WO2009053709A1

WO2009053709A1 - Process for the preparation of medetomidine

Info

Publication number: WO2009053709A1
Application number: PCT/GB2008/003613
Authority: WO
Inventors: Rasik Somaiya; Muhammad Raza; Jonathan Cranke; Kristian Bragg
Original assignee: Norbrook Laboratories Limited
Priority date: 2007-10-24
Filing date: 2008-10-24
Publication date: 2009-04-30
Also published as: GB2453982A; AR068952A1; GB0720891D0; PE20091088A1; UY31415A1; CL2008003185A1; GB2453982B

Abstract

A process of preparing Medetomidine of Formula (I) or an acid addition salt thereof, which process comprises: (i) reacting 2,3-dimethyl-methylbenzylalcohol with N-trimethylsilylimidazole, and, if desired, converting the Medetomidine to an acid addition salt thereof.

Description

Process for the Preparation of Medetomidine

The present invention relates to a process for the preparation of 4- [1- (2 , 3-dimethylphenyl) ethyl] -IH- imidazole of the formula (I) :

Formula (I) or an acid addition salt thereof.

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.

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 2 , 3-dimethylmagnesium bromide ; (ii) heating 4-imidazolecarboxylic acid methyl ester in dry THF to about 50 ⁰C 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-[[α-(2,3- dimethylphenyl) αt-methyl] hydroxymethyl] imidazole; (iv) heating the 4- [ [a- (2 , 3-dimethylphenyl) a- methyl] hydroxymethyl] imidazole to 136 ⁰C with potassium hydrogen sulphate to form 1- (4-imidazolyl) -1- (2 , 3- dimethylphenyl) -ethylene; and

(v) hydrogenating the 1- (4-imidazolyl) -1- (2, 3- dimethylphenyl) -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- (α-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) - [1- (2 , 3-dimethylphenyl) ethyl] - lH-imidazole, the Ot₂-adrenergic agonist Medetomidine", pp 1021 and 1022 (1991) .

Kudzma et al, Synthesis, "Expedient synthesis of 4 (5) - [1- (2, 3-dimethylphenyl) ethyl] -IH- imidazole, the CK₂-adrenergic agonist Medetomidine", pp 1021 and 1022 (1991) describes another multi-step process for preparing Medetomidine which includes the following process steps: (a) lithiating with Butyl lithium in pentane at -78 ⁰C 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 ⁰C and treated it with butyl lithium and 2 , 3-dimethylbenzoyl chloride to form 1 -N, N-dimethylsulfamoyl -2- (tert- butyldimethylsilyl) -5- (2 , 3-dimethylbenzoyl) imidazole; and

(c) refluxing l-N,N-dimethylsulfamoyl-2- (tert- butyldimethylsilyl) -5- (2 , 3-dimethylbenzoyl) imidazole in 1.5 N hydrochloric acid to produce 4 (5) - [1- (2 , 3- dimethylphenyl ) ethyl ] - IH- imidazole .

This process has the disadvantage of requiring that the reaction process takes place at a temperature of -78 ⁰C 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) :

or an acid addition salt thereof, which process comprises: (i) reacting 2, 3 -dimethyl -methylbenzylalcohol with N- trimethylsilylimidazole, and, if desired, converting the Medetomidine to an acid addition salt thereof.

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-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 . Preferably the Lewis acid is titanium (IV) chloride. The chlorinated solvent can be, for example, Chloroform, methylene chloride or 1, 2-dichloroethane . Preferably 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 . Examples of suitable chlorinated solvents include Chloroform, methylene chloride, 1,2- dichloroethane, anhydrous Chloroform, anhydrous methylene chloride, or anhydrous 1, 2-dichloroethane . Preferably 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 ⁰C, preferably at a temperature of from about 5 to about 35 ⁰C, more preferably at a temperature range of from about 10 to about 35 ⁰C, even more preferably at a temperature of from about 20 to about 35 ⁰C, still even more preferably at a temperature range of from about 20 to about 30 ⁰C, yet even more preferably at a temperature range of from about 20 to 25 ⁰C and most preferably at a temperature of about 25 ⁰C. 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. Preferably the ratio of 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.

Secondly, when a Lewis acid is present the Lewis acid is generally present in excess of the dimethyl-methylbenzyl alcohol. Preferably 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.

In a preferred embodiment 2, 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.

In a further preferred embodiment 2 , 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. 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 -methylbenzyl alcohol has the following structure :

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 this embodiment R is methyl .

In a preferred embodiment 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. 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 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.

In a preferred embodiment the 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. Preferably the 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 ⁰C, preferably at a temperature of from about -10 to about 50 ⁰C, more preferably at a temperature of from about -10 to about 30 ⁰C, 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 ⁰C, and most preferably at a temperature of about 20 ⁰C.

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.

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 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 ⁰C, even more preferably at a temperature range of from about -10 to about 20 ⁰C, even more preferably at a temperature of from about 0 to about

20 ⁰C, still even more preferably at a temperature range of from about 10 to about 20 ⁰C, and most preferably at a temperature of about 20 ⁰C to form 2 , 3 -dimethyl -α-benzyl alcohol. This is worked up with a chlorinated solvent, preferably methylene chloride. 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:

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 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 2, 3-dimethylbenzylhalide used,

wherein X = Br, Cl or I

may, for example, be 2 , 3-dimethylbenzylbromide or

2, 3-dimethylbenzyliodide. 2 , 3-dimethylbenzylbromide 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-dimethylbenzylbromide 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 ⁰C, even more preferably at a temperature of from about 5 to about 30 ⁰C, yet even more preferably at a temperature of from about 5 to about 20 ⁰C, 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 ⁰C.

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.

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 2 , 3-dimethylbenzyl aldehyde; (ii) adding the 2, 3-dimethylbenzyl aldehyde to a solution of methylmagnesium halide to form 2, 3-dimethyl- methylbenzylalcohol ; and

(iii) reacting the 2 , 3 -dimethyl -methylbenzylalcohol with N- trimethylsilylimidazole in the presence of titanium (IV) chloride in anhydrous methylene chloride at a temperature of less than or equal to about 45 ⁰C.

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 salt which can be formed is, for instance, a hydrochloride.

Preferably, the acid addition salt of Medetomidine 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. Kudzma et al , Synthesis, "Expedient Synthesis of 4 (5) - [1- (2 , 3-Dimethylphenyl) ethyl] -IH- imidazole, the Oi₂-adrenergic agonist Medetomidine" , 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 ⁰C.

It has now been found that the 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.

To make the chloride addition salt of Medetomidine 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 ⁰C to about 150 ⁰C, preferably at a temperature of from about 120 ⁰C to about 130 ⁰C, 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 .

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 vacuum at a temperature of from about 50 ⁰C to about 100 ⁰C, more preferably from about 60 to 90 ⁰C, even more preferably from about 75 to about 90 ⁰C, and most preferably 80 ⁰C 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.

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.

(4)

(6)

(D

Step 1

Sodium ethoxide, 2 , 3-dimethylbenzylbromide and 2-nitropropane in ethanol at about 20 ⁰C. Workup with a solution of sodium hydroxide. Step 2

Methylmagnesium chloride solution 3M in THF at about 20 ⁰C. Workup with methylene chloride. Step 3

N-trimethylsilylimidazole, titanium (IV) chloride (TiCl₄) anhydrous methylene chloride (CH₂Cl₂) at about 30 ⁰C. Workup with methylene chloride.

Step 4

Medetomidine free base was mixed with 36 - 37% hydrochloride solution and toluene. Dean-Stark Apparatus used.

Claims

1. A process of preparing Medetomidine of Formula (I) :

or an acid addition salt therefore, which process comprises: (i) reacting 2 , 3-dimethyl -methylbenzylalcohol with N-trimethylsilylimidazole, and, if desired, converting the Medetomidine to an acid addition salt thereof.

2. The process according to claim 1 wherein the

2, 3 -dimethyl -methylbenzyl alcohol is prepared by adding 2 , 3-dimethylbenzyl 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.

5. The process according to claim 4 wherein the concentration of the Grignard reagent in solution is about 3 Molar.

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 ⁰C.

7. 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 50 ⁰C.

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 ⁰C.

9. The process according to claim 6 wherein the preparation of dimethyl -methylbenzyl alcohol is carried out at a temperature of about 20 ⁰C.

10. The process according to any one of claims 2 to 9 wherein the preparation of dimethyl-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.

12. The process according to claim 11 wherein the THF has a water content of from about 10 to about 250 ppm.

13. The process according to claim 11 wherein the THF has a water content of from about 30 to about 150 ppm.

14. The process according to claim 11 wherein the THF has a water content of about 100 ppm.

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-dimethylbenzylhalide with an alkoxide and 2 -nitropropane .

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-dimethylbenzyl 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-dimethylbenzyl aldehyde from

2 , 3 -dimethylbenzylhalide takes place at a temperature of at least about 5 ⁰C.

21. 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 ⁰C to about

60 ⁰C

22. 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 ⁰C to about

40 ⁰C

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 ⁰C.

24. 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 20 ⁰C.

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 ⁰C to about 20 ⁰C.

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 ⁰C.

27. The process according to any one of the preceding claims wherein process step (i) is carried out in the presence of a Lewis acid.

28. The process according to claim 27 wherein the Lewis acid is a metal halide.

29. The process according to claim 28 wherein the metal halide is titanium (IV) chloride.

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 methylene chloride.

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 ⁰C.

33. The process according to claim 32 wherein process step (i) is carried out at a temperature of from about 20 to about 30 ⁰C.

34. The process according to claim 32 wherein process step (i) is carried out at a temperature of from about 20 to about 25 ⁰C.

35. The process according to claim 32 wherein process step (i) is carried out at a temperature of about 25 ⁰C.

36. The process according to any one of the preceding 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) :

or an acid addition salt thereof, which process comprises: (i) reacting 2 , 3 -dimethyl -methylbenzylalcohol 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 ⁰C, and, if desired, converting the Medetomidine to an acid addition salt thereof.

39. A process of preparing Medetomidine of Formula (I) :

or an acid addition salt thereof, which process comprises:

(i) reacting a 2 , 3-dimethylbenzylhalide with an alkoxide and 2-nitropropane to form 2 , 3-dimethylbenzyl aldehyde;

(ii) adding the 2 , 3-dimethylbenzyl aldehyde to a solution of methylmagnesium halide to form 2 , 3-dimethyl- methylbenzylalcohol ; and

(iii) reacting the 2 , 3 -dimethyl -methylbenzylalcohol with N-trimethylsilylimidazole in the presence of titanium (IV) chloride in anhydrous methylene chloride at a temperature of less than or equal to about 45 ⁰C, and, if desired, converting the Medetomidine to an acid addition salt thereof .

862910 ; HFP; HFF