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WO2007056417A2 - Synthese de sodium trihydrate d’alendronate - Google Patents

Synthese de sodium trihydrate d’alendronate Download PDF

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Publication number
WO2007056417A2
WO2007056417A2 PCT/US2006/043422 US2006043422W WO2007056417A2 WO 2007056417 A2 WO2007056417 A2 WO 2007056417A2 US 2006043422 W US2006043422 W US 2006043422W WO 2007056417 A2 WO2007056417 A2 WO 2007056417A2
Authority
WO
WIPO (PCT)
Prior art keywords
water
sodium
synthesis
alendronic acid
alendronate sodium
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/US2006/043422
Other languages
English (en)
Other versions
WO2007056417A3 (fr
Inventor
Tomas O'ceallaigh
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of WO2007056417A2 publication Critical patent/WO2007056417A2/fr
Publication of WO2007056417A3 publication Critical patent/WO2007056417A3/fr
Anticipated expiration legal-status Critical
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)]
    • 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

Definitions

  • This invention describes a process for the synthesis of alendronate sodium trihydrate from the reaction of alendronic acid, either anhydrous or in a hydrated state, in an aqueous slurry with sodium hydroxide in water.
  • the pH is adjusted into the range 4.3 — 4.4, the solution is concentrated and the sodium salt thus formed is isolated by crystallization from water.
  • the current manufacturing process for alendronate sodium trihydrate is a three step manufacturing process that relies on the use of a continuous reactor for the production of sodium
  • This invention provides processes for the preparation of a compound of formula I:
  • I comprising the steps : a) reacting alendronic acid with strong base in water; b) adjusting the pH to between 4.3 and 4.4; c) concentrating the solution; d) crystallizing the salt from water.
  • a slurry of alendronic acid in water is reacted with a strong base. This step is performed at a temperature of about 40 0 C to about 6O 0 C. In a subclass of the invention, this step is performed at a temperature of about 58°C to about 60 0 C.
  • the alendronic acid is anhydrous or hydrated. In a subclass of the invention, the alendronic acid is monohydrated.
  • the strong base is sodium hydroxide, sodium carbonate or sodium hydrogen carbonate. In a subclass of the invention, the strong base is sodium hydroxide.
  • the pH is adjusted to between 4.3 and 4.4.
  • the pH can be adjusted with sodium hydroxide or hydrochloric acid, or with other acids and bases as is known in the art.
  • the solution is then concentrated by methods known in the art, including distillation and reverse osmosis.
  • the solution is concentrated by distillation.
  • alendronate sodium trihydrate salt is crystallized from water. This crystallization can also be performed with seeding.
  • Schemes 1 & 2 describe processes for the synthesis of alendronate sodium trihydrate from the reaction of alendronic acid (either anhydrous or hydrated) in an aqueous slurry with sodium hydroxide in water at temperature of 58 — 60°C.
  • the pH is adjusted into the range 4.3 — 4.4, the solution is concentrated and the sodium salt thus formed is isolated by crystallization.
  • the batch is filtered at 58 - 60 0 C & concentrated to a final volume of 0.132 Its (228 g/lt) where it is cooled to 0 - 5°C (2°C actual) and aged for a minimum of 10 hours. The batch is then isolated and washed with 10 mis of DIW pre-cooled to 1-5°C.
  • the batch is dried to a LOD specification of 16.1 - 17.1 % w/w.

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)

Abstract

La présente invention concerne un procédé pour la synthèse d’un sodium trihydraté d’alendronate à partir de la réaction d’acide alendronique, à l’état anhydre ou hydraté, dans une pâte aqueuse avec de l’hydroxyde de sodium dans de l’eau. Le pH est ajusté de manière à être situé entre 4,3 et 4,4, la solution est concentrée et le sel de sodium ainsi obtenu est isolé de l’eau par cristallisation.
PCT/US2006/043422 2005-11-07 2006-11-03 Synthese de sodium trihydrate d’alendronate Ceased WO2007056417A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73417905P 2005-11-07 2005-11-07
US60/734,179 2005-11-07

Publications (2)

Publication Number Publication Date
WO2007056417A2 true WO2007056417A2 (fr) 2007-05-18
WO2007056417A3 WO2007056417A3 (fr) 2007-07-05

Family

ID=37944596

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/043422 Ceased WO2007056417A2 (fr) 2005-11-07 2006-11-03 Synthese de sodium trihydrate d’alendronate

Country Status (3)

Country Link
AR (1) AR058168A1 (fr)
TW (1) TW200736268A (fr)
WO (1) WO2007056417A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5510517A (en) * 1993-08-25 1996-04-23 Merck & Co., Inc. Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids
CA2197267C (fr) * 1997-02-11 2000-02-08 Yong Tao Procede pour la preparation de l'acide 4-amino-1-hydroxybutylidene-1,1-bisphosphonique ou de ses sels
HUP0203078A3 (en) * 1998-08-27 2005-01-28 Teva Pharma Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof

Also Published As

Publication number Publication date
TW200736268A (en) 2007-10-01
WO2007056417A3 (fr) 2007-07-05
AR058168A1 (es) 2008-01-23

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