NZ700640B2

NZ700640B2 - Method for preparation of medetomidine

Info

Publication number: NZ700640B2
Application number: NZ700640A
Authority: NZ
Inventors: Robert Bujok; Stephan Elzner; Anna Kulesza; Krzysztof Wojciechowski; Zbigniew Wrobel; Doerwald Florencio Zaragoza
Original assignee: Lonza Ltd
Priority date: 2012-05-08
Filing date: 2012-11-15
Publication date: 2016-07-01

Abstract

The technical problem of the invention relates to a method for the preparation of medetomidine starting from 1-bromo-2,3-dimethylbenzene and acetone. Medetomidine is the compound of formula (XX) and is an alpha2 adrenergic agonist, which is currently being used as a veterinary sedative and analgesic and is evaluated as anesthetic. The solution to the problem involves a method which comprises a step (N) and a step (M1); step (M1) comprises a reaction (M1-reac); reaction (M1-reac) is a reaction between a compound selected from the group consisting of a compound of formula (XXI), a hydrate of the compound of formula (XXI) and a hemiacetal of the compound of formula (XXI); said hemiacetal of the compound of formula (XXI) being the product of an addition reaction between the aldehyde as depicted in formula (XXI) and an alcohol selected from the group consisting of tert-butanol and isopropanol, and a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv); reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof; reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof; solvent (M-solv) is selected from the group consisting of N,N-dimethylformamide, C1-6 alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof; and wherein the compound of formula (XXI) is prepared in the step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of a compound of formula (XXII) with a catalyst (N-cat); catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O-C1-4 alkyl)3, SnCl4, TiCl4, Ti(O C1-4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures thereof. and is evaluated as anesthetic. The solution to the problem involves a method which comprises a step (N) and a step (M1); step (M1) comprises a reaction (M1-reac); reaction (M1-reac) is a reaction between a compound selected from the group consisting of a compound of formula (XXI), a hydrate of the compound of formula (XXI) and a hemiacetal of the compound of formula (XXI); said hemiacetal of the compound of formula (XXI) being the product of an addition reaction between the aldehyde as depicted in formula (XXI) and an alcohol selected from the group consisting of tert-butanol and isopropanol, and a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv); reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof; reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof; solvent (M-solv) is selected from the group consisting of N,N-dimethylformamide, C1-6 alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof; and wherein the compound of formula (XXI) is prepared in the step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of a compound of formula (XXII) with a catalyst (N-cat); catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O-C1-4 alkyl)3, SnCl4, TiCl4, Ti(O C1-4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures thereof.

Description

WO 11155 METHOD FOR PREPARATION OF MEDETOMIDINE The invention discloses a method for the preparation ofmedetomidine starting from I-bromo 2,3-dimethylbenzene and acetone.

Medetomidine is the compound ula (XX) and is an alpha2 adrenergic agonist, which is currently being used as veterinary sedative and analgesic and is evaluated as anesthetic.

~ (XX) Medetomidine is a 4-alkylimidazole. 4-Alkylimidazoles without additional substituents at the nitrogen moiety are usually es oftwo tautomers. For instance, in the case of medetomidine, two tautomeric forms, represented by compound ula (XX) and compound ula (XX-T), (XX-T) will usually interconvert ifmedetomidine is dissolved or in a non-crystalline state. Ifone of the tautomeric forms prevails or ifthey are present in equal amounts is dependent on various factors, such as pH, solvent or temperature.

In the text, formula (XX) is used for medetomidine, and is meant to comprise both tautomeric forms as well as their mixture.

US 2010/0048915 A ses a method for the preparation tomidine by reaction of halogenated oles with 2,3-dimethylbenzaldehyde using Grignard reagents.

Cordi et ai., Synth. Commun. 1996,26, 1585-1593, discloses the preparation of medetomidine by reaction of4-imidazolcarboxaldehyde with 2,3-dimethylphenylmagnesium bromide.

WO 00/42851 A discloses the use of medetomidine for inhibition of marine biofouling on surfaces.

Previously disclosed methods of preparation of medetomidine often use protecting groups, for example triphenylmethyl (trityl) residues, which entails high material consumption and the need for protection/deprotection steps. Consequently, these syntheses are long and expensive.

Furthermore rather ive and non-readily available starting materials are used.

There was a need for a synthetic route, which does not need protecting groups, starts with less expensive substrates, avoids large amounts of waste and has satisfying yields.

In the following text, halogen means F, Cl, Br or I, preferably Cl, Br or I; "alkyl" means linear or branched alkyl; if not ise stated. Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and the like; "cyclic alkyl" or "cyclo alkyl" are intended to include cyclo aliphatic, bicyclo tic and tricycle aliphatic residues; "alkane" means a linear or branched alkane; "alkanol" means a hydroxyalkane, with alkane having the meaning as d above also with its preferred embodiments; Ac acetyl; tBu tertiary butyl; DBU 1,8-diazabicyclo[5.4.0]undecene; DABCO 1,4-diazabicyclo[2.2.2]octane; DIPEA N-ethyl-N,N-diisopropylamine; DMA N,N-dimethylacetamide; DMF N,N-dimethylformamide; EDTA-Na2 ethylene diamine tetraacetic acid disodium; hexanes mixture of isomeric s; NMP ylpyrrolidone; OTf trifluoromethanesulfonate, also known as triflate; MPS KHSO5, also known as potassium peroxymonosulfate or ium monopersulfate, and marketed as a triple salt with the formula 2 KHSO5 KHSO4 K2SO4 under the trade names Caroat® and Oxone®, therefore KHSO5 is often used in form of this triple salt; salen ligand obtained from a condensation of salicylaldehyde or of a substituted laldehyde derivative with ethylene diamine or with a substituted ne diamine; sulfamic acid HO-SO2-NH2; TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl; THF tetrahydrofuran; xylene 1,2-dimethylbenzene, 1,3-dimethylbenzene, l,4-dimethylbenzene or a mixture thereof; if not otherwise stated.

Subject of the invention is a method for preparation of medetomidine, the method comprises a step (N) and a step (M1); step (M1) comprises a reaction (M1-reac); reaction ac) is a on between a compound selected from the group consisting of compound of formula (XXI), the hydrate of compound of formula (XXI) and a hemiacetal of compound of a (XXI), said hemiacetal of compound of formula (XXI) being the product of an addition reaction n the aldehyde as depicted in formula (XXI) and an alcohol selected from the group consisting of tert-butanol and isopropanol, and a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv); reagent (M-reag) is selected from the group ting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, amidobenzenesulfonylmethyl isocyanide and mixtures thereof; reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p- toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and es thereof; solvent v) is selected from the group consisting ofN,N-dimethylformamide, C I-6 alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof; and wherein nd of formula (XXI) is prepared in the step (N); step (N) ses a reaction (N-reac); reaction (N-reac) is a reaction ound offormula (XXII) with a catalyst (N-cat); (XXII) catalyst (N-cat) is selected from the group ting ofacetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCI, HBr, H2S04, HN03, H3P04, HCI04, BCh, BBr3, BF30Et2, BF3SMe2, BF3THF, MgClz, MgBr2' MgJz, AICh, AI(O-C I _4 alkyl)3, SnCI4, TiCI4, Ti(O-CI _4 alkyl)4, ZrCI4, Bi20 3, BiCh, ZnClz, PbClz, FeCh, ScCh, NiClz, Yb(OTf)3, Yb(CI)3, GaCh, AlBr3, Ce(OTf)3, LiCI, Cu(BF4)2, CU(OTf)2, NiBr2(PPh3)2, NiBr2, NiClz, Pd(OAc)2, PdClz, PtClz, InCh, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures f.

Preferably, reagent (M-reag) is selected from the group consisting ofp-toluenesulfonylmethyl nide, benzenesulfonylmethyl isocyanide and mixtures thereof; more preferably, reagent (M-reag) is p-toluenesulfonylmethyl isocyanide.

Preferably, reagent (M-A) is selected from the group consisting ofammonia, ic acid, ptoluenesulfonamide , benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide and mixtures thereof; more ably, reagent (M-A) is selected from the group consisting ofammonia, ptoluenesulfonamide , benzenesulfonamide, formamide, 4- acetamidobenzenesulfonamide, amine and mixtures thereof; even more preferably, reagent (M-A) is selected from the group consisting ofammonia, p- toluenesulfonamide, formamide, and mixtures thereof; especially, reagent (M-A) is ammonia or formamide.

Preferably, solvent (M-solv) is selected from the group consisting ofN,N- dimethylformamide, methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, water, formamide, 1,2-dimethoxyethane, NMP, toluene, itrile, propionitrile, ethyl ate, N,N-dimethylacetamide, acetamide and mixtures thereof; more preferably, solvent (M-solv) is selected from the group ting ofN,N- dimethylformamide, methanol, ethanol, ethyl carbamate, ide, acetamide and mixture thereof. ably, reaction (M l-reac) is done in the presence ofa compound (M-comp), compound (M-comp) is ed from the group consisting ofammonia, tritylamine, NaCN, KCN, piperidine, DBU, DABCO, triethylamine, tributylamine, 4- dimethylaminopyridine, pyridine, tBuOK, tBuONa, NaHC03, Na2C03, (NH4)HC03, (NH4)2C03, KHC03, K2C03, NaOAc, KOAc, NaOH, KOH, Ca(OH)2, KF and mixtures thereof; preferably, compound (M-comp) is selected from the group consisting nia, tritylamine, NaCN, KCN, piperidine, tBuOK, tBuONa, KOH, K2C03, Na2C03, KF and mixtures thereof; more preferably, compound (M-comp) is selected from the group consisting of ammonia, NaCN, KCN, piperidine, tBuOK, tBuONa, K2C03, Na2C03, KF and mixtures thereof; even more preferably, compound (M-comp) is selected from the group consisting of a, NaCN, K2C03, tBuOK, tBuONa, Na2C03 and mixtures thereof; especially, compound (M-comp) is selected from the group ting ofammonia, NaCN, tBuOK, tBuONa, Na2C03 and mixtures thereof; more especially, compound (M-comp) is NaCN or ammonia.

The reagent (M-A) can be used as such or in form ofa solution in a solvent (M-A). Solvent (M-A) is identical or different from solvent (M-solv), preferably identical, and comprises the same group ofsolvents as solvent (M-solv), also with respect to all ofthe red embodiments ofsolvent (M-solv).

When t (M-A) is ammonia, then reagent (M-A) is ably used in form of a solution, preferably in form ofa solution in methanol.

In case ofethyl carbamate, formamide and acetamide, reagent (M-A) can be cal with solvent (M-solv) and can be used as solvent (M-solv).

Preferably, the reaction temperature ofreaction (Ml-reac) is from -10 to 250°C, more preferably from 0 to 200 °C, even more preferably from 10 to 180°C.

The reaction (M ) can be done in a system, that is closed or open to the atmosphere; preferably the reaction (M 1-reac) is done in a closed .

In a closed system, the pressure depends mainly on the boiling point ofthe solvent (M-solv), on the amount nia used, and on the reaction temperature ofreaction (M1- reac); preferably, the reaction (Ml-reac) is done at a pressure offrom atmospheric pressure to 20 bar, more preferably offrom atmospheric pressure to 10 bar, even more preferably offrom atmospheric pressure to 5 bar.

Preferably, the reaction time ofreaction (Ml-reac) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more ably from 2 h to 24 h.

Reaction (Ml-reac) may be ted at a constant temperature, or the temperature may be modified during the progress ofthe reaction. For instance, the reaction may be run for a certain time at first temperature, and then for a given time at second temperature different from the first temperature; alternatively, the temperature may be modified continuously during the reaction.

Preferably, from 1.0 to 10 mol lents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents ofreagent (M-reag) are used, the mol equivalents being based on the mol of compound offormula (XXI).

When one or more reagents (M-A) different from ammonia, formamide and ethyl carbamate are used, the total amount ofsubstances different from ammonia, formamide and ethyl carbamate used as reagent (M-A) is preferably from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents, the mol equivalents being based on the mol ound of formula (XXI).

When ammonia, formamide, ethyl carbamate or mixtures thereof are used as reagent (M-A), preferably from 1.0 to 100 mol equivalents, more preferably from 1.1 to 50 mol lents, even more ably from 1.1 to 30 mol equivalents ofammonia, formamide, ethyl carbamate or mixtures thereof are used, the mol equivalents being based on the mol of compound offormula (XXI).

When one or more substances selected from the group ammonia, ide and ethyl carbamate, and one or more substances different from ammonia, formamide and ethyl carbamate are used as reagent (M-A), the given amounts for ammonia, formamide and ethyl carbamate, and the given amounts for the one or more substances different from a, formamide and ethyl carbamate, add up to the total amount ofreagent (M-A); the total amount ofreagent (M-A) is preferably from 1.0 to 100 mol equivalents, more preferably from 1.1 to 50 mol equivalents, even more ably from 1.1 to 30 mol equivalents, the mol equivalents being based on the mol of compound offormula (XXI).

Preferably from 1 to 15 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents ofcompound (M-comp) are used, the mol equivalents being based on the mol of compound offormula (XXI). ably, the amount ofsolvent (M-solv) is from 0.5 to 20 fold, more ably from 1 to fold, even more preferably offrom 2 to 5 fold, ofthe weight ofcompound offormula (XXI).

Preferably, the reaction (Ml-reac) is done under inert atmosphere.

When amine is used as t (M-A), the product ofreaction (Ml-reac) may be N-trityl medetomidine and the trityl residue would have to be removed. 2012/072796 Preferably in this case, the method for preparation ofmedetomidine comprises a further step (M2); step (M2) is done after step (Ml); step (M2) ses a on (M2-reac); reaction (M2-reac) is the treatment ofthe product ofreaction (Ml-reac) with an acid (M-acid detrit). Acid (M-acid detrit) is preferably selected from the group consisting ofacetic acid, propionic acid, formic acid, Hel or mixtures thereof.

Acid (M-acid detrit) can be used as an aqueous solution.

Any sequence ofthe reaction ofreagent (M-reag) and ofreagent (M-A) with the nd of formula (XXI) in reaction (Ml-reac) can be used: compound offormula (XXI) can first be reacted with reagent (M-reag) and then t (MA ) added; compound ula (XXI) can first be reacted with reagent (M-A) and then t (M- reag) added; or compound offormula (XXI) can simultaneously be d with t (M-reag) and with reagent (M-A), this embodiment is preferably suited for the case that reagent (M-A) and solvent (M-solv) are identical and are formamide, ethyl carbamate or acetamide; preferably formamide.

Preferably, compound offormula (XXI) is first reacted with reagent (M-reag) and then reagent (M-A) added; compound offormula (XXI) is simultaneously d with reagent (M-reag) and with reagent (M-A).

Step (Ml) can therefore be done in three alternatives, the three alternatives are alternative (MI-Al), alternative (MI-A2) and alternative (MI-A3).

Alternative (MI-Al) comprises two steps, a step (MI-Al-l) and a step -2); step (MI-Al-l) comprises a reaction (MI-Al-l); reaction (MI-Al-l) is a reaction of compound offormula (XXI) with reagent (M-reag) in the presence ofcompound (M-comp) and in a solvent (M-solv); step (MI-AI-2) comprises a reaction (MI-AI-2). on (MI-AI-2) is a reaction ofthe reaction product ofreaction (MI-Al-l) with reagent (M-A) in the presence ofcompound (M-comp) and in a solvent (M-solv).

Preferably, the reaction temperature ofreaction (MI-Al-l) is from -10 to 250°C, more preferably from 0 to 200 °C, even more preferably from 10 to 180°C.

Preferably, the reaction temperature ofreaction (MI-AI-2) is from 20 to 250°C, more preferably from 50 to 200 °C, even more preferably from 80 to 180°C. ably from 0.01 to 1 mol equivalents, more preferably from 0.1 to 0.5 mol equivalents, even more ably from 0.2 to 0.3 mol lents of compound (M-comp) are used in reaction (MI-Al-l), the mol equivalents being based on the mol ofcompound offormula (XXI).

Preferably from 1 to 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even more preferably from 1 to 3 mol equivalents ofcompound (M-comp) are used in reaction (MI-AI-2), the mol equivalents being based on the mol ofcompound offormula (XXI).

Alternative (MI-A2) comprises two steps, a step -1) and a step (MI-A2-2); step (MI-A2-1) comprises a reaction (MI-A2-1); reaction (MI-A2-1) is a reaction ofcompound offormula (XXI) with reagent (M-A) in a solvent (M-solv); step (MI-A2-2) comprises a on (MI-A2-2). reaction (MI-A2-2) is a reaction ofthe on t ofreaction (MI-A2-1) with reagent (M-reag) in the presence ofcompound (M-comp) and in a solvent (M-solv).

Preferably, the reaction temperature ofreaction -1) is from 0 to 250°C, more ably from 10 to 200 °C, even more preferably from 20 to 180°C.

Preferably, the reaction temperature ofreaction (MI-A2-2) is from -10 to 250°C, more preferably from 0 to 200 °C, even more ably from 20 to 180°C.

In case ofreagent (M-A) not being ammonia and tritylamine, reaction (MI-A2-1) can be done in the presence of an acid (MI-A2-1); acid (MI-A2-1) is selected from the group consisting ofp-toluenesulfonic acid, methanesulfonic acid and benzenesulfonic acid; preferably from 0.01 to 1 mol equivalents, more preferably from 0.05 to 0.5 mol equivalents, even more preferably from 0.1 to 0.3 mol lents ofacid (MI-A2-1) are used in reaction (MI-A2-1), the mol equivalents being based on the mol ofcompound offormula (XXI).

Preferably from 1 to 10 mol equivalents, more ably from 1 to 5 mol equivalents, even more preferably from 1 to 3 mol equivalents ound (M-comp) are used in reaction (MI-A2-2), the mol equivalents being based on the mol ofcompound offormula (XXI).

Alternative (MI-A3) comprises a step (MI-A3-1) step (MI-A3-1) comprises a reaction (MI-A3-1); reaction (MI-A3-1) is a on of compound offormula (XXI) with reagent (M-reag) and with with reagent (M-A) in a solvent (M-solv).

Preferably, the reaction temperature ofreaction (MI-A3-1) is from 0 to 250°C, more preferably from 20 to 200 °C, even more preferably from 50 to 180°C.

Reaction (MI-A3-1) can be done in the presence ofcompound (M-comp); preferably from 1 to 10 mol lents, more preferably from 1 to 5 mol equivalents, even more preferably from 1 to 3 mol equivalents ofcompound (M-comp) are used in reaction (MI-A3-1), the mol equivalents being based on the mol of nd offormula (XXI).

In case of all these three alternatives, reagent (M-reag), reagent (M-A), compound (M-comp) and solvent (M-solv) are as defined herein, also with all their preferred embodiments.

When the reaction (Ml-reac) is completed, medetomidine can be isolated by standard methods such as evaporation ofvolatile ents, extraction, washing, drying, concentration, filtration, crystallization, distillation, tography and any combination thereof. ably, the volatile components ofthe reaction mixture are removed by evaporation under d pressure. ably, the reaction mixture resulting from reaction (Ml-reac) or the reaction mixture resulting from reaction (M2-reac) can be extracted with a solvent (M-extract), solvent (M-extract) is preferably selected from the group consisting ofwater, toluene, benzene, , chlorobenzene, dichloromethane, chloroform, acetic acid CI-8 alkyl ester and ations thereof; the acetic acid CI-8 alkyl ester is preferably an acetic acid CI-4 alkyl ester, more preferably selected from the group consisting ofethyl acetate, pyl acetate and butyl acetate; preferably solvent ract) is selected from the group consisting of toluene, dichloromethane, ethyl acetate, pyl acetate and mixtures thereof.

The extraction can be ed by filtration and concentration of the extract.

Preferably, after an extraction with a t (M-extract), the extract resulting from the extraction with solvent (M-extract) can be extracted with an aqueous solution of an acid (M- acid). Acid d) is preferably selected from the group consisting of oxalic acid, citric acid, maleic acid, fumaric acid, tartaric acid, NH4Cl, HCl, HBr, H2SO4, H3PO4 and mixtures thereof.

The extract resulting from the extraction with an aqueous solution of acid (M-acid) can be washed with a solvent (M-wash).

Preferably, solvent (M-wash) is selected from the group consisting of toluene, benzene, xylene, chlorobenzene, dichloromethane, chloroform, acetic acid C1-8 alkyl ester and mixtures thereof; the acetic acid C1-8 alkyl ester is preferably an acetic acid C1-4 alkyl ester, more preferably selected from the group consisting of ethyl acetate, pyl acetate and, butyl acetate.

The product can be isolated by concentration of the extract, that was washed with solvent (M- wash).

In one embodiment, the t ion is a method for the preparation of medetomidine, the method comprises a step (N) and a step (M1); step (M1) comprises a reaction (M1-reac); reaction (M1-reac) is a reaction between a compound selected from the group consisting of a compound of formula (XXI), a hydrate of the compound of formula (XXI) and a hemiacetal of the compound of formula (XXI): said hemiacetal of the compound of formula (XXI) being the t of an addition reaction between the aldehyde as depicted in formula (XXI) and an alcohol selected from tertbutanol and isopropanol, and a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv); reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof; reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, ptoluenesulfonamide , benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof; solvent v) is selected from the group consisting of N,N-dimethylformamide, C1-6 alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof; and wherein the compound of formula (XXI) is prepared in the step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of a compound of formula (XXII) with a catalyst (N-cat); catalyst ) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, rsulfonic acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, 2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O-C1-4 alkyl)3, SnCl4, TiCl4, Ti(O-C1-4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, 3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, PPh3)2, NiBr2, NiCl2, )2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon d with inorganic acid and mixtures thereof.

In another red ment, the reaction mixture ing from reaction (M1-reac) or the reaction mixture resulting from reaction (M2-reac) can be, without above mentioned extraction with solvent (M-extract), acidified by mixing with an aqueous solution of acid (M- acid). The mixture, that is thereby obtained, can be washed with solvent h), and the product can be isolated by concentration.

If the deprotonated medetomidine is to be isolated, a suspension or solution of the salt of medetomidine, preferably an aqueous sion or on of the salt of medetomidine, can be basified by addition of a base (M-basify) or of an aqueous solution of base (M-basify); preferably base (M-basify) is selected from the group consisting of NaHCO3, Na2CO3, NaOH and mixtures thereof.

Preferably, base (M-basify) is added in such an amount, that the pH ofthe resulting e is from 7 to 12, more preferably from 8 to 10, even more preferably from 8 to 9.

After the addition ofbase ify), an aqueous phase can be extracted with solvent (M- extract), followed by isolation ofthe t by concentration ofthe t.

Preferably, any washing ofany organic phase after reaction (M l-reac) or after reaction (M2- reac) can be done with water, with base (M-basify), with an aqueous solution ofbase (M- basify) or with brine.

Preferably, any extraction of any s phase after reaction (Ml-reac) or after on (M2-reac) is done with solvent (M-extract).

Preferably, the reaction mixture after reaction (M l-reac) or after reaction (M2-reac) is first concentrated under reduced pressure, then diluted with water and acidified with acid (M-acid) as bed above, washed with solvent (M-wash), preferably solvent (M-wash) is toluene, basified with base (M-basify), preferably base (M-basify) is an aqueous solution ofNaHC03, and then extracted with solvent (M-extract), preferably solvent (M-extract) is selected from the group ting oftoluene, dichloromethane, pyl acetate and ethyl acetate; followed by isolation ofthe product by concentration ofthe extract.

In another preferred embodiment, medetomidine is purified after reaction (M 1-reac) or after reaction (M2-reac) by chromatography.

Any organic phase can be dried, preferably over MgS04 or Na2S04.

Any concentration is preferably done by distillation, preferably under d pressure.

Medetomidine can be purified, preferably by crystallization or distillation under reduced pressure, more preferably by crystallization from a mixture ofcyclohexane and toluene, even more ably from cyclohexane:toluene 99: 1 v/v .

Medetomidine may also be converted into a salt by mixing with an acid (M-acid salt), acid d salt) is preferably used as aqueous solution, acid d salt) is preferably ed from the group consisting ofacetic acid, oxalic acid, HCI and H2S04; then it can be isolated by filtration and purified by recrystallization in a t st), solvent (M-cryst) is preferably selected from the group ting ofwater, ethanol, methanol, isopropanol, acetonitrile, hexane, cyclohexane, heptane, toluene, ethyl acetate and es thereof; recrystallization can be repeated using a different solvent (Mcryst). ably, the acidic inorganic solid substance is aluminosilicates.

Preferably, the acidic ion exchange resin is selected from the group ting ofcopolymers ofstyrene and divinylbenzene and ofperfluorinated branched or linear polyethylenes, these polymers being functionalized with S03H groups; more preferably, the acidic ion exchange resin is selected from the group consisting of copolymers ofstyrene and divinylbenzene containing more than 5% ofdivinylbenzene, preferably being macroreticular, and ofperfluorinated polyethylenes, these polymers being functionalized with S03H groups.

Preferably, the inorganic acid, with which the carbon was treated, is selected from the group consisting ofHCl, H2S04and HN03.

Preferably, the catalyst (N-cat) is selected from the group consisting ofacetic acid, formic acid, trifluoroacetic acid, esulfonic acid, p-toluenesulfonic acid, HCI, HBr, H2S04, H3P04, BCh, BF30Et2, MgCh, MgBr2, AICh, ZnCh, Cu(BF4)2, aluminosilicates, acidic ion exchange resins, carbon treated with HCI, H2S04or HN03, and mixtures thereof; more preferably, the catalyst (N-cat) is selected from the group consisting ofacetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, HCI, H2S04, BF30Et2, Cu(BF4)2, aluminosilicates, acidic ion exchange resins, and mixtures thereof.

Preferably, reaction (N-reac) is done in a solvent (N-solv); solvent (N-solv) is selected from the group consisting ofwater, tert-butanol, panol, acetonitrile, nitrile, THF, methyl-THF, NMP, dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, chlorobenzene, hexane, cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and mixtures thereof; preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, form, toluene, cyclohexane, ethyl acetate, acetic acid, formic acid and mixtures thereof; more ably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2- dimethoxyethane, dichloromethane, 1,2-dichloroethane, e, ethyl acetate and es thereof; even more ably from acetonitrile, THF, 2-methyl-THF, dichloromethane, toluene, ethyl acetate and mixtures thereof.

The catalyst (N-cat) can be used in a pure form or as hydrate.

The catalyst (N-cat) can be used as a solution in solvent (N-solv).

Preferably, the molar ratio n catalyst (N-cat) and compound offormula (XXII) is from 1: 1000 to 10: 1, more preferably from 1: 100 to 5: 1, even more preferably from 1:20 to 1: 1, especially from 1: 10 to 1:2.

Preferably, the reaction temperature ofreaction (N-reac) is from -20 to 200°C, more preferably from 0 to 150 °C, even more preferably from 10 to 100°C.

The reaction (N-reac) can be done in a system, that is closed or open to the atmosphere.

In a closed system, the pressure depends mainly on the boiling point ofa solvent (N-solv) and on the reaction temperature ofreaction (N-reac).

Preferably, the on (N-reac) is done at a pressure offrom 0.01 bar to 20 bar, more preferably offrom 0.1 to 10 bar, even more preferably offrom atmospheric pressure to 5 bar.

More preferably, the on (N-reac) is done in an open system.

Preferably, the on time ofreaction (N-reac) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h to 24 h. atively, reaction (N-reac) can be done as a continuous gas-phase reaction by passing the evaporated compound of formula (XXII) over the catalyst ). This gas-phase reaction can be done in the presence of an inert gas, the inert gas is preferably selected from the group consisting of nitrogen, a noble gas and carbon dioxide.

After on c), compound of formula (XXI) can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation, chromatography and any combination f.

Compound of formula (XXI) can be obtained in step (N) as the aldehyde as depicted in formula (XXI), but also in form of its hydrate or etal. The hemiacetal of compound of formula (XXI), which can result as product from step (N), can be the product of an addition reaction between the aldehyde as depicted in a (XXI) and an alcohol selected from the group consisting of tert-butanol and isopropanol.

Also this e and this hemiacetal can be ly used in step (M1).

When compound of formula (XXI) is obtained from reaction (N-reac) in form of its hydrate or of a hemiacetal, the hydrate or the hemiacetale can be converted into the aldehyde by standard reactions known to the person skilled in the art.

Preferably, compound of formula (XXII) is prepared in a step (O) or in two steps, the two steps are step (O1) and step (O2); step (O) comprises a reaction (O-reac); reaction (O-reac) is a reaction of compound of formula (XXIII), with a reagent (O-reag); reagent (O-reag) is selected from the group consisting of peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, tert-butylhydroperoxide, oyl peroxide, hydroperoxide, oxygen, air, sodium hypochlorite, KHSO5, Na2O2, aqueous H2O2, H2O2 ved in acetic acid, H2O2 dissolved in trifluoroacetic acid, and mixtures thereof; step (01) comprises a reaction (Ol-reac); reaction (01-reac) is a reaction ofcompound of formula (XXIII) with water and with a compound (01-comp); compound (Ol-comp) is selected from the group ting ofbromine, N-bromosuccinimide, chlorine, N-chlorosuccinimide, , N-iodosuccinimide, IBr, BrCI, and mixtures thereof; step (02) comprises a reaction (02-reac); reaction (02-reac) is a reaction ofthe on product from reaction ac) with a base (02-base); base (02-base) is ed from the group consisting ofsodium hydroxide, potassium hydroxide, calcium hydroxide and mixture thereof.

Preferably, reagent (O-reag) is selected from the group consisting ofperacetic acid, tertbutylhydroperoxide , oxygen, air, sodium hypochlorite, aqueous H20 2, H20 2 dissolved in acetic acid, H20 2 dissolved in trifluoroacetic acid, and mixtures thereof; more preferably, reagent (O-reag) is aqueous H20 2.

Preferably, reaction (O-reac) is done in a solvent (O-solv); solvent v) is selected from the group ting ofwater, aqueous ons of NaHC03, Na2C03, (NH4)HC03, C03, KHC03or K2C03, benzene, toluene, NMP, e, acetone, ethyl acetate, methylethylketone, tert-butanol, acetonitrile, chloroform, dichloromethane and mixtures thereof; preferably from water, aqueous solutions ofNaHC03, Na2C03, KHC03or K2C03, toluene, dioxane, acetone, ethyl e, methylethylketone, tert-butanol, acetonitrile, dichloromethane and mixtures thereof.

Reaction (O-reac) can be done in the presence ofa catalyst (O-cat); catalyst (O-cat) is selected from the group consisting oftrifluoroacetic acid, trifluoroacetone, Mn(salen) x, aldehydes, N-methylmorpholine e, 2,2,6,6-tetramethylpiperidine l-oxyl and mixtures thereof; aldehydes are preferably isobutyraldehyde or benzaldehyde.

Reaction (O-reac) can be done in the presence ofa buffer (O-bu±); preferably, buffer (O-bu±) is an aqueous buffer and is selected from the group consisting of K2C03 / EDTA-Na2 buffer, phosphate buffer and other buffers known by the skilled person; more ably, buffer ) is an K2C03 / EDTA-Na2 buffer.

Preferably, the reaction ature ofreaction (O-reac) is from -20 to 100°C, more ably from -10 to 80°C, even more preferably from 0 to 50 °C.

The reaction (O-reac) can be done in a system, that is closed or open to the atmosphere. lOIn a closed system, the pressure depends on the boiling point ofa solvent (O-solv) and on the reaction ature ofreaction (O-reac).

Preferably, the on (N-reac) is done at a pressure offrom 0.01 bar to 20 bar, more preferably offrom 0.1 to 10 bar, even more ably offrom atmospheric pressure to 5 bar.

More preferably the reaction (O-reac) is done in an open system.

Preferably, the reaction time ofreaction (O-reac) is from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h to 24 h.

After the reaction (O-reac), the compound of formula (XXII) can be isolated by standard methods such as evaporation tile components, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof.

Preferably, reaction (OI-reac) and reaction (02-reac) are conducted in solvent (O-solv), with solvent (O-solv) as defined above, also with all its preferred embodiments.

Preferably, the reaction temperatures ofreaction (OI-reac) and tion (02-reac) are identical or different and ndently from each other from -20 to 100°C, more preferably from -10 to 80°C, even more preferably from 0 to 50 0c.

Reaction (0l-reac) and reaction (02-reac) can independently from each other be done in systems, that are closed or open to the here.

In a closed system, the re depends on the boiling point ofa solvent (O-solv) and on the reaction temperature ofreaction (0l-reac) and reaction (O-reac) respectively.

Preferably, reaction (OI-reac) and reaction (02-reac) are independently from each other done at res offrom 0.01 bar to 20 bar, more ably offrom 0.1 to 10 bar, even more preferably offrom atmospheric pressure to 5 bar.

More preferably, reaction ac) and reaction (02-reac) are done in a open system.

Preferably, the reaction times ofreaction ac) and ofreaction (02-reac) are independently from each other from 30 min to 72 h, more preferably from 1 h to 48 h, even more preferably from 2 h to 24 h.

The reaction product ofreaction (OI-reac) and the compound offormula (XXII) from reaction (02-reac) can be isolated by standard methods such as evaporation ofvolatile components, extraction, washing, drying, concentration, filtration, crystallization, distillation, tography and any combination thereof.

Reaction (OI-reac) and reaction (02-reac) can be done consecutively without isolation ofthe reaction product ofreaction (OI-reac), they can be done in one pot.

Preferably, compound offormula (XXII) is not isolated, step (N) is done ly after step (0) or step (02) respectively in one pot. For this, catalyst (N-cat) is simply added to the reaction mixture resulting from reaction (O-reac) or from reaction (02-reac) respectively.

Preferably, compound offormula (XXIII) is prepared in a step (P); step (P) ses a on (P-reac); in reaction c) the compound offormula (XXIV) is exposed to a temperature (P-temp); (XXIV) temperature (P-temp) is from 0 to 300°C.

Preferably, temperature p) is from 5 to 200°C, more preferably from 100 to 150 °C.

WO 11155 Reaction (P-reac) can be done in a solvent (P-solv); t (P-solv) is selected from the group consisting ofbenzene, e, xylene, hexane, heptane, 1,2-dichloroethane, NMP, dichloromethane, chloroform and mixtures thereof; preferably from benzene, toluene, xylene, dichloromethane and mixtures thereof.

Preferably, on (P-reac) is done in the presence of a catalyst (P-cat); catalyst (P-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, esulfonic acid, benzenesulfonic acid, enesulfonic acid, camphorsulfonic acid, HCI, HBr, H2S04, KOH, NaOH, KHS04, HN03, H3P04, HCI04, BCh, BBr3, BF30Et2, BF3SMe2, BF3THF, MgCh, MgBr2, Mgh, AICh, AI(O-C I _4alkyl)3, h, Ah03, SnCI4, TiCI4, Ti(O-CI _4alkyl)4, ZrCI4, Bi20 3, BiCh, ZnCh, PbCh, FeCh, Yb(OTf)3, Yb(CI)3, GaCh, AlBr3, Ce(OTf)3, LiCI, acidic insoluble inorganic solid, acidic ion exchange resins, carbon treated with an inorganic acid, and es thereof; preferably from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, H2S04, KHS04, H3P04, acidic insoluble inorganic solid, acidic ion exchange resins, carbon treated with an inorganic acid, and mixtures thereof. ably, the acidic insoluble inorganic solid is acidic aluminosilicates or silica gel.

Preferably, the inorganic acid, with which the carbon was treated, is ed from the group consisting ofHCl, H2S04 and HN03.

Preferably, the acidic ion exchange resin is selected from the group consisting ofcopolymers ofstyrene and divinylbenzene and ofperfluorinated branched or linear polyethylenes, these polymers being functionalized with S03H groups; more preferably, the acidic ion exchange resin is selected from the group consisting of copolymers ofstyrene and divinylbenzene containing more than 5% nylbenzene, preferably being macroreticular, and ofperfluorinated polyethylenes, these polymers being functionalized with S03H groups.

When reaction (P-reac) is done in the presence ofa catalyst (P-cat), temperature (P-temp) is preferably from 0 to 200°C, more preferably from 10 to 150 °C, even more preferably from to 100°C.

Reaction (P-reac) can be done in gas phase by passing evaporated compound offormula (XXIV) through a heated tube, the heated tube can be charged with a catalyst ).

After reaction (P-reac), the compound of a (XXIII) can be isolated by standard methods such as evaporation ofvolatile ents, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof.

Preferably, compound of formula (XXIV) is ed in three steps, the three steps are a step (Ql), a step (Q2) and a step (Q3); step (Q 1) comprises a reaction (Q l-reac) by a reaction ofcompound of formula (XXV) with a t (Q l-reag); Q is Br, CI, or I; reagent (Q l-reag) is selected from the group consisting oflithium, magnesium, aluminum, zinc, m, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium, sec-butyllithium and mixtures thereof; step (Q2) comprises a reaction (Q2-reac); reaction (Q2-reac) is a reaction ofthe on product ofreaction (Ql-reac) with e; in step (Q3) comprises a reaction (Q3-reac); reaction (Q3-reac) is a reaction ofthe reaction product ofreaction (Q2-reac) with a reagent (Q3-reag); reagent (Q3-reag) is selected from the group consisting ofwater, methanol, ethanol, oxalic acid, citric acid, NH4CI, HCI, HBr, HN03, H2S04, H3P04, acetic acid, propionic acid, formic acid and mixtures thereof.

Preferably, Q is Bf.

Preferably, reagent (Ql-reag) is selected from the group consisting oflithium, magnesium, um, isopropylmagnesium chloride, isopropylmagnesium bromide and mixtures f.

Reaction (Ql-reac) can be catalyzed with a catalyst (Ql-cat).

Catalyst (Ql-cat) is selected from the group consisting ofiodine, 1,2-dibromoethane, TiCl4, AlCh, PbCb, BiCh, LiCl and mixtures thereof.

Preferably, reagent (Q3-reag) is water or aqueous NH4Cl.

Preferably, reaction ac) is performed in a solvent (Ql-solv).

Preferably, reaction (Q2-reac) is performed in a solvent (Q2-solv).

Preferably, reaction (Q3-reac) is med in a solvent (Q3-solv).

Preferably, solvent (Ql-solv), solvent (Q2-solv) and t (Q3-solv) are identical or ent and independently from each other selected from THF, methyl-THF, NMP, diethylether, methyl-tert-butylether, methoxycyciopentane, ropylether, 1,2- dimethoxyethane, tri CI -4 alkyl amine and mixtures thereof; more preferably from THF, 2-methyl-THF, 1,2-dimethoxyethane, methyl-tert-butylether, methoxycyciopentane, tri CI -4 alkyl amine and mixtures thereof; even more preferably from the group consisting ofTHF, 2-methyl-THF, 1,2- dimethoxyethane, triethylamine, and mixtures thereof.

Preferably the solvent (Ql-solv), solvent (Q2-solv) and solvent (Q3-solv) are identical.

The reaction atures ofreaction (Ql-reac), ofreaction ac) and ofreaction (Q3- reac) are identical or different and idependently from each other preferably from -100 to 150 °C, more preferably from -60 to 100°C, and even more preferably from -20 to 80°C.

Reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac) can be done at a constant temperature, or the temperature may be modified during the progress ofthe reactions. For instance, the reactions can run for a n time at first temperature, and then for a subsequent time at a second temperature different from the first ature. Alternatively, the temperature may be modified continuously during the reaction.

The reaction times ofreaction (Ql-reac), tion (Q2-reac) and ofreaction (Q3-reac) are identical or different and idependently from each other preferably from 30 min to 48 h, more preferably from 1 to 24 h, even more ably from 2 to 12 h.

The amounts ofsolvent (Q 1-solv), ofsolvent (Q2-solv) and ent lv) are are identical or ent and idependently from each other preferably from 2 to 40 fold, more preferably from 3 to 10 fold, even more preferably from 5 to 7 fold, ofthe weight of compound offormula (XXV), ofthe weight ofthe reaction product ofreaction (Q 1-reac) and ofthe weight ofthe reaction product ofreaction (Q2-reac) respectively. ably, from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents ofreagent (Q 1-reag) are used, the mol equivalents being based on the mol of compound offormula (XXV).

Preferably, from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents, even more preferably from 1.1 to 3 mol equivalents ofacetone are used, the mol equivalents being based on the mol ofcompound offormula (XXV).

Preferably, from 1.0 to 100 mol equivalents, more preferably from 1.1 to 50 mol equivalents, even more preferably from 1.1 to 30 mol equivalents ofreagent (Q3-reag) are used, the mol equivalents being based on the mol ofcompound offormula (XXV) or ofthe mol ofthe reaction product ofreaction (Q2-reac).

Preferably, reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac) are done at atmospheric pressure.

Preferably, on (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac) are done under inert atmosphere. Preferably, the inert atmosphere is achieved by the use ifan inert gas selected from the group consisting ofargon, another noble gas, lower boiling alkane, nitrogen and mixtures f.

The lower boiling alkane is ably a CI-3 alkane, i.e. methane, ethane or propane.

WO 11155 After reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac), the reaction product of reaction (Q l-reac), the reaction t ofreaction (Q2-reac) and compound offormula (XXIV) respectively can be ed by standard methods such as evaporation ofvolatile ents, extraction, washing, drying, concentration, crystallization, distillation, chromatography and any combination thereof.

Preferably, the reaction product ofreaction (Q l-reac) and the reaction product ofreaction (Q2-reac) are not isolated.

Preferably, reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac) are done utively; preferably, reaction (Q l-reac), reaction (Q2-reac) and reaction (Q3-reac) are done in one pot.

In another red embodiment, reaction (Ql-reac) and reaction (Q2-reac) can be done in one pot by adding reagent (Q l-reag) to a mixture ofcompound offormula (XXV) and e in a solvent (Ql-solv); reaction (Q3-reac) is done thereafter, preferably in the same pot.

Compound offormula (XXIV) is preferably isolated using conventional methods, such as ation ofvolatile components, hydrolysis and optional acidification ofthe boiling residue, extraction, and distillation.

Any aqueous phase can be extracted, preferably the extraction is done with a t (Q- extract). Solvent (Q-extract) is benzene, toluene, ethyl acetate, or isopropyl acetate.

Any organic phase can be dried, preferably with magnesium sulphate.

Any concentration is ably done by distillation, preferably under reduced pressure.

The compound offormula (XXIV) can be purified, ably by crystallization or distillation under reduced pressure.

Medetomidine and compounds of formula (XXI) and (XXII) are chiral nds, and the formulae comprise any enantiomer as well as any mixture of enantiomers of midine, of the compounds of formula (XXI), or of formula (XXII) respectively.

Enantiomers can be separated by a tional procedure previously disclosed in organic chemistry, such as repeated crystallizations of the (+) tartaric acid salt in alcoholic media, as disclosed for medetomidine in Cordi et al., Synth. Commun. 1996, 26, 1585-1593.

Compounds of formula (XXV) are known compounds and can be prepared according to known methods.

The progress of any of the reactions reaction (M1-reac), reaction (M2-reac), reaction (N-reac), reaction (O-reac), reaction (O1-reac), reaction (O2-reac), reaction (P-reac), reaction ac), reaction (Q2-reac) and reaction (Q3-reac) can be monitored by standard techniques, such as r magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), High performance Liquid Chromatography (HPLC), Liquid Chromatography Mass Spectrometry (LCMS), or Thin Layer Chromatography (TLC), and work-up of the reaction mixture can start, when the conversion of the starting material exceeds 95%, or when no more starting material can be detected. The time required for this to occur will depend on the e reaction temperature and the e concentrations of all reagents, and may vary from batch to batch.

In l, any organic phase can be dried, preferably over MgSO4 or Na2SO4, if not stated otherwise.

Compared to prior art, the method of the present invention offers several advantages: Importantly, the whole carbon framework of medetomidine is built in few chemical steps, using cheap ts only. No protecting groups are needed and the overall amount of al used is therefore reduced, the batch size based on molar amounts is increased.

In particular no trityl or acetal protection groups are used and no protection of the imidazoles is necessary. Thereby the number and amount of reagents needed is reduced, and no ting or deprotecting steps being needed the waste is reduced, contrary to when for example a trityl or acetal ting group is used. The method has good yields. 2012/072796 Methods IH and l3C NMR spectra were recorded on a Varian VNMRS 500 (500 MHz for IH and 125 MHz for l3C) ments in CDCh. Chemical shifts are expressed in parts per million referred to TMS and coupling constants (1) in hertz.

EI means Electron ionization mass spectra (70 eV), they were obtained on an 4 spectrometer.

ESI means Electron spray ionization mass spectra THF was distilled from sodiumlbenzophenone ketyl prior to use; the obtained ous THF is called "dry THF" in the following text. e 1: 2-(2,3-Dimethylphenyl)propanol, compound of formula (XXIV), prepared via an organomagnesium intermediate I-Bromo-2,3-dimethylbenzene (compound offormula (XXV), n Qis Br; 8.43 g, 45.6 mmol) was ved in dry THF (15 mL) and placed in dropping funnel. Separately, Mg wire (1.10 g, 45.3 mmol) in dry THF (5 mL) was placed in a flask equipped with the above mentioned ng funnel, a stirrer, and a reflux condenser. The I-bromo-2,3- dimethylbenzene solution (1.0 mL) was added via a dropping funnel and the reaction was initiated by the addition of 1,2-dibromoethane (3 drops), and then the rest ofthe I-bromo-2,3- dimethylbenzene solution was added. The content ofthe dropping funnel was added at such a rate to maintain slight reflux. After completion ofthe addition, the mixture was refluxed for 1 h and then cooled to 0 °C. A solution ofdry acetone (4.2 mL, 58 mmol) in dry THF (15 mL) was added dropwise and the mixture was stirred at a temperature between 0 and 20°C for 3 h.

The mixture was poured into saturated NH4CI aqueous solution (100 mL) extracted with hexane (5 times with 50 mL each), dried with Na2S04 and evaporated under reduced pressure.

The main product was isolated via silica gel column chromatography with hexane:ethyl acetate as eluent (v/v 15:1 to 10:1 gradient), to yield 3.50 g (47%) ofthe title compound.

IH NMR: 1.68 (s, 6H), 1.70 (s, IH), 2.29 (s, 3H), 2.50 (s, 3H), 7.03 to 7.10 (m, 2H), 7.29 to 7.32 (m, IH). l3C NMR: 17.72,21.08,31.24,73.71,123.11,125.02,129.02, 135.09, 138.69, 145.47.

MS (EI): 164 (12),149 (35),146 (100),131,116,105,91.

Example 2: 2-(2,3-Dimethylphenyl)propanol, compound of formula (XXIV), prepared via an organolithium intermediate I-Bromo-2,3-dimethylbenzene und offormula (XXV), wherein Qis Br; 4.25 g, 23.0 mmol) was dissolved in dry THF (20 mL) in a flask equipped with a thermometer and a stirring bar. The mixture was cooled to -78°C. llithium (1.6 M in , 17.5 mL, 28.0 mmol) was added dropwise via a syringe, keeping the temperature below -70°C. When the addition was complete, the mixture was ined at -78 °C and stirred at this temperature for 1 h. A on ofdry acetone (1.85 mL, 25.2 mmol) in dry THF (5 mL) was then added at -78°C. The mixture was stirred at -78 °C for 30 min, the cooling bath was removed, and the mixture was allowed to reach room temperature. The mixture was poured into saturated aqueous NH4CI solution (100 mL), extracted with hexane (4 times with 50 mL each), dried over Na2S04, and purified by via silica gel column chromatography using hexane:ethyl acetate as eluent (v/v 32:1) to give 3.45 g (91 %) ofthe title compound.

The measured NMR a were identical to those recorded in example 1.

Example 3: 1,2-Dimethyl(2-propenyl)benzene, compound of formula (XXIII) -Dimethylphenyl)propan01, compound of formula (XXIV), prepared according to either example 1 or example 2, (1.10 g, 6.70 mmol), was dissolved in benzene (20 mL), and p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 3 h. Silica gel (200 mg) was added, and stirring was continued for ca. 16 hours, and then the reaction mixture was refluxed for 30 min. After cooling to room temperature, the mixture was filtered, washed with aqueous K2C03 solution, tionally dried, and concentrated under reduced pressure, to yield 0.90 g (92%) ofthe title compound.

IH NMR: 2.02 (m, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 4.82 (m, IH), 5.17 (m, IH), 6.97 (m, IH), 7.05 (m, 2H).

Example 4: 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII) A buffer was prepared by dissolving K2C03 (20.7 g) and EDTA-Na2 (11.5 mg) in water (100 mL). 1,2-Dimethyl(2-propenyl)benzene, nd offormula (XXIII), prepared according to example 3 (0.90 g, 6.16 mmol), was dissolved in a mixture ofdichloromethane and acetonitrile (v/v 1:1, 60 mL), and the buffer prepared as described above (9.3 mL) was added. To the ing mixture, first 1,1,I-trifluoroacetone (60 ~L) and then hydrogen de (30% in water, 6.2 mL, 60.7 mmol) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL), the organic phase was separated, and the aqueous phase was extracted with dichloromethane (2 times with 50 mL each). The combined organic phases were dried over Na2S04, trated under reduced pressure, and the residue was purified by via silica gel column chromatography using hexane:ethyl acetate as eluent (v/v 32:1) to give 851 mg (85%) ofthe title compound.

IH NMR: 1.59 (s, 3H), 2.28 (s, 3H), 2.31 (s, 3H), 2.83 (br d, J = 5.4, IH), 2.98 (d, J = 5.4 Hz, IH), 7.08 (m, 2H), 7.21 (m, IH).

MS (EI): 162, 147, 133, 117 (100).

Example 5: 2-(2,3-Dimethylphenyl)propanal, nd of formula (XXI) 2-(2,3-Dimethylphenyl)methyloxirane, nd of formula (XXII), prepared according to example 4 (0.84 g, 5.18 mmol), was dissolved in dry dichloromethane (50 mL) and powdered Cu(BF4)2 hydrate (318 mg) was added at room temperature. After 2 h at room temperature, the mixture was washed with water, dried over Na2S04 and concentrated under reduced pressure to yield 0.84 g (100%) ofthe title product.

IH NMR: 1.40 (d, J = 7.1 Hz, 3H), 2.25 (s, 3H), 2.32 (s, 3H), 3.89 (qd, J = 7.1,1.0 Hz, IH), 6.89 to 6.92 (m, IH), 7.12 (m, 2H), 9.67 (d, J = 1.0 Hz, IH).

Example 6: Medetomidine 2-(2,3-Dimethylphenyl)propanal, compound ula (XXI), prepared according to example 5 (2.43 g, 15.0 mmol) and enesulfonylmethyl nide (2.73 g, 14.0 mmol) were mixed with EtOH (30 mL). To the stirred suspension powdered NaCN (73 mg, 1.5 mmol) was added. The mixture was stirred for 1 h at room temperature, and then evaporated under reduced pressure to s. The residue was placed in an ampoule and treated with MeOH saturated with NH3 (50 mL). The ampoule was heated to 110°C in an oil bath for three days.

This experiment was repeated once more (2-(2,3-Dimethylphenyl)propanal: 3.24 g, 20.0 mmol; enesulfonylmethyl isocyanide: 3.90 g, 20.0 mmol).

Both reaction mixtures were combined, evaporated to dryness, dissolved in romethane (150 mL) and washed with 10% (w/w) aqueous Na2C03 (200 mL) and then with water (200 mL), tionally dried, evaporated under reduced pressure and purified by via silica gel column chromatography using dichloromethane : methanol as eluent (v/v 15:1 to 10:1 gradient), to yield 3.0 g (44%) ofmedetomidine as a sticky oil. Medetomidine was crystallized from toluene:cyclohexane, and then recrystallized from aqueous ethanol.

IH NMR: 1.56 (d, J = 7.2 Hz, 3H), 2.18 (s, 3H), 2.25 (s, 3H), 4.35 (q, J = 7.2 Hz, 1H), 6.66 (s, 1H), 6.93 (dd, J = 6.6, 2.2 Hz, 1H), 6.99 to 7.05 (m, 2H), 7.30 (d, J = 1.1 Hz, 1H), 9.84 (broad s, 1H). l3e NMR: 14.65,20.72,20.88, 14.12, 117.61, , 125.53, 127.91, 134.05, 134.60, 136.76,141.11,143.23.

MS (ESI): 201 [M+Ht

Claims

1. A method for the preparation of medetomidine, the method comprises a step (N) and a step (M1); 5 step (M1) comprises a reaction (M1-reac); reaction (M1-reac) is a on between a compound selected from the group consisting of a compound of formula (XXI), a e of the compound of formula (XXI) and a hemiacetal of the compound of formula (XXI): said hemiacetal of the compound of formula (XXI) being the t of an addition reaction between the de as depicted in formula (XXI) and an alcohol selected from tertbutanol and isopropanol, 15 and a reagent (M-reag) and a reagent (M-A) in a t (M-solv); reagent g) is selected from the group consisting of enesulfonylmethyl isocyanide, oromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof; 20 reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, ptoluenesulfonamide , benzenesulfonamide, amidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof; solvent (M-solv) is selected from the group ting of N,N-dimethylformamide, C1-6 alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl 25 carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof; and wherein the compound of formula (XXI) is prepared in the step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of a compound of formula (XXII) with a catalyst (N-cat); catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, esulfonic acid, enesulfonic acid, camphorsulfonic 5 acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O-C1-4 alkyl)3, SnCl4, TiCl4, Ti(O-C1-4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with 10 inorganic acid and mixtures thereof.

2. The method according to claim 1, n reaction (M1-reac) is a reaction between a compound of formula (XXI) or the hydrate of the compound of formula (XXI): and a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv). 20

3. The method according to claim 1 or claim 2, wherein reaction (M1-reac) is a reaction between a compound of formula (XXI): and a t (M-reag) and a t (M-A) in a solvent (M-solv).

4. The method ing to any one of claims 1 to 3, wherein reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide and mixtures thereof.

5. The method according to any one of claims 1 to 4, wherein reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide and mixtures thereof. 10

6. The method according to any one of claims 1 to 5, wherein solvent (M-solv) is selected from the group consisting of N,N-dimethylformamide, methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, water, formamide, 1,2-dimethoxyethane, NMP, e, acetonitrile, propionitrile, ethyl carbamate, methylacetamide, acetamide and mixtures thereof.

7. The method according to any one of claims 1 to 6, wherein reaction (M1-reac) is done in the presence of a compound (M-comp), compound (M-comp) is selected from the group consisting of a, tritylamine, NaCN, KCN, piperidine, DBU, DABCO, ylamine, ylamine, 4-dimethylaminopyridine, pyridine, tBuOK, tBuONa, , Na2CO3, 20 (NH4)HCO3, (NH4)2CO3, KHCO3, K2CO3, NaOAc, KOAc, NaOH, KOH, Ca(OH)2, KF and mixtures thereof.

8. The method according to claim 7, wherein compound (M-comp) is selected from the group consisting of ammonia, tritylamine, NaCN, KCN, piperidine, tBuOK, tBuONa, KOH, 25 K2CO3, Na2CO3, KF and mixtures thereof.

9. The method according to any one of claims 1 to 8, wherein the compound of a (XXI) is first reacted with the reagent (M-reag) and then reagent (M-A) is added; 30 nd of formula (XXI) is first reacted with the reagent (M-A) and then the reagent (M- reag) is added; compound of formula (XXI) is simultaneously reacted with the t (M-reag) and with the reagent (M-A).

10. The method ing to any one of claims 1 to 9, wherein the catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, enesulfonic acid, HCl, HBr, H2SO4, H3PO4, BCl3, BF3OEt2, MgCl2, MgBr2, AlCl3, 5 ZnCl2, Cu(BF4)2, aluminosilicates, acidic ion exchange resins, carbon treated with HCl, H2SO4 or HNO3, and mixtures f.

11. The method according to any one of claims 1 to 10, wherein reaction (N-reac) is done in a solvent (N-solv); 10 solvent (N-solv) is selected from the group consisting of water, tert-butanol, isopropanol, itrile, propionitrile, THF, methyl-THF, NMP, dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, chlorobenzene, hexane, exane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and mixtures thereof. 15

12. The method according to any one of claims 1 to 11, wherein the compound of formula (XXII) is prepared in a step (O) or in two steps, the two steps are step (O1) and step (O2); step (O) comprises a on (O-reac); reaction (O-reac) is a reaction of a compound of formula (XXIII), with a reagent (O-reag); reagent (O-reag) is selected from the group consisting of peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, tert-butylhydroperoxide, dibenzoyl peroxide, cumenehydroperoxide, oxygen, air, sodium 25 hypochlorite, KHSO5, Na2O2, s H2O2, H2O2 dissolved in acetic acid, H2O2 dissolved in trifluoroacetic acid, and mixtures f; step (O1) ses a reaction (O1-reac); reaction (O1-reac) is a reaction of a compound of formula (XXIII) with water and with a compound (O1-comp); compound (O1-comp) is selected from the group consisting of bromine, N-bromosuccinimide, chlorine, N-chlorosuccinimide, iodine, N-iodosuccinimide, IBr, BrCl, and mixtures thereof; step (O2) comprises a reaction (O2-reac); 5 reaction (O2-reac) is a reaction of the reaction t from reaction (O1-reac) with a base (O2-base); base (O2-base) is selected from the group ting of sodium hydroxide, potassium hydroxide, calcium hydroxide and mixtures thereof. 10

13. The method according to claim 12, n reagent (O-reag) is ed from the group consisting of peracetic acid, tert-butylhydroperoxide, oxygen, air, sodium hypochlorite, s H2O2, H2O2 dissolved in acetic acid, H2O2 dissolved in trifluoroacetic acid, and mixtures thereof. 15

14. The method according to claim 12 or claim 13, wherein the compound of formula (XXIII) is prepared in a step (P); step (P) comprises a on (P-reac); in reaction (P-reac) a compound of formula (XXIV) is exposed to a temperature (P-temp); temperature (P-temp) is from 0 to 300 °C.

15. The method according to claim 14, wherein the compound of formula (XXIV) is ed 25 in three steps, the three steps are a step (Q1), a step (Q2) and a step (Q3); step (Q1) comprises a reaction (Q1-reac) by a reaction of a compound of formula (XXV) with a t (Q1-reag); Q is Br, Cl, or I; reagent (Q1-reag) is selected from the group consisting of lithium, magnesium, aluminium, 5 zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium e, ithium, sec-butyllithium and mixtures f; step (Q2) comprises a reaction ac); reaction (Q2-reac) is a reaction of the reaction product of reaction (Q1-reac) with acetone; in step (Q3) comprises a reaction ac); 10 reaction (Q3-reac) is a reaction of the reaction product of reaction (Q2-reac) with a reagent (Q3-reag); reagent (Q3-reag) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, NH4Cl, HCl, HBr, HNO3, H2SO4, H3PO4, acetic acid, propionic acid, formic acid and mixtures thereof.

16. A method according to claim 1, substantially as hereinbefore described, with reference to any one of the Examples.