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WO2007010556A1 - Procede de production d'acide 4-amino-1-hydroxybutylidene-1,1-bisphosphonique ou sels de celui-ci - Google Patents

Procede de production d'acide 4-amino-1-hydroxybutylidene-1,1-bisphosphonique ou sels de celui-ci Download PDF

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Publication number
WO2007010556A1
WO2007010556A1 PCT/IN2006/000255 IN2006000255W WO2007010556A1 WO 2007010556 A1 WO2007010556 A1 WO 2007010556A1 IN 2006000255 W IN2006000255 W IN 2006000255W WO 2007010556 A1 WO2007010556 A1 WO 2007010556A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
hydroxybutylidene
acid
salts
bisphosphonic acid
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/IN2006/000255
Other languages
English (en)
Inventor
Girij Pal Singh
Harishchandra Sambhaji Jadhav
Narotham Venkata Maddireddy
Dhananjai Srivastava
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.)
Lupin Ltd
Original Assignee
Lupin Ltd
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 Lupin Ltd filed Critical Lupin Ltd
Publication of WO2007010556A1 publication Critical patent/WO2007010556A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)

Definitions

  • the invention relates to an improved industrial process for the production of 4- amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
  • 4-amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid commonly known as Alendronic acid is an antihypercalcemic agent effective in the treatment or prevention of diseases involving hypercalcemia of pregnancy, Paget's disease and osteoporosis.
  • Alendronic acid is marketed as its monosodium salt tri hydrate represented by formula (I) under the brand name FOSAMAX by Merck.
  • ⁇ -amino-1- hydroxyalkylidene-1 ,1-bisphosphonic acids in general and 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid in particular.
  • the synthesis consists of reacting the corresponding ⁇ -amino acid with a mixture of phosphorus acid and one of the three phosphorus chlorides PCI 3 , POCI 3 or PCI 5 , quenching the reaction mixture with water or a non-oxidizing aqueous acid followed by heating to hydrolyze the phosphorous intermediates to the final product.
  • US Patent No. 4,407,761 teaches a process to prepare 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid wherein the reaction is carried out at about 100 °C in chlorobenzene as a diluent which does not solubilize the reaction components and serves only as a heat transfer agent.
  • the process is unsuitable for large scale production as the reaction remain a two phase system and gradually thickens into a non-stirrable mass with local solidification.
  • methanesulfonic acid has safety concerns. Methansulfonic acid reacts with PCI 3 and under adiabatic conditions the reaction becomes self- heating at 85 °C and an uncontrolled exotherm occurs at >140 0 C. This fact was recognized by the inventors in Example 1 of US 4,922,007. The inventors in a subsequent publication J. Org. Chem., 1995, 60, 8310-8312 have mentioned about the safety concerns.
  • the object of the present invention is to provide a process to prepare 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid or salts that overcomes the non homogeneity, solidification and safety problems associated with prior art synthesis.
  • the present invention provides a process for the production of 4- amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof which comprises: (a) reacting 4-aminobutyric acid with a suitable phosphonating agent in a solvent such as sulfolane
  • the present invention involves the phosphonylation of 4-aminobutyric acid with a suitable phosphonating agent selected from: a mixture of phosphorous acid and
  • PCI 3 a mixture of phosphorous acid and PCI 5 , a mixture of phosphorous acid and
  • POCl 3 in a solvent such as sulfolane, diglyme and diphenyl oxide, followed by hydrolysis of the resulting mixture using water and then recovering 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
  • the phosphonylation reaction is carried out in a solvent such as sulfolane, diglyme and diphenyl oxide at a suitable temperature between 30 °C to 80 ° v r ->,
  • the process of the present invention may also be carried out in other solvents such diglyme and diphenyl oxide.
  • the phosphonylation of 4-amino butyric acid is preferably carried out using phosphorous acid and phosphorous trichloride
  • hydrolysis is carried out by adding water and heating to about 80 0 C to 100 °C in water.
  • the 4-amino-1-hydroxybutylidene-1 ,1- bisphosphonic acid or its salt is isolated by adjusting the pH to 4 to 4.5 by the addition of a base such as aq. NaOH or aq. KOH.
  • 4-amino-1-hydroxybutylidene-1 ,1 -bisphosphonic acid is isolated as its sodium salt.
  • Figure 1 shows the powder X-ray diffraction pattern for the 4-amino-1- hydroxybutylidene-1 ,1 -bisphosphonic acid mono sodium trihydrate obtained by the process disclosed in the present invention.
  • 4-amino-1-hydroxybutylidene-1 ,1 -bisphosphonic acid monosodium trihydrate in a pharmaceutical composition is useful for treatment of some bone disorders, such as osteoporosis and hypercalcemia of malignancy.

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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)

Abstract

L'invention concerne un procédé de préparation d'acide 4-amino-1-hydroxybutylidène-1,1-bisphosphonique ou des sels de celui-ci consistant: (a) à faire réagir de l'acide 4-aminobutyrique avec un mélange d'acide phosphoreux et de trichlorure phosphoreux dans un solvant sélectionné parmi : sulfolane, diglyme et l'oxyde de diphényle ; (b) à hydrolyser le mélange de réaction obtenu à l'étape (a) avec de l'eau ; et (c) à récupérer l'acide 4-amino-1-hydroxybutylidène-1,1-bisphosphonique ou des sels de celui-ci.
PCT/IN2006/000255 2005-07-20 2006-07-18 Procede de production d'acide 4-amino-1-hydroxybutylidene-1,1-bisphosphonique ou sels de celui-ci Ceased WO2007010556A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN636/KOL/2005 2005-07-20
IN636KO2005 2005-07-20

Publications (1)

Publication Number Publication Date
WO2007010556A1 true WO2007010556A1 (fr) 2007-01-25

Family

ID=37420743

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000255 Ceased WO2007010556A1 (fr) 2005-07-20 2006-07-18 Procede de production d'acide 4-amino-1-hydroxybutylidene-1,1-bisphosphonique ou sels de celui-ci

Country Status (1)

Country Link
WO (1) WO2007010556A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008056129A1 (fr) * 2006-11-06 2008-05-15 Hovione Inter Limited Procédé de préparation des acides biphosphoniques et de leurs sels
CN101284848B (zh) * 2008-06-10 2013-09-11 石药集团欧意药业有限公司 一种阿仑膦酸的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044831A2 (fr) * 2003-08-21 2005-05-19 Sun Pharmaceutical Industries Limited Procede d'elaboration de composes d'acide bisphosphonique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044831A2 (fr) * 2003-08-21 2005-05-19 Sun Pharmaceutical Industries Limited Procede d'elaboration de composes d'acide bisphosphonique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008056129A1 (fr) * 2006-11-06 2008-05-15 Hovione Inter Limited Procédé de préparation des acides biphosphoniques et de leurs sels
CN101284848B (zh) * 2008-06-10 2013-09-11 石药集团欧意药业有限公司 一种阿仑膦酸的合成方法

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