CN101033225A - Process of preparing troipisetron - Google Patents
Process of preparing troipisetron Download PDFInfo
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- CN101033225A CN101033225A CN 200710010815 CN200710010815A CN101033225A CN 101033225 A CN101033225 A CN 101033225A CN 200710010815 CN200710010815 CN 200710010815 CN 200710010815 A CN200710010815 A CN 200710010815A CN 101033225 A CN101033225 A CN 101033225A
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Abstract
This invention relates to a synthesizing technology for preparing tropisetron with chloro 1, 3-dimethyl-2-chlorin imidazoline as the condensation agent, in which, indole-3-formic acid is reacted with tropaic alcohol for 12-24h under room temperature then to be cooled, filtered and cleaned to get the objective product tropisetron, and the mol ration of the indole-3-formic acid, tropaic alcohol and chloro 1, 3-dimethyl-2-chlorin imidazoline for condensation reaction, and the option is 1:1-1.5:1-1.5.
Description
Technical field
The invention belongs to the fine chemical product production field, particularly a kind of preparation technology of antiemetic tropisetron.
Background technology
In the chemistry of Tropisetron hydrochloride (Tropisetron hydrochloride) is by name-assorted nitrogen dicyclo [3.2.1] the oct-3-yl ester hydrochloride of 1H-Indole-3-Carboxylic Acid-8-methyl-8-, it is high selectivity 5-HT3 receptor antagonist, be applicable to the nausea and vomiting that causes after prevention and treatment children and adult cancer chemotherapy, radiotherapy and the operation, Fig. 1 seen in its chemical structural formula.
As existing preparation method, (US4797406 has introduced in US4789673) with indole-3-carboxylic acid and oxalyl chloride reaction, obtaining 3-indoles formyl chloride with methylene dichloride and normal hexane processing at United States Patent (USP), tropine lithium alkoxide with tropanol generation under the n-Butyl Lithium activation reacts then, obtain tropisetron through aftertreatment, last and hydrochloric acid salify makes Tropisetron hydrochloride, and its reaction principle is seen Fig. 2, this process is handled very complicated, step is loaded down with trivial details, and reagent consumption is many, and reaction yield only is 20%.
As the improvement of aforesaid method in document (the synthetic improvement of Tropisetron hydrochloride, the Huaihai Institute of Technology journal, 2003,12 (4), 41～43) yield with 50% in obtains tropisetron, but still used the activator of expensive butyllithium, and use inflammable, explosive tetrahydrofuran (THF) to be reaction solvent in a large number as condensation reaction.
At nearest document (West China pharmaceutical journal, 2004,19 (6): 433～434) in the report, introduced a kind of technological process of improved synthetic tropisetron, this method has been saved butyllithium and tetrahydrofuran (THF), but still will by behind first synthesis of indole-3-formyl chloride again with the tropanol condensation, yield is 60%.This method has still used oxalyl chloride as acylating reagent, unavoidably has a large amount of byproduct hydrogen chloride gas to produce, and still exists obvious deficiency as the large-scale production process.
Summary of the invention
The present invention is intended to overcome the deficiencies in the prior art part and the synthesis technique of a kind of high yield, tropisetron safe, pollution-free, easy and simple to handle is provided, to satisfy requirement of massive production.
The object of the present invention is achieved like this: the present invention adopts chloro 1,3-dimethyl-2-climiqualine prepares tropisetron as condensing agent, in inert solvent, with indole-3-carboxylic acid and tropanol at chloro 1, under 3-dimethyl-2-climiqualine and the organic bases effect, under room temperature, reacted 12～24 hours, and after cooling, filtration, carrying out washing treatment, obtained described purpose product.
Indole-3-carboxylic acid of the present invention, tropanol and chloro 1,3-dimethyl-2-climiqualine carries out the mol ratio of condensation reaction can select 1: 1～2: 1～3; Be preferably 1: 1～1.5: 1～1.5.
In addition, organic bases of the present invention can be selected triethylamine, pyridine, 4-N, N-picoline, N, and a kind of or its mixture in the methylphenylamine is preferably triethylamine or pyridine.
The mol ratio of organic bases of the present invention and indole-3-carboxylic acid can select 1: 1～3, be preferably 1: 1～and 1.5.
Inert solvent of the present invention is ethyl acetate, propyl acetate, butylacetate, methylene dichloride, 1, and a kind of or its mixture in the 2-ethylene dichloride is preferably ethyl acetate, 1, the 2-ethylene dichloride.
The consumption of above-mentioned inert solvent is 5～30 times of indole-3-carboxylic acid by percentage to the quality, preferred 10～20 times.
The condensing agent chloro 1 that the present invention relates to, 3-dimethyl-2-climiqualine can make (see figure 3) as chlorination reagent by solid phosgene.
In the technology of the synthetic tropisetron of the present invention, adopt chloro 1,3-dimethyl-2-climiqualine directly reacts as the condensing agent of reaction, has avoided the first formation acyl chlorides technological process of condensation again.Target product purity height of the present invention, selectivity is good, and the yield height is easy and simple to handle, safe and reliable, is fit to large-scale production, can satisfy the requirement of field of medicaments.
Description of drawings
The invention will be further described below in conjunction with the drawings and specific embodiments.Protection scope of the present invention is not subjected to the restriction of this embodiment.
Fig. 1 is a process flow sheet of the present invention;
Fig. 2 is the structural formula of Tropisetron hydrochloride of the present invention;
Fig. 3 is the reaction principle figure of preparation Tropisetron hydrochloride in the prior art;
Fig. 4 is a preparation chloro 1 in the prior art, 3-dimethyl-2-climiqualine reaction principle figure.
Embodiment
Reference example
In three mouthfuls of reaction flasks of 1000ml, add 1,3-dimethyl-2-imidazolone (34.2 grams, 0.3 mole), tetracol phenixin (400 milliliters) stirs the carbon tetrachloride solution that slowly drips solid phosgene down and (contains solid phosgene 30 grams, 0.1 mole, 100 milliliters in tetracol phenixin), reaction mixture keeps below 5 ℃, vigorous stirring 0.5 hour, and room temperature reaction is after 1 hour, be warming up to 50 ℃, kept 4 hours.The question response product is cooled to room temperature, and filtration, a small amount of tetracol phenixin washing obtain lily crystalline product chloro 1,3-dimethyl-2-climiqualine 49 grams, yield 96.6%, fusing point: 85～86 ℃.
With indole-3-carboxylic acid (16.1 grams, 0.1 mole), chloro 1,3-dimethyl-2-climiqualine (11.4 grams, 0.1 mole), tropanol (14.1 grams, 0.1 mole) is dissolved in the ethyl acetate (200 milliliters), stir and to splash into triethylamine (10.1 restrain 0.1 mole) down, again in room temperature reaction 12 hours.Add entry (60 milliliters), regulate pH=9～10 with 15% sodium hydroxide, water washing is to neutrality, drying.Concentrate and obtain the light yellow solid product, add dehydrated alcohol (300 milliliters), after the dissolving, cooling adds concentrated hydrochloric acid down, makes pH=2～3, carry out underpressure distillation and obtain the Tropisetron Hydrochloride crude product, filter, the dehydrated alcohol recrystallization, (liquid chromatogram measuring purity is greater than 99.76% to obtain white crystalline product 24.3 grams,), yield 76.1%; Fusing point: 283～285 ℃, the spectrum of product is consistent with bibliographical information.
With indole-3-carboxylic acid (16.1 grams, 0.1 mole), chloro 1,3-dimethyl-2-climiqualine (13.7 grams, 0.12 mole), tropanol (14.1 grams, 0.1 mole) is dissolved in the ethyl acetate (200 milliliters), stir and to splash into triethylamine (15.2 restrain 0.15 mole) down, again in room temperature reaction 18 hours.Add entry (60 milliliters), regulate pH=9～10 with 15% sodium hydroxide, water washing is to neutrality, drying.Concentrate and obtain the light yellow solid product, add dehydrated alcohol (300 milliliters), after the dissolving, cooling adds concentrated hydrochloric acid down, makes pH=2～3, carry out underpressure distillation and obtain the Tropisetron Hydrochloride crude product, filter, the dehydrated alcohol recrystallization, (liquid chromatogram measuring purity is greater than 99.84% to obtain white crystalline product 25 grams,), yield 78.3%; Fusing point: 283～285 ℃.
Embodiment 3
With indole-3-carboxylic acid (16.1 grams, 0.1 mole), chloro 1,3-dimethyl-2-climiqualine (11.4 grams, 0.1 mole), tropanol (14.1 grams, 0.1 mole) is dissolved in the ethyl acetate (200 milliliters), stir and to splash into pyridine (7.9 restrain 0.1 mole) down, and in room temperature reaction 12 hours.Add entry (60 milliliters), regulate pH=9～10 with 15% sodium hydroxide, water washing is to neutrality, drying.Concentrate and obtain the light yellow solid product, add dehydrated alcohol (300 milliliters), after the dissolving, cooling adds concentrated hydrochloric acid down, makes pH=2～3, carry out underpressure distillation and obtain the Tropisetron Hydrochloride crude product, filter, the dehydrated alcohol recrystallization, (liquid chromatogram measuring purity is greater than 99.25% to obtain white crystalline product 21.7 grams,), yield 68.1%; Fusing point: 283～285 ℃.
Embodiment 4
With indole-3-carboxylic acid (16.1 grams, 0.1 mole), chloro 1,3-dimethyl-2-climiqualine (11.4 grams, 0.1 mole), tropanol (14.1 grams, 0.1 mole) be dissolved in 1, in the 2-ethylene dichloride (150 milliliters), splash into triethylamine (15.2 grams under stirring, 0.15 mole), and in room temperature reaction 12 hours.Add entry (60 milliliters), regulate pH=9～10 with 15% sodium hydroxide, water washing is to neutrality, drying.Concentrate and obtain the light yellow solid product, add dehydrated alcohol (300 milliliters), after the dissolving, cooling adds concentrated hydrochloric acid down, makes pH=2～3, carry out underpressure distillation and obtain the Tropisetron Hydrochloride crude product, filter, the dehydrated alcohol recrystallization, (liquid chromatogram measuring purity is greater than 99.45% to obtain white crystalline product 23.2 grams,), yield 72.8%; Fusing point: 283～285 ℃.
Embodiment 5
With indole-3-carboxylic acid (16.1 grams, 0.1 mole), chloro 1,3-dimethyl-2-climiqualine (13.7 grams, 0.12 mole), tropanol (16.9 grams, 0.12 mole) is dissolved in the ethyl acetate (200 milliliters), stir and to splash into triethylamine (15.2 restrain 0.15 mole) down, again in room temperature reaction 24 hours.Add entry (60 milliliters), regulate pH=9～10 with 15% sodium hydroxide, water washing is to neutrality, drying.Concentrate and obtain the light yellow solid product, add dehydrated alcohol (300 milliliters), after the dissolving, cooling adds concentrated hydrochloric acid down, makes pH=2～3, carry out underpressure distillation and obtain the Tropisetron Hydrochloride crude product, filter, the dehydrated alcohol recrystallization, (liquid chromatogram measuring purity is greater than 99.16% to obtain white crystalline product 20 grams,), yield 62.7%; Fusing point: 281～283 ℃.
Claims (10)
1, the preparation technology of tropisetron is characterized in that: in inert solvent, with indole-3-carboxylic acid and tropanol at chloro 1, under 3-dimethyl-2-climiqualine and the organic bases effect, under room temperature, reacted 12～24 hours, and after cooling, filtration, carrying out washing treatment, obtained described purpose product.
2, the preparation technology of tropisetron according to claim 1 is characterized in that: the mol ratio that indole-3-carboxylic acid, tropanol and chloro 1,3-dimethyl-2-climiqualine carry out condensation reaction is 1: 1～2: 1～3; Be preferably 1: 1～1.5: 1～1.5.
3, the preparation technology of tropisetron according to claim 1 and 2 is characterized in that: described organic bases is triethylamine, pyridine, 4-N, N-picoline, N, and a kind of or its mixture in the methylphenylamine is preferably triethylamine or pyridine.
4, the preparation technology of tropisetron according to claim 3 is characterized in that: the mol ratio of described organic bases and indole-3-carboxylic acid is 1: 1～3, be preferably 1: 1～and 1.5.
5, the preparation technology of tropisetron according to claim 1 and 2, it is characterized in that: described inert solvent is ethyl acetate, propyl acetate, butylacetate, methylene dichloride, 1, a kind of or its mixture in the 2-ethylene dichloride is preferably ethyl acetate, 1, the 2-ethylene dichloride.
6, the preparation technology of tropisetron according to claim 3, it is characterized in that: described inert solvent is ethyl acetate, propyl acetate, butylacetate, methylene dichloride, 1, a kind of or its mixture in the 2-ethylene dichloride is preferably ethyl acetate, 1, the 2-ethylene dichloride.
7, the preparation technology of tropisetron according to claim 4, it is characterized in that: described inert solvent is ethyl acetate, propyl acetate, butylacetate, methylene dichloride, 1, a kind of or its mixture in the 2-ethylene dichloride is preferably ethyl acetate, 1, the 2-ethylene dichloride.
8, the preparation technology of tropisetron according to claim 1 and 2 is characterized in that: the consumption of described inert solvent is 5～30 times of indole-3-carboxylic acid by percentage to the quality, preferred 10～20 times.
9, the preparation technology of tropisetron according to claim 3 is characterized in that: the consumption of described inert solvent is 5～30 times of indole-3-carboxylic acid by percentage to the quality, preferred 10～20 times.
10, the preparation technology of tropisetron according to claim 4 is characterized in that: the consumption of described inert solvent is 5～30 times of indole-3-carboxylic acid by percentage to the quality, preferred 10～20 times.
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101787021A (en) * | 2010-03-05 | 2010-07-28 | 王明 | High-purified tropisetron hydrochloride compound |
| CN101838266B (en) * | 2009-02-17 | 2012-01-04 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN102351857A (en) * | 2011-08-23 | 2012-02-15 | 天津市汉康医药生物技术有限公司 | Tropiseiron hydrochloride compound |
| CN102367251A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | More stable tropisetron compound and pharmaceutical composition thereof |
| CN102367252A (en) * | 2011-11-03 | 2012-03-07 | 天津市汉康医药生物技术有限公司 | Tropisetron hydrochloride compound |
| CN102532128A (en) * | 2010-12-17 | 2012-07-04 | 北大方正集团有限公司 | Synthetic method of tropisetron and prepare method of hydrochloric acid tropisetron |
| CN102584815A (en) * | 2011-01-14 | 2012-07-18 | 湖南康普医药研究院 | Method for preparing tropisetron hydrochloride on large scale |
| CN101717359B (en) * | 2009-07-15 | 2012-09-05 | 北京成宇药业有限公司 | Method for synthesizing indapamide |
| CN102887893A (en) * | 2012-10-24 | 2013-01-23 | 齐鲁制药有限公司 | Preparation method of tropisetron |
| CN104945397A (en) * | 2015-07-30 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Tropisetron hydrochloride medicine compound for treating nausea and vomit as well as preparation method thereof |
| CN105367478A (en) * | 2015-06-03 | 2016-03-02 | 北京成宇药业有限公司 | Preparation process of zafirlukast |
| CN106831754A (en) * | 2015-12-03 | 2017-06-13 | 康普药业股份有限公司 | A kind of preparation method of Tropisetron HCl |
| CN110845493A (en) * | 2019-11-04 | 2020-02-28 | 重庆植恩药业有限公司 | Preparation method of tropisetron hydrochloride |
-
2007
- 2007-04-02 CN CNB2007100108158A patent/CN100503601C/en not_active Expired - Fee Related
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101838266B (en) * | 2009-02-17 | 2012-01-04 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN101717359B (en) * | 2009-07-15 | 2012-09-05 | 北京成宇药业有限公司 | Method for synthesizing indapamide |
| CN101787021A (en) * | 2010-03-05 | 2010-07-28 | 王明 | High-purified tropisetron hydrochloride compound |
| CN102532128A (en) * | 2010-12-17 | 2012-07-04 | 北大方正集团有限公司 | Synthetic method of tropisetron and prepare method of hydrochloric acid tropisetron |
| CN102532128B (en) * | 2010-12-17 | 2014-11-12 | 北大方正集团有限公司 | Synthetic method of tropisetron and prepare method of hydrochloric acid tropisetron |
| CN102584815A (en) * | 2011-01-14 | 2012-07-18 | 湖南康普医药研究院 | Method for preparing tropisetron hydrochloride on large scale |
| CN102351857B (en) * | 2011-08-23 | 2013-06-12 | 天津市汉康医药生物技术有限公司 | Tropiseiron hydrochloride compound |
| CN102351857A (en) * | 2011-08-23 | 2012-02-15 | 天津市汉康医药生物技术有限公司 | Tropiseiron hydrochloride compound |
| CN102367251A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | More stable tropisetron compound and pharmaceutical composition thereof |
| CN102367251B (en) * | 2011-08-26 | 2012-11-07 | 贺金凤 | More stable tropisetron compound and pharmaceutical composition thereof |
| CN102367252A (en) * | 2011-11-03 | 2012-03-07 | 天津市汉康医药生物技术有限公司 | Tropisetron hydrochloride compound |
| CN102887893A (en) * | 2012-10-24 | 2013-01-23 | 齐鲁制药有限公司 | Preparation method of tropisetron |
| CN105367478A (en) * | 2015-06-03 | 2016-03-02 | 北京成宇药业有限公司 | Preparation process of zafirlukast |
| CN105367478B (en) * | 2015-06-03 | 2019-01-04 | 北京成宇药业有限公司 | The preparation process of zafirlukast |
| CN104945397A (en) * | 2015-07-30 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Tropisetron hydrochloride medicine compound for treating nausea and vomit as well as preparation method thereof |
| CN106831754A (en) * | 2015-12-03 | 2017-06-13 | 康普药业股份有限公司 | A kind of preparation method of Tropisetron HCl |
| CN110845493A (en) * | 2019-11-04 | 2020-02-28 | 重庆植恩药业有限公司 | Preparation method of tropisetron hydrochloride |
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| CN100503601C (en) | 2009-06-24 |
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