FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
"Improved method for the preparation of Desloratadine with reduced levels of organic solvents".
CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD, 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TITLE : Improved method for the preparation of Desloratadine with reduced levels of
organic solvents

FIELD OF THE INVENTION
The present invention relates to preparation of Desloratadine with substantially free of
organic solvents. The present invention further relates to a process for the preparation of desloratadine which results in desloratadine wherein the content of chloroform and hexane in desloratadine always remains below the maximimum allowable limit set by ICH guidelines.
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BACKGROUND OF THE INVENTION
US 4659716 describes the preparation of Desloratadine form Loratadine by first reacting Loratadine with sodium hydroxide in ethanol(70 %) [ see example-Ill column-16] at reflux for 24 hours. About 50 % of the solvent is removed by distillation from the reaction mixture , a small amount of ice water is added and acidified with acetic acid. Acetate salt is extracted in chloroform, concentrated and precipitated with hexane to give crude acetate [m.p. 197-200°C], recrystallized from benzene-hexane to give pure compound having m.p. 199-200 C.
The acetate salt prepared by above mentioned process is converted to desloratadine as per process given in Example-5 [US 4659716] as follows.
Acetate salt is dissolved in a minimum amount of water and the solution is made basic with a dilute aqueous solution of potassium carbonate. A pink colored oil is separated. The organic material is extracted with chloroform washed with water and the solvent is removed. The residue is triturated with hexane. The product is recrystallized from a large volume of hexane after charcoal decolorization. To give a product with m.p. 151 -152°C.
On repeating the process mentioned in US 4659716,for the preparation of desloratadine from desloratadine acetate , we found that the product is not recrystallizable from hexane, and as it is not dissolving in hexane charcoal treatment could not be given. Moreover the compound is pinkish in color. The product prepared by following this [US 4659716] process, gives a high level contamination of residual solvents which could not be removed even after prolonged drying.
By following process mentioned in US 4659716, we obtained desloratadine having content of chloroform of about ppm 4257 [against ICH limit of max 60 ppm], and hexane of about ppm 450 [ against ICH limit of max 290 ppm ]. US 465916 [ in example VI ] describes preparation of desloratadine by reacting 8-
chloroazatadine in benzene with cyanogen bromide in benzene to give after filtration, concentration of filtrate,treating with petroleum ether or hexane followed by filtration and
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recrystallization in ethanol/water to give 8-chloro-6,ll-dihydro-ll(l-cyano-4-
piperidylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine in 89% yield.
A solution of this N-cyano compound in concentrated hydrochloride acid is treated in glacial acetic acid and water at reflux temp for 20 hours . The solvents are removed in vacuo and the residue is dissolved in water and neutralized with ammonium hydroxide.
The material is extracted several times with chloroform, chloroform extracts washed with water and concentrated to dryness and the residue is triturated with petroleum ether or hexane to yield desloratadine in 93% yield having m.p. 149-151°C, which after recrystallization from hexane gives pure compound having m.p. 150-151 C. Following this process also we get very high degree of contamination of chloroform and hexane in desloratadine .
The methods described in prior art are not satisfactory as the material produced as per these processes contain high levels of solvents beyond the acceptable ICH limits.
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SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process of preparation of desloratadme
having content of chloroform and hexane which satisfy ICH requirement.
It is another object of the present invention to provide an improved process of preparation of desloratadine which does not use any organic solvent in the conversion of desloratadine acid salt to desloratadine
By following our process we get about 38 ppm of chloroform and 249 ppm of n-hexane. The ICH limit for chloroform is 60 ppm and ICH limit for n-hexane is 290 ppm.
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DETAILED DESCRIPTION
In accordance with present invention desloratadine is prepared from desloratadine acid salt such as desloratadine acetate in steps as follows by method A or B Method A
(a) basifying desloratadine acid salt [ such as desloratadine acetate] in aqueous medium , extracting desloratadine free base in chloroform, separating organic layer and concentrating up to about 10-20% of initial volume,
(b) adding water followed by distilling chloroform azeotropically, followed by distilling about 90 % of water,
(c) removing water using hexane , followed by isolating desloratadine from reaction mass at about 20-25 C.
Method B
(a) basifying desloratadine acid salt [ such as desloratadine acetate] in aqueous medium, using base preferably aqueous carbonate solution, followed by heating to 65-70°C for about 6-12 hours, cooling the reaction mass to room temperature.
(b) Isolating desloratadine by filtration / centrifugation and drying.
The present invention is illustrated by following non-limiting examples
Example-1
Sodium hydroxide (150 gms) was taken in specially denatured spirit 500 ml (70 %) and
stirred for about 30 minutes.
Loratadine [ 100 gm ] was added and heated to 80-85° and stirred at same temperature
(for about 12 hours ) till % of Loratadine is < 1% on TLC . Ethanol was distilled out
completely under vacuum at 45-50°C . The reaction mass was cooled to 20-25°C.
Chloroform (500 ml) was added and stirred for 15 minutes. The pH was adjusted to 5.5
to 6.5 using acetic acid at 15-20°C. The reaction mass was stirred for about 30 minutes.
Water (1 L) was charged, and stirred for 30 minutes. Layers were separated, aqueous
phase was extracted with chloroform (200 ml, 100 ml) .The combined organic layer was
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washed with 10 % brine (100 ml x 2). Chloroform layer was treated with activated carbon , filtered using hyflo and dried over anhydrous sodium sulfate. The chloroform was
distilled out under vacuum at 40°C. n-Hexane (100 ml ) was used to strip off residual chloroform at 40-45°C under vacuum. n-Hexane (500 ml) was added and stirred for 3 hours at 40-45°C , cooled to 10-15°C filtered and washed with 100 ml n-hexane and dried at 60-65°C under vacuum for 6-8 hours to give crude desloratadine acetate (85 gms.)
Purification of crude desloratadine acetate :
crude desloratadine acetate (85 gms) was taken in isopropyl alcohol ( 850 ml), heated to reflux. Water (42.5 ml) was added. A clear soln was obtained at reflux temperature , activated Carbon was added , stirred for 30 min at reflux , filtered over hyflo bed, washed with isopropyl alcohol(85 ml ), isopropyl alcohol is distilled till solid is separated , cooled to 20-30°C , stirred for 30 min filtered and washed with chilled isopropyl alcohol (85 ml )followed by drying at 60-65°C under vacuum for 6-8 hours to give of pure desloratadine acetate (70-75 gms.)
Desloratadine acetate (50 gms) was taken in water (250 ml ) and stirred for 30 minutes. Activated carbon (2.5 gms) was added to it and stirred for 30 minutes. The solution was filtered on hyflo and washed with 50 ml of water and basified with 10 % aqueous K2CO3 up to 9 to 10 pH. Chloroform (200 ml ) was added to it and stirred for 30 minutes and layers were separated. The aqueous layer was extracted with chloroform ( 50 ml x 3) ,and combined organic phase was washed with water (100 ml x 2).The organic layer was treated with activated charcoal and filtered and washed with chloroform (50 ml). Choroform was distilled till 10 to 20 % of chloroform remains in the flask. Water (100 ml) was added to it and chloroform was removed azeotropically at about 60-65°C , and repeat this operation with water (25 ml) for second time and with water ( 12.5 ml) for the third time , finally vacuum was applied to give oily mass. n-Hexane (100 ml) was added to the oily mass and water was removed using Dean & Stark separator. The reaction mass was cooled to room temperature (25-3 0°C). The reaction mass was filtered and
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washed with n-Hexane (50 ml). The material was dried at 55-60 C under vacuum for about 10 to 12 hours.
Wet cake = 40-45 gms
Dry weight = 35-40 gms.
Example-2
Water (250 ml ) was charged at room temperature. Desloratadine acetate (50 gms) was
added and stirred for 30 minutes. Activated carbon (2.5 gms) was added to it and stirred
for 30 minutes. The solution was filtered on hyflo and washed with 50 ml of water.
The charcoal treatment was repeated and the filtrate was basified with 10 % aqueous
K2CO3 up to 9 to 10 pH. The reaction mass was heated to 65-70 C for about 6-12 hours,
the solid material was separated. The reaction mass was cooled to room temperature and
solid was separated by filtration followed by washing with water and drying at 55-60 C
under vacuum for 10 to 12 hours
Wet cake = 60 gms
Dry wt= 40 gms.
Chloroform= 18 ppm
n-Hexane= 18 ppm
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