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WO2008107777A2 - Procédé amélioré de préparation de desloratadine comportant des taux réduits de solvants organiques - Google Patents

Procédé amélioré de préparation de desloratadine comportant des taux réduits de solvants organiques Download PDF

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Publication number
WO2008107777A2
WO2008107777A2 PCT/IB2008/000498 IB2008000498W WO2008107777A2 WO 2008107777 A2 WO2008107777 A2 WO 2008107777A2 IB 2008000498 W IB2008000498 W IB 2008000498W WO 2008107777 A2 WO2008107777 A2 WO 2008107777A2
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WO
WIPO (PCT)
Prior art keywords
desloratadine
purified
chloroform
hexane
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2008/000498
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English (en)
Other versions
WO2008107777A3 (fr
Inventor
Sanjay Muktawat
Sanjay Laxmanbhai Patel
Udai Pratap Singh
Ravi Ponnaiah
Bakulesh Mafatlal Khamar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cadila Pharmaceuticals Ltd
Original Assignee
Cadila Pharmaceuticals Ltd
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Filing date
Publication date
Application filed by Cadila Pharmaceuticals Ltd filed Critical Cadila Pharmaceuticals Ltd
Publication of WO2008107777A2 publication Critical patent/WO2008107777A2/fr
Anticipated expiration legal-status Critical
Publication of WO2008107777A3 publication Critical patent/WO2008107777A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • 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

Definitions

  • TITLE IMPROVED METHOD FOR THE PREPARATION OF DESLORATADINE WITH REDUCED LEVELS OF ORGANIC SOLVENTS.
  • 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.
  • 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:
  • US4659716 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.
  • formed salt is extracted with chloroform, concentrated and precipitated with hexane to give crude acetate salt having melting point 197-200 0 C.
  • the crude acetate salt is recrystallized using benzene-hexane to give pure acetate salt compound having m.p. 199-200 0 C.
  • 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 °- 152 0 C.
  • 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.
  • 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 fo ⁇ namide, tetrahydrofuran, diethylcarbonate, and may be selected from the group consisting of chloroform, ethyl acetate and Ci -C 4 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
  • 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 fo ⁇ n by addition of excess water and isolating the crystals.
  • 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.
  • 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.
  • 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.
  • 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 25-30 0 C, drying the material at 55-60 0 C under reduced pressure.
  • 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.
  • the reaction comprises; a. basifying Desloratadine acetate in aqueous medium, heating the reaction mass between 50-90 0 C preferably between 65-70 0 C 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.
  • 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. K 2 CO 3 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 60-65 0 C. 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 25-30 0 C and product was filtered and washed with n-Hexane (50 ml). The product was dried at 55-60 0 C under vacuum for about 10 to 12 hours. (37.5 gms)
  • 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 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de Desloratadine avec des taux réduits de solvants organiques ainsi qu'un procédé de fabrication de Desloratadine avec des taux réduits de chloroforme et d'hexane dans la Desloratadine afin de se conformer aux spécifications de l'ICH. L'invention concerne aussi à la Desloratadine sous la forme d'un mélange de formes polymorphiques 1 et 2.
PCT/IB2008/000498 2007-03-06 2008-03-05 Procédé amélioré de préparation de desloratadine comportant des taux réduits de solvants organiques Ceased WO2008107777A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN422MU2007 2007-03-06
IN422/MUM/2007 2007-03-06

Publications (2)

Publication Number Publication Date
WO2008107777A2 true WO2008107777A2 (fr) 2008-09-12
WO2008107777A3 WO2008107777A3 (fr) 2009-12-23

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PCT/IB2008/000498 Ceased WO2008107777A2 (fr) 2007-03-06 2008-03-05 Procédé amélioré de préparation de desloratadine comportant des taux réduits de solvants organiques

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985003707A1 (fr) * 1984-02-15 1985-08-29 Schering Corporation 8-CHLORO-6,11-DIHYDRO-11-(4-PIPERIDYLIDENE)-5H-BENZO AD5,6 BDCYCLOHEPTA AD1,2-b BD PYRIDINE ET SES SELS, LEURS PROCEDES DE PRODUCTION ET COMPOSITIONS PHARMACEUTIQUES CONTENANT SES COMPOSES
US20060100435A1 (en) * 2002-09-24 2006-05-11 Sanjay Suri Process for the production of desloratadine
PT1507531E (pt) * 2003-03-12 2007-03-30 Teva Pharma Composições farmacêuticas estáveis de desloratadina

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WO2008107777A3 (fr) 2009-12-23

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