Synthesis of macrolides with hydrazide fragments from tetrahydropyran and 2,6-pyridinedicarboxylic acid Текст научной статьи по специальности «Химические науки»

Macrolides Макролиды

Макрогэтэроцмклы

http://macroheterocycles.isuct.ru

Communication Сообщение

DOI: 10.6060/mhc140374y

Synthesis of Macrolides with Hydrazide Fragments from Tetrahydropyran and 2,6-Pyridinedicarboxylic Acid

Gumer Yu. Ishmuratov, Marina P. Yakovleva,@ Mariya A. Shutova, Niyaz R. Yaubasarov, Rinat R. Muslukhov, Evgeny M. Viripaev, and Alexander G. Tolstikov

Dedicated to the Corresponding Member of Russian Academy of Sciences Oscar I. Koifman

on the occasion of his 70th Anniversary

Institute of Organic Chemistry, Ufa Scientific Centre of RAS, 450054 Ufa, Russia ®Corresponding author E-mail: insect@anrb.ru

The synthesis of two potentially useful 23- and 29-membered macrolides containing a pyridine ring and dihydrazide fragments was developed starting from tetrahydropyran. It was based on [1+1]-condensation of 7'-oxooctyl-7-oxooctanoate and bis(7-oxooctyl)hexanedioate with 2,6- pyridinedicarboxylic acid hydrazide. The structure of the macrocycles obtained was confirmed using by IR and NMR spectroscopy and mass spectrometry.

Keywords: Tetrahydropyran, macrolides with dihydrazide fragments, [1+1]-condensation, synthesis.

Синтез макролидов с гидразидными фрагментами из производных тетрагидропирана и 2,6—пиридиндикарбоновой кислоты

Г. Ю. Ишмуратов, М. П. Яковлева,@ М. А. Шутова, Н. Р. Яубасаров, Р. Р. Муслухов, Е. М. Вырыпаев, А. Г. Толстиков

Посвящается член-корреспонденту РАН Оскару Иосифовичу Койфману по случаю его 70-летнего юбилея

Институт органической химии Уфимского научного центра Российской академии наук, 450054 Уфа, Россия @E-mail: insect@anrb.ru

Исходя из тетрагидропирана разработан синтез двух потенциально полезных 23- и 29-членных макролидов, содержащих пиридиновое кольцо, сложноэфирные группы и гидразидные фрагменты, на основе [1+1]-конденсации 7'-оксооктил-7-оксооктаноата и бис(7-оксооктил)гександиоата с гидразидом 2,6-пиридиндикарбоновой кислоты. Структура полученных соединений была подтверждена с помощью ИК и ЯМР спектроскопии и масс-спектрометрии.

Ключевые слова: Тетрагидропиран, макролиды с гидразидными фрагментами, [1+1]-конденсация, синтез.

We previously proposed the synthesis from tetrahydropyran (1) of a,o>-diketones 2 and 3 containing one (2) or two (3) ester groups.[1,2] Their [l+l]-condensation with hydrazine hydrate or dihydrazides of malonic, glutaric, adipic,[1,2] azelaic, sebacic, 7-oxabicyclo[2.2.1]heptenoic[3] and tartaric[4,5] acids led to macroheterocycles containing one or two ester groups and azine or dihydrazide fragments. One of the synthesized macrolides 4 showed a significant (at the level of erythromycin) antibacterial activity in vitro and in vivo against the museum and field strains of pathogenic microorganisms (Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa).16

In continuation of these studies we performed [1+1]-condensation of a,o>-diketone (2) or (3) with 2,6-pyridinedicarboxylic acid hydrazide (5) that was prepared using the standard method.[7]

Introduction of 2,6-pyridinedicarboxylic acid to the macrocyclic fragment is due to the fact that its derivatives exhibit a wide range of pharmacological activity (such as, antibacterial, anti-inflammatory, anticoagulant and anti-tumor),[8] and derivatives of 2,6-pyridinedicarboxylic acid are widely used in chemistry of a complex formation.[9]

Experimental

Analyzes were performed on the equipment at the Center for the Collective Use «Chemistry» of the Institute of Organic Chemistry of Ufa Scientific Centre of the Russian Academy of Sciences. IR spectra were recorded on the device IR Prestige-21 Shimadzu (Fourier Transform Spectrophotometer - Shimadzu) in thin layer. NMR spectra were recorded in CDCl3 and D2O with TMS internal standard on a Bruker AM-300 spectrometer (operating frequency 300.13 MHz for 'H; 75.47 MHz for 13C). TLC monitoring used Sorbfil SiO2 (Russia).

Mass spectra were recorded on a LC/MS 2010 EV Shimadzu instrument (syringe input, sample solution in CH3CN at flow rate 60 ^L/min) using electrospray ionization (ESI) method with a simultaneous recording of positive and negative ions at capillary potentials 4.5 and -3.5 kV, respectively. The temperature of the capillary interface was 200 °C; the flow of a nebulizer gas (dry N2) was 0.8 L-min-1. HPLC analysis was performed on a Shimadzu LC-20AD liquid chromatograph with an SPD-M20A diodematrix detector (Shimadzu, Japan) using a Phenomenex column (250x4.6 mm) and Luna C18 sorbent (5 ^m). The mobile phase was H2O:CH3CN (95:5) at the flow rate of 1 mL/min. The analytical wavelength was 215 nm.

2,6-Pyridinedicarboxylic acid hydrazide, 5. 1H NMR (D2O) 5 ppm: 4.62 (4H, s, NH2), 8.15 (3H, s, Ar-H), 10.60 (2H, s, NH). 13C NMR (D2O) 5 ppm: 123.82 (d, C-3, C-5), 139.46 (d, C-4), 148.41 (s, C-2, C-62, 162.02 (s, C(O)NH). IR (KBr) vmax cm1: 3270 (NHNH2), 1689 (C(O)NH).

Synthesis of macrocyclic compounds 6 and 7 (general procedure). The 2,6-pyridinedicarboxylic acid hydrazide (5, as described in [6]) (0.244 g, 1.0 mmol) in 1.8 mL of H2O, was slowly added under vigorous stirring to 1.0 mmol of a,ro-diketones 2 or 3 in 8.5 mL of dioxane. The mixture was stirred for 48 h (monitoring TLC) and dioxane was evaporated under reduced pressure. The residue was dissolved in 20 mL of CH2Cl2, and washed with water (3x5 mL), dried with MgSO4, and evaporated. The residue was stirred with 10 ml of hexane, and the solution was separated by decanting. The precipitate represented a macroheterocycle 6 or 7.

5,19-Dimethyl-12-oxa-3,4,20,21-tetraaza-1(2,6)-pyridi-nacyclodocosaphane-4,19-diene-2,11,22-trione, 6. Yield 0.104 g

(37%). m/z C23H33NP4 (443.25) (ESI, /re.at.ve, %): (Scan+): 444.2 (2.2) [M+H]+, 466.4 (39.1) [M+Na]+, 484.35 (26.8) [M+Na+H20]+; (Scan-): 442.3 (73.7) [M-H]-, 460.35 (41.7) [M-H+H20]. 1H NMR (CDCl3) 8 ppm: 1.20-1.41 (2H, m, H-26), 1.47-1.70 (10H, m, H-4, H-5, H-6, H-23, H-24), 2.08 (6H, s, CH3-8, CH3-21), 2.28 (2H, t, J 7.4, H-3), 2.42 (4H, t, J 8.0, H-7, H-22), 8.09 (1H, t, J 7.7, H-14), 8.45 (2H, t, J 7.7, H-13, H-15), 10.25 (2H, s, NH). 13C NMR (CDCl3) 5 ppm: 15.41 (q, CH3-8, CH3-21), 25.72 (t, C-5), 28.43 (t, C-6, C-23), 28.56 (t, C-25), 28.65 (t, C -4), 28.74 (t, C-24), 34.07 (t, C-26), 39.08 (t, C-3), 43.42 (t, C-22), 43.57 (t, C-7), 64.26 (t, C-27), 126.16 (d, C-13, C-15), 139.45 (d, C-14), 148.56 (s, C-12, C-16), 158,97 (s, C-8, C-21), 161.04 (s, C-11, C-18), 173.75 (s, C-2). IR (KBr) v cm-1: 3337 (NH), 1731 (CH2COO), 1699 (CONH), 1635 (C=N).

5,26-Dimethyl-12,19-dioxa-3,4,27,28-tetraaza-1(2,6)-pyridinacyclotriokonte-4,19-diene-2,13,18,29-tetraone, 7.

Yield 0.139 g (35%). m/z C^^O, (557.32) (ESI, 7^, %): (Scan+): 558.4 (2.3) [M+H]+, 280.35 (100) [M+Na]+, 598.3 (16.2) [M+Na+H20]+; (Scan-): 556.35 (100) [M-H]-, 574.35 (20.4) [M-H+H20]-, 592.35 (2.0) [M-H+2H20]-. 1H NMR (CDCl3) 8 ppm: 1.31 -1.42 (8H, m, H-11, H-12, H-31, H-32), 1.60-1.68 (8H, m, H-4, H-5, H-13, H-30), 2.18 (6H, s, CH3-15, CH3-28), 2.28-2.32 (4H, m, H-10, H-33), 2.42 (4H, t, J 6.8, H-14, H-29), 2.51 (4H, t, J 6.8, H-3, H-6), 4.07 (4H, t, J 6.7, H-9, H-34), 8.11 (1H, t, J 7.6, H-21), 8.47 (2H, d, J7.6, H-20, H-22), 10.20 (2H, s, NH). 13C NMR (CDCl3) 8 ppm: 15.27 (q, CH3-15, CH3-28), 23.59 (t, C-11, C-32), 24.30 (t, C-4, C-5), 25.71 (t, C-13, C-30), 28.41 (t, C-12, C-31), 33.90 (t, C-10, C-33), 39.12 (t, C-3, C-6), 43.56 (t, C-14, C-29), 64.29 (t, C-9, C-34), 126.26 (d, C-20, C-22), 139.46 (d, C-21), 148.55 (s, C-19, C-23), 158.83 (s, C-15, C-28), 160.85 (s, C-18, C-25), 173.44 (s, C-2, C-7). IR (KBr) vmax cm-1: 3343 (NH), 1735 (CH2C00), 1683 (CONH), 1634 ^N)."™

Results and Discussion

[1+1]-Condensation of a,ra-diketones 2 or 3 with a 2,6-pyridinedicarboxylic acid dihydrazide (5) in dioxane-water system under high dilution at room temperature resulted in potentially biologically active 23- (6) and 29- (7) -membered macroheterocycles containing a pyridine ring and dihydrazide fragments and one or two ester groups with ~40% conversion of the initial 2 or 3.

The structures of the synthesized macroheterocycles 6 and 7 were confirmed by IR, 1H NMR, and 13C NMR spectroscopy and GC/MS. The chemical purity (~95%) was established by HPLC. The IR spectrum of compounds 6 and 7 do not have any absorption bands in the region of 1718 cm-1 (6) and 1703 cm-1 (7), which are characteristic for the ketone groups of key intermediates 2 and 3. The IR spectra of 6 and 7 contain bands at 1630 cm-1 (C=N), 16641671 cm-1 (CONH), and 3354-3455 cm-1 (NH). This proves that macrocycles with hydrazide groups have been formed. Structures of the macrocycles 6 and 7 were studied using 13C NMR and 1H NMR spectrometry. The NMR spectra of 6 and 7 were analyzed by comparison with those of the starting compounds 2 and 3 and hydrazide of dicarboxylic acids 5. The 13C NMR spectra of the reaction products 6 and 7 did not show any signals of carbonyl carbon atoms of initial compounds 2 and 3 (208.86 ppm and 208.99 ppm in 6 and 208.66 ppm in 7). Furthermore, 1H NMR spectra of the macrocycles 6 and 7 did not show resonances of the hydrazine group (NH2NH) (~4.63 ppm). These facts indicated that the products were not the linear substitution products. 13C NMR spectra of 6 and 7 contained resonances for ester C atoms

M. P. Yakovleva et al.

(173.75 (6) and 173.44 ppm (7)) and resonances of NH-C=O groups of the starting dihydrazides (162.02 ppm) that were shifted (161.04 ppm (6) and 160.85 ppm (7)). There were also singlets for C=N (158.97 ppm (6) and 158.83 ppm (7)) and two quartets for c/'s-CH3 (15.41 ppm (6) and 15.27 ppm (7)), the chemical shifts of which corresponded to C atoms of two magnetically equivalent CH3-C=N groups. The appearance of triplets (43.42 and 43.57 ppm (6), 43.56 ppm (7)) for two CH2C=N groups also confirmed that the formation of hydrazides (CH2C=N-NH-C=O). 'H NMR spectra of 6 and 7 showed downfield resonances (10.25 ppm (6) and 10.20 ppm (7)), the chemical shifts and integrated intensities of which corresponded to two protons of NHC=O groups in the macrocycles.

All these spectral data indicate that macrocycles 6 and 7 were formed. This was also confirmed by mass

spectra. Mass spectra of the synthesized compounds 6 and 7 were studied using electrospray ionization (ESI) with simultaneous recording of positive and negative ions at capillary potentials of 4.5 and 3.5 kV, respectively. Very intensive peaks for protonated MH+ and deprotonated [M-H]- ions in addition to their ionic associates with ions (Na+, K+) and molecules (H2O) were recorded in the mass-spectrometric study of 6 and 7. This may be considered to be a proof of existence of the compounds with appropriate molecular weights.

Conclusions

The synthesis of two potentially biologically and pharmacologically active 23- and 29-membered macrolides

containing pyridine ring and dihydrazide fragments was developed starting from tetrahydropyran as available petrochemical product. It was based on [1+1]-condensation of 7-oxooctyl-7-oxooctanoate and bis(7-oxooctyl)hexanedioate with 2,6-pyridinedicarboxylic acid hydrazide. The evidence is given for the structure of the obtained macrocycles using IR and NMR spectroscopy and mass spectrometry.

References

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2. Ishmuratov G.Yu., Mingaleeva G.R., Yakovleva M.P., Shakhanova O.O., Muslukhov R.R., Tolstikov A.G. Russ. J. Org. Chem. 2011, 47, 1416-1425 [Zh. Org. Khim. 2011, 47, 1392-1400 (in Russ.)].

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4. Ishmuratov G.Yu., Yakovleva M.P., Mingaleeva G.R., Shutova M.A., Muslukhov R.R., Viripaev E.M., Tolstikov A.G. Russ. Chem. Bull., Int. Ed. 2013, 62, 217-219 [Izv. Akad. Nauk, Ser. Khim. 2013, 216-218 (in Russ.)].

5. Ishmuratov G.Yu., Yakovleva M.P., Mingaleeva G.R., Shutova M.A., Muslukhov R.R., Vyrypaev E.M., Tolstikov A.G. Chem. Nat. Compds 2013, 49, 691-693. [Khim. Prirod. Soed. 2013, 592-594 (in Russ.)].

6. Ishmuratov G.Yu., Ismagilova A.F., Mingaleeva G.R., Chudov I.V., Yakovleva M.P., Muslukhov R.R., Kashipov R.N., Tolstikov A.G. Butlerov Commun. 2009, 16, 21-25.

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Received 04.03.2014 Accepted 19.03.2014