Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF DESLORATADINE

Abstract

The present invention relates to an improved process for the preparation of compound of formula (I), 8-chloro-6,11 -dihydro-11 -(4-piperidinylidene)-5H-benzo[5 56]cyclohepta[ 1,2-b]pyridine (Desloratadine) or its pharmaceutically acceptable salts thereof, by reacting a compound of formula (II), 4-(8-Chloro-5,6-dihydro-llH-benzo[5,6]cyclohepta[l,2-b]pyridin-ll-ylidene)-l piperidinecarboxylic acid ethyl ester (Loratadine) with sodium hydroxide in a solvent mixture of toluene and polyethylene glycol (PEG 400) at reflux temperature.

Full Text

Field of the invention The present invention relates to an improved process for the preparation of compound of formula (I), 8-chloro-6,11 -dihydro-11 -(4-piperidinyIidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine (Desloratadine) or its pharmaceutically acceptable salts thereof, by reacting a compound of formula (II), 4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[ 1,2-b]pyridin" 11-ylidene)-1 piperidinecarboxylic acid ethyl ester (Loratadine) with sodium hydroxide in a solvent mixture of toluene and polyethylene glycol (PEG 400) at reflux temperature. Baclcground of the invention Desloratadine, known as 8-chloro-6,11-dihydro-1 l-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[ 1 ,2-b]pyridine, has the following structure: Desloratadine is currently marketed as Clarinex in the United States. Clarinex is prescribed as an antihistamine for prevention or treatment of allergenic reactions, which may result in symptoms such as sneezing, itchy eyes and hives. U.S. Pat. No. 4,659,716 discloses descarbonylethoxyloratadine, which possesses antihistaminic properties with substantially no sedative properties. This U.S. Patent also discloses methods of making descarbonylethoxyloratadine and using it to treat allergic reactions in mammals. In Example V, the 716 patent prepares desloratadine in the solid state and discloses: "Extract the organic material with chloroform, wash with water and remove the solvent. Triturate the residue with hexane. Recrystallize from a large volume of hexane after charcoal decolorization to obtain the product, m.p. 151°C to 152°C. In Example VI, B, desloratadine is also prepared in the solid state: "The material is extracted several times with chloroform, the chloroform extracts washed with water and concentrated to dryness, and the residue triturated with petroleum ether or hexane to yield 11.5 grams (93%) m. p. 149°-151 °C. After recrystallization from hexane, the product melts at 150°C to 151°C. U. S. Pat. No. 6,506,767 disclose two polymorphic forms of desloratadine, labeled Forms I and II (syn. form 1 and form 2). The XRPD peaks and the FTIR spectrum for the forms are also disclosed in the 767 patent. According to this patent 767 patent, discloses certain alcoholic solvents, e.g., hexanol and methanol produce 100% polymorph form 1, but others, e. g., 3-methyl-1-butanol and cyclohexanol produce significant amounts of form 2. Chlorinated solvents, e. g. , dichloromethane produce form 1 substantially free of form 2. Ether solvents such as dioxane produced form 1 substantially free of form 2 but other alkane ethers, e.g., di-isopropyl ether produced form 1 with significant amounts of form 2 and di-n-butyl ether favored formation of form 2. Ketones such as methyl isobutyl ketone produced crystalline polymorph form 1 essentially free of form 2 but methyl butyl ketone produced 8:1 ratio of form 1 to form 2. Use of methyl isobutyl ketone is preferred to produce crystalline polymorph form 1 essentially free of form 2. Only ethyl acetate and di-n-butyl ether were found to produce crystalline polymorph form 2 substantially free of form 1. Use of di-n-butyl ether is preferred for producing crystalline form 2 substantially free of form 1. According to this patent the polymorph form obtained from U.S. Pat. No. 4,659,716 is a mixture of form I and form 11. Teva Patent WO2004/080461 claims a pharmaceutical composition of desloratadine comprising of a mixture of crystalline form desloratadine I and II in a weight to weight ratio of about 25% to about 75% of either form to the other and a pharmaceutically acceptable excipient. None of the prior art references discloses or claims the use of solvent mixture toluene and polyethylene glycol (PEG 400) for hydrolysis of Loratadine. We focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) in good yield and high purity. The disclosed process has advantages over the processes described in the above-mentioned prior art documents. Objectives of the invention The main objective of the present invention is to provide an improved process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts thereof, using sodium hydroxide for hydrolysis of compound of formula (II) in the presence of solvent mixture toluene and polyethylene glycol (PEG 400). Another objective of the present invention is to provide a process for the preparation of compound of formula (I) in polymorphic mixture of Form I and II and its pharmaceutically acceptable salts in good yield and high purity. Summary of the invention Accordingly, the present invention provides an improved process for the preparation of Desloratadine of formula (I) and its pharmaceutically acceptable salts thereof, the method of preparing Desloratadine comprising the steps of: i.) reacting 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[l,2- b]pyridin-11 -ylidene)-1 -piperidinecarboxylic acid ethyl ester (Loratadine) with sodium hydroxide in a solvent mixture of toluene and polyethylene glycol (PEG 400) at reflux temperature. ii) adding a mixture of water and toluene to the reaction mixture, where by two phases are obtained; iii) separating the organic phase; iv) concentrating the separated organic phase; v) dissolving the obtained concentrate in a toluene : methylisobutyl ketone (MIBK) mixture followed by the addition of Isopropylether (IPE) at 60° C. vi) cooling the slurry mass to 5° C to 10° C; vii) isolating Desloratadine by filtration. The process is shown in the scheme given below Detailed description of the invention In an embodiment of the present invention, the reaction step is performed in a solvent. The solvent is selected from the group consisting of toluene, xylene and polyethylene glycol (PEG 400) or mixtures thereof. The most preferred solvent mixture for this reaction is toluene with polyethylene alcohol (PEG 400). In another embodiment of the present invention, the reacting step is preferably performed at a temperature of about 45° C to about 160° C. Most preferably; the reaction step is performed at a temperature of about 100°C to about 160°C. In yet another embodiment of the present invention the starting material of this invention is prepared according to the literature available in the prior art. In still another embodiment of the present invention the compound of formula (I) obtained is in the mixture of polymorph I and II, wherein one of the polymorph is in the range of less than 25% over other and vice versa. The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention. Example 1 To a solution of loratadine (50 gms) in toluene (200 ml), polyethylene glycol 400 (100 ml) was added and stirred. Sodium hydroxide (50 gms) was added to the above reaction mixture and refluxed for 2 hours. The course of the reaction was monitored by HPLC and after completion of the reaction, water (750 ml) and toluene (100 ml) was added and stirred well. The organic layer was separated out; the aqueous layer was extracted with toluene (2 X 100 ml). The combined organic layer was washed with water (2 X 250 ml) followed by brine (I X 250 ml) and evaporated the solvent under vacuum. Recrvstallization: The obtained solid was dissolved in the mixture of toluene : methylisobutyl ketone (1:1 v/v) at 85°C, followed by the addition of IPE at 60°C and cooled to 5° C to 10° C. The obtained solid was filtered off This recrystallization may be repeated to obtain the derived quality of Desloratadine. Yield: 19.0 gms(- 48.0%). We Claim: (1) A process for preparing Desloratadine of formula (I), said process comprises reacting 4-(8-Chloro-556-dihydro-1 lH-benzo[5,6]cyclohepta[ 152-b]pyridin-11 -ylidene)-1 - piperidine carboxylic acid ethyl ester of formula (II), (Loratadine) with alkali hydroxide in a solvent mixture of aromatic hydrocarbon and polyethylene glycol at reflux temperature. (2) The process of claim 1, wherein said alkali hydroxide is sodium hydroxide. (3) The process of claim 1, wherein said solvent mixture is toluene and polyethylene glycol 400.

Documents:

1110-CHE-2005 AMENDED CLAIMS 20-11-2012.pdf

1110-CHE-2005 AMENDED CLAIMS 20-09-2011.pdf

1110-CHE-2005 AMENDED PAGES OF SPECIFICATION 20-11-2012.pdf

1110-CHE-2005 CORRESPONDENCE OTHERS 20-11-2012.pdf

1110-CHE-2005 CORRESPONDENCE OTHERS 12-08-2013.pdf

1110-CHE-2005 FORM-3 20-09-2011.pdf

1110-CHE-2005 AMENDED CLAIMS 24-11-2010.pdf

1110-CHE-2005 CORRESPONDENCE OTHERS 20-09-2011.pdf

1110-CHE-2005 EXAMINATION REPORT REPLY RECIEVED 24-11-2010.pdf

1110-che-2005-abstract.pdf

1110-che-2005-claims.pdf

1110-che-2005-correspondnece-others.pdf

1110-che-2005-correspondnece-po.pdf

1110-che-2005-description(complete).pdf

1110-che-2005-description(provisional).pdf

1110-che-2005-form 1.pdf

1110-che-2005-form 3.pdf

1110-che-2005-form 5.pdf

1110-che-2005-form 9.pdf

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