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WO2008073125A1 - Analogues de la moxonidine, procédés de préparation et utilisations de ceux-ci - Google Patents

Analogues de la moxonidine, procédés de préparation et utilisations de ceux-ci Download PDF

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Publication number
WO2008073125A1
WO2008073125A1 PCT/US2006/061948 US2006061948W WO2008073125A1 WO 2008073125 A1 WO2008073125 A1 WO 2008073125A1 US 2006061948 W US2006061948 W US 2006061948W WO 2008073125 A1 WO2008073125 A1 WO 2008073125A1
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WO
WIPO (PCT)
Prior art keywords
dmaia
iso
precipitate
moxonidine
compound
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/US2006/061948
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English (en)
Inventor
Oded Arad
Vladimir Naddaka
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.)
Wavelength Pharmaceuticals Ltd
Perrigo Co
Original Assignee
Chemagis Ltd
Perrigo Co
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 Chemagis Ltd, Perrigo Co filed Critical Chemagis Ltd
Priority to PCT/US2006/061948 priority Critical patent/WO2008073125A1/fr
Publication of WO2008073125A1 publication Critical patent/WO2008073125A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Moxonidine (4-chloro-5-(iniidazoline-2-ylan ⁇ dno)-6-methoxy-2-i ⁇ iethyl- pyrimidine), has the structural formula (I) below and is used as an antihypertensive drug.
  • moxonidine was approved for treating hypertension in Germany in 1991 and is currently commercially available in Europe, e.g., in Germany, Austria and in the UK.
  • U.S. patent No. 4,323,570 (hereinafter the '570 patent) describes a method of preparing moxonidine (I) by reacting 4,6-dichloro-2-melhyl-5-(l-aoetyl-2-imidazolin-2-yl)- aminopyrimidme (II) (hereinafter DMAIA) with about 2 equivalents of sodium methoxide in methanol under reflux.
  • Moxonidine is obtained by crystallization from nitromethane having a melting point of 217-219°C.
  • the hydrochloride salt of moxonidine is described in example 25, to produce a product havaing a melting point of 189°C.
  • Example 1 of the '570 patent describes the synthesis of 4,6-dichloro-2-methyl ⁇ 5 ⁇ (l-acetyl-2-imidazolin-2-yl)-amino ⁇ yrimidine (DMAIA) by reacting 20 g (0.112 moles. 1 equiv.) of 5-amino-4,6-dichloro-2 ⁇ memylpyrimidine of formula (III) with 15 g (0.117 moles, LVM255699
  • a drug manufacturer must submit data demonstrating that the product intended for marketing complies with the regulations with regard to the content of impurities.
  • Regulations typically require thai the allowed content of an unidentified impurity should not exceed O. ⁇ wt%, while the allowed content of an identified impurity should not exceed 0.15 wt% (or as U.S. regulations may require for generic drugs, twice of the level observed for an identified impurity in the originator's material).
  • the regulatory authority checks the submitted data in order to ensure that the drug is free of impurities and is suitable for marketing.
  • the drug manufacturer usually submits to the regulatory authority analytical data demonstrating that the content of each impurity is in accordance with the regulations.
  • the present invention provides a process for isolating iso-DMAIA from a mixture containing DMAIA and iso-DMAIA, which process preferably includes: LVM 255699
  • iso-DMAIA can be obtained having a purity of at least about 98.5% (based on HPLC), preferably having a purity greater than 99%, e.g., having a purity of 99.8%.
  • an organic solvent in accordance with the present invention e.g., from DMF
  • a crystalline solid comprising iso-DMAIA can be obtained.
  • the present invention also provides a crystalline form of iso-DMAIA, which can be used, e.g., as a standard for determining the purity and/or monitoring the production of DMAIA or moxonidine.
  • the crystalline ⁇ so- DMAIA produces a unique X-ray powder diffraction pattern. The strong diffraction peaks at 15.6, 19-4, and 29.7 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
  • the present invention also provides a process of preparing compound VI, which process preferably includes: reacting iso-DMAIA with a base, e.g., a methoxide in an organic solvent, to produce a reaction product containing compound VI; isolating the reaction product; arid optionally purifying the reaction product, e.g., by crystallizing compound VI from an organic solvent
  • a base e.g., a methoxide in an organic solvent
  • the methoxide can be introduced into the reaction (e.g., by adding a methoxide salt) and/or formed in situ, e.g., by reaction of at least one compound capable of generating methoxide, e.g., methanol in the presence of a base.
  • Compound VI can be used, e.g., as a standard for determining the purity and/or monitoring the production of moxonidine.
  • compound VI can be obtained, e.g., via crystallization from an organic solvent, having a LVM255699
  • compound VI is crystallized from an organic solvent, e.g., DMSO, to produce a crystalline solid comprising compound VI.
  • organic solvent e.g., DMSO
  • the present invention also provides a crystalline form of compound VI.
  • the crystalline compound VI produces a unique X-ray powder diffraction pattern. The strong diffraction peaks at 1 Ll, 13.1, 15.8, 18.2, 20.5, 22.8,
  • the present invention also provides a process for preparing 4,6-dichloxo ⁇ 2- methyl-5-(l-acetyl-2- ⁇ m ⁇ dazolin-2-yl)-aminopyrimidinc (DMAIA) by reacting 5-amino-4 s 6- dichloro-2-methylpyrimidine (III) with l-acetyl-2-im ⁇ dazolidin-2-one (IV), which process preferably includes: heating a mixture containing compounds III and IV in the presence of less than 15 equivalents of POCI3 for less than 10 hours, to produce a reaction product containing DMAIA; cooling the reaction product, e.g., to room temperature, and adding to the reaction mixture, e.g., drop-wise, cold water and a base to precipitate DMAIA; and collecting the precipitate, e.g., by filtration.
  • DMAIA 4,6-dichloxo ⁇ 2- methyl-5-(l-acetyl-2- ⁇ m ⁇ dazolin-2-yl)-
  • the present invention further provides a process for converting the DMAIA into moxinidine, to produce moxonidine.
  • the DMAIA can be converted into moxonidine using any suitable method for performing the conversion.
  • the DMAIA produced in accordance with the present invention can be reacted with methoxide, e.g., in accordance with conventional methods, to produce moxonidine.
  • the analysis of moxonidine drug samples in accordance with the present invention can be carried out using any suitable method that may be useful for monitoring a production process, e.g., Thin Layer Chromatography (TLC) High Pressure Liquid Chromatography (HPLC), Capillary Electrophoresis, and the like, and combinations thereof.
  • TLC Thin Layer Chromatography
  • HPLC High Pressure Liquid Chromatography
  • Capillary Electrophoresis and the like, and combinations thereof.
  • production samples are monitored using HPLC.
  • the present invention provides a method of testing the purity of moxonidine, which includes analyzing a production sample of moxonidine by HPLC to determine the content of compound V atid/or compound VI in the production sample.
  • An exemplary HPLC chromatogram from analysis of a moxonidine production sample is depicted in Figure 7.
  • Figure 1 depicts the X-ray powder diffraction pattern of an exemplary crystalline form of iso-DMAIA.
  • Figure 2 depicts the DSC curve of an exemplary crystalline form of iso-DMAIA.
  • Figure 3 depicts the infra-red (IR) spectrum of an exemplary crystalline form of iso-DMAIA.
  • Figure 4 depicts the X-ray powder diffraction pattern of an exemplary crystalline form iso-moxonidine.
  • Figure 5 depicts the DSC curve of an exemplary crystalline form of compound VI.
  • Figure 6 depicts the infra-red (IR) spectrum of an exemplary crystalline form of compound VI.
  • Figure 7 depicts the HPLC chromatogram of a production sample of moxonidine prepared from DMAIA containing iso-DMAIA as an impurity.
  • an impurity 1-[1 -[(4,6-dichloro-2 ⁇ metiiyl-5-pyrimidinyl)imino3ethyl]-2-imidazolidinone of the formula (V) (iso-DMAIA), is produced in the synthesis of DMAIA and may be converted into l-[l-[(4-chloro-2-methyl-6-methoxy-5-pyrimidinyl)imino]ethyl]-2-imidazolidinone of formula (VI), as depicted in Scheme 4.
  • the crude product, obtained in the process for preparing DMAIA 5 may contain as much as 35% of the unwanted iso-DMAIA, and that the unwanted iso-DMAIA may be converted into l-[l-[(4-chloro-2-methyl-6-niethoxy-5-pyriinidin.yl)- imino] ethyl] -2-imidazolidinone (VI).
  • the present invention provides a process for isolating iso-DMAIA. from a mixture containing DMAIA and iso-DMAIA, which process preferably includes: adding water to a mixture containing DMAIA and iso-DMAIA and cooling to precipitate iso-DMAIA as a first precipitate; dissolving the first precipitate in a first organic solvent, optionally at elevated temperature, and cooling to precipitate iso-DMAIA as a solid; separating the solid, e.g., by filtration, to produce a filtrate; adding water to the solid and cooling to precipitate iso-DMAIA as a second precipitate and isolating the second precipitate; dissolving the second precipitate in a second organic solvent, optionally at elevated temperature, and cooling for sufficient time to produce iso-DMAIA crystals; collecting the crystals, e.g., by filtration and, optionally, washing and drying the crystals.
  • the first and second organic solvents are selected from methanol, ethanol, l-propanol, 2-propanol, 1-butanol, 2-butanoI, tetrahydrofuran (THF), water, acetonitrile, N,N-dimethylfo: ⁇ namide (DMF), N,N-dimethylacetarnide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP) 5 and the like, and mixtures thereof.
  • An exemplary first organic solvent is DMSO and an exemplary second organic solvent is DMF.
  • iso-DMAIA can be obtained having a purity of at least about 98.5% (based on HPLC), preferably having a purity greater than 99%, e.g., having a purity of 99.8%.
  • the present invention also provides a crystalline form of iso-DMAIA.
  • iso-DMAIA which can be used, e.g., as a standard for determining the purity and/or monitoring the production of DMAlA or moxonidine.
  • the crystalline iso-DMAIA of the present invention produces a unique X-ray powder diffraction pattern, e.g., as shown in Figure 1 and Table 1 (below). The strong diffraction peaks at 15.6, 19.4 ? and 29.7i-.0.2 degrees 2 ⁇ are most characteristic of this form.
  • the crystalline iso-DMAIA of the present invention also produces a characteristic DSC curve as depicted in Figure 2, and a characteristic infra-red (IR) spectrum as depicted in Figure 3.
  • the present invention also provides a process for preparing compound VI, which process preferably includes: reacting iso-DMAIA with a base, e.g., a methoxide in an organic solvent, to produce a reaction product containing compound VI; isolating the reaction product; and optionally purifying the reaction product, e.g., by crystallizing compound VI from an organic solvent.
  • a base e.g., a methoxide in an organic solvent
  • the methoxide can be introduced into the reaction (e.g., by adding a methoxide salt) and/or by forming methoxide in situ, e.g., by reaction of at least one compound capable of generating methoxide, e.g. ? methanol in the presence of a base.
  • a base e.g., a methoxide in an organic solvent
  • the process includes adding at least one base selected from lithium methoxide, sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, and the like, and combinations thereof.
  • a preferred methoxide salt is sodium methoxide.
  • the organic solvent used in the reaction can include, e.g., methanol, tetrahydrofuran (THF), toluene, dimethyl sulfoxide (DMSO), and the like, and mixtures thereof.
  • the base is not a methoxide salt
  • the organic solvent is methanol.
  • Compound VI can be used, e.g., as a standard for determining the purity and/or monitoring the production of moxonidine.
  • compound VI can be obtained, e.g., via crystallization from an organic solvent, having a purity of at least about 98.5 wt% (by HPLC) 9 preferably having a purity greater than 99 wt%, e.g., having a purity of 99.7 wt%.
  • compound VI is crystallized from an organic solvent, e.g., DMSO, to produce compound VI as a crystalline solid.
  • the present invention also provides a crystalline form of compound VI.
  • the crystalline compound VI of the present invention produces a unique X-ray powder diffraction pattern as depicted in Figure 4 and Table 2 (below).
  • the strong diffraction peaks at 11.1, 13.1. 15,8, 18.2, 20.5, 22.8, 25.8, 26.4 and 28.1 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
  • the crystalline compound VI of the present invention also produces a characteristic DSC curve as depicted in Figure 5, and a characteristic infra-red (IR) spectrum as depicted in Figure 6.
  • the present invention also provides a process for preparing 4,6-dichloro-2- methyl-5-(l-acetyl-2-imidazolin-2-yl)-am ⁇ no ⁇ yriraidine (DMAIA) from 5-am ⁇ no-4,6- dichloro-2-methylpyri ⁇ iidme (III) and l-acetyl ⁇ 2-imidazolidin-2-one (IV).
  • DAIA 4,6-dichloro-2- methyl-5-(l-acetyl-2-imidazolin-2-yl)-am ⁇ no ⁇ yriraidine
  • process preferably includes: heating a mixture of compounds III and IV in the presence of less than 15 equivalents of POCI 3 for less than 10 hours,, to produce a reaction product containing DMAIA; cooling the reaction product, e.g., to room temperature, and adding to the reaction mixture, e.g., drop-wise,, cold water and a base to precipitate DMAIA; and isolating the precipitate, e.g., by filtration.
  • the relative amount of POCI 3 used in the reaction is less than 5 equivalents OfPOCl 3 per 1 equivalent of compound III, and more preferably less than 3 equivalents of POCI 3 per 1 equivalent of compound III.
  • the reaction time is about 7 hours (about one seventh of the time required according to example 1 of the '570 patent).
  • the reaction product and a base are added simultaneously, optionally drop- wise, to cold water followed by precipitation of the product, which obviates the need to distill otT excess POCI3 as required in the conventional process.
  • the base is selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like, and LVM 255699
  • a preferred base for quenching the condensation reaction mixture is sodium hydroxide (NaOH).
  • the present invention further provides a process for converting the DMAIA produced in accordance with the present invention into moxinidine.
  • the DMAIA can be converted into moxonidine using any suitable method for performing the conversion.
  • the DMAIA produced in accordance with the present invention can be reacted with methoxide, e.g., in accordance with conventional methods or as otherwise described herein, to produce moxonidine.
  • Certain amounts of impurities may be formed when moxonidine is prepared from DMAIA, as detailed herein.
  • isolated and/or purified samples of such impurities may be used for determining the purity of moxonidine in accordance with the present invention.
  • the analysis of moxonidine drug samples in accordance with the present invention can be carried out using any suitable method that may be useful for monitoring a. production process, e.g., using a separation technology such as, e.g., Thin Layer Chromatography, High Pressure Liquid Chromatography (HPLC), and Capillary Electrophoresis, and the like, and combinations thereof.
  • production samples are monitored using HPLC.
  • the present invention provides a method of testing the purity of moxonidine, which includes analyzing a production sample of moxonidine by HPLC to determine the content of compound V and/or compound VI in the production sample.
  • An exemplary HPLC chromatogram from analysis of a moxonidine production sample is depicted in Figure 7.
  • the sample contained 93.25% of moxonidine, 1.48% of 4,6- dichloro-2-niethyl-5-(2-imidazolin-2-yl)-aminopyrimidine (compound VII) and 5.27% of 4,6- dimethoxy-2-methyl-(2-imidazolin-2-yl)-aminopyrimidine (compound VIII). Then, water (100 ml) was added, and the mixture was cooled and vacuum dried. A sample of the thus obtained solid was taken, dissolved in the HPLC eluent mixture and injected to the HPLC system.
  • the sample contained 93.22% of moxonidine, 1.45% of 4,6-dichloro-2-metliyl-5-(2- imidazolin-2-yl)-aminopyrimidine and 5.32% of 4,6-dimethoxy-2-methyl-(2-imidazolin-2- yl)-aminopyrimidine.
  • the solid was heated under reflux in nitromethane (250 ml) for half an hour and the hot mixture was filtered. The filtrate was kept at 5°C overnight.
  • This example describes the preparation of 4,6-dichloro-2-methyl-5-(l -acetyl-2- imidazolin -2-yl)-aminopyrimidine (DMAIA).
  • reaction mixture and 46% aqueous sodium hydroxide solution (200 ml) were added drop-wise simultaneously from two separate dropping funnels to a 1 liter flask, fitted with a stirrer and containing cold water (300 ml), in such a pace that kept the internal temperature below 70° C and pH below 10.
  • the reaction mixture was cooled to 45° C and a precipitate was collected by filtration and washed with water (200 ml).
  • the precipitate was dried at 80 0 C to obtain 55 g of a solid (containing 55% of DMAIA and 35% of iso-DMAIA, according to HPLC).
  • This example describes the preparation of l-[l-[(4,6-dichloro ⁇ 2-methyl-5 ⁇ pyrimidinyl)-imirjo]ethyl]-2-ir ⁇ idazoHdinone (iso-DMAIA, V).
  • This example describes the preparation of moxonidine from DMAIA containing 5.7% of iso-DMAIA.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de la moxonidine, la 1-[1-[(4,6-dichloro-2-méthyl-6-5-pyrimidinyl)imino]éthyl]-2-imidazolidinone de formule (V) et la 1-[1-[(4-chloro-2-méthyl-6-méthoxy-5-pyrimidinyl)imino]éthyl]-2-imidazolidinone de formule (VI), lesquels peuvent être utilisés pour tester la pureté ou suivre la production de la moxonidine; et un procédé servant à préparer les dérivés. L'invention concerne également un procédé amélioré servant à préparer la 4,6-dichloro-2-méthyl-5-(1-acétyl-2-imidazolin-2-yl)aminopyrimidine (DMAIA) et un procédé d'utilisation du procédé pour produire de la moxonidine.
PCT/US2006/061948 2006-12-12 2006-12-12 Analogues de la moxonidine, procédés de préparation et utilisations de ceux-ci Ceased WO2008073125A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2586779A1 (fr) * 2011-10-24 2013-05-01 Hetero Research Foundation Procédé pour la préparation de moxonidine
WO2014037391A1 (fr) * 2012-09-07 2014-03-13 WÖRWAG PHARMA GmbH & Co. KG Synthèse de moxonidine à l'aide de bases organiques
EP2765131A1 (fr) 2013-02-08 2014-08-13 Arevipharma GmbH Procédé de production de monoxidine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4323570A (en) * 1978-11-15 1982-04-06 Beiersdorf Aktiengesellschaft Substituted aminopyrimidines
US5599931A (en) * 1992-02-20 1997-02-04 Bracco S.P.A. Process for separating stereoisomers of folinic acid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4323570A (en) * 1978-11-15 1982-04-06 Beiersdorf Aktiengesellschaft Substituted aminopyrimidines
US5599931A (en) * 1992-02-20 1997-02-04 Bracco S.P.A. Process for separating stereoisomers of folinic acid

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANDREWS ET AL.: "Bis(2-Amino-5-bromopyrimidinium) Tetrahalometallates: Crystal structures of (2-amino-5-bromopyrimidinium)2 MC14 (M = Co, Zn)", JOURNAL OF COORDINATION CHEMISTRY, vol. 59, no. 13, September 2006 (2006-09-01), pages 1451 - 1465 *
BIN ET AL.: "On the Mechanism of Condensation between 5-Amino-4,6-dichloro-2-methylpyrimidine and 1-Acetyl-2-imidazolin-2-one", CHINESE CHEMICAL LETTERS, vol. 13, no. 3, 2002, pages 207 - 210 *
HOLT ET AL.: "Allosteric modulation of semicarbazide-sensitive amine oxidase activities in vitro by imidazoline receptor ligands", BRITISH JOURNAL OF PHARMACOLOGY, vol. 143, no. 4, August 2004 (2004-08-01), pages 495 - 507 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2586779A1 (fr) * 2011-10-24 2013-05-01 Hetero Research Foundation Procédé pour la préparation de moxonidine
WO2014037391A1 (fr) * 2012-09-07 2014-03-13 WÖRWAG PHARMA GmbH & Co. KG Synthèse de moxonidine à l'aide de bases organiques
EP2765131A1 (fr) 2013-02-08 2014-08-13 Arevipharma GmbH Procédé de production de monoxidine
US9040697B2 (en) 2013-02-08 2015-05-26 Arevipharma Gmbh Process for the production of moxonidine

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