GB2453982A - Chemical process for the preparation of Medetomidine - Google Patents

Chemical process for the preparation of Medetomidine Download PDF

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GB2453982A
GB2453982A GB0720891A GB0720891A GB2453982A GB 2453982 A GB2453982 A GB 2453982A GB 0720891 A GB0720891 A GB 0720891A GB 0720891 A GB0720891 A GB 0720891A GB 2453982 A GB2453982 A GB 2453982A
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Rasik Somaiya
Muhammad Raza
Jonathan Cranke
Kristian Bragg
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Norbrook Laboratories Ltd
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Norbrook Laboratories Ltd
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Priority to ARP080104589A priority patent/AR068952A1/en
Priority to UY31415A priority patent/UY31415A1/en
Priority to PE2008001820A priority patent/PE20091088A1/en
Priority to CL2008003185A priority patent/CL2008003185A1/en
Priority to PCT/GB2008/003613 priority patent/WO2009053709A1/en
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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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

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Abstract

A process for preparing Medetomidine which comprises reacting 2,3-dimethyl-methylbenzylalcohol with N-trimethylsilylimidazole; a Lewis acid may be present (e.g. titanium chloride, TiCl4). The 2,3-dimethyl-methylbenzylalcohol may be prepared by adding dimethylbenzaldehyde to a solution of a Grignard reagent (e.g. methylmagnesium chloride).

Description

Chemical Process The present invention relates to a process for the preparation of 4-(l-(2, 3-Dimethylphenyl)ethyl)-1H-imidazole of the formula (I): CH3 CR3 CH3LN Formula (I) The compound of formula (I) is also known as Medetomidine.
Medetomidine, first described in EP-A-72615, is a selective and potent non-narcotic alpha 2-adrenergic agonist which has been shown to have anti-hypertensive activity as well as sedative analgesic effects when administered to animals.
The Medetomidine drug is sold for veterinary applications in the form of its hydrochloride salt under the trade name of Domitor �. Its effects can be reversed by administration of 4-(2-Ethyl-2, 3-dihydro-1H-indeny-2-yl)-].H-imidazole, also known as Atipamezole, a 2-adrenergic receptor antagonist.
There are a number of known processes to prepare Medetomidine and its acid addition salts thereof.
EP-A-72615 describes a multi-step process for preparing Medetomidine which includes the following process steps: (i) adding 2,3-Dimethylbromobenzene in dry Tetrahydrofuran (THF) to a boiling solution of 213-Dimethylmagnesiumbromjcje; (ii) heating 4-Imidazolecarboxylic acid methyl ester in dry THF to about 50 °C and then adding it to the solution of step (i) and a Methylmagnesium bromide solution; (iii) refluxing the reaction mixture for several hours, cooled and then acidifying it to form 4-((a-(2,3-Dimethyiphenyl) a-methyl] hydroxymethyl] imidazole; (iv) heating the 4-[(cr-(2,3-Dimethylphenyl)a-methyl]hydroxymethyl]imidazole to 136 °C with Potassium hydrogen sulphate to form].-(4-Imidazolyl)-1-(2,3-dimethylphenyl)-ethylene; and (v) hydrogenating the l-(4-Imidazolyl)-1-(2, 3-dimethyiphenyl) -ethylene with Palladium-on-carbon catalyst in concentrated hydrochloric acid under a hydrogen atmosphere, with stirring or the use of metallic sodium in liquid ammonia to obtain 4-(a-Methyl-2,3-dimethylbenzyl) imidazole.
This process has the disadvantages of requiring high temperatures and a hydrogenation step. Both of these requirements are dangerous and not ideal for the industrial manufacture of Medetomidine. This process also has the disadvantage that Medetomidine is produced at a low yield, namely about 17%, according to Kudzma et al, Synthesis, "Expedient Synthesis of 4(5) -[l-(2, 3-Dimethylphenyl)ethyl]- 1H-imidazo].e, the cx2-Adrenergic Agonist Medetomidine", pp 1021 and 1022 (1991) Kudzma et al, Synthesis, "Expedient Synthesis of 4(5)-(1- (2, 3-Dimethylpheriyl)ethyl]-1H-imidazole, the a2-Adrenergic Agonist Medetontidine", pp 1021 and 1022 (1991) describes another multi-step process for preparing Medetomidine which includes the following process steps: -3-.
(a) lithiating with Butyl lithium in pentane at -78 °C 1-(N,N-Dimethylsulfamoyl)imidazole in dry THF to give a 2-Lithioimidazole; (b) treating the Lithioimidazole with tert-Butyldimethylsilyl chloride and allowing it to warm to room temperature to give a bis-protected imidazole; (b) cooling the bis-protected imidazole to -78 °C and treated it with Butyl lithium and 2,3-dimethylbenzoyl chloride to form l-N,N-Dimethylsulfarnoyl-2-(tert-butyldimethylsilyl)-5-(2, 3-dimethylbenzoyl)imidazole; and (C) refluxing l-N,N-Diniethylsulfamoyl-2-(tert-butyldimethylsilyl) -5-(2, 3-dimethylbenzoyl) imidazole in 1.5 N Hydrochloric acid to produce 4(5)-El-(2, 3-Dirnethyiphenyl) ethyl] -1H-imidazole.
This process has the disadvantage of requiring that the reaction process takes place at a temperature of -78 °C in the presence of Butyl lithium which is highly flammable and corrosive.
It has now been surprisingly found that Medetomidine can be prepared at relatively moderate temperatures with easier to handle and less dangerous reactants. This process of preparing Medetomidine is, therefore, more industrially friendly than the current processes to form Medetomidine.
The present invention provides a process of preparing Medetomidine of Formula (I): CH3 CH3 cH3JyL; which comprises: Ci) reacting 2,3-Dimethyl-methylbenzylalcoho]. with N-Trimethylsilylimidazole.
Optionally, Medetomidine is then converted into an acid addition salt. In a preferred embodiment the hydrochloride salt of Medetomidine of Formula (I) is formed using concentrated Hydrochloric Acid.
The present invention will now be further described. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
2,3-Dimethyl-methylbenzyl alcohol is reacted with N-Trimethylsilylimidazole.
In a preferred embodiment the 2,3-Dimethyl-methylbenzy3.
alcohol is reacted with N-Triinethylsilylimidazole in the presence of a Lewis Acid, optionally in the presence of a chlorinated solvent.
The Lewis acid can be a metal halide such as Titanium (IV) chloride, Aluminium chloride, Iron (III) chloride, Zinc chloride, Boron trifluoride or Niobium pentachloride.
Preferably the Lewis acid is Titanium (IV) chloride.
The chlorinated solvent can be Chloroform, Methylene chloride or 1,2-dichioroethane. Preferably the chlorinated solvent is anhydrous, more preferably the chlorinated solvent is anhydrous Chloroform, anhydrous Methylene chloride or anhydrous 1,2-dichioroetharie, most preferably anhydrous Chloroform. Anhydrous defines where the water content is less than about 250 ppm of water, preferably less than about 100 ppm.
The reaction mixture is worked up with a chlorinated solvent. Examples of suitable chlorinated solvents include Chloroform, Methylene chloride, 1,2-Dichioroethane, anhydrous Chloroform, anhydrous Methylene chloride, or anhydrous l,2-Dichloroethane. Preferably the chlorinated solvent is eitrier crLLorororm or Metnyi.ene chloride, even more preferably Chloroform and most preferably anhydrous Chloroform. Anhydrous defines where the water content is less than about 250 ppm of water, preferably less than about ppm. The chlorinated solvent can be the same or different to the chlorinated solvent used in the reaction of 2,3-Dimethyl-methylbenzyl alcohol with N-Trimethylsilylimidazole This reaction step takes place at a temperature of less than or equal to about 45 °C, preferably at a temperature of from about 5 to about 35 °C, more preferably at a temperature range of from about 10 to about 35 °C, even more preferably at a temperature of from about 20 to about 35 °C, still even more preferably at a temperature range of from about 20 to about 30 °C, yet even more preferably at a temperature range of from about 20 to 25 °C and most preferably at a temperature of about 25°C.
The typical reaction time is from about 2 to about 20 hours, preferably from about 3 to about 17 hours, even more preferably from about 5 to about 15 hours, and most preferably from about 5 to about 10 hours.
The trimethylsilylimidazole is present in excess of the Dimethyl-methylbenzyl alcohol. Preferably the ratio of Dimethyl-methylbenzyl alcohol: N-Trimethylsilylimidazole is about 1:6 molar, preferably about 1:5 molar, more preferably about 1:4 molar and most preferably about 1:3 molar.
Secondly, when a Lewis acid is present the Lewis Acid is present in excess of the Dimethyl-me'thylbenzyl alcohol.
Preferably the ratio of Dimethyl-rnethylbenzyl alcohol: Lewis acid about 1:6 molar, preferably about 1:5 molar, more preferably about 1:3.5 molar and most preferably about 1:2.2 molar.
In a preferred embodiment 2,3-Dimethyl-methylbenzyl alcohol is reacted with N-Trimethylsilylimidazo].e in the presence of a Lewis acid in a chlorinated solvent, preferably an anhydrous chlorinated solvent, and most preferably anhydrous Chloroform.
In a further preferred embodiment 2,3-Dimethyl-methyj.benzyl alcohol is reacted with N-Trimethylsilylixnidazole in the presence of Titanium (IV) chloride in a chlorinated solvent, preferably an anhydrous chlorinated solvent, and most preferably anhydrous chloroform.
In one embodiment the 2,3-Dimethyl-methylbenzyl alcohol is prepared by adding 2,3-Dimethylbenzyl aldehyde to a solution of a Grignard reagent optionally in a solvent, such as Tetrahydrofuran (THF), optionally under an inert atmosphere.
2,3-Dimethyl-methylbenzy]. alcohol has the following structure: CH3 OH CH3 A Grignard Reagent is an organometallic compound of Magnesium with the general formula RMgX, where R is an organic group and X is a Halogen atom.
In a preferred embodiment R is a C1-C6 alkyl, preferably a C1-C4 alkyl, more preferably a C1-C3 alkyl, most preferably a C1 or C2 alkyl, and most preferably a C1 alkyl.
In a preferred embodiment X is Chlorine, Bromine or Iodine, preferably chlorine.
Even more preferably the Grignard reagent is a Methylmagnesium halide. Suitable examples include Methylmagnesium bromide, Methylmagnesium iodide or Methylmagnesjum chloride. Preferably the Methylmagnesium halide is Methylmagnesium bromide or Methylmagnesium chloride. Most preferably the Methylmagnesium halide used is Methylmagnesium chloride.
The concentration of the Grignard reagent in solution is at a concentration of from about 0.1M to about 7M, preferably from about 1M to about 5M, more preferably from about 2M to about 4M and most preferably about 3M.
Examples of suitable solvents include Tetrahydrofuran, Dioxanes, Ethers such as Diethyl ether, Toluene,, Hexane and Heptane. Preferably the solvent is Tetrahydrofuran (THF). In an even more preferred embodiment the THF has a preferred range of water from about 10 to about 500 ppm, preferably from about 10 to about 25Oppm, more preferably from about 30 to about 150 ppm, and most preferably with less than about ppm of water. Anhydrous is defined where the water content is less than about 250 ppm, preferably less than iS about.i.O0 ppm.
In a preferred embodiment the reaction is carried out under an inert atmosphere such as Nitrogen, Argon or Helium.
The reaction mix is worked up with a chlorinated solvent Preferably the chlorinated solvent is Chloroform.
This reaction step of preparing 2,3-Dimethyl-rnethylberizyl alcohol takes place at a temperature of less than or equal to about 50 °C, preferably at a temperature of from about -to about 50 °C, more preferably at a temperature of from about -10 to about 30 °C, even more preferably at a temperature range of from about -10 to about 20 °C, even more preferably at a temperature of from about 0 to about 20 °C, still even more preferably at a temperature range of from about 10 to about 20°C, and most preferably at a temperature of about 20°C.
The typical reaction time for preparing 2,3-Dimethyl-methylbenzyl alcohol is from about 1 to about 24 hours, preferably from about 5 to about 20 hours, even more preferably from about 10 to about 15 hours, and most preferably about 10 hours.
The reactants used can be in the ratio of from about 5:1 molar to about 1:5 molar, preferably about 4:1 molar to about 1:4 molar, preferably about 3:1 molar to about 1:3 molar, more preferably about 2:1 molar to about 1:2 molar, even more preferably about 1:1 molar to about 1:1.2 molar, yet even more preferably 1:1.1 and most preferably about 1:1.05 molar, 2,3-Dimethylbenzyl aldehyde:Grignard reagent.
In a preferred embodiment the 2,3-Dimethyl-methylbenzyl alcohol is prepared by adding 2,3-Dimethylbenzyl aldehyde to a solution of Methylmagnesium chloride in THF.
In a further preferred embodiment the 2,3-Dimethyl-- methylbenzyl alcohol is prepared by adding 2,3-Dimethylbenzyl aldehyde to Methylmagnesium chloride at 3M in TI-IF preferably at a temperature of less than or equal to about 50 °C, preferably at a temperature of from about -10 to about 50 °C, more preferably at a temperature of from about -10 to about 30 °C, even more preferably at a temperature range of from about -10 to about 20 °C, even more preferably at a temperature of from about 0 to about 20 °C, still even more preferably at a temperature range of from about 10 to about 20°C, and most preferably at a temperature of about 20°C to form 2,3-Dimethy1-c-benzyl -10 -alcohol. This is worked up with a Chlorinated solvent preferably Chloroform.
In one embodiment the 2,3-Dimethylbenzyl aldehyde can be prepared by reacting a 2,3-Dimethylbenzylhalide with an alkoxide and 2-Nitropropane, optionally in a polar solvent.
2,3-Dimethylbenzyl aldehyde has the following structure: CH3 0 The alkoxide used may, for example, be Sodium ethoxide, Potassium ethoxide, Sodium methoxide, Potassium methoxide, Sodium tertbutoxide or Potassium tertbutoxide. Preferably the alkoxide is Sodium ethoxide.
The reaction mixture is worked up with an alkali metal hydroxide. The alkali metal hydroxide used may, for example, be Sodium hydroxide or Potassium hydroxide. Sodium hydroxide is preferred.
The 2, 3-Dimethylbenzylhalide used, CH3 CH 3_.rJ X wherein X = Br, Cl or I -11 - may, for example, be 2,3-Dimethylbenzylbromide or 2,3-Dimethylbenzyliodide. 2, 3-Dimethylbenzylbromjde is preferred.
The polar solvent may, for example, be a C2 to C6 alcohol.
Examples of suitable C2 to C6 alcohols include, Industrial methylated spirit (IMS), Ethanol or Propanol.. Ethanol is preferred.
In a preferred embodiment the alkoxide is Sodium Ethoxide, the 2, 3-Dimethylbenzylhalide is 2, 3-Diinethylbenzylbromide and the polar solvent is Ethanol.
The reaction to prepare 2,3-Dimethylbenzyl aldehyde is suitably carried out at a temperature of at least about 5 °C, preferably at a temperature of from about 5 to about 60 °C, more preferably at a temperature of from about 5 to about 40°C, even more preferably at a temperature of from about 5 to about 30°C, yet even more preferably at a temperature of from about 5 to about 20°C, yet even more preferably at a temperature range of from about 10 to about 20°C and most preferably at a temperature of about 20 °C.
The typical reaction time is preferably from about 2 to about 10 hours, more preferably from about 4 to about 7 hours and most preferably about 5 hours.
The alkoxide is present in the concentration of from about 0.5 to about 3 molar, preferably from about 0.8 to about 3 molar, more preferably from about 1 to about 1.5 molar and most preferably from about 1 to about 1.1 molar.
-12 -The reactants used can be in the ratio of from about 5:1 molar to about 1:5 molar, preferably about 4:1 molar to about 1:4 molar, preferably about 3:1 molar to about 1:3 molar, more preferably about 2:1 molar to about 1:2 molar, even more preferably about 1:1 molar to about 1:1.2 molar, and most preferably about 1:1.04 molar, 2,3-Dimethylbenzyl bromide: 2-Nitropropane.
In a preferred embodiment the Medetomidine of Formula (I) is prepared by a process which comprises: (i) reacting a 2,3-Dimethylbenzylhalide with an alkoxide and 2-Nitropropane to form a 2,3-Dimethylbenzyl aldehyde; (ii) adding the 2,3-Dimethylbenzyl aldehyde to a solution of Nethylmagnesium halide to form 2,3-Dimethyl-methyibenzylalcohol; and (iii) reacting the 2,3-Dimethyl-methylbenzylalcohol with N-Trimethylsilylimidazole in the presence of Titanium (IV) chloride in a anhydrous Chloroform at a temperature of less than or equal to about 45 °C.
The intermediate products formed at some or all stages of the process to form Medetomidine can be optionally extracted and purified to isolate impurities using standard techniques.
Optionally, Medetomidine can be converted into an acid addition salt from both organic and inorganic acids using standard methods. The acid addition salts which can be formed are, for instance, Chlorides, Hydrochiorides, Bromides, Tosylates, Suiphates, Nitrates, Phosphates, Sulfonates, Formates, Tartarates, Maleates, Citrates, Benzoates, Salicylates and Ascorbates.
-13 -Preferably, the acid addition salt of Medetomidjne which can be formed is a Hydrochloride as it is more stable and most cost effective.
Various processes are known to isolate Medetomidine Hydrochloride as a crystalline salt.
Kudama et al, Synthesis, "Expedient Synthesis of 4(5)-(1- (2, 3-Dimethylphenyl)ethyl]-1H_imjdazole, the c2-Adrenergic Agonist Mecietomjdjne', pp 1021 and 1022 (1991), for example, describes a process for preparing the hydrochloride salt of Medetomidine by the in situ reduction of Medetomidine with Li/NH3/NH4C1 at -78 °C.
It has now been found that the hydrochloride salt (formula II) of Medetomidine can be prepared using concentrated Hydrochloric acid.
Cl-i CH CH3 CH3 HCl Concentrated Hydrochloric acid is comparatively easy to handle, less toxic and is more cost effective.
To make the chloride addition salt of Medetomjdjne the concentration range of Hydrochloric acid is from between about 25 to about 36%, more preferably from between about 35 to about 36%, and most preferably about 36%.
-14 -The Hydrochloric Acid can be added together with Toluene to the Medetomidine free base.
The reaction mixture can then be heated at a temperature of from about 115°C to about 150°C, preferably at a temperature of from about 120°C to about 130 °C, thus distilling off excess water. The distillation of water is continued until no more water is distilled. In a preferred embodiment a Dean-Stark apparatus can be used.
Once the distillation is complete, the crystallisation of Medetomidine hydrochloride is suitably carried out at room temperature.
i Depending on the scale of the manufacture of Medetomidine hydrochloride the crystallisation can take from between about 3 and about 4 hours for a small scale production and from about 10 to about 13 hours for a large scale production.
The crystalline product can be recovered from the solution by conventional methods such as centrifugation or filtering.
The crystalline product can be washed with suitable solvent and dried at elevated temperatures. Preferably, the wet product is dried in vacuun at a temperature of from about 50°c to about 100 °C, more preferably from about 60 to 90 even more preferably from about 75 to about 90 °C, and most preferably 80 °C for at least about 10 hours, and preferably to a constant weight. The vacuum range is preferably from about -1000 to about -1750 mbar and most preferably from about -1000 to -900 mbar.
-15 -If desired, the product can be purified by repeating the above step or by any other suitable process, for example crystallisation, chromatography or solvent slurry.
The following Example further illustrates the present invention.
Example 1 FH3
H3C J. H3C itIIIIi::J Br Stepi JiIIIIi::i7 (2) epz
OH
Step H3C\,_/!...c, (6) (4) Step 4 H3 CH3 * HCI (1) Step 1 -16 - Sodium Ethoxide, 213-Dimethylbenzylbromide and 2-Nitropropane in Ethanol at about 20°C. Workup with a solution of Sodium hydroxide. Step2
Methylmagnesium chloride solution 3M in THF at about 20°C.
Workup with Chloroform.
Step 3 N-Trimethylsjlyljmjdazole, Titanium (IV) chloride (TIC14) anhydrous Chloroform (CHC13) at about 30°C. Workup with Chloroform. . ,s
Step 4 Medetomidine free base was mixed with 36 -37% Hydrochloride solution and Toluene. Dean-Stark Apparatus used.

Claims (39)

  1. -17 -Claims 1. A process of preparing Medetomidine of Formula (I): CH3 CH3 CH3%5LcN which comprises: (i) reacting 2,3-Dimethyl-methylbenzylalcohol with N-Trimethylsjlyljmjdazole.
  2. 2. The process according to claim 1 wherein the 2,3-Dimethyl-methylbenzyl alcohol is prepared by adding 2,3-Diinethylbenzyl aldehyde to a solution of a Grignard reagent.
  3. 3. The process according to claim 2 wherein the Grignard reagent is a Methylmagnesium halide.
  4. 4. The process according to claim 3 wherein the Methylmagnesium halide is Methylmagnesium chloride.
  5. 5. The process according to any one of claims 2 to 4 wherein the concentration of the Grignard reagent in solution is from about 0.1 Molar to about 7 Molar.
  6. 6. The process according to claim 5 wherein the concentration of the Grignard reagent in solution is about 3 Molar.
  7. 7. The process according to any one of claims 2 to 6 wherein the preparation of 2,3-Dimethyl-methylbenzyl alcohol -18 -is carried out at a temperature of less than or equal to about 50 °C.
  8. 8. The process according to claim 7 wherein the preparation of 2,3-Dimethyl-methylbenzyl alcohol is carried out at a temperature of from about -10 to about 50°C.
  9. 9. The process according to claim 7 wherein the preparation of 213-Dimethyl-methylbenzy]. alcohol is carried out at a temperature of from about -10 to about 30°C.
  10. 10. The process according to claim 7 wherein the preparation of Dimethyl-methylbenzy]. alcohol is carried out at a temperature of about 20°C. i
  11. 11. The process according to any one of claims 2 to 10 wherein the preparation of Dimethyl-methylbenzyj. alcohol is carried out in the presence of a solvent.
  12. 12. The process according to claim 11 wherein the solvent is Tetrahydrofuran (THF).
  13. 13. The process according to claim 12 wherein the TFIF has a water content of from about 10 to about 500 ppm.
  14. 14. The process according to claim 13 wherein the THF has a water content of from about 10 to about 250 ppm.
  15. 15. The process according to claim 13 wherein the THF has a water content of from about 30 to about 150 ppm.
    -19 -
  16. 16. The process according to claim 13 wherein the THF has a water content of about lOOppm.
  17. 17. The process according to any one of claims 2 to 16 wherein the 2,3-Dimethylbenzyl a].dehyde is prepared by reacting a 2,3-Dimethylbenzylhalide with an alkoxide and 2-Nit ropropane.
  18. 18. The process according to claim 17 wherein the alkoxide is Sodium ethoxide.
  19. 19. The process according to claim 17 or 18 wherein the 2, 3-Dimethylbenzylhalide is 2, 3-Dimethylbenzylbromide.
  20. 20. The process according to any one of claims 17 to 19 wherein the preparation of 3-Dimethylbenzyl aldehyde is carried out in a polar solvent.
  21. 21. The process according to claim 20 wherein the polar solvent is Ethanol.
  22. 22. The process according to any one of claims 17 to 21 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhaljcle takes place at a temperature of at least about 5 °C.
  23. 23. The process according to claim 22 wherein the formation of 2,3-Dimethylberizy]. aldehyde from 2,3-Dimethylbenzylhaljde takes place at a temperature of from about 5 °C to about 60°C -20 -
  24. 24. The process according to claim 22 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhalide takes place at a temperature of from about 5 °C to about 40°C
  25. 25. The process according to claim 22 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhalide takes place at a temperature of from about 5 to about 30°C.
  26. 26. The process according to claim 22 wherein the formation of 2,3-Dimethylbenzyj. aldehyde from 2,3-Dimethylbenzylhalide takes place at a temperature of from about 5 to about 20°C.
  27. 27. The process according to claim 22 wherein the formation of 2,3-uimetriylbenzyl aldehyde from 2,3-Dimethylbenzylhalide takes place at a temperature of from about 10 °C to about 20°C.
  28. 28. The process according to claim 22 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhaijde takes place at a temperature of about 20 °C.
  29. 29. The process according to any one of the preceding claims wherein process step (1) is carried out in the presence of a Lewis acid.
  30. 30. The process according to claim 29 wherein the Lewis acid is a metal halide.
  31. 31. The process according to claim 30 wherein the metal halide is Titanium (IV) chloride.
    -21 -
  32. 32. The process according to any one of the preceding claims wherein process step (i) is carried out in a chlorinated solvent
  33. 33. The process according to claim 32 wherein the chlorinated solvent is anhydrous chloroform.
  34. 34. The process according to any one of the preceding claims wherein process step (i) is carried out at a temperature of less than or equal to about 45 °C.
  35. 35. The process according to claim 34 wherein process step (i) is carried out at a temperature of from about 20 to about 30°C.
  36. 36. The process according to claim 34 wherein process step (i) is carried out at a temperature of from about 20 to about 25°c.
  37. 37. The process according to claim 34 wherein process step (1) is carried out at a temperature of about 25 °C.
  38. 38. The process according to any one of the preceding claims wherein the resulting Medetomidine is converted into an acid addition salt.
  39. 39. A process of preparing Medetomidine of Formula (I): CH3 CH3 CH3)JN which comprises: (i) reacting a 2,3-Dimethylbenzylhalide with an alkoxide and 2-Nitropropane to form a 2,3-Dimethylbenzyl aldehyde; (ii) adding the 2,3-Dimethylbenzyl aldehyde to a solution of Methylmagnesium halide to form 2,3-Dimethyl-xnethylbenzylalcohol; and (iii) reacting the 2,3-Dimethyl-methylbenzylalcohol with N-Trimethylsilylimidazole in the presence of Titanium (IV) chloride in anhydrous chloroform at a temperature of less than or equal to about 45 °C. S... * S I.e. * ,
    :.: ** 20 e6a91o HFP HF? S..
    S I. * S * *5*
    S S..
    S
    39. The process according to claim 38 wherein the Medetomjdjne is converted into Medetomidjne hydrochloride.
    40. A process of preparing Medetomidine of Formula (I): -22 -CH3 CH3 CH3JN which comprises: (i) reacting 2,3-Dimethyl-methylbenzylalcohol with N-Trimethylsilyljmjdazole in the presence of a Lewis acid in a chlorinated solvent at a temperature of less than or equal to about 45 °C.
    41. A process of preparing Medetomidine of Formula (I): CH3 CH3 CH3yL1LN which comprises: (i) reacting a 2,3-Dimethylbenzylhaljde with an alkoxide and 2-Nitropropane to form a 2,3-Dimethylbenzyl aldehyde; (ii) adding the 2,3-Dimethylbenzy]. aldehyde to a solution of Methylmagnesium halide to form 2,3-Dimethyl-methylbenzylalcohol; and (iii) reacting the 2,3-Dimethyl-nlethylbenzylalcohol with N-Trimethylsilylimidazole in the presence of Titanium (IV) chloride in anhydrous chloroform at a temperature of less than or equal to about 45 °C. c)3
    Amendments to the Claims have been filed as follows Claims 1. A process of preparing Medetomidine of Formula (I): CH3 CH3 CH3LN which comprises: (i) reacting 213-Dirnethyl-methylbenzyla].cohol with N-Trimethylsilyljmjdazole.
    2. The process according to claim 1 wherein the 2,3-Dimethyl-methylbenzyl alcohol is prepared by adding 2,3-DimethylbenzyJ. aldehyde to a solution of a Grignard reagent.
    3. The process according to claim 2 wherein the Grignard reagent is Methylmagnesium chloride.
    4. The process according to claim 2 or 3 wherein the *:*::* concentration of the Grignard reagent in solution is from about 0.1 Molar to about 7 Molar. **S. * a. * . a
    * 20 5. The process according to claim 4 wherein the concentration of the Grignard reagent in solution is about 3 * Molar. * 0 * ,*.
    S
    6. The process according to any one of claims 2 to 5 wherein the preparation of 2,3-Dimethyl-methylbenzyl alcohol is carried out at a temperature of less than or equal to about 50 °C.
    7. The process according to claim 6 wherein the preparation of 2,3-Dimethyl-methylbenzy]. alcohol is carried out at a temperature of from about -10 to about 50°C.
    8. The process according to claim 6 wherein the preparation of 2,3-Dimethyl-methylbenzyl alcohol is carried out at a temperature of from about -10 to about 30°C.
    9. The process according to claim 6 wherein the preparation of Dimethyl-methylbenzy3. alcohol is carried out at a temperature of about 20°C.
    10. The process according to any one of claims 2 to 9 wherein the preparation of Diniethyl-methylbenzyl alcohol is carried out in the presence of a solvent which is Tetrahydrofuran (THF).
    11. The process according to claim 10 wherein the THF has a water content of from about 10 to about 500 ppm.
    **,*** 20 :.:: 12. The process according to claim 11 wherein the THF has a S..
    water content of from about 10 to about 250 ppm. * SS * S * *.* I
    13. The process according to claim 11 wherein the THF has a : 25 water content of from about 30 to about 150 ppm. II. -
    * 14. The process according to claim 11 wherein the THF has a water content of about lOOppm.
    15. The process according to any one of claims 2 to 14 wherein the 2,3-Dimethylbenzyl aldehyde is prepared by reacting a 2,3-Dimethylbenzylhaljde with an alkoxide and 2-Nit ropropane.
    16. The process according to claim 15 wherein the alkoxide is Sodium ethoxide.
    17. The process according to claim 15 or 16 wherein the 2, 3-Dimethylbenzylhalide is 2, 3-Dimethylbenzylbromide.
    18. The process according to any one of claims 15 to 17 wherein the preparation of 3-Dimethylbenzyi. aldehyde is carried out in a polar solvent.
    19. The process according to claim 18 wherein the polar solvent is Ethanol.
    20. The process according to any one of claims 15 to 19 wherein the formation of 2,3-DimethylbenzyJ. aldehyde from 2,3-Dimethylbenzylhaljde takes place at a temperature of at least about 5 °C. * S * S5
    21. The process according to claim 20 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhaljde takes place at a temperature of from about 5 °C to about 60°C *S.
    * 22. The process according to claim 20 wherein the formation of 2,3-Dimethylbenzyj. aldehyde from 2,3-Dimethylbenzylhaljde takes place at a temperature of from about 5 DC to about 40°C 23. The process according to claim 20 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhalide takes place at a temperature of from about 5 to about 30°C.
    24. The process according to claim 20 wherein the formation of 2,3-Dimethylbenzy]. aldehyde from 2,3-Dimethylbenzylhalicle takes place at a temperature of from about 5 to about 20°C.
    25. The process according to claim 20 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhalide takes place at a temperature of from about 10 °C to about 20°C.
    26. The process according to claim 20 wherein the formation of 2,3-Dimethylbenzyl aldehyde from 2,3-Dimethylbenzylhalide takes place at a temperature of about 20 °C.
    27. The process according to any one of the preceding claims wherein process step (1) is carried out in the *..20 presence of a Lewis acid. * I. *.** * .
    28. The process according to claim 27 wherein the Lewis : . acid is a metal halide. *
    I
    *, 25 29. The process according to claim 28 wherein the metal : halide is Titanium (IV) chloride. S..
    S
    30. The process according to any one of the preceding claims wherein process step (i) is carried out in a chlorinated solvent 31. The process according to claim 30 wherein the chlorinated solvent is anhydrous chloroform.
    32. The process according to any one of the preceding claims wherein process step (i) is carried out at a temperature of less than or equal to about 45 °C.
    33. The process according to claim 32 wherein process step (1) is carried out at a temperature of from about 20 to about 30°C.
    34. The process according to claim 32 wherein process step (i) is carried out at a temperature of from about 20 to about 25°C.
    35. The process according to claim 32 wherein process step (i) is carried out at a temperature of about 25 °C.
    36. The process according to any one of the preceding **,.20 claims wherein the resulting Medetomidine is converted into an acid addition salt.
    37. The process according to claim 36 wherein the Medetomidine is converted into Medetomidine hydrochloride.
    : 38. A process of preparing Medetomidine of Formula (I): CH3 CH3 which comprises: (i) reacting 213-Dimethyl-methylbenzylalcoho3. with N-Trimethylsilylimidazole in the presence of a Lewis acid in a chlorinated solvent at a temperature of less than or equal to about 45 °C.
GB0720891A 2007-10-24 2007-10-24 Chemical process for the preparation of Medetomidine Expired - Fee Related GB2453982B (en)

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GB0720891A GB2453982B (en) 2007-10-24 2007-10-24 Chemical process for the preparation of Medetomidine
ARP080104589A AR068952A1 (en) 2007-10-24 2008-10-22 PROCEDURE FOR THE PREPARATION OF MEDETOMIDINE
UY31415A UY31415A1 (en) 2007-10-24 2008-10-22 PROCEDURE FOR THE PREPARATION OF MEDETOMIDINE
PE2008001820A PE20091088A1 (en) 2007-10-24 2008-10-23 PROCESS FOR THE PREPARATION OF MEDETOMIDINE
CL2008003185A CL2008003185A1 (en) 2007-10-24 2008-10-24 Procedure for the preparation of medetomidine that considers the coupling between a silyimidazole and a derivative of benzyl alcohol.
PCT/GB2008/003613 WO2009053709A1 (en) 2007-10-24 2008-10-24 Process for the preparation of medetomidine

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WO2011070069A1 (en) 2009-12-09 2011-06-16 I-Tech Ab Process for preparation of medetomidine
CN101921234B (en) * 2009-06-12 2012-05-30 中国中化股份有限公司 Method for preparing dexmedetomidine
WO2013011155A3 (en) * 2012-05-08 2013-04-04 Lonza Ltd Method for preparation of medetomidine
WO2012172119A3 (en) * 2012-05-08 2013-04-04 Lonza Ltd Method for the preparation of medetomidine
US20150099889A1 (en) * 2012-06-28 2015-04-09 Lonza Ltd Method for preparation of medetomidine with chloroacetone
US9126914B1 (en) 2012-06-28 2015-09-08 Lonza Ltd. Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal with chloroacetone
US9126915B2 (en) 2012-05-08 2015-09-08 Lonza Ltd. Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal

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KR101932206B1 (en) * 2011-07-22 2018-12-24 캠브렉스 칼스코가 아베 New processes for preparing 4-substituted imidazoles
CN106588777A (en) * 2015-10-16 2017-04-26 江苏开元医药化工有限公司 Industrial preparation method of dexmedetomidine hydrochloride
WO2023182903A1 (en) 2022-03-22 2023-09-28 Общество с ограниченной ответственностью "ВИК-здоровье животных" Method for producing medetomidine and its derivatives
CN114671811A (en) * 2022-04-14 2022-06-28 南京正科医药股份有限公司 Racemization recovery method of dexmedetomidine resolution byproduct

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CN101921234B (en) * 2009-06-12 2012-05-30 中国中化股份有限公司 Method for preparing dexmedetomidine
CN102753532A (en) * 2009-12-09 2012-10-24 I-技术有限公司 Process for preparation of medetomidine
WO2011070069A1 (en) 2009-12-09 2011-06-16 I-Tech Ab Process for preparation of medetomidine
CN102753532B (en) * 2009-12-09 2015-05-13 I-技术有限公司 Process for preparation of medetomidine
CN104245679B (en) * 2012-05-08 2016-03-02 隆萨有限公司 The preparation method of medetomidine
WO2013011155A3 (en) * 2012-05-08 2013-04-04 Lonza Ltd Method for preparation of medetomidine
WO2012172119A3 (en) * 2012-05-08 2013-04-04 Lonza Ltd Method for the preparation of medetomidine
CN104245679A (en) * 2012-05-08 2014-12-24 隆萨有限公司 Method for preparation of medetomidine
US9045433B2 (en) 2012-05-08 2015-06-02 Lonza Ltd. Method for preparation of medetomidine
EA025950B1 (en) * 2012-05-08 2017-02-28 Лонца Лтд. Method for preparation of medetomidine
US9126915B2 (en) 2012-05-08 2015-09-08 Lonza Ltd. Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal
US20150099889A1 (en) * 2012-06-28 2015-04-09 Lonza Ltd Method for preparation of medetomidine with chloroacetone
US9156793B2 (en) 2012-06-28 2015-10-13 Lonza Ltd. Method for preparation of medetomidine with chloroacetone
US9434694B2 (en) 2012-06-28 2016-09-06 Lonza Ltd. Method for preparation of medetomidine with chloroacetone
US9126914B1 (en) 2012-06-28 2015-09-08 Lonza Ltd. Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal with chloroacetone

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