EP0519984A1 - Process for preparing hydroxyalkyl-1 nitro-5 imidazoles - Google Patents

Process for preparing hydroxyalkyl-1 nitro-5 imidazoles

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Publication number
EP0519984A1
EP0519984A1 EP91906063A EP91906063A EP0519984A1 EP 0519984 A1 EP0519984 A1 EP 0519984A1 EP 91906063 A EP91906063 A EP 91906063A EP 91906063 A EP91906063 A EP 91906063A EP 0519984 A1 EP0519984 A1 EP 0519984A1
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chosen
general formula
carbon atoms
process according
nitro
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German (de)
French (fr)
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Michel Lavigne
Bernadette Mandard-Cazin
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members

Definitions

  • the present invention relates to a new process for the preparation of 1-hydroxyalkyl-5-nitro imidazoles.
  • 1-hydroxyethyl-2-methyl-5-nitroimidazole or metronidazole
  • 2-hydroxypropyl 2-methyl-5-nitroimidazole
  • ( hydroxy-3 propyl) -1 methyl-2 nitro-5 imidazole or ternidazole
  • n is equal to 2 or 3
  • one or more carbon atoms of the alkylene chain may be substituted by one or more methyl radicals and R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms or a phenyl radical, the phenyl radicals being optionally substituted by one or more identical or different atoms or radicals, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon or nitro atoms, can be obtained with good yields by the action of an oxide of alkylene in which one or more carbon atoms may be substituted by one or more methyl radicals, on a complex of sulfuric anhydride with an imidazole derivative of general formula:
  • R is defined as above and X represents a radical eliminable by hydrolysis or alcoholysis such as a hydroxymethyl, alkoxymethyl radical in which the alkyl part contains 1 to 4 carbon atoms, acyloxymethyl in which the acyl part contains 1 to 4 acyl carbon atoms containing 1 to 4 carbon atoms or an allyl or arylmethyl ethylenic radical followed by acid hydrolysis or alcoholysis of the condensation product thus obtained.
  • X represents a radical eliminable by hydrolysis or alcoholysis such as a hydroxymethyl, alkoxymethyl radical in which the alkyl part contains 1 to 4 carbon atoms, acyloxymethyl in which the acyl part contains 1 to 4 acyl carbon atoms containing 1 to 4 carbon atoms or an allyl or arylmethyl ethylenic radical followed by acid hydrolysis or alcoholysis of the condensation product thus obtained.
  • the co plexation of sulfuric anhydride with the imidazole derivative of general formula (II) is generally carried out at a temperature between 0 and 50 ° C. using equimolar amounts of sulfuric anhydride and the imidazole derivative of general formula (II) by operating in an organic solvent chosen from aliphatic or aromatic hydrocarbons, optionally halogenated such as xylene, methylene chloride, 1,2-dichloroethane, ethers such as dioxane, esters such than ethyl acetate or organic acid anhydrides such as acetic anhydride.
  • an organic solvent chosen from aliphatic or aromatic hydrocarbons, optionally halogenated such as xylene, methylene chloride, 1,2-dichloroethane, ethers such as dioxane, esters such than ethyl acetate or organic acid anhydrides such as acetic anhydride.
  • the condensation of the complex formed with the alkylene oxide is generally conducted at a temperature between 20 and 100 ° C using 1 to 2 moles of alkylene oxide per mole of imidazole derivative of general formula (II).
  • the product of condensation is transformed into product of general formula (I), at a temperature between 60 and 120 ° C, or by hydrolysis using an aqueous solution of a strong mineral acid such as, for example, sulfuric acid or hydrochloric acid , or by alcoholysis using an alcohol such as, for example, methanol or ethanol.
  • the product of general formula (I) is extracted according to the usual techniques after alkalization of the reaction mixture at a pH close to 10.
  • the product of general formula (I) is isolated according to the usual techniques without prior treatment of the reaction mixture.
  • nitroimidazole derivative of general formula (II) can be prepared under the conditions described in English patent GB 1,026,631.
  • the metronidazole yield is 48% compared to acetoxymethyl-1 methyl-2 nitro-4 imidazole used and 95% compared to acetoxymethyl-2 methyl-2 nitro-4 imidazole, - the transformation rate of acetoxymethyl-1 methyl-2 nitro-4 imidazole is 50%.
  • the reaction mixture was then held at 90 ° C for 3 hours.
  • the dioxane is withdrawn by means of a filtering finger.
  • 12 cm3 of concentrated sulfuric acid and 40 cm3 of water are added to the solid obtained.
  • the mixture is heated at 85 ° C for 3 hours.
  • the assay of the reaction mixture by HPLC shows that the yield of metronidazole is 51% relative to the acetoxymeth l-1 methyl-2-nitro-4 imidazole used and 89% relative to acetoxymethyl-1 methyl- 2 transformed nitro-4 imidazole.
  • the assay of the acidic aqueous phase by HPLC shows that the yield of metronidazole is 50% relative to the 2-methyl-4-nitro (or -5) imidazole used and 85% relative to the 2-methyl-4-nitro (or -5) transformed imidazole.

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

Abstract

Procédé de préparation d'hydroxyalkyl-1 nitro-5 imidazoles de formule générale (I) par action d'un oxyde d'alkylène sur un complexe de l'anhydride sulfurique avec un dérivé de l'imizadole de formule générale (II), suivie de l'hydrolyse acide ou de l'alcoolyse du produit obtenu. Dans les formules générales (I) et (II), R représente hydrogène, alkyle, phénylalkyle ou phényle (éventuellement substitué). Dans la formule génerale (I), n est égal à 2 ou 3 et un ou plusieurs atomes de carbone de la chaîne alkylène peuvent être substitués par un ou plusieurs radicaux méthyle. Dans la formule générale (II), X représente un groupement éliminable par hydrolyse acide ou alcoolyse.Process for the preparation of 1-hydroxyalkyl-5-nitroimidazoles of general formula (I) by the action of an alkylene oxide on a complex of sulfur trioxide with an imizadole derivative of general formula (II), followed acid hydrolysis or alcoholysis of the product obtained. In general formulas (I) and (II), R represents hydrogen, alkyl, phenylalkyl or phenyl (optionally substituted). In general formula (I), n is equal to 2 or 3 and one or more carbon atoms of the alkylene chain may be substituted by one or more methyl radicals. In general formula (II), X represents a group which can be removed by acid hydrolysis or alcoholysis.

Description

PROCEDE DE PREPARATION D'HYDROXYALKYL-1 NITRO-5 IMIDAZOLES PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 NITRO-5 IMIDAZOLES
La présente invention concerne un nouveau procédé de préparation d'hydroxyalkyl-1 nitro-5 imidazoles.The present invention relates to a new process for the preparation of 1-hydroxyalkyl-5-nitro imidazoles.
Parmi les dérivés de l'imidazole, l'hydroxyéthyl-1 méthyl-2 nitro-5 imidazole (ou métronidazole), l' (hydroxy-2 propyl)-1 méthyl-2 nitro-5 imidazole (ou secnidazole) et l'(hydroxy-3 propyl)-1 méthyl-2 nitro-5 imidazole (ou ternidazole) présentent un intérêt tout particulier du fait de leurs propriétés thérapeutiques remarquables.Among the imidazole derivatives, 1-hydroxyethyl-2-methyl-5-nitroimidazole (or metronidazole), 2-hydroxypropyl) -1 2-methyl-5-nitroimidazole (or secnidazole) and ( hydroxy-3 propyl) -1 methyl-2 nitro-5 imidazole (or ternidazole) are of particular interest because of their remarkable therapeutic properties.
Il est connu de préparer le métronidazole par action d'un excès d'oxyde d'éthylène sur le méthyl-2 nitro-4 (5) imidazole dans les conditions décrites dans le brevet français FR 1 379 915. Les rendements ne sont cependant pas satisfaisants.It is known to prepare metronidazole by the action of an excess of ethylene oxide on 2-methyl-4-nitro (5) imidazole under the conditions described in French patent FR 1 379 915. The yields are however not satisfactory.
D'après le brevet belge BE 679 609, il est connu de préparer des aryl-2 hydroxyalkyl-1 nitro-5 imidazoles par action directe d'un excès d'éρoxy-1,2 alkane avec un complexe equimolaire d'un aryl-2 nitro-4 (5) imidazole et d'un acide de Lewis, choisi parmi, par exemple, l'éthérate de trifluorure de bore, le chlorure d'étain, l'anhydride sulfurique, le chlorure de titane, le chlorure d'aluminium ou le chlorure d'antimoine. II a maintenant été trouvé, et c'est ce qui fait l'objet de la présente invention, que les hydroxyalkyl-1 nitroimidazoles, de formule générale :According to the Belgian patent BE 679 609, it is known to prepare 2-aryl-1-hydroxyalkyl-5-nitro imidazoles by direct action of an excess of 1,2-eρoxy-alkane with an equimolar complex of an aryl- 2 nitro-4 (5) imidazole and a Lewis acid, chosen from, for example, boron trifluoride etherate, tin chloride, sulfuric anhydride, titanium chloride, chloride aluminum or antimony chloride. It has now been found, and this is the subject of the present invention, that 1-hydroxyalkyl nitroimidazoles, of general formula:
dans laquelle n est égal à 2 ou 3, et un ou plusieurs atomes de carbone de la chaîne alkylene peuvent être substitués par un ou plusieurs radicaux méthyle et R représente un atome d'hydrogène ou un radical alkyle contenant 1 â 4 atomes de carbone ou un radical phénylalkyle dont la partie alkyle contient 1 à 4 atomes de carbone ou un radical phényle, les radicaux phényles étant éventuellement substitués par un ou plusieurs atomes ou radicaux, identiques " ou différents, choisis parmi les atomes d'halogène et les radicaux alkyles contenant 1 à 4 atomes de carbone ou nitro, peuvent être obtenus avec de bons rendements par action d'un oxyde d'alkylene dans lequel un ou plusieurs atomes de carbone peuvent être substitués par un ou plusieurs radicaux méthyle, sur un complexe de l'anhydride sulfurique avec un dérivé de l'imidazole de formule générale : in which n is equal to 2 or 3, and one or more carbon atoms of the alkylene chain may be substituted by one or more methyl radicals and R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms or a phenyl radical, the phenyl radicals being optionally substituted by one or more identical or different atoms or radicals, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon or nitro atoms, can be obtained with good yields by the action of an oxide of alkylene in which one or more carbon atoms may be substituted by one or more methyl radicals, on a complex of sulfuric anhydride with an imidazole derivative of general formula:
dans laquelle R est définis comme précédemment et X représente un radical eliminable par hydrolyse ou alcoolyse tel qu'un radical hydroxyméthyle, alcoxyméthyle dont la partie alkyle contient 1 à 4 atomes de carbone, acyloxyméthyle dont la partie acyle contient 1 à 4 atomes de carbone acyle contenant 1 à 4 atomes de carbone ou un radical éthylénique allylique ou arylméthyle suivie de l'hydrolyse acide ou de l'alcoolyse du produit de condensation ainsi obtenu.in which R is defined as above and X represents a radical eliminable by hydrolysis or alcoholysis such as a hydroxymethyl, alkoxymethyl radical in which the alkyl part contains 1 to 4 carbon atoms, acyloxymethyl in which the acyl part contains 1 to 4 acyl carbon atoms containing 1 to 4 carbon atoms or an allyl or arylmethyl ethylenic radical followed by acid hydrolysis or alcoholysis of the condensation product thus obtained.
La co plexation de l'anhydride sulfurique avec le dérivé de l'imidazole de formule générale (II) est généralement effectuée à une température comprise entre 0 et 50*C en utilisant des quantités équimolaires d'anhydride sulfurique et du dérivé de l'imidazole de formule générale (II) en opérant dans un solvant organique choisi parmi les hydrocarbures aliphatiques ou aromatiques, éventuellement halogènes tels que le xylène, le chlorure de méthylène, le dichloro-1,2 éthane, les éthers tel que le dioxanne, les esters tel que l'acétate d'éthyle ou les anhydrides d'acides organiques tel que l'anhydride acétique.The co plexation of sulfuric anhydride with the imidazole derivative of general formula (II) is generally carried out at a temperature between 0 and 50 ° C. using equimolar amounts of sulfuric anhydride and the imidazole derivative of general formula (II) by operating in an organic solvent chosen from aliphatic or aromatic hydrocarbons, optionally halogenated such as xylene, methylene chloride, 1,2-dichloroethane, ethers such as dioxane, esters such than ethyl acetate or organic acid anhydrides such as acetic anhydride.
La condensation du complexe formé avec l'oxyde d'alkylene est généralement effectuée à une température comprise entre 20 et 100*C en utilisant de 1 à 2 moles de l'oxyde d'alkylene par mole de dérivé de l'imidazole de formule générale (II). Généralement le produit de condensation est transformé en produit de formule générale (I), à une température comprise entre 60 et 120*C, soit par hydrolyse au moyen d'une solution aqueuse d'un acide minéral fort tel que, par exemple, l'acide sulfurique ou l'acide chlorhydrique, soit par alcoolyse au moyen d'un alcool tel que, par exemple, le méthanol ou l'éthanol.The condensation of the complex formed with the alkylene oxide is generally conducted at a temperature between 20 and 100 ° C using 1 to 2 moles of alkylene oxide per mole of imidazole derivative of general formula (II). Generally the product of condensation is transformed into product of general formula (I), at a temperature between 60 and 120 ° C, or by hydrolysis using an aqueous solution of a strong mineral acid such as, for example, sulfuric acid or hydrochloric acid , or by alcoholysis using an alcohol such as, for example, methanol or ethanol.
Lorsque l'hydrolyse est effectuée au moyen d'une solution aqueuse d'acide minéral fort, le produit de formule générale (I) est extrait selon les techniques habituelles après alcalinisation du mélange réactionnel à un pH voisin de 10. Lorsque l'on effectue une alcoolyse, le produit de formule générale (I) est isolé selon les techniques habituelles sans traitement préalable du mélange réactionnel.When the hydrolysis is carried out using an aqueous solution of strong mineral acid, the product of general formula (I) is extracted according to the usual techniques after alkalization of the reaction mixture at a pH close to 10. When carrying out an alcoholysis, the product of general formula (I) is isolated according to the usual techniques without prior treatment of the reaction mixture.
Pour la mise en oeuvre du procédé, il n'est pas nécessaire d'isoler le produit de condensation intermédiaire, l'hydrolyse ou 1'alcoolyse pouvant être enchaînées dans le même appareil.For the implementation of the process, it is not necessary to isolate the intermediate condensation product, the hydrolysis or the alcoholysis which can be chained in the same apparatus.
Le dérivé du nitroimidazole de formule générale (II) peut être préparé dans les conditions décrites dans le brevet anglais GB 1 026 631.The nitroimidazole derivative of general formula (II) can be prepared under the conditions described in English patent GB 1,026,631.
Les exemples suivants, donnés à titre non limitatif, montrent comment l'invention peut être mise en pratique.The following examples, given without limitation, show how the invention can be put into practice.
EXEMPLE 1EXAMPLE 1
Dans un ballon muni d'un agitateur, on introduit 19,9 g (0,10 mole) d'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole et 150 cm3 de dichloro-1,2 éthane. A cette solution on ajoute, à 20βC, en 10 minutes, 8,0 g (0,10 mole) d'anhydride sulfurique. Un précipité se forme. On maintient l'agitation pendant 1 heure, puis on ajoute en 15 minutes, une solution de 4,4 g (0,10 mole) d'oxyde d'éthylène dans 85 cm3 de dichloro-1,2 éthane, à 5*C. La suspension est maintenue pendant 3 heures à 5*C. On soutire le dichloro-1,2 éthane au moyen d'un doigt filtrant. Au solide obtenu on ajoute 2 cm3 d'acide sulfurique concentré et 20 cm3 d'eau. Le mélange réactionnel est chauffé à 85*C pendant 1 heure. Après refroidissement, le dosage par chromatographie liquide à haute performance (CLHP) montre que : le rendement en métronidazole est de 48 % par rapport à l'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole mis en oeuvre et de 95 % par rapport à l'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole transformé, - le taux de transformation de l'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole est de 50 %.19.9 g (0.10 mole) of 1-acetoxymethyl-2-methyl-4-nitro-imidazole and 150 cm3 of 1,2-dichloroethane are introduced into a flask fitted with an agitator. To this solution, 8.0 g (0.10 mole) of sulfuric anhydride is added at 20 β C over 10 minutes. A precipitate forms. Stirring is continued for 1 hour, then a solution of 4.4 g (0.10 mole) of ethylene oxide in 85 cm3 of 1,2-dichloroethane is added over 15 minutes at 5 ° C. . The suspension is kept for 3 hours at 5 ° C is drawn off the 1,2-dichloroethane by means of a filter finger. To the solid obtained is added 2 cm3 of concentrated sulfuric acid and 20 cm3 of water. The reaction mixture is heated at 85 ° C for 1 hour. After cooling, the assay by high performance liquid chromatography (HPLC) shows that: the metronidazole yield is 48% compared to acetoxymethyl-1 methyl-2 nitro-4 imidazole used and 95% compared to acetoxymethyl-2 methyl-2 nitro-4 imidazole, - the transformation rate of acetoxymethyl-1 methyl-2 nitro-4 imidazole is 50%.
EXEMPLE 2EXAMPLE 2
Dans un ballon muni d'un agitateur, on introduit 39,6 g (0,2 mole) d'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole et 150 cm3 de dioxanne. Puis on ajoute en parallèle d'une part 16 g (0,2 mole) d'anhydride sulfurique et, d'autre part, une solution de 8,8 g (0,2 mole) d'oxyde d'éthylène dans 17 cm3 de dioxanne, en maintenant la température à 45*C.39.6 g (0.2 mole) of 1-acetoxymethyl-2-methyl-4-nitro-imidazole and 150 cm 3 of dioxane are introduced into a flask fitted with an agitator. Then one adds in parallel on the one hand 16 g (0.2 mole) of sulfuric anhydride and, on the other hand, a solution of 8.8 g (0.2 mole) of ethylene oxide in 17 cm3 of dioxane, maintaining the temperature at 45 ° C.
Le mélange réactionnel est ensuite maintenu à 90*C pendant 3 heures. On soutire le dioxanne au moyen d'un doigt filtrant. Au solide obtenu, on ajoute 12 cm3 d'acide sulfurique concentré et 40 cm3 d'eau. Le mélange est chauffé à 85*C pendant 3 heures. Le dosage du mélange réactionnel par CLHP montre que le rendement en métronidazole est de 51 % par rapport à l'acétoxyméth l-1 méthyl-2 nitro-4 imidazole mis en oeuvre et de 89 % par rapport à l'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole transformé.The reaction mixture was then held at 90 ° C for 3 hours. The dioxane is withdrawn by means of a filtering finger. To the solid obtained, 12 cm3 of concentrated sulfuric acid and 40 cm3 of water are added. The mixture is heated at 85 ° C for 3 hours. The assay of the reaction mixture by HPLC shows that the yield of metronidazole is 51% relative to the acetoxymeth l-1 methyl-2-nitro-4 imidazole used and 89% relative to acetoxymethyl-1 methyl- 2 transformed nitro-4 imidazole.
EXEMPLE 3EXAMPLE 3
Dans un ballon muni d'un agitateur, on introduit 40 g (0,2 mole) d'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole et 100 cm3 de dichloro-1,2 éthane. A la solution maintenue à 20βC, on ajoute simultanément 16,3 g (0,21 mole), en 40 minutes, d'anhydride sulfurique et 14 g (0,24 mole) d'oxyde de propylène.40 g (0.2 mole) of 1-acetoxymethyl-2-methyl-4-nitro-imidazole and 100 cm3 of 1,2-dichloroethane are introduced into a flask fitted with an agitator. To the solution maintained at 20 β C, 16.3 g (0.21 mole) are added simultaneously, in 40 minutes, sulfuric anhydride and 14 g (0.24 mole) of propylene oxide.
Le mélange réactionnel est maintenu à 20*C pendant 1 heure puis à 75*C pendant 3 heures 30 minutes. On ajoute alors 2 cm3 d'acide sulfurique concentré et 50 cm3 d'eau et chauffe à 90*C pendant 3 heures. La phase aqueuse est décantée. Le dosage par CLHP montre que le rendement en secnidazole est de 14,5 % par rapport à l'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole mis en oeuvre et de 31 % par rapport à l'acétoxyméthyl-1 méthyl-2 nitro-4 imidazole transformé. EXEMPLE 4The reaction mixture was maintained at 20 ° C for 1 hour and then at 75 ° C for 3 hours 30 minutes. 2 cm3 of concentrated sulfuric acid and 50 cm3 of water are then added and the mixture is heated at 90 ° C. for 3 hours. The aqueous phase is decanted. The assay by HPLC shows that the secnidazole yield is 14.5% relative to the acetoxymethyl-1 methyl-2-nitro-4 imidazole used and 31% relative to acetoxymethyl-1 methyl-2-nitro -4 transformed imidazole. EXAMPLE 4
Dans un ballon muni d'un système d'agitation et d'une colonne à distiller, on introduit 17,3 g (0,136 mole) de méthyl-2 nitro-4 (ou -5) imidazole et 70 cm3 d'anhydride acétique. La suspension est chauffée à 95*C pendant 30 minutes jusqu'à dissolution du méthyl-2 nitro-4 ou (-5) imidazole. On ajoute alors 40 cm3 de xylène et élimine l'acide acétique formé par distillation azéotropique à 95 'C sous pression réduite (200 mm de mercure ; 27 kPa) . Au mélange réactionnel refroidi à 5*C, on ajoute en 20 minutes, 10,9 g (0,136 mole) d'anhydride sulfurique. La solution est agitée pendant 30 minutes à 5*C. On ajoute alors une solution de 6 g (0,136 mole) d'oxyde d'éthylène dans 20 cm3 d'anhydride acétique en maintenant le mélange réactionnel à 5*C. On chauffe ensuite pendant 2 heures à 75βC. Le mélange réactionnel est concentré à sec à l'évaporateur rotatif. On ajoute 2,5 cm3 d'acide sulfurique concentré et 20 cm3 d'eau sur l'extrait sec. On chauffe à 85*C pendant 1 heure.17.3 g (0.136 mole) of 2-methyl-4-nitro (or -5) imidazole and 70 cm 3 of acetic anhydride are introduced into a flask equipped with a stirring system and a distillation column. The suspension is heated at 95 ° C. for 30 minutes until the 2-methyl-4-nitro or (-5) imidazole is dissolved. 40 cm3 of xylene are then added and the acetic acid formed is removed by azeotropic distillation at 95 ° C. under reduced pressure (200 mm of mercury; 27 kPa). To the reaction mixture, cooled to 5 ° C., 10.9 g (0.136 mol) of sulfuric anhydride are added over 20 minutes. The solution was stirred for 30 minutes at 5 ° C. is then added a solution of 6 g (0.136 mole) of ethylene oxide in 20 cm3 of acetic anhydride while maintaining the reaction mixture at 5 ° C. is then heated for 2 hours at 75 β C. the reaction mixture is concentrated to dryness on a rotary evaporator. 2.5 cm3 of concentrated sulfuric acid and 20 cm3 of water are added to the dry extract. It is heated to 85 ° C for 1 hour.
Le dosage de la phase aqueuse acide par CLHP montre que le rendement en métronidazole est de 50 % par rapport au méthyl-2 nitro-4 (ou -5) imidazole mis en oeuvre et de 85 % par rapport au méthyl-2 nitro-4 (ou -5) imidazole transformé. The assay of the acidic aqueous phase by HPLC shows that the yield of metronidazole is 50% relative to the 2-methyl-4-nitro (or -5) imidazole used and 85% relative to the 2-methyl-4-nitro (or -5) transformed imidazole.

Claims

REVENDICATIONS
1 - Procédé de préparation d'hydroxyalkyl-1 nitroimi- dazoles de formule générale :1 - Process for the preparation of 1-hydroxyalkyl nitroimidazoles of general formula:
dans laquelle n est égal à 2 ou 3 et un ou plusieurs atomes de carbone de la chaîne alkylene peuvent être substitués par un ou plusieurs radicaux méthyle et R représente un atome d'hydrogène ou un radical alkyle contenant 1 à 4 atomes de carbone ou un radical phénylalkyle dont la partie alkyle contient 1 à 4 atomes de carbone ou un radical phényle, les radicaux phényles étant éventuellement substitués par un ou plusieurs atomes ou radicaux, identiques ou différents, choisis parmi les atomes d'halogène et les radicaux alkyles contenant 1 à 4 atomes de carbone et nitro, caractérisé en ce que l'on fait réagir un oxyde d'alkylene dans lequel un ou plusieurs atomes de carbone peuvent être substitués par un ou plusieurs radicaux méthyle sur un complexe de l'anhydride sulfurique avec un dérivé de l'imidazole de formule générale : in which n is equal to 2 or 3 and one or more carbon atoms of the alkylene chain may be substituted by one or more methyl radicals and R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms or a phenyl radical, the phenyl radicals being optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon and nitro atoms, characterized in that an alkylene oxide is reacted in which one or more carbon atoms can be substituted by one or more methyl radicals on a complex of sulfuric anhydride with a derivative of the imidazole of general formula:
dans laquelle R est défini comme précédemment et X représente un radical eliminable par hydrolyse acide ou par alcoolyse en opérant éventuellement dans un solvant organique à une température comprise entre 20 et 100*C, puis effectue une hydrolyse acide ou une alcoolyse sur le produit de condensation obtenu et isole l'hydroxyalkyl-1 nitroimidazole. 2 - Procédé selon la revendication 1 caractérisé en ce que l'on opère dans un solvant organique choisi parmi les hydrocarbures aliphatiques ou aromatiques éventuellement halogènes, les éthers, les esters ou les anhydrides d'acides organiques. wherein R is defined as above and X represents a leaving group by acid hydrolysis or by alcoholysis optionally working in an organic solvent at a temperature between 20 and 100 ° C and then carried out by acid hydrolysis or alcoholysis of the condensation product obtained and isolates 1-hydroxyalkyl nitroimidazole. 2 - Process according to claim 1 characterized in that one operates in an organic solvent chosen from aliphatic or aromatic hydrocarbons optionally halogenated, ethers, esters or anhydrides of organic acids.
3 - Procédé selon la revendication 2 caractérisé en ce que le solvant est choisi parmi le xylène, le chlorure de méthylène, le dichloro-1,2 éthane, le dioxanne, l'acétate d'ethyle et l'anhydride acétique.3 - Process according to claim 2 characterized in that the solvent is chosen from xylene, methylene chloride, 1,2-dichloroethane, dioxane, ethyl acetate and acetic anhydride.
4 - Procédé selon la revendication 1 caractérisé en ce que l'hydrolyse est effectuée au moyen d'une solution aqueuse d'un acide minéral fort choisi parmi l'acide sulfurique et l'acide chlorhydrigue.4 - Process according to claim 1 characterized in that the hydrolysis is carried out by means of an aqueous solution of a strong mineral acid chosen from sulfuric acid and hydrochloric acid.
5 - Procédé selon la revendication 1 caractérisé en ce que 1'alcoolyse est effectuée au moyen d'un alcool choisi parmi le méthanol et l'éthanol.5 - Process according to claim 1 characterized in that the alcoholysis is carried out by means of an alcohol chosen from methanol and ethanol.
6 - Procédé selon la revendication 1 caractérisé en ce que l'hydroxyalkyl-1 nitroi idazole obtenu est le métronidazole, le secnidazole ou le ternidazole. 6 - Process according to claim 1 characterized in that the hydroxyalkyl-1 nitroi idazole obtained is metronidazole, secnidazole or ternidazole.
EP91906063A 1990-03-12 1991-03-11 Process for preparing hydroxyalkyl-1 nitro-5 imidazoles Withdrawn EP0519984A1 (en)

Applications Claiming Priority (2)

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FR9003087 1990-03-12
FR9003087A FR2659326A1 (en) 1990-03-12 1990-03-12 PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 NITRO-5 IMIDAZOLES.

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JP (1) JPH05505187A (en)
CN (1) CN1055536A (en)
AU (1) AU7471791A (en)
CA (1) CA2081372A1 (en)
FI (1) FI923866A0 (en)
FR (1) FR2659326A1 (en)
HU (1) HU208676B (en)
IE (1) IE910801A1 (en)
IL (1) IL97512A0 (en)
NZ (1) NZ237380A (en)
PT (1) PT97014A (en)
WO (1) WO1991013877A1 (en)
YU (1) YU42991A (en)
ZA (1) ZA911768B (en)

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CN100376559C (en) * 2006-05-22 2008-03-26 浙江苏泊尔制药有限公司 Method for preparing secnidazole
CN102321028B (en) * 2011-06-30 2013-12-25 湖北省宏源药业有限公司 Method for synthesizing 2-methyl-5-nitroimidazole-1-ethanol
CN104072424A (en) * 2013-03-29 2014-10-01 黄冈师范学院 Environmental novel co-production technology of metronidazole and composite fertilizer
CN104177297B (en) * 2013-05-20 2016-09-28 东港市宏达制药有限公司 A kind of metronidazole API synthesis clean production method
CN103539745B (en) * 2013-10-11 2015-09-02 黄冈赛康药业有限公司 A kind of preparation method of secnidazole

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FR1379915A (en) * 1963-12-17 1964-11-27 Rhone Poulenc Sa Process for the preparation of imidazole derivatives
FR1035872A (en) * 1965-04-16 1953-09-01 William Prym Process for the production of slide closures
DE2359625A1 (en) * 1973-11-30 1975-06-05 Basf Ag PROCESS FOR THE PREPARATION OF 1-HYDROXYALKYL-5-NITROIMIDAZOLE
FR2625998B1 (en) * 1988-01-15 1990-06-08 Rhone Poulenc Sante PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 METHYL-2 NITRO-5 IMIDAZOLES
DE68904436T2 (en) * 1988-01-15 1993-07-29 Rhone Poulenc Sante METHOD FOR PRODUCING 1-ALKYL-5-NITRO-IMIDAZOLES.

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CN1055536A (en) 1991-10-23
FR2659326A1 (en) 1991-09-13
PT97014A (en) 1991-10-31
ZA911768B (en) 1991-12-24
HUT61530A (en) 1993-01-28
IL97512A0 (en) 1992-06-21
YU42991A (en) 1994-01-20
IE910801A1 (en) 1991-09-25
FI923866A (en) 1992-08-28
HU9202920D0 (en) 1992-11-30
WO1991013877A1 (en) 1991-09-19
NZ237380A (en) 1992-02-25
AU7471791A (en) 1991-10-10
HU208676B (en) 1993-12-28
FI923866A0 (en) 1992-08-28
CA2081372A1 (en) 1991-09-13

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