WO2009053709A1 - Procede de preparation de medetomidine - Google Patents

Procede de preparation de medetomidine Download PDF

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Publication number
WO2009053709A1
WO2009053709A1 PCT/GB2008/003613 GB2008003613W WO2009053709A1 WO 2009053709 A1 WO2009053709 A1 WO 2009053709A1 GB 2008003613 W GB2008003613 W GB 2008003613W WO 2009053709 A1 WO2009053709 A1 WO 2009053709A1
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WO
WIPO (PCT)
Prior art keywords
process according
temperature
medetomidine
dimethylbenzyl
aldehyde
Prior art date
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PCT/GB2008/003613
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English (en)
Inventor
Rasik Somaiya
Muhammad Raza
Jonathan Cranke
Kristian Bragg
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Norbrook Laboratories Limited
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Publication of WO2009053709A1 publication Critical patent/WO2009053709A1/fr

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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
    • 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
    • A61P25/04—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • 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

Definitions

  • the present invention relates to a process for the preparation of 4- [1- (2 , 3-dimethylphenyl) ethyl] -IH- imidazole of the 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-lH-indeny-2-yl) -IH- imidazole, also known as Atipamezole, a 2-adrenergic receptor antagonist.
  • 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 2 , 3-dimethylmagnesium bromide ; (ii) heating 4-imidazolecarboxylic acid methyl ester in dry THF to about 50 0 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-[[ ⁇ -(2,3- dimethylphenyl) ⁇ t-methyl] hydroxymethyl] imidazole; (iv) heating the 4- [ [a- (2 , 3-dimethylphenyl) a- methyl] hydroxymethyl] imidazole to 136 0 C with potassium hydrogen sulphate to form 1- (4-imidazolyl) -1- (2 , 3-
  • 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) - [1- (2 , 3-dimethylphenyl) ethyl] - lH-imidazole, the Ot 2 -adrenergic agonist Medetomidine", pp 1021 and 1022 (1991) .
  • This process has the disadvantage of requiring that the reaction process takes place at a temperature of -78 0 C in the presence of butyl lithium which is highly flammable and corrosive .
  • 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) :
  • Medetomidine is then converted into an acid addition salt.
  • the hydrochloride salt of Medetomidine of Formula (I) is formed using concentrated hydrochloric acid.
  • the 2 , 3-dimethyl-methylbenzyl alcohol is reacted with N-trimethylsilylimidazole 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 .
  • the Lewis acid is titanium (IV) chloride.
  • the chlorinated solvent can be, for example, Chloroform, methylene chloride or 1, 2-dichloroethane .
  • the chlorinated solvent is anhydrous, more preferably the chlorinated solvent is anhydrous Chloroform, anhydrous methylene chloride or anhydrous 1 , 2-dichloroethane, most preferably anhydrous methylene chloride.
  • Anhydrous defines where the water content is less than about 250 ppm of water, preferably less than about 100 ppm.
  • the reaction mixture may, for example, be worked up with a chlorinated solvent .
  • suitable chlorinated solvents include Chloroform, methylene chloride, 1,2- dichloroethane, anhydrous Chloroform, anhydrous methylene chloride, or anhydrous 1, 2-dichloroethane .
  • the chlorinated solvent is either Chloroform or methylene chloride, even more preferably methylene chloride and most preferably anhydrous methylene chloride.
  • Anhydrous defines where the water content is less than about 250 ppm of water, preferably less than about 100 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 may, for example, take place at a temperature of less than or equal to about 45 0 C, preferably at a temperature of from about 5 to about 35 0 C, more preferably at a temperature range of from about 10 to about 35 0 C, even more preferably at a temperature of from about 20 to about 35 0 C, still even more preferably at a temperature range of from about 20 to about 30 0 C, yet even more preferably at a temperature range of from about 20 to 25 0 C and most preferably at a temperature of about 25 0 C.
  • the typical reaction time is typically 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, for example, present in excess of the dimethyl-methylbenzyl alcohol.
  • N-trimethylsilylimidazole is from 1:2 molar to 1:8 molar, for example, about 1:2 molar to about 1:6 molar, about 1:2 molar to about 1:5 molar, even more preferably 1:2 molar to about 1:4 molar and most preferably about 1:3 molar.
  • the Lewis acid when a Lewis acid is present the Lewis acid is generally present in excess of the dimethyl-methylbenzyl alcohol.
  • the ratio of dimethyl-methylbenzyl alcohol: Lewis acid is about 1:2 molar to about 1:8 molar, for example about 1:2 molar to about 1:6 molar, about 1:2 molar to about 1:5 molar, about 1:2 molar to about 1:3.5 molar and most preferably about 1:2.2 molar.
  • 3 -dimethyl -methylbenzyl alcohol is reacted with N-trimethylsilylimidazole in the presence of a Lewis acid in a chlorinated solvent, preferably an anhydrous chlorinated solvent, and most preferably anhydrous methylene chloride.
  • 3-dimethyl-methylbenzyl alcohol is reacted with N-trimethylsilylimidazole in the presence of titanium (IV) chloride in a chlorinated solvent, preferably an anhydrous chlorinated solvent, and most preferably anhydrous methylene chloride.
  • a chlorinated solvent preferably an anhydrous chlorinated solvent, and most preferably anhydrous methylene chloride.
  • 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.
  • a Grignard reagent optionally in a solvent, such as tetrahydrofuran (THF)
  • 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.
  • R is methyl
  • X is chlorine, bromine or iodine, preferably chlorine .
  • the Grignard reagent is a methylmagnesium halide. Suitable examples include methylmagnesium bromide, methylmagnesium iodide or methylmagnesium 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 generally about 0. IM to about 7M, preferably from about IM to about 5M, more preferably from about 2M to about 4M and most preferably about 3M.
  • suitable solvents include tetrahydrofuran, dioxanes, ethers such as diethyl ether, toluene, hexane and heptane.
  • the solvent is tetrahydrofuran (THF) .
  • THF tetrahydrofuran
  • the THF has a preferred range of water content from about 10 to about 500 ppm , preferably from about 10 to about 250 ppm, more preferably from about 30 to about 150 ppm, and most preferably with less than about 100 ppm of water.
  • Anhydrous is defined where the water content is less than about 250 ppm , preferably less than about 100 ppm.
  • reaction is carried out under an inert atmosphere such as nitrogen, argon or helium.
  • the reaction mix may, for example, be worked up with a chlorinated solvent.
  • a chlorinated solvent is Chloroform or methylene chloride.
  • This reaction step of preparing 2, 3 -dimethyl -methylbenzyl alcohol generally takes place at a temperature of less than or equal to about 50 0 C, preferably at a temperature of from about -10 to about 50 0 C, more preferably at a temperature of from about -10 to about 30 0 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
  • 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, for example, 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.
  • the 2 , 3 -dimethyl -methylbenzyl alcohol is prepared by adding 2 , 3-dimethylbenzyl aldehyde to a solution of methylmagnesium chloride in THF.
  • the 2 , 3 -dimethyl - methylbenzyl alcohol is prepared by adding 2,3- dimethylbenzyl aldehyde to methylmagnesium chloride at 3M in THF 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 0 C, even more preferably at a temperature range of from about -10 to about 20 0 C, even more preferably at a temperature of from about 0 to about
  • 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.
  • 3-dimethylbenzyl aldehyde has the following structure:
  • the alkoxide used may, for example, be sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium tertbutoxide or potassium tertbutoxide .
  • the alkoxide is sodium ethoxide.
  • the reaction mixture may, for example, be 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 polar solvent may, for example, be a C 2 to C 6 alcohol.
  • suitable C 2 to C 6 alcohols include, Industrial methylated spirit (IMS), ethanol or propanol . Ethanol is preferred.
  • the alkoxide is sodium ethoxide
  • the 2 , 3-dimethylbenzylhalide is 2
  • 3-dimethylbenzylbromide 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 0 C, even more preferably at a temperature of from about 5 to about 30 0 C, yet even more preferably at a temperature of from about 5 to about 20 0 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 0 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 generally present in a 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.
  • the reactants used can, for example, 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.
  • the Medetomidine of Formula (I) is prepared by a process which comprises:
  • 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 .
  • Medetomidine can be converted into an acid addition salt from both organic and inorganic acids using standard methods.
  • the acid addition salt which can be formed is, for instance, a hydrochloride.
  • the acid addition salt of Medetomidine which can be formed is a hydrochloride as it is more stable and most cost effective.
  • hydrochloride salt (formula II) of Medetomidine can be prepared using concentrated hydrochloric acid.
  • Concentrated hydrochloric acid is comparatively easy to handle, less toxic and is more cost effective.
  • the concentration range of hydrochloric acid is generally from about 25 to about 36%, more preferably from about 35 to about 36%, and most preferably about 36%.
  • 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 0 C to about 150 0 C, preferably at a temperature of from about 120 0 C to about 130 0 C, thus distilling off excess water.
  • the distillation of water is continued until no more water is distilled.
  • a Dean-Stark apparatus can be used.
  • 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.
  • the wet product is dried in vacuum at a temperature of from about 50 0 C to about 100 0 C, more preferably from about 60 to 90 0 C, even more preferably from about 75 to about 90 0 C, and most preferably 80 0 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.
  • the product can be purified by repeating the above step or by any other suitable process, for example crystallisation, chromatography or solvent slurry.
  • any other suitable process for example crystallisation, chromatography or solvent slurry.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Pain & Pain Management (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

L'invention concerne un procédé de préparation de médétomidine de formule (I) :, ou un sel d'addition acide de celle-ci. Ce procédé consiste : (i) à mettre en réaction de l'alcool 2,3-diméthyl-méthylbenzylique avec N-triméthylsilylimidazole et, éventuellement, à convertir la médétomidine en un sel d'addition acide.
PCT/GB2008/003613 2007-10-24 2008-10-24 Procede de preparation de medetomidine WO2009053709A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0720891.1 2007-10-24
GB0720891A GB2453982B (en) 2007-10-24 2007-10-24 Chemical process for the preparation of Medetomidine

Publications (1)

Publication Number Publication Date
WO2009053709A1 true WO2009053709A1 (fr) 2009-04-30

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PCT/GB2008/003613 WO2009053709A1 (fr) 2007-10-24 2008-10-24 Procede de preparation de medetomidine

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AR (1) AR068952A1 (fr)
CL (1) CL2008003185A1 (fr)
GB (1) GB2453982B (fr)
PE (1) PE20091088A1 (fr)
UY (1) UY31415A1 (fr)
WO (1) WO2009053709A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014428A1 (fr) 2011-07-22 2013-01-31 Cambrex Karlskoga Ab Nouveaux procédés pour la préparation d'imidazoles 4-substitués
CN106588777A (zh) * 2015-10-16 2017-04-26 江苏开元医药化工有限公司 一种盐酸右美托咪定的工业化制备方法
WO2023182903A1 (fr) 2022-03-22 2023-09-28 Общество с ограниченной ответственностью "ВИК-здоровье животных" Procédé de production de médétomidine et de ses dérivés

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101921234B (zh) * 2009-06-12 2012-05-30 中国中化股份有限公司 一种制备美托咪啶的方法
CN102753532B (zh) * 2009-12-09 2015-05-13 I-技术有限公司 美托咪定的制备方法
SG11201405611SA (en) 2012-05-08 2014-11-27 Lonza Ag Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal
EA025950B1 (ru) * 2012-05-08 2017-02-28 Лонца Лтд. Способ получения медетомидина
WO2012172119A2 (fr) * 2012-05-08 2012-12-20 Lonza Ltd Procédé de préparation de médétomidine
AU2012285678B2 (en) 2012-06-28 2016-02-25 Lonza Ltd Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal with chloroacetone
JP5777841B2 (ja) * 2012-06-28 2015-09-09 ロンザ・リミテッド クロロアセトンを用いてメデトミジンを調製するための方法
CN114671811A (zh) * 2022-04-14 2022-06-28 南京正科医药股份有限公司 一种右美托咪定拆分副产物的外消旋化回收方法

Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0072615A1 (fr) * 1981-07-10 1983-02-23 Farmos Group Ltd. Dérivés d'imidazole substitués, leur application et utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0072615A1 (fr) * 1981-07-10 1983-02-23 Farmos Group Ltd. Dérivés d'imidazole substitués, leur application et utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUDZMA L V ET AL: "Expedient synthesis of 4(5)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazo le, the [alpha]2-adrenergic agonist medetomidine", SYNTHESIS 1991 DE, no. 11, 1991, pages 1021 - 1022, XP002511098, ISSN: 0039-7881 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014428A1 (fr) 2011-07-22 2013-01-31 Cambrex Karlskoga Ab Nouveaux procédés pour la préparation d'imidazoles 4-substitués
CN103748077A (zh) * 2011-07-22 2014-04-23 坎布雷卡尔斯库加公司 用于制备4-取代咪唑类的新方法
KR20140068888A (ko) * 2011-07-22 2014-06-09 캠브렉스 칼스코가 아베 4-치환 이미다졸의 신규 제조방법
JP2014520901A (ja) * 2011-07-22 2014-08-25 カンブレックス カルルスクーガ アクチ ボラケット ４−置換イミダゾールの新規な調製プロセス
US8962862B2 (en) 2011-07-22 2015-02-24 Cambrex Karlskoga Ab Processes for preparing 4-substituted imidazoles
CN103748077B (zh) * 2011-07-22 2016-08-17 坎布雷卡尔斯库加公司 用于制备4-取代咪唑类的方法
CN106588777A (zh) * 2015-10-16 2017-04-26 江苏开元医药化工有限公司 一种盐酸右美托咪定的工业化制备方法
WO2023182903A1 (fr) 2022-03-22 2023-09-28 Общество с ограниченной ответственностью "ВИК-здоровье животных" Procédé de production de médétomidine et de ses dérivés

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CL2008003185A1 (es) 2009-03-06
AR068952A1 (es) 2009-12-16
GB2453982B (en) 2009-09-16
PE20091088A1 (es) 2009-07-20
UY31415A1 (es) 2009-05-29
GB2453982A (en) 2009-04-29
GB0720891D0 (en) 2007-12-05

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