CN101348480A - Novel synthetic method of loratadine - Google Patents
Novel synthetic method of loratadine Download PDFInfo
- Publication number
- CN101348480A CN101348480A CNA2007100700371A CN200710070037A CN101348480A CN 101348480 A CN101348480 A CN 101348480A CN A2007100700371 A CNA2007100700371 A CN A2007100700371A CN 200710070037 A CN200710070037 A CN 200710070037A CN 101348480 A CN101348480 A CN 101348480A
- Authority
- CN
- China
- Prior art keywords
- loratadine
- ticl
- novel synthesis
- low valent
- 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.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing a drug of Loratadine. The prior art has stricter requirement on reaction conditions and is difficult to control, with higher price of raw materials and catalysts, high production cost; and high content of impurities in the final products and a great amount of produced pollutants. The invention comprises the following steps that tricyclic ketone and 4-Ethoxycarbon piperidone undergo condensation in an inertia solvent by a low valent titanium, followed by acid hydrolysis to obtain Loratadine. The invention lowers the cost on the basis of the ensured yield rate through using the low valent titanium, and has mild operation condition, easy control, generally no pollution, stable technology, and good repeatability.
Description
Technical field
The present invention relates to a kind of preparation method of Loratadine medicine.
Background technology
Loratadine (loratadine) is the antihistamine drug of new generation of a kind of long-acting, no sedative effect, no anticholinergic effect, effect with the anti-periphery histamine H1-receptor of selectivity, in the therapeutic dose scope, there is not drowsiness effect, be applicable to shed tears, sneeze, allergic rhinitis, acute or chronic urticaria disease and other anaphylaxis dermatosis, its chemistry is by name: 4-(8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11 alkene)-the 1-piperidine carboxylate, English name: Loratadine.According to the literature, the synthetic route of this Loratadine drug utilization intermediate tricycle kentones mainly contains following two classes: a class is the Grignard reagent synthetic route, and another kind of is the phosphoric acid ester synthetic route.
The Grignard reagent synthetic route: with the tricycle kentones is raw material, reacts with Grignard reagent in solvent, and the product of generation and Vinyl chloroformate react the crude product that obtains compound (1).Grignard reagent that uses in this method and solvent are relatively stricter, wayward to the requirement of moisture; Because the price of Grignard reagent is higher, causes the production cost height.
The phosphoric acid ester synthetic route: tricycle kentones and 4-p diethylaminobenzoic acid ester group-N-ethoxycarbonyl piperidines carries out building-up reactions under the effect of LDA (diisopropylamine lithium), obtains the crude product of compound (1) after refluxing.But this method need be separated the isomer that produces in the reaction process, and then carried out hydrogenation in the process of preparation raw material 4-p diethylaminobenzoic acid ester group-N-ethoxycarbonyl piperidines, and process hazard is big, operates loaded down with trivial details, wayward; Foreign matter content in the final product is higher, and the pollutent of generation is many.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, and a kind of novel synthesis of Loratadine is provided, and by the use of low valent titanium reagent, makes synthesis technique stable, good reproducibility; On the basis that guarantees yield, reduce cost, reduce and pollute.
For this reason, the present invention adopts following technical scheme: the novel synthesis of Loratadine, its step is as follows: 1) tricycle kentones and 4-ethoxy carbon back piperidone carry out condensation, 2 by low valent titanium reagent in inert solvent) obtain the target product Loratadine through acid hydrolysis again.The route of aforesaid method is as follows:
The novel synthesis of described Loratadine in inert solvent, is used TiCl
X/ M prepares described low valent titanium reagent, TiCl
XBe TiCl
2, TiCl
3, TiCl
4In one or two or more kinds mix reagent, M is a kind of and mixture more than two kinds in potassium, sodium, magnesium, aluminium, the zinc.Low valent titanium reagent can be recycled, and is pollution-free substantially to environment.
The novel synthesis of described Loratadine, the temperature of reaction in the step 1) are-10～50 ℃, and this reaction conditions gentleness is easy to control.
The novel synthesis of described Loratadine, described inert solvent are any one or two kinds of above mixed solvents in normal hexane, toluene, dimethylbenzene, tetrahydrofuran (THF), methyltetrahydrofuran, the sherwood oil.
The novel synthesis of described Loratadine, step 2) acid described in is any one or two kinds of above mixtures in sulfuric acid, acetate, hydrochloric acid, the sulfonic acid.
Compare with the method in the above-mentioned existing document, the present invention has the following advantages: 1) the raw material 4-ethoxycarbonyl piperidone market of reacting used is on sale in a large number, and raw material is easy to get, and it is low that price has the used raw material of method relatively now, and production cost is low; 2) by the use of low valent titanium reagent, on the basis that guarantees yield, reduced cost, the operational condition gentleness, easy to control, pollution-free substantially, process stabilizing, good reproducibility.
The present invention is further illustrated below in conjunction with embodiment.
Embodiment
Embodiment 1
Tricycle kentones 10g and 4-ethoxycarbonyl piperidone 7.4g are dissolved in the 50ml hexane solution, and be standby.
In the 250ml flask, drop into magnesium powder 6.6g and 120ml normal hexane; Stir temperature control to 10 ℃; Drip titanium tetrachloride 12ml, control 30 minutes and drip; 10 ℃ of insulations 30 minutes; Drip hexane solution dripped in 30 minutes; Finish, be incubated 2 hours; Good heat insulation adds 2 vitriol oils, temperature rising reflux 3 hours; Finish, add entry 100g, stirred 30 minutes; Separatory, water layer is adding the 40ml n-hexane extraction 2 times; Merge oil reservoir, with 50ml washing 2 times; Finish, concentrate out normal hexane 150ml, cool to crystallizing at room temperature, obtain the Loratadine crude product.Use the acetonitrile recrystallization, get the 11g white solid.Yield 70%, 132～136 ℃ of fusing points.
Embodiment 2
Tricycle kentones 10g and 4-ethoxycarbonyl piperidone 7.4g are dissolved in the 40ml toluene solution, and be standby.
In the 250ml flask, drop into aluminium powder 7.4g and 120ml toluene; Stir temperature control to 20 ℃; Drip titanium tetrachloride 12ml, control 30 minutes and drip; 20 ℃ of insulations 30 minutes; Drip toluene solution dripped in 30 minutes; Finish, be incubated 2 hours; Good heat insulation adds 2 vitriol oils, temperature rising reflux 3 hours; Finish, add entry 100g, stirred 30 minutes; Separatory, water layer is adding 40ml toluene extraction 2 times; Merge oil reservoir, with 50ml washing 2 times; Finish, reclaim toluene, add acetonitrile and cool to crystallizing at room temperature, obtain the Loratadine crude product to doing.Use the acetonitrile recrystallization, get the 11.2g white solid.Yield 71.3%, 132～136 ℃ of fusing points.
Embodiment 3
Tricycle kentones 10g and 4-ethoxycarbonyl piperidone 7.4g are dissolved in 40ml methyltetrahydrofuran solution, and be standby.
In the 250ml flask, drop into magnesium powder 6.6g and 120ml methyltetrahydrofuran; Stir temperature control to 0 ℃; Drip titanium tetrachloride 12ml, control 30 minutes and drip; 0 ℃ of insulation 30 minutes; Drip methyltetrahydrofuran solution dripped in 30 minutes; Finish, be incubated 2 hours; Good heat insulation adds 2 vitriol oils, temperature rising reflux 3 hours; Finish, reclaim methyltetrahydrofuran to doing; Add entry 100g and sherwood oil, stirred 30 minutes; Separatory, water layer is adding the 40ml petroleum ether extraction 2 times; Merge oil reservoir, with 50ml washing 2 times; Finish, concentrate out sherwood oil 150ml, cool to crystallizing at room temperature, obtain the Loratadine crude product.Use the sherwood oil recrystallization, get the 11.3g white solid.Yield 72%, 132～136 ℃ of fusing points.
Inert solvent described in the foregoing description also can adopt other dimethylbenzene, tetrahydrofuran (THF) equal solvent; The vitriol oil can use any one or two kinds of above mixtures in acetate, hydrochloric acid, the sulfonic acid to replace; Magnesium or aluminium powder can use any one or two kinds of above mixtures in potassium, sodium, the zinc to replace; Titanium tetrachloride can be used TiCl
2, TiCl
3Or the mixture of itself and the above two is replaced.
Protection scope of the present invention is not limited to the foregoing description, and technical scheme all and of the present invention technology contents identical or that be equal to all falls in its protection domain.
Claims (5)
1, the novel synthesis of Loratadine, its step is as follows: 1) tricycle kentones and 4-ethoxy carbon back piperidone carry out condensation, 2 by low valent titanium reagent in inert solvent) obtain Loratadine through acid hydrolysis again.
2, the novel synthesis of Loratadine according to claim 1 is characterized in that using TiCl in inert solvent
X/ M prepares described low valent titanium reagent, TiCl
XBe TiCl
2, TiCl
3, TiCl
4In one or two or more kinds mix reagent, M is a kind of and mixture more than two kinds in potassium, sodium, magnesium, aluminium, the zinc.
3, the novel synthesis of Loratadine according to claim 1 and 2 is characterized in that the temperature of reaction in the step 1) is-10～50 ℃.
4, the novel synthesis of Loratadine according to claim 3 is characterized in that described inert solvent is one or more the mixed solvent in normal hexane, toluene, dimethylbenzene, tetrahydrofuran (THF), methyltetrahydrofuran, the sherwood oil.
5, the novel synthesis of Loratadine according to claim 4 is characterized in that step 2) described in acid be one or more mixture in sulfuric acid, acetate, hydrochloric acid, the sulfonic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100700371A CN101348480A (en) | 2007-07-17 | 2007-07-17 | Novel synthetic method of loratadine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100700371A CN101348480A (en) | 2007-07-17 | 2007-07-17 | Novel synthetic method of loratadine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101348480A true CN101348480A (en) | 2009-01-21 |
Family
ID=40267474
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100700371A Pending CN101348480A (en) | 2007-07-17 | 2007-07-17 | Novel synthetic method of loratadine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101348480A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109897027A (en) * | 2019-04-28 | 2019-06-18 | 梯尔希（南京）药物研发有限公司 | A kind of synthetic method of 3- hydroxyl Desloratadine metabolin |
| WO2023284782A1 (en) * | 2021-07-14 | 2023-01-19 | 复旦大学 | Method for screening compound for treating or preventing mhtt-related neurodegenerative diseases, target protein, and compound |
-
2007
- 2007-07-17 CN CNA2007100700371A patent/CN101348480A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109897027A (en) * | 2019-04-28 | 2019-06-18 | 梯尔希（南京）药物研发有限公司 | A kind of synthetic method of 3- hydroxyl Desloratadine metabolin |
| CN109897027B (en) * | 2019-04-28 | 2021-11-02 | 梯尔希（南京）药物研发有限公司 | Synthesis method of 3-hydroxychloroloratadine metabolite |
| WO2023284782A1 (en) * | 2021-07-14 | 2023-01-19 | 复旦大学 | Method for screening compound for treating or preventing mhtt-related neurodegenerative diseases, target protein, and compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN88101234A (en) | Acetylenes disubstituted with heteroaryl and tetralinyl having retinoid-like activity | |
| CN1765857A (en) | Extractive distillation separation method of normal hexane and methylcyclopentane | |
| CN102108059A (en) | Method for synthesizing doxylamine succinate | |
| CN102030706A (en) | Method for preparing 6-hydroxy-2(1H)-quinolone in ionic liquid by using one-pot method | |
| CN106946915A (en) | A kind of high-purity, method to chlorophenylboronic acid is prepared in high yield | |
| CN101348480A (en) | Novel synthetic method of loratadine | |
| CN105732484A (en) | Preparation method of Nimodipine | |
| CN104262110B (en) | One prepares the method for the 4-tertiary butyl-2-(α-methylbenzyl) phenol | |
| CN103664481A (en) | Method for refining petrobenzene and thiophene by adopting double-partition-wall extraction rectifying tower | |
| CN103772261B (en) | Preparation method of bazedoxifene | |
| CN103833560A (en) | Preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol | |
| CN102344407A (en) | 3-droperidol derivative and preparation method thereof | |
| CN104926605A (en) | Benzene-propanol azeotrope rectification separation method based on choline chloride further-co-melting solvent | |
| CN101429091B (en) | Decolorization method for recycling vinyl benzene with abstraction distillation | |
| CN101229988B (en) | Method for refining high-purity anthracene and carbazole from crude anthracene | |
| CN102786403B (en) | Preparation method for 4-tertiary butyl-4'-methoxy dibenzoyl methane | |
| CN104774174A (en) | Asymmetric synthesis method of S-carbinoxamine | |
| CN105820111A (en) | Preparation method of catalyst and method for preparing 2,2-dipyridyl through catalysis by virtue of catalyst | |
| CN102992949B (en) | Industrialized recycling method for o-chlorobenzaldehyde residual liquor | |
| CN102001913B (en) | Method for synthesizing 2-chloro-3-fluorobromobenzene | |
| CN104892381B (en) | A kind of recoverying and utilizing method of C14 aldehyde rectification low boiling by-product | |
| CN101575262A (en) | Method for reducing content of 2-methylnaphthalene impurity | |
| CN102174012A (en) | Preparation method of nimodipine | |
| CN103183680A (en) | Method for preparing asenapine | |
| CN105348046A (en) | Method for recycling 4-cumylphenol from phenolic tar |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090121 |