Classifications

• • 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

• the present invention relates to a process for the preparation of moxonidine and, more generally, to a compound having the following structural formula (I):
• Moxonidine (4-chloro-N- (imidazolidin-2-ylidene) -6-methoxy-2-methyl-pyrimidin-5-amine) has the structural formula (Ia) shown below and is used as a hypotensive drug.
• Moxonidine was approved in Germany in 1991 and is currently in Europe, eg. In Germany, Austria and the United Kingdom.
• moxonidine is obtained by crystallization from nitromethane.
• EP 1 873 151 describes an improved process for the preparation of moxonidine by means of alkali metal hydroxides, carbonates and bicarbonates under milder conditions (ambient to reflux temperature and lower molar excess of the base). Boiling sodium methoxide is highly corrosive and toxic. Although the alkali metal hydroxides, carbonates and bicarbonates are less corrosive and toxic, the preparation according to the improved process disclosed in EP 1 873 151 takes place in suspension and the recovery of the reaction product must be achieved by dissolving in acetic acid and precipitation by means of ammonium hydroxide happen.
• German patent application DE 29 37 023 A1 describes substituted 5- (2-imidazolin-2-yl) -aminopyrimidines having the general structural formula (III) and their physiologically acceptable acid addition salts.
• the substituents R1, R2 and R3 may be the same or different and represent a hydrogen or halogen atom, an alkoxy, alkylthio or alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms, at least one of Substituents R1, R2 and R3 represents an alkylthio or cycloalkyl group, and wherein R4 represents a hydrogen atom or an aliphatic or aromatic acyl group or their physiologically acceptable acid addition salts.
• German Patent Application DE 28 49 537 A1 also describes substituted 5- (2-imidazolin-2-yl) -aminopyrimidines having the general structural formula (III)
• R 1, R 2 and R 3, which may be the same or different, are a hydrogen or halogen atom, an alkoxy or alkyl group having 1 to 4 carbon atoms and R 4 is a hydrogen atom or an aliphatic or aromatic acyl group or their physiologically acceptable acid addition salts.
• This process in which acetone in particular is used as polar aprotic solvent and which is carried out at temperatures between 5 ° C and 60 ° C, allows 2-amino-4-chloro-6-alkoxypyrimidines and especially 2-amino-4-chloro To produce -6-methoxypyrimidine in an economical and environmentally friendly way and thereby to achieve a high yield and purity.
• the present invention provides, in a first aspect, a process for the preparation or synthesis of moxonidine (4-chloro-N- (imidazolidin-2-ylidene) -6-methoxy-2-methylpyrimidin-5-amine).
• DAIA 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimidine
• the inventors completed the exemplary embodiments 10 to 12 mentioned in EP 1 873 151 and found moxonidine as the reaction product in all cases. Further, in the cited examples for obtaining the reaction product, as already mentioned, it is necessary to add acetic acid and water to the reaction mixture. In this case, however, the methanol used in the reaction must be discarded and can not be reused. The precipitation of moxonidine occurs after concentration to 1/3 of the solution and by adding ammonium hydroxide. If the DMAIA used at the beginning was dyed, it is also the final product. To decolorize the product, it is necessary to add activated carbon after dissolving all the precipitates, to heat the solution for about 30 minutes and then to filter.
• the moxonidine thus obtained contained between 0.7% and 1% of the impurities 4,6-dimethoxy-2-methyl-5- (2-imidazolin-2-yl) -aminopyrimidine of the formula (IV) and 4,6-dichloro 2-methyl-5- (2-imidazolin-2-yl) -aminopyrimidine of the formula (V) as described in Examples 1, 2 and 3 of EP 1 873 151.
• the present invention advantageously allows moxonidine to be produced in a particularly economical and yet environmentally friendly manner, with simultaneously acceptable yields and with a very pronounced purity.
• DAIA 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimidine
• methanol suspension or methanolic suspension
• the 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimi- din (DMAIA) can in the methanol suspension in a proportion of 5 wt .-% to 40 wt. -%, in particular 10 wt .-% to 30 wt .-% and preferably 12 wt .-% to 15 wt .-%, based on the total weight of the methanol suspension, are present.
• the reaction between 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimidine and the at least one organic base is carried out in solution.
• At least one organic base as used in reference to the present invention may comprise one, i.e. a single, base or a plurality of bases, i.e. two or more bases.
• the at least one organic base is used in an amount of 1 molar equivalent to 10 molar equivalents, in particular 2 molar equivalents to 8 molar equivalents, and preferably 4 molar equivalents to 5 molar equivalents per one mol of 4,6-dichloro-2-methyl-5- ( 1-acetyl-2-imidazolin-2-yl) -aminopyrimidine (DMAIA) used.
• DAIA 4,6-dichloro-2-methyl-5- ( 1-acetyl-2-imidazolin-2-yl) -aminopyrimidine
• the at least one organic base may be an aliphatic base and / or an aromatic base.
• the at least one organic base may be a branched or unbranched base.
• the at least one organic base is an unbranched aliphatic base.
• the at least one organic base is selected from the group comprising triethylamine (TEA), diethylamine, monoethylamine, trimethylamine, dimethylamine, monomethylamine, benzylmethylamine and mixtures thereof.
• TAA triethylamine
• diethylamine diethylamine
• monoethylamine trimethylamine
• dimethylamine dimethylamine
• monomethylamine benzylmethylamine
• the reaction is carried out in a temperature range from 20 ° C to 65 ° C, in particular 20 ° C to 60 ° C and preferably 50 ° C to 60 ° C.
• the reaction can be carried out in particular at ambient temperature, i. H. in a temperature range of 20 ° C to 30 ° C, are performed.
• reaction may be carried out for a period of 6 hours to 30 hours, more preferably 6 hours to 24 hours, preferably 6 hours to 10 hours.
• the progress of the reaction is monitored, in particular by the use of high performance liquid chromatography (HPLC).
• HPLC high performance liquid chromatography
• the consumption of by-products such as, for example, 4,6-dimethoxy-2-methyl-5- (2-imidazolin-2-yl) -aminopyrimidine and / or 4,6-dichloro-2-methyl-5 - (2-imidazolin-2-yl) -aminopyrimidine monitored, in particular by high performance liquid chromatography (HPLC).
• by-products such as, for example, 4,6-dimethoxy-2-methyl-5- (2-imidazolin-2-yl) -aminopyrimidine and / or 4,6-dichloro-2-methyl-5 - (2-imidazolin-2-yl) -aminopyrimidine monitored, in particular by high performance liquid chromatography (HPLC).
• HPLC high performance liquid chromatography
• the methanol or the methanol-containing solvent mixture is removed, typically after completion of the reaction, to obtain a residue or crude moxonidine, preferably by distillation.
• the methanol or methanol-containing solvent mixture is removed with an excess of the at least one organic base, preferably by distillation.
• the methanol or methanol-containing solvent mixture can be reused.
• water is added to the residue or to the crude moxonidine, which usually leads to a suspension.
• the suspension can be cooled to produce a precipitate which can be separated by filtration.
• the filtered precipitate can be washed before drying, if necessary several times. All in all, the following steps are preferably carried out to isolate moxonidine:
• the invention also relates, in a more general aspect, to a process for the preparation of a compound of the following structural formula (I)
• DAIA 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimidine
• the radical R may be selected from the group consisting of linear, that is to say uncaptured, aliphatic radical, branched aliphatic radical, cycloaliphatic radical, halogenated aliphatic radical and combinations thereof.
• the radical R may in particular be an aliphatic radical which is selected from the group comprising alkyl radical, alkenyl radical, alkynyl radical and combinations thereof.
• the radical R is an alkyl radical.
• the radical R may be selected from the group comprising methyl radical, ethyl radical, n-propyl radical, 2-propyl radical, n-butyl radical, tert-butyl radical, n-pentyl radical, n-hexyl radical, cyclohexyl radical, allyl radical, 2-butenyl radical, 3 Butenyl, 2-propynyl, 2-butynyl, 3-butynyl, 3-pentynyl, 4-pentynyl and combinations thereof.
• the radical R is a methyl radical.
• the radical R may be selected from the group consisting of linear, i. unbranched, aromatic radical, in particular linear alkylaromatic radical, branched aromatic radical, in particular branched alkylaromatic radical, cycloaromatic radical, nitrated aromatic radical, halogenated aromatic radical and combinations thereof.
• radical R may contain aliphatic and aromatic groups.
• the alcohol provided for the preparation of the compound having the structural formula (I) according to the invention may be selected from the group consisting of linear, ie. unbranched, aliphatic alcohol, branched aliphatic alcohol, halogenated aliphatic alcohol, and mixtures thereof.
• the aliphatic alcohol may in particular be selected from the group comprising alkanols, alkenols, alkynols and mixtures thereof.
• the alcohol can be selected from the group comprising methanol, ethanol, n-propanol, 2-propanol, n-butanol, tert-butanol, n-pentanol, n-hexanol, cyclohexanol, allyl alcohol, 2-butene-1-ol, 3-Butene-1-ol, 2-propyne-1-ol, 2-butyne-1-ol, 3-butyne-1-ol, 3-pentyne-1-ol, 4-pentyne-1-ol, and mixtures thereof ,
• methanol is used.
• the alcohol may be selected from the group consisting of linear, i. unbranched, aromatic alcohol, in particular linear alkylaromatic alcohol, branched aromatic alcohol, in particular branched alkylaromatic alcohol, cycloaromatic alcohol, nitrated aromatic alcohol, halogenated aromatic alcohol and mixtures thereof.
• the alcohol may contain both aliphatic and aromatic groups.
• the compound of structural formula (I) is a 4-chloro-N- (imidazolidin-2-ylidene) -6-alkoxy-2-methyl-pyrimidin-5-amine, especially selected from the group comprising
• the compound to be prepared is the already mentioned moxonidine (4-chloro-n-imidazolidin-2-ylidene) -6-metoxy-2-methylpyrimidin-5-amine).
• DAIA 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimidine
• DAIA 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimi- din
• the reaction between 4,6-dichloro-2-methyl-5- (1-acetyl-2-imidazolin-2-yl) -aminopyrimidine and the at least one organic base is carried out in solution.
• the alcohol or alcohol-containing solvent mixture is removed, typically after completion of the reaction, to obtain a residue or crude product of the compound of structural formula (I), preferably by distillation.
• the alcohol or alcohol-containing solvent mixture is removed with an excess of the at least one organic base, preferably by distillation.
• the alcohol or alcohol-containing solvent mixture can be reused.
• water is added to the residue or crude product of the compound having the structural formula (I), which generally results in a suspension.
• the suspension can be cooled to produce a precipitate which can be separated by filtration.
• the filtered precipitate can be washed before drying, if necessary several times.
• HPLC measurements of the moxonidine samples were carried out using a HPLC system equipped with a Lichrospher 60 RP select B, 5 ⁇ m, 250 mm ⁇ 4 mm column and a UV sensor operating at 230 nm.
• the analyzes were carried out using a mobile phase consisting of 88% of a buffer solution of the sodium salt of pentanesulfonic acid with a pH of 3.5 (H2SO4).
• Potassium carbonate (2.4 g, 0.0174 mol, 1 molar equivalent) was added to a suspension of DMAIA (5.0 g, 0.0174 mol) in methanol (40 mL) and this mixture heated to 65 ° C for 3 h , The reaction mixture was cooled to ambient temperature and acetic acid (4 ml) and water (35 ml) were added. After stirring for half an hour, the reaction mixture was concentrated to about one quarter of its original volume. A 25% solution of ammonium hydroxide (4 ml) was added and stirred for one hour. The precipitate formed was filtered off, washed with water and dried at 50 ° C.
• Dimethylamine (40% aqueous solution having a specific gravity of 0.885, 3.92 g, 0.087 mol, 5 molar equivalents) was added to a suspension of DMAIA (5.0 g, 0.0174 mol) in methanol (40 mL) and this solution heated to 65 ° C for 6 hours. The methanol with the excess amine was distilled and saved for later use. Thereafter, water was added to the residue. After cooling the precipitate formed, it was filtered off, washed with water and dried at 50 ° C. The result was 3.44 g of crude moxonidine with a yield of 82.02%.

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• 2012
  • 2012-09-07 DE DE102012215896.0A patent/DE102012215896A1/de not_active Withdrawn
• 2013
  • 2013-09-04 EP EP13756905.9A patent/EP2892895A1/fr not_active Withdrawn
  • 2013-09-04 WO PCT/EP2013/068272 patent/WO2014037391A1/fr not_active Ceased

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