Synthetic route optimization of Sumepirin antiepileptic drug candidate 159 D O I: 1 0. 15 82 6/ ch im te ch .2 02 0. 7. 4. 04 M. S. Dzyurkevich, N. V. Shtyrlin, Y. G. Shtyrlin Chimica Techno Acta. 2020. Vol. 7, no. 4. P. 159–168. ISSN 2409–5613 Synthetic route optimization of Sumepirin antiepileptic drug candidate M. S. Dzyurkevich, N. V. Shtyrlin, Y. G. Shtyrlin* Kazan (Volga region) Federal University, 420008, Kremlevskaya str. 18, Kazan, Russia *email: yurii.shtyrlin@kpfu.ru Abstract. In this work we describe the transformation of synthetic route of the antie- pileptic drug candidate Sumepirin starting from discovery stage. Initial method included six step process requiring two steps of purification using colon chromatography and has poor overall yield of target compound. The process developed is convenient, scalable, technological and meet the most of conditions of green chemistry. The overall yield was increased up to 62.5% in four steps without colon chromatography purification which allows to obtain the target compound with purity of 99.5+% which is especially important for the active ingredient. Keywords: pyridoxine; synthetic route optimization; scale-up; purification; antiepileptic drug; technology Received: 15.10.2020. Accepted: 09.12.2020. Published:30.12.2020. © M. S. Dzyurkevich, N. V. Shtyrlin, Y. G. Shtyrlin, 2020 Introduction The  social and medical signifi- cance of epilepsy is determined by its high prevalence. Epilepsy is  one of  the  most common chronic diseases of the nervous system in  the  world, which affects both children and adults. 5% of the population suffers at least one epileptic seizure dur- ing their lifetime. In 70% of cases, epilepsy debuts in childhood and adolescence. Pa- tients with epilepsy may have mental prob- lems including personality changes specific to the disease associated with a mnestic- intellectual defect, affective disorders and so-called epileptic psychoses. According to the WHO, about 50 million people suf- fer from epilepsy, which is about 0.5–1% of  the  world’s population (https://www. who.int/news-room/fact-sheets/detail/ epilepsy). Approximately 5 million new cases are diagnosed worldwide each year. Moreover, 30% of  patients with epilepsy are pharmacoresistant [1]. On the  other hand, existing antiepileptic drugs have a lot of side effects including ataxia, decreased mental ability, drowsiness, dizziness, di- gestive disorders, etc. [2]. Development of effective and safe drugs may significantly improve the quality of life of patients suf- fering from epilepsy. Sumepirin 1 is  a  novel antiepileptic drug candidate developed in  the  Scien- tific and Educational Center of Pharma- ceutics of the Kazan Federal University and having pronounced antiseizure effect and improved safety profile. This compound is pyridoxine-based molecule with residue of methanesulfonic acid in the 6th position of pyridoxine ring (Fig. 1). It has successfully passed preclinical studies in  the  framework of  State pro- 160 gram of  Russian Federation «Develop- ment of  the  Pharmaceutical and Medi- cal Industry» and is planned to undergo the  clinical trials. As  Sumepirin entered preclinical studies stage an  urgent need of the optimization of its method of syn- thesis arised. Preclinical phase involves study of chronical toxicity of a drug can- didate both in  small (e.g. mice or rats) and large (rabbits) animals. The duration of these experiments depends on the ex- pected duration of the course of the drug. Antiepileptic drugs are usually taken for an extended period of time: from months to years. That means that chronical toxic- ity should be studied at least for 6 month of everyday administration of a drug. Dur- ing the discovery stage a general method of synthesis was used which allows prepa- ration of diverse set of 6-substitued pyri- doxine derivatives. This method is not suit- able for large-scale synthesis as required at preclinical trials. This required the de- velopment of more convenient and scalable synthetic approach. Experimental Unless otherwise stated, chemicals are obtained from the commercial suppliers and were used without further purification. 1H and 13C NMR spectra were recorded on a “Bruker AVANCE 400” at operating frequencies of  400.13 and 100.62  MHz, respectively. Chemical shifts were meas- ured with reference to  the  residual peak of  the  solvent (DMSO-d6, 1H, 2.50 ppm, 13C, 39.52 ppm; CDCl3, 1H, 7.26 ppm, 13C, 77.16 ppm). Coupling constants (J) are given in Hertz (Hz). The following abbre- viations are used to  describe coupling: s = singlet; d = doublet; t = triplet. Melting points were determined using a Stanford Research Systems MPA-100 OptiMelt melt- ing point apparatus and are uncorrected. For TLC analysis, silica gel plates from Sorbfil (Krasnodar, Russia) were used with UV light (254 nm) as a developing agent. Column chromatography was performed on silica gel (60–200 mesh) from Acros. High-resolution mass spectroscopy mass spectra were obtained on a  quad- rupole time-of-flight (t, qTOF) AB Sciex Triple TOF 5600 mass spectrometer using turbo-ion spray source (nebulizer gas ni- trogen, positive ionization polarity, needle voltage 5500 V). Recording of the spectra was performed in “TOF MS” mode with a collision energy of 10 eV, declustering po- tential of 100 eV and resolution more than 30,000 full-width half-maximum. Samples with the analyte concentration 5 µmol/L were prepared by dissolving the test com- pounds in a mixture of methanol (HPLC- UV Grade, LabScan) and water (LC–MS Grade, Panreac) in 1:1 ratio. Compounds 3, 4, 5 and 6 were obtained according to published procedures [3–5] without any modifications, unless other- wise is stated. I.  Optimized method of  synthe- sis of  6-(hydroxymethyl)-3,3,8-trime- thyl-1,5-dihydro-[1,3]dioxepino[5,6-c] pyridin-9-ol (4). 143 g (684 mmol) com- pound 3 is  added to  the  2-liter double- necked round bottom flask equipped with N OH OH HO SO3Na Sumepirin (1) Fig. 1. Structure of Sumepirin 1 161 magnetic stirring bar and a thermometer. Solution of  14  g (342 mmol) of  sodium hydroxide in 342 ml of distilled water and 120 ml of freshly distilled formaldehyde solution (37% wt., 1641 mmol, stabilized with 5% methanol) is added to the reac- tion vessel. Mixture is flushed with argon and reaction is carried out under inert at- mosphere at 70 °C for about 5 h. The reac- tion is  controlled by  TCL on silica (elu- ent CHCl3:MeOH = 10:1) until the  spot of starting material completely disappears. After reaction is finished, reaction mixture is cooled down to the room temperature and neutralized by the 1M solution of hy- drochloric acid to  the  pH = 6.5. A  seed of  water-insoluble crystalline form of  4 (10 mg) is added to the solution. Solution is then transferred into the 2-liter beaker and left overnight to  achieve complete crystallization. The  precipitate formed is filtered off, washed 3 times with the 100 ml of distilled water and dried to obtain 154 g (94%) of compound 4 as pale yellow solid; m.p. 182–183 °C. 1H NMR (DMSO- d6), δ, ppm: 1.41 (s, 6Н), 2.33 (s, 3Н), 4.42 (s, 2Н), 4.80 (s, 2Н), 4.82 (s, 2Н). Spectrum is in accordance with the previously pub- lished [4]. II. Synthesis of sodium (9-hydroxy- 3 , 3 , 8 - t r i m e t hy l - 1 , 5 - d i hy d r o - [ 1 , 3 ] dioxepino[5,6-c]pyridin-6-yl)meth- a n e s u l fo n ate ( 7 ) s t a r t i n g f r o m 6-(chloromethyl)-3,3,8-trimethyl-1,5-di- hydro-[1,3]dioxepino[5,6-c]pyridin-9-yl acetate (6). In the 100 ml round bottom flask equipped with mechanical stirring bar a solution of 1.0 g (3.34 mmol) of com- pound 6 in 20 ml of dichloromethane and solution of 0.8 g (6.67 mmol) of sodium sulfite in 30 ml of water were added. 0.01 g (0.03 mmol) of TBAB were added to the re- action mixture and the reaction was car- ried out at  room temperature while vig- orous stirring for 10 h. Then water layer is  separated from the  organic and water is removed under reduced pressure. Dry solid residue is extracted with 3×100 ml of hot isopropyl alcohol. Alcohol extract is evaporated until 30 ml left and white pre- cipitate formed is filtered off and washed with 10 ml of cold isopropyl alcohol. Af- ter drying 0.66  g (61%) of  compound 7 was obtained as white solid; m.p. 197 °C (decomp.). NMR 1H (400 MHz, DMSO- d6), δ, ppm: 1.38 (s, 6Н, C(СН3)2), 2.30 (s, 3Н, СН3), 3.82 (s, 2Н, СН2S), 4.79 (s, 2Н, СН2), 4.90 (s, 2Н, СН2). NMR 13С {1H} (100  MHz, DMSO-d6), δ, ppm: 19.28, 23.73, 57.47, 59.11, 60.97, 101.45, 132.07, 134.18, 140.97, 143.25, 146.78. HRМS-ESI: found [М+Н]+ 326.0667, C12H16NNaO6S, calculated [М+Н]+ 326.0669. III. Synthesis of  sodium (5-hy- droxy-3,4-bis(hydroxymethyl)-6-meth- ylpyridin-2-yl)methanesulfonate (1) starting from sodium (9-hydroxy- 3 , 3 , 8 - t r i m e t hy l - 1 , 5 - d i hy d r o - [ 1 , 3 ] dioxepino[5,6-c]pyridin-6-yl)methane- sulfonate (7). 0.66 g (2.03 mmol) of com- pound 7 is dissolved in 10 ml concentrated hydrochloric acid. The solution was stirred for 1 h at room temperature. After this in- soluble NaCl filtered off (solubility of NaCl in concentrated HCl solution is 0.1% wt.) and 40 ml of isopropanol is added to the fil- trate. After standing for 1 hour a crystalline precipitate is formed. The solid is filtered off, washed with 10 ml of cold isopropanol and dried. Dry solid is dissolved in 15 ml of distilled water and titrated with 0.1 M NaOH solution until pH = 7.2. After drying 0.57 g (98%) of compound 1 was obtained as  white solid; m.p. 265  °C (decomp.). NMR 1H (400 MHz, DMSO-d6), δ, ppm: 2.31 (s, 3H, CH3), 4.04 (s, 2H, CH2), 4.51 (d, 3JHH = 6.3 Hz, 2H, CH2), 4.78 (s, 2H, CH2), 5.17 (t, 3JHH = 6.3 Hz, 1H, OH). NMR 162 13С {1H} (100  MHz, DMSO-d6), δ, ppm: 19.33, 56.80, 57.16, 57.21, 132.07, 132.74, 143.31, 145.04, 148.94. HRМS-ESI: found [М+Н]+ 286.0354, C9H12NNaO6S, calcu- lated [М+Н]+ 286.0356. IV. Modified synthesis of  (9-ace- toxy-3,3,8-trimethyl-1,5-dihydro-[1,3] dioxepino[5,6-c]pyridin-6-yl)methyl acetate (10). 1-liter double-necked round bottom flask equipped with magnetic stir- ring bar and effective reflux condenser is charged with 90 g (376 mmol) of com- pound 4, 55 ml of  triethylamine (395 mmol) and 400 ml of  dichloromethane. 28 ml of acetyl chloride (395 mmol) in 100 ml of dichloromethane is charged into drop funnel which is then attached to the flask. Acetyl chloride is added dropwise to the re- action mixture while stirring to maintain slow boiling. After whole amount is added reaction mixture is stirred for additional 0.5  h and then extracted with 3×200 ml of distilled water and washed with brine. Organic layer is separated, dried over an- hydrous sodium sulfate and evaporated. Residue is  dried under vacuum to  ob- tain 119  g (98%) of  10 as  viscous liquid of yellow to light brown color which may crystallize upon long standing. NMR 1H (400 MHz, DMSO-d6), δ, ppm: 1.48 (s, 6H, CH3), 2.09 (s, 3H, CH3), 2.35 (s, 6H, CH3), 4.72 (s, 2H, CH2), 4.89 (s, 2H, CH2), 5.13 (s, 2H, CH2). Spectrum is in accordance with the previously published [6]. V.  Synthesis of  sodium (9-hydroxy- 3 , 3 , 8 - t r i m e t hy l - 1 , 5 - d i hy d r o - [ 1 , 3 ] dioxepino[5,6-c]pyridin-6-yl)meth- anesulfonate (7) starting from (9-ace- toxy-3,3,8-trimethyl-1,5-dihydro-[1,3] dioxepino[5,6-c]pyridin-6-yl)methyl ac- etate (10). Solutions of 100 g (309 mmol) of  bis-acetate 10 in  400 ml of  methanol and 59  g (464 mmol) of  sodium sulfite in 600 ml of distilled water are prepared separately. Solutions are added to the 2 liter round bottom flask equipped with mag- netic stirring bar while stirring. The  re- sulting mixture is stirred for 6 h at room temperature. The solvents are evaporated under vacuum following the same workup procedure as  described in  synthesis II. The product is dried under vacuum to ob- tain 57 g (57%) of 7 as white solid; m.p. 197  °C (decomp.). NMR 1H (400  MHz, DMSO-d6), δ, ppm: 1.38 (s, 6Н, C(СН3)2), 2.30 (s, 3Н, СН3), 3.82 (s, 2Н, СН2S), 4.79 (s, 2Н, СН2), 4.90 (s, 2Н, СН2). NMR 13С {1H} (100 MHz, DMSO-d6), δ, ppm: 19.28, 23.73, 57.47, 59.11, 60.97, 101.45, 132.07, 134.18, 140.97, 143.25, 146.78. HRМS-ESI: found [М+Н]+ 326.0667, C12H16NNaO6S, calculated [М+Н]+ 326.0669. V I . S y n t h e s i s o f   ( 5 - h y - droxy-3,4-bis(hydroxymethyl)-6-methyl- pyridin-2-yl)methanesulfonic acid (11) starting from 6-(hydroxymethyl)-3,3,8-tri- methyl-1,5-dihydro-[1,3]dioxepino[5,6-c] pyridin-9-ol (4). 15 liter glass reactor equipped with anchor-type stirrer, reflux condenser, heating jacket, thermom- eter and pH-meter is loaded with 1565 g (6540 mmol) of compound 4 and solution of  1262  g (9810 mmol) if sodium sulfite in 5.5 liters of distilled water. The reaction mixture is stirred under reflux conditions for 5 h while maintaining pH at a range be- tween 8.0 and 9.0 by the addition of small portions of concentrated hydrochloric acid (about 300 ml of acid was used). The reac- tion is  controlled by  TCL on silica (elu- ent CHCl3:MeOH = 3:1) until the  spot of  starting material completely disap- pears. Then reaction mixture is  cooled down to the room temperature and neu- tralized with concentrated hydrochloric acid to the pH = 6.5 during 30 minutes. The  precipitate of  by-product is  formed and is  filtered off. Filtrate is  acidified 163 to the pH = 1.0 with concentrated hydro- chloric acid. Acidified mixture is evapo- rated under vacuum until mushy residue is  obtained while absorbing SO2 formed with solution of sodium hydroxide. Resi- due is  heated up until boiling and small portions of water are added until clear so- lution obtained. After cooling to 0°C crys- talline precipitate of product 11 is formed. It is filtered off and washed with 300 ml of  ice-cold distilled water. After drying 1120  g (65%) of  product 11 is  obtained as off-white to pale yellow solid. Filtrate is evaporated until dryness and extracted with 1 liter of boiling water followed by hot filtration. After cooling this filtrate to 0 °C second portion 223  g (13%) of  product 11 was isolated additionally. Overall yield 1343 g (78%); m.p. 250 °С (decomp). NMR 1H (400 MHz, DMSO-d6), δ, ppm: 2.56 (s, 3Н, СН3), 4.27 (s, 2Н, СН2S), 4.70 (s, 2Н, СН2), 4.90 (s, 2Н, СН2). NMR 13С {1H} (100  MHz, DMSO-d6), δ, ppm.: 14.74, 51.57, 55.52, 56.19, 136.44, 138.79, 141.50, 142.95, 151.62. HRМS-ESI: found [М+Н]+ 264.0537, C9H13NO6S, calculated [М+Н] + 264.0536. VI. Synthesis of sodium (5-hydroxy- 3,4-bis(hydroxymethyl)-6-methyl pyridin- 2-yl)methanesulfonate (1) starting from (5-hydroxy-3,4-bis(hydroxymethyl)- 6-methylpyridin-2-yl)methanesulfonic ac- id (11). 15 liter glass reactor equipped with anchor-type stirrer is loaded with 1343 g (5100 mmol) of compound 11 and solution of 204 g (5100 mmol) of sodium hydrox- ide in 2.5 liters of water. Mixture is stirred at room temperature during 6 minutes un- til clear solution is obtained. Then 12 liters of  isopropyl alcohol is  added and white precipitate is  formed immediately. Solid is filtered off, washed with twice with 1 liter of  isopropyl alcohol and dried to  obtain 1427 g (98%) of product 1 as a white solid with purity >99.5% (HPLC); m.p. 265 °C (decomp.). NMR 1H (400 MHz, DMSO- d6), δ, ppm: 2.31 (s, 3H, CH3); 4.04 (s, 2H, CH2), 4.51 (d, 3JHH = 6.3 Hz, 2H, CH2); 4.78 (s, 2H, CH2); 5.17 (t, 3JHH = 6.3 Hz, 1H, OH). NMR 13С {1H} (100 MHz, DMSO-d6), δ, ppm: 19.33, 56.80, 57.16, 57.21, 132.07, 132.74, 143.31, 145.04, 148.94. HRМS-ESI: found [М+Н]+ 286.0354, C9H12NNaO6S, calculated [М+Н]+ 286.0356. Results and discussion The  starting point of  our research was synthetic method described below in Scheme 1. As can be seen overall yield is slightly greater than 18%. Moreover, two steps (c and d) require column chromatography. In case of intermediate 5 chromatography is needed to separate ester by the benzyl group from the desired compound. This also explains poor yield at this step. As  substance 3  has hydroxymethyl group in  the  para- position in  relation to the phenol OH. It makes possible to in- vestigate the possibility of functionalization of this scaffold via meta- quinon methide intermediate. The reactivity of orto- and para-quinon methides intermediates is well studied in non-heterocyclic aromatic struc- tures [7, 8]. But we can barely find any data on its heterocyclic analogs. Acetyl esters 8 and 9 are among usu- al quinone methide precursors [9, 10] (Fig. 2). In  this connection bis-acetic ester 8 that was synthesized earlier in  our re- search group [6] was a good starting point for the  optimization of  synthetic route. It has straightforward synthesis with no need of chromatographic purification. It was shown that use of acetyl chloride in- 164 stead of acetic anhydride as an acylating agent in synthesis of 8 dramatically reduces the reaction time from 30 hours [6] to only 0.5 hour with no need of refluxing condi- tions (Scheme 2). It was shown that bis-acetyl ester 10 can react with primary and secondary amines in  alcohol media [11]. An  attempt was made to investigate reactivity of 10 toward sulfur-containing nucleophile such as so- dium sulfite. Very poor solubility of sodium sulfite in almost any organic media includ- ing alcohols became the main barrier for this reaction. Usual methods like two-phase reaction system (H2O/CH2Cl2) with phase transfer catalyst gave very low yields even after prolonged reaction time. However, it was an indication of the principal possibil- ity of such a reaction. The best results (57% yield of 6) were achieved using mixed sol- vent water/MeOH in 3:2 ratio by the vol- ume. In  this mixture both components of the reaction have significant solubility. Replacement of MeOH with EtOH or any other alcohol significantly reduces the solu- bility of sodium sulfite slowing the reaction and reducing the yield. The development of this synthetic step not only reduces total amount of steps, it allows to avoid chro- matographic purification of  intermedi- ates 5 and 6 which are no longer needed. With this implementation total yield was increased from 18% to 38% with no prin- cipal limitation for the scaling-up. Another optimization was made dur- ing the scaling-up of the process. Original method of the synthesis of 4 includes ex- traction with ethanol during the workup. After the evaporation of ethanol 4 is ob- tained as white solid with significant solu- OH OAc o- or p- OAc OAc o- or p- 8 9 Fig. 2. Structures of acetyl esters 8 and 9 as quinone methide precursors N OH OH HO HCl N O O HO N O O HO OH N O O AcO OH N O O AcO Cl N O O HO SO3Na N OH OH HO SO3Na 2 3 (87%) 4 (80%)* 5 (49%) a b c ef d 6 (90%)7 (61%)1 (98%) Scheme 1. Reagents and conditions: (a) (CH3)2CO, HCl, 0 °C, 12 h [3]; (b) CH2O, NaOH, H2O, 70 °C, 60 h [4]; (c) Ac2O, Et3N, CH2Cl2, r.t., 30 h [5]; (d) MsCl, Et3N, CHCl3, 0 °C to r.t., 10 h [5]; (e) Na2SO3, TBAB, CH2Cl2/H2O, r.t., 10 h; (f ) HCl, H2O, r.t., 1 h * — yield according to non-optimized method [4] 165 bility in water and melting point of 161– 163  °C.  However, the  crystalline solid precipitates from water solutions of 4 after long standing. It was found to have simi- lar NMR spectra as  4 and melting point of  182–183  °C which indicates another crystalline form of the same compound. This finding allows to alter the workup pro- cedure of the synthesis of 4 which consists in  seed induces precipitation of  product from the neutralized mother liquor. This alteration not only simplified the  proce- dure but also improved the yield up to 94% at this step due to more complete precipita- tion. The use of freshly distilled formalde- hyde solution and use of more concentrat- ed reaction mixture (less solvent) allows to dramatically reduce the reaction time from 60 to 6 hours. In some examples o- and p- hydroxym- ethylphenols may play a role of the quinon methide precursors. This examples are usu- ally limited to the reaction with C-nucle- ophiles like base-activated 2-nitropropane [12] or potassium cyanide [13]. Reactions of pyridoxine with different alcohols are described yielding corresponding 4’ — es- ters [14]. The latter do not have much prac- tical significance due to very long reaction time (about 96 hours). The original work [15] and its modern reiteration [16] has evidence of the pos- sibility of  direct reaction between p-hy- droxymethylphenol and sodium hydro- sulfite. This reaction has a good yield and requires refluxing in the water media for only 8 hours. Possible application of this method to  the  direct synthesis of  com- pound 7 starting from 4 allows reducing the total amount of steps. It was found that reaction of  4 with sodium hydrosulfite is not possible as pH of  the  reaction mixture is  slightly acidic (pH = 4–5) and it is enough the remove the dimethylketal protecting group. The re- placement of  hydrosulfite with sulfite gave the  first results as  it makes possi- ble to achieve the partial conversion of 4 to  7. The  conversion was not complete even after prolonged refluxing. Usually it reaches 60–70% in  6  hours and does not change after. This process is believed to  be reversible (Fig.  3) and the  conver- sion observed corresponds to the equilib- rium. The changes of pH of the reaction mixture were observed during the process: from pH = 11 at  the  start to  pH = 13.5 at the equilibrium. The addition of small amounts of  acid to  control pH makes it possible to reach complete conversion. It was found that optimal pH for the reaction is in range between 8.0 and 9.0. Under this pH controlled conditions reaction com- pletes in 5 hours of refluxing. It was found to be unpractical to iso- late compound 7 before the deprotection N O O HO OH 4 a N O O O O Ac Ac 10 (98%) b N O O HO SO3Na 7 (57%) Scheme 2. Reagents and conditions: (a) AcCl, NEt3, CH2Cl2, r.t. 0.5 h; (b) Na2SO3, H2O/MeOH, r.t., 6 h 166 step as  it requires extraction with huge amount of  isopropyl alcohol. Deprotec- tion step may be done by the acidification of the reaction mixture from the previous step with the  isolation of  sulfonic acid 11 as it has limited solubility in cold wa- ter. The  overall optimized synthesis of  1 is shown in Scheme 3. N O O HO OH N O O HO SO3Na Na2SO3 H2O, ∆ + NaOH 4 7 Fig. 3. Preparation of compound 7 from 4 with sodium sulfite N OH OH HO ·HCl N O O HO N O O HO OH N OH OH HO SO3H N OH OH HO SO3Na 2 3 (87%) 4 (94%)* a b c, d e 11 (78%)1 (98%) Scheme 3. Reagents and conditions: (a) (CH3)2CO, HCl, 0 °C, 12 h [3]; (b) CH2O, NaOH, H2O, 70 °C, 6 h; (c) Na2SO3, H2O, pH = 8.0–9.0, reflux, 5 h; (d) HCl, pH = 1.0, 0.5 h, r.t.; (e) NaOH, H2O, r.t., 0.1 h * — yield according to optimized method of synthesis (see experimental) 167 Conclusions Thus, the total yield of the final method of synthesis of the antiepileptic drug can- didate Sumepirin 1 starting prom pyri- doxine hydrochloride was increased from 18% to 62.5%. As the result of optimiza- tion the amount of steps was reduced from six to  four. It is  also important that this method is  environment-friendly: at  first step reagent (acetone) is used as a solvent and any other step is carried out in water media; good level of atom economy was achieved due to elimination of chloride and acetyl protecting or leaving groups from the synthetic route. Unfortunately, it does not seem to be possible not to use the di- methylketal protecting group because OH groups in 4’ and 6’ positions of pyridoxine ring have very similar reactivity. Acknowledgements This work was supported by subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities (project number 0671-2020-0053). References 1. Janmohamed M, Brodie MJ, Kwan P. Pharmacoresistance — Epidemiology, mecha- nisms, and impact on epilepsy treatment. Neuropharmacology. 2020;168:107790 doi:10.1016/j.neuropharm.2019.107790 2. 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