WO2003093282A1 - Preparation of biphosphonic acids and salts thereof - Google Patents

Preparation of biphosphonic acids and salts thereof Download PDF

Info

Publication number
WO2003093282A1
WO2003093282A1 PCT/IB2002/004941 IB0204941W WO03093282A1 WO 2003093282 A1 WO2003093282 A1 WO 2003093282A1 IB 0204941 W IB0204941 W IB 0204941W WO 03093282 A1 WO03093282 A1 WO 03093282A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
process according
reaction
salts
solvents
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/IB2002/004941
Other languages
German (de)
French (fr)
Other versions
WO2003093282A8 (en
Inventor
Lorenzo De Ferra
Stefano Turchetta
Pietro Massardo
Paolo Casellato
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.)
Chemi SpA
Original Assignee
Chemi SpA
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 Chemi SpA filed Critical Chemi SpA
Priority to EP02807339A priority Critical patent/EP1504012B9/en
Priority to AT02807339T priority patent/ATE452899T1/en
Priority to US10/512,930 priority patent/US7332603B2/en
Priority to AU2002367897A priority patent/AU2002367897A1/en
Priority to DE60234870T priority patent/DE60234870D1/en
Priority to JP2004501421A priority patent/JP2005523938A/en
Publication of WO2003093282A1 publication Critical patent/WO2003093282A1/en
Anticipated expiration legal-status Critical
Publication of WO2003093282A8 publication Critical patent/WO2003093282A8/en
Ceased legal-status Critical Current

Links

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)]
    • 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)
    • 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
    • C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • 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
    • 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
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to a process for preparing bisphosphonic acids and their pharmacologically active salts.
  • M-i, M 2 , M 3 , M are selected from H, and a monovalent cation. Belonging to this class of molecules are the following compounds used in the treatment of osteoporosis (see Table 1 ) according to the different meaning that R- ⁇ may assume.
  • R Q[-
  • WO9834940 employs polyalkylene glycols as reaction solvents for synthesizing alendronic acid; however, these solvents have a high cost and are difficult to eliminate from the finished product, given their high boiling point
  • WO0049026 starting from a nitrogen-protected derivative of ⁇ -aminopropionic acid to prevent the known problems of stirrability of the reaction mixture, use is made of orthophosphoric acid as the reaction means.
  • WO0110874 regards the use of methanesulphonic anhydride as the solvent for producing alendronic acid, but the high cost of the solvent renders the method difficult to apply at an industrial level.
  • the solvent used is economically advantageous and easy to recover and recycle.
  • M M 4 are preferably selected from the cations of the alkaline metals, H, cations of aliphatic or cyclolaliphatic amines, and more preferably are sodium and/or H.
  • the temperature at which the aforesaid ionic solvents are liquid is preferably between 20°C and 100°C.
  • liquid ionic solvents are meant the -onium salts selected from the group consisting of ammonium, sulphonium or phosphonium salts. Possible examples of said solvents are given below:
  • each R may be independently H, a linear or branched C- 1 -C20 al yl group, a cycloalkyl containing from 5 to 6 carbon atoms, alkylene aryl, or aryl;
  • R 2 is H or a linear or branched C 1 -C 18 alkyl group,
  • X " is an anion selected from the group consisting of halogenide, BF 4 " , PF 6 " , or AICI 4 " .
  • Particularly preferred is tributylammonium chloride, which melts at approximately 60°C.
  • reaction solvent tributylammonium chloride
  • a 3-litre reactor provided with a Dean-Stark trap and drip funnel is charged with 150 ml of toluene and 334.3 g of tributylamine.
  • the solution is cooled to 25-30°C and from the drip funnel there are added 152.6 ml of 33% aqueous hydrochloric acid, in the meantime controlling that the temperature does not exceed 40°C.
  • the homogeneous solution thus obtained is then distilled in vacuum conditions (50 mmHg) until the internal temperature reaches 80°C and no more liquid is distilled from the reactor.
  • the mixture thus obtained consists of tributylammonium chloride and is ready for use in the subsequent reactions of formation of bisphosphonic acids.
  • EXAMPLE 1B Preparation of sodium alendronate To the liquid phase obtained in Example 1 , kept at 70°C, there are added 79.5 g of phosphorous acid and subsequently 100 g of ⁇ -aminobutyric acid. The temperature of the mixture is brought to 60°C, and from the drip funnel there are added 266.4 g of phosphorus trichloride during an interval of approximately one hour, maintaining the internal temperature between 60°C and 65°C. Subsequently, the reaction mixture is kept under stirring for two hours at 60°C, and then is cooled to 20°C. There are added 410 ml of deionized water, keeping the temperature of the reaction mixture below 40°C.
  • the temperature is brought up to 90°C and kept in these conditions for 2 hours.
  • 1093 ml of 30% aqueous sodium hydroxide are added to the reaction mixture, until the final pH is 11-12.
  • the resulting top layer, consisting of tributylamine is separated off.
  • the tributylamine may be subsequently treated with aqueous hydrochloric acid, as described in Example 1A, to re-obtain tributylammonium hydrochlorate as the reaction solvent.
  • the aqueous phase is treated with 33% aqueous hydrochloric acid to bring the pH of the solution to 4.3 + 0.1.
  • the aqueous phase is then dripped on 7000 ml of methanol under stirring, causing the separation of a heavy precipitate, which is then filtered and washed with 500 ml of methanol.
  • zoledronic acid 20 of tributylammonium chloride prepared as in Example 1A, are put into a 100-ml flask provided with coolant, magnetic stirrer, drip funnel and thermometer. The solid is melted at 60°C, then 3.2 g of phosphorous acid and 5.0 g of 2-(1- imidazyl)-acetic acid are added. The temperature of the mixture is then brought up to 65-70°C, and from the drip funnel there are slowly added 10.9 g of PCI 3 . Once the addition is completed, the mixture is brought up to 80°C and kept under these conditions for two hours, at the end of which 20 ml of deionized water are added.
  • the mixture is brought to 90°C and is kept under these conditions for 2 hours. It is then cooled down to room temperature, and 50 ml of 33% NaOH are added to the mixture, until a pH of the mixture > 12 is reached.
  • the two phases that have formed are separated, and 20 ml of toluene are added to the aqueous bottom phase, stirring the mixture for 15 min.
  • the phases are once more separated, and the aqueous phase is brought to pH 1 by addition of 33% HCI.
  • the aqueous solution is then dripped on 300 ml of methanol. The solid that precipitates is filtered and washed with 50 ml of methanol.

Landscapes

  • 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)
  • Polyamides (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A process for preparing bisphosphonic acids, characterized in that the reaction of synthesis is conducted in a reaction means consisting of bisphosphonic acids.

Description

PREPARATION OF BIPHOSPHONIC ACIDS AND SALTS THEREOF
Field of the invention
The present invention relates to a process for preparing bisphosphonic acids and their pharmacologically active salts.
State of the art
The bisphosphonic acids and their salts, which form the subject of the present patent application are compounds described by the following structural formula:
Figure imgf000002_0001
(1)
in which M-i, M2, M3, M are selected from H, and a monovalent cation. Belonging to this class of molecules are the following compounds used in the treatment of osteoporosis (see Table 1 ) according to the different meaning that R-\ may assume.
TABLE 1 :
R = Q[-|3 Etidronic acid Zoledronic acid
Risedronic acid
inodronic acid
Figure imgf000003_0001
R = H2N^^ 2 Pamidronic acid
Alendronic acid Neridronic acid Olpadronic acid
Ibandronic acid
Figure imgf000003_0002
As regards the methods of synthesis, these compounds are synthesized starting from the corresponding carboxylic acid according to the synthetic scheme appearing in Diagram 1
Figure imgf000003_0003
Starting from the acid, by subsequent salification of the acid protons, the various salts may be obtained.
A problem that is commonly encountered in the preparation of these compounds is the formation, during the reaction, of very dense unstirrable masses, which render the industrial synthesis of these substances problematical. In the literature various documents have been published which describe techniques of synthesis of the compounds listed in Table 1.
US4621077, which regards alendronic acid and neridronic acid, describes the use of chlorobenzene as the solvent in the synthesis. The application of this technique leads to obtaining solid and unstirrable masses in the course of the reaction. A series of other patents (US4407761 , US4327039, US4304734, US4267108, US4054598) envisages the use of chlorobenzene as reaction solvent, but also in these cases the drawback described above is again met with. US4922007, US5019651 and US5510517, as well as J. Orq. Chem. 60, 8310, (1995), envisage the use of methanesulphonic acid as reaction solvent. This makes it possible to obtain stirrable masses in the course of the reaction. However, this technique, as reported in J. Org. Chem. 60, 8310, (1995), involves risks of safety in that this solvent gives rise to uncontrollable reactions in the reaction conditions, when the temperature of the reacting mixtures exceeds 85°C. WO9834940 employs polyalkylene glycols as reaction solvents for synthesizing alendronic acid; however, these solvents have a high cost and are difficult to eliminate from the finished product, given their high boiling point In WO0049026, starting from a nitrogen-protected derivative of β-aminopropionic acid to prevent the known problems of stirrability of the reaction mixture, use is made of orthophosphoric acid as the reaction means. The derivatization of the starting product in any case renders the method of synthesis unwieldy and involves the need for introducing additional steps for protection and deprotection. US5792885 synthesizes pamidronic acid starting from a nitrogen-protected derivative of γ-aminobutyric acid, in aromatic hydrocarbons as the reaction solvents. This method presents the same drawbacks illustrated for the method described in WO0049026.
WO0110874 regards the use of methanesulphonic anhydride as the solvent for producing alendronic acid, but the high cost of the solvent renders the method difficult to apply at an industrial level. Technical problem
The need was thus felt to have available a general process for preparing the compounds described in Table 1 which would not present the drawbacks of the processes known to the art. Summary of the invention The present applicant has now unexpectedly found that, using as the reaction solvents in the synthesis of the compounds described in Diagram 1 the so-called ionic liquids, it is possible to convert the raw materials into the desired products, avoiding the drawbacks of the processes known to the prior art.
In addition, the solvent used is economically advantageous and easy to recover and recycle.
Consequently, forming the subject of the present invention are processes for preparing the active principles described in Table 1 , comprising the reaction of the appropriate raw materials with phosphorous acid and phosphorus trichloride, subsequent treatment with acid water and possible final treatment with an aqueous solution of a hydroxide of an alkaline metal, characterized in that the reaction is conducted in ionic liquids at a temperature of between 15°C and 120°C. Detailed description of the invention
M M4 are preferably selected from the cations of the alkaline metals, H, cations of aliphatic or cyclolaliphatic amines, and more preferably are sodium and/or H. The temperature at which the aforesaid ionic solvents are liquid is preferably between 20°C and 100°C. By liquid ionic solvents are meant the -onium salts selected from the group consisting of ammonium, sulphonium or phosphonium salts. Possible examples of said solvents are given below:
Figure imgf000005_0001
Figure imgf000005_0002
in which each R may be independently H, a linear or branched C-1-C20 al yl group, a cycloalkyl containing from 5 to 6 carbon atoms, alkylene aryl, or aryl; R2 is H or a linear or branched C1-C18 alkyl group, X" is an anion selected from the group consisting of halogenide, BF4 ", PF6 ", or AICI4 ". Particularly preferred is tributylammonium chloride, which melts at approximately 60°C. These solvents are moreover easy to prepare with methods of a conventional type, do not create problems of safety in so far as they do not cause uncontrollable reactions, and moreover afford the undoubted advantages that they may be recovered and re-used for several production cycles. The following examples are provided by way of non-limiting illustrations of the process that forms the subject of the present invention. EXAMPLE 1A
Formation of the reaction solvent (tributylammonium chloride) A 3-litre reactor provided with a Dean-Stark trap and drip funnel is charged with 150 ml of toluene and 334.3 g of tributylamine. The solution is cooled to 25-30°C and from the drip funnel there are added 152.6 ml of 33% aqueous hydrochloric acid, in the meantime controlling that the temperature does not exceed 40°C. The homogeneous solution thus obtained is then distilled in vacuum conditions (50 mmHg) until the internal temperature reaches 80°C and no more liquid is distilled from the reactor. The mixture thus obtained consists of tributylammonium chloride and is ready for use in the subsequent reactions of formation of bisphosphonic acids. EXAMPLE 1B Preparation of sodium alendronate To the liquid phase obtained in Example 1 , kept at 70°C, there are added 79.5 g of phosphorous acid and subsequently 100 g of γ-aminobutyric acid. The temperature of the mixture is brought to 60°C, and from the drip funnel there are added 266.4 g of phosphorus trichloride during an interval of approximately one hour, maintaining the internal temperature between 60°C and 65°C. Subsequently, the reaction mixture is kept under stirring for two hours at 60°C, and then is cooled to 20°C. There are added 410 ml of deionized water, keeping the temperature of the reaction mixture below 40°C. At the end of addition, the temperature is brought up to 90°C and kept in these conditions for 2 hours. After cooling to 10°C, 1093 ml of 30% aqueous sodium hydroxide are added to the reaction mixture, until the final pH is 11-12. The resulting top layer, consisting of tributylamine is separated off. The tributylamine may be subsequently treated with aqueous hydrochloric acid, as described in Example 1A, to re-obtain tributylammonium hydrochlorate as the reaction solvent.
The aqueous phase is treated with 33% aqueous hydrochloric acid to bring the pH of the solution to 4.3 + 0.1. The aqueous phase is then dripped on 7000 ml of methanol under stirring, causing the separation of a heavy precipitate, which is then filtered and washed with 500 ml of methanol.
There are obtained 1366 g of crude sodium alendronate, which is then dissolved at 75°C in 3600 ml of deionized water. The solution is then filtered at 75°C and left to crystallize by means of slow cooling, until the mixture reaches 5°C. The crystalline solid obtained is filtered and washed with 2 x 100 ml of deionized water and then dried at 50°C for 12 hours, to obtain 97.8 g of sodium alendronate (31% yield).
EXAMPLE 2
Preparation of zoledronic acid 20 of tributylammonium chloride, prepared as in Example 1A, are put into a 100-ml flask provided with coolant, magnetic stirrer, drip funnel and thermometer. The solid is melted at 60°C, then 3.2 g of phosphorous acid and 5.0 g of 2-(1- imidazyl)-acetic acid are added. The temperature of the mixture is then brought up to 65-70°C, and from the drip funnel there are slowly added 10.9 g of PCI3. Once the addition is completed, the mixture is brought up to 80°C and kept under these conditions for two hours, at the end of which 20 ml of deionized water are added. The mixture is brought to 90°C and is kept under these conditions for 2 hours. It is then cooled down to room temperature, and 50 ml of 33% NaOH are added to the mixture, until a pH of the mixture > 12 is reached. The two phases that have formed are separated, and 20 ml of toluene are added to the aqueous bottom phase, stirring the mixture for 15 min. The phases are once more separated, and the aqueous phase is brought to pH 1 by addition of 33% HCI. The aqueous solution is then dripped on 300 ml of methanol. The solid that precipitates is filtered and washed with 50 ml of methanol. To the filtered solid there are added 70 ml of deionized water, and the mixture is heated to 80°C and kept under these conditions for 1 hour. Then the solution is cooled to room temperature. A white solid precipitates, which is filtered and washed with 20 ml of deionized water to obtain 4.2 g of the desired product, which is dried at 50°C under vacuum for 6 hours. The weight of the dry product is 2.8 g.
EXAMPLE 3
Preparation of risedronic acid
The same procedure of preparation as the one described in Example 3 is followed, using 5.4 g of 2.-(3-pyridyl)-acetic acid instead of 2-(1-imidazyl)-acetic acid; 3.5 g of the desired product are obtained.
EXAMPLE 4
Preparation of sodium pamidronate
The same procedure of preparation as the one described in Example 1 is followed, using 86.4 g of β-aminopropionic acid instead of γ-aminobutyric acid; 81.5 g of the desired product are obtained.

Claims

1. A process for preparing bisphosphonic acids and their salts of formula (1_),
Figure imgf000009_0001
(1) in which Ri has the meanings indicated in the following Table 1 :
R _ H3 Etidronic acid
R Zoledronic acid
Risedronic acid
Figure imgf000009_0002
R = γ ^T Minodronic acid
j**^ CH
R = HjN^^^ 2 Pamidronic acid
R = H2 ^^^^CH2 Alendronic acid
R Neridronic acid
R = ^N^^^ Olpadronic acid
R1 = — "^ — /sN' χ/ Ibandronic acid
and in which Mi, M2, M3, M are selected from H, and a monovalent cation, comprising the reaction of acids of formula RrC02H, in which Ri has the aforesaid meanings, with acids and phosphorus trichloride, characterized in that the reaction is conducted in ionic liquids as the reaction solvents, at a temperature of between 15°C and 120°C.
2. The process according to Claim 1 , characterized in that the temperature at which the aforesaid ionic solvents are liquids is between 20°C and 100°C.
3. The process according to Claim 1 or Claim 2, characterized in that the ionic liquids used as the solvents are selected from the group consisting of salts of ammonium, sulphonium or phosphonium.
4. The process according to Claim 3, characterized in that said -onium salts are selected from the group consisting of
Figure imgf000010_0001
Figure imgf000010_0002
in which each R may be independently H, a linear or branched C-1-C20 alkyl group, a cycloalkyl containing from 5 to 6 carbon atoms, alkylene aryl, or aryl; R2 is H or a linear or branched C1-C18 alkyl group, X" is an anion selected the group consisting of halogenide, BF4 ", PFβ", and AICU".
5. The process according to either Claim 3 or Claim 4, characterized in that said -onium salt is tributylammonium chloride.
6. The process according to any one of Claims 1-5, characterized in that M1-M4 are selected from the cations of an alkaline metal, H or the cations of aliphatic or cycloaliphatic amines.
7. The process according to Claim 6, characterized in that M1-M4 are selected from H and/or sodium.
PCT/IB2002/004941 2002-04-29 2002-11-25 Preparation of biphosphonic acids and salts thereof Ceased WO2003093282A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP02807339A EP1504012B9 (en) 2002-04-29 2002-11-25 Preparation of biphosphonic acids and salts thereof
AT02807339T ATE452899T1 (en) 2002-04-29 2002-11-25 PRODUCTION OF BISPHOSPHONIC ACIDS AND SALTS THEREOF
US10/512,930 US7332603B2 (en) 2002-04-29 2002-11-25 Preparation of biphosphonic acids and salts thereof
AU2002367897A AU2002367897A1 (en) 2002-04-29 2002-11-25 Preparation of biphosphonic acids and salts thereof
DE60234870T DE60234870D1 (en) 2002-04-29 2002-11-25 PREPARATION OF BISPHOSPHONES AND SALTS THEREOF
JP2004501421A JP2005523938A (en) 2002-04-29 2002-11-25 Process for producing bisphosphonic acids and salts thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2002MI000908A ITMI20020908A1 (en) 2002-04-29 2002-04-29 ALENDRONATE SODIUM PREPARATION PROCESS
ITMI2002A000908 2002-04-29

Publications (2)

Publication Number Publication Date
WO2003093282A1 true WO2003093282A1 (en) 2003-11-13
WO2003093282A8 WO2003093282A8 (en) 2007-09-07

Family

ID=11449800

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2002/004941 Ceased WO2003093282A1 (en) 2002-04-29 2002-11-25 Preparation of biphosphonic acids and salts thereof

Country Status (10)

Country Link
US (1) US7332603B2 (en)
EP (1) EP1504012B9 (en)
JP (1) JP2005523938A (en)
KR (1) KR20050025162A (en)
AT (1) ATE452899T1 (en)
AU (1) AU2002367897A1 (en)
DE (1) DE60234870D1 (en)
ES (1) ES2338540T3 (en)
IT (1) ITMI20020908A1 (en)
WO (1) WO2003093282A1 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075860A3 (en) * 2003-02-27 2005-02-17 Teva Pharma Process for purification of zoledronic acid
WO2005063717A1 (en) * 2003-12-26 2005-07-14 Natco Pharma Limited An improved process for the preparation of zoledronic acid
WO2007125521A3 (en) * 2006-05-02 2008-01-10 Ranbaxy Lab Ltd Polymorphic form of zoledronic acid and processes for their preparation
EP1923394A1 (en) * 2006-11-16 2008-05-21 Sandoz A/S Reagent and use thereof for the production of bisphosphonates
JP2008525432A (en) * 2004-12-28 2008-07-17 ザクラディ ファルマチョイッチネ ポルファルマ エスエイ [1-Hydroxy-2- (3-pyridinyl) ethylidene] bisphosphonic acid and method for producing hemi-5-hydrate monosodium salt
US7435827B2 (en) 2003-07-03 2008-10-14 Teva Pharmaceutical Industries Ltd Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
US7563918B2 (en) 2004-08-23 2009-07-21 Teva Pharmaceutical Industries Ltd. Solid and crystalline ibandronate sodium and processes for preparation thereof
US7611722B2 (en) 2001-12-24 2009-11-03 Teva Pharmaceutical Industries Ltd. Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it
EP1931326A4 (en) * 2005-09-12 2009-12-16 Reddys Lab Ltd Dr Crystalline trihydrate of zoledronic acid
WO2010050830A1 (en) * 2008-10-31 2010-05-06 Zakłady Farmaceutyczne Polpharma Sa Process for the preparation of [1-hydroxy-2-(1h-imidazol-1-yl)- ethylidene]bisphosphonic acid
EP2192126A1 (en) 2008-11-26 2010-06-02 Synthon B.V. Process for making zoledronic acid
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
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts
CN106632483A (en) * 2016-12-20 2017-05-10 青岛辰达生物科技有限公司 Tenofovir disoproxil preparation method

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040052843A1 (en) * 2001-12-24 2004-03-18 Lerner E. Itzhak Controlled release dosage forms
KR100681282B1 (en) * 2002-05-17 2007-02-12 테바 파마슈티컬 인더스트리즈 리미티드 A method for preparing bisphosphonic acids and the salts there of using certain diluents
EP1571152B1 (en) * 2004-03-03 2007-08-08 CHEMI S.p.A. Amorphous 3-Pyridil-1-Hydroxyethyliden-1,1-Biphosphonic acid monosodium salt and process for the preparation thereof .
US8071574B2 (en) 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
WO2007083240A2 (en) * 2006-01-20 2007-07-26 Aurobindo Pharma Limited An improved process for the preparation of bisphosphonic acids
JP5354858B2 (en) * 2006-05-09 2013-11-27 株式会社Ａｄｅｋａ Polyester resin composition containing metal salt of sulfonamide compound
US20100317859A1 (en) * 2007-05-16 2010-12-16 Actavis Group Ptc Ehf Process for the Preparation of Risedronate Sodium
WO2009050731A2 (en) * 2007-06-20 2009-04-23 Alkem Laboratories Ltd Novel process for preparing risedronic acid
US8080323B2 (en) * 2007-06-28 2011-12-20 Kennametal Inc. Cutting insert with a wear-resistant coating scheme exhibiting wear indication and method of making the same
KR100877667B1 (en) * 2007-06-28 2009-01-08 보령제약 주식회사 Method for preparing risedronate
JP5258370B2 (en) * 2008-05-08 2013-08-07 ダイト株式会社 Industrial production method of risedronic acid
US20100130746A1 (en) * 2008-11-26 2010-05-27 Martin Kas Process for Making Zoledronic Acid
CA2769633C (en) * 2009-07-31 2017-06-06 Thar Pharma, Llc Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US20160016982A1 (en) 2009-07-31 2016-01-21 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
WO2011016738A1 (en) 2009-08-05 2011-02-10 Zaklady Farmaceutyczne Polpharma Sa A process for the synthesis of 1-hydroxy-3-(n-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate
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
WO2012071517A2 (en) 2010-11-24 2012-05-31 Thar Pharmaceuticals, Inc. Novel crystalline forms
WO2017208070A1 (en) 2016-05-31 2017-12-07 Grünenthal GmbH Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3366676A (en) * 1965-03-30 1968-01-30 Procter & Gamble Use of amine solvents in the preparation of ethane-1-hydroxy-1, 1-diphosphonic acid
DE3700772A1 (en) * 1987-01-13 1988-07-21 Inst Khim Kinetiki I Gorenija Process for the preparation of 1-functionally substituted alkylidene-1,1-diphosphonic acids and their mixtures
SU1719405A1 (en) * 1985-07-02 1992-03-15 Институт Химической Кинетики И Горения Со Ан Ссср Method of preparation of higher 1-oxyalkyledene-1,1-diphosphonic acids or their mixtures or salts
WO2001057052A1 (en) * 2000-02-01 2001-08-09 The Procter & Gamble Company Process for making geminal bisphosphonates
GB2378444A (en) * 2001-06-28 2003-02-12 Rhodia Cons Spec Ltd A carrier/solvent system comprising an amine hydrochloride, phosphorous acid & optionally phosphoric acid

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3262971A (en) * 1962-10-12 1966-07-26 Monsanto Res Corp Phosphorus compounds
DE2534391C2 (en) 1975-08-01 1983-01-13 Henkel KGaA, 4000 Düsseldorf 1-Hydroxy-3-aminoalkane-1,1-diphosphonic acids
DE2745083C2 (en) 1977-10-07 1985-05-02 Henkel KGaA, 4000 Düsseldorf Hydroxydiphosphonic acids and processes for their preparation
DE2943498C2 (en) 1979-10-27 1983-01-27 Henkel KGaA, 4000 Düsseldorf Process for the preparation of 3-amino-1-hydroxypropane-1,1-diphosphonic acid
DE3016289A1 (en) 1980-04-28 1981-10-29 Henkel KGaA, 4000 Düsseldorf METHOD FOR PRODUCING OMEGA-AMINO-1-HYDROXYALKYLIDEN-1,1-BIS-PHOSPHONIC ACIDS
US4304734A (en) 1980-10-16 1981-12-08 Vysoka Skola Chemicko-Technologicka 6-Amino-1-hydroxyhexylidene diphosphonic acid, salts and a process for production thereof
IT1201087B (en) 1982-04-15 1989-01-27 Gentili Ist Spa PHARMACOLOGICALLY ACTIVE BIPPHOSPHONES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS
US4922007A (en) 1989-06-09 1990-05-01 Merck & Co., Inc. Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
US5019651A (en) 1990-06-20 1991-05-28 Merck & Co., Inc. Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof
US5510517A (en) 1993-08-25 1996-04-23 Merck & Co., Inc. Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids
KR100192215B1 (en) 1996-09-03 1999-06-15 강재헌 Process for producing 3-amino-1-hydroxypropane-1,1-diphosphonic acid
CA2197267C (en) 1997-02-11 2000-02-08 Yong Tao Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
EP1169326B1 (en) 1999-02-17 2004-07-14 Teva Pharmaceutical Industries Ltd. Process for preparing alendronic acid
ES2153794B1 (en) 1999-08-06 2001-10-16 Medichem Sa PROCEDURE FOR OBTAINING THE 4-AMINO-1-HYDROXIBUTILIDEN-1,1-BISPHOSPHONIC ACID AND ITS TRIHYDRATED MONOSODIC SALT.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3366676A (en) * 1965-03-30 1968-01-30 Procter & Gamble Use of amine solvents in the preparation of ethane-1-hydroxy-1, 1-diphosphonic acid
SU1719405A1 (en) * 1985-07-02 1992-03-15 Институт Химической Кинетики И Горения Со Ан Ссср Method of preparation of higher 1-oxyalkyledene-1,1-diphosphonic acids or their mixtures or salts
DE3700772A1 (en) * 1987-01-13 1988-07-21 Inst Khim Kinetiki I Gorenija Process for the preparation of 1-functionally substituted alkylidene-1,1-diphosphonic acids and their mixtures
WO2001057052A1 (en) * 2000-02-01 2001-08-09 The Procter & Gamble Company Process for making geminal bisphosphonates
GB2378444A (en) * 2001-06-28 2003-02-12 Rhodia Cons Spec Ltd A carrier/solvent system comprising an amine hydrochloride, phosphorous acid & optionally phosphoric acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 117, no. 23, 7 December 1992, Columbus, Ohio, US; abstract no. 234254, MIKHALIN, N. V. ET AL: "Method of preparation of higher 1-hydroxyalkylidene-1,1-diphosphonic acids or their mixtures or salts" XP002235748 *
EZRA A. ET AL.: "A peptide prodrug approach for improving bisphosphonate oral absorption", JOURNAL OF MEDICINAL CHEMISTRY., vol. 43, no. 20, 2000, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 3641 - 3652, XP002235747, ISSN: 0022-2623 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7611722B2 (en) 2001-12-24 2009-11-03 Teva Pharmaceutical Industries Ltd. Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it
WO2004075860A3 (en) * 2003-02-27 2005-02-17 Teva Pharma Process for purification of zoledronic acid
US7582768B2 (en) * 2003-07-03 2009-09-01 Teva Pharmaceutical Industries Ltd Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
US7687636B2 (en) * 2003-07-03 2010-03-30 Teva Pharmaceutical Industries Ltd Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
US7589211B2 (en) * 2003-07-03 2009-09-15 Teva Pharmaceutical Industries Ltd Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
US7435827B2 (en) 2003-07-03 2008-10-14 Teva Pharmaceutical Industries Ltd Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
WO2005063717A1 (en) * 2003-12-26 2005-07-14 Natco Pharma Limited An improved process for the preparation of zoledronic acid
US7563918B2 (en) 2004-08-23 2009-07-21 Teva Pharmaceutical Industries Ltd. Solid and crystalline ibandronate sodium and processes for preparation thereof
JP2008525432A (en) * 2004-12-28 2008-07-17 ザクラディ ファルマチョイッチネ ポルファルマ エスエイ [1-Hydroxy-2- (3-pyridinyl) ethylidene] bisphosphonic acid and method for producing hemi-5-hydrate monosodium salt
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
EP1924587B1 (en) * 2005-07-28 2014-03-05 Gador S.A. 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
EP1931326A4 (en) * 2005-09-12 2009-12-16 Reddys Lab Ltd Dr Crystalline trihydrate of zoledronic acid
WO2007125521A3 (en) * 2006-05-02 2008-01-10 Ranbaxy Lab Ltd Polymorphic form of zoledronic acid and processes for their preparation
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts
WO2008058722A1 (en) * 2006-11-16 2008-05-22 Sandoz A/S Reagent and use thereof for the production of bisphosphonates
EP1923394A1 (en) * 2006-11-16 2008-05-21 Sandoz A/S Reagent and use thereof for the production of bisphosphonates
WO2010050830A1 (en) * 2008-10-31 2010-05-06 Zakłady Farmaceutyczne Polpharma Sa Process for the preparation of [1-hydroxy-2-(1h-imidazol-1-yl)- ethylidene]bisphosphonic acid
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
EP2192126A1 (en) 2008-11-26 2010-06-02 Synthon B.V. Process for making zoledronic acid
CN106632483A (en) * 2016-12-20 2017-05-10 青岛辰达生物科技有限公司 Tenofovir disoproxil preparation method

Also Published As

Publication number Publication date
AU2002367897A8 (en) 2003-11-17
ITMI20020908A1 (en) 2003-10-29
EP1504012B1 (en) 2009-12-23
ITMI20020908A0 (en) 2002-04-29
JP2005523938A (en) 2005-08-11
US20050288509A1 (en) 2005-12-29
ES2338540T3 (en) 2010-05-10
EP1504012B9 (en) 2010-04-28
EP1504012A1 (en) 2005-02-09
ATE452899T1 (en) 2010-01-15
WO2003093282A8 (en) 2007-09-07
AU2002367897A1 (en) 2003-11-17
KR20050025162A (en) 2005-03-11
US7332603B2 (en) 2008-02-19
DE60234870D1 (en) 2010-02-04

Similar Documents

Publication Publication Date Title
EP1504012B9 (en) Preparation of biphosphonic acids and salts thereof
US7528280B2 (en) Process for the preparation of biphosphonic acids
US7439385B2 (en) Process for the preparation of biphosphonic derivatives
JP4642762B2 (en) Method for producing bisphosphonic acid compound
US7872144B2 (en) Process for producing biphosphonic acids and forms thereof
KR100688287B1 (en) Method for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and its trihydrate monosodium salt
RU2425049C2 (en) Method of producing biphosphonic acids and their salts
WO2014091386A2 (en) An improved process for preparation of minodronic acid
US8076483B2 (en) Process for the preparation of pure risedronic acid or salts
US20070066569A1 (en) Process for the preparation of bisphosphonic acid
US8003820B2 (en) Process for preparing bisphosphonic acids
EP1798236A1 (en) Process for the preparation of 3-pyridyl-1-hydroxyethylidene-1,1- biphosphonic acid and hydrated forms thereof
EP2609101B1 (en) Process for the preparation of 3-(n-methyl-n-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid salt or derivatives thereof
CA2689504A1 (en) Processes for manufacturing bisphosphonic acids
WO2008035131A1 (en) An improved process for the preparation of bisphosphonic acid
WO2013109198A1 (en) Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b
WO2009034580A1 (en) Improved process for the preparation of risedronate sodium hemipentahydrate

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2004501421

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 1020047017332

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2002807339

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2002807339

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020047017332

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 10512930

Country of ref document: US