CA2585027A1 - Process for the preparation of bisphosphonates - Google Patents

Process for the preparation of bisphosphonates Download PDF

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Publication number
CA2585027A1
CA2585027A1 CA002585027A CA2585027A CA2585027A1 CA 2585027 A1 CA2585027 A1 CA 2585027A1 CA 002585027 A CA002585027 A CA 002585027A CA 2585027 A CA2585027 A CA 2585027A CA 2585027 A1 CA2585027 A1 CA 2585027A1
Authority
CA
Canada
Prior art keywords
process according
methyl
bisphosphorylation
formula
monohydrate
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.)
Granted
Application number
CA002585027A
Other languages
French (fr)
Other versions
CA2585027C (en
Inventor
Friedrich Baetz
Bernd Junghans
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.)
F Hoffmann La Roche AG
Original Assignee
Friedrich Baetz
Bernd Junghans
F.Hoffmann-La Roche Ag
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 Friedrich Baetz, Bernd Junghans, F.Hoffmann-La Roche Ag filed Critical Friedrich Baetz
Publication of CA2585027A1 publication Critical patent/CA2585027A1/en
Application granted granted Critical
Publication of CA2585027C publication Critical patent/CA2585027C/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

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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 System
    • 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, i.e. RP(=X)(XH)2 (X = S, 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 System
    • 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, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, 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

Abstract

The invention relates to a novel multi step synthesis of 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate, of the formula

Claims (16)

1. A process for the preparation of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate of the formula I

said process comprising:

(a) condensation of N-pentylamine with benzaldehyde to produce the N-benzylidene-N-pentylamine of formula II

(b) transformation of the N-benzylidene-N-pentylamine into the N-methyl-N-pentylamine with a methylating agent (c) conversion of the N-methyl-N-pentylamine with methyl acrylate into the N-methyl-N-pentyl-p-alanine methylester of the formula III

(d) hydrolysis of N-methyl-N-pentyl-.beta.-alanine methyl ester and subsequent formation of the hydrohalogenide to produce the compound of the formula IV

wherein X is a halogen, (e) bisphosphorylation of the compound of formula IV by means of phosphoryl chloride and phosphorous acid and by the formation of the monosodium salt, monohydrate.
2. Process according to claim 1, characterized in that the condensation in step a) is performed in a suitable solvent at a temperature of 40°C to 90°C.
3. Process according to claim 1 or 2, characterized in that the transformation in step b) is performed at a temperature of of 80°C to 110°C.
4. Process according to claims 1 to 3, characterized in that the transformation in step b) is performed with dimethyl sulfate as methylating agent.
5. Process according to claims 1 to 4, characterized in that the conversion in step c) is performed in a suitable solvent at a reaction temperature of 10°C to 65°C.
6. Process according to claims 1 to 5, characterized in that the bisphosphorylation in step e) is performed in the presence of a non aromatic solvent.
7. Process according to claim 6, characterized in that the solvent is diethyl carbonate.
8. Process according to claims 1 to 7, characterized in that in the bisphosphorylation in step e) the molar ratio N-methyl-N-pentyl-.beta.-alanine hydrochloride / phosphoryl chloride / phosphorous acid is selected from 1: 3:
3 to 1:
1,4: 2,4.
9. Process according to claims 1 to 8, characterized in that in the bisphosphorylation in step e) the reaction temperature is selected from 60°C to 100°C.
10. Process according to claims 1 to 9, characterized in that the formation of the monosodium salt, monohydrate is effected by adjusting the pH of the aqueous reaction mixture to about 3, 5 to 6, with an aqueous solution of sodium hydroxide.
11. A process for the preparation of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate of the formula I

said process comprising bisphosphorylation of the compound of formula IV

wherein X is a halogen, by means of phosphoryl chloride and phosphorous acid and by the formation of the monosodium salt, monohydrate.
12. Process according to claim 11, characterized in that the bisphosphorylation is performed without solvent.
13. Process according to claim 12, characterized in that the solvent is diethyl carbonate.
14. Process according to claims 11 to 13, characterized in that the molar ratio N-methyl-N-pentyl-.beta.-alanine hydrochloride / phosphorous oxychloride /
phosphorus acid is selected from 1:3: 3 to 1: 1, 4: 2, 4.
15. Process according to claims 11 to 14, characterized in that the bisphosphorylation is performed at reaction temperature of 60°C to 100°C.
16. Process according to claims 11 to 15, characterized in that the formation of the monosodium salt, monohydrate is effected by adjusting the pH of the aqueous reaction mixture to about 3.5 to 6, with an aqueous solution of sodium hydroxide.
CA2585027A 2004-10-29 2005-10-25 Process for the preparation of bisphosphonates Expired - Fee Related CA2585027C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP04105407.3 2004-10-29
EP04105407 2004-10-29
PCT/EP2005/011404 WO2006045578A2 (en) 2004-10-29 2005-10-25 Process for the preparation of ibandronate

Publications (2)

Publication Number Publication Date
CA2585027A1 true CA2585027A1 (en) 2006-05-04
CA2585027C CA2585027C (en) 2010-05-18

Family

ID=36097233

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2585027A Expired - Fee Related CA2585027C (en) 2004-10-29 2005-10-25 Process for the preparation of bisphosphonates

Country Status (13)

Country Link
US (1) US7214818B2 (en)
EP (1) EP1807090B9 (en)
JP (1) JP4560548B2 (en)
KR (1) KR100880061B1 (en)
CN (1) CN101048165B (en)
AT (1) ATE497769T1 (en)
CA (1) CA2585027C (en)
DE (1) DE602005026310D1 (en)
ES (1) ES2359415T3 (en)
IL (1) IL182690A (en)
MX (1) MX2007005114A (en)
TW (1) TWI293304B (en)
WO (1) WO2006045578A2 (en)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006002348A2 (en) * 2004-06-23 2006-01-05 Teva Pharmaceutical Industies Ltd. Solid and crystalline ibandronic acid
WO2007074475A2 (en) * 2005-12-27 2007-07-05 Natco Pharma Limited Novel polymorphic forms of ibandronate
CA2652420C (en) 2006-06-23 2014-01-14 Cipla Limited Process for the synthesis of ibandronate sodium
AU2007270897A1 (en) * 2006-07-03 2008-01-10 Generics [Uk] Limited Novel process for the preparation of bisphosphonic acids
EP2046342A4 (en) * 2006-07-28 2011-05-04 Reddys Lab Ltd Dr Crystalline form a of ibandronic acid and process for the preparation
EP1966227A1 (en) * 2006-11-16 2008-09-10 Teva Pharmaceutical Industries Ltd. Crystalline forms of ibandronate sodium
CA2570949A1 (en) * 2006-12-12 2008-06-12 Apotex Pharmachem Inc. Ibandronate sodium propylene glycol solvate and processes for the preparation thereof
WO2008125483A2 (en) * 2007-04-11 2008-10-23 F. Hoffmann-La Roche Ag Multi step synthesis of ibandronate
EP2316841A1 (en) * 2007-04-19 2011-05-04 Dr. Reddy's Laboratories Limited Ibandronate sodium polymorphs
US20090042839A1 (en) * 2007-08-09 2009-02-12 Sharon Avhar-Maydan Crystalline forms of ibandronate sodium
US20090075944A1 (en) * 2007-09-15 2009-03-19 Protia, Llc Deuterium-enriched ibandronate
WO2009093258A2 (en) * 2008-01-24 2009-07-30 Fleming Laboratories Limited A new and improved process for the preparation of ibandronate sodium monohydrate
EP2180003A1 (en) 2008-10-21 2010-04-28 Zentiva, k.s. Preparation of ibandronate trisodium
EP2192126B1 (en) 2008-11-26 2013-03-27 Synthon B.V. Process for making zoledronic acid
US20100130746A1 (en) * 2008-11-26 2010-05-27 Martin Kas Process for Making Zoledronic Acid
CN101863919B (en) * 2010-07-05 2011-11-23 武汉同源药业有限公司 Preparation method of compound sodium ibandronate
CN102093416B (en) * 2011-03-17 2013-07-24 南京恒生制药有限公司 Method for synthesizing sodium ibandronate
CN103012155A (en) * 2012-11-29 2013-04-03 张家港市大伟助剂有限公司 Preparation method of N-methyl-pentylamine
CN103396332A (en) * 2013-08-19 2013-11-20 四川协力制药有限公司 3-[(N-methyl-N-pentyl)amino]propionic acid hydrochloride preparation method
CN104628768A (en) * 2015-03-06 2015-05-20 江苏正大清江制药有限公司 Preparation method of sodium ibandronate
CN114524925B (en) * 2020-11-23 2023-11-14 华润化学材料科技股份有限公司 Titanium catalyst and preparation method and application thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3919321A (en) * 1966-11-08 1975-11-11 Hoffmann La Roche Halo-substituted-5H-dibenzo{8 a,d{9 cyclohepten-5-ones
US4220611A (en) * 1978-06-29 1980-09-02 Sandoz, Inc. Polyoxyalkylene bridged phosphate esters
DE3623397A1 (en) 1986-07-11 1988-01-14 Boehringer Mannheim Gmbh NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
DE3808074A1 (en) 1988-03-11 1989-09-21 Henkel Kgaa METHOD FOR PRODUCING AZACYCLOALKANE-2,2-DIPHOSPHONIC ACIDS
DE3822650A1 (en) 1988-07-05 1990-02-01 Boehringer Mannheim Gmbh NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
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
PE20011065A1 (en) 2000-02-01 2001-11-21 Procter & Gamble PROCESS FOR MANUFACTURING GEMINAL BISPHOSPHONATES
DE60331724D1 (en) 2002-05-17 2010-04-29 Teva Pharma USE OF CERTAIN SOLVENTS FOR THE PREPARATION OF BISPHOSPHONIC ACIDS

Also Published As

Publication number Publication date
KR100880061B1 (en) 2009-01-22
DE602005026310D1 (en) 2011-03-24
EP1807090B1 (en) 2011-02-09
WO2006045578A3 (en) 2006-08-17
KR20070070246A (en) 2007-07-03
WO2006045578A2 (en) 2006-05-04
IL182690A0 (en) 2007-09-20
JP2008517964A (en) 2008-05-29
IL182690A (en) 2011-07-31
CN101048165A (en) 2007-10-03
ES2359415T3 (en) 2011-05-23
US20060094898A1 (en) 2006-05-04
TWI293304B (en) 2008-02-11
CA2585027C (en) 2010-05-18
EP1807090A2 (en) 2007-07-18
EP1807090B9 (en) 2011-11-09
TW200621792A (en) 2006-07-01
JP4560548B2 (en) 2010-10-13
ATE497769T1 (en) 2011-02-15
CN101048165B (en) 2010-12-01
MX2007005114A (en) 2007-06-26
US7214818B2 (en) 2007-05-08

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