CN102653535A - Rupatadine free alkali and preparation method thereof - Google Patents
Rupatadine free alkali and preparation method thereof Download PDFInfo
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- CN102653535A CN102653535A CN2011104101544A CN201110410154A CN102653535A CN 102653535 A CN102653535 A CN 102653535A CN 2011104101544 A CN2011104101544 A CN 2011104101544A CN 201110410154 A CN201110410154 A CN 201110410154A CN 102653535 A CN102653535 A CN 102653535A
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- rupatadine
- free alkali
- rupatadine free
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Abstract
The invention discloses a rupatadine free alkali. The invention is characterized in that an Optimelt full-automatic micro melting point instrument (SRS Stanford Research Systems) determines that the melting point of the rupatadine free alkali ranges from 129 DEG C to 135 DEG C, and the DSC absorption peak of the rupatadine free alkali determined by a differential scanning calorimeter is 133.5 DEG C. The product purification is simple to operate; the obtained novel rupatadine free alkali is a crystalline powder substance with favorable dispersity and stability, and can be directly used for preparing medicines; and the solvent for preparing the rupatadine free alkali disclosed by the invention has very high solubility for various rupatadines, and is easy for separation and further purification.
Description
[technical field]
The present invention relates to the biological medicine technology field, relate in particular to a kind of Rupatadine free alkali and preparation method thereof.
[background technology]
Rupatadine and salt thereof have antihistamine and antagonism platelet activation factor (PAF) dual function, are a kind of novel cpds of treatment seasonality and catarrhus perennialis, once take tens milligrams and can obviously reduce because the anaphylaxis that histamine brings out.
This medicine went on the market in Europe in 2003; Be applied to treatment of allergic rhinitis and spring fever, have vast market prospect, the Rupatadine structural formula is seen Formula I as follows; Formal name used at school is: 8-chloro-6; 11-dihydro-11-[1-[(5-methyl-3-pyridyl) methyl]-4-piperidines subunit]-5H-benzo [5,6] suberane is [1,2-b] pyridine also.
Formula I
Synthetic and the purposes of Rupatadine is at EP577957; US5407941, CN101497606 and Journal of Medicinal Chemistry 1994,37 (17); All have open among the 2697-2703; Rupatadine can be synthetic by following several routes: route one: adopt the reaction of Desloratadine and 5-methylnicotinic acid to generate the Rupatadine acid amides, then reduction of amide is obtained the Rupatadine free alkali, concrete chemical formula is seen Formulae II; Route two: adopt Desloratadine and 3-methyl-5-monochloromethyl pyridine reaction to generate the Rupatadine free alkali, concrete chemical reaction is seen Formulae II I; US5407941 and Journal of Medicinal Chemistry 1994,37 (17), the method that two pieces of documents of 2697-2703 provide is that the synthetic Rupatadine is used the silicagel column purifying, and the Rupatadine free alkali of preparation is unformed powder, and fusing point is clamored 8-61 ℃.That this powder very easily bonds is agglomerating, caking, and unstable.
Formulae II
Formulae II I
Though the Rupatadine free alkali of CN101497606 reported method preparation does not pass through the silicagel column purifying, purity is also higher, and its fusing point also is 58-61 ℃, is unformed powder.
The Rupatadine free alkali purity of above-mentioned bibliographical information is not high, is unformed powder, and fusing point is low; Character is unstable; Easily the moisture absorption, rotten is difficult to directly be used for pharmaceutical applications, therefore generally all employing and mineral acid or organic acid; Fumaric acid salify particularly, the Rupatadine salt that makes is applied to pharmaceutical applications again.
WO2006103688A1 provides a kind of method for preparing the Rupatadine free alkali; This method is with a kind of Rupatadine xln that is called as Type B of preparation such as normal hexane, normal heptane, ether, isopropyl ethers; Fusing point 110-115 ℃, differential heat scan (DSC) thermal absorption peak is at 112 ℃.This method be Rupatadine in the presence of solvent by the unformed Type B crystal that is converted into, can make Powdered crystal Rupatadine free alkali by unformed.Even under the solvent heating condition that this method is used to the Rupatadine free alkali solubleness all very little; Having whole conversion process all is the solid-liquid inhomogeneous reaction, and solid-liquid disperses to be difficult to evenly, and transformation time is long; Product is carried impurity easily secretly; Problems such as quality product is low, simultaneously, this method can not be further purified the product in this prepared.
The Rupatadine of above-mentioned several method preparation, the purge process complicated operation, products obtained therefrom purity is difficult to further raising, can't it directly be used for pharmaceutical applications.
[summary of the invention]
The present invention addresses the above problem a kind of novel Rupatadine free alkali that can directly be used for pharmaceutical applications is provided; This novel Rupatadine free alkali has good dispersiveness and stable crystalline powder shape material, and the preparation method who provides a kind of easy handling, suitable economy of large scale to produce this novel Rupatadine free alkali.
The technical scheme that the present invention addresses the above problem is: a kind of Rupatadine free alkali; It is characterized in that; Measure through the full-automatic micro-fusing point appearance of Optimelt (SRS Stanford Research Systems); Its melting range is at 129-135 ℃, and the Rupatadine free alkali DSC absorption peak of measuring through DSC is 133.5 ℃.
The said method for preparing the Rupatadine free alkali is characterized in that, adopts ETHYLE ACETATE heating for dissolving Rupatadine; The mode of crystallisation by cooling prepares said Rupatadine free alkali then, and the temperature of heating guarantees under the situation of solvent for use amount, to be heated to the Rupatadine dissolving with all forms, and heating and temperature control is at 40-80 ℃; Cooling temperature generally is controlled at 0-30 ℃; After the cooling crystallization, adopt conventional solid-liquid separating method to separate, dry then.
Wherein heating and temperature control is at 50-70 ℃, and cooling temperature is controlled between 4-20 ℃.
The invention has the beneficial effects as follows: purified product simple to operate; The novel Rupatadine free alkali that obtains is to have good dispersiveness and stable crystalline powder shape material; Can directly be used for pharmacy; And it is very high to various types of Rupatadine solubleness to be used for preparing the solvent that Rupatadine free alkali that the present invention proposes adopts, and is easy to separate and further purifies.
[embodiment]
In order to make the object of the invention, technical scheme and advantage clearer, following examples are further elaborated to the present invention.Should be appreciated that specific embodiment described herein only in order to explanation the present invention, and be not used in qualification the present invention.
The present invention adopts ETHYLE ACETATE heating for dissolving Rupatadine; The mode of crystallisation by cooling prepares novel Rupatadine free alkali then; The temperature of heating guarantees under the situation of solvent for use amount, to be heated to the Rupatadine dissolving with all, and heating and temperature control preferably is controlled at 50-70 ℃ at 40-80 ℃.Cooling temperature generally is controlled at 0-30 ℃, is lower than 0 ℃, and energy consumption improves, and crystallization yield can't significantly improve; Be higher than 30 ℃, crystallization yield can reduce.Preferably be controlled between 4-20 ℃.After the cooling crystallization, adopt conventional solid-liquid separating method to separate, dry then, obtain novel Rupatadine free alkali of the present invention.
Embodiment is following:
Embodiment 1
In the 250ml single necked round bottom flask, add 4.30g (0.01 mole) Rupatadine acid amides, 3.78g (0.1 mole) Peng Qinghuana adds the 50ml THF again, places on the ice bath induction stirring.Other gets the 1140g trifluoroacetic acid, is dissolved in the 10ml THF being configured to solution, and this solution was splashed in 30 minutes in the above-mentioned flask, then temperature of charge is elevated to 30 ℃, keeps 2 hours.Material is cooled to 0 ℃ with ice bath, slowly splashes into 10% hydrochloric acid soln of 50ml, on Rotary Evaporators, boil off most of THF then, add 100ml water then; Be heated to backflow, kept 10 minutes, be cooled to 0 ℃, add the sodium hydroxide solution of 6 mol; Reach about 8 up to the pH value, use ethyl acetate extraction, use siccative dry then; Boil off solvent, obtain Rupatadine 3.11g, yield 74.76%.HPLC purity 98.0%.Fusing point 58-60 degree.
Embodiment 2
Adopt the Rupatadine of embodiment 1 preparation,, stir boiling off adding 30ml ETHYLE ACETATE in the sample bottle of solvent; Dissolving continues to stir 2 hours, separates out white solid; Filtration cakes torrefaction is filtered in ice-water bath cooling 1 hour; Obtain the 2.5g white crystalline powder, HPLC purity 99.8%, fusing point 129.2-130.5 ℃.
Embodiment 3
In the Rupatadine of embodiment 1 preparation, add the 30ml hexanaphthene, stirred 10 hours, filter, obtain off-white color crystalline powder 3.09g, HPLC purity 96.5%, fusing point 110-115 ℃.
Embodiment 4
In the Rupatadine free alkali of embodiment 3 preparations, add 30ml ETHYLE ACETATE, heating for dissolving, cool to room temperature filters, and drying obtains the 2.40g white crystalline powder, and fusing point 129.5-130.7 ℃, HPLC purity 99.9%.
Embodiment 5
53.1g Rupatadine fumarate (HPLC purity 93.4%) is suspended in the 500ml deionized water, splashes into 4 moles every liter sodium hydroxide solution pH to 9.0, add the 200ml methylene dichloride, vibration, separatory; Organic phase is through anhydrous magnesium sulfate, and evaporated under reduced pressure adds 400ml ETHYLE ACETATE, stirring and dissolving; Continue to stir 2 hours, separate out white solid, ice-water bath cooling 1 hour is filtered; Filtration cakes torrefaction obtains the 35.6g white crystalline powder, HPLC purity 99.9%, fusing point 129.2-130.5 ℃.
The above is merely preferred embodiment of the present invention, not in order to restriction the present invention, all any modifications of within spirit of the present invention and principle, being done, is equal to and replaces and improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. Rupatadine free alkali; It is characterized in that; Measure through the full-automatic micro-fusing point appearance of Optimelt (SRS Stanford Research Systems), its melting range is at 129-135 ℃, and the Rupatadine free alkali DSC absorption peak of measuring through DSC is 133.5 ℃.
2. prepare the method for Rupatadine free alkali according to claim 1, it is characterized in that, adopt the Rupatadine of the various forms of ETHYLE ACETATE heating for dissolving; The mode of crystallisation by cooling prepares said Rupatadine free alkali then, and the temperature of heating guarantees under the situation of solvent for use solubleness, to be heated to the Rupatadine dissolving with all forms, and heating and temperature control is at 40-80 ℃; Cooling temperature generally is controlled at 0-30 ℃; After the cooling crystallization, adopt conventional solid-liquid separating method to separate, dry then.
3. according to the said method for preparing the Rupatadine free alkali of claim 2, it is characterized in that wherein heating and temperature control is at 50-70 ℃, cooling temperature is controlled between 4-20 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011104101544A CN102653535A (en) | 2011-12-09 | 2011-12-09 | Rupatadine free alkali and preparation method thereof |
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| CN2011104101544A CN102653535A (en) | 2011-12-09 | 2011-12-09 | Rupatadine free alkali and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0577957A1 (en) * | 1992-05-22 | 1994-01-12 | J. URIACH & CIA. S.A. | 8-Chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine |
| WO2006103688A1 (en) * | 2005-04-01 | 2006-10-05 | Hetero Drugs Limited | A novel crystalline form of rupatadine free base |
| CN1865259A (en) * | 2005-05-19 | 2006-11-22 | 北京德众万全医药技术有限公司 | Process for preparing piperidine derivative |
| CN1985816A (en) * | 2005-12-22 | 2007-06-27 | 汕头大学医学院 | Oral disintegrated rupatadine tablet and its preparing method |
-
2011
- 2011-12-09 CN CN2011104101544A patent/CN102653535A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0577957A1 (en) * | 1992-05-22 | 1994-01-12 | J. URIACH & CIA. S.A. | 8-Chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine |
| WO2006103688A1 (en) * | 2005-04-01 | 2006-10-05 | Hetero Drugs Limited | A novel crystalline form of rupatadine free base |
| CN1865259A (en) * | 2005-05-19 | 2006-11-22 | 北京德众万全医药技术有限公司 | Process for preparing piperidine derivative |
| CN1985816A (en) * | 2005-12-22 | 2007-06-27 | 汕头大学医学院 | Oral disintegrated rupatadine tablet and its preparing method |
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Application publication date: 20120905 |