CN104610225B - Preparation method of desloratadine - Google Patents
Preparation method of desloratadine Download PDFInfo
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- CN104610225B CN104610225B CN201410849605.8A CN201410849605A CN104610225B CN 104610225 B CN104610225 B CN 104610225B CN 201410849605 A CN201410849605 A CN 201410849605A CN 104610225 B CN104610225 B CN 104610225B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a preparation method of desloratadine. The preparation method comprises the following steps: (1) dissolving loratadine into an alcohol solvent with the volume concentration of 55-75% under the protection of nitrogen, adding potassium hydroxide, heating to 70-75 DEG C, beginning reflux reaction, controlling the temperature of the reflux reaction to keep a gradient change within 70-100 DEG C, and refluxing till complete reaction of the loratadine; (2) adding an ethyl acetate solvent into a completely reacted reaction solution for extracting, draining out a water layer, repeating the extracting step for 2-3 times, washing by using water, and crystallizing, decolorizing and recrystallizing to obtain desloratadine. By the preparation method, the technical problems that in the prior art, the product desloratadine cannot meet a requirement for purity, contains many impurities, and cannot meet requirements on clinical application are solved.
Description
Technical field
The invention belongs to technical field of medicine synthesis is and in particular to a kind of method preparing high-purity Desloratadine.
Background technology
Desloratadine, chemical name is 8- chloro-6,11-dihydro -11 (4- piperidylidene) -5h- benzo -5,6 heptane 1,
2-b pyridine, is the long-acting tricyclic antidepressantss antihistaminic of non-sedating, is the active metabolite of Loratadine, can be by optionally
Antagonism periphery h1 receptor, the related symptoms of Reduce allergy rhinitis or chronic idiopathic urticaria.Desloratadine and the first generation
Compare with second filial generation antihistamine drug, there is strong, rapid-action, the low advantage of long action time, toxicity of effect, study at present
Confirm that Desloratadine is better than Loratadine and other antihistaminics in terms of improving allergic rhinitises nasal obstruction symptom, there is generation
Similar Decongestant effect.
Because Desloratadine is the metabolite of Loratadine, its pharmacological mechanism is similar to Loratadine, except can block
Outside histamine and h1 receptor binding, other anti-inflammatory activities are also had to include: 1. suppression ige and non-ige mediation basophilic/mastocyte synthesis
Il-4, il-13, il-6 and il-8 ability；2. the inflammatory cell membrane stabilizing action such as basophilic/mastocyte, suppression histamine, prostate
The inflammatory mediators such as element discharge；3. the adhesion molecule expression such as suppression rantes；4. stop eosinophilic granulocyte interior inflammatory cell across
Endothelium motion and the effect such as inflammatory cell chemotactic and infiltration；5. anti-adhesion molecule is as selected albumen p expression；6. suppression histamine,
Ltc4, pgd2ige dependent release；7. suppression neutrophil activation release reactive oxygen free radical.
Compared with the anti-allergy action of Loratadine, Desloratadine effect is higher, and side effect is less, such as: 1. exist
Desloratadine is higher to peripheral nervouss h1 histamine receptor selectivity ratios Loratadine and long action time, and the mankind are administered orally ground chlorine
The drug effect of Lei Tading is approximately 10 to 20 times of Loratadine, is approximately 2.5 to 4 times of Loratadine in animal；2. due to Desloratadine
Not easily pass through blood brain barrier, no Central nervous depressant, to ethanol also no invigoration effect, therefore psychomotor is caused to ethanol
Change no invigoration effect；3. do not find cholinolytic effect；4. Desloratadine acardia toxicity, schering-plough grinds
Study carefully and studied confirmation, compared with the second filial generation antihistamine drug such as Loratadine, high dose Desloratadine does not produce to experimenter
Cardiac toxicity, in the research, 24 health volunteers are administered orally Desloratadine Tablets or 45mg/ days (quantities 9 of syrup
Times) or placebo, continuous 10 days, period carried out 31 electrocardiogram monitorings, and qtc extends amplitude and is less than 6.5% (or 24msec),
Oral Desloratadine Tablets or syrup experimenter maximum qtc are 433msec, and taking placebo maximum qtc is 429msec, between pr
Phase and qrs time zero difference, show that Desloratadine Tablets or syrup have no significant effect to Electrocardiograph index, are a kind of safe and effective
Antihistaminic；5. Loratadine is also better than for human bronchial's smooth muscle cell h1 receptor acting；6. zoopery confirmation can
Significantly inhibit allergic bronchospasm reaction and allergic cough.
Studied by above pharmacological mechanism, it is known that Desloratadine is one kind there is multipath antagonism alterative inflammation
Matter Claritin.Develop multiple methods preparing Desloratadine in prior art, be former usually with Loratadine
Material, obtains Desloratadine through potassium hydroxide or sodium hydroxide hydrolysis, and product yield is 48-93%.Separately have Loratadine
Be added in the ethanol solution containing sodium hydroxide, back flow reaction, products therefrom through glacial acetic acid, chloroform extraction etc. process ground chlorine thunder he
Determine acetate, be then dissolved in water, with the alkalization of dilute solution of potassium carbonate, with chloroform extraction, extracting solution is washed, and concentrates, and adds
Hexane impregnates, and through recrystallization, obtains Desloratadine.But the Desloratadine of above-mentioned known method synthesis is usually present purity and reaches
Less than requiring, the problems such as impurity is many, Desloratadine product is led to be unfavorable for its clinical practice.
Content of the invention
For this reason, the technical problem to be solved is that the method preparing Desloratadine in prior art exists producing
Thing purity is low, is not suitable for directly carrying out the problem of clinical practice, and then provides a kind of side preparing high-purity Desloratadine
Method.
For solving above-mentioned technical problem, the invention provides a kind of preparation method of Desloratadine, comprise the steps:
(1) Loratadine shown in modus ponens a-i is dissolved in the alcohols solvent that volumetric concentration is 55-75% under nitrogen protection
In, it is subsequently adding potassium hydroxide and stirs, and be rapidly heated and proceed by back flow reaction to 70-75 DEG C, subsequently control described
Back flow reaction changes in 70-100 DEG C in gradient, is back to described Loratadine reaction completely；
(2) add the ethyl acetate solvent extraction 20-30min of 1/3-1/2 volume times in the reactant liquor to after reaction completely, protect
Hold extraction temperature and be 0-30 DEG C, stand 20-30min, release water layer and repeat above-mentioned extraction step 2-3 time, extract then to gained
Add pure water to wash in liquid 2-3 time, then carry out crystallizing, decolour and recrystallization process, obtain final product the Desloratadine shown in a-ii；
The preparation method of described Desloratadine, in described step (1), the gradient alternating temperature program of described back flow reaction
Particularly as follows: quickly reaction temperature is warming up to 80-85 DEG C by 70-75 DEG C, and keep reacting 2-3h；Subsequently it is rapidly heated to 100
DEG C, and keep reacting 2-3h；Subsequent fast cooling is to 80-85 DEG C, and keeps reacting 2-3h；Subsequently fast cooling is to 70-75 DEG C,
Until reaction is completely.
The preparation method of described Desloratadine, in described step (1), the gradient alternating temperature program of described back flow reaction
Particularly as follows: quickly reaction temperature is warming up to 100 DEG C by 70-75 DEG C, and keep reacting 2-3h；Subsequently fast cooling is to 80-85
DEG C, and keep reacting 2-3h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 2-3h；Subsequently again fast cooling to 80-85 DEG C,
Until reaction is completely.
The preparation method of described Desloratadine, in described step (1), the gradient alternating temperature program of described back flow reaction
Particularly as follows: quickly reaction temperature is warming up to 80-85 DEG C by 70-75 DEG C, and keep reacting 2-3h；Subsequently fast cooling is to 70
DEG C, and keep reacting 2-3h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 2-3h；Subsequently again fast cooling to 80-85 DEG C,
Until reaction is completely.
Also include, with thin layer chromatography detection described Loratadine reaction whether completely step, specifically including: negating should
Liquid spotting on lamellae, ethyl acetate with volume ratio as 1-3:1: petroleum ether is launched for developing solvent, if described reaction
The point of liquid disappears, then terminate described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears.
The preparation method of described Desloratadine, in described step (1), described alcohols solvent is volumetric concentration
65% ethanol.
The preparation method of described Desloratadine, in described step (2), described developing solvent ethyl acetate: petroleum ether
Volume ratio be 2:1.
The preparation method of described Desloratadine, in described step (2), described crystallisation step is specifically, to washing
Add anhydrous sodium sulfate stirring that 6-10h is dried in the extract obtaining afterwards, be filtered to remove sodium sulfate, the described filtrate of heating to 45-
65 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, crystal to be separated out, cool down described filtrate to 15-25 DEG C, stand crystallize 4-8h
To crystallizing completely, then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 45-55 DEG C and 4-8h is dried, obtain final product ground chlorine thunder he
Determine crystal crude product.
The preparation method of described Desloratadine, in described step (2), described decolorization process is specifically, to drying
Add ethyl acetate in Desloratadine crude product afterwards, and be heated to 70-80 DEG C, Desloratadine crude product described in stirring and dissolving,
It is subsequently adding activated carbon to carry out decolouring 20-40min to decolouring completely, filter, obtain final product the Desloratadine after decolouring.
The preparation method of described Desloratadine, in described step (2), described re-crystallization step will be specifically, will take off
Desloratadine after color is cooled to 15-25 DEG C, and stirring and crystallizing 4-8h, to crystallizing completely, then filters and with ethyl acetate drift
Wash, reduce pressure and be warming up to 45-55 DEG C and 6-8h is dried, obtain final product Desloratadine.
The invention provides the Desloratadine that a kind of preparation method by above-mentioned Desloratadine is prepared from.
The technique scheme of the present invention has the advantage that compared to existing technology
(1) preparation method of Desloratadine of the present invention, by controlling the temperature of back flow reaction at 70-100 DEG C
Inside change in gradient, so that Loratadine is reacted completely in the alcohols solvent containing potassium hydroxide, reduces side reaction and occurs, fall
The low pair such as formoxyl Desloratadine, acetyl group Desloratadine Desloratadine isomer, N-methyl Desloratadine
The generation of product, improves the content of target Desloratadine in product, further increases target product Desloratadine
Purity, the purity of the Desloratadine preparing reaches more than 99%, and purity averagely reaches 99.34%, reaches as high as
99.80%, meet target Desloratadine purity and the correlation about content of material in existing Desloratadine standard substance
Standard, is suitable for the application of clinic；
(2) preparation method of Desloratadine of the present invention, by being extracted to product using ethyl acetate solvent
Take, the strict amount controlling extractant to add, extraction time and extraction temperature, further increase the pure of product Desloratadine
Degree, so that the purity of product reaches more than 99%, meets the requirement of clinical practice；
(3) preparation method of Desloratadine of the present invention, by reacting liquid spotting on lamellae, with acetic acid
Ethyl ester: petroleum ether is launched for developing solvent, whether observing response is carried out completely, accurately can judge reaction end, can grasp
The property made is strong, further increases the content of Desloratadine in product；
(4) preparation method of Desloratadine of the present invention, processes ground chlorine by crystallization, decolouring and re-crystallization step
Lei Tading crude product, improves the content of Desloratadine in product, reduce the content of impurity so that preparation Desloratadine
Product meets the requirements；
(5) preparation method of Desloratadine of the present invention, by limiting the concentration of action solvent alcohols solvent
For 55-75%, compared to existing technology used in reaction dissolvent concentration low, due to reducing the concentration of action solvent, significantly carry
The high safety coefficient of reaction.
Specific embodiment
Described Loratadine crude drug in following embodiments of the present invention can be selected for commercially available prod, and manufacturer is Shanghai
Schering Plough pharmaceutical Co. Ltd.
The syntheti c route of the following embodiment of the present invention is as follows:
Embodiment 1
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 75%
The alcohol solvent of 138l in, be subsequently adding potassium hydroxide 30kg (535.7mol) and stir, and be rapidly heated to 70-75 DEG C
Proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder he
Fixed react completely, the gradient alternating temperature program of described back flow reaction particularly as follows: reaction temperature is quickly warming up to 80 DEG C by 75 DEG C, and
Keep reaction 3h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 2h；Subsequent fast cooling is to 85 DEG C, and keeps reacting 3h；
Subsequently fast cooling is to 70 DEG C, complete up to reaction；
With thin layer chromatography detection described Loratadine reaction whether completely, specifically include: extract reaction solution point sample in thin layer
On plate, ethyl acetate with volume ratio as 1:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears, eventually
Only described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 20min of 1/2 volume times in the reactant liquor after reaction completely, keep extraction
Take temperature to be 0-30 DEG C, stand 20min, release water layer and repeat above-mentioned extraction step 3 times, pure then to adding in gained extract
Water is washed 2 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 12.5kg (88mol) is added to stir
Mix and 6h is dried, be filtered to remove sodium sulfate, heat described filtrate to 45 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 15 DEG C of standing crystallize 4h to crystallizing completely, then filters and with ethyl acetate rinsing, decompression, control
Vacuum processed is below -0.08mpa, and is warming up to 45 DEG C 8h is dried, and obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 70 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 20min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 25 DEG C, stirring and crystallizing 4h is to crystallization
Completely, then filter and with ethyl acetate rinsing, decompression, control vacuum is below -0.078mpa, and is warming up to 45 DEG C of dryings
8h, obtains final product described Desloratadine.
Embodiment 2
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 55%
The methanol solvate of 163l in, be subsequently adding potassium hydroxide 60kg (1071.4mol) and stir, and be rapidly heated to 70-75
DEG C proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder
He is fixed to react completely, and the gradient alternating temperature program of described back flow reaction is particularly as follows: be quickly warming up to 100 by 75 DEG C by reaction temperature
DEG C, and keep reacting 2h；Subsequent fast cooling is to 85 DEG C, and keeps reacting 2h；Subsequently it is rapidly heated to 100 DEG C, and keep anti-
Answer 3h；Subsequently fast cooling is to 80 DEG C, complete up to reaction again；
With thin layer chromatography detection described Loratadine reaction whether completely, specifically include: extract reaction solution point sample in thin layer
On plate, ethyl acetate with volume ratio as 3:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears, eventually
Only described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 30min of 1/3 volume times in reaction completely reactant liquor, keep extraction
Temperature is 0-30 DEG C, stands 30min, releases water layer and repeats above-mentioned extraction step 2 times, then to adding pure water in gained extract
Washing 3 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 25kg (176.1mol) is added to stir
Mix and 10h is dried, be filtered to remove sodium sulfate, heat described filtrate to 65 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 25 DEG C of standing crystallize 8h to crystallizing completely, then filters and with ethyl acetate rinsing, reduce pressure and rise
Temperature is dried 4h to 55 DEG C, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 80 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 40min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 15 DEG C, stirring and crystallizing 8h is to crystallization
Completely, then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 55 DEG C and 6h is dried, obtain final product Desloratadine.
Embodiment 3
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 65%
The propanol solvent of 138l in, be subsequently adding potassium hydroxide 40kg (714.3mol) and stir, and be rapidly heated to 70-75 DEG C
Proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder he
Fixed react completely, the gradient alternating temperature program of described back flow reaction particularly as follows: reaction temperature is quickly warming up to 85 DEG C by 70 DEG C, and
Keep reaction 2h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 3h；Subsequent fast cooling is to 80 DEG C, and keeps reacting 2h；
Subsequently fast cooling is to 75 DEG C, complete up to reaction；
(2) add the ethyl acetate solvent extraction 25min of 1/3 volume times in the reactant liquor after reaction completely, keep extraction
Take temperature to be 0-30 DEG C, stand 30min, release water layer and repeat above-mentioned extraction step 3 times, pure then to adding in gained extract
Water is washed 3 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 12.5kg (88mol) is added to stir
Mix and 6h is dried, be filtered to remove sodium sulfate, heat described filtrate to 50 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 22 DEG C of standing crystallize 5h to crystallizing completely, then filters and with ethyl acetate rinsing, decompression, control
Vacuum processed is below -0.08mpa, and is warming up to 48 DEG C 7h is dried, and obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 73 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 25min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 23 DEG C, stirring and crystallizing 5h is to crystallization
Completely, then filter and with ethyl acetate rinsing, decompression, control vacuum is below -0.078mpa, and is warming up to 49 DEG C of dryings
7h, obtains final product described Desloratadine.
Embodiment 4
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 55%
The benzyl alcohol solvent of 163l in, be subsequently adding potassium hydroxide 50kg (893mol) and stir, and be rapidly heated to 70-75 DEG C
Proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder he
Fixed react completely, the gradient alternating temperature program of described back flow reaction particularly as follows: reaction temperature is quickly warming up to 100 DEG C by 70 DEG C,
And keep reacting 3h；Subsequent fast cooling is to 80 DEG C, and keeps reacting 3h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting
2h；Subsequently fast cooling is to 85 DEG C, complete up to reaction again；
(2) add the ethyl acetate solvent extraction 28min of 1/2 volume times in reaction completely reactant liquor, keep extraction
Temperature is 0-30 DEG C, stands 27min, releases water layer and repeats above-mentioned extraction step 2 times, then to adding pure water in gained extract
Washing 3 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 15kg (105.6mol) is added to stir
Mix and 8h is dried, be filtered to remove sodium sulfate, heat described filtrate to 60 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 18 DEG C of standing crystallize 5h to crystallizing completely, then filters and with ethyl acetate rinsing, reduce pressure and rise
Temperature is dried 7h to 50 DEG C, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 75 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 34min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 19 DEG C, stirring and crystallizing 7h is to crystallization
Completely, then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 55 DEG C and 7h is dried, obtain final product Desloratadine.
Embodiment 5
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 60%
The alcohol solvent of 150l in, be subsequently adding potassium hydroxide 45kg (803.6mol) and stir, and be rapidly heated to 70-75 DEG C
Proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder he
Fixed react completely, described back flow reaction gradient alternating temperature program particularly as follows: reaction temperature is quickly warming up to 85 DEG C by 70 DEG C,
And keep reacting 2h；Subsequent fast cooling is to 70 DEG C, and keeps reacting 3h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting
2h；Subsequently fast cooling is to 85 DEG C, complete up to reaction again；
(2) add the ethyl acetate solvent extraction 25min of 5/12 volume times in reaction completely reactant liquor, keep extraction
Temperature is 0-30 DEG C, stands 25min, releases water layer and repeats above-mentioned extraction step 2 times, then to adding pure water in gained extract
Washing 2 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 18kg (126.8mol) is added to stir
Mix and 8h is dried, be filtered to remove sodium sulfate, heat described filtrate to 55 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 20 DEG C of standing crystallize 6h to crystallizing completely, then filters and with ethyl acetate rinsing, reduce pressure and rise
Temperature is dried 6h to 50 DEG C, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 75 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 30min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 20 DEG C, stirring and crystallizing 6h is to crystallization
Completely, then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 50 DEG C and 7h is dried, obtain final product Desloratadine.
Embodiment 6
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 65%
The alcohol solvent of 150l in, be subsequently adding potassium hydroxide 45kg (803.6mol) and stir, and be rapidly heated to 70-75 DEG C
Proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder he
Fixed react completely, the gradient alternating temperature program of described back flow reaction particularly as follows: reaction temperature is quickly warming up to 80 DEG C by 75 DEG C, and
Keep reaction 3h；Subsequent fast cooling is to 70 DEG C, and keeps reacting 2h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 3h；
Subsequently fast cooling is to 80 DEG C, complete up to reaction again；
With thin layer chromatography detection described Loratadine reaction whether completely step, specifically include: extract reaction solution point sample
On lamellae, ethyl acetate with volume ratio as 2:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears
Lose, then terminate described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 25min of 5/12 volume times in reaction completely reactant liquor, keep extraction
Temperature is 0-30 DEG C, stands 25min, releases water layer and repeats above-mentioned extraction step 2 times, then to adding pure water in gained extract
Washing 2 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 18kg (126.8mol) is added to stir
Mix and 8h is dried, be filtered to remove sodium sulfate, heat described filtrate to 55 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 20 DEG C of standing crystallize 6h to crystallizing completely, then filters and with ethyl acetate rinsing, reduce pressure and rise
Temperature is dried 6h to 50 DEG C, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 75 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 30min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 20 DEG C, stirring and crystallizing 6h is to crystallization
Completely, then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 50 DEG C and 7h is dried, obtain final product Desloratadine.
Embodiment 7
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 75%
The alcohol solvent of 138l in, be subsequently adding potassium hydroxide 30kg (535.7mol) and stir, and be rapidly heated to 70-75 DEG C
Proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder he
Fixed react completely, the gradient alternating temperature program of described back flow reaction particularly as follows: reaction temperature is quickly warming up to 83 DEG C by 73 DEG C, and
Keep reaction 2.5h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 2.5h；Subsequent fast cooling is to 83 DEG C, and keeps reacting
2.5h；Subsequently fast cooling is to 73 DEG C, complete up to reaction；
With thin layer chromatography detection described Loratadine reaction whether completely, specifically include: extract reaction solution point sample in thin layer
On plate, ethyl acetate with volume ratio as 1:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears, eventually
Only described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 20min of 1/2 volume times in the reactant liquor after reaction completely, keep extraction
Take temperature to be 0-30 DEG C, stand 20min, release water layer and repeat above-mentioned extraction step 3 times, pure then to adding in gained extract
Water is washed 2 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 12.5kg (88mol) is added to stir
Mix and 6h is dried, be filtered to remove sodium sulfate, heat described filtrate to 45 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 15 DEG C of standing crystallize 4h to crystallizing completely, then filters and with ethyl acetate rinsing, decompression, control
Vacuum processed is below -0.08mpa, and is warming up to 45 DEG C 8h is dried, and obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 70 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 20min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 25 DEG C, stirring and crystallizing 4h is to crystallization
Completely, then filter and with ethyl acetate rinsing, decompression, control vacuum is below -0.078mpa, and is warming up to 45 DEG C of dryings
8h, obtains final product described Desloratadine.
Embodiment 8
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 55%
The methanol solvate of 163l in, be subsequently adding potassium hydroxide 60kg (1071.4mol) and stir, and be rapidly heated to 70-75
DEG C proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder
He is fixed to react completely, and the gradient alternating temperature program of described back flow reaction is particularly as follows: be quickly warming up to 100 by 73 DEG C by reaction temperature
DEG C, and keep reacting 2.5h；Subsequent fast cooling is to 83 DEG C, and keeps reacting 2.5h；Subsequently it is rapidly heated to 100 DEG C, and protect
Hold reaction 2.5h；Subsequently fast cooling is to 83 DEG C, complete up to reaction again；
With thin layer chromatography detection described Loratadine reaction whether completely, specifically include: extract reaction solution point sample in thin layer
On plate, ethyl acetate with volume ratio as 3:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears, eventually
Only described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 30min of 1/3 volume times in reaction completely reactant liquor, keep extraction
Temperature is 0-30 DEG C, stands 30min, releases water layer and repeats above-mentioned extraction step 2 times, then to adding pure water in gained extract
Washing 3 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 25kg (176.1mol) is added to stir
Mix and 10h is dried, be filtered to remove sodium sulfate, heat described filtrate to 65 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 25 DEG C of standing crystallize 8h to crystallizing completely, then filters and with ethyl acetate rinsing, reduce pressure and rise
Temperature is dried 4h to 55 DEG C, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 80 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 40min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 15 DEG C, stirring and crystallizing 8h is to crystallization
Completely, then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 55 DEG C and 6h is dried, obtain final product Desloratadine.
Embodiment 9
The preparation method of the Desloratadine described in the present embodiment, comprises the steps:
(1) Loratadine 15kg shown in modus ponens a-i (39.17mol) is dissolved in volumetric concentration under nitrogen protection is 65%
The alcohol solvent of 150l in, be subsequently adding potassium hydroxide 45kg (803.6mol) and stir, and be rapidly heated to 70-75 DEG C
Proceed by back flow reaction, subsequently control described back flow reaction to change in gradient in 70-100 DEG C, be back to described chlorine thunder he
Fixed react completely, the gradient alternating temperature program of described back flow reaction particularly as follows: reaction temperature is quickly warming up to 83 DEG C by 73 DEG C, and
Keep reaction 2.5h；Subsequent fast cooling is to 70 DEG C, and keeps reacting 2.5h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting
2.5h；Subsequently fast cooling is to 83 DEG C, complete up to reaction again；
With thin layer chromatography detection described Loratadine reaction whether completely step, specifically include: extract reaction solution point sample
On lamellae, ethyl acetate with volume ratio as 2:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears
Lose, then terminate described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 25min of 5/12 volume times in reaction completely reactant liquor, keep extraction
Temperature is 0-30 DEG C, stands 25min, releases water layer and repeats above-mentioned extraction step 2 times, then to adding pure water in gained extract
Washing 2 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, in the extract obtaining to after washing, anhydrous sodium sulfate 18kg (126.8mol) is added to stir
Mix and 8h is dried, be filtered to remove sodium sulfate, heat described filtrate to 55 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, wait to separate out
Crystal, cools down described filtrate to 20 DEG C of standing crystallize 6h to crystallizing completely, then filters and with ethyl acetate rinsing, reduce pressure and rise
Temperature is dried 6h to 50 DEG C, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 75 DEG C,
Desloratadine crude product described in stirring and dissolving, is subsequently adding activated carbon and carries out the 30min that decolours, filter, obtain final product the ground chlorine after decolouring
Lei Tading；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 20 DEG C, stirring and crystallizing 6h is to crystallization
Completely, then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 50 DEG C and 7h is dried, obtain final product Desloratadine.
Comparative example 1
The preparation method of the Desloratadine described in the present embodiment is essentially identical with the preparation process of above-described embodiment 1, area
It is not only that the temperature constant during back flow reaction in the present embodiment is 70 DEG C, prepare described Desloratadine.
Comparative example 2
The preparation method of the Desloratadine described in the present embodiment is essentially identical with the preparation process of above-described embodiment 1, area
It is not only that the temperature constant during back flow reaction in the present embodiment is 85 DEG C, prepare described Desloratadine.
Comparative example 3
The preparation method of the Desloratadine described in the present embodiment is essentially identical with the preparation process of above-described embodiment 1, area
It is not only that the temperature constant during back flow reaction in the present embodiment is 100 DEG C, prepare described Desloratadine.
Comparative example 4
The preparation method of the Desloratadine described in the present embodiment is essentially identical with the preparation process of above-described embodiment 1, area
Be not only that back flow reaction described in the present embodiment gradient alternating temperature program particularly as follows: controlling reaction temperature by 70 DEG C in 8h
Ramped thermal is to 85 DEG C, and keeps this temperature to be reacted, the described Desloratadine preparing.
Comparative example 5
The preparation method of the Desloratadine described in the present embodiment is essentially identical with the preparation process of above-described embodiment 1, area
Be not only that back flow reaction described in the present embodiment gradient alternating temperature program particularly as follows: temperature is rapidly heated to 85 by 70 DEG C
DEG C, and keep reacting 4h, subsequently it is rapidly heated to 100 DEG C, and reacted at a temperature of keeping this, the described ground chlorine preparing
Lei Tading.
Effect example
To the relevant material in the Desloratadine preparing in above-described embodiment 1-9, comparative example 1-5 and target ground chlorine
Lei Tading is measured, and relevant material adopts Syrups by HPLC, and the content of Desloratadine adopts titration measuring.
Described relevant substance-measuring method is as follows:
1st, total miscellaneous mensure
The preparation of need testing solution: take the Desloratadine 10mg of preparation, accurately weighed, put in 50ml measuring bottle, plus flowing
Phase solution dissolves and is diluted to scale, as need testing solution；
The preparation of contrast solution: precision measures the need testing solution 1ml of above-mentioned preparation, puts in 100ml measuring bottle, plus mobile phase
Solution is diluted to scale, as contrast solution；
Chromatographic condition and system suitability:
According to high effective liquid chromatography for measuring, it is filler with octadecylsilane chemically bonded silica；With volume ratio as 20:80
Acetonitrile-water phase (in described aqueous phase contain biphosphate ammonium concentration be 0.05mol/l, tetrabutylammonium iodide concentration be 0.001mol/
L, with phosphoric acid tune ph value to 2.6) it is mobile phase, Detection wavelength is 238nm, and flow velocity is 1.0ml/min, and theoretical version number is with ground chlorine thunder
He determines peak calculating and should be not less than 2500.
Assay method:
Take contrast solution 10ul injection chromatograph of liquid, conditioning instrumentation sensitivity, make contrast solution main constituent chromatograph peak height
For the 10～25% of full scale, then take need testing solution 10ul injection chromatograph of liquid, record chromatogram is to main constituent chromatographic peak
The twice of retention time.
As aobvious impurity peaks in need testing solution chromatogram, measure the sum of each impurity peak area, contrast solution should be cannot be greater than
Main peak area 1.0%
2nd, the mensure of Loratadine
The preparation of need testing solution: take the Desloratadine 20mg of preparation, accurately weighed, put in 50ml measuring bottle, plus acetonitrile
Dissolve and be diluted to scale, as need testing solution；
The preparation of reference substance solution: take Loratadine reference substance 10mg, plus acetonitrile dissolves and dilutes and makes every 1ml containing 4 μ g
Solution, as reference substance solution；
Chromatographic condition and system suitability:
According to high effective liquid chromatography for measuring, it is filler with octadecylsilane chemically bonded silica；With volume ratio as 65:35
Acetonitrile-water phase (containing 0.003mol/l sodium lauryl sulphate, 1% acetic acid, 1.5% triethylamine in described aqueous phase) is flowing
Phase, Detection wavelength is 238nm, and flow velocity is 1.0ml/min, and number of theoretical plate is calculated with Loratadine peak and should be not less than 2500.
Assay method:
Take need testing solution and reference substance solution each 10ul injection chromatograph of liquid, Loratadine peak face in need testing solution
Amass and should cannot be greater than the 1/2 (0.5%) of reference substance solution main peak area.
3rd, carbamylation Loratadine measures:
The preparation of need testing solution: take the Desloratadine 10mg of preparation, accurately weighed, put in 50ml measuring bottle, plus flowing
Phased soln is simultaneously diluted to scale and shakes up, as need testing solution；
The preparation of contrast solution: precision measures need testing solution 1ml, puts in 100ml measuring bottle, plus mobile phase is diluted to scale
Shake up, as contrast solution.
The preparation of reference substance solution: take carbamylation Loratadine reference substance 10mg, put in 50ml measuring bottle, plus flowing mixes
Solve and be diluted to scale, as reference substance solution.
Chromatographic condition and system suitability:
According to high effective liquid chromatography for measuring, it is filler with octadecylsilane chemically bonded silica；With volume ratio as 65:35
Acetonitrile-water phase (containing 0.003mol/l sodium lauryl sulphate, 1% acetic acid, 1.5% triethylamine in described aqueous phase) is flowing
Phase, Detection wavelength is 238nm, and flow velocity is 1.0ml/min, and number of theoretical plate is calculated with Desloratadine peak and should be not less than 2500.
Assay method:
Take contrast solution 10ul injection chromatograph of liquid, conditioning instrumentation sensitivity, make contrast solution main constituent chromatograph peak height
For the 10～25% of full scale, then take need testing solution and reference substance solution each 10ul injection chromatograph of liquid, record chromatogram
Twice to main constituent chromatographic peak retention time.
In need testing solution chromatogram, the peak area of carbamylation Loratadine should cannot be greater than contrast solution main peak area
1/2 (0.5%)
Described Desloratadine method for detecting purity is as follows:
Take the Desloratadine about 0.1g of preparation, accurately weighed, acetic acid 20ml on the rocks, mercuric acetate test solution 5ml, heated and stirred
Make dissolving, let cool, according to potentiometric titration, slowly titrated with 0.1mol/l perchloric acid titration liquid, the 0.1mol/l perchloric acid of every 1ml
Volumetric solution is equivalent to the c of 15.54mg19h19cln2.
Described Desloratadine is 8- chloro- 6,11- dihydro -11- (4- piperidylidene) -5h- benzo-[5,6] ring in heptan [1,2-
B] pyridine.Calculate by dry product, containing Desloratadine (c19h19cln2) 99.0% must not be less than.
The effect data of each embodiment of table 1
Compare discovery by the above results, the purity of the Desloratadine that method of the present invention prepares reaches 99%
More than, purity averagely reaches 99.34%, reaches as high as 99.80%, and in described Desloratadine, his fixed limit degree of impurity chlorine thunder is all little
In 0.3%, less than bound requirements；Carbamylation Loratadine limit is respectively less than 0.5%, less than bound requirements；Total impurities limit
It is not more than 1.0%.It is indicated above that method of the present invention significantly improves the purity of Desloratadine, the limit of impurities shows
Writing and reduce, meeting the purity of target Desloratadine and the relevant criterion about material in said determination method, thus solving
In prior art, the Desloratadine purity of preparation does not reach requirement, the limit of impurities high it is impossible to directly apply to asking of clinic
Topic.
Obviously, above-described embodiment is only intended to clearly illustrate example, and the not restriction to embodiment.Right
For those of ordinary skill in the art, can also make on the basis of the above description other multi-forms change or
Change.There is no need to be exhaustive to all of embodiment.And the obvious change thus extended out or
Change among still in the protection domain of the invention.
Claims (2)
1. a kind of preparation method of Desloratadine is it is characterised in that comprise the steps:
(1) Loratadine 15kg shown in modus ponens a-i be dissolved under nitrogen protection the 163l that volumetric concentration is 55% methanol molten
In agent, it is subsequently adding potassium hydroxide 60kg and stirs, and be rapidly heated and proceed by back flow reaction to 70-75 DEG C, subsequently control
Make described back flow reaction to change in gradient in 70-100 DEG C, be back to described Loratadine reaction completely, described back flow reaction
Gradient alternating temperature program particularly as follows: reaction temperature is quickly warming up to 100 DEG C by 73 DEG C, and keep react 2.5h；Subsequently quick
It is cooled to 83 DEG C, and keep reacting 2.5h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 2.5h；Subsequent fast cooling again is extremely
83 DEG C, until reaction is completely；
With thin layer chromatography detection described Loratadine reaction whether completely, specifically include: extract reaction solution point sample on lamellae,
Ethyl acetate with volume ratio as 3:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears, terminates institute
State back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 30min of 1/3 volume times in reaction completely reactant liquor, keep extraction temperature
For 0-30 DEG C, stand 30min, release water layer and repeat above-mentioned extraction step 2 times, then to adding pure water washing in gained extract
3 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, add anhydrous sodium sulfate 25kg stirring that 10h is dried in the extract obtaining to after washing, filter
Remove sodium sulfate, heat described filtrate to 65 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, crystal to be separated out, cooling is described
Filtrate, to 25 DEG C of standing crystallize 8h to crystallizing completely, is then filtered and with ethyl acetate rinsing, is reduced pressure and be warming up to 55 DEG C of dryings
4h, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 80 DEG C, stirring
Dissolve described Desloratadine crude product, be subsequently adding activated carbon carry out decolour 40min, filter, obtain final product the ground chlorine thunder after decolouring he
Fixed；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 15 DEG C, stirring and crystallizing 8h is complete to crystallizing,
Then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 55 DEG C and 6h is dried, obtain final product Desloratadine；
2. a kind of preparation method of Desloratadine is it is characterised in that comprise the steps:
(1) Loratadine 15kg shown in modus ponens a-i be dissolved under nitrogen protection the 150l that volumetric concentration is 65% ethanol molten
In agent, it is subsequently adding potassium hydroxide 45kg and stirs, and be rapidly heated and proceed by back flow reaction to 70-75 DEG C, subsequently control
Make described back flow reaction to change in gradient in 70-100 DEG C, be back to described Loratadine reaction completely, described back flow reaction
Gradient alternating temperature program particularly as follows: reaction temperature is quickly warming up to 83 DEG C by 73 DEG C, and keep react 2.5h；Subsequently fast prompt drop
Temperature is to 70 DEG C, and keeps reacting 2.5h；Subsequently it is rapidly heated to 100 DEG C, and keep reacting 2.5h；Subsequently again fast cooling to 83
DEG C, until reaction is completely；
With thin layer chromatography detection described Loratadine reaction whether completely step, specifically include: extract reaction solution point sample in thin
On laminate, ethyl acetate with volume ratio as 2:1: petroleum ether is launched for developing solvent, if the point of described reactant liquor disappears,
Terminate described back flow reaction；Conversely, then continuing described back flow reaction until the point of described reactant liquor disappears；
(2) add the ethyl acetate solvent extraction 25min of 5/12 volume times in reaction completely reactant liquor, keep extraction temperature
For 0-30 DEG C, stand 25min, release water layer and repeat above-mentioned extraction step 2 times, then to adding pure water washing in gained extract
2 times；Then the extract after washing is carried out crystallizing, decolours and recrystallization process, specific as follows:
In described crystallisation step, add anhydrous sodium sulfate 18kg stirring that 8h is dried in the extract obtaining to after washing, filter
Remove sodium sulfate, heat described filtrate to 55 DEG C of evaporation and concentration, and recovered under reduced pressure ethyl acetate, crystal to be separated out, cooling is described
Filtrate, to 20 DEG C of standing crystallize 6h to crystallizing completely, is then filtered and with ethyl acetate rinsing, is reduced pressure and be warming up to 50 DEG C of dryings
6h, obtains final product Desloratadine crude product；
In described decolorization process, add ethyl acetate in dried Desloratadine crude product, and be heated to 75 DEG C, stirring
Dissolve described Desloratadine crude product, be subsequently adding activated carbon carry out decolour 30min, filter, obtain final product the ground chlorine thunder after decolouring he
Fixed；
In described re-crystallization step, the Desloratadine after decolouring is cooled to 20 DEG C, stirring and crystallizing 6h is complete to crystallizing,
Then filter and with ethyl acetate rinsing, reduce pressure and be warming up to 50 DEG C and 7h is dried, obtain final product Desloratadine；
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| CN109020950A (en) * | 2017-06-09 | 2018-12-18 | 浙江普利药业有限公司 | A kind of Desloratadine preparation process |
| CN111848575A (en) * | 2020-06-28 | 2020-10-30 | 山东达因海洋生物制药股份有限公司 | Desloratadine crystal form IV and preparation method thereof |
| CN112047923A (en) * | 2020-09-07 | 2020-12-08 | 上海阿达玛斯试剂有限公司 | Preparation method of desloratadine |
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| EP1860105A1 (en) * | 2006-05-24 | 2007-11-28 | Ranbaxy Laboratories Limited | Process for the preparation of desloratadine |
| EP1862462A1 (en) * | 2006-04-10 | 2007-12-05 | Ranbaxy Laboratories Limited | Process for the preparation of desloratadine |
| CN103804357A (en) * | 2014-01-02 | 2014-05-21 | 珠海金鸿药业股份有限公司 | Rupatadine fumarate compound as well as synthesis method and pharmaceutical composition thereof |
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| CZ200798A3 (en) * | 2004-07-07 | 2007-06-20 | Egis Gyogyszergyár Nyrt. | Novel desloratadine pseudopolymorph prepared with the aid of carbon dioxide |
| US20080287481A1 (en) * | 2006-09-08 | 2008-11-20 | Mayur Devjibhai Khunt | Process for the preparation of desloratadine polymorph mixtures |
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| EP1862462A1 (en) * | 2006-04-10 | 2007-12-05 | Ranbaxy Laboratories Limited | Process for the preparation of desloratadine |
| EP1860105A1 (en) * | 2006-05-24 | 2007-11-28 | Ranbaxy Laboratories Limited | Process for the preparation of desloratadine |
| CN103804357A (en) * | 2014-01-02 | 2014-05-21 | 珠海金鸿药业股份有限公司 | Rupatadine fumarate compound as well as synthesis method and pharmaceutical composition thereof |
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