Method for producing dexmedetomidine and pharmaceutically acceptable salts thereof

Abstract

The invention relates to the field of pharmaceutical chemistry and describes a method for producing dexmedetomidine and pharmaceutically acceptable salts thereof. The invention solves the technical problem of developing an inexpensive dexmedetomidine synthesis method that produces minimal waste. The technical result consists in providing greater efficiency by increasing the degree of extraction of dexmedetomidine from a racemic mixture. This result is achieved by enriching medetomidine with an S-enantiomer in the early stages of synthesis, using an effective method for recovering "chiral waste", as well as separated amine.

Description

[0001] Method for obtaining dexmedetomidine and its pharmaceutically acceptable salts

[0002] Field of technology

[0003] The invention relates to the field of pharmaceutical chemistry and describes a method for producing dexmedetomidine and its pharmaceutically acceptable salts.

[0004] State of the art

[0005] Dexmedetomidine (1), the pharmacologically active β-enantiomer of medetomidine, is a highly selective β-adrenergic receptor agonist.

[0006] Dexmedetomidine was approved by the FDA in late 1999 for use in humans (as hydrochloride) as a drug for analgesia and sedation in intensive care units. Dexmedetomidine has a strong sympatholytic effect due to a decrease in the release of norepinephrine from sympathetic nerve endings. The sedative effect is due to the inhibition of excitation of the locus coeruleus, the main noradrenergic nucleus, which is located in the brainstem (locus coeruleus). It is through this system that the mechanism of natural slow-wave sleep is realized. Thus, the effect of dexmedetomidine closely matches the natural mechanism of human sleep. Unlike opioids and other sedatives such as propofol, benzodiazepines and barbiturates, dexmedetomidine does not cause dose-dependent respiratory depression even at 10-fold exceedance of therapeutic doses (Venn, R.; Hell, J.; Grounds, M.; Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care. Crit. Care 2000, 4, 302-308; Ebert, T.; Hall, J.; Barney, J. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000, 93, 382-394). These unique properties of dexmedetomidine have led to high interest in this drug in hospital therapy, especially in neurosurgical departments (Aryan, H.; Box, K.; Ibrahim, D. et al. Safety and efficacy of dexmedetomidine in neurosurgical patients. Brain Inj. 2006, 20, 791-798).

[0007] Currently, two main methods for the production of dexmedetomidine substance have been described: separation of racemic medetomidine into enantiomers (classical technology) and asymmetric hydrogenation (new generation synthesis).

[0008] The classical resolution of the racemic base medetomidine (2) into enantiomers is accomplished using -(+)-tartaric acid (L-(+)-TA), (-)-O,O'-dibenzoyl-L-tartaric acid (L-DBTA) and (+)-O,O'-di- / ?-toluoyl-O-tartaric acid (D-

[0009] (DTTA).

[0010] However, this separation method usually allows the isolation of the desired S-enantiomer in very modest yields (Table 1)

[0011] Table 1. Yield of dexmedetomidine (1) upon resolution of the racemate using enantiomerically pure tartaric acids

[0012] Thus, the average yield during separation of the racemate (according to the above sources of information) is 37-40%. In fact, this means that from 1 kg of racemic base 2 with a yield of 42%, only 0.21 kg of the S-enantiomer can be obtained (calculated for the content of the 5-enantiomer of 0.5 kg per 1 kg of the racemic mixture). The low degree of extraction of dexmedetomidine with the classical approach is due primarily to the properties specific to this molecule, consisting of a small difference in the solubility of the formed diastereomeric salts.

[0013] A higher yield of the product can be achieved by sequential crystallization first with D-(-)-tartaric acid (enrichment) and then with L-(+)-tartaric acid (4 recrystallizations, yield 46.7%; W02013069025A1, 2013), or, alternatively, first with D-(+)-DBTA and then with L-(-)-DBTA (yield 55%; CN101671305A, 2010). However, in both cases, the expensive D-enantiomer of tartaric acid or its bis-benzoylated derivative is used. In addition, due to the high solubility of D-tartaric acid in water (596 g / L at 25 °C; Yalkowsky, SH; Yan, H. Handbook of aqueous solubility data; Taylor & Francis Group, CRC Press; 2010; pp. 100.) and the tendency to form a supersaturated solution, the process of regeneration of the separating agent is difficult to implement.

[0014] The use of other resolving agents such as (5)-(+)-BNDHP and (7?)-(-)-BNDHP (CN101671305 A, 2010) has also been reported, however, due to the high cost of the latter, the resolution process becomes commercially unacceptable.

[0015] The second very significant drawback of the classical method of separating me-detomidine (2) into enantiomers using optically active acids is the formation of waste enriched in the A-enantiomer (levome-detomidine, 3), which cannot be racemized to an equilibrium mixture of enantiomers by a safely scalable method.

[0016] The method for racemization of waste after isolation of dexmedetomidine, containing up to 75% of the A-isomer, described in patent US8877941B2 (2013), in addition to the low percentage of recovery of racemic medetomidine (28.2%), in our opinion, has a significant drawback, consisting in the use of explosive benzoyl peroxide in substoichiometric quantities (2.34 kg of benzoyl peroxide per 1 kg of a mixture enriched with levometomidine) according to the following scheme of the process of racemization of “chiral waste” enriched with levometomidine 3:

[0017] Since most of the described methods for the synthesis of the starting racemic dexmedetomidine include a large number of stages, and due to the structural features of the molecule (in particular, the sterically loaded aromatic cycle) allow obtaining the target product with a yield of <30%, the low yield of the 5-enantiomer at the separation stage and the impossibility of recycling waste, with subsequent repeated separation, in total significantly increases the cost of the production process of the dexmedetomidine substance, and also leads to the formation of undesirable “chiral waste”.

[0018] Another method for obtaining dexmedetomidine is asymmetric catalytic hydrogenation of the olefin precursor 4 (Table 2).

[0019] Table 2. Synthesis of dexmedetomidine by asymmetric hydrogenation

[0020] NIYA a CAS 136705-64-1. b (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,la:3,4-a']dinaphthalen-4-yl)bis(l-phenylethyl)amine, CAS 380230-02-4;C CAS 277306-29-3. d CAS 528814-26-8.

[0021] This approach has an important advantage over the classical separation of medetomidine enantiomers using chiral acids, namely, minimization of the formation of levometomidine, which, as we mentioned earlier, cannot be racemized in a convenient and safe way. In patent CN108147999B (2018), the authors do not report the enantiomeric excess obtained directly after hydrogenation, but isolate the product by crystallization with L-tartaric acid, which allows achieving high optical purity (ee>99%). Hayashida et al. in patent JP2018039757A (2018) report an ee of 89.2% in the case of a MonoPhos class ligand (0.15 mmol substrate), and 94.8% ee when using Josiphos SL-J002-2 (6.81 mmol substrate). However, when scaling the process up to 520 g of olefin 4, the authors of patent WO2021089878A1 (2021) obtained lower ee values ​​(79.3%). The highest enantiomeric excess (>99%) is reported in patent CN109912508A (2019). In this case, the authors use 2.1 wt% of ligand and 2.05 wt% rhodium catalyst. Patent CN112979553A (2021) reports a successful attempt to carry out asymmetric hydrogenation using Pd / C as a catalyst and (A,5)-DuanPhos ligand (ee>99° / o), but in this case the authors had to use 70 wt% ligand. Considering that (A,5)-DuanPhos is currently one of the most expensive ligands, the use of even a few weight percent of the ligand leads to a very high overall cost of the production process.

[0022] Despite the minimization of the formation of the undesirable / / -enantiomer during asymmetric hydrogenation, and the formation of a relatively small amount of “chiral waste” after final purification (less than 0.3 kg per 1 kg of product pre-enriched to 90% with the ^-enantiomer), the disadvantage of the method is the high cost of ligands and catalysts.

[0023] Since the use of other, cheaper ligands in the synthesis process does not allow for the proper optical purity of the final substance in accordance with USP requirements (no more than 1% levometomidine in the final API), further enrichment of the product with the 5-enantiomer is necessary by multiple crystallization of diastereomeric salts.

[0024] An enzymatic method for the resolution of racemic medetomidine has also been reported. Thus, the authors of patent CN106749028B (2017) report a method for the separation of enantiomers using enantioselective enzymatic hydrolysis of preformed amides, in particular immobilized Candida antarctica lipase (Novozym 435). Despite the high yield of the product at the separation stage and the elegance of the process, this approach has significant drawbacks, in particular, it involves the formation of amides using toxic and allergenic condensing agents such as D / TU-dicyclohexylcarbodiimide, and, similar to the classical approach to the separation of racemic medetomidine using chiral acids, leads to the formation of "chiral waste".

[0025] To increase the recovery of dexmedetomidine from the racemic mixture, attempts have also been made to pre-modify the medetomidine molecule by introducing auxiliary functional groups. In particular, the authors of patent CN106632053 (2017) report a method based on the preliminary sulfonation of racemic medetomidine, followed by separation using enantiomerically pure ethyl lysine ester, followed by alkaline hydrolysis of the resulting diastereomeric salt, with simultaneous removal of the auxiliary sulfo group. In addition to increasing the number of synthesis stages due to the need to introduce auxiliary groups, the method uses hazardous, volatile, toxic and inconvenient to handle liquid sulfur trioxide. In addition to the problems associated with the safety of the process, despite the high degree of extraction of the 5-enantiomer (according to the authors, from 87.9 to 94.2%), taking into account the maximum content of dexmedetomidine in the equilibrium racemic mixture (0.50 kg per 1.0 kg of racemate) separation by this method results in the formation of 0.53-0.56 kg of waste enriched with levometomidine, similar to the enzymatic separation method.

[0026] Thus, there is still a need to develop a waste-free and inexpensive method for synthesizing dexmedetomidine that does not require the use of expensive chiral phosphine ligands and rhodium-based catalysts, hazardous reagents, and results in the formation of a minimal amount of waste enriched in levometomidine.

[0027] ESSENCE OF THE INVENTION

[0028] The technical problem solved by the invention is to develop a waste-free and inexpensive method for synthesizing dexmedetomidine.

[0029] The technical result consists in increasing the efficiency due to increasing the degree of extraction of dexmedetomidine from the racemic mixture.

[0030] The result is achieved by preliminary enrichment of medetomidine with the S'-enantiomer at the early stages of synthesis, an effective method for regenerating "chiral waste" as well as the separating amine.

[0031] BRIEF DESCRIPTION OF DRAWINGS

[0032] The invention is explained by illustrative material, where Fig. 1 shows a general diagram of the process for synthesizing the substance dexmedetomidine (1) and dexmedetomidine hydrochloride (1*HCl), a reaction diagram explaining the claimed method, Fig. 2 shows a flow diagram of the process for separating acid 10 into enantiomers, including the regeneration of (+)-ADPE 11 and racemization of acid 14 enriched in the R-enantiomer.

[0033] List of abbreviations

[0034]

[0035] DETAILED DESCRIPTION OF THE INVENTION

[0036] The process of synthesis of dexmedetomidine (1) begins with the production of organomagnesium reagent 6 (Fig. 1)

[0037] The starting compound for the preparation of 6 is commercially available 2,3-dimethylbromobenzene 5, which reacts with magnesium turnings in a suitable organic solvent such as THF to form reagent 6 in high yield (90%). Subsequent reaction of the resulting reagent 6 with ethyl 2-bromopropionate 7 in the presence of a catalyst (Co(acac)3 / TMEOA; from 2 to 10 mol%) leads to the formation of ethyl 2-arylpropionate 8.

[0038] This catalytic system has been previously described in the literature (Cahiez, G.; Chaboche, C.; Duplais, C.; Moyeux, A. A new efficient catalytic system for the chemoselective cobalt-catalyzed cross-coupling of aryl Grignard reagents with primary and secondary alkyl bromides. Org. Lett. 2009, 11(2), 277-280).

[0039] The optimum temperature range in this case is from 0 to -15 °C, preferably from -5 to -10 °C. The preparation of the organomagnesium compound 6 and the subsequent cross-coupling are carried out in an atmosphere of an inert gas, such as nitrogen or argon, preferably argon.

[0040] Subsequent quenching is carried out with dilute aqueous solutions of mineral acids such as H2SO4 or HCl, preferably HCl.

[0041] Extraction of the cross-coupling product 8 can be performed with a water-immiscible organic solvent such as ethyl acetate, propyl acetate, butyl acetate, hexane, heptane, petroleum ether, or toluene, preferably heptane. Before extraction of the quenched reaction mixture, the reaction solvent can be removed under vacuum, which facilitates the extraction process and reduces the amount of waste.

[0042] Removal of cobalt traces from the crude cross-coupling product 8 is achieved by a short (~10 min) wash with 36% hydrochloric acid, followed by a wash with aqueous solutions of complexing agents such as EDTA, NaiEDTA or Na4EDTA. The achievable residual Co level in the crude product 8 is < 1 ppm (ICP-OES).

[0043] The resulting crude ester 8 contains an admixture of the homocoupling by-product 9 can be used in the next step without further purification.

[0044] The next stage involves alkaline hydrolysis of crude ester 8 containing biphenyl 9 impurity under the action of alkali metal hydroxides such as NaOH or KOH, optimally NaOH, in a water-alcohol medium, optimally water-methanol or water-ethanol, followed by distillation of the water-alcohol mixture. This results in the formation of a readily water-soluble sodium or, respectively, potassium salt of racemic acid 10, and precipitation of the substantially water-insoluble by-product biphenyl 9, which can be readily removed by filtration or extraction with a suitable organic solvent such as petroleum ether, heptane or toluene, preferably petroleum ether. Acidification of the aqueous phase with dilute aqueous solutions of mineral acids such as H2SO4 or HCl, preferably HCl, results in precipitation of a crystalline precipitate of the product 10, which can be separated by filtration or centrifugation, followed by drying. The overall yield of the product in the two stages is 90%. The purity of the resulting acid 10 is >99a% according to HPLC.

[0045] The resulting acid 10 is then subjected to the classical process of separation into enantiomers by forming diastereomeric salts with chiral amines, optimally with (15,27?)-(+)-1,2-diphenyl-2-aminoethanol 11

[0046] The optimal solvent for crystallization in this case is ethanol. Heating an alcohol solution of racemic acid 10 and amino alcohol 11 until all solids are completely dissolved, followed by smooth cooling, leads to crystallization of salt 12 the crystallization process is repeated a total of 2-3 times, monitoring the enantiomeric purity after each crystallization using chiral HPLC, until the content of the individual S'-enantiomer of acid 10 in the salt is at least 98.5%.

[0047] The resulting salt is then decomposed with dilute aqueous solutions of mineral acids, preferably H3PO4, in a two-phase system of water-organic solvent, such as ethyl acetate, / / -propyl acetate, / / -butyl acetate or toluene, preferably toluene. The optimum temperature range in this case is from 60 to 80 °C, preferably 80 °C.

[0048] After separation, the organic phase is concentrated in vacuo to obtain the S-enantiomer of acid 15

[0049] 15 In the case of using toluene as a solvent in the acid extraction stage 15, the organic phase can be concentrated to dryness, since toluene is a suitable solvent for the next stage. In this case, the toluene solution is concentrated to an acid content of 15 ~30 wt%, and is used in the next stage without additional preparation. The use of toluene in this case has a favorable effect on the residual water content, due to the formation of an azeotropic mixture.

[0050] The combined alcohol mother liquor obtained at the crystallization stage containing salt 13 enriched in the 7?-enantiomer of acid 10 (er KS ~ 65:35) is concentrated in a vacuum.

[0051] The regenerated ethanol is then reused in the crystallization stage of diastereomeric salts after adjusting the strength, and the wet salt 13 is decomposed with dilute aqueous solutions of mineral acids in a two-phase water-organic solvent system, similar to the procedure described above for salt 12, directly in the reactor in which the concentration was carried out,

[0052] After phase separation, the combined aqueous phase from both processes containing the dihydrogen phosphate (+)-ADPE 11 is sent for regeneration. Neutralization of the acidic solution of the amino alcohol salt 11 with alkali metal hydroxides such as NaOH or KOH, preferably KOH, or with an ammonia solution leads to the precipitation of the crystalline base 11 without loss of enantiomeric purity. The degree of regeneration of the separating chiral amine achieved in this case is >95%.

[0053] The organic phase contains predominantly the 7?-enantiomer 14 (63 to 65%) concentrated in a vacuum, and the resulting solid product is sent to the racemization stage without further purification.

[0054] The racemization of the acid 14 can be carried out with strong bases such as Z-BuOK, NaOH or KOH, preferably with Z-BuOK, in high-boiling alcohols such as / / -butanol, z-butanol, / / -amyl alcohol, z-amyl alcohol, zz-hexanol, / / -heptanol, / / -octanol, 2-ethyl-1-hexanol (isooctanol), propylene glycol, preferably in isooctanol. The optimum temperature range in this case is from 100 to 170 °C, preferably 165 °C. The reaction time depends on the process temperature and is from 2 hours (in the case of isooctanol) to 18 hours (in the case of / / -butanol). Subsequent dilution of the reaction mixture with water leads to the transition of the corresponding sodium or potassium salt into the aqueous phase, from which, after acidification, the racemic acid 10 is obtained in high purity.

[0055] In addition, the process of racemization of the 7?-enantiomer-enriched acid 14 can be carried out without a solvent, by heating the melt for 3 hours at 225 °C. Fig. 2 shows a flow diagram of the above-described process technology, including the separation of racemic acid 10 into enantiomers, the regeneration of the resolving amine 11, and the racemization of the undesired 7?-enantiomer of acid 14.

[0056] The racemized acid 10 is then re-introduced into the resolution cycle, which allows for almost complete conversion of the racemic acid 10 to the S-enantiomer in a few cycles.

[0057] The reaction of acid 15 with a slight excess (1.25 equiv) of thionyl chloride in a suitable organic solvent, preferably toluene (0.5 l per 1 mol of acid 15), at room temperature in the presence of a catalytic amount of DMF (from 2.5 to 5 mol%) leads to the net conversion of acid 15 to acid chloride 16 which, after removal of the solvent in vacuo, is used without further purification in the next step, which involves the reaction of 16 with dimethylsulfoxonium methylide 17 generated in a suitable organic solvent such as THF from trimethylsulfoxonium salts, e.g. trimethylsulfoxonium iodide 18 under the action of strong bases, preferably potassium tert-butoxide. The optimum temperature range for the generation step of ylide 17 is from 65 to 45 °C, preferably 45 °C.

[0058] The resulting ylide 17 is then reacted with acid chloride 16 to obtain compound 19.

[0059] The optimum temperature range for the reaction step of compound 16 and ylide 17 is from 0 to -15 °C, preferably -10 °C. The optimum molar ratio of 16:17 is 1:2.1. Both the generation of ylide 17 and the subsequent synthesis of 19 are performed in an inert gas atmosphere such as nitrogen or argon, preferably argon.

[0060] The trimethylsulfoxonium chloride formed as a by-product directly reacts in the reaction mixture with the excess iodide ions, which leads to anion exchange and precipitation of the less soluble trimethylsulfoxonium iodide, thus regenerating the starting salt 18 in a yield of up to 80%, which can be separated by filtration and reused in the next synthesis cycle.

[0061] In the next step, the obtained compound 19 is reacted with hydrogen bromide (as a solution in AcOH) in a suitable organic solvent such as THF or 2-MeTHF, which leads to the formation of a-haloketone 20

[0062] The optimum temperature range for the reaction step of compound 19 with HBr is from 0 to 2 °C at the time of mixing the components, after which the temperature should be increased from 55 to 65 °C, preferably 55 °C.

[0063] The process of synthesis of a-haloketone 20 is accompanied by the formation of a by-product in the form of a mixture of diastereomeric sulfoxides 21 which are then removed from the product by aqueous washing of a solution of the crude a-haloketone 20 in hydrocarbon solvents such as hexane, heptane or petroleum ether, preferably heptane.

[0064] Bromoketone 20 is not stable when stored at room temperature and completely decomposes in <2 weeks, but it can be easily stabilized by adding MgO (0.1 wt%) and storing at low temperature. The MgO-stabilized product can be stored for >3 months at -20 °C without noticeable signs of decomposition or racemization.

[0065] In the next step, compound 20 is reacted with an alkali metal azide such as sodium azide or potassium azide, preferably sodium azide, to produce a compound of formula 22

[0066] The reaction can be carried out either under phase-transfer catalysis (NaNs, 5 mol% TBAI, water-MTBE, 45 °C, 2 h) or in a separate solvent such as THF (NaNs, 5 mol% TBAI, 25 °C, 20 h). Subsequent removal of the solvent in vacuo gives the crude product suitable for use in the next step without further purification. Azidoketone 22 is stable upon storage and mechanical action.

[0067] The reduction of azidoketone 22 can be carried out by known methods, in particular, this patent discloses a method based on the catalytic hydrogenation of 22 in the presence of H2-Pd / C and organic (preferably methanesulfonic, i-toluenesulfonic, camphorsulfonic) or mineral (hydrochloric, hydrobromic, sulfuric) acids, not limited to the listed acids, to obtain the corresponding salts of aminoketone 23a-23f

[0068]

[0069] Optimal solvents for the hydrogenation process are lower alcohols such as methanol, ethanol and / / -propanol, preferably methanol. The optimum pressure range is from 3 to 5 bar.

[0070] In the next step, the aminoketone salt 23 is reacted with an alkali metal thiocyanate such as sodium thiocyanate, potassium thiocyanate, or ammonium thiocyanate to form thione 24 in high yield.

[0071] The optimal solvent for carrying out this reaction is water. The optimal temperature range at the stage of cyclization of the aminoketone salts is from 80 to 100 °C, preferably 95 °C. The practically water-insoluble thione 24 precipitates as a solid substance, which can be separated by filtration or centrifugation.

[0072] Desulfurization of compound 24, for example with Raney nickel, leads to the formation of the S-enantiomer-enriched product 1

[0073] Since a small amount of racemization of the stereocenter is observed at each step during the synthesis process, starting with the step of obtaining ylide 19, the overall contribution of each step results in the production of product 1 containing typically 87 to 93% dexmedetomidine.

[0074] Increasing the enantiomeric purity of the obtained dexmedetomidine base 1 from 87-93% to >99% can be accomplished by crystallizing the S-enantiomer-enriched product with chiral organic acids, for example in the form of a salt with L-(+)-tartaric acid 25

[0075] The preparation of the final API involves precipitation of the purified dexmedetomidine base 1 from the organic acid salt by the action of alkalis, filtration of the product, and drying, followed by reaction with hydrogen chloride in a suitable organic solvent such as acetone or ethyl acetate to obtain the pharmaceutically acceptable salt 1*HCl

[0076] The new method for obtaining dexmedetomidine that we propose allows to a large extent:

[0077] 1. Due to preliminary enrichment of the product with the S-enantiomer (up to ~90%) at the early stages of synthesis, it is possible to reduce the amount of non-regenerable “chiral waste” enriched with levometomidine by approximately 4 times (from 0.78-0.84 kg of waste from 1 kg of racemic medetomidine in classical separation, to 0.20-0.23 kg of waste from 1 kg of product pre-enriched with the S-enantiomer in the proposed method), which is comparable in efficiency to the method of catalytic asymmetric hydrogenation, leading to the formation of a product with a predominance of the desired S-enantiomer.

[0078] 2. Unlike methods involving the use of catalytic asymmetric hydrogenation, the new approach we propose completely eliminates the need to use expensive and difficult-to-access chiral phosphine ligands, as well as rhodium-based catalysts.

[0079] 3. The use as an intermediate of a compound from the well-studied and synthetically readily available class of 2-arylpropionic acids, capable of easy enolization and, consequently, racemization of the chiral center in the a-position to the carboxyl group under the action of strong bases, in particular cheap hydroxides and alcoholates of alkali metals, provides the possibility of simple regeneration of “chiral waste” without the use of explosive benzoyl peroxide.

[0080] 4. An efficient, safe and highly profitable (>95% in one cycle) process for recycling waste acid 10 enriched in the / ^-enantiomer, as well as a high percentage of regeneration of the separating amine 11, ensures almost quantitative extraction of (5')-2-(2,3-dimethylphenyl)propionic acid 15 from the racemate in 2-3 cycles.

[0081] 5. The method does not require the introduction and, accordingly, subsequent removal of protective or auxiliary functional groups throughout the entire process.

[0082] 6. All intermediates, except for the stages associated with the crystallization of diastereomeric salts, are used in subsequent stages without additional purification.

[0083] EXPERIMENTAL PART

[0084] General methods

[0085] The starting material 2,3-dimethylbromobenzene (5; CAS 576-23-8) was purchased from commercial suppliers and further distilled under vacuum before use. Magnesium turnings (Turnings for Grignard Reaction) from Fisher Chemical were oven-dried at 120 °C for 20 h and activated with iodine (2 g per 200 g magnesium). All solvents and reagents were purchased from commercial suppliers and were used without further purification and preparation, except for THF. THF (ACS 99.6%) was distilled under argon (with the addition of ~0.1% hydroquinone) before use and dried over activated molecular sieves 3A (100 g / L) for 3 days. Molecular sieve activation was achieved by heating in a muffle furnace at 320 °C for 8 h with periodic purging with dry air. To create an inert atmosphere, grade 5.0 argon was used without additional purification.The concentration of 2,3-dimethylphenylmagnesium bromide was determined by direct iodometric titration in a saturated solution of lithium chloride in dry THF according to the method of Paul Knochel (Krasovskiy, A.; Knochel, P. Convenient titration method for organometallic zinc, magnesium, and lanthanide reagents. Synthesis 2006, (5), 0890-0891). All glassware and parts of glass apparatus used in the stage of preparation of the organomagnesium reagent, cross-coupling, and synthesis of ylide 19 were dried in a drying oven at 120 °C for 20 hours. Glass reactors (15 and 30 L) were dried before handling moisture-sensitive compounds by circulating hot coolant (120 °C) for 20 h, with a continuous flow of dry nitrogen (100 mL / min) through the bottom valve. 'H and. 13 NMR data were recorded on an Agilent 400 MHz spectrometer (400 MHz for 'H and 101 MHz for 13C). Chemical shifts are expressed in parts per million relative to the residual signals of the deuterated solvents used. The residual content of heavy metals was determined on an iCAP 6300 Duo inductively coupled plasma optical emission spectrometer (Thermo Scientific). The residual water content in the intermediates was measured using a V20S KF titrator (Mettler Toledo). Monitoring of the completeness of the reactions and assessment of the chromatographic purity of the intermediates were carried out using an Alliance (Waters) HPLC system with a photodiode array detector (PDA).

[0086] Analytical conditions

[0087] Method A

[0088] Instrument: Waters Alliance HPLC;

[0089] Column: SunFire C 18, 3.5 cm, 2.1 mm * 150 mm;

[0090] Eluent A: MeCN;

[0091] Eluent B: H2O + H3PO4 (600 c1 85% H3PO4 per 1000 ml H2O)

[0092] Elution mode: gradient;

[0093] Ratio of eluents A and B:

[0094] Column thermostat temperature: 40 °C;

[0095] Detection wavelength: 215 pt.

[0096] Method B

[0097] Instrument: Waters Alliance HPLC;

[0098] Column: CHIRALCEL OJ-H, 5 pm, 4.6 mm x 250 mm;

[0099] Eluent A: n-hexane;

[0100] Eluent B: isopropanol;

[0101] Ratio of eluents A and B: 94:6;

[0102] Elution mode: isocratic;

[0103] Flow rate: 1.00 ml / min;

[0104] Column thermostat temperature: 25 °C;

[0105] Detection wavelength: 220 pt. Note: Before analyzing diastereomeric salts, 2-3 mg of the corresponding salt is shaken in a test tube with 1 ml hexane and 500 µl 10% HCl until completely dissolved, after which the hexane phase is directly analyzed by HPLC.

[0106] Method C

[0107] Instrument: Waters Alliance HPLC;

[0108] Column: SunFire C 18, 3.5 pm, 2.1 mm * 150 mm;

[0109] Eluent A: MeCN;

[0110] Eluent B: H2O + H3PO4 (600 pl 85% H3PO4 per 1000 ml H2O)

[0111] Elution mode: gradient;

[0112] Ratio of eluents A and B:

[0113] Column thermostat temperature: 40 °C;

[0114] Detection wavelength: 215 pt.

[0115] Method D

[0116] Instrument: Waters Alliance HPLC;

[0117] Column: CHIRALCEL OJ-H, 5 pm, 4.6 mm x 250 mm;

[0118] Eluent: 100% / -heptane;

[0119] Elution mode: isocratic;

[0120] Flow rate: 0.70 ml / min;

[0121] Column thermostat temperature: 25 °C;

[0122] Detection wavelength: 220 pt.

[0123] Note: Before analysis, (5)-2-(2,3-dimethylphenyl)propionyl chloride (16; 5 μl) was dissolved in methanol (100 μl), and the solution was kept for 15 min at room temperature. The resulting solution of methyl (5)-2-(2,3-dimethylphenyl)propionate was diluted with water (300 μl) and / / -heptane (300 μl). The mixture was shaken for 1-2 min on a shaker, the heptane layer was separated, diluted to 1.5 ml with / / -heptane, and analyzed under the conditions given for Method D.

[0124] Method E Instrument: Waters Alliance HPLC;

[0125] Column: CHIRALCEL OJ-H, 5 pm, 4.6 mm x 250 mm;

[0126] Eluent A: n-heptane;

[0127] Eluent B: isopropanol;

[0128] Elution mode: isocratic;

[0129] Ratio of eluents A and B: 95:5;

[0130] Flow rate: 1.00 ml / min;

[0131] Column thermostat temperature: 25 °C;

[0132] Detection wavelength: 220 pt.

[0133] Note: Prior to analysis, (5)-2-(2,3-dimethylphenyl)propionyl chloride (16; 5 μL) was dissolved in MTBE (200 μL), and the resulting solution was added dropwise to a solution of n-propylamine (50 μL) in MTBE (200 μL). The suspension was stirred for 1–2 min, quenched with water (300 μL), and shaken for 1–2 min on a shaker. The organic layer (100 μL) was separated and evaporated under a stream of air in a 1.5-mL vial. The crystalline amide was dissolved in isopropanol (100 μL), diluted to 1.5 mL with w-heptane, and analyzed under the conditions given for Method E.

[0134] Method F

[0135] Instrument: Waters Alliance HPLC;

[0136] Column: SunFire C 18, 3.5 pm, 2.1 mm 150 mm;

[0137] Eluent A: MeCN;

[0138] Eluent B: H2O + H3PO4 (600 pl 85% H3PO4 per 1000 ml H2O)

[0139] Elution mode: gradient;

[0140] Ratio of eluents A and B:

[0141] Column thermostat temperature: 40 °C;

[0142] Detection wavelength: 215 pt.

[0143] Method G

[0144] Instrument: Waters Alliance HPLC; Column: CHIRALCEL OJ-H, 5 ct, 4.6 mm x 250 mm;

[0145] Eluent: 100% n-pentane;

[0146] Elution mode: isocratic;

[0147] Flow rate: 0.60 ml / min;

[0148] Column thermostat temperature: 25 °C;

[0149] Detection wavelength: 220 pt.

[0150] Method H

[0151] Instrument: Waters Alliance HPLC;

[0152] Column: CHIRALCEL OJ-H, 5 pm, 4.6 mm x 250 mm;

[0153] Eluent A: n-hexane;

[0154] Eluent B: isopropanol;

[0155] Elution mode: isocratic;

[0156] Ratio of eluents A and B: 75:25;

[0157] Flow rate: 1.00 ml / min;

[0158] Column thermostat temperature: 25 °C;

[0159] Detection wavelength: 220 pt.

[0160] Note: Before analysis, aminoketone salt 23 (10 mg) was suspended in ethyl acetate (1.0 mL), N'-dimethylcarbamoyl chloride (16 μL), and DIPEA (50 μL) were added. The mixture was stirred at 25 °C monitoring the conversion of the starting aminoketone to the N,N-dimethylcarbamoyl derivative. After 2 h, HPLC analysis showed >99% conversion of the starting aminoketone (Method C). An aliquot of the solution (50 μL) was diluted with ethyl acetate (300 μL) and 5% hydrochloric acid (300 μL). The mixture was shaken on a shaker for 5 min, the organic layer (350 μL) was separated and evaporated under a stream of air in a 1.5 mL vial. The residue was dissolved in isopropanol (300 µl), diluted with w-hexane to 1.5 ml, and analyzed under the conditions given for Method H. A derivative of racemic 1-amino-3-(2,3-dimethylphenyl)butan-2-one was similarly prepared for use as a standard reference for identifying the retention time of the minor enantiomer.

[0161] Method I

[0162] Instrument: Waters Alliance HPLC;

[0163] Column: CHIRALCEL OJ-H, 5 pm, 4.6 mm x 250 mm;

[0164] Eluent A: n-hexane;

[0165] Eluent B: isopropanol;

[0166] Elution mode: isocratic; Ratio of eluents A and B: 90: 10;

[0167] Flow rate: 1.00 ml / min;

[0168] Column thermostat temperature: 25 °C;

[0169] Detection wavelength: 220 fps.

[0170] Method J (USP 43-NF38, Dexmedetomidine hydrochloride, p. 1302)

[0171] Instrument: Waters Alliance HPLC;

[0172] Column: CHIRALPAK AGP, 5 pm, 4.0 mm * 150 mm;

[0173] Eluent A: MeCN;

[0174] Eluent B: Buffer: 1.0 L of Na2HPO4*2H2O solution (5.34 g / L) is placed in a 2000 mL beaker and the pH is adjusted to 7.0 with a KH2PO4 solution (4.08 g / L; about 700-800 mL);

[0175] Elution mode: isocratic;

[0176] Ratio of eluents A and B: 17.5:82.5;

[0177] Flow rate: 1.00 ml / min;

[0178] Column thermostat temperature: 25 °C;

[0179] Detection wavelength: 220 pt.

[0180] Method K (USP 43-NF38, Dexmedetomidine hydrochloride, p. 1302)

[0181] Instrument: Waters Alliance HPLC;

[0182] Column: XBridge VEN C18, 3.5 pm, 4.6 mm * 150 mm;

[0183] Eluent A: MeOH;

[0184] Eluent B: Buffer: dissolve 0.89 g NaHPCE^H2O in 900 ml water and adjust the pH to 7.0 with a solution of NaHPCE^H2O (16.0 g / l). Transfer the resulting solution quantitatively into a 1000 ml volumetric flask and bring the volume of the solution to the mark with water.

[0185] Elution mode: isocratic;

[0186] Ratio of eluents A and B: 60:40;

[0187] Flow rate: 1.00 ml / min;

[0188] Column thermostat temperature: 40 °C;

[0189] Detection wavelength: 220 pt.

[0190] 2,3-dimethylphenylmagnesium bromide (6). Pre-activated magnesium turnings (189.6 g; 7.8 mol; 1.2 equiv) and dry THF (1.0 L) were loaded into a 10 L dry glass reactor with a thermostatically controlled jacket, equipped with an overhead stirrer with a hermetically sealed seal, a reflux condenser, a thermocouple, valves for inert gas introduction and reagent supply, and filled with argon. 80-100 mL of a solution of 2.3-dimethylbromobenzene (5; 1.20 kg; 6.5 mol; 1.0 equiv) in dry THF (4.85 L) were added to the reactor using a peristaltic pump. After the reaction had started (from 3 to 5 min) and the temperature had begun to rise, the remaining portion of the aryl bromide solution 5 in THF was added with stirring (from 230 to 250 rpm) at such a rate as to maintain the internal temperature without external heating or cooling in the range from 48 to 52 °C (the flow rate of solution 5 was about 0.85 l / hour).After adding all of the solution 5, the reaction mixture was stirred for 1 hour at a temperature of 50 to 55 °C, cooled to room temperature, and the prepared solution with excess magnesium was poured into a storage container. The concentration of 6 in the resulting solution (6.50 l) according to titration results was 0.90 M. Yield 90%.

[0191] Ethyl 2-(2,3-dimethylphenyl)propionate (8).

[0192] Cobalt(III) acetylacetonate (99.0 g; 0.278 mol; 5.0 mol%), ethyl 2-bromopropionate (7; 1006.0 g; 1 equiv; 5.56 mol), TMEDA (32.3 g; 0.278 mol; 5.0 mol%), and dry THF (2.45 L) were loaded into a 30 L dry glass reactor with a thermostatically controlled jacket, equipped with an overhead stirrer with a hermetic seal, a thermocouple, and valves for introducing an inert gas and feeding reagents, in a countercurrent of argon. The reaction mixture was cooled to -10 °C and a solution of 6 (6.50 L; 0.90 M; 5.85 mol; 1.05 equiv) was added with stirring (230 rpm) using a peristaltic pump at a rate of 1 L / h maintaining the internal temperature between -8 and -10 °C. After the addition of all of the solution 6, the blue-green reaction mixture containing an abundant precipitate of magnesium bromide was stirred at -10 °C for another 1 h. The reactor was charged with 10% hydrochloric acid (10.0 kg) pre-cooled to 0 °C, sodium chloride (3.0 kg) and / / -heptane (4.0 L).The phases were stirred for 15-20 min, the light green organic phase was separated, and the aqueous phase was re-extracted with 1 / 3-heptane (2x2.0 L). The combined emerald green organic extract was concentrated in vacuo without further treatment (to a volume of ~3 L) and washed successively with 36% hydrochloric acid (1.0 L, 10 min), water (1.0 L, 5 min), 5% Na2EDTA solution (2x1.0 L, 20 min each), water (1.0 L, 5 min), and the residual 1 / 3-heptane was removed on a rotary evaporator. The crude product was used in the next step without further purification. Yield 1217 g (theoretical yield 1146.3 g). Transparent light yellow liquid with a slight pleasant odor. ' NMR (400 MHz, CDCI3) 5 7.18-7.05 (m, ZH), 4.23-4.09 (m, 2H), 4.03 (q, J = 7.1 Hz, 1H), 2.33 (s, 3H), 2.29 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H);. 13 C NMR (101 MHz, CDCI3) 8 175.1, 139.3, 137.1, 134.3, 128.7, 125.8, 124.4, 60.7, 42.0, 21.1, 18.2, 15.2, 14.3; t R12.85 min (purity 82.78a%, HPLC method A). Residual cobalt content 0.71 ppm (ICP-OES).

[0193] / >a-2-(2,3-dimethylphenyl)propionic acid (10).

[0194] Water (2.5 L) and sodium hydroxide (556.0 g; 13.9 mol; 2.5 equiv) were loaded into a 10 L glass reactor with a thermostatically controlled jacket and an overhead stirrer with a hermetic seal and a reflux condenser. After dissolving the alkali, a solution of crude ethyl 2-(2,3-dimethylphenyl)propionate (8; 1.21 kg) in methanol (2.50 L) was loaded into the reactor. The emulsion was heated to boiling (heat carrier temperature in the reactor jacket 100 °C) with stirring for 1 hour, after which the heating temperature was increased to 110 °C, and ~2.8 L of distillate (at atmospheric pressure) was distilled from the reactor without interrupting the process. A transparent light-yellow aqueous solution containing the sodium salt of acid 10 was cooled to 23 °C, the resulting crystalline precipitate of by-product 2,2',3,3'-tetramethylbiphenyl (9) was extracted with petroleum ether (fraction 40-70; 2x1.0 l), diluted with water (10.0 l), cooled to 3 °C and, with good stirring, acidified dropwise with 36% hydrochloric acid (1.42 kg; 14.0 mol), maintaining the temperature of the mixture in the range from 8 to 12 °C. The separated white crystalline precipitate of acid 10 was filtered, washed on the filter with water (4x3.0 l), and dried in a vacuum oven at 55 °C / 5 mmHg for 48 hours. Yield 886.5 g (90.0% in 2 stages). Residual water content according to Karl Fischer titration (KF) <0.15%. White crystalline powder practically insoluble in water. t. ra 91.5-93.5 °C; 'H NMR (400 MHz, CDCI3) 8 7.22-7.04 (m, ZN), 4.07 (q, J = 7.1 Hz, 1H), 2.32 (s, 3H), 2.29 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCI3) 8 181.4, 138.4, 137.3, 134.6, 129.1, 126.0, 124.6, 41.7, 21.2, 17.8, 15.3; t R 8.49 min (purity 99.55a%, HPLC method A). Residual cobalt content 0.06 ppm (ICP- OES). Concentration of the organic extract in vacuo gave 40.23 g of by-product 2,2',3,3'-tetramethylbiphenyl (9). Colorless transparent large prisms. 1 пл116–118 °C; ' Н NMR (400 MHz, CDC13) 8 7.17-7.08 (m, 4H), 6.99-6.94 (m, J = 7.0 Hz, 2H), 2.34 (s, 6H), 1.96 (s, 6H); °C NMR (101 MHz, CDCh) 8 142.5, 136.8, 134.7, 128.6, 127.4, 125.2, 20.7, 16.6; tR 15.54 min (purity 99.72a%, HPLC method A).

[0195] (5)-2-(2,3-dimethylphenyl)propionate (15,2 / ?)-(+)-2-amino-1,2-diphenylethanol (12).

[0196] A 30 L glass reactor with a thermostatically controlled jacket and an overhead stirrer was charged with / ?Ag / -2-(2,3-dimethylphenyl)propionic acid (10; 850.2 g; 4.77 mol), (15',27?)-(+)-2-amino-1,2-diphenylethanol (11; 1017.4 g; 4.77 mol), and ethanol (70 vol %; 16.58 L). The reaction mixture was heated (40 to 43 °C) and stirred (80 rpm) until all solids were completely dissolved (20-30 min). The clear solution was cooled to 10±0.2 °C, stirring was stopped, and the reactor was seeded with pure salt 12 (0.5 g; er SR = 99.8 : 0.2). The solution was kept at 10±0.2 °C for 3 h, after which the temperature was gradually decreased from 10 to 0 °C over 8 h (cooling rate -0.02 °C / min). After cooling to 0 °C, the crystallization process was allowed to complete for 12 h at 0 °C (total time 23 h), the product was filtered, washed on the filter with cold (0 °C) ethanol (50 vol%; 3.0 L), and dried at 50 °C / 0.03 mmHg for 20 h. Yield 552 g (59.1%; er SR = 90.5 9.5).Off-white light powder. The obtained salt 12 (552 g) was dissolved with stirring (120 rpm) in ethanol (50 vol.%; 5.52 l) heated to 75 °C, the transparent solution was cooled to 60±0.5 °C, stirring was stopped and a seed of pure salt 12 (0.5 g) was added to the reactor. The solution was maintained for 1 hour at 60±0.5 °C, after which the temperature was gradually lowered from 60 to -5 °C over 18 hours (cooling rate -0.06 °C / min). After cooling to -5 °C, the crystallization process was allowed to complete for 5 h at -5 °C (total time 24 h), the product was filtered, washed on the filter with cold (-6 °C) ethanol (50 vol%; 2x1.0 L), and dried at 50 °C / 0.03 mmHg for 20 h. Yield 445.8 g (47.7%; er SR = 98.75 : 1.25). Fine needles of off-white color. The obtained salt 12 (445.6 g) was dissolved with stirring (80 rpm) in ethanol (50 vol%; 3.12 L) heated to 75 °C, the clear solution was cooled to 60±0.5 °C, stirring was stopped and the reactor was seeded with pure salt 12 (0.1 g). The solution was maintained at 60±0.5 °C for 2 h, after which the temperature was gradually decreased from 60 to -10 °C over 14.5 h (cooling rate -0.08 °C / min). After cooling to -10 °C, the crystallization process was allowed to complete for 8 h at -10 °C (total time 24.5 h), the product was filtered, washed on the filter with cold (-12 °C) ethanol (50 vol%; 1.0 L), and dried at 50 °C / 0.03 mmHg for 16 h. Yield 409.8 g (43.9%). Long, thin white needles. 1. пл 97.5-101.5 °C; [a] 25 D = +91.5° (with 1.0, MeOH); er S:X = 99.82 : 0.18 (t R 8.46 min (R-enantiomer 14), t R10.13 min (S-enantiomer 15); HPLC method B). ' NMR (400 MHz, DMSO-t / b) 5 7.25-7.09 (m, J = 26.5, 9.3 Hz, YUN), 7.09-6.98 (m, J = 14.5, 6.9 Hz, 3H), 6.20 (d. 4, 8 =2H) ( 1H), 4.10 (d, J = 3.9 Hz, 1H), 3.84 (q, J = 13.5, 6.8 Hz, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H); 13 C NMR (101 MHz, DMSO-76) 5 176.9, 142.5, 140.9, 140.7, 136.1, 134.0, 128.2, 127.7, 127.5, 127.3, 126.7, 126.8, 75.7, 60.9, 42.4, 20.7, 18.5, 14.9. t R 1.23 min (amine), 8.52 min (acid) (purity 99.85a%, HPLC method A).

[0197] Regeneration of the / {-enantiomer-enriched 2-(2,3- dimethylphenyl)propionic acid (14) and (+)-ADPE (11).

[0198] The combined alcohol mother liquor from the crystallization stage (31.2 L) was concentrated in vacuo (50 mmHg) at 55-60 °C to -10 L. The resulting thick suspension of the precipitated salt was diluted with water (10.0 L) and toluene (3.0 L), heated to 80 °C with stirring (at this point, all the precipitated salt dissolves in toluene, and two transparent phases are formed), and a mixture of 85% orthophosphoric acid (644.0 g; 5.58 mol; 1.5 equiv) and water (650 mL) was added over 15 min. The phases were stirred at 80 °C for 1 h, separated, and the aqueous phase was re-extracted with toluene (3.0 L). The combined organic extract was washed with 5% orthophosphoric acid solution (2x1.0 L), saturated aqueous sodium chloride solution (2.0 L) and concentrated in vacuo. The crystalline residue was dried at 45 °C / 5 mmHg for 16 h. The product was used in the next racemization step without further purification. Yield of 2-(2,3-dimethylphenyl)propionic acid 655.5 g (98.8%). Light yellow crystalline powder, tnji 87.5-91.5 °C; [a]. 25 D = -33.4° (c 4.0, MeOH); er R:S = 63.6 : 36.4 (1R 8.61 min (R-enantiomer 14), 1R 10.19 min (S'-enantiomer 15); HPLC method B); ' H and 13 With NMR the data are similar to those given for 10 above; 1R 8.42 min (purity 99.60a%, HPLC method A).

[0199] The aqueous phase containing (+)-ADPE dihydrogen phosphate was cooled to 70 °C and pumped into a 30 L glass reactor (feed rate 4 L / min) containing a preheated (70 °C) stirred (200-250 rpm) solution of potassium hydroxide (1.166 kg; 86 wt% KOH; 17.87 mol; 3.2 equiv) in water (4.0 L). The suspension of the precipitated crystalline (+)-ADPE base (11) was cooled to 5 °C, stirred at low speed (80 rpm) for 16 h, filtered, washed with water (3 x 2.0 L), and dried at 50 °C / 0.03 mmHg for 48 h. Yield 766.8 g (96.5% recovery). White crystalline powder, practically insoluble in water. 1 пл 141- 141.6 °C; [a] 25 D= +6.0° (c 1.0, EtOH); ' NMR (400 MHz, DMSO-t / 6) 5 7.27-7.13 (m, YN), 5.26 (d, J = 3.8 Hz, 1H), 4.63-4.57 (m, 1H), 3.95 (s, J = 5.9 Hz, 1. 1H); 13 C NMR (101 MHz, DMSO-t / b) 5 143.7, 143.1, 127.8, 127.4, 127.3, 127.0, 126.8, 126.3, 77.6, 61.4; t R 6.53 min (purity 99.92a%, HPLC method C).

[0200] Racemization of / {-enantiomer-enriched 2-(2,3- dimethylphenyl)propionic acid (14).

[0201] A 30 L jacketed steel reactor equipped with an overhead stirrer and a reflux condenser was charged with R-enantiomer-enriched 2-(2,3-dimethylphenyl)propionic acid (14; 655.5 g; 3.68 mol; 1.0 equiv; er RS ​​= 63.6 : 36.4) and 2-ethylhexanol (3.68 L). The mixture was stirred at 50 °C until acid 14 was completely dissolved (5-10 min), the reactor was filled with dry argon, and powdered potassium mpem-butoxide (619.0 g; 5.52 mol; 1.5 equiv) was charged. The reactor heating temperature was increased to 165-170 °C, and stirring was continued (60-70 rpm) for 2 hours, maintaining a slight excess argon pressure (20-30 mmHg) in the reactor to protect the reaction mixture from atmospheric carbon dioxide. After 2 hours, HPLC analysis showed complete racemization (Method B). The reaction mixture was cooled to ~80 °C, water was added (7.36 L), stirred for 20-30 min, the clear lower aqueous layer containing the potassium salt of acid 10 was separated, cooled to 30-35 °C and acidified with 36% hydrochloric acid (517 mL; 1.1 equiv). The white crystalline precipitate was filtered, washed with water (3x3.0 L), and dried at 50 °C / 0.03 mmHg for 16 h. Yield 640.1 g (97.6%). The degree of recovery of acid 10 in 1 cycle of separation / regeneration / racemization (RRR) was 96.5%. White crystalline powder, tnji 93-94.8 °C; er R:S = 50.1 : 49.9 (1R 8.57 min (R-enantiomer 14), 1R 10.01 min (S-enantiomer 15); HPLC method B); ' H i. 13 With NMR the data are similar to those given for 10 above; 1R 8.47 min (purity 99.80a%, HPLC method A).

[0202] Isolation of (5)-2-(2,3-dimethylphenyl)propionic acid (15) from salt and regeneration of (+)-ADPE (11).

[0203] (5)-2-(2,3-dimethylphenyl)propionate (lS,2R)-(+)- was loaded into a 30-L glass reactor with a thermostatically controlled jacket and an overhead stirrer.

[0204] 2-amino-1,2-diphenylethanol (12; 1308.7 g; 3.34 mol), water (10.0 L) and toluene (6.0 L).

[0205] The mixture was heated to 80 °C and a mixture of 85% orthophosphoric acid (578.1 g; 5.01 mol; 1.5 equiv) and water (580 mL) was added with stirring (200-250 rpm) over 15 min. The phases were stirred at 80 °C for 1 h, separated and the aqueous phase re-extracted with toluene (2 x 1.0 L). The combined organic extracts were washed with a solution of orthophosphoric acid (50 g of 85% H3PO4) in water (1.0 L), saturated aqueous sodium chloride solution (3.0 L) and concentrated in vacuo at 50 °C. The resulting light yellow oil crystallized on standing overnight. The product was used in the next step without further purification. Yield of (S)-2-(2,3-dimethylphenyl)propionic acid 580.8 g (97.5%). Light yellow crystals. 1 пл 46.7-47.2 °C; [a] 25 D = +107.5° (with 1.0, MeOH); er = 99.5 : 0.5 (t R8.43 min (R-enantiomer 14), tR 10.11 min (S-enantiomer 15); HPLC method B); ' H and 13 With NMR the data are similar to those given for 10 above; 1R 8.48 min (purity 98.0a%, HPLC method A).

[0206] The combined aqueous phase containing (+)-ADPE dihydrogen phosphate was cooled to 70 °C and pumped into a 30 L glass reactor (feed rate 4 L / min) containing a preheated (70 °C) stirred (200-250 rpm) solution of potassium hydroxide (1.137 kg; 86 wt% KOH; 17.43 mol; 3.2 equiv) in water (3.75 L). The suspension of the precipitated crystalline (+)-ADPE base (11) was cooled to 2 °C, stirred at low speed (80 rpm) for 16 h, filtered, washed with water (4 x 3.0 L), and dried at 60 °C / 0.03 mmHg for 48 h. Yield 676.0 g (94.8%). White crystalline powder, practically insoluble in water. 1 пл 141.7-142.5 °C; [a] 25 o = +6.0° (c 1.0, EtOH); 'N and 13With NMR the data are similar to those given for 11 above; 1R 6.67 min (purity 99.93a%, HPLC method C).

[0207] (*U)-2-(2,3-Dimethylphenyl)propionyl chloride (16).

[0208] A 10 L glass reactor with a thermostatically controlled jacket, equipped with an overhead stirrer with a hermetically sealed seal and filled with argon were charged with (5)-2-(2,3-dimethylphenyl)propionic acid (15; 578.0 g; 3.24 mol; 1.0 equiv), dry toluene (1.62 L) and A,A-dimethylformamide (5.92 g; 81.0 mmol; 2.5 mol%). The mixture was stirred until completely dissolved, and thionyl chloride (482.3 g; 4.05 mol; 1.25 equiv) was added in one portion. Smooth gas evolution began without foaming or any signs of heating (Caution! Use a gas scrubber to absorb HCl and SO2 or exhaust gases into an exhaust device!). The clear solution was stirred at room temperature until gas evolution ceased. HPLC analysis of an aliquot quenched with w-propanol after 4 h showed >99.7% conversion (Method A). The solution was concentrated in vacuo at 40 °C. The crude product was used in the next step without further purification. Yield 715.8 g (100%; theoretical yield 637.8 g).Transparent light yellow liquid, er SK = 99.5 0.5 (derivatization with methanol; tR 22.62 min (methyl (R)-2-(2,3-dimethylphenyl)propionate), tR 25.47 min (methyl (5)-2-(2,3-dimethylphenyl)propionate); HPLC method D); A similar ratio of enantiomers was obtained by derivatization with n-propylamine (tR 7.65 min (( / ?)-2-(2,3-dimethylphenyl)-A-propylpropionamide), IR 8.33 min ((5)-2-(2,3-dimethylphenyl)-A-propylpropionamide); HPLC method E); ' NMR (400 MHz, CDC13) 5 7.16-7.14 (m, 2H), 7.09-7.04 (m, 1H), 4.43 (q, J = 7.0 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H);. 13 C NMR (101 MHz, CDCI3) 8 176.0, 137.8, 136.4, 134.7, 129.9, 126.3, 124.9, 54.1, 21.2, 18.5, 15.4.

[0209] (35)-1-[dimethyl(oxido)-k 6 -sulfanylidene]-3-(2,3-dimethylphenyl)butan-2-one (19).

[0210] Trimethylsulfoxonium iodide (18; 1.50 kg; 6.81 mol; 2.1 equiv), dry THF (6.13 L) were charged into a 10 L dry jacketed glass reactor with a thermostatically controlled overhead stirrer and filled with argon, and potassium m cm-butoxide (764.8 g; 6.81 mol; 2.1 equiv) was added with stirring. The reactor was wrapped in aluminum foil (to protect from light), the reaction mixture was heated to 45 °C and stirred for 2 h. The suspension was cooled to - 10 °C and a solution of crude (5)-2-(2,3-dimethylphenyl)propionyl chloride (16; 715.1 g; calculated pure substance 637.1 g; 3.24 mol; 1 equiv) in dry THF (2.23 L) was added with stirring (500 rpm) at a rate of about 1 L / h, maintaining the internal temperature of the mixture between -9.8 and -10.2 °C. Analysis of an aliquot after 1 h of stirring at -10 °C after addition of 16 showed >99% conversion of 16 (Method A). The suspension was concentrated in vacuo (at a temperature not exceeding 35 °C), diluted with water (7.2 L) and ethyl acetate (5.0 L), stirred for 10 min, the phases were separated, the aqueous phase was filtered from the precipitate of trimethylsulfoxonium iodide, and re-extracted with ethyl acetate (3.0 and 2.0 L). The combined organic extract was dried with sodium sulfate (250 g) and concentrated in vacuo at 35 °C. The crystalline residue was dried in vacuo at 25 °C for 8 h. Yield 778.3 g (95.2%). Light yellow fine crystalline powder. 1. пл 91.2-92.7 °C; er = 96.2 : 3.8 (1R 28.85 min (R-enantiomer), 1R 30.65 min (5-enantiomer); HPLC method B); 'H NMR (400 MHz, CDCI3) 5 7.15 (d, J = 7.5 Hz, 1H), 7.09-7.00 (m, 2H), 4.16 (s, 1H), 3.78 (q, J = 7.1 Hz, 1H), 3.35 (s, 3H), 3.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 1.43 (d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCI3) 5 192.8, 141.5, 136.8, 134.7, 128.2, 125.7, 124.9, 68.8, 47.2, 42.3, 42.2, 21.1, 18.2, 15.4; 1R 6.96 min (purity 96.40a%, HPLC method F). Yield of reduced trimethyl sulfoxonium iodide 558.8 g (78.3%). Light yellow finely crystalline powder. Mass fraction of 18 according to the results of argentometric titration 99.1%.

[0211] (5)-1-bromo-3-(2,3-Dimethylphenyl)butan-2-one (20).

[0212] A dry 10 L jacketed glass reactor fitted with an overhead stirrer with a sealed argon gas was charged with a solution of compound 19 (776.5 g, 3.07 mol, 1.0 equiv) in dry THF (7.76 L). The solution was cooled to 0 °C and a 33% solution of hydrogen bromide in glacial acetic acid (829.8 g, 3.38 mol, 1.1 equiv) was added over 40 min maintaining the internal temperature between 0.5 and 1.5 °C. The resulting light yellow suspension was stirred for an additional 20 min at 0 °C and then heated to 55 °C. After 1.5 h of heating at 55 °C, HPLC analysis of an aliquot indicated >99.5% conversion of starting material 19 (Method A). The clear yellow solution was concentrated in vacuo at 30 °C, and the residue was partitioned between water (6.0 L) and heptane (6.0 L). The phases were stirred for 15 min, the aqueous layer was separated, and the heptane extract was re-washed with water (6 x 5.0 L), monitoring the removal of by-product sulfoxide 21 by HPLC (Method A).The solution was concentrated in vacuo at 35 °C. The crude product was used in the next step without further purification. Yield 566.0 g (72.1%). Transparent dark yellow oil, lacking lachrymatory action, crystallizing on standing into long needles, er SK = 94.9 : 5.1 (1R 19.33 min (R-enantiomer), 1R 20.72 min (S'-enantiomer); HPLC method D); ' NMR (400 MHz, CDCI3) 8 7.12-7.04 (m, 2H), 6.88-6.81 (w, J = 6.8, 2.2 Hz, 1H), 4.39 (q, J = 6.8 Hz, 1H), 3.79 (dd, J = 39.8, 12.7 Hz, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H);. 13 C NMR (101 MHz, CDCI3) 8 202.8, 138.1, 138.0, 134.6, 129.4, 126.4, 124.9, 46.7, 33.3, 21.2, 17.3, 15.4; t R12.79 min (purity 95.34a%, HPLC method A). The combined aqueous phase (~36 L) containing the by-product sulfoxide 21 was extracted with chloroform (5x2.0 L), the extract was concentrated in vacuo at 35 °C, the residue was dissolved in ethyl acetate (2.0 L), washed with saturated aqueous sodium bicarbonate solution (2.0 L), dried over sodium sulfate, filtered and the ethyl acetate was removed in vacuo at 35 °C. Yield 186.43 g (25.4%; mixture of diastereomers). Clear light orange oil with a sulfurous odor. 'H NMR (400 MHz, CDCI3) 5 7.11-7.04 (m, 2H), 6.81 (t, J = 6.5 Hz, 1H), 4.14 (q, J = 6.8 Hz, 1H), 3.80-3.40 (dd, 2H), 2.64 (s, 3H), 2.28 (d, 6H), 1.36 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCI3) 8 202.7, 138.2, 137.3, 134.9, 129.5, 126.4, 125.3, 60.9, 52.3, 38.7, 21.2, 16.5, 15.3 (Major diastereomer); ' H NMR (400 MHz, CDCI3) 8 7.11-7.04 (m, 2H), 6.81 (t, J = 6.5 Hz, 1H), 4.08 (q, J = 6.8 Hz, 1H), 3.80-3.40 (dd, 2H), 2.57 (s, 3H), 2.31 (d, 6H), 1.36 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCI3) 8 203.2, 138.3, 137.5, 134.7, 129.5, 126.4, 125.2, 64.6, 51.4, 39.7, 21.2, 16.5, 15.4 dimeric (Monomeric); 1R 7.22 min (purity 99.73a%, HPLC method A);

[0213] (5)-1-azido-3-(2,3-dimethylphenyl)butan-2-one (22).

[0214] A 10 L jacketed glass reactor fitted with an overhead stirrer with a seal and a reflux condenser was charged with a solution of sodium azide (171.2 g, 2.63 mol, 1.2 equiv) in water (2.20 L), TBAI (40.5 g, 5 mol%, 109.7 mmol), and a solution of bromoketone 20 (560.0 g, 2.19 mol, 1.0 equiv) in MTBE (2.2 L). The two-phase system was stirred (300 rpm) at 45 °C. After 2 h, HPLC analysis showed 100% conversion of the starting bromoketone 20 to azidoketone 22 (Method A). The organic phase was separated, washed with water (2.0 L), 1% aqueous sodium thiosulfate solution (1.0 L), water (2.0 L), and concentrated in vacuo at 30 °C. The crude product was used in the next hydrogenation step without further purification. Yield 475.8 g (99.8%). Clear yellow oil, er SR = 94.8 : 5.2 (1R 36.64 min (S-enantiomer), 1R 39.39 min (R-enantiomer); HPLC method G); 'H NMR (400 MHz, CDCI3) 8 7.12-7.05 (m, 2H), 6.92-6.84 (m, J = 5.8, 3.3 Hz, 1H), 4.06 (q, J = 6.9 Hz, 1H), 3.80 (dd, J = 3.4 Hz, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 1.40 (d, J = 6.9 Hz, 3H);. 13 C NMR (101 MHz, CDCI3) 8 205.4, 138.0, 137.7, 134.3, 129.4, 126.5, 124.9, 56.1, 47.6, 21.1, 16.8, 15.3; t R 12.24 min (purity 94.64a%, HPLC method A).

[0215] (5)-1-amino-3-(2,3-dimethylphenyl)butan-2-one mesylate (23a).

[0216] A 30 L jacketed steel hydrogenation reactor equipped with an overhead stirrer was charged with a solution of azidoketone 22 (475.5 g; 2.18 mol; 1.0 equiv) in methanol (4.0 L). The reactor was filled with argon, and a solution of methanesulfonic acid (216.7 g; 99% concentration; 2.23 mol; 1.02 equiv) in methanol (0.75 L) and 10% palladium on carbon (47.5 g; 10 wt%) were added sequentially. The reactor was pumped with hydrogen to a pressure of 3.5 bar, after which the pressure was released to 0.2 bar. The reactor was flushed with hydrogen twice more, the reactor was thermostatted (25 °C), stirring was started (100 rpm), and the hydrogenation process was continued under a pressure of 3.5 bar. After 22 h, HPLC analysis showed >99% conversion of the starting azidoketone 22 to the aminoketone mesylate 23a (Method C). The catalyst was filtered through a GFA filter, washed with methanol (0.3 L), and the clear, light yellow filtrate was concentrated to dryness in vacuo at 35 °C. MTBE (2.0 L) and n-heptane (0.05) were added to the crystalline residue.50 L), the suspension was stirred for 20 min, filtered, the precipitate was washed on the filter with a mixture of MTBE (2.0 L) and n-heptane (0.50 L), and then with pure n-heptane (2.0 L). The product was dried in vacuum (3 mmHg) at 25 °C for 18 hours. Yield 569.2 g (90.5%). Pale yellow pearly crystalline powder. 1. пл 145-147 °C; er SR = 94.4 : 5.6 (Derivatization with L / L-dimethylcarbamoyl chloride; 1R 4.73 min (V?-enantiomer), 1R 5.63 min (5-enantiomer); HPLC method H); 1 H NMR (400 MHz, DMSO-t / b) 5 8.01 (s, ZN), 7.12-7.05 (m, 2H), 6.91-6.84 (m, J = 6.7, 2.3 Hz, 1H), 4.25 (q, J = 6.9 Hz, 1H), 3.79 (dd, J = 136.2, 18.0 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 1.30 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) 5 204.5, 137.8, 137.2, 134.6, 128.9, 125.9, 124.9, 46.2, 45.8, 39.7, 20.7, 16.7, 15.0; t R 6.89 min (purity 99.14a%, HPLC method C).

[0217] 4-[(5)-1-(2,3-dimethylphenyl)ethyl]-1,3-dihydro-2H-imidazole-2-thione (24).

[0218] A 10 L glass reactor with a thermostatically controlled jacket, fitted with an overhead stirrer with a sealed condenser, and a reflux condenser was charged with aminoketone mesylate (23a; 567.3 g; 1.97 mol; 1.0 equiv), potassium thiocyanate (959.2 g; 9.87 mol; 5.0 equiv), and water (1.97 L). The reactor was purged with argon, and the mixture was heated with stirring (200-250 rpm), maintaining an internal temperature of 93 to 95 °C for 45 h. The suspension was cooled to 20 °C, diluted with water (5.0 L), filtered, and the precipitate was washed with water (3x3.0 L), isopropanol cooled to 0 °C (1.0 L), and a mixture of isopropanol and n-heptane (1:2 by volume; 2x1.5 L). The product was dried in vacuum (0.03 mmHg) at 40 °C for 18 hours. Yield 413.3 g (90.1%). Pale yellow, shiny, pearlescent finely crystalline powder, odorless. 1 пл 244-245 °C (with decomposition); [a] 23 D = +10.5° (from 1.0, MeOH); = 87.4 : 12.6 (t R 6.32 min (5-enantiomer), t R9.56 min ( / ^-enantiomer); HPLC method I); ' Н NMR (400 MHz, DMSO-t / e) 5 11.83 (s, 1H), 11.70 (s, 1H), 7.03-7.00 (m, 2H), 6.95-6.90 (m, J = 8.5, 4.4 Hz, = 1H (6), 6 7.1 Hz, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 1.38 (d, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO-D,) 5 160.4, 141.7, 136.3, 133.7, 133.6, 127.9, 125.4, 123.9, 111.4, 31.8, 14.9;, 19.4; t R 7.00 min (purity 99.86a%, HPLC method A).

[0219] The crude basis of dexmedetomidine (1).

[0220] A 10 L jacketed glass reactor fitted with an overhead stirrer with a sealed gasket, filled with argon and containing a freshly prepared suspension of Raney nickel (-0.94 kg, 16 mol, 10 equiv) in ethanol (4.62 L, 96 vol %) was charged with thione 24 (370.0 g, 1.59 mol). The reactor was purged with argon and the suspension was stirred (350 rpm) under argon at 27 °C while monitoring the conversion by HPLC. After 16 h of stirring, analysis showed 99.8% conversion (HPLC starting 24 content 0.2a%; method C). To complete the reaction, the suspension was heated for 1 h at 40 °C (conversion >99.9%, starting 24 content by HPLC 0.06a%), cooled to 25 °C, the suspension was allowed to settle (15-20 min), and the product solution was siphoned off from the precipitate under a slight pressure of argon (0.2 bar). A fresh portion of ethanol (4.0 l; 96 vol.%) was poured into the reactor, the suspension was stirred for 1 h, the precipitate was allowed to settle, and the alcohol phase was decanted.The washing was repeated once more (Caution! The slurry consisting of nickel(II) sulfide and unreacted Raney nickel is still pyrophoric! Avoid drying and contact of the slurry with air!), the combined alcohol solution of the product was filtered through a pad of celite, concentrated on a rotary evaporator, and the residue was dried in vacuo (5 mmHg) for 12 hours. Yield 282.9 g (88.7%). Off-white crystalline powder. t. ra 130.5-132 °C; [a] 23 D = +55.5° (with 1.0, MeOH); er SiR = 87.1 : 12.9 (t R 4.37 min (R-enantiomer, levomedetomidine), tR 6.49 min (S-enantiomer, dexmedetomidine); HPLC method J); ' H NMR (400 MHz, CDCI3) 8 10.36 (s, 1H), 7.23 (s, 1H), 7.04-6.97 (m, 2H), 6.94-6.88 (m, J = 6.5, 2.5 Hz, 1H), 6.65 (s, 1H), 4.37 (q, J = 7.1 Hz, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCI3) 8 143.3, 141.2, 136.9, 134.6, 134.2, 128.1, 125.7, 124.8, 117.3, 34.2, 21.0, 20.8, 14.8; t R6.36 min (purity 99.94a%, HPLC method K). Residual metal content: Co 0.02 ppm, Pd 0.59 ppm, Ni 10.2 ppm (ICP-OES).

[0221] Dexmedetomidine L-(+)-tartrate (25).

[0222] Crude dexmedetomidine base (1; 276.0 g; 1.37 mol; er S': / = 87.1 : 12.9) was dissolved in 90% ethanol (2.0 L) directly in the evaporation flask of a rotary evaporator under gentle heating (<50 °C), and the resulting yellow solution was filtered through a GF / A filter. The clear filtrate was transferred to a 10 L glass reactor with a thermostatically controlled jacket, equipped with an overhead stirrer with a sealed seal, and a reflux condenser. L-(+)-tartaric acid (206.8 g; 1.37 mol; 1.0 equiv) and 90% ethanol (1.70 L) were added to the reactor with a solution of crude base 1, the suspension was heated with stirring (heat carrier temperature 80 °C) for 30-40 min, after which water was added in small portions (10 ml) until almost complete dissolution was achieved (about 100 ml). Stirring was stopped, the solution was cooled from 80 to 20 °C at a rate of 0.25 °C / min, after which the crystallization process was allowed to complete within 14 hours.The coarse crystalline precipitate was filtered, washed on the filter with ethanol cooled to 10 °C (90 vol %; 1.0 L), and dried at 50 °C for 16 h. Yield 343.3 g (81.6%; er : R = 97.5 : 2.5). The obtained salt 25 (343.3 g) was dissolved in hot 90% ethanol (1.80 L; heating temperature 85 °C), stirring was stopped, the solution was cooled from 85 to 20 °C at a rate of 0.25 °C / min, after which the crystallization process was allowed to complete over 18 h. The crystalline precipitate was filtered, washed on the filter with ethanol cooled to -10 °C (96 vol %; 1.0 L), and dried at 50 °C for 16 h. Yield 304.55 g (72.4%; er S:R = 99.76 : 0.24).

[0223] The combined alcoholic mother liquor from all crystallizations was concentrated to dryness in vacuo. The residue (178.2 g; er S:R = 62.8 : 37.2) was dissolved in hot 90% ethanol (0.675 L; heating temperature 80 °C), stirring was stopped, and the solution was cooled from 80 to 20 °C at a rate of 0.1 °C / min (10 h). In the temperature range from 75 to 60 °C, the clear solution was seeded with pure dexmedetomidine L-(+)-tartrate (1.0 g), and after cooling to 20 °C, the crystallization process was allowed to complete for 8 h. The crystalline precipitate was filtered, washed on the filter with ethanol cooled to -10 °C (90 vol %; 0.40 L), and dried at 50 °C for 16 h. Yield 92.52 g (22.0%; er SR = 82.3 : 17.7). The obtained salt (92.52 g) was dissolved in hot 90% ethanol (0.375 L; heating temperature 80°C), stirring was stopped, the solution was cooled from 80 to 20 °C at a rate of 0.1 °C / min (10 hours), after which the crystallization process was allowed to complete for 10 hours.The crystalline precipitate was filtered, washed on the filter with ethanol cooled to -10 °C (90 vol.%; 0.25 L), and dried at 50 °C for 16 h. Yield 75.12 g (17.9%; er SR = 98.1 : 1.9). The resulting salt (75.12 g) was suspended in 90% ethanol (0.35 L) and heated (85 °C) with stirring for 2 h. The temperature of the solution was stabilized at 80 °C, stirring was stopped, the solution was cooled from 80 to 20 °C at a rate of 0.25 °C / min, after which the crystallization process was allowed to complete for 12 h. The crystalline precipitate was filtered, washed on the filter with ethanol cooled to -10 °C (90 vol.%; 0.20 L), and dried at 50 °C for 16 h. Yield 65.88 g (15.7%; er SR = 99.72 : 0.28). Total yield 370.43 g (88.1%). Coarsely crystalline pearlescent shiny powder of white color. 1. пл 180-181 °C; [a] 23 D= +58.0° (c 1.0, MeOH); 1R 4.87 min (levomedetomidine), 1R 7.19 MIN (dexmedetomidine); HPLC method J); ' H NMR (400 MHz, DMSO-t / b) 5 8.34 (s, 5H), 7.91 (s, 1H), 6.99 (d, J = 4.6 Hz, 2H), 6.91- 6.86 (m, 2H), 4.37 (H, J 4.1), 4.37 (H, J 4.1). 2.24 (s, 3H), 2.21 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) 5 173.7, 143.1, 139.9, 136.3, 134.6, 133.6, 127.7, 125.4, 124.3, 116.6, 20.8.1, 30.7.1, 14.5; t R 6.35 min (purity 99.84a%, HPLC method K). Residual metal content: Co 0.02 ppm, Pd below detection limit (<0.02 ppm), Ni 1.27 ppm (ICP-OES).

[0224] The purified base of dexmedetomidine (1

[0225] A 5 L glass reactor equipped with an overhead stirrer was charged with dexmedetomidine L-(+)-tartrate (25; 368.25 g; 1.05 mol; er SR = 99.7 : 0.3) and water (2.0 L), and a solution of sodium hydroxide (92.5 g; 2.31 mol; 2.2 equiv) in water (0.80 L) was added with stirring (120-140 rpm) over 30 min. The resulting suspension of dexmedetomidine base was stirred for another 10 min, filtered, the precipitate was washed on the filter with water (3x1.0 L), and dried at 50 °C / 0.05 mmHg for 16 h. Yield 207.2 g (98.4%). White crystalline powder, easily soluble in methanol and ethanol, slightly soluble in acetone, practically insoluble in water. ra 148.5-150.5 °C; [a] 22 D = +75.5° (with 1.0, MeOH); er SiR = 99.74 : 0.26 (t R 4.80 min (7?-enantiomer, levometomidine), t R 7.41 min (S-enantiomer, dexmedetomidine); HPLC method J); ' H and 13 With NMR the data are similar to those given for 1 above; t R6.35 min (purity 99.95a%, HPLC method K). Residual metal content: Co 0.02 ppm, Pd below detection limit, Ni 0.5 ppm (ICP-OES);

[0226] Dexmedetomidine hydrochloride (1*HCl).

[0227] A 3 L glass reactor equipped with an overhead stirrer was charged with dexmedetomidine base (1; 205.0 g; 1.02 mol; erg 5:7? = 99.74 : 0.26) and acetone (2.0 L). The suspension was cooled (2.5 to 3 °C), and 36% hydrochloric acid (96 mL; 1.12 mol; 1.1 equiv) was added dropwise with stirring. The resulting colorless solution was filtered through a GF / A filter and concentrated in vacuo on a rotary evaporator. The resulting oil was seeded with crystalline dexmedetomidine hydrochloride (0.30 g) and kept under vacuum (<10 mmHg) at room temperature for 1 h in a rotating (20 rpm) evaporating flask. Ethyl acetate (2.0 L) was added to the crystallized residue, and ~1 L of the distillate was distilled off on a rotary evaporator at atmospheric pressure (bath temperature 85 °C) to remove water. The crystal suspension was diluted with ethyl acetate (1.0 L), cooled to room temperature, filtered, and the remaining crystals were washed from the walls with ethyl acetate (0.25 l), and the product was quickly transferred to glass trays for drying. The product was dried in vacuum at 50 °C for 88 hours. Yield 235.3 g (97.1%). Microscopic hygroscopic needles of white color, extremely easily soluble in water. t. ra 155-157 °C; [a] 22 D = +54.0° (c 1.0, H2O); er 5:7? = 99.90 : 0.10 (t R 4.47 min (7?- enantiomer, levometomidine), t R 6.86 min (5-enantiomer, dexmedetomidine); HPLC method J); 'H NMR (400 MHz, DMSO-d6,) 5 9.06 (s, 1H), 7.45 (s, 1H), 7.06-7.00 (m, 2H), 6.89-6.85 (m, 1H), 4.52 (q, J = 7.1 Hz, 1H), 2.24 (d, J = 4.3 Hz, 6H), 1.52 (d, J = 7.1 Hz, 3H); 13 C NMR (DMSO-<76, 101 MHz) 5 141.1, 137.4, 136.7, 133.9, 133.8, 128.3, 125.7, 124.1, 115.7, 31.8, 20.7, 20.4, 14.6; t R 6.40 min (purity 99.98a%, HPLC method K). Residual metal content: Co below detection limit, Pd below detection limit, Ni 0.5 ppm (ICP-OES);

Claims

AMENDED CLAUSE OF THE INVENTION received by the International Bureau on February 25, 2025 (02 / 25 / 2025) 1. Method for obtaining dexmedetomidine of structural formula 1 or a pharmaceutically acceptable salt thereof, comprising obtaining an organomagnesium reagent of structural formula 6 by reaction of 2.3-dimethylbromobenzene of formula 5 with metallic magnesium, followed by cross-coupling of reagent 6 with ethyl 2-bromopropionate 7 to obtain a compound of formula 8 alkaline hydrolysis of the resulting compound 8 and subsequent acidification of the aqueous phase to precipitate the racemic acid of formula 10 crystallization of racemic acid 10 with (+)-ADPE formula 11 to obtain a diastereomeric salt of formula 12 43 AMENDED SHEET (ARTICLE 19) decomposition of diastereomeric salt 12 in an acidic medium to isolate the desired S-enantiomer of the acid of formula 15 decomposition of the diastereomeric salt 13 containing the undesired 7?-enantiomer obtained in the crystallization stage of the racemic acid 10 for the isolation of the 7?-enantiomer-enriched acid of formula 14 regeneration of acid 10 by racemization of acid 14 enriched in the unwanted R-enantiomer under the action of strong bases to an equilibrium mixture of enantiomers, and reuse of the racemized acid 10 in a crystallization cycle with (+)-ADPE of formula 11, reaction of acid 15 with thionyl chloride to obtain the acid chloride of formula 16 generation of dimethylsulfoxonium methylide of formula 17 in situ from trimethylsulfoxonium salts, for example, trimethylsulfoxonium iodide of formula 18 44 AMENDED SHEET (ARTICLE 19) and a strong base, followed by the addition of acid chloride 16, to obtain a compound of formula 19 reaction of compound 19 with hydrogen bromide in a mixture of acetic acid and THF to obtain the a-bromoketone of formula 20 followed by aqueous washing of a solution of a-bromoketone 20 in a hydrocarbon solvent, reaction of a-bromoketone 20 with an alkali metal azide to obtain a-azidoketone of formula 22 reduction of a-azidoketone 22, using Hr-Pd / C in the presence of organic or mineral acids, to obtain the corresponding aminoketone salts, cyclization of the aminoketone salts with potassium thiocyanate, to obtain a compound of formula 24 desulfurization of compound 24 using Raney nickel to yield a product containing 87 to 93% dexmedetomidine.

2. The method according to item 1, in which methanesulfonic or p-toluenesulfonic or camphorsulfonic acid is selected as the organic acids, and hydrochloric or hydrobromic or sulfuric acid is selected as the mineral acids, with the production of the corresponding aminoketone salts of formulas 23a-23f 45 AMENDED SHEET (ARTICLE 19) 3. The method according to claim 1, comprising increasing the enantiomeric purity to >99% of the obtained dexmedetomidine 1 by obtaining a salt of dexmedetomidine 1 with L-(+)-tartaric acid 25 and its crystallization, precipitation of purified dexmedetomidine base 1 from salt 25 under the action of alkali, followed by reaction with hydrogen chloride in acetone, evaporation, and azeotropic drying with ethyl acetate to obtain a pharmaceutically acceptable dexmedetomidine hydrochloride salt of formula 1 46 AMENDED SHEET (ARTICLE 19)

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