WO2008107777A2

WO2008107777A2 - Improved method for the preparation of desloratadine with reduced levels of organic solvents

Info

Publication number: WO2008107777A2
Application number: PCT/IB2008/000498
Authority: WO
Inventors: Sanjay Muktawat; Sanjay Laxmanbhai Patel; Udai Pratap Singh; Ravi Ponnaiah; Bakulesh Mafatlal Khamar
Original assignee: Cadila Pharmaceuticals Ltd
Current assignee: Cadila Pharmaceuticals Ltd
Priority date: 2007-03-06
Filing date: 2008-03-05
Publication date: 2008-09-12
Anticipated expiration: 2009-09-06
Also published as: WO2008107777A3

Abstract

The present invention relates to an improved method for the preparation of Desloratadine with reduced levels of organic solvents. Further the invention also relates to a process for the preparation of Desloratadine containing reduced level of chloroform and hexane in Desloratadine to meet ICH specifications. The invention also relates to provide Desloratadine in mixture of polymorphic form 1 and form 2.

Description

TITLE: IMPROVED METHOD FOR THE PREPARATION OF DESLORATADINE WITH REDUCED LEVELS OF ORGANIC SOLVENTS.

FIELD OF THE INVENTION The present invention relates to an improved method for the preparation of

Desloratadine with reduced levels of organic solvents. Further the invention also relates to a process for the preparation of Desloratadine containing reduced level of chloroform and hexane in Desloratadine to meet ICH specifications. The invention also relates to provide Desloratadine in mixture of polymorphic form 1 and form 2.

BACKGROUND OF THE INVENTION

Desloratadine is marketed by Calrinex® name under different dosage forms and route. Desloratadine is chemically named as 8-chloro-6, 1 1 -dihydro- l l -(4-piperdinylidene)- 5H-benzo[5,6]-cyclohepta91,2-b]pyridine and has the following structure:

Desloratadine

US4659716 (US '716 patent) discloses process for the preparation of Desloratadine from Loratadine by reaction using 70% sodium hydroxide solution in ethanol followed by acidifying with glacial acetic acid to form acetate salt. Thus formed salt is extracted with chloroform, concentrated and precipitated with hexane to give crude acetate salt having melting point 197-200⁰C. The crude acetate salt is recrystallized using benzene-hexane to give pure acetate salt compound having m.p. 199-200⁰C.

The acetate salt is further converted to Desloratadine as described in example 05 of US '716 patent. The acetate salt prepared from Loratadine is dissolved in a minimum amount of water and the solution is made basic with a dilute aqueous solution of potassium carbonate. Pink coloured oil is separated. The organic material is extracted with chloroform, washed with water. The solvent is removed under reduced pressure followed by triturating with hexane. The product is recrystallized by large volume of hexane involving decolorization with charcoal to obtain Desloratadine, m.p. 151 °- 152⁰C. US '716 patent discloses the laboratory scale process for preparation of Desloratadine from Desloratadine acetate. It was observed that the product was not recrystallizable due to insolubility even using large volume of hexane. The product with or without the treatment of hexane is in pink colour which contains high level of residual solvents (chloroform content is about 4257 ppm and hexane is about 450 ppm). The residual solvent could not be removed even after prolonged drying. US '716 patent is resulting with high level of residual solvent which does not meet the ICH specifications.

The preparation of Desloratadine as per example 06 in US '716 patent comprises;

• reaction of 8-chloroazatadine in dry benzene, with solution of cyanogen bromide. The solution is filtered and concentrated to a small volume. The product is precipitated by addition of petroleum ether or hexane which is filtered and recrystallized using ethanol / water to yield the product (8-chloro-6,l 1 -dihydro- l . l(l-cyano-4-piperidylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine) in 89% yield. • treatment of the solution of N-cyano compound with con. HCI, glacial acetic acid and water at reflux temp under stirring for 20 hours. The solvent is removed under reduced pressure and the residue is dissolved in water and neutralized with ammonium hydroxide.

• the product is extracted several times using chloroform followed by washing the chloroform extracts with water and concentrating to dryness and further triturating the residue with petroleum ether or hexane to yield Desloratadine 93%, m.p. 149- 151⁰C. Pure compound is obtained by recrystallizing from hexane. The end product prepared by US '716 patent, contains high levels of chloroform and hexane which is not possible to remove even after prolonged drying of resulting product. US Patent 6,506,767 discloses two polymorphic forms of Desloratadine. The process for preparing Desloratadine form 1 contains <1% of Desloratadine form 2. The process for preparing Desloratadine form 2 contains about 15% of Desloratadine form 1.

US2004/0229896 discloses pharmaceutical compositions of Desloratadine comprising a mixture of crystalline polymorphic form I and form II in a ratio of about 25% to about 75% of either form to the other and pharmaceutically acceptable excipient.

US2004/0242619 discloses a process for preparing crystalline Desloratadine form 1. The process involves preparing a solution of Desloratadine in a solvent and recovering the crystalline form 1. Solvent is selected from the group consisting of acetonitrile, di-methyl foπnamide, tetrahydrofuran, diethylcarbonate, and may be selected from the group consisting of chloroform, ethyl acetate and Ci -C₄ alcohol.

EPl 860105 patent discloses a process for preparation of Desloratadine form-2 comprises: providing a solution of Desloratadine in a suitable solvent and recovering form-2 by spray drying/agitated thin film drying technique. Suitable solvents may include organic solvents or mixtures of organic solvents with or without water. The organic solvents used are alkyl acetates and dipolar aprotic solvents.

EPl 862462 discloses process for the preparation of Desloratadine form 1 essentially free of for 2. The process comprises hydrolysis of Loratadine, extracting the reaction mixture with a first solvent and partially recovering the first solvent, adding a second solvent to the residue and isolating Desloratadine form 1. The first solvent is selected from the group comprising of alkyl acetates, ethers, acetonitrile, N,N-dimethylformamide, chlorinated hydrocarbons, alcohols and/or mixtures thereof and second solvent is selected from the group comprising of ketones, alcohols, chlorinated hydrocarbons, ethers, acetonitrile, N,N- dimethylformainide, acetonitrile and mixture thereof.

EP 1542986 discloses process for the preparation of Desloratadine. The process comprises reacting Loratadine with neat alcohol in presence of inorganic base, precipitating the compound in crystalline foπn by addition of excess water and isolating the crystals.

The methods for preparation of Desloratadine described in prior art are not satisfactory as the material produced by following these processes is coloured, contains high level of impurities, and high levels of residual solvents beyond the acceptable ICH specifications.

SUMMARY OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of Desloratadine, wherein the chloroform content is about 60 ppin or less and/or hexane content is about 290 ppm or less. Another aspect of the present invention is to provide an improved process for the commercial scale production of Desloratadine. Another aspect of the invention is to provide Desloratadine with very low residual solvents. Yet another aspect of the invention is to provide the Desloratadine obtained in mixture of polymorphic form 1 and form 2.

BRIEF DESCRIPTION OF DRAWINGS:

Figure 1 : Depicts the powder X-ray diffraction pattern of standard Desloratadine containing a mixture of 10% form 1 & 90% form 2. Figure 2: Depicts the comparison of x-ray diffraction pattern of standard (as in fig. 1 ) with x- ray diffraction pattern of Desloratadine obtained by following our process of preparing Desloratadine.

Figure 3: Depicts the comparison of peak of our sample with standard Desloratadine.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention Desloratadine is prepared from Loratadine.

Loratadine is hydrolyzed in the presence of a base in a suitable solvent under reflux to prepare Desloratadine acetate which can be converted to Desloratadine. The base is selected from alkali metal hydroxides, preferably sodium hydroxide. Alcoholic solvents are used as suitable solvent for hydrolysis of Loratadine.

In a preferred embodiment of the invention the process for the preparation of Desloratadine comprising the steps of; a. basifying Desloratadine acetate in aqueous medium, extracting Desloratadine in chloroform, separating chloroform layer and concentrating it till 10% of chloroform remains in the reaction mass, b. adding a mixture of water and hexane to the reaction mass, distilling chloroform, hexane and water under vacuum between 50-75 C, repeating the addition of water & hexane till the chloroform content reduced to <60 ppm (as per ICH specifications) in ^• the reaction mass. The ratio of water & hexane in a mixture is from about 1 :9 to 9: 1 , preferably from 1 :3 to 1 : 1 , c. isolating Desloratadine from the reaction mass by adding hexane under stirring between 25-30⁰C, drying the material at 55-60⁰C under reduced pressure.

In another embodiment of the invention the reaction comprises; a. basifying Desloratadine acetate in aqueous medium, extracting Desloratadine free base in chloroform, separating chloroform layer and concentrating till about 10% of chloroform remains in the reaction mass, b. adding water in the reaction mass, followed by distillation of chloroform azeotropically till 90% of water remains in reaction mass, c. removing water azeotropically by adding hexane to obtain Desloratadine.

In yet another embodiment of the invention the reaction comprises; a. basifying Desloratadine acetate in aqueous medium, heating the reaction mass between 50-90⁰C preferably between 65-70⁰C for about 6-12 hours, cooling the reaction mass to room temperature so as to remove chloroform and/or hexane, b. separating Desloratadine and drying it. Desloratadine acetate is basified with carbonates of alkali metal such as sodium carbonate, potassium carbonate, lithium carbonate, preferably by using potassium carbonate Desloratadine isolated by following the above mentioned process contains a mixture of 10% form 1 & 90% form 2. Desloratadine obtained by the process as mentioned in preferred embodiment of the invention contains about 38 ppm of chloroform and 249 ppm of n-hexane. The ICH limit for chloroform is 60 ppm and for n-hexane is 290 ppm.

The present invention is further illustrated by following non-limiting examples.

Example-1: Preparation of Desloratadine acetate

Sodium hydroxide (150 gms) was taken in an aq. ethanol 500 ml (70%) and stirred for about 30 minutes. Loratadine [100 gm] was charged to reaction medium and heated at 80-85 with stirring for about 12 hours. Ethanol was distilled under vacuum at 45-50⁰C. The reaction medium was cooled to 20-25⁰C. Chloroform (500 ml) was added and stirred for 15 minutes.

The pH was adjusted at ~5.5 - 6.5 using acetic acid with stirring. Water (I L) was charged.

Layer was allowed to separate; aqueous phase was extracted with chloroform (200 ml, 100 ml). The combined organic layer was washed with 10 % brine (100 ml x T). Chloroform layer was treated with activated carbon and filtered by using hyflo and dried over anhydrous sodium sulfate.

The chloroform was distilled under vacuum at 40⁰C followed by addition of n-Hexane

(100 ml ) to strip off residual chloroform at 40-45⁰C under vacuum. n-Hexane (500 ml) was added and stirred. The reaction medium was cooled washed with 100 ml n-hexane and dried at 60-65⁰C under vacuum for 6-8 hours to give crude Desloratadine acetate (85 gms).

ExampIe-2: Purification of crude Desloratadine acetate

Crude Desloratadine acetate (85 gms) was taken to isopropyl alcohol (850 ml) and heated to reflux. Water (42.5 ml) was added to obtained clear solution at reflux temperature.

Activated carbon was added and stirred for 30 min, filtered over hyflo bed. The reaction medium was washed with isopropyl alcohol (85 ml). Solvent is distilled till solid is separated and cooled to 20-30⁰C, stirred for 30 min filtered and washed with chilled isopropyl alcohol (85 ml) followed by drying at 60-65⁰C under vacuum for 6-8 hours to give of pure Desloratadine acetate (70-75 gms)

Example-3: Preparation of Desloratadine free base Desloratadine acetate (50 gms) was taken in water (250 ml). Activated carbon (2.5 gms) was added and stirred. The solution was filtered on hyflo and washed with 50 ml of water. 10 % aq. K₂CO₃ was added to give pH -10 to 12. Chloroform (200 ml) was added and stirred for 30 minutes. Layer was allowed to separate and aqueous layer was extracted with chloroform (50 ml x 3). The organic layer was washed with water (100 ml x 2) and treated with activated charcoal. The traces were filtered and washed with chloroform (50 ml). Chloroform was distilled till about 10 to 20 % of chloroform remains in the flask. Water (100 ml) was added to it and chloroform was removed azeotropically at about 60-65⁰C. The product get separated as oily mass. n-Hexane (100 ml) was added to the oily mass and water was removed using Dean & Stark separator. The reaction mixture was cooled at 25-30⁰C and product was filtered and washed with n-Hexane (50 ml). The product was dried at 55-60⁰C under vacuum for about 10 to 12 hours. (37.5 gms)

Example-4 Preparation of Desloratadine

Desloratadine acetate (50 gms) and water (250 ml) were charged at room temperature in reaction vassal 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 10 to 12 pH. The reaction mixture was heated to 65-70⁰C for about 6-12 hours, the solid material was separated and cooled to room temperature. The solid was filtered and washed with water. The product on drying at 55-60⁰C under vacuum for 10 to 12 hours.

(Yield: 40 gms).

The solvent levels of chloroform and hexane are 38 ppm and 249 ppm respectively, which are below the ICH limit for chloroform 60 ppm and for n-hexane 290 ppm.

Claims

We claim:

1. A purified desloratadine containing desloratadine having a chloroform content of less than 60 ppm.

2. The purified desloratadine of claim-1, wherein the chloroform content is less than 60 ppm and the hexane content is less than 290 ppm.

3. The purified desloratadine of claim-1, wherein the chloroform content is less than 50 ppm.

4. The purified desloratadine of claim-1, wherein the hexane content is less than 270 ppm.

5. The purified desloratadine of claim-1 , wherein the chloroform content is less than 40 ppm.

6. The purified desloratadine of claim-1, wherein the hexane content is less than 250 ppm.

7. The purified desloratadine of claim-1, wherein the purified desloratadine comprises form-1 desloratadine and form-2 desloratadine.

8. The purified desloratadine of claim-7, wherein a ratio of form-1 desloratadine to form-2 desloratadineis from about 80:20 to about 99: 1.

9. The purified desloratadine of claim-8, wherein the ratio is from about 85: 15 to about 95:5.

10. The purified desloratadine of claim-9, wherein the ratio is about 90: 10.

11. A process for the preparation of purified desloratadine comprising adding a base to a desloratadine containing substance in an aqueous medium , lemoving chloroform from the aqueous medium, adding water to the aqueous medium and subsequently further removing chloroform from the aqueous medium.

12. The process of claim-11 , further comprising adding hexane to the aqueous medium.

13. The process of claim-12, further comprising removing hexane from the aqueous medium.

14. The process of claim-11, wherein the desloratadine containing substance comprising desloratadine acetate.

15. The process of claim-1 1, further comprising removing the purified desloratadine from the aqueous medium.

16. A process for the preparation of purified desloratadine comprising: a. preparing desloratadine acetate containing chloroform and hexane, reacting loratadine with a base in an aqueous alcohol medium, removing an alcohol, adding chloroform and acidifying to produce said desloratadine acetate, b. subsequently basifying said desloratadine acetate in an aqueous medium to remove atleast a portion of said chloroform and said hexane from said desloratadine acetate.

17. A process for the preparation of a purified desloratadine comprising: a. adding a base to a desloratadine containing substance in an aqueous medium, and b. producing the purified desloratadine wherein the purified desloratadine comprises desloratadine having a chloroform content of less than 60 ppm or a hexane content of less than 290 ppm.

18. A process for preparation of desloratadine as claimed in claim 1 1 or 16 wherein the base is selected from alkali metal carbonates.

19. A process for preparation of Desloratadine as claimed in claim 1 1 or 16 wherein the alkali metal carbonates is any of sodium carbonate, potassium carbonate, lithium carbonate.

20. A process for preparation of Desloratadine as claimed in claim 1 1 or 16 wherein base is potassium carbonate.

Dated this on 03^rd day of March, 2008