium hydroxide are then dropped into. The mixture obtained is kept under stirring until complete solution of the solid. The aqueous phase is removed while the organic phase is used for the following preparation.
- This mixture is kept under stirring at 45-50°C for at least 5 hours, and then heated to 65-70°C for at least 2 hours. Upon completion of the reaction, the reaction mixture is distilled to obtain a dense but stirrable residue.
- EXAMPLE 3 Preparation of 4-(2-dimethylaminoethoxy)benzylamine dihydrochloride 1 1.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine dissolved in sec-butanol and DMF obtained as described in the previous example are charged into a reactor and 12.7 kg of 37% hydrochloric acid are added dropwise. The pH is checked to ensure it is ⁇ 1.0 and the precipitated mixture is stirred at 45-50°C for at least 30 minutes. The mixture is cooled to 0-5°C, centrifuged and the precipitate washed with 1 1.5 kg of sec-butanol. It is dried under vacuum at 70-80°C.
- reaction mixture After adding the reaction mixture dropwise, the reaction mixture thus obtained is stirred at 75-80°C for at least two hours.
- 40.5 kg of deionized water are added, 1 1.5 kg of 30% ammonia are added dropwise and the reaction mixture is taken to 55-60°C until complete solution.
- the aqueous phase is separated and removed.
- 27.0 kg of deionized water are added and the mixture is cooled to 40-45 °C until obtaining a good degree of precipitation.
- the mixture is then centrifuged, the precipitate is washed with 10.1 kg of deionized water and the same quantity of toluene.
- a sample of product is taken and the loss of weight determined; this analysis shows that the wet product contains 16 kg of dry itopride.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Process for preparing itopride hydrochloride comprising: a) Reacting 4-hydroxybenzaldehyde with 2-dimethylaminoethyl chloride in the 5 presence of a weak inorganic base to obtain 4-(2-dimethylaminoethoxy)- benzaldehyde, b) Reacting 4-(2-dimethylaminoethoxy)-benzaldehyde with hydroxylamine hydrochloride in an acid environment to obtain 4-(2-dimethylaminoethoxy)- benzaldoxime hydrochloride, 10 c) Reacting of 4-(2-dimethylaminoethoxy)-benzaldoxime hydrochloride in the presence a reducing agent to 4-(2-dimethylaminoethoxy)-benzylamine, d) Reacting 4-(2-dimethylaminoethoxy)-benzylamine with veratric acid chloride in the presence of a tertiary amine to obtain itopride, e) Salifying itopride with hydrochloric acid to obtain itopride hydrochloride, 15 characterized in that the reducing agent employed in step (c) is powdered zinc.
Description
PROCESS FOR PREPARING ITOPRIDE HYDROCHLORIDE Field of the invention
The present invention relates to a process for preparing itopride hydrochloride. State of the art Itopride hydrochloride, characterized by the following formula
.HCI
is a drug capable of activating motor function.
In EP306827 the relative synthesis is described, involving the following steps: 4- hydroxybenzaldehyde is reacted with 2-dimethylaminoethyl chloride in the presence of a weak inorganic base to obtain 4-(2-dimethylaminoethoxy)- benzaldehyde, which is reacted with hydroxylamine hydrochloride to obtain 4-(2- dimethylaminoethoxy)-benzaldoxime, subsequently reduced by catalytic hydrogenation, in particular using Nickel Raney, to 4-(2-dimethylaminoethoxy)- benzylamine, which is subsequently reacted with veratric acid chloride in the presence of a tertiary amine to obtain itopride, which is then salified with an ethanol solution in which gaseous hydrochloric acid is dissolved. This process has a drawback caused by the use, in the reducing step of the oxime to the corresponding amine, of hydrogen, in other words a highly explosive gas and moreover at high pressure (50 kg/cm 2 ) for which expensive equipment (autoclaves and hydrogen lines) must be used.
Moreover it is necessary to use a costly and easily flammable catalyst like Nickel Raney, which moreover is highly polluting, and therefore its disposal requires costly and laborious processes for the treatment of waste water.
Summary of the invention
The Applicant has now found that with the process forming the object of the present invention the aforesaid drawbacks can be overcome.
In particular, the process of the present invention differs mainly for the use in reducing step of 4-(2-dimethylaminoethoxy)-benzaldoxime to 4-(2- dimethylaminoethoxy)-benzylamine of powdered Zinc as reducing agent.
Detailed description of the invention
In particular, the process according to the present invention which comprises the following steps: a) Reacting 4-hydroxy-benzaldehyde
c) reducing 4-(2-dimethylaminoethoxy)-benzaldoxime hydrochloride in the presence of a reducing agent to 4-(2-dimethylaminoethoxy)-benzylamine
d) reacting 4-(2-dimethylaminoethoxy)-benzylamine with veratric acid chloride to obtain itopride
e) salifying itopride with hydrochloric acid to obtain itopride hydrochloride, is characterized in that in the reducing step (c) of 4-(2-dimethylaminoethoxy)- benzaldoxime hydrochloride to 4-(2-dimethylaminoethoxy)-benzylamine powdered Zinc is used as reducing agent.
The reducing reaction is preferably carried out in an acidic aqueous solution of an organic acid, preferably concentrated acetic acid, more preferably 80% in weight. According to a particularly preferred solution, the reducing reaction (c) is carried out directly on the reaction mixture obtained from step (b) and not on the previously isolated benzaldoxime.
This represents a further advantage compared to the process described in
EP306827 where the reducing reaction is carried out on the previously isolated benzaldoxime.
Preferably, 4-(2-dimethylaminoethoxy)-benzylamine obtained from reducing reaction (c) is salified with hydrochloric acid to obtain the corresponding dihydrochloride salt. In this way the benzylamine is isolated from the impurities and by-products obtained in the reducing reaction, to obtain an HPLC purity higher than 98%. In this way and unlike the case of the process described in EP306827, the itopride in step (d) is obtained with high purity; therefore, not only is it no longer necessary to purify it through crystallization prior to salification, but wet itopride separated by means of simple centrifugation of the reaction mixture obtained from step (d) of the process of the invention, is actually used as starting reactant during salification step (c). Another preferred embodiment of the process forming the subject of the present invention is based on the fact that in the salification reaction of itopride, to obtain the corresponding itopride hydrochloride, concentrated aqueous hydrochloric acid (37%) in an alcohol solvent, preferably sec-butanol, is used instead of gaseous hydrochloric acid dissolved in an alcohol solvent. In fact, with this type of salification, a product is obtained with a purity higher than 99.8% and which therefore does not require further purification by means of crystallization which cause inevitable decreases of the reaction yield. Therefore, a further subject of the present invention is a salification process of itopride with hydrochloric acid characterized in that concentrated aqueous hydrochloric acid is used in an alcohol solution, in which the alcohol is preferably sec-butanol.
Step (a) is preferably carried out in phase transfer in the presence of a catalyst consisting of a quaternary ammonium salt.
Even more preferably, in step (a) a mixture of ethyl acetate, toluene and water is used as the solvent and the quaternary ammonium salt is tetrabutylammonium bromide.
The following examples of the process to prepare itopride hydrochloride and the relative intermediates according to the present invention are indicated for illustrative and non-limiting purposes. EXAMPLE 1 - Preparation of 4-(2-dimethylaminoethoxy)benzaldehyde 17.5 kg of 2-dimethylaminoethylchloride hydrochloride, 75 kg of deionized water and 2.50 kg of toluene are charged into a batch, 17.5 kg of 30% sodium hydroxide are then dropped into. The mixture obtained is kept under stirring until complete solution of the solid. The aqueous phase is removed while the organic phase is used for the following preparation. 10 kg of 4-hydroxy-benzaldehyde, 12.5 kg of potassium carbonate, 0.27 kg of tetrabutylammonium bromide and 70 kg of ethyl acetate are charged into a reactor. The mixture obtained is heated under reflux and then the aforesaid toluene solution is added dropwise. The mixture is kept under stirring and reflux for at least 5 hours. 50 kg of deionized water are then added, the mixture obtained is stirred for at least 5 minutes, the aqueous phase is removed and the organic phase is distilled, to obtain an oily residue. The residue is cooled to 20-30°C and 35 kg of 80% acetic acid are added dropwise. The reaction mixture is then stirred for 5 minutes until complete solution. A solution containing 13.5 kg of 4-(2-dimethylaminoethoxy)-benzaldehyde is obtained. Reaction yield referred to 4-hydroxybenzaldehyde: 85.33% EXAMPLE 2 - Preparation of 4-(2-dimethylaminoethoxy)-benzylamine 27 kg of 80% acetic acid are charged into a reactor, 5.3 kg of hydroxylamine hydrochloride are added, the mixture is cooled to 0-5 °C and the solution prepared in the previous step containing 13.5 kg of 100% 4-(2-dimethylaminoethoxy)- benzaldehyde in acetic solution is added. The reaction mixture is kept at 0-5°C for at least 2 hours.
When the reaction is complete, 10.8 kg of powdered zinc are added in portions, allowing the temperature to rise up to a maximum of 50 °C.
This mixture is kept under stirring at 45-50°C for at least 5 hours, and then heated to 65-70°C for at least 2 hours. Upon completion of the reaction, the reaction mixture is distilled to obtain a dense but stirrable residue.
20.3 kg of deionized water are then added to the residue thus treated, the mixture thus obtained is cooled to 20-30°C and 54 kg of 30% ammonia are added dropwise. The reaction mixture is then stirred at 20-30°C for at least 10 minutes, the pH is checked to ensure it is above 9.5. The reaction mixture is then extracted at 20-25 °C with 40.5 kg of methylene chloride. The organic phase is separated while the aqueous phase is reextracted with 27 kg of methylene chloride and the mixture is stirred for at least 5 minutes; the organic phase is added to the previous organic phase. Then the solvent is removed until an oily residue is obtained. 54 kg of sec-butanol and 20.3 kg of N, N - dimethylformamide are added. The solution thus obtained contains 11.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine Yield: 84.7%.
EXAMPLE 3 - Preparation of 4-(2-dimethylaminoethoxy)benzylamine dihydrochloride 1 1.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine dissolved in sec-butanol and DMF obtained as described in the previous example are charged into a reactor and 12.7 kg of 37% hydrochloric acid are added dropwise. The pH is checked to ensure it is <1.0 and the precipitated mixture is stirred at 45-50°C for at least 30 minutes. The mixture is cooled to 0-5°C, centrifuged and the precipitate washed with 1 1.5 kg of sec-butanol. It is dried under vacuum at 70-80°C. 13.5 kg of 4-(2- dimethylaminoethoxy)benzylamine dihydrochloride are obtained with HPLC purity higher than 98%. Reaction yield calculated on the 4-(2-dimethylaminoethoxy)- benzylamine 85.8%. EXAMPLE 4 - Preparation of itopride 10.1 kg of veratric acid and 27.0 kg of toluene are charged into a reactor, the mixture is heated under reflux (105-1 15°C) and 7.4 kg of thionyl chloride are added dropwise. The mixture is kept under reflux for at least 2 hours, and is
distilled under vacuum, to obtain an oily residue which 10.1 kg of toluene are added to. The solution is then brought to 20-50°C, and the aforesaid reaction mixture is added dropwise to a stainless steel reactor, which 13.5 kg of 4-(2- dimethylaminoethoxy)-benzylamine dihydrochloride, 81 kg of toluene, 11.5 kg of triethylamine, were previously charged into, at a temperature ranging from 75 to 80°C.
After adding the reaction mixture dropwise, the reaction mixture thus obtained is stirred at 75-80°C for at least two hours. Upon completion of the reaction, 40.5 kg of deionized water are added, 1 1.5 kg of 30% ammonia are added dropwise and the reaction mixture is taken to 55-60°C until complete solution. The aqueous phase is separated and removed. 27.0 kg of deionized water are added and the mixture is cooled to 40-45 °C until obtaining a good degree of precipitation. The mixture is then centrifuged, the precipitate is washed with 10.1 kg of deionized water and the same quantity of toluene. A sample of product is taken and the loss of weight determined; this analysis shows that the wet product contains 16 kg of dry itopride.
Reaction yield compared to 4-(2-dimethylaminoethoxy) benzylamine dihydrochloride: 88.3%. EXAMPLE 5 - Preparation of itopride hydrochloride The equivalent wet product corresponding to 16 kg of dry itopride coming from Example 4 and 56 kg of sec-butanol are charged into a reactor and heated to 50- 55 °C until solution. 4.8 kg of 37% hydrochloric acid are added dropwise, the pH is checked to ensure it is <2.0, and the mixture is stirred at 50-55 °C for at least 30 minutes; it is cooled to 15-25 °C and it is then centrifuged, the precipitate is washed with 16.0 kg of sec-butanol. The product is then dried at 70-80°C. 16.5 kg of itopride hydrochloride with HPLC purity higher than 99.8% are obtained. Reaction yield compared to itopride: 93.7%.
Claims
1. Process for preparing itopride hydrochloride comprising: a) Reacting 4-hydroxybenzaldehyde with 2-dimethylaminoethyl chloride in the presence of a weak inorganic base to obtain 4-(2-dimethylaminoethoxy)- benzaldehyde, b) Reacting 4-(2-dimethylaminoethoxy)-benzaldehyde with hydroxylamine hydrochloride in an acid environment to obtain 4-(2-dimethylaminoethoxy)- benzaldoxime hydrochloride, c) Reducing 4-(2-dimethylaminoethoxy)-benzaldoxime hydrochloride in the presence of a reducing agent to 4-(2-dimethylaminoethoxy)-benzylamine, d) Reacting 4-(2-dimethylaminoethoxy)-benzylamine with veratric acid chloride in the presence of a tertiary amine to obtain itopride, e) Salifying itopride with hydrochloric acid to obtain itopride hydrochloride, characterized in that the reducing agent employed in step (c) is powdered zinc.
2. Process as claimed in claim 1 , characterized in that the reducing reaction of step (c) is carried out in an acidic aqueous solution of an organic acid.
3. Process as claimed in claim 2, characterized in that said organic acid is concentrated acetic acid.
4. Process as claimed in claim 3, characterized in that said concentrated 80% acetic acid by weight.
5. Process as claimed in claim 1 -4, characterized in that the reducing reaction of step (c) is carried out directly on the reaction mixture obtained from step (b).
6. Process as claimed in any one of claims 1 -5, characterized in that 4-(2- dimethylaminoethoxy)-benzylamine obtained from the reducing reaction of step (c) is salified with hydrochloric acid to obtain the corresponding dihydrochloride salt.
7. Process as claimed in any one of claims 1 -6, characterized in that concentrated aqueous hydrochloric acid in an alcohol solvent is used in the salification reaction of the itopride of step (e).
8. Process for salifying itopride to the corresponding itopride hydrochloride with a purity higher than 99.8% consisting in treating said itopride with concentrated aqueous hydrochloric acid (37%) in an alcohol solvent.
9. Process as claimed in claim 7 or 8, characterized in that said alcohol is sec- butanol.
10. Process as claimed in any one of claims 1 -7, 9 characterized in that step (a) is carried out in phase transfer catalysis in the presence of a catalyst consisting of a quaternary ammonium salt.
1 1. Process as claimed in claim 10, characterized in that in step (a) a mixture of ethyl acetate, toluene and water is used as the solvent and the quaternary ammonium salt is tetrabutylammonium bromide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20042168 ITMI20042168A1 (en) | 2004-11-12 | 2004-11-12 | PREPARATION PROCESS OF CHLORIDATED ITOPRIDE |
| ITMI2004A002168 | 2004-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006051079A1 true WO2006051079A1 (en) | 2006-05-18 |
Family
ID=35840312
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2005/055839 Ceased WO2006051079A1 (en) | 2004-11-12 | 2005-11-09 | Process for preparing itopride hydrochloride |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | ITMI20042168A1 (en) |
| WO (1) | WO2006051079A1 (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101000362B1 (en) | 2008-07-22 | 2010-12-13 | 하나제약 주식회사 | New Manufacturing Method of Itopride |
| CN103351305A (en) * | 2013-05-24 | 2013-10-16 | 浙江金伯士药业有限公司 | 4-(2-dimethylaminoethoxy)benzylamine preparation method |
| KR101374939B1 (en) | 2013-10-18 | 2014-03-14 | 제일약품주식회사 | Novel intermediate salts for preparing itopride hydrochloride, methods for preparing thereof and methods for preparing itopride hydrochloride using thereof |
| KR101508565B1 (en) | 2008-05-27 | 2015-04-03 | 이범찬 | A novel process for the preparation of itopride and novel intermediate compounds obtained therefrom |
| CN105985257A (en) * | 2015-10-13 | 2016-10-05 | 威海迪素制药有限公司 | Preparation method of itopride hydrochloride |
| CN106748821A (en) * | 2016-12-14 | 2017-05-31 | 安徽省诚联医药科技有限公司 | 4‑（2 Dimethylaminoethoxies）The preparation method of benzylamine |
| KR101819771B1 (en) * | 2013-01-10 | 2018-01-18 | 연세대학교 산학협력단 | method for preparing itopride using micro flow reactor |
| CN111679029A (en) * | 2020-07-29 | 2020-09-18 | 珠海润都制药股份有限公司 | Method for detecting p-hydroxybenzaldehyde in itopride hydrochloride |
| CN113009003A (en) * | 2019-12-22 | 2021-06-22 | 珠海润都制药股份有限公司 | Method for detecting related substances in itopride hydrochloride preparation |
| CN113720947A (en) * | 2021-10-18 | 2021-11-30 | 珠海润都制药股份有限公司 | Detection method of demethylitopride nitrosamine |
| CN117843518A (en) * | 2023-09-23 | 2024-04-09 | 迪嘉药业集团股份有限公司 | Preparation method and application of itopride hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0306827A1 (en) * | 1987-09-05 | 1989-03-15 | Hokuriku Pharmaceutical Co.,Ltd | Amide compounds, process for preparing the same, and composition for activating gastric motor function containing the same |
| EP0388188A1 (en) * | 1989-03-15 | 1990-09-19 | Suntory Limited | Benzoxepin derivatives |
-
2004
- 2004-11-12 IT ITMI20042168 patent/ITMI20042168A1/en unknown
-
2005
- 2005-11-09 WO PCT/EP2005/055839 patent/WO2006051079A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0306827A1 (en) * | 1987-09-05 | 1989-03-15 | Hokuriku Pharmaceutical Co.,Ltd | Amide compounds, process for preparing the same, and composition for activating gastric motor function containing the same |
| EP0388188A1 (en) * | 1989-03-15 | 1990-09-19 | Suntory Limited | Benzoxepin derivatives |
Non-Patent Citations (1)
| Title |
|---|
| JUN SAKAGUCHI ET AL: "Synthesis, Gastrointestinal Prokinetic Activity and Structure-Activity Relationships of Novel N-[[2-(Dialkylamino)ethoxy]benzyl]- benzamide Derivatives", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 40, no. 1, 1992, pages 202 - 211, XP002152593, ISSN: 0009-2363 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101508565B1 (en) | 2008-05-27 | 2015-04-03 | 이범찬 | A novel process for the preparation of itopride and novel intermediate compounds obtained therefrom |
| KR101000362B1 (en) | 2008-07-22 | 2010-12-13 | 하나제약 주식회사 | New Manufacturing Method of Itopride |
| KR101819771B1 (en) * | 2013-01-10 | 2018-01-18 | 연세대학교 산학협력단 | method for preparing itopride using micro flow reactor |
| CN103351305A (en) * | 2013-05-24 | 2013-10-16 | 浙江金伯士药业有限公司 | 4-(2-dimethylaminoethoxy)benzylamine preparation method |
| CN103351305B (en) * | 2013-05-24 | 2014-10-08 | 浙江金伯士药业有限公司 | 4-(2-dimethylaminoethoxy)benzylamine preparation method |
| KR101374939B1 (en) | 2013-10-18 | 2014-03-14 | 제일약품주식회사 | Novel intermediate salts for preparing itopride hydrochloride, methods for preparing thereof and methods for preparing itopride hydrochloride using thereof |
| CN105985257B (en) * | 2015-10-13 | 2018-04-17 | 威海迪素制药有限公司 | A kind of preparation method of Itopride Hydrochloride |
| CN105985257A (en) * | 2015-10-13 | 2016-10-05 | 威海迪素制药有限公司 | Preparation method of itopride hydrochloride |
| CN106748821A (en) * | 2016-12-14 | 2017-05-31 | 安徽省诚联医药科技有限公司 | 4‑（2 Dimethylaminoethoxies）The preparation method of benzylamine |
| CN113009003A (en) * | 2019-12-22 | 2021-06-22 | 珠海润都制药股份有限公司 | Method for detecting related substances in itopride hydrochloride preparation |
| CN111679029A (en) * | 2020-07-29 | 2020-09-18 | 珠海润都制药股份有限公司 | Method for detecting p-hydroxybenzaldehyde in itopride hydrochloride |
| CN113720947A (en) * | 2021-10-18 | 2021-11-30 | 珠海润都制药股份有限公司 | Detection method of demethylitopride nitrosamine |
| CN117843518A (en) * | 2023-09-23 | 2024-04-09 | 迪嘉药业集团股份有限公司 | Preparation method and application of itopride hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI20042168A1 (en) | 2005-02-12 |
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