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WO2007029155A2 - Procede de preparation ameliore d'une base de celiprolol pure - Google Patents

Procede de preparation ameliore d'une base de celiprolol pure Download PDF

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Publication number
WO2007029155A2
WO2007029155A2 PCT/IB2006/053073 IB2006053073W WO2007029155A2 WO 2007029155 A2 WO2007029155 A2 WO 2007029155A2 IB 2006053073 W IB2006053073 W IB 2006053073W WO 2007029155 A2 WO2007029155 A2 WO 2007029155A2
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WO
WIPO (PCT)
Prior art keywords
celiprolol
acid
base
crude
acetate
Prior art date
Application number
PCT/IB2006/053073
Other languages
English (en)
Other versions
WO2007029155A3 (fr
Inventor
Naresh Kumar
Sandeep Nayyar
Manu Mahendru
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2007029155A2 publication Critical patent/WO2007029155A2/fr
Publication of WO2007029155A3 publication Critical patent/WO2007029155A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/189—Purification, separation, stabilisation, use of additives

Definitions

  • the present invention relates to an improved process for preparing pure celiprolol base in monohydrate form by crystallizing crude celiprolol base in one or more carboxylic acid ester solvents and its conversion to pharmaceutically acceptable acid addition salts, for example, celiprolol hydrochloride Form I in high purity.
  • Celiprolol a beta-blocker class antihypertensive agent, is chemically N'-(3-acetyl-4- (3-((l,l-dimethylethyl)amino)-2-hydroxypropoxy)phenyl)-N,N-diethyl urea and is disclosed in U.S. Patent No. 4,034,009. Celiprolol is represented by Formula (I)
  • Medically used aryloxy-propanolamines should be prepared in high purity levels.
  • medical preparations containing aryloxy-propanolamines should either contain no or only traces of by-products from its synthesis.
  • Current industrial synthetic processes for the preparation of l-aryloxy-3-amino-2-propanols form crude products containing many impurities, the removal of which is very difficult.
  • Such industrial synthetic processes include, for example, reacting a corresponding l-aryloxy-2, 3 -epoxy -propane with an amine as described in /. Med. Chem. 1971, 14(6), 511-513.
  • Impurity B 1,3-bis [3-acetyl-4- [3-[(l,l-dimethylethyl) amino] -2-hydroxy- propoxy] phenyl] urea.
  • Impurity E l,l'-[[(l,l-dimethylethyl) imino] bis [(2-hydroxypropane-l, 3-diyl) oxy (3- acetyl-1, 4-phenylene)]] bis (3,3-diethylurea)
  • Various processes are disclosed in purifying aryloxy-propanolamines.
  • U.S. Patent No. 4,849,530 describes the purification of celiprolol base via diphenyl acetate salt of celiprolol. The method involves converting the salt into the base, which comprises multiple stages, rendering this method undesirable in preparing such compounds on an industrial scale.
  • celiprolol base having a melting point of 110-117 0 C for the preparation of celiprolol hydrochloride does not consistently result in Form I.
  • celiprolol base which has been dried at a temperature below 70 0 C, more preferably below 55 0 C with a moisture content of less than 5 % w/w and having melting point 80-100 0 C, leads to consistently forming Form I celiprolol hydrochloride.
  • Such a celiprolol base is characterized by its distinct infrared spectrum, melting point and x-ray powder diffraction pattern differing from the celiprolol base melting above 110 0 C.
  • the moisture content in the celiprolol base may vary from 2-5 % w/w but it generally remains as a monohydrate (4.5 % w/w water content).
  • a process for the preparation of pure celiprolol base in monohydrate form comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature, and isolating the celiprolol base.
  • the process can include one or more of the following embodiments.
  • the solution of crude celiprolol base can be obtained by extracting a reaction mixture taken from the last step of a process in which crude celiprolol base is formed using one or more carboxylic acid ester solvents to obtain a solution of crude celiprolol base.
  • the one or more carboxylic acid ester solvents can be selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof.
  • ambient temperature can be between about 10 0 C to about 40 0 C.
  • the celiprolol base can be isolated by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof.
  • crystallization or precipitation can be carried out at a temperature from about 0 0 C to about 25 0 C.
  • the celiprolol base can be dried at a temperature from ambient temperature to about 80 0 C.
  • the celiprolol base can be substantially free of impurities having less than 0.20 % of total impurities, preferably less than about 0.1 % of total impurities.
  • the process further comprises the conversion of celiprolol base monohydrate to a pharmaceutically acceptable acid addition salts of celiprolol base by contacting celiprolol base monohydrate with one or more acids.
  • the one or more acids can be selected from hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, glycolic acid, lactic acid, malic acid, benzoic acid, salicylic acid, nicotinic acid, cyclohexylsulfonic acid, diphenylacetic acid, methanesulfonic acid, amidosulfonic acids or mixtures thereof.
  • the acid addition salt of celiprolol base is celiprolol hydrochloride Form I.
  • From I comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature; isolating the celiprolol base having essentially free of impurity C and E and converting celiprolol base into celiprolol hydrochloride Form I.
  • the celiprolol hydrochloride Form I has total impurities of less than about 0.1 %.
  • a process for preparing pure celiprolol base in monohydrate form comprising the steps of: a. providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature; b. isolating the celiprolol base in monohydrate form.
  • Acid addition salts provided by such processes include, for example, celiprolol hydrochloride Form I in high purity.
  • a reaction mixture taken from the last step of a process in which crude celiprolol base is formed can be extracted using one or more carboxylic acid ester solvents to obtain a solution of crude celiprolol base.
  • the extracted solution may be used as such without any further isolation steps.
  • Crude celiprolol base may be obtained from any synthetic route described in the prior art, including those described in, for example, U.S. Patent No. 4,034,009 and Canadian Patent Nos. 1,061,342 and 1,061,341, which are incorporated herein by the reference.
  • Suitable carboxylic acid ester solvents include, for example, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof.
  • Ambient temperatures are temperatures in the range of about 10 0 C to about 40 0 C.
  • Celiprolol base can be isolated by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof. Crystallization or precipitation may be performed at a temperature from about 0 0 C to about 25 0 C over about 2 hours to about 15 hours in some embodiments.
  • seed crystals may be added in order to improve the yield of celiprolol base.
  • Celiprolol base can be dried at temperatures from ambient temperature to about 80 0 C.
  • Celiprolol base obtained by the processes described herein is in monohydrate form having water content of about 4-5 %.
  • the amount of impurities B, C and E, as well as other impurities present in the final product vary with the solvent of crystallization.
  • celiprolol base substantially free of impurities may be isolated with about 0.20 % or less total impurity content including impurity B.
  • Processes described herein provides celiprolol base substantially free of impurities that contains no more than 0.20 % of total impurities. In contrast, previously known processes provide celiprolol base having impurity levels of about 1 to 2 %.
  • Celiprolol base obtained by the process described herein may be converted to its corresponding pharmaceutically acceptable acid addition salts.
  • Acids which are suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, glycolic acid, lactic acid, malic acid, benzoic acid, salicylic acid, nicotinic acid, cyclohexylsulfonic acid, diphenylacetic acid, methanesulfonic acid, amidosulfonic acids and the like.
  • acid addition salts of celiprolol base may be prepared by adding respective acid in the mixture of celiprolol base and solvent followed by isolation.
  • Celiprolol hydrochloride Form I may be obtained by the process given in PCT Application No. WO 01/08633, which is incorporated herein by reference.
  • the European pharmacopoeia specifications for related substances of celiprolol hydrochloride are as follows: any one specified impurity: NMT 0.2%; any other impurity (known/unknown): NMT 0.1 %; total impurities: NMT 0.5 %.
  • Celiprolol hydrochloride obtained by celiprolol base prepared by present process has total impurities less than 0.1 %, which meets/exceeds the European pharmacopoeia requirements.
  • aqueous layer was washed with ethyl acetate (100 mL) and was mixed with activated carbon (5 g).
  • the pH of aqueous layer was adjusted to above 10 with sodium hydroxide solution (37 %).
  • the resulting solution was extracted twice with ethyl acetate
  • celiprolol base was dried at 30-35 0 C.
  • Example-2 Preparation of Celiprolol hydrochloride Form I: Celiprolol base (44 g) having water content of 4-5% was dissolved in a mixture of acetone (695 mL) and water (13.5 mL). The resulting clear solution was treated with activated carbon, filtered on a hyflo bed, which was washed with acetone (114 mL). The filtrate was cooled to 15-20 0 C and seeded with 1.7 g of celiprolol hydrochloride (Form-I). Concentrated hydrochloric acid (11.5 g) was then added to the reaction mixture to adjust the pH to 5.8-6.3 and the reaction mixture was stirred for 30 minutes at 15-20 0 C. Celiprolol hydrochloride was filtered and dried under vacuum.

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

Abstract

La présente invention porte sur un procédé de préparation amélioré d'une base de céliprolol pure sous forme de monohydrate, procédé consistant à cristalliser une base de céliprolol brute dans un ou plusieurs solvants d'esters d'acide carboxylique, et sur sa conversion en sels d'addition acide acceptables d'un point de vue pharmaceutique, par exemple, l'hydrochlorure de céliprolol de formule (I) de haute pureté.
PCT/IB2006/053073 2005-09-05 2006-09-01 Procede de preparation ameliore d'une base de celiprolol pure WO2007029155A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2360DE2005 2005-09-05
IN2360/DEL/2005 2005-09-05

Publications (2)

Publication Number Publication Date
WO2007029155A2 true WO2007029155A2 (fr) 2007-03-15
WO2007029155A3 WO2007029155A3 (fr) 2007-08-30

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034009A (en) * 1973-12-20 1977-07-05 Chemie Linz Aktiengesellschaft 4-Ureido-2-acyl phenoxypropanolamine
WO2001008633A2 (fr) * 1999-07-30 2001-02-08 Ranbaxy Laboratories Limited Forme amelioree d'hydrochlorure de celiprolol de forme i

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034009A (en) * 1973-12-20 1977-07-05 Chemie Linz Aktiengesellschaft 4-Ureido-2-acyl phenoxypropanolamine
WO2001008633A2 (fr) * 1999-07-30 2001-02-08 Ranbaxy Laboratories Limited Forme amelioree d'hydrochlorure de celiprolol de forme i

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOSHI, RAMESH A. ET AL: "A New and Improved Process for Celiprolol Hydrochloride" ORGANIC PROCESS RESEARCH & DEVELOPMENT , 5(2), 176-178 CODEN: OPRDFK; ISSN: 1083-6160, 2001, XP002429670 *
SMITH, LESLIE HAROLD ET AL: ".beta.-Adrenergic blocking agents. 10. (3-Amino-2- hydroxypropoxy)anilides" JOURNAL OF MEDICINAL CHEMISTRY, 14(6), 511 -13 CODEN: JMCMAR; ISSN: 0022-2623, 1971, XP002429671 cited in the application *

Also Published As

Publication number Publication date
WO2007029155A3 (fr) 2007-08-30

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