RU2791397C1 - Method for obtaining medetomidine and derivatives - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: compound 1-bromo-3-(2,3-dimethylphenyl)butan-2-one is presented for the preparation of medetomidine and its derivatives of the structural formula 5. In another embodiment, a method is provided for synthesizing compound 5 to obtain medetomidine and its derivatives, a method for producing medetomidine as a copper (I) complex of formula 3, methods for producing medetomidine of formula 2, a method for producing medetomidine derivative 4-[1-(2,3-dimethylphenyl) ethyl]-1,3-dihydro-2H-imidazole-2-thione of formula 24.

EFFECT: group of inventions provides new synthetic ways of obtaining medetomidine, which are safer and rather cheap when introduced into industrial production. In addition, the advantages of the developed synthetic route are the wide possibilities to modify the molecule of the final product, medetomidine, and obtain various derivatives with biological activity.

8 cl

Description

Technical field

The invention relates to the field of pharmaceutical chemistry and describes a method for producing medetomidine and its derivatives.

State of the art

Medetomidine is a synthetic drug that is a racemic mixture of two stereoisomers of 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. Medetomidine is a potent α2-adrenergic receptor agonist, which causes its dose-dependent analgesic and/or sedative effect. By acting on invertebrate G protein-coupled octopamine receptors, medetomidine inhibits the attachment of mollusks, which is used to prevent biological fouling of the underwater hulls of marine vessels.

Most of the described methods for the preparation of medetomidine are based on the use of precursors that already contain an imidazole ring, such as 4(5)-imidazolecarboxylic acid methyl ester (US4544664A, 1985), N-(trimethylsilyl)imidazole (WO2009/53709, 2009; CN105254567, 2016; CN106749027 , 2017; CN106588777, 2017; CN111253316, 2020 and CN112979552, 2021), 4(5)-acetylimidazole (CN105884691, 2016), 4(5)-iodimidazole (CN106083724, 2016), (1-trityl-1H -yl)boronic acid (CN108147999, 2018), 4(5)-imidazolecarbaldehyde (CN107857731, 2018 and KR2021/12112, 2021), 1-dimethylsulfamoyl-2-(tert-butyldimethylsilyl)imidazole (CN109608400, 2019), 1H-imidazole -4-carbonitrile (WO2021/89878, 2021).

However, the preparation of the above precursors is a separate multistage process, often requiring special reaction conditions, since in most cases these compounds are not commercially available.

In particular, patent CN109608400 describes the reaction with n-butyllithium at -78°C to obtain a key precursor (1-dimethylsulfamoyl-2-(tert-butyldimethylsilyl)imidazole), which requires the use of low-temperature cryogenic units and specially designed reactors.

(1-trityl-1H-imidazol-4-yl)boronic acid used in the method for producing medetomidine described in patent CN108147999 is also not a commercially available precursor, the preparation of which is a separate multi-stage technological process.

The disadvantage of medetomidine synthesis methods based on the interaction of N-(trimethylsilyl)imidazole with 1-(1-chloroethyl)-2,3-dimethylbenzene (CN105254567, 2016; CN106749027, 2017; CN111253316, 2020 and CN112979552, 2021), or 1-( 2,3-dimethylphenyl)ethanol (WO2009/53709, 2009 and CN106588777, 2017) by the Friedel-Crafts reaction, is the use of a large excess of Lewis acid, which, in the patents under consideration, uses titanium tetrachloride.

The second synthetic approach to the production of medetomidine is the creation of an imidazole cycle from precursors that do not initially contain it. In this case, as a rule, linear rather than convergent schemes of synthesis are used, and the imidazole ring is usually created in the last stages. In particular, this approach in relation to the production of medetomidine is described in the present invention.

Currently, there are only a very small number of documents that disclose this approach in relation to the production of medetomidine. In particular - patents FI77858C (1982), WO2011070069A1 (2011), WO2012/172122 (2012), WO2012/172120 (2012), WO2013/14428 (2013), WO2016/120635 (2016), CN106518812 (2016) ).

One of the first methods for obtaining medetomidine, including the creation of an imidazole ring, is described in patent FI77858C (1982), and is based on the Brederick reaction (Hellmut Bredereck. Chem. Ber. 1953, 86, 88). Despite the moderate yield (about 30% at the last stage), the reaction is easy to perform and does not require special conditions. However, this patent does not describe a method for the synthesis of a key precursor that is introduced into the Brederick reaction, but based on the approaches to the synthesis of α-haloketones known at the time of publication of patent FI77858C (excluding direct halogenation), the most widely used method is based on the interaction of diazomethane with halides carboxylic acids, followed by reaction of the resulting diazoketone with the corresponding one pot hydrogen halide (Nierenstein M. The action of diazomethane on some aromatic acyl chlorides. J. Chem. Soc. Trans. 1915, 107, 1491-1494). Since diazomethane and diazoketones are extremely explosive and also toxic compounds, the production of medetomidine using this technology has serious disadvantages, in particular, a high explosion hazard that occurs when the process is scaled up.

The preparation by the authors of this precursor by direct halogenation of the corresponding carbonyl compound, in our opinion, is ruled out, because so far no practical approach to the synthesis of 3-(2,3-dimethylphenyl)-2-butanone 7 has been described in the literature. The only publication in which 3-(2,3-dimethylphenyl)-2-butanone 7 was mentioned as a component of a complex difficult-to-separate mixture of isomeric ketones resulting from the rearrangement of 1,5,8-trimethyl-6-methylidene-tricyclo[3.2.1.0 ^{2 .7} ]oct-3-en-8-endo-ola is an article by Gabriele Mukherjee-Müller et al. (Helv. Chim. Acta 1977, 60, 1758-1780).

Patent WO2011070069A1 (2011) describes a synthetic method in which the imidazole ring is created in a multi-step process starting from commercially available 2,3-dimethylbenzoic acid. The method under consideration, however, has a significant drawback, which consists in the need to carry out the hydrogenation reaction under pressure (the hydrogenation reaction in this synthesis is used in 2 stages), which requires the use of special equipment (steel reactor), as well as gaseous hydrogen.

Patents WO2013/14428 (2013) and WO2016/120635 (2016) describe a method for producing medetomidine based on the condensation of 2-bromo-3-(2,3-dimethylphenyl)butanal with formamidine acetate in excess of 25% aqueous ammonia and ethanol. The described method involves a small number of steps, is practical, but also requires a reaction under pressure.

A method for producing medetomidine, including the creation of an imidazole ring, described in patent WO2012/172122 (2012) and WO2012/172120 (2012), and based on the interaction of 2-(2,3-dimethylphenyl)-1-propanal with toluenesulfonylmethyl isocyanide according to the Van Loysen reaction ((a) Albert M. Van Leusen. Tetrahedron Lett. 1972, 2369-2372; (c) J. Org. Chem. 1977, 42, 7, 1153-1159) has significant drawbacks and limitations. In particular, the need for chromatographic purification of the medetomidine base, and the use of toxic sodium cyanide. In addition, similarly to patent WO2013/14428 (2013) discussed above, the reaction leading to the formation of the imidazole ring is also carried out under pressure.

The method for the synthesis of medetomidine, described in patent CN106518812 (2017), is also based on the Van Loysen reaction and has similar disadvantages to patents WO2012/172122 (2012) and WO2012/172120 (2012), discussed above.

Thus, there is currently a need to develop new synthetic routes for the production of medetomidine, which are safer and fairly cheap when introduced into industrial production. The advantage of the synthetic route developed by us is the wide possibilities for modifying the molecule of the final product (medetomidine) and obtaining various derivatives with biological activity.

In addition, our proposed new method for the production of medetomidine and its derivatives compares favorably with the methods published in patents WO2013/14428 (2013) and WO2016/120635 (2016) in the following parameters:

1. Synthesis of 3-(2,3-dimethylphenyl)-2-butanone 7 , the key precursor of medetomidine, is carried out using a one-pot methodology, in which the cross-coupling reaction, which makes it possible to significantly complicate the carbon skeleton, and the removal of the protective group are carried out in one stage , which greatly reduces the total number of synthesis steps.

2. Intermediates: 1-bromo-3-(2,3-dimethylphenyl)butan-2-one 5, 3-(2,3-dimethylphenyl)-2-oxobutyl acetate 4 , and N-[3-(2, 3-dimethylphenyl)-2-oxobutyl]-N-formylformamide 22 can be used at subsequent stages without additional purification

3. Since the described synthesis method is based on the creation of an imidazole ring, there is no need to use hard-to-reach precursors that already contain an imidazole ring.

4. All reactions described in the proposed method for producing medetomidine are carried out at atmospheric pressure, which eliminates the need for special equipment, such as a high pressure reactor

5. The reactions described in the proposed method for producing medetomidine, requiring cooling or heating, are carried out at moderately low (-15°C) or moderately high temperatures (≤130°C paths A and B, and ≤160°C path C), which eliminates the need for special equipment such as low temperature cryogenic systems and specially designed reactors.

SUMMARY OF THE INVENTION

The method according to the present invention is disclosed in the following reaction schemes:

The starting compound for the preparation of 3-(2,3-dimethylphenyl)butan-2-one 7 is commercially available 2,3-dimethylbromobenzene 11 ,

which can also be obtained from 2,3-dimethylaniline 13

according to literature methods (synthesis according to a modified method from J. Chem. Soc. 1940, 16-18 is described below).

The reaction begins with the production of 2,3-dimethylaniline hydrobromide from 2,3-dimethylaniline 13 and 40% hydrobromic acid. Salt without isolation and purification is introduced into the reaction with nitrous acid generated in situ from sodium nitrite and hydrobromic acid, taken in excess.

Since the diazotization process proceeds exothermically, it is necessary to carefully control the internal temperature in the reactor, not allowing it to rise above 0°C, which is achieved by changing the rate of addition of the sodium nitrite solution.

Exceeding the specified temperature leads to a significant drop in the yield of the product, due to the occurrence of side processes and decomposition of the diazonium salt 12 ,

which is already observed to some extent at 0°C.

Freshly precipitated powdered copper is added to a solution of 2,3-dimethylphenyldiazonium bromide 12 , and the temperature of the solution is raised above 28°C, which causes decomposition of the diazonium salt with the release of gaseous nitrogen and the formation of 2,3-dimethylbromobenzene 11 .

Carrying out the process of decomposition of the diazonium salt 12 at a sufficient stirring speed makes it possible to avoid foaming of the reaction mixture due to nitrogen evolution, and to ensure a smooth process.

After spontaneous cessation of temperature rise, the reaction mixture is briefly (20-30 minutes) heated to 70-75°C to complete the process, cooled, and extracted with a light organic solvent such as hexane, heptane, or a light fraction of petroleum ether. The use of pentane is not recommended due to the low boiling point, which leads to significant solvent losses during the processing and recovery process.

Since a significant amount of 2,3-dimethylphenol 25 is formed in the process of diazotization,

washing the extract with aqueous solutions of strong bases such as sodium hydroxide or potassium hydroxide is a necessary operation. Separation of product 11 from resinous impurities is achieved by steam distillation from an alkaline solution.

The use of heavy solvents (methylene chloride, chloroform) for the extraction of 2,3-dimethylbromobenzene 11 is not recommended, because of their density close to the density of the reaction mixture, and also because of the tendency of the latter to give a stable emulsion in an alkaline medium, which greatly complicates the process washing the organic phase with alkaline solutions to remove impurities 2,3-dimethylphenol 25 .

Compound structure 14 ,

used in the next step can be synthesized from commercially available 3-bromo-2-butanone (structure 15 )

according to the standard procedure described, for example, in Greene's Protective Groups in Organic Synthesis 2006.

The starting 3-bromo-2-butanone 15 can also be obtained by bromination of readily available methyl ethyl ketone 17

molecular bromine in an aqueous solution of acetic acid according to literature methods (for example, Rec. Trav. Chim. Pays-Bas 1946, 65, 691).

Since the bromination reaction of methyl ethyl ketone 17 leads to the formation of two regioisomers, 3-bromo-2-butanone 15 and 1-bromo-2-butanone 16 ,

before setting the protective group, the mixture must be separated by vacuum distillation on an efficient distillation column. A column 800 mm high and 30 mm in diameter filled with Raschig rings provides 3-bromo-2-butanone 15 containing ≤5% of regioisomer 16 according to NMR. HPLC, or GC, can also be used to evaluate the 15:16 ratio of regioisomers in the distillate.

The interaction of 3-bromo-2-butanone 15 with ethylene glycol in the presence of catalytic amounts of p-toluenesulfonic acid monohydrate in toluene, with simultaneous azeotropic distillation of the water formed during the reaction, leads to the formation of ethylene ketal 14 .

The next stage includes obtaining 2,3-dimethylphenylmagnesium bromide 10

from 2,3-dimethylbromobenzene 11 , interaction of the resulting organomagnesium reagent with 2-(1-bromoethyl)-2-methyl-1,3-dioxolane 14 and removal of the protective group.

The listed reactions are carried out in one reaction vessel (one pot), without isolation and purification of intermediate intermediates, and lead to the production of ketone 7

Obtaining the Grignard reagent 10 begins with a direct reaction of 2,3-dimethylbromobenzene 11 and magnesium metal in dry tetrahydrofuran (THF) at a temperature not exceeding 50°C (optimally 48-50°C). Short-term heating is required to complete the reaction (70-75°C, 45-60 minutes)

Solvent pretreatment (THF) involves distillation under argon atmosphere and drying with activated 3A molecular sieves. To remove hydroperoxides from THF, standard methods described in the literature can be used, such as sorption with activated alumina, treatment with Dowex-1 anion exchange resin, and distillation with the preliminary addition of hydroquinone ((a) Zakharov L.N. Safety in chemical laboratories 1991; (c) Donald E. Clark Peroxides and peroxide-forming compounds Chem Health Saf 2001, 8, 5, 12-22).

The optimal concentration of 2,3-dimethylphenylmagnesium bromide 10 in the solution is 0.8-1 M. Above this concentration, the viscosity of the solution increases, which complicates the process of its addition during cross-coupling.

Determination of the concentration and yield of 2,3-dimethylphenylmagnesium bromide 10 in the prepared solution can be performed by titrating an accurate sample of iodine dissolved in a saturated solution of lithium chloride in THF until the brown color of the solution disappears (Paul Knochel. Convenient Titration Method for Organometallic Zinc, Magnesium, and Lanthanide Reagents Synthesis 2006, 5, 890-891).

Establishing the concentration of the organomagnesium reagent in solution by determining the degree of conversion of the starting 2,3-dimethylbromobenzene 11 using GC, followed by extrapolation of the obtained data, cannot be regarded as a correct method for assessing the yield of the organomagnesium reagent, due to the occurrence of a side reaction with the formation of biphenyl 9

Reaction of 2,3-dimethylphenylmagnesium bromide 10 with 2-(1-bromoethyl)-2-methyl-1,3-dioxolane 14 in the presence of 10 mol% cobalt acetylacetonate (III) and 10 mol% N,N,N',N' -tetramethylethylenediamine (TMEDA) in THF at 0°C leads to the formation of a new C-C bond, and the formation of a cyclic ketal 8

Cyclic ketal 8 is easily cleaved in an acidic medium (10% hydrochloric acid, hydrolysis rate<5 min, UPLC monitoring), which makes it possible to carry out the deprotection process simultaneously with the quenching of the reaction mixture.

As a result of optimization of the cross-coupling reaction, it was found that a decrease in the amount of catalyst from 10 to 5 mol% leads to a decrease in the yield of ketone 7 from 87.2 to 60%.

After extraction with a non-polar solvent (heptane) and concentration in vacuo, ketone 7 contains a significant amount (≥20% according to NMR data) of ethylene glycol, which is formed as a result of the cleavage of the protecting group and is distilled in vacuo along with the product, which leads to a broadening of the distillation temperature range to 10°C, and as a result, to a decrease in yield, due to the need to separate a larger amount of pre-run before the start of collecting the main fraction.

Removal of ethylene glycol impurity from 3-(2,3-dimethylphenyl)butan-2-one 7 before vacuum distillation is carried out by repeated washing of the product with water. Due to the density of ketone 7 , which is close to that of water, the washing process is complicated by the formation of a stable emulsion. Preliminary dilution of crude ketone 7 with hexane, or another light non-polar solvent (~1:1.5 vol.), makes it possible to completely avoid the formation of an emulsion during the washing process. The completeness of the removal of ethylene glycol impurities is controlled by NMR spectroscopy, by the disappearance of the methylene group signal (3.76 ppm, s, CDCl ₃ ), or by GC.

The second by-product formed during the cross-coupling reaction is 2,2',3,3'-tetramethylbiphenyl 9 , which must also be separated before the distillation process, since it is volatile in vacuum and serves as a source of contamination of the target ketone 7 in end of the distillation process.

Efficient removal of most of the 2,2',3,3'-tetramethylbiphenyl (>95% by HPLC) is achieved by diluting crude ketone 7 with methanol (1:1 vol.), followed by crystallization of biphenyl 9 at -15...-20°C in within 2 days. The crystallization time can be reduced to about 20 hours by seeding the solution obtained from the VAT residue of crystalline 9 .

Removal of traces of cobalt compounds can be carried out by sorption of the latter by activated (120°C, 20 h) silica gel with a particle size of 40-63 μm in a non-polar organic solvent such as hexane.

At the next stage, the resulting 3-(2,3-dimethylphenyl)butan-2-one 7 is brominated with molecular bromine at the terminal methyl group to form 1-bromo-3-(2,3-dimethylphenyl)butan-2-one 5

The optimal solvent providing the highest regioselectivity is methanol. The bromination process proceeds in a wide temperature range (from -15°C to room temperature), however, the amount of by-products (di- and tribromo derivatives) formed during the reaction, as well as its rate, are extremely dependent on both the temperature and the concentration of the initial ketone in solution.

Bromination at room temperature (20-25°C) occurs already at the moment of adding bromine, and ends in a few minutes. However, with this mode of bromination, the amount of impurities of polybrominated products greatly increases (HPLC area of the target product 5 ≤49%).

When carrying out the bromination reaction at -12°C, the rate of formation of polybrominated impurities is significantly slowed down (HPLC area 5 81%, HPLC area of dibromoketone<5%), however, it takes about 28 hours to achieve a degree of conversion of the original ketone>95% (HPLC).

The optimum temperature range for bromination is from -5 to -8°C.

The use of the stoichiometric bromine:ketone 7 results in only ≤85% conversion of the latter (HPLC). To achieve complete conversion of the initial ketone, at least 1.15 equivalents of bromine is required, optimally 1.20-1.25 equivalents of bromine.

Control over the course of side processes is also achieved by the degree of dilution of the solution. The use of less than 10 ml of solvent per 1 g of ketone leads to a sharp increase in side processes accompanied by the formation of polybrominated impurities. The optimal concentration of ketone 7 in solution is in the range of 0.18-0.22 mol/l.

The addition of bromine to the methanolic ketone solution should be carried out as quickly as possible, preferably in one portion, since with slow addition, or dropwise addition, a noticeable amount (> 10% HPLC area) of an impurity of the regioisomeric bromination product 20 is formed

To complete the reaction, it may be necessary to increase the temperature to 0°C (after about 17-18 hours), and hold at this temperature until the bromine color disappears completely. In the case of incomplete conversion of the original ketone 7 may require the addition of additional portions of bromine, which allows to achieve >97% (HPLC) conversion 7 .

1-Bromo-3-(2,3-dimethylphenyl)butan-2-one dimethyl acetal formed during the bromination reaction 6

easily cleaved one pot without isolation (hydrolysis rate at pH 3<2 min, UPLC) by excess hydrogen bromide contained in the reaction mixture after dilution with water, resulting in the formation of 1-bromo-3-(2,3-dimethylphenyl)butane-2- she 5 , which is used in the next step without further purification. Product 5 is not stable at room temperature and darkens quickly, but can be stored at -18°C for several weeks without significant degradation.

The use of acetic acid, esters such as ethyl acetate or halogenated hydrocarbons as solvents leads to the formation of predominantly highly substituted 3-bromo-3-(2,3-dimethylphenyl)butan-2-one 20 .

The use of pyridinium perbromide bromide (PHBP, 19 ) in THF, ethyl acetate, or glacial acetic acid as a brominating agent also results in almost exclusively 3-bromo-3-(2,3-dimethylphenyl)butan-2-one 20 , and a small the amount of impurity of polybrominated compounds.

3-(2,3-dimethylphenyl)-2-oxobutyl acetate (structure 4 ), which is a precursor for the formation of the imidazole ring in the medetomidine molecule, in the case of synthesis along route A (Scheme 1)

prepared by reacting 1-bromo-3-(2,3-dimethylphenyl)butan-2-one 5 with potassium acetate (~3 eq) in a suitable organic solvent (acetonitrile, DMF, DMSO) at room temperature.

In the case of using low-boiling solvents (such as acetonitrile), 4 can be isolated from the reaction mixture by simply concentrating the solution in vacuo, after pre-filtering the precipitate of potassium bromide and excess potassium acetate.

Removal of traces of acetonitrile is achieved by washing a solution of 4 in a non-polar solvent (hexane, heptane, MTBE, ethyl acetate, etc.) with water, followed by concentration. The resulting 3-(2,3-dimethylphenyl)-2-oxobutyl acetate 4 is quite pure and can be used at the next stage of the synthesis without additional purification.

Acetonitrile regenerated (>90%) during processing of the reaction mixture can be used without additional preparation at the next charge (at this stage of synthesis), without deteriorating the quality of the product 4 .

Carrying out the reaction in methanol at room temperature leads to a low conversion of the starting 1-bromo-3-(2,3-dimethylphenyl)butan-2-one (<60% in 43.5 hours). Increasing the reaction temperature in the case of using methanol as a solvent to increase the conversion leads to a sharp increase in side processes, which gives a product unsuitable for use in the next stage without additional purification.

The advantage of carrying out the reaction in DMF or DMSO is the reduction of the reaction time from 18-20 hours (in the case of acetonitrile) to 5-6 hours (DMF), however, in this case, dilution of the reaction mixture with a large volume of water (3-5 vol.), followed by extraction of the product with a low-boiling organic solvent (hexane, heptane, MTBE, ethyl acetate, etc.).

The final stage of the process includes the formation of an imidazole ring, with the formation of medetomidine in the form of a copper (I) complex 3 ,

isolation of the free base of medetomidine 2 ,

removing traces of copper, and obtaining a pharmaceutically acceptable salt such as medetomidine hydrochloride 1

The interaction of 3-(2,3-dimethylphenyl)-2-oxobutyl acetate 4 with formaldehyde, ammonia and copper (II) acetate in an aqueous-alcoholic solution according to the Weidenhagen reaction (Weidenhagen R. Chem. Ber. 1935, 68, 1953) leads to the formation of a copper (I) complex of medetomidine 3 .

The optimal alcohol co-solvent for carrying out the reaction is n-propanol, which provides complete solubility of the starting 3-(2,3-dimethylphenyl)-2-oxobutyl acetate 4 in aqueous ammonia solution. The optimal amount of n-propanol is from 10 to 15 ml per 1 g of 3-(2,3-dimethylphenyl)-2-oxobutyl acetate 4 . In this case, the precipitation of the copper (I) complex of medetomidine during the reaction occurs in the form of a well-formed crystalline precipitate.

The use of a smaller volume of n-propanol leads to incomplete dissolution 4 and, as a result, to the formation of an emulsion, which in turn leads to the precipitation of the medetomidine copper complex on the walls of the reactor and on the stirrer in the form of a dense deposit, which complicates the filtration process. In addition, due to the reaction proceeding on the surface of droplets, and not in a homogeneous medium, incomplete conversion of the initial 4 occurs, and, as a result, a drop in the yield of the product and its contamination with an unreacted precursor.

The use of a larger volume of n-propanol is impractical due to the solubility of complex 3 , which can lead to a decrease in its yield. The reaction proceeds at the boiling point of the solution (62-72°C), and ends in 2 hours. A shorter heating time (<1.5 h) results in a drop in the yield of copper complex 3 from 80.9 to 58.5% at this stage. The use of methanol, ethanol or isopropanol as co-solvents also leads to precipitation of the copper complex of medetomidine on the walls of the reactor, due to their insufficient dissolving power with respect to 4 .

The traditional method for isolating free imidazoles from the copper complex is to precipitate copper as copper(I) sulfide under the action of hydrogen sulfide gas. However, this method cannot be considered as a scalable industrially acceptable process due to the high toxicity of hydrogen sulfide.

The method described by us avoids the use of hydrogen sulfide, and is based on the use of non-toxic chelators.

The optimal chelating agent is diethylenetriaminepentaacetic acid pentasodium salt (Na ₅ DTPA). The optimal molar ratio of metal: complexing agent in this case is in the range of 1: 1.2-1.5.

Tetrasodium salt of ethylenediaminetetraacetic acid (Na ₄ EDTA) has insufficient chelating ability with respect to the copper (I) complex of medetomidine, which leads to low conversion of the initial complex and incomplete release of medetomidine base even when using a 3-5-fold molar excess of a chelating agent and a long holding time reactions (>4 days).

The equilibrium shift of the process is also achieved by continuous extraction of the medetomidine base into the organic phase, which facilitates the reaction due to the constant removal of the product from the surface of the copper complex crystals. To increase the reaction rate, it is necessary to ensure thorough mixing of the phases.

The use of free acids, such as EDTA or DTPA, as well as their incompletely substituted salts, such as the disodium salt of ethylenediaminetetraacetic acid (Na ₂ EDTA) as chelating reagents, to isolate the free base of medetomidine 2 from the copper complex 3 , leads to the formation of resinous products complex composition, probably due to the presence of free carboxyl groups, simultaneously interacting with the main nitrogen atom of the imidazole ring and the copper ion.

The formation of a pharmaceutically acceptable salt, such as medetomidine 1 hydrochloride, occurs by reacting medetomidine 2 base with an acid, such as hydrochloric acid, in a suitable organic solvent. Due to the high solubility of medetomidine 1 hydrochloride in water, when using concentrated (35-38%) hydrochloric acid in acetone, problems with crystallization of the product may occur. In this case, to initiate crystallization, it is necessary to add a seed, in the form of a small amount of crystals of pure medetomidine hydrochloride. The seeding at the stage of salt formation favorably affects the crystallization process, which occurs immediately, or almost immediately after the addition of concentrated hydrochloric acid. It takes about a day to complete the crystallization process 1 . The yield of medetomidine hydrochloride can be increased from 56.2 to 60-65% (based on 2 stages) by concentrating the mother liquor (up to approximately 1/3 of the original volume) after filtering the main portion of the crystals, followed by cooling the water-acetone solution for 20 -25 hours in the freezer.

Replacing formaldehyde at the stage of formation of the copper complex with other aldehydes is a convenient way to obtain medetomidine derivatives having a substituent in position 2 of the imidazole ring.

An alternative method for the formation of an imidazole fragment in the medetomidine molecule is route B (Scheme 2).

In this case, 1-bromo-3-(2,3-dimethylphenyl)butan-2-one 5 is reacted with sodium diformylamide 21

in a suitable organic solvent such as acetonitrile, resulting in intermediate 22,

which can be used in the next step without further purification.

The starting, commercially available sodium diformylamide 21 used in the synthesis of compound 22 can also be obtained by literature methods from sodium methoxide and formamide in high yield (for example, (a) Allenstein E. Chem. Ber. 1967, 100, 3551; (b) US5599986A).

Acid hydrolysis of compound 22 leads to the formation of aminoketone hydrochloride 23

The final step of the process (Route B; Scheme 2) involves the formation of a 2-mercapto-substituted imidazole ring, followed by desulfurization leading to the formation of medetomidine 2 .

The interaction of 1-amino-3-(2,3-dimethylphenyl)butan-2-one hydrochloride 23 with potassium thiocyanate in aqueous solution according to the Marckwald reaction (Marckwald W. Ber. Dtsch. Chem. Ges. 1892, 25, 2354) leads to formation of 4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazole-2-thione 24

The reaction proceeds smoothly when aminoketone hydrochloride 23 is heated with an excess (4-5 eq) of potassium thiocyanate in an aqueous solution at the boiling temperature. The optimum heating time is 2.5 to 3.5 hours. The reaction product 24 is practically insoluble in water, in contrast to the starting reagents, and crystallizes out of the solution as the reaction progresses, which greatly simplifies the process of its isolation. If necessary, 4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazole-2-thione 24 can be purified by crystallization from aqueous ethanol (~65% v/v).

Gentle removal of the mercapto group in compound 24 using Raney nickel in an alcohol medium leads to the formation of medetomidine 2 in high yield. Best results are obtained using Raney nickel grades W-4 and W-5 (see Robert L. Augustine. Heterogeneous Catalysis for the Synthetic Chemist 1996 for a classification).

The creation of an imidazole ring in the medetomidine molecule can also be performed directly in one step by reacting 1-amino-3-(2,3-dimethylphenyl)butan-2-one hydrochloride 23 with formamide (Scheme 3. Pathway C). Despite a moderate yield (~40%), the reaction is very easy to perform. Since formamide is used in excess (~10 equiv), and acts in the reaction both as a solvent and as a reagent, and also has a high boiling point (210°C), before extracting the medetomidine base from the reaction mixture, it is advisable to hydrolyze the excess formamide using concentrated hydrochloric acid (1 hour, room temperature).

experimental part

List of abbreviations

Abbreviation Meaning AAS Atomic absorption spectroscopy acac Acetylacetonate AcOH Acetic acid ACOK potassium acetate aq Water solution area Chromatographic Peak Area d doublet dd Doublet of doublets DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol GC Gas chromatography HPLC High Performance Liquid Chromatography m Multiplet Me ₂ CO Acetone MeCN Acetonitrile MeOH methanol MeONa Sodium methylate MTBE Methyl tert-butyl ether _Na2EDTA Ethylenediaminetetraacetic disodium salt
acids _Na4EDTA Tetrasodium salt of ethylenediaminetetraacetic
acids _Na5DTPA Pentasodium salt of diethylenetriaminepentaacetic
acids NMR Nuclear magnetic resonance n-PrOH n-propanol one pot One-pot synthesis PHBP Pyridinium perbromide bromide PhMe Toluene p-TsOHxH ₂ O Para-toluenesulfonic acid monohydrate q quadruplet Raney Ni Raney Nickel Reflux Refluxing RF Retention ratio RT Room temperature s Singlet THF Tetrahydrofuran TMEDA N,N,N',N'-Tetramethylethylenediamine tR retention time UPLC Ultra performance liquid chromatography

General Methods

The starting 2,3-dimethylaniline 13 was purchased from Sigma-Aldrich (99%, CAS 87-59-2) and used without further purification. All experiments in which an inert atmosphere was used were performed according to the standard technique using the Schlenk line. Argon 99.999% (Linde Gas) was used as an inert gas without additional purification. All solvents and reagents were purchased from commercial suppliers and used without further purification or preparation, except for THF and methanol. THF (ACS 99.6%) was distilled in an argon atmosphere (with the addition of ~0.1% hydroquinone) before use, and dried on activated 3A molecular sieves (100 g/l) for 65 hours. The methanol used in the bromination reaction was dried with activated 3A molecular sieves (45 g/l) for 168 hours. Molecular sieves were activated by heating in vacuum (0.01 mmHg) at 300–320°C for 3 hours. For the synthesis of the organomagnesium reagent, Turnings for Grignard Reaction magnesium shavings from Fisher Chemical were used, which were stored in an oven at 120°C. Determination of the concentration of 2,3-dimethylphenylmagnesium bromide was carried out by direct iodometric titration in a saturated solution of lithium chloride in dry THF according to the method of Paul Knochel. Parts of glass installations (with the exception of large volume reactors) used in the preparation of organomagnesium reagent 10 and cross-coupling were dried in an oven at 120°C for 24 hours. The glass reactors were dried before handling moisture sensitive compounds in a rotary vane pump vacuum (0.01 mmHg) by heating with a coolant for 2 hours at 90°C, and filled with argon in three pumping/filling cycles. The ¹ H and ¹³ C NMR spectra were recorded on an Agilent 400 MHz spectrometer (400 MHz for ¹ H and 100 MHz for ¹³ C) in CDCl ₃ and D ₆ -DMSO. Chemical shifts are expressed in ppm relative to the residual signals of the deuterated solvents used. The determination of the residual content of heavy metals was carried out on an Agilent Technologies 240 AA atomic absorption spectrometer. To prepare samples for the determination of heavy metals, a MARS One microwave decomposition system was used. A mixture of 70% nitric acid and 30% hydrogen peroxide (10:1 vol., 180°C, 25 min) was used as an oxidizing agent for sample mineralization. TLC analysis was performed on ALUGRAM Xtra SIL G/UV ₂₅₄ aluminum plates (Macherey-Nagel). The plates were visualized with a 254 nm ultraviolet lamp. The completeness of the reactions and the evaluation of the chromatographic purity of the intermediates were monitored using an Alliance HPLC system (Waters) with a photodiode array detector (PDA).

Analytical conditions

Method A

Instrument: Waters Alliance HPLC; Column XBridge C18, 3.5 µm, 4.6 mm x 150 mm; Eluent A: MeCN; Eluent B: H ₂ O + 0.15% vol. ₅₀ % _H3PO4 ; Eluent ratio A:B: 50:50; Isocratic elution mode; Flow rate 1.50 ml/min; Temperature 40°C; Injection volume 10 µl; Detection wavelength: 190-350 nm.

Method B

Instrument: Waters Alliance HPLC; Column XBridge C18, 3.5 µm, 4.6 mm x 150 mm; Eluent A: MeCN; Eluent B: H ₂ O + 0.15% vol. ₅₀ % _H3PO4 ; Eluent ratio A:B: 30:70; Isocratic elution mode; Flow rate 1.00 ml/min; Temperature 40°C; Injection volume 10 µl; Detection wavelength: 190-350 nm.

Method C

Instrument: Waters Alliance HPLC; Column XBridge C18, 3.5 µm, 4.6 mm x 150 mm; Eluent A: MeCN; Eluent B: H ₂ O + 0.15% vol. ₅₀ % _H3PO4 ; Gradient: 0-1.20 min 30% A, 1.20-12.00 min 30-90% A, 12.00-15.00 min 90% A, 15.01-18.00 min 90-30% A; Flow rate 1.20 ml/min; Temperature 40°C; Injection volume 10 µl; Detection wavelength: 190-350 nm.

experimental part

2,3-dimethylbromobenzene (11)

(Modified procedure J. Chem. Soc. 1940, 16-18)

In a 10 l glass reactor with a thermostatically controlled jacket, equipped with a mechanical stirrer, pre-cooled to -10°C, load 3747.5 g (22.23 mol; 4.0 eq) of 48% hydrobromic acid and 750 ml of deionized water. The solution is cooled to 4...5°C, and with stirring (250-300 rpm), 673.45 g (5.55 mol; 1.0 eq) of 2,3-dimethylaniline 13 is added from a dropping funnel within 45 minutes, at such a rate that the temperature of the reaction mixture was kept in the range of 4...5°C. The resulting suspension of beige crystalline 2,3-dimethylaniline hydrobromide is cooled to -1 ... -2 ° C, and a solution of 421.8 g (6.12 mol; 1.10 eq) of sodium nitrite in 680 ml of deionized water is added from a dropping funnel over 2 hours, with this speed so that the temperature of the reaction mixture is kept in the range of 0 ... -2°C (the temperature of the coolant in the reactor jacket is -15°C). After adding the sodium nitrite solution, the temperature of the reaction mixture was raised to 0° C. and the tan solution of 2,3-dimethylphenyldiazonium bromide 12 was stirred for 15 minutes to complete the diazotization process. Further, the stirrer speed is increased (up to 450-500 rpm), a suspension of 100 g of freshly deposited copper powder in 350 ml of deionized water is introduced into the reactor, and the coolant temperature in the reactor jacket is increased to 30°C. When the reaction mixture is heated to 28...30°C, the exothermic process of decomposition of the diazonium salt begins with a spontaneous increase in the temperature of the reaction mixture to 60°C for 4-5 minutes. After the cessation of spontaneous temperature rise, heating and circulation of the coolant in the reactor jacket are started, and the violet-black reaction mixture is heated at 70°C for 30 minutes. The reaction mixture is cooled to room temperature, and extracted with 2×1000 ml of light petroleum ether (40-70). The lower aqueous layer is drained through the bottom outlet, and the dark organic phase is successively washed in the reactor with 4 L of deionized water (10 minutes), and 4×4 L of 2.5% sodium hydroxide solution (10 minutes each) to remove 2,3-dimethylphenol impurities. The organic phase is separated and concentrated in vacuo (<40°C). The resulting orange-red oil is steam distilled from a solution containing 50 g of sodium hydroxide in 1 liter of deionized water, collecting 3.5 liters of distillate. The transparent lower layer of light orange color is separated, and intensively stirred for 40 minutes with 100 ml of concentrated sulfuric acid on a magnetic stirrer. The lower dark red sulfuric acid layer is separated in a separating funnel, and the upper, light yellow organic layer is washed with 2×600 ml of saturated sodium bicarbonate solution. The aqueous phase is extracted with 3×100 ml of methylene chloride. The combined organic phase is dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting 2,3-dimethylbromobenzene is subjected to fractional distillation in a vacuum using a 300 mm high Vigreux reflux condenser with an evacuated jacket, collecting a fraction with a _{bp of} 76.2-76.5°C/6 mmHg.

Yield 391.8 g (38.1%). Colorless liquid with a characteristic xylene-like odor. ¹ H NMR (400 MHz, _CDCl3 ) δ 7.43 (d, 1H), 7.11 (d, 1H), 6.97 (t, 1H), 2.40 (s, 3H), 2.36 (s, 3H); ¹³ С (100 MHz, CDCl ₃ ) δ 138.61, 136.24, 130.34, 128.97, 126.88, 125.67, 21.39, 19.51; tR 11.33 min (HPLC Area 99.7%, method A).

3-bromo-2-butanone (15)

(modified procedure Rec. Trav. Chim. Pays-Bas 1946, 65, 691).

1200 ml of deionized water, 300 ml of glacial acetic acid, and 360.5 g (447.8 ml; 5.0 mol) of methyl ethyl ketone 17 are charged into a 3 L glass reactor with a thermostatically controlled jacket equipped with a mechanical stirrer with a hermetic seal, an addition funnel with a tube for pressure equalization and a reflux condenser. 800.0 g (257.9 ml; 5.0 mol; 1.0 eq) of bromine are charged into the dropping funnel. The solution in the reactor is heated to 70° C. and bromine is added dropwise over 4 hours, at such a rate that the yellow color that appears at the beginning has time to disappear with the addition of subsequent portions of bromine. During the addition of bromine, an emulsion is formed, and then the reaction mixture separates into 2 phases. After adding all the bromine, the reaction mixture is stirred at 70°C for another 30 minutes, then cooled to room temperature, and diluted with 1 l of cold water (2°C). The lower light yellow layer is separated through the bottom outlet of the reactor, and washed with 3x400 ml of a saturated sodium bicarbonate solution (on a magnetic stirrer, in a loosely closed 1000 ml conical flask), until the evolution of carbon dioxide ceases, and then with 400 ml of deionized water. The resulting mixture of regioisomeric bromobutanones 15/16 (546.1 g) was dried with anhydrous granular calcium chloride, filtered, and separated by vacuum distillation on a distillation column (filled with Raschig rings) 800 mm high with an evacuated jacket. The first portion of the distillate (about 10 ml) with t _bp 58-60°C/38 mmHg is separated, then the main fraction of 3-bromo-2-butanone 15 is collected with t _bp 61-63°C/38 mmHg, then the intermediate fraction with t _bp 64-77°C/38 mmHg, and finally a fraction of 1-bromo-2-butanone 16 with _bp 77-78°C/38 mmHg. Running the vacuum distillation process at too low a speed will cause the distillate to turn yellow.

3-bromo-2-butanone (15)

Yield 279.74 g (37.0%). Light yellow liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.37 (q, 1H), 2.34 (s, 3H), 1.71 (d, 3H); ¹³ С (100 MHz, СDCl ₃ ) δ 202.11, 48.28, 26.04, 20.20. Content of regioisomeric 1-bromobutan-2-one 16 <5% (NMR). tR 5.35 min (HPLC Area 96.9%, method B).

1-bromo-2-butanone (16)

Yield 48.15 g (6.4%). Yellow liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.87 (s, 2H), 2.65 (q, 2H), 1.09 (t, 3H); ¹³ С (100 MHz, СDCl ₃ ) δ 209.92, 52.65, 29.13, 9.35; tR 4.64 min (HPLC Area 88.9%, method B).

2-(1-bromoethyl)-2-methyl-1,3-dioxolane (14)

259.12 g (1.71 mol) of freshly distilled 3-bromo-2-butanone 15 , 117.2 g (1.88 mol; 1.10 eq) of ethylene glycol, 1.58 g (8.30 mmol; 0.0048 eq) of para-toluenesulfonic acid monohydrate and 800 ml of toluene . The flask is equipped with a 50 ml Dean-Stark trap under reflux, and the reaction mixture is refluxed with stirring on a magnetic stirrer until no more water droplets separate in the receiver (31 ml; 3.5 hours). As the reaction proceeds, the lower ethylene glycol layer disappears. The clear, colorless solution is cooled to room temperature, washed with 500 ml of 2% sodium hydrogen carbonate solution, and 2x150 ml of deionized water. The organic layer is separated, dried with anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator (35°C/10 mmHg), focusing on the distillation volume (760-780 ml). The product is distilled in vacuum, collecting a fraction with t _bp 43.5-44.5°C/0.016 mmHg.

Yield 271.93 g (81.2%). Colorless liquid with no lachrymatory action. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.05 (q, 1H), 3.99 (m, 4H), 1.67 (d, 3H), 1.45 (s, 3H); ¹³ С (100 MHz, СDCl ₃ ) δ 109.96, 64.74, 53.22, 21.22, 20.65; tR 8.11 min (HPLC Area 88.2%, method B).

3-(2,3-dimethylphenyl)butan-2-one (7)

33.90 g (1.39 mol; 1.05 eq.) . The flask is evacuated and filled with dry argon for 3 cycles. About 0.8 g of iodine is added to the flask, and the flask is heated with hot air until the iodine sublimes. After cooling the flask to room temperature, the magnesium is covered with 147 ml of dry THF and a magnetic anchor is placed in the flask. A solution of 245.67 g (1.32 mol; 1.0 eq) of 2,3-dimethylbromobenzene 11 in 1000 ml of dry THF is loaded into an addition funnel. About 40-50 ml of solution is added to magnesium shavings from a dropping funnel in one portion. The reaction starts immediately after adding the first portion of the solution from the dropping funnel, the iodine color disappears and the temperature rises rapidly (<1 min) to 48°C. After the temperature of the reaction mixture stops rising, the solution is immediately added from the dropping funnel with active stirring (1300-1500 rpm), at such a rate that the temperature of the reaction mixture is maintained in the range of 47-49°C without external heating or cooling ( about 5 hours). After all 2,3-dimethylbromobenzene was added, the dark reaction solution was refluxed for 45 minutes at 70-75° C. to complete the reaction. The solution is cooled in an argon atmosphere. The concentration of 2,3-dimethylphenylmagnesium bromide 10 in the resulting solution, determined by the method of Paul Knochel, is 0.99 mol/l. The yield of 2,3-dimethylphenylmagnesium bromide is 92.7%. The resulting solution 10 is directly used in the next step without further preparation.

A 5 L glass reactor with a thermostatically controlled jacket, equipped with a mechanical stirrer with a hermetic closure, a thermocouple, and a stopcock for introducing inert gas is pumped out (<0.1 mmHg) and dried for 2 hours at 90°C. The reactor is cooled to room temperature and filled with dry argon (3 pump/fill cycles). 41.93 g (10 mol%; 117.7 mmol) of cobalt (III) acetylacetonate, 520 ml of dry THF, 17.65 ml (13.67 g; 10 mol%; 117.7 mmol) of TMEDA, and 229.67 g (1.177 mmol) of ; 1.0 eq) 2-(1-bromoethyl)-2-methyl-1,3-dioxolane 14 . The suspension is cooled to 0...-1°C, and with stirring (300-400 rpm) for 180 minutes, a solution of 2,3-dimethylphenylmagnesium bromide 10 prepared in the previous stage is added to the reactor for 180 minutes using a peristaltic pump, at a rate of 6.9- 7 ml/min, carefully maintaining the internal temperature in the range from 0 to -1°C (the temperature of the coolant in the jacket of the reactor, providing good control of the reaction from -10 to -12°C). As the solution of the Grignard reagent is added, the color of the reaction mixture changes from green to blue-blue, and a bulk precipitate of magnesium bromide crystallizes out of the solution. After adding all of 2,3-dimethylphenylmagnesium bromide (1.05 eq), the temperature of the reaction mixture was raised to 20° C. and stirring was continued for 1 hour. 1460 ml of 9% hydrochloric acid are slowly (over 2-3 minutes) added to the reaction mixture under good stirring (400 rpm), and stirring is continued for 40 minutes. During the addition of hydrochloric acid, the color of the reaction mixture rapidly changes from blue-blue to green, and then orange. In this case, the entire crystalline precipitate of magnesium bromide goes into solution. HPLC analysis of an aliquot of the reaction mixture, taken after 30 minutes of stirring, shows 100% conversion of intermediate ketal 8 to ketone 7 . The reaction mixture consisting of 2 phases (upper, light yellow organic, and lower pink-red aqueous) is diluted with 500 ml of n-heptane, the phases are stirred for 15 minutes, and the lower aqueous layer is drained through the bottom outlet of the reactor. The organic phase is washed successively with 2x500 ml of deionized water and 500 ml of saturated sodium hydrogen carbonate solution. The organic phase is dried with sodium sulfate, filtered and concentrated in vacuo (45°C). The obtained orange-yellow oil (224.0 g) was diluted with 240 ml of methanol, and 100 mg of 2,2',3,3'-tetramethylbiphenyl 9 was introduced into the solution as a seed. The solution is kept in a freezer (-18°C) during the day. The suspension of crystals of precipitated 2,2',3,3'-tetramethylbiphenyl 9 is filtered on a Schott funnel and washed with 2×50 ml of cold methanol. The filtrate was concentrated in vacuo, the residue was diluted with 300 ml of hexane, and successively washed to remove ethylene glycol impurities with 1 l of deionized water (10 min), 1 l of 1% aqueous Na ₂ EDTA solution (2 hours), 1 l of saturated aqueous sodium chloride solution (10 min). The completeness of the removal of ethylene glycol is monitored using ¹ N NMR by the disappearance of the signal of the methylene groups (3.76 ppm, s, CDCl ₃ ). The organic phase is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product is distilled under vacuum using a 300 mm high Vigreux reflux condenser with an evacuated jacket. A Perkin receiver is used as a collection of distillate. The fraction with t _bp up to 68-69°C/ 0.024 mmHg is separated, and the main fraction of the product is collected, with t _bp 69-72°C/ 0.024 mmHg.

The resulting amber 3-(2,3-dimethylphenyl)butan-2-one 7 was diluted with 250 ml of hexane and stirred for 1.5 h with 10 g of silica gel (40-63 μm, dried at 120°C for 20 h). The orange-colored silica gel is filtered on a Schott funnel, washed with 3x20 ml of hexane, and the filtrate is concentrated in vacuo on a rotary evaporator. The residue is kept under vacuum (<0.1 mmHg, RT, 30 min) to remove traces of hexane. Yield 161.22 g (77.7%) . Another 19.63 g of product can be isolated by extraction of the combined aqueous phase (4 L) obtained after quenching the reaction mixture with 2 x 200 ml of heptane, followed by purification as described above.

3-(2,3-dimethylphenyl)butan-2-one (7)

Total yield 180.85 g (87.2%). Light yellow liquid. ¹ H NMR (400 MHz, _CDCl3 ) δ 7.08 (d, 2H), 6.91 (t, 1H), 3.97 (q, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.01 (s, 3H), 1.35 (d, 3H); ¹³ C (100 MHz, _СDCl3 ) δ 209.63, 139.22, 137.61, 134.50, 128.90, 126.18, 124.99, 50.58, 28.44, 21.14, 16.93, 15.33; tR 4.88 min (HPLC Area 99.2%, method A).

2,2',3,3'-tetramethylbiphenyl (9)

Yield 10.08 g (7.2%). White crystalline substance. ¹ H NMR (400 MHz, _CDCl3 ) δ 7.14 (m, 4H), 6.96 (d, 2H), 2.34 (s, 6H), 1.96 (s, 6H); ¹³ С (100 MHz, CDCl ₃ ) δ 142.48, 136.79, 134.67, 128.63, 127.41, 125.19, 20.68, 16.55; tR 42.3 min (HPLC Area 98.8%, method A).

1-bromo-3-(2,3-dimethylphenyl)butan-2-one (5)

A 5 L glass reactor with a temperature-controlled jacket, equipped with a mechanical stirrer with a hermetic seal, a thermocouple and a stopcock for introducing an inert gas is evacuated (<0.1 mmHg) and dried for 2 hours at 90°C. The reactor is cooled to room temperature and filled with dry argon (3 pumping/filling cycles). 114.57 g (0.65 mol; 1.0 equiv) of 3-(2,3-dimethylphenyl)butan-2-one 7 in 3420 ml of anhydrous methanol was charged into a dried reactor in a countercurrent of argon. The solution is cooled to -10°C and, with stirring (250 rpm), a freshly prepared solution of 124.65 g (0.78 mol; 1.20 equiv.) ) bromine in 592 ml of methanol (temperature rises to -9°C). The temperature of the reaction mixture is smoothly raised to -5...-6°C, and stirring is continued at this temperature for 18 hours, while monitoring the progress of the reaction using HPLC (method A). Next, the temperature of the reaction mixture (light orange) is gradually raised to 0°C, an additional 5.0 g (0.03 mol) of bromine is added and stirring is continued for 2.5-3 hours to complete the reaction, monitoring the conversion of the starting ketone using HPLC (method A ). After complete completion of the reaction (initial ketone conversion >97%), the clear solution is poured into a 10 L stirred reactor containing 7200 ml of deionized water pre-cooled to 0.5°C. The resulting white emulsion is stirred for 30 minutes and extracted with 4×300 ml of methylene chloride. The organic extract is separated through the bottom outlet of the reactor, combined and washed with 1 L of saturated aqueous sodium hydrogen carbonate solution (300 rpm, 30 minutes), 1 L of deionized water (300 rpm, 30 minutes), and dried with anhydrous sodium sulfate. The solution is filtered and the solvent is removed in vacuo (<30° C.). The residue is used directly in the next step without further purification.

Yield 171.57 g (84.8%). Light yellow transparent oil with no lachrymatory action. ¹ H NMR (400 MHz, _CDCl3 ) δ 7.08 (d, 2H), 6.85 (t, 1H), 4.39 (q, 1H), 3.79 (dd, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 1.40 (d, 3H); ¹³ C (100 MHz, _СDCl3 ) δ 202.70, 138.10, 138.01, 134.54, 129.40, 126.43, 124.95, 46.75, 33.25, 21.04, 17.29, 15.34; tR 8.16 min (HPLC Area 82.0%, method A).

3-bromo-3-(2,3-dimethylphenyl)butan-2-one (20)

8.0 g (45.4 mmol; 1.0 equiv) of 3-(2,3-dimethylphenyl)butan-2-one 7 in 80 ml of ethyl acetate. The solution is cooled to 5°C, a weak flow of argon (100 ml/min) is started, and with good stirring (300 rpm), 15.25 g (47.6 mmol; 1.05 eq) of perbromide bromide are sprinkled through a plastic funnel in portions of approximately 500-600 mg pyridinium 19 , with an interval of approximately 1 min. The color of the reagent instantly disappears, and a crystalline white flocculent precipitate of pyridinium hydrobromide begins to fall out of the solution. It takes about 30 minutes to add all the reagent. The reaction mixture is stirred for 40 minutes at 5°C, and then an additional 1.5 g of pyridinium perbromide bromide is added (total amount of brominating reagent 16.75 g). The reaction mixture is stirred for 10 minutes and diluted with 100 ml of deionized water. Stirring is continued for 5 minutes to dissolve the precipitate of pyridinium hydrobromide, drain the lower aqueous phase and repeat the washing of the organic phase with another 100 ml of deionized water, actively stirring the layers for 5 minutes. . The layers are stirred vigorously for 40 minutes at room temperature, separated, and the light yellow ethyl acetate layer is finally washed with 50 ml of deionized water. The aqueous phase is extracted with 20 ml of ethyl acetate, the combined organic extract is dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo at 40°C. The residue is kept under vacuum to remove traces of ethyl acetate.

Yield 12.0 g (72.5%). Light orange oil that crystallizes in the freezer (-18°C) into yellow needles. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (m, 2H), 7.16 (m, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.09 (s, 3H); ¹³ С (100 MHz, _СDCl3 ) δ 203.10, 138.75, 138.57, 133.86, 130.64, 126.19, 126.11, 73.48, 29.79, 25.29, 20.84, 17.16; tR 7.58 min (HPLC Area 70%, Method A)

3-(2,3-dimethylphenyl)-2-oxobutyl acetate 4 (Pathway A)

191.4 g (1.95 mol; 3.5 eq) of potassium acetate and 1000 ml of acetonitrile are charged into a 2 L round bottom flask. A solution of 171.57 g of crude 1-bromo-3-(2,3-dimethylphenyl)butan-2-one (calculated content of pure 5 140.68 g; 0.55 mol) in 850 ml of acetonitrile is added to the flask in one portion, and the suspension is stirred on a magnetic stirrer (1500 rpm) at room temperature (21°C), monitoring the progress of the reaction using HPLC (method A). After completion of the reaction (19 hours, >99% conversion), the crystalline precipitate of potassium bromide and excess potassium acetate is filtered on a Schott funnel and washed on the filter with 2x200 ml of acetonitrile. The clear light yellow filtrate was concentrated in vacuo (<40° C.) and the residue was diluted with 300 ml MTBE. The organic phase is washed with 2x500 ml of deionized water, the aqueous phase is further extracted with 2x50 ml of MTBE and the combined organic phase is dried over anhydrous sodium sulfate. The solution is filtered and the solvent is removed in vacuo (<35° C.). The residue is used directly in the next step without further purification.

Yield 158.07 g (84.8%). Yellow oil. tR 4.54 min (HPLC Area 69.3%, method A).

A sample of compound 4 was purified for NMR analysis by flash chromatography (silica gel 60, hexane-ethyl acetate 9:1, Rf 0.16). Purified compound 4 is a white waxy mass. ¹ H NMR (400 MHz, _CDCl3 ) δ 7.08 (d, 2H), 6.91 (t, 1H), 4.53 (dd, 2H), 4.04 (q, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.09 (s, 3H), 1.39 (d, 3H); ¹³ C (100 MHz, _СDCl3 ) δ 204.59, 170.26, 137.86, 137.80, 134.34, 129.27, 126.36, 125.13, 67.08, 46.93, 21.10, 20.48, 16.73, 15.30.

Medetomidine hydrochloride 1 (Route A)

A 10 L glass jacketed reactor equipped with a mechanical stirrer, a thermocouple, and an efficient reflux condenser is charged with a solution of 158.07 g of crude 3-(2,3-dimethylphenyl)-2-oxobutyl acetate (calculated pure 4,109.54 g; 0.467 mol) in 1700 ml n-propanol. A solution of 268.72 g (1.34 mol) of copper (II) acetate monohydrate in 2529 ml (2293.9 g; 33.6 mol) of 25% aqueous ammonia solution is added to the reactor with stirring (160 rpm) in one portion. The homogeneous dark blue solution was stirred for 3 minutes and 490 ml (6.64 mol) of 37% formalin were added in one portion to the reactor. The reaction mixture is heated to boiling (heating temperature 100°C) with stirring (160 rpm) for 2 hours. Approximately 10-15 minutes after the start of heating, precipitation of the crystalline copper (I) complex of medetomidine 3 begins. After 2 hours of heating, the reaction suspension is cooled to 16-18°C for 1 hour, and stirring is continued for another 30 minutes at 16-18°C. The precipitate is filtered on a Schott funnel, and successively washed with 1 l of 25% aqueous n-propanol , 1 liter of deionized water and 2x250 ml of acetone. The resulting dark yellow fine crystalline powder was dried in vacuum (6 mmHg) at room temperature for 12 hours. The yield of the copper (I) complex of medetomidine was 99.68 g (58.1% in 3 stages).

2850 g (0.566 mol; 1.50 eq) of a 10% aqueous solution of the pentasodium salt of diethylenetriaminepentaacetic acid (Na ₅ DTPA) and 99.68 g (0.377 mol) of the obtained copper (I) complex of medetomidine 3 are loaded into a 10 l glass reactor equipped with a mechanical stirrer, suspended in 2 liters of ethyl acetate. The phases are stirred (300-350 rpm) at room temperature (23°C) for 24 hours until all solids are completely dissolved. The dark ethyl acetate layer is separated from the intense blue aqueous phase. The aqueous phase is extracted with 2x200 ml of ethyl acetate. The combined organic phase containing medetomidine base was transferred to a 5 L stirred glass reactor and washed successively with 2x500 ml of 0.5% aqueous Na ₅ DTPA solution (30 min each) and 500 ml of saturated aqueous sodium chloride solution (30 min). Medetomidine is removed from the ethyl acetate phase by sequential extraction with 500 ml and 2x350 ml of 10% aqueous acetic acid solution (stirring at 300-400 rpm, 10 minutes for each portion). The medetomidine-depleted ethyl acetate layer was concentrated in vacuo to ~200 ml and an additional 2x300 ml of 10% aqueous acetic acid solution was taken up. The combined aqueous extract (1800 ml) containing medetomidine acetate was transferred to a 5 L stirred glass reactor and extracted successively with 3 x 200 ml MTBE to recover minor impurities. At the same time, the water phase becomes brighter. The dark organic extract (MTBE) was washed once with 100 ml of deionized water, the aqueous phase was combined with the extract containing medetomidine acetate, and the organic phase was discarded. mechanical stirrer, cooled to 8-10°and neutralized with stirring 350 ml of 25% aqueous ammonia solution. The separated medetomidine base 2 was extracted with 3x250 ml of ethyl acetate, the organic layer was washed once with 250 ml of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo (carefully, foaming is possible). The product is a substance of honey-like consistency, amber color, foaming in a vacuum and solidifying in the form of a fragile mother-of-pearl foam. Yield of crude medetomidine base 65.74 g.

The base of medetomidine 2 is dissolved in 250 ml of dry acetone, directly in the flask in which the concentration was carried out. A clear dark solution is cooled to -10°C, and 1.0 g of crystalline medetomidine hydrochloride is added as a seed. The cooled solution with stirring (500-600 rpm) is acidified dropwise with 28.0 ml of 36% hydrochloric acid to pH 2-3. At the same time, the crystallization of a well-shaped precipitate of medetomidine hydrochloride 1 begins. The crystallization process is allowed to complete at -18...-20°C for 23 hours, the product is filtered on a Schott funnel, washed with 3x100 ml of cold (2-3°C) dry acetone, and dried in vacuum at 40°C for 12 hours.

The yield of medetomidine hydrochloride is 50.25 g (56.2% in 2 stages) . Off-white fine crystalline powder (HPLC Area 95.3%, method C). Residual copper content 3.7 ppm (AAS).

For purification, the product is crystallized from acetone containing 3.85% (vol.) water (approximately 9.5 ml of solvent per 1 g of medetomidine hydrochloride). Yield 90% (one purification step, HPLC Area 98.5%, method C). After crystallization twice, the yield is 78-82% (HPLC area 99.5%, method C). Residual copper content after recrystallization <1 ppm (AAS).

White fine crystalline powder. ¹ H NMR (400 MHz, D ₆ -DMSO) δ 9.02 (s, 1H), 7.48 (s, 1H), 7.04 (m, 2H), 6.83 (m, 1H), 4.51 (q, 1H), 2.26 ( s, 3H), 2.24 (s, 3H), 1.51 (d, 3H); ¹³ C (100 MHz, D ₆ -DMSO) δ 141.04, 137.36, 136.71, 134.07, 133.78, 128.30, 125.69, 124.05, 115.80, 31.88, 20.61, 20.31, 14.51; tR 3.11 min (HPLC method C).

Sodium diformylamide 21 (Pathway B)

In a 500 ml round bottom flask filled with argon, 28.42 g (526 mmol) of powdered sodium methoxide and 100 ml of dry methanol are charged (be careful, warm up!), and stirred until complete dissolution. 47.39 g (1.052 mol; 2.0 eq) of formamide are added dropwise to the resulting solution over 2–3 min. The flask is refluxed and the solution is heated at reflux temperature for 1 hour while stirring on a magnetic stirrer. Next, the solution is cooled slightly, and the reflux condenser is changed to a distillation bridge with a descending condenser, and a Claisen nozzle equipped with a thermometer, and an addition funnel containing 132 ml of toluene. The methanol is distilled off by measuring the volume of distillate with a graduated cylinder, and after collecting about 80 ml of distillate, the addition of toluene from the addition funnel is started, at such a rate as to maintain a constant volume of solution in the distilling flask. The distillate is collected until the vapor temperature in the Claisen nozzle reaches 110°C (the total volume of the distillate is about 150 ml). The white suspension is cooled to room temperature and filtered on a Schott funnel. The product was washed with 80 ml THF and dried in vacuo (0.05 mmHg) for 1 hour at room temperature. The resulting product is used directly in the next step without further purification.

Yield 45.68 g (91.4%). White fine crystalline powder.

N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide 22 (Pathway B)

38.46 g (404.7 mmol; 1.4 eq) of diformylamide sodium21, and 400 ml of acetonitrile (water content<0.05%). A solution of 87.50 g of crude 3-(2,3-dimethylphenyl)-1-bromobutan-2-one is added in one portion to the resulting suspension with stirring on a magnetic stirrer5(chromatographic purity 82%; 281.2 mmol) in 400 ml of acetonitrile. The reaction mixture was stirred on a magnetic stirrer in an argon atmosphere at room temperature for 20 hours, after which the flask was refluxed and heated at reflux temperature for 2 hours to achieve conversion of the starting compound5>99% (HPLC method A). The hot dark yellow solution is filtered on a Schott funnel, and the precipitate of inorganic salts is washed with 50 ml of acetonitrile. The clear filtrate is concentrated in vacuo (40° C.) and the dark yellow oil obtained is washed with 350 ml of deionized water while stirring on a magnetic stirrer for 10 minutes. The product is extracted with 300 ml of methylene chloride, the organic phase is separated, and washed with 350 ml of deionized water. The aqueous phase is re-extracted with 30 ml of methylene chloride and the combined organic phase is concentrated in vacuo. The resulting yellow viscous oil is diluted with 250 ml of hexane, directly in the same flask in which the concentration was carried out, and the flask is heated in an oil bath (90°C) under reflux with stirring on a magnetic stirrer for 30 minutes. The mixture is cooled, the upper hexane layer carefully drained and discarded, and the remaining oil is washed again with 100 ml of hexane. The hexane layer is re-drained and the residual hexane is removed from the product in vacuo. The residue is used directly in the next step without further purification.

Yield 51.24 g (63.3%). Yellow viscous oil. ¹ H NMR (400 MHz, _CDCl3 ) δ 8.88 (s, 2H), 7.10 (m, 2H), 6.95 (m, 1H), 4.30 (dd, 2H), 4.03 (q, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.42 (d, 3H); ¹³ C (100 MHz, _СDCl3 ) δ 209.80, 163.27, 138.01, 137.73, 134.60, 129.50, 126.53, 125.59, 48.58, 46.11, 21.10, 16.79, 15.39; tR 3.15 min (HPLC Area 85.9%, method A).

1-amino-3-(2,3-dimethylphenyl)butan-2-one hydrochloride 23 (Pathway B)

47.26 g of crude N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide 22 (chromatographic purity 85.9%; 164.1 mmol) obtained in the previous step are dissolved in 600 ml of 99% ethanol, and to the obtained 65.0 ml of 36% (764 mmol; 4.6 eq) hydrochloric acid is added in one portion to a clear yellow solution. The flask is refluxed and the solution is heated to boiling under argon while stirring on a magnetic stirrer. HPLC analysis of an aliquot of the reaction mixture taken after 15 minutes shows >99% conversion of starting compound 22 to aminoketone 23 (HPLC method A). The violet-red solution is concentrated in vacuo and the crystalline residue is dried at 40°C/2 mmHg for 1 hour (on a rotary evaporator). The residue is suspended in 350 ml of diethyl ether, the suspension of crystals is stirred for 10-15 minutes on a magnetic stirrer, filtered on a Schott funnel, and washed with 3x100 ml of acetone. The resulting aminoketone hydrochloride 23 (24.91 g) was recrystallized from a mixture of 315 ml of acetone and 30 ml of deionized water, and dried in vacuum (6 mmHg) at room temperature for 12 hours.

Yield 22.0 g (58.8%). Colorless shiny needles. ¹ H NMR (400 MHz, D ₆ -DMSO) δ 8.40 (s, 3H), 7.08 (m, 2H), 6.88 (m, 1H), 4.25 (q, 1H), 3.73 (dd, 2H), 2.26 ( s, 3H), 2.21 (s, 3H), 1.29 (d, 3H); ¹³ C (100 MHz, D ₆ -DMSO) δ 204.41, 137.95, 137.22, 134.53, 128.83, 125.92, 125.00, 46.37, 45.45, 20.66, 16.58, 15.01; tR 3.10 min (HPLC Area 97.3%, method B).

4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazole-2-thione 24 (Pathway B)

In a 250 ml round bottom flask, 12.63 g (55.4 mmol) of 1-amino-3-(2,3-dimethylphenyl)butan-2-one hydrochloride 23 and 70 ml of deionized water are charged. The suspension of crystals is heated in an oil bath to 50-55°C and stirred for 5 minutes. 26.95 g (277.3 mmol; 5.0 eq) of potassium thiocyanate are added to the suspension with stirring on a magnetic stirrer in one portion, the flask is equipped with a reflux condenser, and the reaction is heated mixture at 125-130°C (bath temperature). After approximately 10 minutes of heating, all solids dissolve to form a clear yellowish solution, from which, on further heating (approximately 30-40 minutes), the product begins to precipitate. After completion of the reaction (total heating time 3 hours 20 minutes), the crystal suspension is cooled to room temperature, and then to 0°C. The crystals are filtered on a Schott funnel, washed with 3x100 ml of deionized water, and a minimum amount of cold 96% ethanol. The product is dried under vacuum (6 mmHg) at room temperature for 12 hours.

Yield 9.42 g (73.1%). Light yellow fine-crystalline shiny powder, odorless. ¹ H NMR (400 MHz, D ₆ -DMSO) δ 11.83 (s, 1H), 11.70 (s, 1H), 7.02 (m, 2H), 6.92 (m, 1H), 6.50 (s, 1H), 4.15 ( q, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 1.38 (d, 3H); ¹³ C (100 MHz, D ₆ -DMSO) δ 141.71, 136.26, 133.71, 133.58, 133.44, 127.89, 125.36, 123.93, 111.40, 31.79, 20.61, 19.92, 14.39; tR 9.49 min (HPLC Area 98.9%, method B).

Medetomidine 2 (Route B)

7.90 g (34.0 mmol) of 4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-thione 24 and 50 ml of 99 % ethanol. In a countercurrent of argon, 35 ml of a freshly prepared suspension of Raney nickel W-4 in 99% ethanol (nickel content in the suspension 0.28 g/ml; 9.8 g; 167 mmol; 4.9 equiv) is transferred into a flask and the contents are stirred for 1.5 hours at room temperature for magnetic stirrer. After 1.5 hours of stirring, a second portion (35 ml; 4.9 eq) of a suspension of Raney nickel W-4 in 99% ethanol is added and stirring is continued at room temperature for 3.5 hours. After the indicated time, a third portion (10 ml; 2.8 g; 47.7 mmol; 1.4 eq) of a suspension of Raney nickel W-4 in 99% ethanol is added, the flask is refluxed, and the reaction mixture is heated under stirring in an inert atmosphere for 2 hours at 95°C to complete the reaction (conversion of the starting compound 24 ≥99.5%). The black suspension is cooled to room temperature and filtered on a Schott funnel. The light yellow clear filtrate is further filtered through a GFA filter and concentrated in vacuo. The resulting light yellow transparent viscous oil of medetomidine base crystallizes into a porous light mass after removing traces of ethanol in vacuo (0.05 mmHg) at room temperature for 20 hours.

Yield 5.85 g (86%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.56 (s, 1H), 7.30–6.62 (m, 5H), 4.35 (q, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 1.56 ( d, 3H); ¹³ C (100 MHz, _CDCl3 ) δ 143.38, 141.31, 136.87, 134.60, 134.16, 128.04, 125.65, 124.77, 117.26, 34.23, 21.01, 20.85, 14.76; tR 3.12 min (HPLC Area 98.0%, method C).

Medetomidine 2 (Route C)

1.29 g (5.66 mmol) of 1-amino-3-(2,3-dimethylphenyl)butan-2-one hydrochloride 23 and 2.55 g (56.6 mmol; 10 eq) of formamide are weighed into a 30 ml glass vial. The vial is purged with argon, a magnetic anchor is placed inside, capped, and the reaction mixture is heated at 160° C. for 2 hours (analysis of an aliquot of the reaction mixture after this time shows >99% conversion of the original 23 ). The reaction mixture is cooled to room temperature, and diluted with 9.63 ml of 36% hydrochloric acid. The homogeneous, transparent yellow solution is stirred on a magnetic stirrer at room temperature for 1 hour to hydrolyze the excess formamide, the precipitated ammonium chloride suspension is diluted with 10 ml of deionized water, and the aqueous phase is extracted with 2x5 ml of ethyl acetate to remove minor impurities. The aqueous phase is cooled to -3...-5°C, and neutralized with 12 ml of 25% aqueous ammonia solution. The separated oil is extracted with 2×10 ml of ethyl acetate, the combined organic extract is washed with 10 ml of deionized water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained base of medetomidine in the form of a light yellow oil foams in a vacuum, and after complete removal of traces of ethyl acetate, it crystallizes in the form of a bulk porous cream-colored mass.

The product can be purified by crystallization from a mixture of cyclohexane-toluene (9:1 v/v), or converted to the hydrochloride by the standard procedure described above.

Yield 0.43 g (38%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.56 (s, 1H), 7.30–6.60 (m, 5H), 4.36 (q, 1H), 2.27 (s, 3H), 2.18 (s, 3H), 1.56 ( d, 3H); ¹³ C (100 MHz, _CDCl3 ) δ 143.38, 141.31, 136.87, 134.60, 134.16, 128.04, 125.65, 124.77, 117.26, 34.23, 21.01, 20.85, 14.76; tR 3.12 min (HPLC Area 95.2%, method C).

Claims (36)

1. Connection 1-bromo-3-(2,3-dimethylphenyl)butan-2-one to obtain medetomidine and its derivatives of the structural formula 5

. 2. Method for the synthesis of compound 5 to obtain medetomidine and its derivatives, including cobalt-catalyzed cross-coupling of a substituted aryl magnesium halide 10

with carbonyl-protected 3-bromo-2-butanone 14

deprotection of one pot to obtain 3-(2,3-dimethylphenyl)butan-2-one 7

followed by halogenation of 3-(2,3-dimethylphenyl)butan-2-one 7 with molecular bromine to obtain the starting 1-bromo-3-(2,3-dimethylphenyl)butan-2-one 5

. 3. A method for obtaining a derivative of medetomidine in the form of a copper (I) complex of formula 3,

including the interaction of compound 5 according to claim 1 with potassium acetate to obtain 3-(2,3-dimethylphenyl)-2-oxobutyl acetate 4,

and a multicomponent reaction of compound 4 with formaldehyde and copper (II) acetate in an aqueous-alcoholic solution of ammonia. 4. Method for obtaining medetomidine of formula 2,

in which the medetomidine base 2 is isolated from the copper (I) complex 3 according to claim 2 by reacting 3 with the pentasodium salt of diethylenetriaminepentaacetic acid (Na ₅ DTPA). 5. The method of claim 4 wherein the pharmaceutically acceptable salts of medetomidine 2 are prepared by reacting the free base of medetomidine 2 with acids in a suitable organic solvent, e.g. medetomidine 1 hydrochloride

reaction of the free base of medetomidine 2 with hydrochloric acid in acetone. 6. Method for producing 4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazole-2-thione medetomidine derivative of formula 24,

including the interaction of compound 5 according to claim 1 with sodium diformylamide 21

to obtain N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide 22,

acid hydrolysis of compound 22 to obtain 1-amino-3-(2,3-dimethylphenyl)butan-2-one hydrochloride 23,

and reaction 23 with potassium thiocyanate. 7. Method for obtaining medetomidine of formula 2

including desulfurization of derivative 24 according to item 5. 8. Method for obtaining medetomidine of formula 2,

including the interaction of compound 5 according to claim 1 with sodium diformylamide 21 to obtain N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide 22, acid hydrolysis 22 to obtain 1-amino-3-(2 ,3-dimethylphenyl)butan-2-one hydrochloride 23 And its interaction with formamide.