Process for the preparation of metomidine and derivatives thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry and discloses a process for obtaining metomidine of formula 2 and its derivatives of formula 3 and formula 24 from a starting compound 5.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry and describes a method for preparing medetomidine and its derivatives. Background Technology

[0002] Medetomidine is a synthetic drug, a racemic mixture of two stereoisomers of 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. Medetomidine is a potent α2-adrenergic receptor agonist with dose-dependent analgesic and / or sedative effects. By acting on G protein-coupled octopamine receptors in invertebrates, medetomidine inhibits mollusc attachment and is used to prevent biofouling on the underwater hulls of marine vessels.

[0003] Most of the described methods for producing metomididine are based on using precursors that already contain an imidazole ring, such as methyl 4(5)-imidazolium carboxylate (US4544664A, 1985), N-(trimethylsilyl)imidazolium (WO2009 / 53709, 2009; CN105254567, 2016; CN106749027, 2017; CN106588777, 2017; CN111253316, 2020 and CN112979552, 2021), 4(5)-acetylimidazolium (CN1058 84691, 2016), 4(5)-iodoimidazole (CN106083724, 2016), (1-triphenylmethyl-1H-imidazol-4-yl)boronic acid (CN108147999, 2018), 4(5)-imidazolium formaldehyde (CN107857731, 2018 and KR2021 / 12112, 2021), 1-dimethylaminosulfonyl-2-(tert-butyldimethylsilyl)imidazolium (CN109608400, 2019) and 1H-imidazolium-4-formonitrile (WO2021 / 89878, 2021).

[0004] However, the preparation of the above precursors is a separate, multi-stage process that usually requires special reaction conditions because these compounds are not commercially available in most cases.

[0005] In particular, patent CN109608400 describes the reaction with n-butyllithium at -78°C to obtain a key precursor (1-dimethylaminosulfonyl-2-(tert-butyldimethylsilyl)imidazolium), which requires the use of a low-temperature unit and a specially designed reactor.

[0006] The (1-triphenylmethyl-1H-imidazol-4-yl)boronic acid used in the method for preparing metomididine described in patent CN108147999 is also not a commercially available precursor. Its preparation is a separate, multi-stage process.

[0007] The method for synthesizing metopridine 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) via the Friedel-Crafts reaction has the disadvantage of using a large amount of excess Lewis acid (titanium tetrachloride in this patent).

[0008] A second synthetic method for preparing medetomidine involves generating an imidazole cycle from an initially imidazole-free precursor. In this case, a linear rather than convergent synthetic scheme is used as a rule, and the imidazole ring is typically generated in the final stage. Specifically, this method relating to the production of medetomidine is described in this invention.

[0009] Currently, very few documents disclose methods related to the production of metoprimidine. Specifically, patents FI77858C (1982), WO2011070069A1 (2011), WO2012 / 172122 (2012), WO2012 / 172120 (2012), WO2013 / 14428 (2013), WO2016 / 120635 (2016), CN106518812 (2017), and CN111217756 (2020).

[0010] One of the first methods for obtaining metomididine is described in patent FI77858C (1982), involving the generation of the imidazole ring, and it is based on the Bredereck reaction (Hellmut Bredereck. Chem. Ber. 1953, 86, 88). Although its yield is moderate (about 30% in the final stage), the reaction is readily carried out and does not require special conditions. However, this patent does not describe any method for synthesizing the key precursor that introduces the Bredereck reaction, but is based on the synthetic methods of α-haloketones known at the time of publication of patent FI77858C (excluding direct halogenation), the most widely used method being based on the interaction of diazomethane with a carboxylic acid halide, followed by a one-pot reaction of the resulting diazonium ketone with the corresponding hydrogen halide (Nierenstein M. Effects of diazomethane on some aromatic acyl chlorides. J. Chem. Soc. Trans. 1915, 107, 1491-1494). Because diazomethane and diazonium are highly explosive and toxic compounds, the use of this technology to produce metoprimidine has serious drawbacks, especially the high risk of explosion when the process is scaled up.

[0011] In our view, the precursor was not prepared by the authors via direct halogenation of the corresponding carbonyl compound, as no practical method for synthesizing 3-(2,3-dimethylphenyl)-2-butanone 7 has been described in the literature to date. 3-(2,3-dimethylphenyl)-2-butanone 7 is mentioned as being composed of 1,5,5,8-trimethyl-6-methylene-tricyclo[3.2.1.0] 2.7 The only publicly available information on the components of the complex, difficult-to-separate mixture of isomeric ketones produced by the rearrangement of oct-3-en-8-ols is the paper by Gabriele Mukheree-Méler et al. (Helv. Chim. Acta 1977, 60, 1758–1780).

[0012] Patent WO2011070069A1 (2011) discloses a synthetic method for producing an imidazole ring in a multi-step process starting from commercially available 2-dimethylbenzoic acid. However, this method has significant drawbacks, namely, the need for hydrogenation under pressure (which is carried out in two stages in this synthesis), the use of specialized equipment (a steel reactor), and gaseous hydrogen.

[0013] Patents WO2013 / 14428 (2013) and WO2016 / 120635 (2016) describe methods for preparing metopridine based on the condensation of 2-bromo-3-(2,3-dimethylphenyl)butanal with formamidine in more than 25% ammonia and ethanol. These methods involve few steps and are highly practical, but require reaction under pressure.

[0014] The methods for producing metopridine disclosed in patents WO2012 / 172122 (2012) and WO2012 / 172120 (2012), which involve the formation of an imidazole ring, based on the Van Loysen reaction of the interaction between 2-(2,3-dimethylphenyl)-1-propanal and toluenesulfonyl methyl isocyanate ((a) Albert M. Van Leusen. Tetrahedron Lett. 1972, 2369-2372; (b) J. Org. Chem. 1977, 42, 7, 1153-1159), have significant drawbacks and limitations. In particular, chromatographic purification of the metopridine base is required, and toxic sodium cyanide is used. Furthermore, similar to the aforementioned patent WO2013 / 14428 (2013), the reaction leading to the formation of the imidazole ring is also carried out under pressure.

[0015] The method for synthesizing metoprimidine described in patent CN106518812 (2017) is also based on the Van Loysen reaction and has similar drawbacks to the aforementioned patents WO2012 / 172122 (2012) and WO2012 / 172120 (2012).

[0016] Therefore, it is necessary to develop novel synthetic routes for the production of medemididine that are safer and significantly cheaper for industrial production. The advantage of our developed synthetic route lies in its ability to modify the final product (medemididine) molecule and obtain various bioactive derivatives.

[0017] Furthermore, our claimed new method for producing metoprimidine and its derivatives is superior to the methods disclosed in patents WO2013 / 14428 (2013) and WO2016 / 120635 (2016) in the following parameters:

[0018] The synthesis of 1,3-(2,3-dimethylphenyl)-2-butanone 7 (a key precursor of metomididine) was carried out in a one-pot process, in which the cross-coupling reaction significantly complicated the carbon skeleton and the removal of protecting groups was carried out in one stage, which greatly reduced the total number of synthetic steps.

[0019]

[0020] 2. Intermediates 1-bromo-3-(2,3-dimethylphenyl)but-2-one 5,3-(2,3-dimethylphenyl)-2-oxobutylacetate 4 and N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide 22 can be used in subsequent steps without further purification.

[0021]

[0022] 3. Since the described synthetic method is based on the generation of the imidazole ring, it is not necessary to use hard-to-reach precursors that already contain such a ring.

[0023] 4. All reactions described in the proposed method for preparing medetomidine are carried out at atmospheric pressure, which eliminates the need for specialized equipment such as high-pressure reactors.

[0024] 5. Any reaction described in the disclosed methods for producing metoprimidine that require cooling or heating is carried out at moderately low (-15°C) or moderately high (≤130°C, routes A and B, and ≤160°C, route C) temperatures, which eliminates the need for specialized equipment such as cryogenic systems and specially designed reactors. Summary of the Invention

[0025] The method according to the invention is disclosed in the following reaction scheme:

[0026] Option 1. Route A

[0027]

[0028] Option 2. Route B

[0029]

[0030] Option 3. Route C

[0031]

[0032] The starting compound for preparing 3-(2,3-dimethylphenyl)but-2-one 7 was commercially available 2,3-dimethylbromobenzene 11.

[0033]

[0034] Alternatively, it can be obtained from 2,3-dimethylaniline 13 according to the methods described in the literature.

[0035]

[0036] The method was improved from J. Chem. Soc. 1940, 16-18, discussed below.

[0037] The reaction begins with the production of 2-dimethylaniline hydrobromide from 13% 2-dimethylaniline and 40% hydrobromic acid. The unrefined and unpurified salt is then introduced into the reaction with nitrous acid generated in situ from sodium nitrite and excess absorbed hydrobromic acid.

[0038] Since the diazotization process is exothermic, the internal temperature of the reactor must be carefully controlled and not allowed to rise above 0°C. This is achieved by changing the rate at which the sodium nitrite solution is added.

[0039] Due to diazonium salt 12

[0040]

[0041] Side reactions and decomposition can occur, and exceeding the specified temperature will lead to a significant decrease in product yield, which has already been observed to some extent below 0.

[0042] Freshly precipitated copper powder is added to a solution of 2,3-dimethylphenyldiazobromide 12, and the solution temperature is raised to above 28°C to decompose the diazonium salt, releasing gaseous nitrogen and generating 2,3-dimethylbromobenzene 11.

[0043] Decomposition of diazonium salt 12 at a sufficiently fast stirring speed can prevent the reaction mixture from foaming due to nitrogen evolution and ensure a smooth process.

[0044] After the temperature spontaneously stops rising, briefly (20-30 minutes) heat the reaction mixture to 70-75°C to complete the process. After cooling, extract with a light organic solvent such as n-hexane, heptane, or light petroleum ether. The use of pentane is not recommended due to its low boiling point, which would result in significant solvent loss during processing and recovery.

[0045] Because a large amount of 2,3-dimethylphenol is formed during the diazotization process.

[0046]

[0047] Washing the extract with a strong alkaline aqueous solution such as sodium hydroxide or potassium hydroxide is a necessary step. Product 11 can be separated from resin impurities by steam distillation from the alkaline solution.

[0048] It is not recommended to use heavy solvents (dichloromethane, chloroform) to extract 2,3-dimethylbromobenzene 11, because their density is close to that of the reaction mixture, and they tend to form stable emulsions in alkaline media, which makes the process of washing the organic phase with alkaline solutions to remove 2,3-dimethylphenol 25 impurities very complicated.

[0049] Structure 14 used in the next step

[0050] The compound can be obtained from commercially available 3-bromo-2-butanone (structure 15) according to standard procedures described, for example, in Greene's Protective Groups in Organic Synthesis 2006.

[0051]

[0052] Medium synthesis.

[0053] The starting material, 3-bromo-2-butanone 15, can also be readily obtained by molecular bromination of methyl ethyl ketone 17 in an aqueous acetic acid solution according to the literature method (e.g., Rec. Trav. Chim. Pays-Bas 1946, 65, 691).

[0054]

[0055] To obtain.

[0056] The bromination of methyl ethyl ketone 17 results in the formation of two regioisomers: 3-bromo-2-butanone 15 and 1-bromo-2-butanone 16.

[0057]

[0058] Therefore, the mixture should be separated by vacuum distillation on an efficient distillation column before introducing protecting groups. According to NMR, a column 800 mm high and 30 mm in diameter packed with Raschig rings provides 3-bromo-2-butanone 15 containing ≤5% regioisomer 16. HPLC or GC can also be used to evaluate the 15:16 ratio of regioisomers in the distillate.

[0059] The interaction between 3-bromo-2-butanone 15 and ethylene glycol in toluene in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate, along with the water formed during the azeotropic distillation reaction, leads to the formation of ethylene ketal 14.

[0060] The next stage includes the preparation of 2,3-dimethylphenyl magnesium bromide 10 from 2,3-dimethylbromobenzene 11.

[0061]

[0062] The resulting organomagnesium reagent reacts with 2-(1-bromoethyl)-2-methyl-1,3-dioxolane-14 and removes the protecting group.

[0063] The listed reactions are carried out in one pot, without the need for separation and purification of any intermediate products, to produce ketone 7.

[0064]

[0065] The preparation of Grignard reagent 10 begins with the direct reaction of 2,3-dimethylbromobenzene 11 and metallic magnesium in dry tetrahydrofuran (THF) at a temperature not exceeding 50°C (optimal temperature is 48-50°C). To complete the reaction, short-term heating (70-75°C, 45-60 minutes) is required.

[0066] Pretreatment of the solvent (tetrahydrofuran) involved 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 adsorption with activated alumina, treatment with Dowex-1 anion exchange resin, and initial addition of hydroquinone during distillation ((a) Zakharov LN Safety in chemical laboratories 1991; (b) Donald E. Clark. Peroxides and peroxide-forming compounds. Chem. Health Saf. 2001, 8, 5, 12-22).

[0067] The optimal concentration of 2,3-dimethylphenyl magnesium bromide 10 in solution is 0.8–1 M. Above this concentration, the solution viscosity increases, which complicates the addition process during cross-coupling.

[0068] The concentration and yield of 2,3-dimethylphenyl magnesium bromide 10 in the prepared solution can be analyzed by titrating an exact weight of iodine dissolved in a saturated lithium chloride solution in tetrahydrofuran until the brown color of the solution disappears (Paul Knochel. Convenient Titration Method for Organo-metallic Zinc, Magnesium, and Lanthanide Reagents. Synthesis 2006, 5, 890-891).

[0069] The initial conversion of 2,3-dimethylbromobenzene 11 was estimated using GC, and the obtained data were then extrapolated to analyze the concentration of organomagnesium reagents in solution. However, due to the side reaction forming biphenyl 9, this method cannot be considered the correct approach for assessing the yield of organomagnesium reagents.

[0070]

[0071] The reaction of 2,3-dimethylphenyl magnesium bromide 10 with 2-(1-bromoethyl)-2-methyl-1,3-dioxolane 14 in THF in the presence of 10 mol% cobalt(III) acetylacetonate and 10 mol% N,N,N',N'-tetramethylethylenediamine (TMEDA) results in the formation of a new bond and a cyclic ketal 8.

[0072]

[0073] Cyclic ketal 8 is readily cleaved in acidic media (10% hydrochloric acid, hydrolysis rate less than 5 minutes, UPLC monitoring), which makes it possible to carry out the deprotection process and quench the reaction mixture simultaneously.

[0074] After optimizing the cross-coupling reaction, it was found that reducing the catalyst dosage from 10 mol% to 5 mol% resulted in a decrease in the yield of ketone 7 from 87.2% to 60%.

[0075] After extraction with a nonpolar solvent (heptane) and concentration in a vacuum, ketone 7 contained a large amount (≥20%) of ethylene glycol, which was formed after the cleavage of the protecting group. This glycol was distilled together with the product in a vacuum, which resulted in an expansion of the distillation temperature range to 10°C, thereby reducing the yield, as more early fractions needed to be separated before the main fractions could be collected.

[0076] Ethylene glycol can be removed from 3-(2,3-dimethylphenyl)but-2-one 7 by repeated washing with water prior to vacuum distillation. Since the density of ketone 7 is close to that of water, the washing process becomes complicated by the formation of a stable emulsion. Preliminary dilution of the crude ketone 7 with n-hexane or other light, nonpolar solvents (~1:1.5 vol.) can completely avoid the formation of any emulsion during washing. Whether the ethylene glycol impurity has been completely removed can be controlled by nuclear magnetic resonance spectroscopy (disappearance of the methylene signal (3.76 ppm, s, CDCl3)) or gas chromatography.

[0077] The second byproduct formed in the cross-coupling reaction is 2,2',3,3'-tetramethylbiphenyl 9, which must also be separated before the distillation process because it is volatile in a vacuum and is a source of contamination for the target ketone 7 at the end of the distillation process.

[0078] Diluting crude ketone 7 with methanol (1:1 by volume) and then crystallizing biphenyl at -15...-20°C for 92 days effectively removed most of the 2,2',3,3'-tetramethylbiphenyl (HPLC results showed greater than 95%). Introducing crystalline compound 9 as a seed crystal into the solution obtained from the residue shortened the crystallization time to approximately 20 hours.

[0079] Trace amounts of cobalt compounds can be removed by adsorbing them onto activated silica gel with a particle size of 40-63 μm in a nonpolar organic solvent (such as hexane) (120 °C, 20 hours).

[0080] In the next stage, the generated 3-(2,3-dimethylphenyl)-2-butanone 7 is brominated at its terminal methyl group to form 1-bromo-3-(2,3-dimethylphenyl)-2-butanone 5.

[0081]

[0082] Methanol is the best solvent to provide the highest regioselectivity. The bromination process is carried out over a wide temperature range (from -15°C to room temperature); however, the amount and rate of byproducts (dibromo and tribromo derivatives) formed during the reaction are highly dependent on the temperature and concentration of the starting ketone in the solution.

[0083] Bromination at room temperature (20-25°C) occurs instantly upon the addition of bromine and ends within minutes. However, using this bromination method, the amount of impurities in the polybrominated products is significantly increased (HPLC area of ​​the target product ≤ 49%).

[0084] When bromination is performed at -12°C, the formation rate of polybrominated impurities is significantly slowed down (HPLC area of ​​581%, HPLC area of ​​dibromoketone <5%); however, it takes about 28 hours to achieve a conversion of >95% (HPLC) of the starting ketone.

[0085] The optimal temperature range for bromination is -5 to -8°C.

[0086] Using a stoichiometric ratio of bromine to ketone results in a conversion rate of only ≤85% for the latter (HPLC). To achieve complete conversion of the starting ketone, at least 1.15 equivalents of bromine are required, optimally 1.20–1.25 equivalents.

[0087] The degree of solution dilution can also be used to control the process on the other side. Using less than 10 ml of solvent per 1 g of ketone leads to a sharp increase in side reactions that accompany the formation of polybrominated impurities. The optimal concentration of ketone 7 in solution is in the range of 0.18-0.22 mol / L.

[0088] The addition of bromine to the methanol solution of the ketone should be carried out as quickly as possible, preferably in a partial manner, because slow or dropwise addition will result in the formation of a significant amount (HPLC area > 10%) of the regioisomeric bromination product 20, which is an impurity.

[0089]

[0090] To complete the reaction, the temperature may need to be raised to 0°C (after approximately 17-18 hours) and maintained at that temperature until the bromine color completely disappears. If the conversion of the starting ketone 7 is incomplete, additional bromine may need to be introduced, which could increase the conversion of compound 7 to greater than 97% (HPLC).

[0091] 1-Bromo-3-(2,3-dimethylphenyl)but-2-one dimethyl acetal 6 is formed during bromination.

[0092]

[0093] The reaction mixture contained excess hydrogen bromide, which readily cleaved in a single pot after dilution with water without separation (hydrolysis rate less than 2 minutes at pH 3, UPLC), forming 1-bromo-3-(2,3-dimethylphenyl)but-2-one 5, which can be used in the next step without further purification. Product 5 is unstable at room temperature and rapidly darkens in color, but can be stored at -18°C for several weeks without significant degradation.

[0094] Using acetic acid, esters (such as ethyl acetate) or halogenated hydrocarbons as solvents will primarily produce 3-bromo-3-(2,3-dimethylphenyl)but-2-one 20, which has the highest degree of substitution.

[0095] When pyridine hydrobromic acid perbromide (PHBP, 19) is used as a brominating agent in tetrahydrofuran, ethyl acetate, or glacial acetic acid, it almost always produces only 3-bromo-3-(2,3-dimethylphenyl)but-2-one 20, as well as a small amount of polybrominated impurities.

[0096] 3-(2,3-Dimethylphenyl)-2-oxobutylacetic acid ester (structure 4)

[0097]

[0098] It is a precursor for forming the imidazole ring in the metomididine molecule. Its synthetic route is A (scheme 1). The preparation method is to react 1-bromo-3-(2,3-dimethylphenyl)but-2-one with potassium acetate (~3 eq) in a suitable organic solvent (acetonitrile, DMF or DMSO) at room temperature.

[0099] When using a low-boiling-point solvent (such as acetonitrile), compound 4 can be separated from the reaction mixture simply by concentrating the solution in a vacuum and pre-filtering the potassium bromide precipitate and excess potassium acetate.

[0100] The solution of compound 4 in a nonpolar solvent (n-hexane, heptane, MTBE, ethyl acetate, etc.) was washed with water and then concentrated to remove acetonitrile. The resulting 3-(2,3-dimethylphenyl)-2-oxobutylacetate 4 was of high purity and could be used in the next stage of synthesis without further purification.

[0101] The acetonitrile (greater than 90%) regenerated during the processing of the reaction mixture can be used in the next feed (this stage of synthesis) without additional preparation and without reducing the quality of product 4.

[0102] The reaction was carried out in methanol at room temperature, and the initial conversion of 1-bromo-3-(2,3-dimethylphenyl)-2-butanone was low (less than 60% conversion within 43.5 hours).

[0103] When methanol is used as a solvent to improve conversion, increasing the reaction temperature leads to a sharp increase in side reactions, resulting in a product that is unsuitable for use in the next stage and requires no further purification.

[0104] The advantage of reacting in DMF or DMSO is that the reaction time is reduced from 18-20 hours (acetonitrile) to 5-6 hours (DMF); however, in this case, the reaction mixture needs to be diluted with a large amount of water (3-5 volumes) to separate the product, and then the product is extracted with a low-boiling organic solvent (hexane, heptane, MTBE, ethyl acetate, etc.).

[0105] The final stage of this process involves the formation of an imidazole ring and the formation of a copper(I) complex of metomididine.

[0106]

[0107] Separation of the free base 2 of metomididine

[0108]

[0109] After removing trace amounts of copper, a pharmaceutically acceptable salt is obtained, such as medemidin hydrochloride 1.

[0110]

[0111] According to the Weidenhagen reaction (Weidenhagen R. Chem. Ber. 1935, 68, 1953), 3-(2,3-dimethylphenyl)-2-oxobutylacetate 4 interacts with formaldehyde, ammonia and copper(II) acetate in an aqueous-alcoholic solution to form a copper(I) complex of metopridine 3.

[0112] The optimal co-solvent for this reaction is n-propanol, which completely dissolves the initial 3-(2,3-dimethylphenyl)-2-oxobutylacetate 4 in aqueous ammonia. The optimal amount of n-propanol is 10 to 15 mL per gram of 3-(2,3-dimethylphenyl)-2-oxobutylacetate 4. In this case, the copper(I) complex of metomididine will preprecipitate during the reaction as a well-crystallized precipitate.

[0113] Using a smaller volume of n-propanol can lead to incomplete dissolution of compound 4, resulting in the formation of an emulsion. This, in turn, causes the copper metoprimidine complex to precipitate as a dense precipitate on the reactor walls and agitator, complicating the filtration process. Furthermore, because the reaction takes place on the surface of droplets rather than in a homogeneous medium, the conversion of the starting compound 4 is incomplete, resulting in a reduced product yield and contamination by unreacted precursors.

[0114] Due to the solubility of complex 3, using a large volume of n-propanol is not feasible, which may lead to a decrease in its yield. The reaction is carried out at the boiling point of the solution (62-72°C) and terminated after 2 hours. Shortening the heating time (less than 1.5 hours) causes the yield of copper complex 3 to decrease from 80.9% to 58.5%. Using methanol, ethanol, or isopropanol as a co-solvent also causes the metomididine copper complex to precipitate on the reactor wall because of their insufficient solubility for compound 4.

[0115] The traditional method for separating free imidazole from copper complexes involves precipitating copper as copper sulfide (I) under the action of hydrogen sulfide gas. However, due to the high toxicity of hydrogen sulfide, this method cannot be considered a scalable and industrially acceptable process.

[0116] Our published method avoids the use of hydrogen sulfide and is based on the use of non-toxic chelating agents.

[0117] The optimal chelating agent is sodium diethylenetriaminepentaacetate (Na5DTPA). In this case, the optimal molar ratio of metal to chelating agent is between 1:1.2 and 1.5.

[0118] The tetrasodium diethylenetriaminetetraacetate (Na4EDTA) has insufficient chelating ability for the copper(I) complex of medetomidine, resulting in low conversion of the initial complex and incomplete release of the medetomidine base even with a chelating agent excess of 3-5 times the molar amount and a long reaction time (>4 days).

[0119] The equilibrium shift in this process is also achieved by continuously extracting the metoprimidine base into the organic phase. The continuous removal of products from the surface of the copper complex crystals promotes the reaction. To accelerate the reaction, it is essential to ensure thorough mixing of the phases.

[0120] Using free acids (such as EDTA or DTPA) and their incompletely substituted salts (such as disodium ethylenediaminetetraacetic acid (Na2EDTA)) as chelating agents, the free base of metopridine 2 is separated from the copper complex 3, forming a resinous complex product. This may be due to the interaction of the free carboxyl group with both the basic nitrogen atom of the imidazole ring and the copper ion.

[0121] Medetomidine base 2 can be reacted with acids such as hydrochloric acid in a suitable organic solvent to produce pharmaceutically acceptable salts such as medetomidine hydrochloride 1. When using concentrated hydrochloric acid (35-38%) in acetone, crystallization may occur due to the high solubility of medetomidine hydrochloride 1 in water. In this case, a small amount of pure medetomidine hydrochloride crystals must be added as a seed to initiate crystallization. Adding the seed during the salt formation stage has a beneficial effect on crystallization, which occurs immediately or almost immediately after the addition of concentrated hydrochloric acid. The yield of medetomidine hydrochloride can be increased from 56.2% to 60-65% (calculated over two stages) by concentrating the mother liquor (to about 1 / 3 of the initial volume) after filtering off the main portion of crystals, and then cooling the water-acetone solution in a freezer for 20-25 hours.

[0122] Replacing formaldehyde with any other aldehyde during the formation of the copper complex is a convenient method to obtain metomididine derivatives with a substituent at the second position of the imidazole ring.

[0123] Another method for forming an imidazole fragment in the metomididine molecule is route B (scheme 2).

[0124] In this case, 1-bromo-3-(2,3-dimethylphenyl)but-2-one 5 and sodium dicarboxamide 21

[0125]

[0126] The reaction occurs in a suitable organic solvent (such as acetonitrile) to give intermediate 22.

[0127]

[0128] It can be used in the next step without further purification.

[0129] Commercially available sodium diformylamide 21, used for the synthesis of compound 22, can also be obtained in high yield from sodium methoxy and formamide by literature methods (e.g., (a) Allenstein E. Chem. Ber. 1967, 100, 3551; (b) US5599986A).

[0130] Acidic hydrolysis of compound 22 leads to the formation of aminoketone dichloride 23.

[0131]

[0132] The final step of the process (Route B, Scheme 2) is to form a 2-mercaptosubstituted imidazole ring, followed by a desulfurization reaction to produce metopridine 2.

[0133] According to the Marckwald reaction (Marckwald W.Ber.Dtsch.Chem.Ges.1892,25,2354), the interaction between 1-amino-3-(2,3-dimethylphenyl)but-2-one hydrochloride 23 and potassium thiocyanate in aqueous solution leads to the formation of 4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-thione 24.

[0134]

[0135] The reaction proceeds smoothly when aminoketone hydrochloride 23 is heated with an excess (4-5 eq) of potassium thiocyanate aqueous solution at boiling point. The optimal heating time is 2.5 to 3.5 hours. Unlike the starting reagent, the reaction product 24 is almost insoluble in water and crystallizes out of solution as the reaction proceeds, which greatly simplifies its separation process. If necessary, 4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-thione 24 can be purified by crystallization from an aqueous ethanol solution (approximately 65% ​​v / v).

[0136] The use of Raney nickel in an alcoholic medium to gently remove the thiol group from compound 24 yields metoprimidine 2 in high yields. The best results are obtained using Raney nickel of grades W-4 and W-5 (see the classification in Robert L. Augustine, 1996, *Heterogeneous Catalysis for the Synthetic Chemist*).

[0137] The formation of the imidazole ring in metoprimidine can also be achieved directly in one step by reacting 1-amino-3-(2,3-dimethylphenyl)but-2-one hydrochloride 23 with formamide (Scheme 3, Route C). Although the yield is low (approximately 40%), the reaction proceeds very readily. Because of the excessive amount of formamide (approximately 10 eq), which acts as both a solvent and reagent in the reaction and has a high boiling point (210 °C), it is best to hydrolyze the excess formamide with concentrated chloric acid (1 h, room temperature) before extracting the metoprimidine base from the reaction mixture.

[0138] experiment

[0139] Abbreviation Table

[0140]

[0141]

[0142]

[0143] General Method

[0144] The starting 2,3-dimethylaniline 13 was purchased from Sigma-Aldrich (99%, CAS 87-59-2) and required no further purification before use. All experiments using an inert atmosphere were performed using Schlenk lines according to standard techniques. Argon 99.999% (Linder Gas) was used as the inert gas and required no further purification. All solvents and reagents, except THF and methanol, were purchased from commercial suppliers and required no further purification or preparation before use. Tetrahydrofuran (ACS 99.6%) was distilled in an argon atmosphere (with ~0.1% hydroquinone added) and dried on activated 3A molecular sieves (100 g / L) for 65 hours before use. The methanol used in the bromination reaction was dried on activated 3A molecular sieves (45 g / L) for 168 hours. The molecular sieves were activated by heating in a vacuum (0.01 mmHg) at 300–320 °C for 3 hours. For the synthesis of organomagnesia reagents, magnesium shavings for Grignard reactions, manufactured by Fisher Chemical, were used and stored in an oven at 120°C. Analysis of 2,3-dimethylphenyl magnesium bromide was performed directly by iodometric titration in a saturated solution of lithium chloride in dry THF, according to the method of Paul Knochel. Some of the glassware used in the preparation of organomagnesia reagent 10 and the cross-coupling stage (except for the large-capacity reactor) was dried in an oven at 120°C for 24 hours. Before handling moisture-sensitive compounds, the glass reactor was evacuated (0.01 mmHg) in a rotary vane pump, heated at 90°C for 2 hours, and then purged with argon in three evacuation / purging cycles. 1 H and 13 C10 NMR spectra were obtained in CDCl3 and D6-DMSO using an Agilent 400MHz spectrometer. 1 H is 400MHz. 13 Recordings were taken at 100 MHz. Chemical shifts are expressed in ppm relative to the residual signal of the deuterated solvent used. Analysis of heavy metal residues was performed on an Agilent Technologies 240AA atomic absorption spectrometer. Samples for heavy metal analysis were prepared using a MARS One microwave decomposition system. A mixture of 70% nitric acid and 30% hydrogen peroxide (volume ratio 10:1, 180 °C, 25 min) was used as the oxidant for sample mineralization. TLC analysis was performed on ALUGRAM Xtra SIL G / UV 254 aluminum plates (Macherey-Nagel). The plate surface was observed using a 254 nm UV lamp. The integrity of the reaction was monitored and the chromatographic purity of intermediates was assessed using an Alliance HPLC system (Waters) with a photodiode detector array (PDA).

[0145] Analysis conditions

[0146] Method A

[0147] Instrument: Waters Alliance HPLC; column XBridge C18, 3.5μm, 4.6mm×150mm; eluent A: MeCN; eluent B: H2O + 0.15% vol. 50% H3PO4; A:B = 50:50; isocratic elution mode; flow rate 1.50ml / min; temperature 40℃; injection volume 10μl; detection wavelength: 190-350nm.

[0148] Method B

[0149] Instrument: Waters Alliance HPLC; Column: XBridge C18, 3.5 μm, 4.6 mm × 150 mm; Eluent A: MeCN; Eluent B: H2O + 0.15% vol. 50% H3PO4; 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.

[0150] Method C

[0151] Instrument: Waters Alliance HPLC; Column: XBridge C18, 3.5μm, 4.6mm×150mm; Eluent A: MeCN; Eluent B: H2O + 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℃; Injection volume: 10 μl; Detection wavelength: 190-350 nm.

[0152] experiment

[0153] 2,3-Dimethylbromobenzene (11)

[0154] (Adapted from J. Chem. Soc. 1940, 16–18)

[0155]

[0156] Add 3,747.5 g (22.23 mol; 4.0 eq) of 48% hydrobromic acid and 750 mL of deionized water to a 10 L glass reactor equipped with a thermostatic jacket and a mechanical stirrer, and pre-cool to -10 °C. Cool the solution to 4...5 °C, and then add 673.45 g (5.55 mol; 1.0 eq) of 2,3-dimethylaniline 13 from a dropping funnel over 45 minutes, stirring (250-300 rpm) at a speed that maintains the temperature of the reaction mixture within the range of 4...5 °C. Cool the resulting beige crystal suspension of 2,3-dimethylaniline hydrobromide to -1...-2 °C, and then add 421.8 g (6.12 mol; 1.10 eq) of sodium nitrite in 680 mL of deionized water from a dropping funnel over 2 hours, at a rate that maintains the temperature of the reaction mixture within the range of 0...5 °C. -2℃ (coolant temperature in reactor jacket is -15℃). After adding dysprosium nitrite solution, the temperature of the reaction mixture is raised to 0℃, and a yellow-brown solution of 2,3-dimethylphenyldiazobromide 12 is stirred for 15 minutes to complete the diazotization process. Then, the stirrer speed is increased (to 450-500 rpm), and 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 raised to 30℃. When the reaction mixture is heated to 28...30℃, the exothermic decomposition process of the diazonium salt begins, and the temperature of the reaction mixture spontaneously rises to 60℃ within 4-5 minutes. After the spontaneous heating stops, the coolant in the reactor jacket begins to heat and circulate, and the purplish-black reaction mixture is heated at 70℃ for 30 minutes. The reaction mixture is cooled to room temperature and extracted with 2 × 1,000 mL of light petroleum ether (40-70). The lower water layer was discharged through the bottom outlet. The dark organic phase was washed sequentially in the reactor with 4 L of deionized water (10 min) and 4 × 4 L of 2.5% sodium hydroxide solution (10 min each) to remove 2,3-dimethylphenol. After separation, the organic phase was concentrated under vacuum (<40°C). An orange-red oil was distilled from a solution of 50 g of sodium hydroxide and 1 L of deionized water, and 3.5 L of the fraction was collected. The clear, light orange lower layer was separated and vigorously stirred with 100 mL of concentrated sulfuric acid on a magnetic stirrer for 40 min. The dark red sulfuric acid lower layer was separated in a separating funnel, and the light yellow organic upper layer was washed with 2 × 600 mL of saturated sodium bicarbonate solution. The aqueous phase was extracted with 3 × 100 mL of methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The obtained 2,3-dimethylbromobenzene was vacuum fractionated using a 300 mm vacuum-jacketed Vigreux column, and fractions with bp of 76.2-76.5 °C / 6 mmHg were collected.

[0157] Yield: 391.8 g (38.1%). Colorless liquid with a characteristic xylene odor. 1H NMR (400MHz, CDCl3) δ7.43 (d, 1H), 7.11 (d, 1H), 6.97 (t, 1H), 2.40 (s, 3H), 2.36 (s, 3H); 13 C(100MHz, CDCl3)δ138.61, 136.24, 130.34, 128.97, 126.88, 125.67, 21.39, 19.51; tR 11.33 min (HPLC area 99.7%, Method A).

[0158] 3-Bromo-2-Butanone (15)

[0159] (Improved from Rec.Trav.Chim.Pays-Bas 1946, 65, 691).

[0160]

[0161] 1,200 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 were injected into a 3-liter glass reactor with a thermostatic jacket, equipped with a sealed mechanical stirrer, a dropping funnel with a pressure equalization tube, and a reflux condenser. 800.0 g (257.9 mL; 5.0 mol; 1.0 equimolar) of bromine was added to the dropping funnel. The solution in the reactor was heated to 70°C, and then bromine was added dropwise over 4 hours at a rate that allowed the initial yellow color to disappear with subsequent bromine additions. During the addition of bromine, an emulsion would form, and the reaction mixture would then separate into two phases. After all the bromine had been added, the reaction mixture was stirred at 70°C for 30 minutes, then cooled to room temperature and diluted with 1 liter of cold water (2°C). The pale yellow lower layer was separated through the bottom outlet of the reactor and then washed with 3 × 400 mL saturated sodium bicarbonate solution (on a magnetic stirrer in a loosely sealed 1000 mL Erlenmeyer flask) until carbon dioxide production ceased, followed by washing with 400 mL deionized water. The resulting 15 / 16 bromoisomer mixture (546.1 g) was dried with anhydrous granular calcium chloride, filtered, and then vacuum distilled in an 800 mm high distillation column (filled with Lagrange rings) with a vacuum jacket. First, a fraction (approximately 10 mL) with a bp of 58–60 °C / 38 mmHg was separated. Then, the major fraction of 3-bromo-2-butanone 15 with a bp of 61–63 °C / 38 mmHg was collected, followed by an intermediate fraction with a bp of 64–77 °C / 38 mmHg, and finally, a fraction of 1-bromo-2-butanone 16 with a bp of 77–78 °C / 38 mmHg was collected. Too low a vacuum distillation rate will cause the distillate to turn yellow.

[0162] 3-Bromo-2-Butanone (15)

[0163] Yield: 279.74g (37.0%). Pale yellow liquid. 1 H NMR (400MHz, CDCl3) δ4.37(q,1H), 2.34(s,3H), 1.71(d,3H); 13 C(100MHz, CDCl3)δ 202.11, 48.28, 26.04, 20.20. The content of isomer 1-bromo-2-butanone 16 was <5% (NMR). tR 5.35 min (HPLC area 96.9%, Method B).

[0164] 1-Bromo-2-butanone (16)

[0165] Yield: 48.15g (6.4%). Yellow liquid. 1 H NMR (400MHz, CDCl3) δ3.87 (s, 2H), 2.65 (q, 2H), 1.09 (t, 3H); 13 C(100MHz, CDCl3)δ209.92, 52.65, 29.13, 9.35; tR 4.64 min (HPLC area 88.9%, method B).

[0166] 2-(1-Bromoethyl)-2-methyl-1,3-dioxolane (14)

[0167]

[0168] 259.12 g (1.71 mol) of freshly distilled 3-bromo-2-butanone, 117.2 g (1.88 mol; 1.10 eq) of ethylene glycol, 1.58 g (8.30 mmol; 0.0048 eq) of p-toluenesulfonic acid monohydrate, and 800 mL of toluene were added to a 2 L round-bottom flask. A 50 mL Dean-Stark trap was fitted to the flask. The reaction mixture was stirred under reflux on a magnetic stirrer until no more water droplets separated from the receiver (31 mL; 3.5 h). As the reaction proceeded, the ethylene glycol colony layer gradually disappeared. The colorless, transparent solution was cooled to room temperature and washed with 500 mL of 2% sodium bicarbonate solution and 2 × 150 mL of deionized water. The organic layer was separated, dried over anhydrous sulfite, filtered, and concentrated on a rotary evaporator (35 °C / 10 mmHg) to a distillation volume of 760–780 mL. The product is distilled in a vacuum, and the fraction with a bp of 43.5-44.5℃ / 0.016mmHg is collected.

[0169] Yield: 271.93g (81.2%). Colorless liquid, no lachrymatory effect. 1H NMR (400MHz, CDCl3) δ4.05 (q, 1H), 3.99 (m, 4H), 1.67 (d, 3H), 1.45 (s, 3H); 13 C(100MHz, CDCl3)δ109.96, 64.74, 53.22, 21.22, 20.65; tR 8.11 min (HPLC area 88.2%, Method B).

[0170] 3-(2,3-Dimethylphenyl)-2-butanone (7)

[0171]

[0172]

[0173] 33.90 g (1.39 mol; 1.05 eq) of magnesium complex was placed in a 2 L double-necked round-bottom flask, which was pre-dried overnight in a desiccator at 120 °C and equipped with a 1 L dropping funnel with a pressure balance arm and a glass-encapsulated thermocouple. Approximately 0.8 g of iodine was added to the flask, and the flask was heated with hot air until the iodine began to sublimate. After cooling the flask to room temperature, the magnesium was covered with 147 mL of dry tetrahydrofuran, and a magnetic anchor was placed in the flask. A solution of 245.67 g (1.32 mol; 1.0 eq) of 2,3-dimethylbromobenzene 11 in 1,000 mL of dry THF was added to the dropping funnel. Approximately 40–50 mL of the solution was added to the magnesium complex in one go from the dropping funnel. The reaction began immediately after the first portion of solution was added from the dropping funnel; the iodine color disappeared, and the temperature rose rapidly (<1 min) to 48 °C. After the temperature of the reaction mixture stops rising, immediately begin adding the solution from the dropping funnel while actively stirring (1300-1500 rpm). The stirring speed should maintain the temperature of the reaction mixture in the range of 47-49°C without external heating or cooling (approximately 5 hours). After adding all of the 2,3-dimethylbromobenzene, reflux the dark reaction solution at 70-75°C for 45 minutes to complete the reaction. Cool the solution under an argon atmosphere. The concentration of 2,3-dimethylphenyl magnesium bromide 10 in the resulting solution was determined to be 0.99 mol / L according to Paul Knochel's method. The yield of 2,3-dimethylphenyl magnesium bromide was 92.7%. The resulting composition 10 solution can be used directly for the next step without further preparation.

[0174] A 5L glass reactor equipped with a temperature-controlled jacket, a sealed mechanical stirrer, a thermocouple, and a stopcock for introducing inert gas was evacuated (<0.1 mmHg) and dried at 90°C for 2 hours. The reactor was cooled to room temperature and purged with dry argon gas (pump / purging cycle 3 times). Under countercurrent argon, 41.93 g (10 mol%; 117.7 mmol) of cobalt 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; 1.0 mmol) of 2-(1-bromoethyl)-2-methyl-1,3-dioxolane-14 were continuously added to the dried reactor. The suspension was cooled to 0...-1°C. While stirring (300-400 rpm), the 2,3-dimethylphenyl magnesium bromide 10 solution prepared in the previous stage was added to the reactor at a rate of 6.9-7 mL / min using a peristaltic pump for 180 minutes, carefully maintaining the internal temperature at 0 to -1°C (the coolant temperature in the reactor jacket was -10 to -12°C, which provided good control of the reaction). With the addition of the Grignard reagent solution, the color of the reaction mixture changed from green to pale blue-blue, and a large amount of magnesium bromide precipitate crystallized from the solution. After adding all of the 2,3-dimethylphenyl magnesium bromide (1.05 eq), the temperature of the reaction mixture was raised to 20°C, and stirring was continued for 1 hour. Under vigorous stirring (400 rpm), 1,460 mL of 9% hydrochloric acid was slowly added to the reaction mixture (2-3 minutes), and stirring was continued for 40 minutes. During the addition of hydrochloric acid, the color of the reaction mixture rapidly changed from pale blue-blue to green, and then to orange. All the magnesium bromide crystals had entered the solution. After stirring for 30 minutes, the aliquots of the reaction mixture were analyzed by HPLC, showing that intermediate ketone 8 was 100% converted to ketone 7. The reaction mixture, consisting of two phases (upper pale yellow organic phase and lower pink aqueous phase), was diluted with 500 mL of n-heptane, stirred for 15 minutes, and then the lower aqueous phase was discharged from the bottom outlet of the reactor. The organic phase was washed successively with 2 × 500 mL of deionized water and 500 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate, filtered, and concentrated under vacuum (45 °C). The resulting orange-yellow oil (224.0 g) was diluted with 240 mL of methanol, and 100 mg of 2,2',3,3'-tetramethylbiphenyl 9 was added to the solution as a seed crystal. The solution was stored in a freezer (-18 °C) for one day. The precipitated suspension of 2,2',3,3'-tetramethylbiphenyl 9 crystals was filtered using a Schott funnel and washed with 2 × 50 mL of cold methanol. The filtrate was concentrated under vacuum; the residue was diluted with 300 mL of hexane and washed successively with 1 L of deionized water (10 min), 1 L of 1% Na2EDTA aqueous solution (2 h), and 1 L of saturated sodium chloride aqueous solution (10 min) to remove ethylene glycol.The integrity of ethylene glycol removal was monitored by the disappearance of the methylene signal (3.76 ppm, s, CDCl3) using 1H NMR.

[0175] The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The product was then vacuum distilled using a 300 mm vacuum-jacketed Vigreux column. The distillate was collected in a Perkin receiver. Fractions with boiling points of 68–69 °C / 0.024 mmHg were discarded, and the major product fraction with boiling points of 69–72 °C / 0.024 mmHg was collected.

[0176] The obtained amber-colored 3-(2,3-dimethylphenyl)but-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 silica gel was filtered through a Schott funnel, washed with 3 × 20 mL of n-hexane, and the filtrate was concentrated under vacuum on a rotary evaporator. The residue was stored under vacuum (<0.1 mmHg, RT, 30 min) to remove traces of hexane. The yield was 161.22 g (77.7%). After quenching the reaction mixture with 2 × 200 mL of heptane, the combined aqueous phases (4 L) were extracted and then purified as described above, yielding an additional 19.63 g of product.

[0177] 3-(2,3-Dimethylphenyl)-2-butanone (7)

[0178] Total yield: 180.85g (87.2%). Pale yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.08 (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(100MHz, CDCl3)δ209.63, 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).

[0179] 2,2',3,3'-Tetramethylbiphenyl(9)

[0180] Yield: 10.08 g (7.2%). White crystalline substance. 1 H NMR (400MHz, CDCl3) δ7.14 (m, 4H), 6.96 (d, 2H), 2.34 (s, 6H), 1.96 (s, 6H); 13C(100MHz, CDCl3)δ142.48, 136.79, 134.67, 128.63, 127.41, 125.19, 20.68, 16.55; tR 42.3 min (HPLC area 98.8%, Method A).

[0181] 1-Bromo-3-(2,3-dimethylphenyl)-2-butanone (5)

[0182]

[0183] A 5L glass reactor equipped with a temperature-controlled jacket, a sealed mechanical stirrer, a thermocouple, and a stopcock for introducing inert gas was evacuated (<0.1 mmHg) and dried at 90°C for 2 hours. The reactor was cooled to room temperature and purged with dry argon (3 pump / purging cycles). 114.57 g (0.65 mol; 1.0 eq) of 3-(2,3-dimethylphenyl)but-2-one 7 and 3,420 mL of anhydrous methanol were injected into the dried reactor under countercurrent argon. The solution was cooled to -10°C, and then a solution of 124.65 g (0.78 mol; 1.20 eq) of bromine in 592 mL of methanol was poured into the reactor with stirring (250 rpm) for 30–35 seconds (temperature rise to -9°C). The temperature of the reaction mixture was steadily raised to -5…-6°C and stirred at this temperature for 18 hours, while the reaction progress was monitored by HPLC (Method A). Next, the temperature of the reaction mixture (light orange) was gradually increased to 0°C, and 5.0 g (0.03 mol) of bromine was added. Stirring continued for 2.5–3 hours to complete the reaction, while monitoring the conversion of the starting ketone using HPLC (Method A). After the reaction was complete (conversion of the starting ketone greater than 97%), the clear solution was poured into a 10 L stirred reactor containing 7,200 mL of deionized water and pre-cooled to 0.5°C. The white emulsion was stirred for 30 minutes and then extracted with 4 × 300 mL of dichloromethane. The organic extract was separated from the bottom outlet of the reactor, combined, and washed with 1 L of saturated sodium bicarbonate aqueous solution (300 rpm, 30 min) and 1 L of deionized water (300 rpm, 30 min), then dried over anhydrous sodium sulfate. The solution was filtered, and the solvent was removed under vacuum (<30°C). The residue was used directly in the next step without further purification.

[0184] Yield: 171.57g (84.8%). Pale yellow, transparent oil; no lachrymatory effect. 1 H NMR (400MHz, CDCl3) δ7.08 (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); 13C(100MHz, CDCl3)δ202.70, 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).

[0185] 3-Bromo-3-(2,3-dimethylphenyl)but-2-one (20)

[0186]

[0187] 8.0 g (45.4 mmol; 1.0 eq) of 3-(2,3-dimethylphenyl)but-2-one 7 from 80 mL of ethyl acetate was placed into a 100 mL glass reaction vessel equipped with a thermostatic jacket, a wide-bladed mechanical stirrer and seals, and a valve for introducing inert gas. The solution was cooled to 5°C, and a weak argon flow (100 mL / min) was introduced. Then, with vigorous stirring (300 rpm), 15.25 g (47.6 mmol; 1.05 eq) of pyridine hydrobromide perbromide 19 was added through a plastic funnel at approximately 500-600 mg increments, approximately every 1 minute. The color of the reagent immediately disappeared, and a white flocculent precipitate of pyridinium hydrobromide began to detach from the solution. It took approximately 30 minutes for all the reagents to be added. The reaction mixture was stirred at 5°C for 40 minutes, and then 1.5 g of pyridinium hydrobromide (total brominating agent 16.75 g) was added. The reaction mixture was stirred for 10 minutes, and then diluted with 100 mL of deionized water. Stirring continued for 5 minutes to dissolve the pyridinium hydrobromide precipitate. The lower aqueous phase was drained, and the organic phase was washed repeatedly with 100 mL of deionized water, with each layer actively stirred for 5 minutes. The aqueous phase was drained from the bottom outlet of the reactor and washed repeatedly with 75 mL of saturated sodium bicarbonate solution. Each layer was vigorously stirred at room temperature for 40 minutes, separated, and finally washed with 50 mL of deionized water to obtain a pale yellow ethyl acetate layer. The aqueous phase was extracted with 20 mL of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum at 40°C. The residue was preserved under vacuum to remove trace amounts of ethyl acetate.

[0188] Yield: 12.0 g (72.5%). Light orange oil, crystallizes into yellow needle-like substances in a freezer (-18°C). 1 H NMR (400MHz, CDCl3) δ7.69(m,2H),7.16(m,1H),2.27(s,3H),2.24(s,3H),2.22(s,3H),2.09(s,3H); 13С(100MHz, СDCl3)δ203.10,138.75,138.57,133.86,130.64,126.19,126.11,73.48,29.79,25.29,20.84,17.16; tR 7.58 min (HPLC area 70%, Method A)

[0189] 3-(2,3-dimethylphenyl)-2-oxobutylacetic acid ester (4-route A)

[0190]

[0191] In a 2-liter round-bottom flask, add 191.4 g (1.95 mol; 3.5 eq) of potassium acetate and 1,000 mL of acetonitrile. Add a solution of 171.57 g of crude 1-bromo-3-(2,3-dimethylphenyl)-2-butanone (calculated content of pure compound 5: 140.68 g; 0.55 mol) in 850 mL of acetonitrile to the flask. Stir the suspension with a magnetic stirrer (1,500 rpm) at room temperature (21 °C) and monitor the reaction progress using high-performance liquid chromatography (Method A). After the reaction is complete (19 hours, conversion >99%), filter the crystalline precipitate of potassium bromide and potassium acetate through a Schott funnel and wash the filter with 2 × 200 mL of acetonitrile. Concentrate the pale yellow, clear filtrate under vacuum (<40 °C), and dilute the residue with 300 mL of MTBE. The organic phase was washed with 2 × 500 mL of deionized water, and the aqueous phase was extracted with 2 × 50 mL of MTBE. The combined organic phases were dried over anhydrous sodium sulfate. The solution was filtered, and the solvent was removed under vacuum (<35°C). The residue was used directly in the next step without further purification.

[0192] Yield 158.07 g (84.8%). tR 4.54 min (HPLC area 69.3%, method A).

[0193] Compound 4 was purified by flash chromatography (silica gel 60, n-hexane-ethyl acetate 9:1, Rf 0.16) for nuclear magnetic resonance analysis. The purified compound 4 was a white waxy substance. 1 H NMR (400MHz, CDCl3) δ7.08 (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 С(100MHz, СDCl3)δ204.59, 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.

[0194] Medetomidine Hydrochloride 1 (Method A)

[0195]

[0196] In a 10-liter glass-jacketed reactor equipped with a mechanical stirrer, thermocouples, and a high-efficiency reflux condenser, 158.07 g of crude 3-(2,3-dimethylphenyl)-2-oxobutyl acetate (calculated amount of pure compound 4: 109.54 g; 0.467 mol) in 1700 mL of n-propanol was added to the reactor in one go, with stirring (160 rpm). After stirring for 3 minutes to form a homogeneous, deep blue solution, 490 mL (6.64 mol) of 37% formamide was added to the reactor in one go. The reaction mixture was heated to boiling (100 °C) and stirred (160 rpm) for 2 hours. After heating for about 10–15 minutes, crystalline copper(I) complex of methyl-toxamide 3 began to precipitate. After heating for 2 hours, the reaction suspension was cooled to 16-18°C for 1 hour, and then stirred for another 30 minutes at 16-18°C. The preprecipitate was filtered through a Schott funnel and washed successively with 1 L of 25% n-propanol aqueous solution, 1 L of deionized water, and 2 × 250 mL of acetone. The resulting deep yellow fine crystalline powder was dried under vacuum (6 mmHg) for 12 hours at room temperature. The yield of the metomididine copper(I) complex was 99.68 g (58.1% yield across the three stages).

[0197] In a 10-liter glass reactor equipped with a mechanical stirrer, 2,850 g (0.566 mol; 1.50 eq) of a 10% aqueous solution of diethylenetriaminepentaacetic acid pentasodium salt (Na5DTPA) and 99.68 g (0.377 mol) of the copper(I) complex of metomididine 3 were added and suspended in 2 liters of ethyl acetate. The mixture was stirred at room temperature (23°C) (300–350 rpm) for 24 hours until all solids were completely dissolved. The dark ethyl acetate layer separated from the deep blue aqueous phase. The aqueous phase was extracted with 2 × 200 mL of ethyl acetate. The combined organic phases containing the metomididine base were transferred to a 5-liter stirred glass reactor and washed successively with 2 × 500 mL of 0.5% Na5DTPA aqueous solution (30 min each) and 500 mL of saturated sodium chloride aqueous solution (30 min each). Medetomidine was removed from the ethyl acetate phase by sequential extraction with 500 mL and 2 × 350 mL of 10% acetic acid aqueous solution (stirring at 300-400 rpm for 10 minutes each). The ethyl acetate layer was concentrated under vacuum to approximately 200 mL, and then the medetomidine was extracted again with 2 × 300 mL of 10% acetic acid aqueous solution. The aqueous extract containing medetomidine acetate (1,800 mL) was transferred to a 5 L stirred glass reactor and extracted sequentially with 3 × 200 mL of MTBE to remove minor impurities. Simultaneously, the aqueous phase became bright. The dark organic extract (MTBE) was washed once with 100 mL of deionized water, and the aqueous phase was combined with the extract containing medetomidine acetate; the organic phase was discarded. The combined pale yellow aqueous phase (1,900 mL) was transferred to a 5 L glass jacketed reactor equipped with a mechanical stirrer, cooled to 8-10 °C, and neutralized with 350 mL of 25% ammonia aqueous solution while stirring. The separated medemididine base 2 was extracted with 3 x 250 mL of ethyl acetate. The organic layer was washed once with 250 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum (note that foaming may occur). The product is a honey-like, amber-colored substance that foams under vacuum and solidifies into fragile, pearly foam. The yield of crude medemididine base was 65.74 g.

[0198] The base of medetomidine 2 was dissolved directly in 250 mL of dry acetone in a flask used for concentration. The dark, clear solution was cooled to -10°C, and then 1.0 g of medetomidine hydrochloride crystals were added as a seed. While stirring (500-600 rpm), 28.0 mL of 36% hydrochloric acid was added dropwise to the cooled solution until the pH reached 2-3. The precipitate formed from medetomidine 1 hydrochloride began to crystallize. The crystallization process was carried out at -18...-20°C for 23 hours. The product was filtered through a Schott funnel, washed with 3 × 100 mL of cold (2-3°C) dry acetone, and then dried under vacuum at 40°C for 12 hours.

[0199] The yield of medetomidine hydrochloride was 50.25 g (56.2%, in two stages). It was a grayish-white fine crystalline powder (HPLC area 95.3%, method C). The residual copper content was 3.7 ppm (AAS).

[0200] During purification, the product was crystallized from acetone containing 3.85% (v / v) water (approximately 9.5 mL of solvent is required per 1 gram of metodemydine hydrochloride). The yield was 90% (one-step purification, HPLC area 98.5%, Method C). After two crystallizations, the yield was 78-82% (HPLC area 99.5%, Method C). The residual copper content after recrystallization was less than 1 ppm (AAS).

[0201] White, fine crystalline powder. 1 H NMR (400MHz, D6-DMSO) δ9.02(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 (100MHz, D6-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).

[0202] Sodium dimethamide 21 (Route B)

[0203]

[0204] Add 28.42 g (526 mmol) of powdered sodium methoxide and 100 mL of dry methanol to a 500 mL round-bottom flask filled with argon (carefully, heat!), and stir until completely dissolved. Add 47.39 g (1.052 mol; 2.0 eq) of formamide dropwise to the resulting solution over 2–3 minutes. Heat the solution at reflux temperature for 1 hour with a magnetic stirrer. Then, slightly cool the solution and replace the reflux condenser with a distillation bridge equipped with a descending condenser and a Claisen nozzle fitted with a thermometer and a dropping funnel containing 132 mL of toluene. Distill the methanol by measuring the volume of the distillate with a graduated cylinder. After collecting approximately 80 mL of distillate, begin adding toluene from the dropping funnel at a rate that maintains a constant volume of solution in the distillation flask. Collect the distillate until the vapor temperature in the Claisen nozzle reaches 110 °C (total volume of distillate approximately 150 mL). Cool the white suspension to room temperature and filter using a Schott funnel. The product was washed with 80 mL of tetrahydrofuran and dried under vacuum (0.05 mmHg) for 1 hour at room temperature. The resulting product was used directly in the next step without further purification.

[0205] Yield: 45.68 g (91.4%). White, fine crystalline powder.

[0206] N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide 22 (Route B)

[0207]

[0208] Argon gas was introduced into a 2L double-necked round-bottom flask (3 pumps / gas cycle), and 38.46 g (404.7 mmol; 1.4 eq) of sodium dimethamide 21 and 400 mL of acetonitrile (water content <0.05%) were added. Under magnetic stirring, a solution of 87.50 g of crude 3-(2,3-dimethylphenyl)-1-bromo-2-butanone 5 (chromatographic purity 82%; 281.2 mmol) in 400 mL of acetonitrile was added in one step to the resulting suspension. The reaction mixture was magnetically stirred at room temperature under argon atmosphere for 20 h, then refluxed for 2 h to achieve a conversion of starting compound 5 greater than 99% (HPLC, Method A). The hot, deep yellow solution was filtered through a Schott funnel, and the inorganic salt precipitate was washed with 50 mL of acetonitrile. The clear filtrate was concentrated under vacuum (40 °C), and the resulting deep yellow oil was washed with 350 mL of deionized water and stirred magnetically for 10 min. The product was extracted with 300 mL of dichloromethane, the organic phase was separated and washed with 350 mL of deionized water. The aqueous phase was then extracted with 30 mL of dichloromethane, and the combined organic phases were concentrated under vacuum. The resulting yellow viscous oil was diluted directly in the same flask used for concentration with 250 mL of n-hexane, and then the flask was heated in an oil bath (90°C) and stirred on a magnetic stirrer for 30 minutes. The mixture was cooled, carefully drained, and the upper n-hexane layer was discarded. The remaining oil was washed again with 100 mL of n-hexane. The n-hexane layer was discarded, and any residual n-hexane in the product was removed under vacuum. The residue was used directly in the next step without further purification.

[0209] Yield: 51.24 g (63.3%). Yellow, viscous, oily substance. 1 H NMR (400MHz, CDCl3) δ8.88(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 С(100MHz, СDCl3)δ209.80,163.27,138.01,137.73,134.60,129.50,126.53,125.59,48.58,46.11,21.10,16.79,15.39; tR 3.15 min (HPLC area 85.9%, Method A).

[0210] 1-Amino-3-(2,3-dimethylphenyl)but-2-one hydrochloride 23 (Route B)

[0211]

[0212] 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 was dissolved in 600 mL of 99% ethanol, and then 65.0 mL of 36% (764 mmol; 4.6 eq) hydrochloric acid was added in one step to the resulting clear yellow solution. The solution was heated to boiling under argon atmosphere while stirring on a magnetic stirrer. After 15 minutes, aliquots of the reaction mixture were analyzed by HPLC, and the results showed that the conversion of starting compound 22 to aminoketone 23 was greater than 99% (HPLC, Method A). The purple-red solution was concentrated under vacuum, and the crystalline residue was dried at 40 °C / 2 mmHg for 1 hour (on a rotary evaporator). The residue was suspended in 350 mL of diethyl ether; the crystal suspension was stirred on a magnetic stirrer for 10–15 minutes, filtered through a Schott funnel, and washed with 3 × 100 mL of acetone. Aminoketone hydrochloride 23 (24.91 g) was recrystallized from a mixture of 315 mL of acetone and 30 mL of deionized water and dried under vacuum (6 mmHg) at room temperature for 12 hours.

[0213] Yield was 22.0 g (58.8%). Colorless, lustrous needle-like substances. 1 H NMR (400MHz, D6-DMSO) δ8.40(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(100MHz, D6-DMSO)δ204.41,137.95,137.22,134.53,128.83,125.92,125.00,46.37,45.45,20.66,16.58,15.01; tR 3.10 min (HPLC area 97.3%, Method B).

[0214] 4-[1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-thione 24 (Route B)

[0215]

[0216] In a 250 mL round-bottom flask, 12.63 g (55.4 mmol) of 1-amino-3-(2,3-dimethylphenyl)but-2-one hydrochloride 23 and 70 mL of deionized water were added. Under magnetic stirring, 26.95 g (277.3 mmol; 5.0 equivocal) of potassium thiocyanate was added to the suspension in one go. The flask was equipped with a reflux condenser, and the reaction mixture was heated at 125–130 °C (bath temperature). After heating for approximately 10 minutes, all solids dissolved, forming a clear, pale yellow solution. Heating continued (for approximately 30–40 minutes), and the product began to precipitate. After the reaction was complete (total heating time 3 hours 20 minutes), the crystalline suspension was cooled to room temperature and then lowered to 0 °C. The crystals were filtered through a Schott funnel and washed with 3 × 100 mL of deionized water and a small amount of 96% cold ethanol. The product was dried under vacuum (6 mmHg) for 12 hours at room temperature.

[0217] Yield: 9.42 g (73.1%). A pale yellow, fine-grained, lustrous powder, odorless. 1 H NMR (400MHz, D6-DMSO) δ11.83(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(100MHz, D6-DMSO)δ141.71,136.26,133.71,133.58,133.44,127.89,125.36,123.93,111.40,31.79,20.61,19.92,14.39; tR 9.49 min (HPLC area 98.9%, Method B).

[0218] Metoprolol 2 (route B)

[0219]

[0220] 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 were placed in a 500 mL Schlenk flask filled with argon. Under countercurrent argon, 35 mL of freshly prepared Raney nickel W-4 suspension in 99% ethanol (nickel content in the suspension was 0.28 g / mL; 9.8 g; 167 mmol; 4.9 equivalent) was transferred to the flask, and the contents were stirred with a magnetic stirrer at room temperature for 1.5 h. After stirring for 1.5 h, a second portion (35 mL; 4.9 equivalent) of Raney nickel W-4 suspension in 99% ethanol was added, and stirring was continued at room temperature for another 3.5 h. After the specified time, a third portion (10 ml; 2.8 g; 47.7 mmol; 1.4 eq) of the suspension of Raneynickel W-4 in 99% ethanol was added. The reaction mixture was heated for 2 hours with stirring at 95°C under an inert atmosphere to ensure complete reaction (conversion of starting compound ≥ 99.5%). The black suspension was cooled to room temperature and filtered using a Schott funnel. The pale yellow, transparent filtrate was further filtered through a GFA filter and concentrated under vacuum. After removing trace amounts of ethanol under vacuum (0.05 mmHg) for 20 hours at room temperature, a pale yellow, transparent, viscous metoprimidine base oil crystallized into a porous, lightweight substance.

[0221] Yield: 5.85g (86%). 1 H NMR (400MHz, CDCl3) δ10.56(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(100MHz, CDCl3)δ143.38,141.31,136.87,134.60,134.16,128.04,125.65,124.77,117.26,34.23,21.01,20.85,14.76; tR 3.12 min (HPLC area 98.0%, method C).

[0222] Metoprolol 2 (route C)

[0223]

[0224] Weigh 1.29 g (5.66 mmol) of 1-amino-3-(2,3-dimethylphenyl)but-2-one hydrochloride 23 and 2.55 g (56.6 mmol; 10 eq) of formamide into a 30 mL glass vial. Purge the vial with argon, place a magnetic anchor inside, cap the vial, and heat the reaction mixture at 160 °C for 2 hours (after which aliquots of the reaction mixture were analyzed, showing a conversion of starting compound 23 greater than 99%). Cool the reaction mixture to room temperature and dilute with 9.63 mL of 36% hydrochloric acid. Stir the homogeneous, clear yellow solution on a magnetic stirrer at room temperature for 1 hour to hydrolyze excess formamide. Dilute the precipitated ammonium chloride suspension with 10 mL of deionized water, and extract the aqueous phase with 2 × 5 mL of ethyl acetate to remove trace impurities. Cool the aqueous phase to -3...-5 °C and neutralize with 12 mL of 25% ammonia solution. The separated oil was extracted with 2 × 10 mL of ethyl acetate. The combined organic extracts were washed with 10 mL of deionized water, dried with sodium sulfate, filtered, and concentrated under vacuum. The resulting pale yellow oily methylphenidate was foamed under vacuum to completely remove traces of ethyl acetate and crystallized into a milky white, porous block.

[0225] The product can be purified by crystallization from a cyclohexane-toluene (9:1 v / v) mixture, or converted to its hydrochloride salt via the standard procedure described above.

[0226] Yield: 0.43g (38%). 1 H NMR (400MHz, CDCl3) δ10.56(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(100MHz, CDCl3)δ143.38,141.31,136.87,134.60,134.16,128.04,125.65,124.77,117.26,34.23,21.01,20.85,14.76; tR 3.12 min (HPLC A area 95.2%, method C).

Claims

1. A method for synthesizing compound 5, said compound 5 being used to synthesize medemidin and its derivatives, characterized in that, Compound 10 With compound 14 Compound 7 was cross-coupled in THF in the presence of 10 mol% cobalt(III) acetylacetonate and 10 mol% N,N,N',N'-tetramethylethylenediamine (TMEDA) and deprotected in a one-pot process under 10% hydrochloric acid. The compound 7 was halogenated with molecular bromine to obtain compound 5. .

2. A method for obtaining compound 3 The method Its features are, Compound 5 is synthesized according to the method of claim 1, and said compound 5 is interacted with potassium acetate to obtain compound 4. And to carry out a multi-component reaction of said compound 4 with formaldehyde and copper acetate (II) in a water-alcohol-ammonia solution.

3. A method for obtaining compound 2 The method Its features are, Compound 3 is obtained by the method according to claim 2, and compound 3 is reacted with the pentasodium salt of diethyltriaminepentaacetic acid (Na5DTPA) to isolate compound 2 from compound 3.

4. A method for obtaining compound 1, characterized in that, Compound 2 is obtained by the method according to claim 3, and compound 1 is obtained by reacting the free base of compound 2 with hydrochloric acid in acetone. .

5. A method for preparing compound 24 The method Its features are, Compound 5 is obtained by the method according to claim 1, and said compound 5 is reacted with compound 21. The interaction yields compound 22. Compound 22 was subjected to acid hydrolysis to give compound 23. And the reaction of said compound 23 with potassium thiocyanate.

6. A method for obtaining compound 2 The method is characterized by, Compound 24 is obtained by the method according to claim 5, and said compound 24 is desulfurized.

7. A method for obtaining compound 2 The method is characterized by, According to claim 1, compound 5 is obtained by the method, and said compound 5 is interacted with sodium dicarboxamide to obtain N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide; N-[3-(2,3-dimethylphenyl)-2-oxobutyl]-N-formylformamide is acidically hydrolyzed to obtain 1-amino-3-(2,3-dimethylphenyl)but-2-one hydrochloride; and This allows 1-amino-3-(2,3-dimethylphenyl)but-2-one hydrochloride to interact with formamide.

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