WO2008073125A1

WO2008073125A1 - Moxonidine analogs, preparation processes and uses therefor

Info

Publication number: WO2008073125A1
Application number: PCT/US2006/061948
Authority: WO
Inventors: Oded Arad; Vladimir Naddaka
Original assignee: Chemagis Ltd; Perrigo Co
Current assignee: Wavelength Pharmaceuticals Ltd; Perrigo Co
Priority date: 2006-12-12
Filing date: 2006-12-12
Publication date: 2008-06-19
Anticipated expiration: 2009-06-12

Abstract

The present invention provides derivatives of moxonidine, 1-[l-[(4,6-dichloro-2-methyl-6-5-pyrimidinyl)imino]ethyl]-2-imidazolidinone of formula (V) and l-[l-[(4-chloro-2-methyl-6-methoxy-5-pyrimidinyl)imino]ethyl]-2-imidazolidinone of formula (VI), which can be used for testing the purity or monitoring the production of moxonidine, and process for preparing the derivatives. Also provided is an improved process for preparing 4,6- dichloro-2-methyl-5-(l-acetyl-2-imidazolin-2-yl)-aminopyrimidine (DMAIA) and a method of utilizing the process to produce moxonidine.

Description

LVM 255699

MOXONIDINE ANALOGS, PREPAJRATION PROCESSES AND USES THEREFOR

BACKGROUND OF THE INVENTION

[0001 j Moxonidine (4-chloro-5-(iniidazoline-2-ylanτdno)-6-methoxy-2-iϊiethyl- pyrimidine), has the structural formula (I) below and is used as an antihypertensive drug.

(D

[0002] 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. [0003] 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. It is stated in example 3 of the '570 patent that 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.

[0004] Czech patent No, 294649 describes a method of preparing moxonidine from DMAJA by methanolysis reaction using alkali metal carbonates e.g., potassium carbonate at 47-52°C or sodium bicarbonate at 65°C. The preparation of moxonidine from DMAIA is demonstrated below in Scheme 1.

Scheme 1

[0005] Example 1 of the '570 patent describes the synthesis of 4,6-dichloro-2-methyl~5~ (l-acetyl-2-imidazolin-2-yl)-aminoρyrimidine (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

2

1.045 equiv.) of l-acetyl-2-imidazolidin-2-one of formula (IV) in 200 ml (2.146 moles, 19.16 equiv.) of phosphorous oxychloride (POCl₃), which serves as a reagent as well as a solvent, for 48 hours at 5O⁰C, followed by distilling off the excess of POCI3 in vacuum. The reaction is detailed in Scheme 2 below.

Scheme 2

48 hours, 50 deg C

ι^v 1.

(0006] The synthesis of DMAIA as taught in the ' 570 patent requires a large excess of POCI₃ and heating the reaction mixture for a long reaction time, e.g., 48 hours, followed by distilling off the excess of POCI₃ in vacuum. POCI₃ is highly toxic and corrosive, and can create environmental problems. The use large excesses OfPOCl₃ and long reaction times are disadvantageous for production on a commercial scale.

[0007] According to an article by Zhong Jun Li et al., Chinese Chemical Letters, Vol. 13, No. 3, 207-210 (2002), the condensation reaction between 5-amino-4,6-dichloro-2- methylpyrimidme (III) and l-acetyl-2-imidazoIidin-2-one (IV) using POCI₃ as reagent as well as solvent produced 4,6-dichloro-2-methyl-5-(l-acetyl-tetrahydro-imidazo-2-ylidene)- aminopyrimidine (Ha) and l-[l-[(4_>6-dichloro-2-methyl-5-pyrimidinyl)imino]ethyl]-2- imidazolidinone (V) (hereinafter "iso-DMAIA"). Zhong Jun Li et al. have reported that the possible products of the condensation are the three compounds depicted in Scheme 3 below, but only compound TIa and V were isolated.

LVM 255699

Scheme 3

V

[0008] According to the health authorities e.g., the FDA and EU health authorities, 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.ϊ 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.

[0009] There is a need in the art for an improved process for preparing DMAIA in high purity and yield without using a large excess of POCI₃ or long reaction times, and an improved process for producing moxonidine from DMAIA. The present invention provides such processes. r

BRIEF SUMMARY OF THE INVENTION

[0010] The present invention provides a process for isolating iso-DMAIA from a mixture containing DMAIA and iso-DMAIA, which process preferably includes: LVM 255699

4 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. tOOll] In accordance with the present invention, 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%. By crystallizing the crude iso-DMAIA from an organic solvent in accordance with the present invention, e.g., from DMF, a crystalline solid comprising iso-DMAIA can be obtained.

{0012] 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. In one embodiment of the present invention, the crystalline ϊso- DMAIA produces a unique X-ray powder diffraction pattern. The strong diffraction peaks at 15.6, 19-4, and 29.7±0.2 degrees 2Θ are most characteristic of this form. [0013 J 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 It will be appreciated that 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. [0014] Compound VI can be used, e.g., as a standard for determining the purity and/or monitoring the production of moxonidine. In accordance with the present invention, compound VI can be obtained, e.g., via crystallization from an organic solvent, having a LVM255699

5 purity of at least about 98.5 wt% (by HPLC), preferably having a purity greater than 99 wt%, e.g., having a purity of 99.7 wt%. Preferably, compound VI Is crystallized from an organic solvent, e.g., DMSO, to produce a crystalline solid comprising compound VI.

[0015] The present invention also provides a crystalline form of compound VI. In one embodiment of the present invention, 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,

25.8, 26.4 and 2S.l±0.2 degrees 20 are most characteristic of this form.

[0016] The present invention also provides a process for preparing 4,6-dichloxo~2- methyl-5-(l-acetyl-2-ϊmϊdazolin-2-yl)-aminopyrimidinc (DMAIA) by reacting 5-amino-4_s6- dichloro-2-methylpyrimidine (III) with l-acetyl-2-imϊdazolidin-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.

[0017] 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. For example, the DMAIA produced in accordance with the present invention can be reacted with methoxide, e.g., in accordance with conventional methods, to produce moxonidine.

[0018] 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. Preferably, production samples are monitored using HPLC. In. a preferred embodiment, 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. LVM255699

6

BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 depicts the X-ray powder diffraction pattern of an exemplary crystalline form of iso-DMAIA.

[0020] Figure 2 depicts the DSC curve of an exemplary crystalline form of iso-DMAIA. [0021 J Figure 3 depicts the infra-red (IR) spectrum of an exemplary crystalline form of iso-DMAIA.

[0022] Figure 4 depicts the X-ray powder diffraction pattern of an exemplary crystalline form iso-moxonidine.

[0023] Figure 5 depicts the DSC curve of an exemplary crystalline form of compound VI. [0024 J Figure 6 depicts the infra-red (IR) spectrum of an exemplary crystalline form of compound VI.

[0025] Figure 7 depicts the HPLC chromatogram of a production sample of moxonidine prepared from DMAIA containing iso-DMAIA as an impurity.

DETAILED DESCRIPTION OF THE INVENTION

[0026] Applicants have discovered that preparing DMAIA according to the example in the '570 patent for preparing moxonidine (reference example 1) produces compounds VII and VIII, respectively, as impurities,

VII VIII

[0027] Without wishing to be bound by any particular theory, it is also believed that 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. LVM 255699

7

Scheme 4

Vl

V

Applicants also have discovered that the crude product, obtained in the process for preparing DMAIA₅ 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).

[0028] According to one embodiment, 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.

[0029] Preferably, 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:πnamide (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. [0030] In accordance with the present invention, 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%. By crystallizing the crude iso-DMAIA from an organic LVM255699

8 solvent in accordance with the present invention, e.g., from DMF, a crystalline solid comprising iso-DMAIA can be obtained.

[0031] 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 DMAlA or moxonidine. In one embodiment, 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 2Θ 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.

Table 1 Crystalline iso-DMAIA - X-ray powder diffraction peak positions and intensities

[0032] 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. It will be appreciated that 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. LVM255699

9

[0033] Preferably, 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. Preferably, when the base is not a methoxide salt, the organic solvent is methanol.

[0034 J Compound VI can be used, e.g., as a standard for determining the purity and/or monitoring the production of moxonidine. In accordance with the present invention, 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%. Preferably, 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. In one embodiment of the present invention, 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 2Θ 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.

LVM 255699

10

Table 2 Crystalline compound VI - X-ray powder diffraction peak positions and intensities

[0035] The present invention also provides a process for preparing 4,6-dichloro-2- methyl-5-(l-acetyl-2-imidazolin-2-yl)-amϊnoρyriraidine (DMAIA) from 5-amϊno-4,6- dichloro-2-methylpyriπiidme (III) and l-acetyl~2-imidazolidin-2-one (IV). which process preferably includes: heating a mixture of 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 isolating the precipitate, e.g., by filtration.

[0036J Preferably, the relative amount of POCI₃ used in the reaction is less than 5 equivalents OfPOCl₃ per 1 equivalent of compound III, and more preferably less than 3 equivalents of POCI₃ per 1 equivalent of compound III. Preferably, the reaction time is about 7 hours (about one seventh of the time required according to example 1 of the '570 patent). In one embodiment, 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. Preferably, 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

11 combinations thereof. A preferred base for quenching the condensation reaction mixture is sodium hydroxide (NaOH).

[0037] 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. For example, 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.

(0038] Certain amounts of impurities,, e.g., compound V and/or compound VI, may be formed when moxonidine is prepared from DMAIA, as detailed herein. In accordance with the present invention, 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. Preferably, production samples are monitored using HPLC. In a preferred embodiment, 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.

EXAMPLES

{0039] The following examples illustrate the practice of the present invention in some of its embodiments, but should not be construed as in any way limiting its scope. Other embodiments will be apparent to one skilled in the art.

[0040] HPLC measurements of moxonidine samples were performed using an HPLC system, equipped with Phenomenex Luna 5μ C8(2) (4,6 x 250 mm) column, and a UV detector operated on 230 nm. Analyses were performed using the following mobile phase, at flow rate of 1.2 ml/minute: Eluent A: 10 mM pentanesulfonic acid, pH = 3.0 with H2SO4; Eluent B: acetonitrile. The eluent HPLC mixture as defined herein is a mixture of 64% Eluent A and 36% Eluent B. The HPLC gradient is detailed below in Table 3. Table 3

COMPARATIVE EXAMPLE 1

[0041] This example describes the preparation and purification of moxonidine as described in the '570 patent.

[0042] 4,6~dicHoro-2-methyl-5-(l-acetyl-2-imidazoHn-2-yl)-aminopyrimidine (10 g) was mixed with a solution of sodium methoxide (NaOCHs) (3.78 g) in methanol (35 ml) and xefluxed for 2 hours. A sample was withdrawn, diluted with the HPLC eluent mixture and injected to the HPLC system. 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. A colorless precipitate was collected by filtration, washed with ethyl acetate and dried at 60⁰C overnight to yϊeld 7.1 g of moxonidine having 93.44% purity by HPLC and containing 1.19% of 4,6- dichloro-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine and 5.37% of 4₅6-dimethoxy-2~ methyl-(2-imidazolin-2-yl)-aminopyrimidine.

EXAMPLE 1

[0043] This example describes the preparation of 4,6-dichloro-2-methyl-5-(l -acetyl-2- imidazolin -2-yl)-aminopyrimidine (DMAIA).

[0044] A mixture of 5-amino-4-6-dichloro-2-me11iylpyrimidine (50 g, 0.281 moles, 1 equiv.), l-acetyl-2-ϊmidazolidin-2-one (40 g_> 0.357 moles, 1.27 equiv.) and phosphorous oxychloride (75 ml, 0.804 moles, 2.86 equiv.) was heated at ~90° C for 7 hours and then cooled to room temperature. The 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 80⁰C to obtain 55 g of a solid (containing 55% of DMAIA and 35% of iso-DMAIA, according to HPLC).

[0045] ^rϊhe solid was dissolved in DMSO (165 ml) at 90° C and activated charcoal (1.4 g) was added to the solution. The mixture was stirred at 90° C for 0.5 hours and then filtered. The filtrate was heated to 90° C and water (38 ml) was added drop-wise. The mixture was cooled to 5° C and kept at this temperature overnight. A solid was separated from the filtrate and collected by filtration, washed with water and 2-propanol and dried at 80⁰C to obtain 21.1 g of DMAIA, having a purity of 93% (by HPLC).

EXAMPLE 2

[0046] This example describes the preparation of l-[l-[(4,6-dichloro~2-methyl-5~ pyrimidinyl)-imirjo]ethyl]-2-irøidazoHdinone (iso-DMAIA, V).

[0Θ47J Water (170 ml) was added to the filtrate, which was obtained from example 1, and the mixture was kept at 5° C for 2 hours. A solid was collected by filtration, washed with water and 2-propanol and dried at 80° C overnight to afford 15.2 g of a product (containing 56% of wo-DMAIA and 42% of DMAIA).

[0048] The product was dissolved at 70° C in DMSO (45 ml). The solution was cooled to ambient temperature and water was added drop- wise until crystallization commenced. The mixture was cooled at 10° C for half an hour to obtain a suspension. The suspension was stirred at ambient temperature for 2 hours, followed by separating the filtrate from the solid (containing 4.5 g DMAIA) by filtration.

[0049] Water (50 ml) was added to the filtrate and the mixture was kept at 5° C overnight. A precipitate was collected by filtration, washed with water and with 2-propanol and dried at 80° C overnight to afford 6.0 g of the crude product (containing 71.7% of iso-OMAΪA and 26.8% of DMAIA).

[0050] The crude product (6.0 g) was dissolved at 50-60° C in DMF (13 ml). The solution was cooled to ambient temperature and kept at this temperature overnight. A precipitate was collected by filtration, washed with water and 2-propanol and dried at 80° C to yield 3.5 g of crude iso-DMAIA, having a purity of 87.1% (by HPLC). [0051] The crude iso-DMAIA (3.5 g) was re-crystallized from DMF to yield 2.0 g iso- DMAΪA (purity by HPLC: 99.8%). ¹H-NMR (300 MHz, DMSOd₆) 6: 2.20 (s, 3H, 2-CH₃), 2.56 (s, 3H₅ -N=CCH₃), 3.43 (t, 2H, NCH₂), 3.96 (t, 3H, NCH₂), 7.68 (s, IH, HNCO). 1³C-NMR (DMSOd₆) δ: 16.70 (2-CH₃), 24.23 (-N=CCH₃), 35.79 (NCH₂), 43.78 (NCH₂), 135.71 (C-5), 151.55 (C-2), 156.58 (C-4, 6), 158.67 (-N=CCH₃), 160.79 (NCO). MS (ESI): m/z = 288.1 [M-I-H⁺],

EXAMPLE 3

[0052] This example describes the preparation of 1 -[l-[(4~chloro-2-methyl-6-methoxy-5- pyrimidinyl)imino]ethyl]"2-imidazolidinone of formula (VI).

[0053] A mixture of iso-DMAIA (1.0 g), methanol (10 ml) and 25% sodium methoxide solution in methanol (0.73 ml, Ll equiv.) was stirred at ambient temperature overnight. Water (10 ml) was then added to the reaction mixture and the mixture was stirred at ambient temperature for 2 hours. A precipitate was collected by filtration, washed with water and dried at 60° C overnight to yield 0;4 g of l-[l-[(4-chloro-2-methyl-6-methoxy-5- pyrimidinyl)imino]ethyl]-2~imidazolidinone_> having a purity of 99.7% (by HPLC). ¹H-NMR (300 MHz, DMSO-d₆) δ: 2.13 (s, 3H, 2-CH₃), 2.48 (s, 3H, -N=CCH₃), 3.40 (t, 2H, NCH₂), 3.93 (t, 5H: 3H of CH₃O and 2H OfNCH₂), 7.54 (s, IH, HNCO). ¹³C-NMR (DMSO-d₆) β: 16.29 (2-CH₃), 24.64 (-N=CCH₃), 35.85 (NCH₂), 43.76 (NCH₂), 54.45 (OCH₃), 124.89 (C- 5), 148.64 (C-2), 156.92 (C-4), 158.7 (C-6), 159.98 (-N=CCH₃), 161.15 (NCO). MS (ESI): m/z - 284.1 [M+H⁺J.

EXAMPLE 4

[0054] This example describes the preparation of moxonidine from DMAIA containing 5.7% of iso-DMAIA.

[0055] A mixture of DMAIA (5.0 g), iso-DMAIA (0.3 g), methanol (25 ml) and 25% sodium methoxide solution in methanol (3.9 mi, 1.1 equiv.) was stirred at ambient temperature overnight. A sample of the reaction mixture was withdrawn and analyzed by HPLC indicating that the reaction mixture contained 87.9% of moxonidine and 9.7% of compound (VI). Water (50 ml) was then added to the reaction mixture and stirring was maintained at ambient temperature for 4 hours. A precipitate was collected by filtration, washed with water and 2-propanol and dried at 60° C overnight to yield 3.9 g of crude Moxoπidine in 73.6% yield, having a purity of 96.66% and containing 0.12% of the impurity VI (by HPLC).

[0056] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0057] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended (.o serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All steps described herein can be performed in any suitable order unless indicated otherwise herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed: No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0058] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading lite foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:

1. A process for isolating iso-DMAIA from a mixture containing DMAIA and iso-DMAIA, the process comprising: adding water to a mixture containing DMAIA and iso-DMAIA, and cooling to precipitate iso-DMAIA a first precipitate; dissolving the first precipitate in a first organic solvent and cooling to precipitate iso- DMAIA a solid; separating the solid; 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 and cooling Io produce iso-DMAIA crystals; and isolating the crystals.

2. The process of claim 1 , wherein the first and second organic solvents are the same or different and each is methanol, ethanol, 1-propanol, 2-propanol_} 1-butanoL, 2- butanol, tetrahydrofuran (THF)₅ water, acetonitrile, N^N-dimethylformarnide (DMF), N₅N- dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP) or a mixture thereof.

3. The process of claim 2, wherein the first organic solvent is DMSO and the second organic solvent is DMF.

4. The process of claim 1 , wherein the iso-DMAIA crystals have a purity of at least about 98.5%.

5. The process of claim 4, wherein iso-DMAIA crystals have a purity of at least about 99.8%.

6. A crystalline solid comprising iso-DMAIA, characterized by an X-ray powder diffraction pattern with characteristic diffraction peaks at 15.6, 19.4, and 29.7±0.2 degrees 20.

7. A compound of the formula:

VI

8. The compound of claim 7, in crystalline form,, characterized by an X-ray powder diffraction pattern having characteristic 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 29.

9. A process for preparing a compound of the formula:

VI the process comprising: reacting iso-DMAIA with methoxide in an organic solvent, to produce a reaction, product containing compound VI; isolating the reaction product; and optionally purifying the reaction product

10. The process of claim 9, wherein the organic solvent is methanol and the base is 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, or a combination thereof.

11. The process of claim 10, wherein, the base is sodium methoxide. IS

12. The process of claim 9, wherein the base is sodium methoxide and the organic solvent is methanol, tetrahydrofuran (THF), toluene, dimethyl sulfoxide (DMSO), or a mixture thereof,

13. The process of claim 9. wherein compound VI is obtained having a purity of at least about 98.5%.

14. The process of claim 13, wherein compound VI is obtained having a purity of at least about 99.7%.

15. A process for preparing 4,6-dichloro-2-methyl-5-( 1 -acetyl~2-imidazolin~2-yl)- aminopyrimidine (DlVLAIA)., the process comprising: heating a mixture of compounds III and IV in the presence of less than 15 equivalents of POCI3 for less than 10 hours, to produce a reaction product comprising DMAIA; cooling the reaction product and adding to the reaction mixture cold water and a base to produce a precipitate; and isolating the precipitate.

16. The process of claim 15, comprising simultaneously adding to cold water the reaction product comprising DMAIA and a base to produce the precipitate,, and isolating the precipitate by filtration.

17. The process of claim 15, wherein the POCI₃ is present in the reaction in an amount of less than 5 equivalents per 1 equivalent of compound III.

18. The process of claim 17, wherein the POCI3 is present in the reaction in an amount of less than 3 equivalents per 1 equivalent of compound III.

19. The process of claim 15, wherein the reaction time is about 7 hours.

20. The process of claim 15, wherein the base is lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof.

21. The process of claim 20, wherein the base is sodium hydroxide.

22. A method for determining the purity of moxonidine, which method comprises analyzing a sample of moxonidine to determine the content of l-[l-[(4,6-dichloro-2-methyl- 6-5-pyrimidinyl)imino]etliyl]-2-imidazolidinone (V) or l-[l-[(4-chloro-2-methyl-6-methoxy- 5-pynmidinyl)iinino]ethyl]-2-knidazo]idiiione (VI) in the sample.

23. The method of claim 22, wherein the moxonidine sample is analyzed by one or more separation technologies selected from gas chromatography, liquid chromatography, and capillary electrophoresis.

24. The method of claim 23, wherein the moxonidine sample is analyzed by HPLC.

25. The method claim 24 comprising injecting the moxonidine sample into an HPLC system equipped with a reversed phase column and under conditions essentially as described herein.

26. The process of claim 15, further comprising converting the DMAIA into moxonidine.

27. The process of claim 26, comprising reacting the DMAIA with methoxide to produce moxonidine.