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)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
  • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

• the present invention relates to a process for the preparation of 3-(N-methyl-N- pentyl) amino- 1-hydroxypropane-l, 1-diphosphonic acid, monosodium salt, monohydrate (Ibandronate) with the following formula
• Ibandronate is one of the most potent antiresorptive drugs that directly inhibit osteoclast activity and present an effective pharmacologic alternative for controlling hypercalcemia. Ibandronate binds to hydroxyapatite in calcified bone, rendering it resistant to hydrolytic dissolution by phosphatases, thereby inhibiting both normal and abnormal bone resorption. This drug increases bone mass and decreases the risk of fractures and is therefore particularly well adapted to bone and calcium metabolic diseases such as for instance osteoporosis or Paget's disease (EP-A 0252504).
• EP 0402152 discloses the preparation of crystalline 4- amino -1- hydroxybutyllidene-1-bisphosphonic acid monosodium trihydrate, carried out in one step in presence of phosphorus trihalide, phosphorous acid and methane sulfonic acid. This process allows the reaction mixture to remain fluid.
• WO 03/097655 discloses the preparation of a bisphosphonic acid including the step of combining a carboxylic acid with phosphorous acid and phosphoryl chloride in the presence of a diluent.
• the said diluent includes aromatic hydrocarbons such as toluene, xylene and benzene or inert silicone fluids such as polydimethylsiloxane and polymethylphenylsiloxane.
• aromatic hydrocarbons such as toluene, xylene and benzene
• inert silicone fluids such as polydimethylsiloxane and polymethylphenylsiloxane.
• Object of the present invention therefore was to find a new process for producing Ibandronate with high yields and with little residual by-products.
• the first step a) of the process of the present invention comprises the condensation of N-pentylamine with benzaldehyde to produce the N-benzylidene-N-pentylamine of formula II. .
• This condensation can be carried out in a suitable solvent such as aliphatic alcohols, at a reaction temperature of 40 0 C to 90 0 C, preferably in methanol at 70 0 C to 75°C.
• a suitable solvent such as aliphatic alcohols
• the second step b) of the process of the present invention comprises the transformation of the N-benzylidene-N-pentylamine into the N-methyl-N-pentylamine with a methylating agent.
• Methylating agents such as methyl halogenides or dimethyl sulfate, but preferably dimethyl sulfate is used.
• the reaction as a rule takes place at a temperature of 80 0 C to 110 0 C, preferably at 90 0 C to 100 0 C.
• the generated benzaldehyde can optionally be removed by steam distillation and the resulting N-methyl-N-pentylamine can be isolated from the aqueous phase by any means known to the skilled in the art such as by addition of a base and extraction of the basic solution with a suitable organic solvent such as an aliphatic ether, preferably with diisopropylether.
• the product can be further purified for instance by distillation.
• a third step (c) of the process of the present invention the N-methyl-N- pentylamine is converted with methyl acrylate into the N-methyl-N-pentyl- ⁇ -alanine methylester of the formula III.
• This conversion can be carried out in a suitable solvent such as an aliphatic alcohol, an aliphatic ether or an ether/alcohol mixture, but preferably in methanol at a reaction temperature of 10 0 C to 65°C, preferably at 15°C to 25 0 C.
• Isolation of the N-methyl-N- pentyl- ⁇ -alanine methyl ester can be performed by techniques known to the skilled in the art such as by distillation.
• step (d) of the process of the present invention the hydrolysis of N-methyl-N- pentyl- ⁇ -alanine methyl ester and subsequent formation of the hydrohalogenide takes place to produce the compound of the formula IV.
• the hydrolysis is usually performed by refluxing the N-methyl-N-pentyl- ⁇ -alanine methyl ester in a diluted mineral acid, but preferably in water at least until no educt ester can be detected any further.
• the resulting N-methyl- N-pentyl- ⁇ - alanine hydrochloride can be isolated by distilling of the water and by a crystallization of the residue in a suitable solvent such as toluene/acetone or methyl ethyl ketone, preferably in methyl ethyl ketone.
• a suitable solvent such as toluene/acetone or methyl ethyl ketone, preferably in methyl ethyl ketone.
• Step (e) of the present invention comprises the bisphosphorylation of the compound of formula IV by means of phosphoryl chloride and phosphorous acid and the formation of the monosodium salt, monohydrate.
• the bisphosphorylation of the N-methyl-N-pentyl- ⁇ -alanine hydrochloride may take place either in the presence of a non aromatic solvent or with no solvent present. It is preferred to use a non aromatic solvent.
• Suitable non aromatic solvents are phosphoric acid esters, phosphonic acid esters or carbonic acid esters.
• Preferred solvent is diethylcarbonate.
• phosphorylating agent a mixture of phosphoryl chloride and phosphorous acid is used.
• the molar ratio N-methyl-N-pentyl- ⁇ -alanine hydrochloride / phosphoryl chloride / phosphorous acid is a rule selected from 1 : 3 : 3 to 1 : 1,4 : 2,4, preferably 1 : 1,6 : 2,4 to 1: 1,4 : 2,4
• reaction temperature is expediently maintained in a range of from 60 0 C to 100 0 C, preferably 80 0 C to 90 0 C.
• the pH of the remaining aqueous reaction mixture is adjusted to a pH from about 3,5 to 6, preferably from 4,4 to 4,5 with an aqueous solution of sodium hydroxide at a temperature in the range of about 20 0 C to 25°C.
• the Ibandronate so obtained can be crystallized in suitable solvents such as aliphatic alcohols/water or aliphatic ketones/water, preferably in ethanol/water and aceton/water.
• suitable solvents such as aliphatic alcohols/water or aliphatic ketones/water, preferably in ethanol/water and aceton/water.
• a further object of the present invention is to provide a process for the preparation of 3-(N-methyl-N-pentyl) amino-l-hydroxypropane-1, 1-diphosphonic acid, monosodium salt, monohydrate of the formula I
• step e) The preferred embodiments of this process are described in step e) as above.
• step e) The description of step e) is incorporated herein by reference.
• the process of the present invention allows to produce the 3-(N-methyl-N-pentyl) amino- 1-hydroxypropane-l, 1-diphosphonic acid, monosodium salt, monohydrate of the formula I in exellent yield and quality.
• N-pentylamine 10O g (I, 15 mol) N-pentylamine was added to 200 ml methanol at a temeperature of 22°C. 121, 8 g (1, 15 mol) benzaldehyde was added. The mixture was refluxed and subsequently, methanol was distilled off. The residual N-benzylidene-N-pentylamine 199,8 g (99, 4 %) was used in the next step.

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• Bioinformatics & Cheminformatics (AREA)
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• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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• 2005
  • 2005-10-18 US US11/252,668 patent/US7214818B2/en not_active Expired - Lifetime
  • 2005-10-25 EP EP05799731A patent/EP1807090B9/en not_active Expired - Lifetime
  • 2005-10-25 ES ES05799731T patent/ES2359415T3/es not_active Expired - Lifetime
  • 2005-10-25 CA CA2585027A patent/CA2585027C/en not_active Expired - Fee Related
  • 2005-10-25 JP JP2007538322A patent/JP4560548B2/ja not_active Expired - Lifetime
  • 2005-10-25 KR KR1020077011938A patent/KR100880061B1/ko not_active Expired - Fee Related
  • 2005-10-25 CN CN2005800371320A patent/CN101048165B/zh not_active Expired - Fee Related
  • 2005-10-25 WO PCT/EP2005/011404 patent/WO2006045578A2/en not_active Ceased
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  • 2005-10-25 DE DE602005026310T patent/DE602005026310D1/de not_active Expired - Lifetime
  • 2005-10-25 AT AT05799731T patent/ATE497769T1/de active
  • 2005-10-27 TW TW094137688A patent/TWI293304B/zh not_active IP Right Cessation
• 2007
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