CN108610266A - A kind of preparation method of Itopride Hydrochloride - Google Patents
A kind of preparation method of Itopride Hydrochloride Download PDFInfo
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- CN108610266A CN108610266A CN201810516579.5A CN201810516579A CN108610266A CN 108610266 A CN108610266 A CN 108610266A CN 201810516579 A CN201810516579 A CN 201810516579A CN 108610266 A CN108610266 A CN 108610266A
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- itopride hydrochloride
- hydrochloride
- itopride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
Abstract
The present invention relates to a kind of preparation methods of Itopride Hydrochloride, belong to bulk pharmaceutical chemicals preparing technical field.The technical scheme is that：A kind of preparation method of Itopride Hydrochloride, with 3,4 dimethoxybenzarnides, formaldehyde and phenol are starting material, and intermediate I, intermediate I and N is made in one kettle way, intermediate II is made by substitution reaction in N dimethyl chloride ethane hydrochlorides, and Itopride Hydrochloride finally is made at salt.The present invention provides a kind of route is briefly convenient, economic and environment-friendly support must example preparation process.
Description
Technical field
The present invention relates to a kind of preparation methods of Itopride Hydrochloride, belong to bulk pharmaceutical chemicals preparing technical field.
Background technology
Itopride Hydrochloride is ground by Hokuriku, Japan pharmacy (being purchased by Abbott Laboratories for 2002, Abbott Laboratories in 2014 are stepped blue purchase)
Hair, nineteen ninety-five September are listed in Japan for the first time, and the various gastrointestinal symptoms for treating chronic gastritis (vomit by abdominal distension, heartburn, nausea
It spits).
1991, Hokuriku, Japan pharmacy made public for the first time the synthetic method of Itopride Hydrochloride, and this method is with para hydroxybenzene
Formaldehyde is starting material, by nucleophilic displacement of fluorine, is condensed into oxime, hydro-reduction obtains key intermediate 4- (N, N- dimethylamino second
Oxygroup) benzylamine；Veratraldehyde is oxidized, and black false hellebore acyl chlorides is made in chloro, then is condensed with 4- (N, N- Dimethylaminoethoxy) benzylamine, at
Salt finally obtains Itopride Hydrochloride.The route is longer, cumbersome, and preparation process uses Raney Ni, not only there is peace
Full hidden danger, and cause environmental pollution.Synthetic route is as follows：
。
CN106748862A reports an Itopride synthetic route, under copper trifluoromethanesulfcomposite effect, passes through bromo
The Ritter reactions of alkane and cyano prepare Itopride.The route uses expensive copper trifluoromethanesulfcomposite, and cost is excessively high,
And cupric waste causes environmental pollution.Synthetic route is as follows：
Invention content
The object of the present invention is to provide a kind of step simplicity, economic and environment-friendly Itopride Hydrochloride preparation methods.
The technical scheme is that：A kind of preparation method of Itopride Hydrochloride, with 3,4- dimethoxybenzarnides,
Formaldehyde and phenol are starting material, and intermediate I, intermediate I and N is made in one kettle way, and N- dimethyl chloride ethane hydrochlorides are by taking
Intermediate II is made in generation reaction, and Itopride Hydrochloride (III) finally is made at salt.Building-up process includes the following steps：
The first step is in the presence of catalyst H β zeolites or silica are with the concentrated sulfuric acid, with 3,4- dimethoxybenzarnides, first
Aldehyde and phenol are starting material synthetic intermediate I；
I
Second step is in the presence of potassium hydroxide, chemical compounds I and N, and the reaction of N- dimethyl chloride ethane hydrochlorides generates compound ii；
II
Third walks compound ii and generates Itopride Hydrochloride (formula III) under hydrogen chloride effect；
。
III
Specific reaction route is as follows：
Preferably, first step intermediatePreparation process in, 3,4- dimethoxybenzarnides, formaldehyde, phenol molar ratio
It is 1:1-2:1-2；Catalyst H β zeolites or silica and concentrated sulfuric acid amount of mixture are 3,4- dimethoxybenzoyls
0.5-1.5 times (W/W)；, the rate of charge of silica and the concentrated sulfuric acid is silica：98% concentrated sulfuric acid=2-4:1 (W/W), reaction
Temperature is 80-100 DEG C.
It is furthermore preferred that first step intermediatePreparation, 3,4- dimethoxybenzarnides, formaldehyde, phenol molar ratio be 1:
1.5-1.8:1.6-1.8.
Preferably, in the preparation process of second step compound ii, compound, N, N- dimethyl chlorides ethane hydrochloride, potassium hydroxide
Molar ratio be 1:1-2:2-3, reaction dissolvent are methanol, back flow reaction.
It is furthermore preferred that in the preparation process of second step compound ii, compound, N, N- dimethyl chlorides ethane hydrochloride, hydrogen
The molar ratio of potassium oxide is 1:1.5: 2.5.
Preferably, in the preparation process of third step support ratio, compound ii is dissolved in 6-10 times of (V/W) ethyl alcohol, 55-65
DEG C be added 30% ethanol solution of hydrogen chloride；The molar ratio of institute's containing hydrogen chloride is 1 in compound ii and 30% ethanolic hydrogen chloride:1-1.5.
Advantageous effect：It is briefly convenient that the beneficial effects of the invention are as follows reaction routes, economic and environment-friendly.Starting material is cheaply easy
, each material obtains Itopride theme skeleton structure, simple operation without a derivative step；Each material of the route is cheap, each to walk
Yield is preferable, at low cost, good economy performance；It avoids polluting high reagent greatly using danger in route, it is environmentally protective.
Specific implementation mode：
For a better understanding of the present invention, it is described further with reference to specific embodiment, but the present invention is not limited to this.
Embodiment 1：CompoundPreparation：
3,4- dimethoxybenzarnides, 18.1 g (0.10 mol), 37% formalin, 8.1 g is taken (to contain formaldehyde 0.10
Mol), 100 mL there-necked flasks are added in 10.0 g of n,N-dimethylacetamide, phenol 18.8g (0.20 mol), 9.0 g of H β zeolites
In, 80 DEG C are warming up to, 12 h, filtering are reacted, filtrate is concentrated to dryness, and obtained solid adds 100.0 g of water, 55-65 DEG C of mashing 2
H, filter, solid it is dry compound23.0 g, yield 88.1%, HPLC purity 97.9%.
Embodiment 2：CompoundPreparation：
3,4- dimethoxybenzarnides, 90.6 g (0.50 mol), 37% formalin, 60.8 g is taken (to contain formaldehyde 0.75
Mol), 94.1 g of phenol (1.0 mol), 30.0 g of silica, 98% concentrated sulfuric acid, 15.0 g, n,N-dimethylacetamide 80.0
G is warming up to 100 DEG C, reacts 10 h, filtering, and filtrate is concentrated to dryness, and obtained solid adds 500.0 g of water, 55-65 DEG C of mashing 2
H, filter, solid it is dry compound132.2 g, yield 92.8%, HPLC purity 98.3%.
Embodiment 3：The preparation of compound ii：
Take compound80.0 g (0.28 mol), 400 mL of methanol, 31.4 g of potassium hydroxide (0.56 mol) are added
In 1000 mL there-necked flasks, stirring is warming up to reflux, and N, 40.3 g of N- dimethyl chlorides ethane hydrochloride (0.28 mol) is taken to be dissolved in
In 80.0 g water, it is slowly added to system, thin-layer chromatography（Solvent ratio dichloromethane:Methanol=10:1）Monitoring to reaction finishes.
Concentration and recovery methanol is added water 400.0 g, 10-30 DEG C, 3 h of stirring and crystallizing, filters, solid it is dry compound ii 82.6
G, yield 90.8%, HPLC purity 98.9%.
Embodiment 4：The preparation of compound III：
71.7 g of compound ii (0.20 mol), 430 mL of absolute ethyl alcohol are taken, is added in 1000 mL there-necked flasks, is heated to
System dissolved clarification controls 55-65 DEG C of temperature, and 30% ethanol solution of hydrogen chloride, 31.6 g (0.26 mol of containing hydrogen chloride), about 1 h is added dropwise
It finishes.Heating is closed, 2-3 h are down to 20 DEG C, move into ice bath, and system is cooled to 0-10 DEG C and continues stirring and crystallizing 3-5 h.It takes out
Filter, it is dry, obtain 67.5 g of white solid, 94.1 % of yield, HPLC purity 99.8%.
Embodiment 5：CompoundPreparation：
3,4- dimethoxybenzarnides, 99.6 g (0.55 mol), 37% formalin, 89.1 g is taken (to contain formaldehyde 1.1
Mol), tri- mouthfuls of 500 mL is added in 90.0 g of n,N-dimethylacetamide, 51.7 g of phenol (0.55 mol), 149.4 g of H β zeolites
In bottle, 100 DEG C are warming up to, reacts 10 h, filtering, filtrate is concentrated to dryness, and obtained solid adds 500.0 g of water, 55-65 DEG C of mashing
2 h, filter, solid it is dry compound124.4 g, yield 87.6%, HPLC purity 98.9%.
Embodiment 6：CompoundPreparation：
3,4- dimethoxybenzarnides, 81.5 g (0.45 mol), 37% formalin, 60.8 g is taken (to contain formaldehyde 0.75
Mol), 75.3 g of phenol (0.80 mol), 40.0 g of silica, 98% concentrated sulfuric acid, 10.0 g, n,N-dimethylacetamide 90.0
G is warming up to 100 DEG C, reacts 10 h, filtering, and filtrate is concentrated to dryness, and obtained solid adds 500.0 g of water, 55-65 DEG C of mashing 2
H, filter, solid it is dry compound120.5 g, yield 93.8%, HPLC purity 98.9%.
Embodiment 7：The preparation of compound ii：
Take compound100.0g (0.35mol), 500 mL of methanol, 58.9 g of potassium hydroxide (1.05 mol) are added 1000
In mL there-necked flasks, stirring is warming up to reflux, and N, 100.8 g of N- dimethyl chlorides ethane hydrochloride (0.70 mol) is taken to be dissolved in
In 200.0 g water, it is slowly added to system, thin-layer chromatography（Solvent ratio dichloromethane:Methanol=10:1）Monitoring is to having reacted
Finish.Concentration and recovery methanol is added water 500.0 g, 10-30 DEG C, 3 h of stirring and crystallizing, filters, solid it is dry compound ii
104.5 g, yield 90.6%, HPLC purity 98.4%.
Embodiment 8：The preparation of compound III：
56.0 g of compound ii (0.16 mol), 560 mL of absolute ethyl alcohol are taken, is added in 1000 mL there-necked flasks, is heated to
System dissolved clarification controls 55-65 DEG C of temperature, and 30% ethanol solution of hydrogen chloride, 29.2 g (0.24 mol of containing hydrogen chloride), about 1 h is added dropwise
It finishes.Heating is closed, 2-3h is down to 20 DEG C, moves into ice bath, and system is cooled to 0-10 DEG C and continues stirring and crystallizing 3-5h.It filters,
It is dry, obtain 57.03 g of white solid, yield 92.4%, HPLC purity 99.5%.
Embodiment 9：The preparation of compound ii：
Take compound40.0 g (0.14 mol), 200 mL of methanol, 19.6 g of potassium hydroxide (0.35 mol) are added 500
In mL there-necked flasks, stirring is warming up to reflux, and N, 30.2 g of N- dimethyl chlorides ethane hydrochloride (0.21 mol) is taken to be dissolved in 60.0
In g water, it is slowly added to system, thin-layer chromatography（Solvent ratio dichloromethane:Methanol=10:1）Monitoring to reaction finishes.Concentration
Recycle methanol, water 200.0 g be added, 10-30 DEG C, 3 h of stirring and crystallizing, filters, solid it is dry 42.5 g of compound ii, receive
Rate 93.8%, HPLC purity 98.7%.
Embodiment 10：The preparation of compound III：
35.8 g of compound ii (0.10 mol), 286 mL of absolute ethyl alcohol are taken, is added in 500 mL there-necked flasks, is heated to
System dissolved clarification controls 55-65 DEG C of temperature, and 30% ethanol solution of hydrogen chloride, 12.2 g (0.10 mol of containing hydrogen chloride), about 1 h is added dropwise
It finishes.Heating is closed, 2-3 h are down to 20 DEG C, move into ice bath, and system is cooled to 0-10 DEG C and continues stirring and crystallizing 3-5 h.It takes out
Filter, it is dry, obtain 36.8 g of white solid, 93.2 % of yield, HPLC purity 99.9%.
Claims (6)
1. a kind of preparation method of Itopride Hydrochloride, characterized in that with 3,4- dimethoxybenzarnides, formaldehyde and phenol are
Starting material, intermediate I, intermediate I and N is made in one kettle way, during N- dimethyl chloride ethane hydrochlorides are made by substitution reaction
Mesosome II is finally made Itopride Hydrochloride (III) at salt, specifically includes following steps：
For the first step with 3,4- dimethoxybenzarnides, formaldehyde and phenol are starting material synthetic intermediate I；
Second step is in the presence of potassium hydroxide, chemical compounds I and N, and the reaction of N- dimethyl chloride ethane hydrochlorides generates compound ii；
Third walks compound ii and generates Itopride Hydrochloride (III) under hydrogen chloride effect；
。
2. according to the preparation method of Itopride Hydrochloride described in claim 1, characterized in that first step intermediatePreparation process
In, 3,4- dimethoxybenzarnides, formaldehyde, phenol molar ratio are 1:1-2:1-2；Catalyst H β zeolites or silica with
Concentrated sulfuric acid amount of mixture is 0.5-1.5 times (W/W) of 3,4- dimethoxybenzoyls；The rate of charge of silica and the concentrated sulfuric acid
For silica：98% concentrated sulfuric acid=2-4:1 (W/W), reaction temperature are 80-100 DEG C.
3. according to the preparation method of Itopride Hydrochloride described in claim 1, characterized in that first step intermediatePreparation process
In, 3,4- dimethoxybenzarnides, formaldehyde, phenol molar ratio are 1:1.5-1.8:1.6-1.8.
4. according to the preparation method of Itopride Hydrochloride described in claim 1, characterized in that the preparation of second step compound ii walks
In rapid, compound, N, N- dimethyl chlorides ethane hydrochloride, the molar ratio of potassium hydroxide be 1:1-2:2-3, reaction dissolvent are first
Alcohol, back flow reaction.
5. according to the preparation method of Itopride Hydrochloride described in claim 1, characterized in that the preparation of second step compound ii walks
In rapid, compound, N, N- dimethyl chlorides ethane hydrochloride, the molar ratio of potassium hydroxide be 1:1.5: 2.5.
6. according to the preparation method of Itopride Hydrochloride described in claim 1, characterized in that third walks the preparation step of support ratio
In rapid, compound ii is dissolved in 6-10 times of (V/W) ethyl alcohol, 55-65 DEG C of 30% ethanol solution of hydrogen chloride of addition；Compound ii and
The molar ratio of institute's containing hydrogen chloride is 1 in 30% ethanolic hydrogen chloride:1-1.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007074386A2 (en) * | 2005-12-28 | 2007-07-05 | Bakulesh Mafatlal Khamar | A novel process for synthesis of itopride and it’s novel intermediate-n-(4-hydroxybenzyl)-3,4-dimethoxybenzamide |
| CN102993038A (en) * | 2012-12-08 | 2013-03-27 | 迪沙药业集团有限公司 | Preparation method of itopride hydrochloride |
| CN107892657A (en) * | 2017-11-05 | 2018-04-10 | 安徽修制药有限公司 | A kind of synthetic method of Itopride Hydrochloride |
-
2018
- 2018-05-25 CN CN201810516579.5A patent/CN108610266A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007074386A2 (en) * | 2005-12-28 | 2007-07-05 | Bakulesh Mafatlal Khamar | A novel process for synthesis of itopride and it’s novel intermediate-n-(4-hydroxybenzyl)-3,4-dimethoxybenzamide |
| CN102993038A (en) * | 2012-12-08 | 2013-03-27 | 迪沙药业集团有限公司 | Preparation method of itopride hydrochloride |
| CN107892657A (en) * | 2017-11-05 | 2018-04-10 | 安徽修制药有限公司 | A kind of synthetic method of Itopride Hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| DURGAIAH CHEVELLA，等: "Three-component synthesis of amidomethylarenes and -heteroarenes over Hβ zeolite under solvent-free conditions", 《CATALYSIS COMMUNICATIONS》 * |
| 杜文双，等: "伊托必利的合成工艺研究", 《沈阳药科大学学报》 * |
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| TA01 | Transfer of patent application right |
Effective date of registration: 20200907 Address after: 264205 Guangzhou East Road South and an East Road East, Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 266440 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
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