WO2005066188A1 - Procede de preparation d'acide 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonique - Google Patents

Procede de preparation d'acide 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonique Download PDF

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Publication number
WO2005066188A1
WO2005066188A1 PCT/IN2004/000320 IN2004000320W WO2005066188A1 WO 2005066188 A1 WO2005066188 A1 WO 2005066188A1 IN 2004000320 W IN2004000320 W IN 2004000320W WO 2005066188 A1 WO2005066188 A1 WO 2005066188A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
imidazol
fomiula
benzyl
Prior art date
Application number
PCT/IN2004/000320
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English (en)
Inventor
Vijaykumar Muljibhai Patel
Trinadha Rao Chitturi
Rajamannar Thennati
Original Assignee
Sun Pharmaceutical Industries 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 Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2005066188A1 publication Critical patent/WO2005066188A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention relates to a process for the preparation of 2 ⁇ (imidazol-l-yl)-l- hydroxyethane- 1 , 1 -diphosphonic acid, compound of formula 1, commonly known as zoledronic acid (INN Name) used as medicament for treatment of diseases associated with impairment of calcium metabolism.
  • United States Patent No. 4,939,130 (Assigned to: Ciba-Geigy Corporation) discloses the preparation of zoledronic acid, compound of formula 1, from imidazol-1-ylacetic acid, compound of formula 2, o Formula 2 by two methods viz.
  • the preparation of the ester involves treating imidazole with the required haloacetates in presence of potassium hydroxide and potassium carbonate in methylene dichloride and facilitator like l,5-bis[(N-benzyl-N,N-diethylammonio)ethyl]ether dichloride (BBDED).
  • BBDED methylene dichloride and facilitator like l,5-bis[(N-benzyl-N,N-diethylammonio)ethyl]ether dichloride
  • Method (a) prepares benzyl esters of imidazol-1 -yl acetic acid in low yield.
  • Method (b) discloses preparation of methyl and malonyl esters of imidazol-1 - ylacetic acid in 70-80% and 49% yield respectively. Hydrolysis of these compounds will further reduce the overall yield of imidazol-1 -ylacetic acid, compound of fomiula 2.
  • the process of the present invention prepares the benzyl ester of imidazol-1 -ylacetic acid, compound of fomiula 3, in greater than 80% yield. All the above mentioned prior art references prepare the haloacetate or trimethylsilyl haloacetate separately and then treat it with imidazole.
  • the process of the present invention prepares the compound of formula 3, by directly reacting imidazole with benzyl alcohol and chloroacetyl chloride in one pot. It does not need a separate unit operation for preparation of the haloacetatae.
  • the benzyl ester of imidazol-1 -ylacetic acid, compound of formula 3 may be prepared in high yields, in one pot in a homogenous system by a novel method without the use of expensive haloacetates.
  • the benzyl 1-imidazolylacetate, compound of fomiula 3 is then converted to imidazol-1 -ylacetic acid, compound of fomiula 2, by catalytic hydrogenolysis or by acid hydrolysis which is further converted to compound of fomiula 1.
  • the object of the present invention is to provide a simple and cost-effective process for the preparation of compound of fomiula 1.
  • Another object of the present invention is to prepare compound of fomiula 3 by a novel process in high yields by simple, convenient and commercially viable method from readily available and cheap reagents.
  • the compound of fomiula 3 can be used as an intermediate for the preparation of imidazole derivatives such as compound of fomiula 1.
  • the present invention provides a process for preparation of 2-(imidazol-l-yl)- 1- hydroxyethane- 1,1 -diphosphonic acid, compound of formula 1, said process comprising Formula 1
  • Formula 2 (c) converting compound of fomiula 2 to compound of fomiula 1.
  • the present invention also provides a process for preparing benzyl 1-imidazolylacetate, compound of formula 3, said process comprising
  • the compound of fo ⁇ nula 3, benzyl 1-imidazolylacetate is prepared by reaction of imidazole with chloroacetyl chloride and benzyl alcohol in an organic solvent.
  • the process of the present invention prepares compound of fomiula 3, benzyl- 1- imidazolyl acetate, in one pot starting from chloroacetyl chloride, benzyl alcohol and imidazole.
  • Imidazole is present in molar excess over chloroacetyl chloride and acts as reactant as well as base.
  • the molar ratio of chloroacetyl chloride: imidazole may be selected in the range from 1 :2 to about 1 :6, preferably 1 :3.
  • the process of the present invention is carried out in absence of additional base.
  • additional inorganic base such as hydroxides, carbonates of alkali and alkaline earth metal salts such as potassium hydroxide &/or potassium carbonate and the like, or an organic base like tertiary alkylamines, such as triethylamine, diisopropylethylamine etc.
  • the reaction mixture of the present invention is homogenous, as imidazole is soluble in organic solvent, and a separate additional base is not used in the reaction. Accordingly the process of the present invention obviates the requirement of a facilitator such as a phase transfer catalyst.
  • the organic solvent may be selected from non-polar solvents like linear or cyclic aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene and the like; aliphatic or aromatic halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, tetrachloroethane, trichloroethane, chlorobenzene, dichlorobenzene and the like; ethereal solvents, such as diethylether, di-isopropylether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate, tert-butyl acetate and the like; or inert polar aprotic solvents such as acetonitrile, sulfolane and the like.
  • the reaction may be carried out at temperature ranging from 30 to 100°C, preferably 40 to 70°C.
  • the compound of formula 3 is thus prepared in high yields by simple, convenient and commercially viable method from readily available, and cheap reagents with reduced number of unit operations.
  • the compound of fomiula 2, imidazol-1 -ylacetic acid is obtained by debenzylating benzyl 1- imidazolyl acetate, compound of formula 3.
  • the debenzylation may be carried by catalytic hydrogenolysis or by acidic hydrolysis.
  • the debenzylation by catalytic hydrogenolysis may be performed in presence of metal catalysts like palladium, platinum, ruthenium or rhodium and the like.
  • the catalytic hydrogenolysis may be carried out in a solvent at atmospheric pressure or at higher pressures, at temperature between 5 and 100°C.
  • the solvent maybe selected from a polar protic solvent such as methanol, ethanol, isopropanol, acetic acid and the like; or in aromatic hydrocarbons such as toluene, or esters such as ethyl acetate, tert-butyl acetate and the like
  • debenzylation may be perfo ⁇ ned by acidic hydrolysis with a mineral or organic acid, wherein mineral acid may be selected from hydrochloric, sulfuric, hydrobromic and the like; and the organic acid may be selected from acetic, oxalic, para- toluenesulfonic, methaesulfonic and the like.
  • Acidic hydrolysis may be earned out by at temperature of about 20 -100 °C for 2-6 hours preferably at about 40 to 70°C.
  • the compound of fomiula 2, imidazol-1 -ylacetic acid is then converted to 2-(imidazol-l- yl)-l-hydroxyethane- 1,1 -diphosphonic acid, compound of fomiula 1 using standard methods known to those skilled in the art such as United States Patent No. 4,939,130.
  • a process disclosed in our copending Indian Patent Application No. 837/MUM/2003 may be used.
  • Example 1 Synthesis of benzyl 1-imidazolyl acetate (compound of formula 3) Chloroacetyl chloride (300g, 2.65mol) was charged slowly at 10-20° C to a stirred mixture containing imidazole (630g, 9.29mol), benzyl alcohol (300ml, 2.92mol) and acetonitrile (900ml). Temperature was raised to 50-55° C and stirred for 12 hours. Acetonitrile was distilled out under vacuum at 55-60° C and finally degassed for lhour at 55-60° C. Water was added to the residue and the product extracted into ethyl acetate. The ethyl acetate extract was washed successively with 10% sodium bicarbonate solution and water and then concentrated and degassed to get 467g of crude benzyl 1-imidazolylacetate compound of formula 3.
  • a suspension of imidazol-1 -ylacetic acid, compound of formula 2 (50g, 0.396mol) and phosphorous acid (48.7g, 0.594mol) in sulfolane (180ml) was heated to 75° C for 30 min.
  • the mixture was cooled to 35-40° C and phosphorous trichloride (117ml, 1.346mol) was gradually introduced while maintaining the temperature between 35-45° C.
  • the mixture was heated to 63-67° C for 3 hours, whereby white solid results. It was then cooled to 0- 5° C and quenched by slow addition of water (500ml) at 0-5° C over a period of 1 hour.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour préparer le composé acide 2-(imidazol-1-yl)-1-hydroxyéthane-1,1-diphosphonique de formule (1). Ce procédé comprend les étapes qui consistent : (a) à faire réagir de l'imidazole avec du chlorure de chloroacétyle et de l'alcool de benzyle dans un système homogène dans un seul récipient, pour obtenir le composé benzyl 1-imidazolylacétate de formule (3) ; (b) à procéder à la débenzylation du composé benzyl 1-imidazolylacétate de formule (3) pour obtenir le composé acide 1-ylacétique de formule (2), et ; (c) à convertir le composé de formule (2) en composé de formule (1).
PCT/IN2004/000320 2003-10-17 2004-10-18 Procede de preparation d'acide 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonique WO2005066188A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1094/MUM/2003 2003-10-17
IN1094MU2003 2003-10-17

Publications (1)

Publication Number Publication Date
WO2005066188A1 true WO2005066188A1 (fr) 2005-07-21

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007109542A2 (fr) * 2006-03-21 2007-09-27 Albemarle Corporation Procede de fabrication d'acides bisphosphoniques
WO2007125521A2 (fr) * 2006-05-02 2007-11-08 Ranbaxy Laboratories Limited Formes polymorphiques de l'acide zolédronique et leurs procédés de synthèse
WO2008056129A1 (fr) * 2006-11-06 2008-05-15 Hovione Inter Limited Procédé de préparation des acides biphosphoniques et de leurs sels
WO2010050830A1 (fr) * 2008-10-31 2010-05-06 Zakłady Farmaceutyczne Polpharma Sa Procédé de préparation d’acide [1-hydroxy-2-(1h-imidazol-1-yl)- ethylidene] biphosphonique
US20100197931A1 (en) * 2005-07-28 2010-08-05 Gador S.A. Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it
US8071574B2 (en) 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
US8882740B2 (en) 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] ZHU J. ET AL: "Synthesis of zoledronic acid", accession no. STN Database accession no. 2003-159671 *
DATABASE CAPLUS LI J. ET AL: "Improved process for the synthesis of zoledronic acid as a new drug for treating hypercalcemia" *
ZHONGGUO XINYAO ZAZHI, vol. 12, no. 1, 2003, pages 39 - 40 *
ZHONGGUO YAOWU HUAXUE ZAZHI, vol. 12, no. 3, 2002, pages 164 - 165 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071574B2 (en) 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
US20100197931A1 (en) * 2005-07-28 2010-08-05 Gador S.A. Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it
US8952172B2 (en) * 2005-07-28 2015-02-10 Gador S.A. Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it
WO2007109542A2 (fr) * 2006-03-21 2007-09-27 Albemarle Corporation Procede de fabrication d'acides bisphosphoniques
WO2007109542A3 (fr) * 2006-03-21 2007-11-01 Albemarle Corp Procede de fabrication d'acides bisphosphoniques
WO2007125521A2 (fr) * 2006-05-02 2007-11-08 Ranbaxy Laboratories Limited Formes polymorphiques de l'acide zolédronique et leurs procédés de synthèse
WO2007125521A3 (fr) * 2006-05-02 2008-01-10 Ranbaxy Lab Ltd Formes polymorphiques de l'acide zolédronique et leurs procédés de synthèse
WO2008056129A1 (fr) * 2006-11-06 2008-05-15 Hovione Inter Limited Procédé de préparation des acides biphosphoniques et de leurs sels
WO2010050830A1 (fr) * 2008-10-31 2010-05-06 Zakłady Farmaceutyczne Polpharma Sa Procédé de préparation d’acide [1-hydroxy-2-(1h-imidazol-1-yl)- ethylidene] biphosphonique
US8524912B2 (en) 2008-10-31 2013-09-03 Zaklady Farmaceutyczne Polpharma Sa Process for the preparation of [1-hydroxy-2-(1H-imidazol-1-yl)- ethylidene]bisphosphonic acid
US8882740B2 (en) 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone

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