Oxidation by HNO 3 at atmospheric pressure of toluenes with electronegative substituents on the benzene ring was studied. A method enabling the corresponding benzoic acids to be obtained in high yields with minimal wastes was developed. The method could be used in the laboratory and in production of medicines.

Haloand nitrobenzoic acids are important starting materials for preparing several medicines. Thus, 4-chlorobenzoic acid is an intermediate for drug substances benoxaprofen [1], bezafibrate [2], bumetanide [3], and indomethacin [4]. 2-Chlorobenzoic acid is used to produce phenazepam [5]; 4-nitrobenzoic acid, in the synthesis of anesthetics butethamine [6] and procaine [7]. However, preparation of the substituted benzoic acids themselves is a complicated process. The main method for producing these compounds consists of oxidation of the corresponding toluenes. Use of oxidants such as KMnO 4 and Na 2 Cr 2 O 7 is associated with the generation of large quantities of aqueous and organic wastes including difficultly recycled precipitates of the corresponding metal oxides and salts. Therefore, these oxidants are limited to laboratory experiments. Methods for oxidizing aliphatic side chains of aromatic compounds by atmospheric O 2 in the presence of catalysts, i.e., transition-metal salts, are known. Homogeneous catalytic systems based on Co and Mn salts and bromide in promoter solvents, e.g., HOAc, are best [8]. Oxidation by this method occurs under forcing conditions and requires high temperatures (up to 220°C) and pressures (up to 3 MPa). Furthermore, explosive concentrations of starting hydrocarbon and solvent (HOAc) vapors with O 2 can form. Oxidation units with complicated designs and a complex process control system in general are required for safe operation. Furthermore, the process is continuous. This method for preparing aromatic carboxylic acids is used mainly in multi-ton installations (e.g., manufacturing of benzoic, phthalic, and other acids) [9]. The side chain in benzene homologs can be oxidized by dilute HNO 3 . However, the reaction is extremely slow under simple reflux, i.e., at ~100°C. For example, a significant part of o-xylene remained unchanged in the reaction mixture and

Изучено окисление толуолов с электроотрицательными заместителями в бензольном кольце азотной кислотой при атмосферном давлении. Разработан способ, позволяющий получать соответствующие бензойные кислоты с высокими выходами при минимальном количестве отходов. Способ может быть реализован как в лабораторной практике, так и на производстве получения лекарственных препаратов.

Предложен новый способ получения феназепама. При создании технологии производства феназепама реализованы общие принципы обеспечения качества субстанций лекарственных средств за счет использования условий и схем синтеза, позволяющих получать максимально чистые соединения.

A new means of preparing phenazepam is proposed. The new manufacturing technology for phenazepam implements the general principles for medicinal substance quality by using synthesis conditions and schemes yielding compounds as pure as possible.

Brominated aromatic compounds are intermediates for drug syntheses [1 – 3]. 3,4-Dimethylaminobenzene (o-xylidine), which is obtained in turn from 4-bromo-o-xylene, is an intermediate in the synthesis of vitamin B 2 [4]. Classical (direct) bromination of o-xylene (I) by liquid Br 2 in the presence of catalytic amounts of iron and iodine is well known [5, 6]. The yield of monobrominated I reaches 89 – 93%. According to the literature [7], monobromo-o-xylene is formed as a mixture of the 3and 4-bromo-o-xylene isomers in a 25:75% ratio. Direct bromination of aromatic compounds suffers from wasteful use of Br 2 , half of which is converted to HBr. This is an economic and ecological problem for large-scale operations. An additional processing unit is necessary to trap the HBr released by the reaction. Waste HBr (off-gas) should be reprocessed to recover expensive bromine. Bromination of I in the presence of H 2 O was proposed in order to avoid the HBr trapping unit [8]. Oxidative bromination is widely used to introduce Br into an aromatic ring and allows more complete utilization of expensive Br 2 . Nitric acid, H 2 O 2 , Cl 2 , and ozone were proposed as oxidants. Thus, H 2 O 2 [9, 10] and NaClO [11] were used for oxidative bromination of I. The present work examines the use of an alkali-metal bromate as the oxidant to produce monobromo-o-xylene. Alkali-metal bromates have been used to synthesize bromoarenes. However, the bromate was used in all published examples not as an oxidant but as a Br donor. Thus, sodium or potassium bromate in the presence of a large excess of H 2 SO 4 is commonly used to introduce Br into a deactivated benzene ring [12]. The reaction occurs under forcing conditions. Part of the starting arene is destroyed because of the elevated temperature and high acidity of the medium (the H 2 SO 4 content in the reaction mixture is 40%) [13]. Japanese researchers proposed the NaBrO 3 /NaHSO 3 system for bromination of alkylarenes. However, the side chain was brominated in addition to the ring. The fraction of á-bromo-o-xylene exceeded 11% for I [14]. Indian researchers used a bromide/bromate mixture in the presence of an excess of a strong mineral acid in order to introduce Br into an aromatic ring [15]. An analysis of the literature showed that a significant excess of the brominating reagents was required if the aforementioned methods were used to introduce Br into an aromatic ring. Furthermore, a significant amount of aqueous waste containing complicated mixtures of inorganic compounds was formed. We studied oxidative bromination by liquid Br 2 or HBr in the presence of an alkali-metal bromate as the oxidant using monobromo-o-xylene as an example. Pharmaceutical Chemistry Journal, Vol. 50, No. 3, June, 2016 (Russian Original Vol. 50, No. 3, March, 2016)

Oxidative bromination of o -xylene with liquid bromine or hydrobromic acid in aqueous solution in the presence of an alkali-metal bromate as the oxidizing agent was studied. The proposed method allowed the amount of wastes to be reduced while maintaining a high yield of bromo- o -xylene, which is used in the synthesis of vitamin B 2 .

Изучено окислительное бромирование o-ксилола жидким бромом или бромистоводородной кислотой в водной среде в присутствии бромата щелочного металла, используемого в качестве окислителя. Предлагаемый метод позволяет сократить количество отходов при сохранении высокого выхода бром-o-ксилола, применяемого в синтезе витамина В2.

Разработан простой и удобный в технологическом плане способ получения 1,2,5-триметилпиперидин-4-она — ключевого соединения в синтезе лекарственного препарата промедол.

A simple and technologically convenient method for the preparation of 1,2,5-trimethylpiperidin-4-one, a key compound in the synthesis of the drug Promedol, was developed.

Разработана методика определения 2-эндо-(6-хлорпиридин-3-ил)-7-азабицикло-[2.2.1]гептана (эпибатидин) и 2-эндо-(6-хлорпиридин-3-ил)-7-азабицикло[2.2.1]гептан-7-ола (биомаркер эпибатидина) в плазме крови на уровне 1 ? 10-5 1 ? 10-3 мг/мл. Методика основана на извлечении компонентов из плазмы крови жидкостно-жидкостной экстракцией и газохроматографическом определении с использованием термоионного или масс-спектрального детекторов. С целью снижения предела обнаружения эпибатидина и его биомаркера при использовании масс-спектрометрического детектора в методику включена стадия дериватизации с помощью N,O-бис(триметилсилил)трифторацетамида или 2,3,4,5,6-пентафторбензилбромида.

A method has been developed for the determination of 2-endo(6′-chloropyridin-3′-yl)-7-azabicyclo[2.2.1]heptane (epibatidine) and 2-endo(6′-chloropyridin-3′-yl)-7-azabicyclo[2.2.1]heptane-7-ol (epibatidine biomarker) in blood plasma at a level of 1 × 10−5–1 × 10−3 mg/mL. The method is based on the extraction of components from blood plasma by liquid-liquid extraction followed by gas-chromatographic determination using thermionic or mass spectrometric detectors. To reduce the limit of detection for epibatidine and its biomarker in using the mass-spectrometric detector, a derivatization stage using N,O-bis(trimethylsilyl)trifluoroacetamide or 2,3,4,5,6-pentafluorobenzyl bromide has been included into the procedure.

A preparative method for the synthesis of analgesic epibatidine, which provides its endo - and exo -isomers with 9.9 and 8.8% yields, respectively, is described.

The problem of pain and analgesia is central in contemporary medicine. The leading place among the multitude of analgesic agents is occupied by opioids. However, opioids have significant disadvantages (respiratory inhibition reaching the level of respiratory arrest, rapidly developing tolerance, and psychological dependence). Thus, creation of new non-narcotic analgesics with high analgesic activity, as high as that of opioids, but not inducing physical dependence, is currently an active area of research. There is significant interest in the alkaloid (-)-epibatidine, identified by Daly in extracts of the skin of the Ecuadorian tree frog Epipedobates tricolor [1]. In mouse experiments, this compound had 200 times more analgesic activity than morphine. Analgesia induced by both (-)-epibatidine and its isomers was not countered by the opiate receptor antagonist naloxone. In addition, the new alkaloid was found to be an agonist of neuronal nicotinic acetylcholine receptors (nAChR). More than 100 studies addressing the synthesis and properties of epibatidine have been published. Most of these are addressed in reviews [2 – 4]. 2-(6-Chloropyridin-3-yl)-7-azabicyclo[2.2.1]heptane can exist as two diastereomers (endo and exo), differing in terms of the position of the 6-chloro-3-pyridine fragment relative to the azabicyclo moiety Of all the methods known for the synthesis of epibatidine, we believe that the method with the greatest potential for preparative-scale synthesis is the scheme reported in [5]. This method of preparing epibatidine has a number of advantages, as it uses available reagents and solvents and does not require expensive catalysts; each stage of the synthesis uses reactions which are classical in organic chemistry. In addition, this method can be used to synthesize both the endo and the exo isomers. However, the total yield of exo-epibatidine is no more than 1.5% in terms of 1-nitropentan-4-one (II) [5]. The aim of the present work was to optimize the synthesis conditions for each stage of this scheme. 1-Nitropentan-4-one (II) was prepared using the method described in [6]. However, use of these synthesis conditions gave a yield of 1-nitropentan-4-one (II) of no more than 45%. With the aim of increasing the yield of II, we proposed slow addition of methylvinylketone to the catalyst suspension (KF/Al 2 O 3 ) at a 15 – 20 fold molar excess of nitromethane, ensuring that the temperature of the mixture did not exceed 26 – 38°C. After distillation of the reaction mix, the excess (unreacted) nitromethane is used in the next synthesis, use of recovered nitromethane having no effect on target compound yield. The yield of II was 72 – 77%.

A new commercially applicable method for the synthesis of the myorelaxant 1,3,5-tris-(2′-diethylbenzylammonioethyl)- 1,3,5-triazine-2,4,6-trione tribromide (isocyuronium bromide) is described.

A new commercially applicable method for the synthesis of the myorelaxant 1,3,5-tris-(2-diethylbenzylammonioethyl)-1,3,5-triazine-2,4,6-trione tribromide (isocyuronium bromide) is described.

A new commercially applicable method for the synthesis of a myorelaxant - 1,3,5-tris-(2'-diethylbenzylammonioethyl)- 1,3,5-triazin-2,4,6-trione tribromide (isocyuronium bromide) - is described.

A number of permethrin derivatives having various substituents (Me, Et, Pr, Ph, PhCH2, PhCH2CH2) in position 2 of the cyclopropane ring were synthesized and assayed for insecticidal activity against typhoid flies, rice weevils, and black bean aphid and juvenile hormone activity against flour beetle chrysalises. The examined compounds showed a weak insecticidal activity. Some derivatives were found to exert knockdown effect analogous to that of commercial pyrethroid tetramethrin; however, unlike permethrin, they exhibited pronounced juvenile hormone activity.

The spatial isomers of the new synthetic analogs of ethyl permithrinic ether and permethrin were investigated by NMR ( 1 H, 13 C, DEPT (distortionless enhancement by polarization transfer), COSY (correlation spectroscopy), CHCORR (heteronuclear (C, H) shift correlation spectroscopy), ROESY (rotating-frame Overhauser effect spectroscopy)). Several tendencies were revealed in the 1 H and 13 C chemical shifts of the α atoms of the substituents in the 2nd and 3rd positions of the cyclopropane ring. For substituents cis -orientated relative to the ester group, the spectra show a paramagnetic shift of the 1 H signals and the diamagnetic shift of the 13 C signals relative to the trans -orientated substituents. The 1 H and 13 C chemical shifts of the α atoms of the substituents in the 2nd and 3rd positions of the cyclopropane ring permit an unambiguous determination of the stereochemistry of ethyl permethrinic ether and permethrin analogs.