- Preparation method of sodium ibandronate
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Relating to the technical field of pharmaceutical synthesis, the invention provides a preparation method of sodium ibandronate. The preparation method includes: taking 3-methylamino propanenitrile as the raw material to prepare 3-(N-methyl-N-n-amylamine)propionic acid hydrochloride, then reacting the 3-(N-methyl-N-n-amylamine)propionic acid hydrochloride with phosphorous acid and phosphorus trichloride to obtain ibandronic acid, and subjecting the ibandronic acid and sodium hydroxide to salification so as to obtain sodium ibandronate. The preparation method of sodium ibandronate provided by the invention reduces the refining frequency, lowers the refining loss, avoids the defects of low yield and long period brought about by a lot of refining steps, and the great harm to human and environment, and has the advantages of simple operation, good process repeatability and easy industrial production.
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Paragraph 0019; 0020; 0023; 0024; 0025; 0028; 0029; 0033
(2017/07/04)
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- Sodium ibandronate of a kind of preparation method of a water composition
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The invention belongs to the field of medicine chemistry synthesis, and relates to a method for preparing a sodium Ibandronate monohydrate. The method comprises that: 1) 3-(N-methylpentylamino)propanoic acid hydrochloride, phosphorous acid and phosphorus trichloride are adopted as starting raw materials and are subjected to a reaction in a 1,3-dimethyl-2-imidazolidinone (DMI) solvent or a DMI-containing mixing solvent to obtain the sodium Ibandronate monohydrate crude product meeting the internal control standard in the one-step manner; and 2) the sodium Ibandronate monohydrate crude product is subjected to recrystallizatio in a methanol/water mixing solvent to obtain the sodium Ibandronate monohydrate meeting the clinical medicinal standard. According to the present invention, defects of low yield, high reagent toxicity, heavy pollution and the like in the prior art are overcome, and the preparation method for the sodium Ibandronate monohydrate represented by the formula (I) is provided, wherein the preparation method has characteristics of high yield, low environmental pollution, and easy purification.
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Paragraph 0071-0074
(2017/03/18)
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- PROCESS FOR THE PREPARATION OF 3-(N-METHYL-N-PENTYL)AMINO-1-HYDROXYPROPANE-1,1-DIPHOSPHONIC ACID SALT OR DERIVATIVES THEREOF
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The present invention relates to an improved process for the preparation of 3-(N-methyl-N- pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, or its derivatives, in substantially pure crystalline form.
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Page/Page column 7-8
(2012/02/02)
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- A PROCESS FOR THE SYNTHESIS OF 1-HYDROXY-3-(N-METHYLPENTYLAMINO) PROPYLIDENE BISPHOSPHONIC ACID MONOSODIUM SALT, MONOHYDRATE
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A process for the synthesis of 1-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate which consists in the reaction of phosphorus trichloride with an aqueous solution of 3-(N-methylpentylamino)propionic acid hydrochloride at a temperature of 0-80°C, removing excess unreacted phosphorus trichloride, hydrolysis of the reaction mixture under reflux, conversion of 1-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonic acid into its monosodium salt using sodium cation-containing alkaline substances, crystallisation using an anti-solvent. Also disclosed is a process for the synthesis of a polymorphic form of 1-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate which consists of initiating and carryout the crystallisation using acetone at a temperature of 0-5°C.
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Page/Page column 9-10
(2011/02/24)
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- PROCESS FOR MAKING 1-HYDROXYALKYLIDENE-1,1-BIPHOSPHONIC ACIDS
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Synthesis of biphosphonate compounds can be carried out using a combination of a halophosphorous compound and water as the phosphonation agent.
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Page/Page column 11
(2011/04/14)
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- A facile preparation of N-methylpentan-l-amine: A key intermediate for ibandronate sodium
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A facile preparation of N-methylpentan-l-amine, which is a key intermediate for the synthesis ibandronate sodium, an anti-osteoclast agent is described. This route is cost effective over the previous methods. Part of this work could be an easy access for the preparation of various N,N-alkyl or aryl amine derivatives.
- Reddyab, V V R M Krishna,Chintamani,Udaykiran,Madhusudhan,Mukkanti
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experimental part
p. 1257 - 1260
(2010/12/24)
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- Preparation of ibandronate trisodium
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The trisodium salt of ibandronate of formula (I): A process of preparing said salt comprises: a) mixing 3-(methylpentylamino)propionic acid hydrochloride, phosphorous acid (in a 2.5-3.5 molar excess with respect to 3-(methylpentylamino)propionic acid hydrochloride), sunflower oil (in an amount of 6-9 volume parts for 1 weight part of 3-(methylpentylamino)propionic acid hydrochloride) and phosphorus trichloride (in a 3-4 molar excess with respect to 3-(methylpentylamino)propionic acid hydrochloride); b) adding water (in an amount of 6-9 volume parts for 1 weight part of 3-(methylpentylamino)propionic acid hydrochloride) and after separation of the phases; c) adjusting pH of the water phase to pH 12.5; d) adding a water-miscible co-solvent and cooling down to precipitate the product or evaporate to dryness. Another process for preparing the trisodium salt of ibandronate comprises admixing the monosodium salt of ibandronate or ibandronic acid or their solvates with water or a mixture water/sodium hydroxide and adjustment of pH to 12.5. Various crystalline, semicrystalline and amorphous forms of trisodium ibandronate are disclosed.
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Page/Page column 5
(2010/05/13)
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- PROCESS FOR THE SYNTHESIS OF IBANDRONATE SODIUM
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The present invention relates to an improved process for the synthesis of Ibandronate sodium of formula (I). The present invention also provides novel processes for the synthesis of 3-[N-(methylpentyl)amino]propionic acid (III).
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Page/Page column 7
(2010/08/07)
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- A NEW AND IMPROVED PROCESS FOR THE PREPARATION OF IBANDRONATE SODIUM MONOHYDRATE
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The present invention discloses a new and an improved process for preparation of Ibandronate sodium monohydrate. According to the process pentylamine is reacted with ethylacrylate to give N-pentyl-β-alanine ethyl ester (XXIV), which on methylation provided N-methyl-N-pentyl-β-alanine ethylester formula (XXV). The reresulting ester on hydrolysis and subsequent treatment with hydrochloric acid furnished 3-(N-methyl-N-pentylamino)propionic acid hydrochloride formula (II). Bisphosphorylation of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride formula (II) with phosphorous acid and phosphorous trichloride followed by hydrolysis and subsequent treatment with a base provided Ibandronate monosodium monohydrate of formula (I).
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Page/Page column 5; 10
(2009/09/05)
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- Crystalline forms of ibandronic acid and processes for the preparation thereof
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A crystalline ibandronic acid characterized by data selected from the group consisting of at least one of a powder x-ray diffraction pattern having peaks at about 4.1, 12.3 and 13.4±0.2 degrees two-theta and at least two more peaks selected from the group consisting of: 8.2, 11.3, 16.2 and 16.9 and 20.8±0.2 degrees two-theta, and by a powder X-ray diffraction pattern depicted in FIG. 1 is provided. Also provided is a crystalline ibandronic acid characterized by data selected from the group consisting of at least one of a powder x-ray diffraction pattern having peaks at about peaks at about 5.2, 11.7, and 18.7±0.2 degrees two-theta and at least two more peaks selected from the group consisting of: 5.8, 10.1, 12.0, 17.1, and 20.0±0.2 degrees two-theta and a powder X-ray diffraction pattern as depicted in FIG. 2. Methods of preparing the crystalline forms are also provided.
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Page/Page column 6
(2009/04/25)
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- CRYSTALLINE FORMS OF IBANDRONATE SODIUM
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Provided are crystalline forms of ibandronate sodium, as well as processes for the preparation thereof.
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Page/Page column 21
(2008/12/05)
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- REAGENT AND USE THEREOF FOR THE PRODUCTION OF BISPHOSPHONATES
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A new liquid reagent is disclosed in form of an ionic liquid containing phosphorous acid and a tertiary amine. The reagent can be used as a replacement of phosphorous acid, where the new reagent as a liquid reagent can be handled using usual equipment for handling liquids and the dosing of the reagent can therefore be controlled more precisely in industrial plants compared to phosphorous acid, which is a solid at ambient temperature. The new liquid reagent is particular suitable for the synthesis of bisphosphonates.
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Page/Page column 10-11
(2008/12/05)
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- PROCESS FOR PREPARING IBANDRONATE
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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
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Page/Page column 2-3
(2008/12/04)
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- CRYSTALLINE FORM A OF IBANDRONIC ACID AND PROCESS FOR THE PREPARATION
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The present invention relates crystalline Form A of Ibandronic acid having Formula (I) and a process for the preparation thereof.
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Page/Page column 24-25
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF IBANDRONATE SODIUM
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Present invention discloses an improved and commercial process for the preparation of ibandronic acid or its monosodium salt. According to the process 3-N-methylaminopropionitrile is reacted with n-pentylbromide to get the tertiary amine of formula-II. Hydrolysis of the nitrile compound of formula-II with hydrochloric acid gave the b-alanine derivative of formula-X. Bis-phosphonylation of the acid compound of formula-X with phorphorous trichloride and phosphorous acid, followed by water hydrolysis gave aqueous ibandronic acid. Treatment of this with sodium hydroxide, followed by dilution of the aqueous solution with methanol gave ibandronate monosodium of formula-Ia as white crystalline solid. Present process utilizes simple raw materials and avoids the column chromatography technique used in the prior art process for isolation of ibandronic acid. Overall yield of ibandronate is more than 60% from the nitrile intermediate of formula-II. Ibandronate is widely used as bone resorption inhibitor.
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Page/Page column 8
(2008/06/13)
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- NOVEL POLYMORPHIC FORMS OF IBANDRONATE
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The present invention relates to novel and stable polymorphic forms of ibandronate monosodium monohydrate of formula I and processes for their preparation. Ibandronate monosodium monohydrate is useful, as bone resorption inhibitor. The novel crystalline forms are designated as Form I, Form II and the amorphous ibandronate monosodium monohydrate as Form III.
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Page/Page column 5
(2008/06/13)
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- Solid and crystalline ibandronate sodium and processes for preparation thereof
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The present invention relates to solid amorphous and crystalline forms of ibandronate sodium.
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Page/Page column 13-14
(2008/06/13)
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- Ibandronate polymorph
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The present invention relates to a new polymorph crystal form of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1 1-diphosphonic acid monosodium salt monohydrate (Ibandronate) with the following formula
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Page/Page column 3-4
(2008/06/13)
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- Ibandronate polymorph
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The present invention relates to a new crystalline polymorph of 3-(N-methyl-N-pentyl) amino-1-hydroxypropane -1,1-diphosphonic acid monosodium salt monohydrate (Ibandronate) with the following formula
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Page/Page column 3-4
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF ALKYL- AND ARYL-DIPHOSPHONIC ACIDS AND SALTS THEREOF
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The invention relates to a process for the preparation of diphosphonic acids by reaction of a carboxylic acid with a mixture of phosphorous acid and phosphorus oxychloride in defined molar ratios and in the absence of solvents. The invention futher relates to ibandronic acid monosodium salt in the amorphous form.
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Page/Page column 6
(2008/06/13)
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