RU2759291C1 - Effective method for the production of hydrazinophenol derivatives - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, specifically to a method for the production of substituted and unsubstituted phenol-containing hydrazine-N,N'-dicarboxylates of the formula indicated below. The method consists in the reaction of hydrazination of substituted and unsubstituted phenols with a single and bicyclic condensed structure (1-naphthols, quinoline-8-ols) with azodicarboxylate esters in the presence of the main catalyst at a room temperature in inert solvents. The subsequent unblocking of N-carboxylate residues in particular cases of Boc-substituted hydrazine derivatives is possible to form N-unsubstituted phenol-containing hydrazines. In the formula, X is CH, N, N⁺-O^- in a fixed position or absent in the absence of a cycle; R is -H, -COOEt, -COOi-Pr, -COOt-Bu; R' is -H, -Me, -Cl, -F; Z is nHCl (n=1-2) in the case when R=N.

EFFECT: proposed method makes it possible to obtain substituted and unsubstituted phenol-containing hydrazine-N,N'-dicarboxylates with yields of 70-99% in one stage based on available ethers of azodicarboxylates.

1 cl, 3 dwg, 1 tbl, 18 ex

Description

The technical field to which the invention relates

This invention relates to the field of organic, bioorganic and medicinal chemistry, namely, to a new and effective method for the synthesis of hydrazinophenols, allowing you to obtain new phenol derivatives of general formula (I).

State of the art

The hydrazinophenol moiety plays an important role in medicinal chemistry in the design of drug candidates. The most famous and studied application of such a fragment is the reaction of the synthesis of indole according to Fischer [F. Zhan, G. Liang, Formation of enehydrazine intermediates through coupling of phenylhydrazines with vinyl halides: entry into the Fischer indole synthesis. / Angew. Chem. Int. Ed., 2013, 52 (4): 1266-1269], which is used in the synthesis of drugs containing an indole fragment, and in the complete synthesis of natural substances, among which candidates for drugs are screened. Among such biologically important substances that can be synthetically obtained from hydrazinophenol by the Fisher reaction are the hormone regulator of circadian rhythms melatonin and the neurotransmitter and growth factor serotonin, as well as derived neurotransmitter hormones-metabolites: 6-hydroxy-1-methyl-1 , 2,3,4-tetrahydro-β-carboline (adrenoglomerulotropin) and 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-β-carboline, respectively. The latter is formed as a result of the non-enzymatic Pictet-Spengler reaction between serotonin and acetaldehyde (a product of the oxidation of ethyl alcohol as a result of alcohol intoxication) or is present in nature as an alkaloid, for example, in cocoa beans [T. Herraiz. Tetrahydro-β-carbolines, Potential Neuroactive Alkaloids, in Chocolate and Cocoa / J. Agric. Food Chem., 2000, 48, 10, 4900-4904]. In addition, hydrazinophenol is an intermediate in the complete synthesis of many alkaloids: type II topoisomerase inhibitors (9-hydroxyellipticine [J. Bonjoch, N. Casamitjana, J. Quirante, M. Rodriguez, J. Bosch. Functionalized 2-azabicyclo [3.3 , 1] nonanes. 6. Studies directed to the synthesis of pentacyclic Strychnos indole alkaloids / J. Org. Chem., 1987, 52 (2), 267-275]), candidates for drugs for the treatment of cholinergic disorders and Alzheimer's disease (( -) - esermethole, (-) - eseroline, (-) - physostigmine (-) - physovenine) [S. Takano, M. Moriya, K. Ogasawara. Enantiocontrolled total syntheses of (-) - physovenine and (-) - physostigmine / J. Org. Chem., 1991, 56 (21): 5982-5984], as well as those with anticancer activity (montamine [LM Blair, J. Sperry. Studies towards the synthesis of montamine: synthesis of the 1,2-bis (indolyl) ethylhydrazine fragment / Tetrahedron Letters, 2013, 54 (15): 1980-1982]) and antimicrobial activity (koeniginequinone B [HJ Knolker, KR Reddy. Indoloquinones, Part 8. Palladium (II) -catalyzed total synthesis of murrayaquinone A, koeniginequinone A, and koeniginequinone B / Heterocycles, 2003, 60 (5): 1049-1052]). The oxidized fragment of 4-hydrazinophenol is also present in the stimulator of the protein nerve growth factor NG-061, obtained from the Penicillium minioluteum F-4627 strain [R. Bhandari, T. Eguchi, A. Serine, Y. Ohashi, K. Kakinuma, M. Ito, K. Mizoue. Structure of NG-061, a Novel Potentiator of Nerve Growth Factor (NGF) Isolated from Penicillium minioluteum F-4627 / J. Antibiotics 1999, 52 (3): 231-234]. 4-Hydrazinophenol is an intermediate in the production of important drugs such as Indomethacin [A.R. Maguire, S.J. Plunkett, S. Papot, M. Clynes, R. O'Connor, S. Touhey. Synthesis of indomethacin analogs for evaluation as modulators of MRP activity / Bioorg. Med. Chem., 2001, 9 (3), 745-762] and Bazedoxifene [H.S. Kwan, P.C. Ha, S.R. Seok, C.S. Her, K.K. Deok, K.D. Hwa, Methods of preparing Bazoedoxifene, Patent KR 10-2018-0095239 (A), date of application: 2017-02-17; H. Lizhi, Preparation method of selective estrogen receptor modulator bazedoxifene and key intermediate thereof, Patent CN 107935906 (A), date of application: 2018-04-20].

Only a small number of arylhydrazines are commercially available or readily synthesized. For the standard synthesis of arylhydrazines, the reduction of diazonium salts is used, which, in turn, are obtained from the corresponding substituted aniline derivatives. Alternatively, Buchwald and Hartwig and colleagues have proposed palladium-catalyzed cross-coupling for the synthesis of arylhydrazines [S. Wagaw, V.N. Yang, S.L. Buchwald. A Palladium-Catalyzed Method for the Preparation of Indoles via the Fischer Indole Synthesis / J. Am. Chem. Soc. 1999,121 (44): 10251-10263; F. Ma, Z. Peng, W. Li, X. Xie and Z. Zhang, Synlett, 2011, 2011 (17), 2555-2558].

The development of the cross-coupling method has led to the fact that in recent decades the hydrazination of aromatic compounds is often carried out using metal complex catalysis. In this case, the catalysts are either Lewis acids with transition metals, or salts of noble metals, or radical initiators, and the optimum temperature for the reaction is 40-70 ° C. The reaction conditions are a weak side of cross-coupling from a technological point of view due to the high cost of the catalyst, the need for a license to work with it and the related accounting. In addition, acidic conditions are destructive for many functionalized compounds; a, the resulting hydrazination products must be carefully isolated and purified from expensive and complex catalysts based on transition metals (due to the need to take into account the catalyst consumption). When obtaining highly pure medicinal substances for pharmaceuticals and medicinal chemistry, hydrazinated products must have a purity level higher than 99.5%.

Currently, the reactions of phenol-containing compounds with esters of azodicarboxylates are described very little. One example of such reactions is the direct hydrazination of phenol with azodicarboxylate esters in equimolar amounts with respect to the phenolic component. However, it leads to the formation of a mixture of oxidation and para-substitution products in a ratio of about 1: 1; the use of an azodicarboxylate ester in excess leads to further oxidation of the resulting by-product 3,3 ', 5,5'-tetraalkyl-4,4'-diphenyldiol to the corresponding diphenylquinone [S.H. Schroeter. Reaction of phenols with ethyl azodicarboxylate / J. Org. Chem. 1969,34 (12): 4012-4015]; in early works such transformations were described as a radically proceeding process [R. Huisgen, F. Jakob, W. Siegel, A. Cadus. Addition reactions of the N, N-double bond. I. Aromatic side-chain addition of azodicarboxylic ester / Justus Liebigs Ann. Chem., 1954, 590 (1): 1-36; L. Horner and W. Naumann. Azo-diacyl-Verbindungen als Analoga des elementaren Sauerstoffs / Justus Liebigs Ann. Chem. 1954, 587 (2): 81-92].

Another example of phenol hydrazination - the use of activated bis (2,2,2-trichloroethyl) azodicarboxylate (BTCEAD) in trifluoromethanesulfonic acid and / or in LiClO ₄ medium - was described by I. Leblanc and colleagues, who proposed a synchronous transformation mechanism [Y. Leblanc, N. Boudreault. Para-Directed Animation of Electron-Rich Arenes with Bis (2,2,2-Trichloroethyl) Azodicarboxylate / J. Org. Chem. 1995,60 (13): 4268-4271].

K.

Chirally Aminated 2-Naphthols - Organocatalytic Synthesis of Non-Biaryl Atropisomers by Asymmetric Friedel-Crafts Amination / Angew. Chem. Int. Ed., 2006, 45 (7): 1147-1151]. И наконец, для аналогичных превращений, отличающихся от рассматриваемых фенол-содержащих реакций, только донорной направляющей группой -NHR вместо -ОН, был постулирован SET механизм (single electron transfer, одноэлектронный перенос) в реакциях 1-аминонафтолов с эфирами азодикарбоксилатов при катализе ацетатом серебра, при этом было отмечено, что аналогичный более короткий анилиновый фрагмент не вступает в эту реакцию [Н. Zhu, S. Sun, Н. Qiao, F. Yang, J. Kang, Y. Wu, Y. Wu. Copper-Catalyzed C4-H Regioselective Phosphorylation/Trifluoromethylation of Free 1-Naphthylamines / Org. Lett., 2018, 20 (3): 620-623]. ОН-фрагмент фенола как направляющая группа в реакциях с азодикарбоксилатами проявляет схожий мезомерный эффект с описываемым NHR-фрагментом. Однако данная реакция протекала по указанному пути только при наличии пиридин-содержащего заместителя R в составе направляющей группы NHR.Later, V. Kinart proposed two methods of hydrazination of phenol and 2-naphthol at once: via the N: → Sn-coordinated metalloene mechanism or by electrophilic substitution via the stabilized Wieland intermediate [W. Kinart, C. Kinart. Catalysis of reactions of allyltin compounds and organotin phenoxides by lithium perchlorate / J. Organomet. Chem., 2006,691 (8): 1441-1451]. In addition, the synthesis of atropisomers has been described - through catalysis by alkaloids of plants of the cinchona family, while the authors mention that the 6-hydroxyquinoline system itself in the catalyst structure also interacts with the initial reagent and, with increasing temperature, is aminated at the 5th position. [S. Brandes, M. Bella, A.

K.

Chirally Aminated 2-Naphthols - Organocatalytic Synthesis of Non-Biaryl Atropisomers by Asymmetric Friedel-Crafts Amination / Angew. Chem. Int. Ed., 2006, 45 (7): 1147-1151]. And finally, for similar transformations that differ from the considered phenol-containing reactions, only by the donor directing group -NHR instead of -OH, the SET mechanism (single electron transfer, one-electron transfer) was postulated in the reactions of 1-aminonaphthols with azodicarboxylate esters catalyzed by silver acetate, it was noted that a similar shorter aniline fragment does not enter into this reaction [N. Zhu, S. Sun, H. Qiao, F. Yang, J. Kang, Y. Wu, Y. Wu. Copper-Catalyzed C4-H Regioselective Phosphorylation / Trifluoromethylation of Free 1-Naphthylamines / Org. Lett., 2018,20 (3): 620-623]. The OH fragment of phenol as a directing group in reactions with azodicarboxylates exhibits a similar mesomeric effect with the described NHR fragment. However, this reaction proceeded along the indicated path only in the presence of a pyridine-containing substituent R in the structure of the NHR guiding group.

Thus, previously in scientific publications, five different mechanisms and approaches to catalysis have been described for reactions related to the described transformation. Each of these methods requires additional stages of thorough purification of the product from the catalyst, in most cases, which contains a transition metal ion.

The carboxylate residue can be unblocked from the hydrazine residue by treatment with an acid or boron trifluoride etherate tert-butyl ester of the product [E.F. Evans, N.J. Lewis. N-tert-Butoxycarbonyl (BOC) Deprotection Using Boron Trifluoride Etherate / Synth. Commun., 1997, 27 (11): 1819-1825], obtaining unsubstituted hydrazines with a phenolic moiety.

Disclosure of the essence of the invention

The essence of the invention lies in the use of esters of azodicarboxylates as hydrazinating agents for obtaining derivatives of a 2- or 4-hydrazinophenol framework in a molecule, in reactions with phenol, 1-naphthol, quinolin-8-ol and quinolin-8-ol N-oxide in the presence of a basic catalyst.

The invention solves the problem of obtaining hydrazine derivatives of phenol and related aromatic compounds in quantitative yields (70-99%) in one stage, starting from the available esters of azodicarboxylates (esters of diazendicarboxylates) using the reaction of electrophilic amination with basic catalysis.

The method of electrophilic hydrazination of phenol derivatives is feasible under general basic catalysis conditions (Fig. 1). For the synthesis, the esters of azodicarboxylates are used, which are commercially available both as individual substances and as solutions in organic solvents. Aromatic hydrocarbons containing phenolic hydroxyl as a directing group irreversibly undergo hydrazinolysis in the presence of inorganic and organic bases with a yield close to quantitative. The reaction makes it possible to obtain o- or n-substituted hydrazinophenols at room temperature, while it should be noted that the high yield of the reaction product does not depend on the amount of loading. Hydrides or amides of alkali metals or other bases (Table 1.) are used as the main catalyst in the reaction, both individually and as a dispersion in mineral or silicone oil in various percentages. It has been shown that, regardless of the type of aromatic system, sodium hydride and lithium amide are the most economically viable (produced annually in large quantities in the world and are readily available commercially) and requiring catalytic amounts (0.05-0.5 molar equivalents for the starting reagents). In this case, the role of the base is to form phenolate and activate the aromatic system, which are necessary for the nucleophilic attack of the azodicarboxylate ester molecule. During the production of phenolate, gaseous by-products such as hydrogen can be obtained, therefore it is recommended to use a calcium chloride tube instead of a stopper or other device that regulates the internal pressure in the reaction vessel. The bases used in the reaction are removed from the reaction mixture by extraction in aqueous-organic phases, followed by quenching with an equimolar amount of acetic or hydrochloric acid. It should be noted that when using hydrides and salts of alkali or alkaline earth metals or lithium amide, regeneration of the catalyst for reuse is impossible, while when using bases based on organic amines, after separation from the reaction product, regeneration of the used base is possible.

Monitoring the progress of the reactions is carried out using TLC and / or HPLC, the approximate time of the process to quantitative yield is from 1 hour (in the case of catalysis with more active sodium hydride) to 24 hours (in the case of catalysis with lithium hydride).

To unblock substituents from the hydrazine residue, it is proposed to carry out the hydrolysis of tert-butyl esters of carboxylates, which in their essence are a protective group (tert-butyloxycarbonyl, or BOC) in the starting diazenes and / or in the final products. Deblocking is carried out using standard methods of classical organic synthesis under mild conditions [E.F. Evans, N.J. Lewis. N-tert-Butoxycarbonyl (BOC) Deprotection Using Boron Trifluoride Etherate / Synth. Commun., 1997, 27 (11): 1819-1825] and leads to N-unsubstituted aromatic hydrazines or their hydrochloride salts (Fig. 2.).

Thus, the proposed method allows us to obtain unsubstituted hydrazines and di (ethyloxycarbonyl), di (isopropyloxycarbonyl) and di (tert-butyloxycarbonyl) esters of phenol hydrazines, 1-naphthol, 8-hydroxyquinoline and 8-hydroxyquinoline N-oxide (Fig. 3) based on the available starting phenolic substrates and azodicarboxylate esters.

The advantages of this method are: the use of readily available reagents, the stereospecificity of the reactions proceeding due to the directing phenolic group in the aromatic structure, the completeness of the conversion of the starting compounds and the high yield of the target compounds.

Below are specific examples of the implementation of the proposed technical solution, but which are not intended to limit the scope of the claims.

Brief Description of Shapes and Tables

Figure 1. Scheme for the preparation of esters of N, N'-dicarboxylates of hydrazines of phenol-containing compounds and the reaction conditions.

Figure 2. Scheme for the preparation of N-unsubstituted hydrazines of phenol-containing compounds and their hydrochlorides, and the reaction conditions.

Figure 3. Examples of the obtained esters of N, N'-dicarboxylates and N-unsubstituted hydrazines of phenol-containing compounds based on the proposed method.

Table 1. Dependence of the yield of products 1b and 7b on the choice of the base-catalyst during the reaction with diisopropyl ethers of azodicarboxylates (similarly for ethyl and tert-butyl ethers). Conditions: 20 ± 5 ° C (unless otherwise indicated in the table), atmospheric pressure, tetrahydrofuran as a solvent (from 200% by volume with respect to the rest of the reagents), calcium chloride tube for the release of the resulting gaseous products.

Implementation of the invention

(Acros Organics), в стеклянных колонках размером 20×200 мм с пористым фильтром. Масс-спектры высокого разрешения регистрировали на приборе Bruker Daltonics micrOTOF-Q II с электрораспылительной ионизацией (ESI HRMS). Измерения проводили в режиме положительно заряженных ионов. Напряжение на капилляре: 4700 V; диапазон сканирования масс m/z 50-3000; калибровка внешняя (Electrospray Calibrant Solution, Fluka); давление на распылителе: 0,4 бар; скорость потока: 3 мкл/мин; газ-распылитель: азот (4 л/мин); температура интерфейса: 200°С. Образцы подавались в распылительную камеру масс-спектрометра после высоко-эффективного жидкостного хроматографа Agilent 1260, оснащенного колонкой Agilent Poroshell 120 ЕС-С18 (3,0×50 мм; 2,7 мкм); скорость потока 0,2 мл/мин; в ВЭЖХ-хроматограф образцы вещества подавали из раствора ацетонитрил-вода 1:1 (5 мкл) и элюировали в линейном градиенте концентраций ацетонитрила (50→100%).The structures of the claimed compounds were confirmed by high resolution NMR and mass spectroscopy. NMR spectra were recorded on a Broker AMX 300 instrument (Germany). Chemical shifts (δ) in ¹ H-NMR are given in parts per million (ppm) and are measured relative to the residual solvent signal: D ₂ O - 4.79 ppm. Spin - spin coupling constants (J) are measured in hertz (Hz). When describing ¹ H-NMR spectra, the following abbreviations are used: s - singlet, br.s - broadened singlet, d - doublet, t - triplet, m - multiplet. Thin layer chromatography was performed on Merck Kieselgel-60 plates with UV detection (λ = 254 nm) and thermal detection (heating the TLC plates to 400 ° C). Column chromatography of the products was carried out on silica gel with a size of 0.035-0.070 mm, 60

(Acros Organics), in glass columns with a size of 20 × 200 mm with a porous filter. High-resolution mass spectra were recorded on a Bruker Daltonics micrOTOF-Q II instrument with electrospray ionization (ESI HRMS). The measurements were carried out in the mode of positively charged ions. Capillary voltage: 4700 V; mass scanning range m / z 50-3000; external calibration (Electrospray Calibrant Solution, Fluka); spray pressure: 0.4 bar; flow rate: 3 μl / min; spray gas: nitrogen (4 l / min); interface temperature: 200 ° С. Samples were fed into the mass spectrometer spray chamber after an Agilent 1260 HPLC equipped with an Agilent Poroshell 120 EC-C18 column (3.0 x 50 mm; 2.7 μm); flow rate 0.2 ml / min; In an HPLC chromatograph, samples of the substance were fed from an acetonitrile-water solution 1: 1 (5 μl) and eluted in a linear gradient of acetonitrile concentrations (50 → 100%).

The following examples illustrate the invention.

Example 1. General method for the synthesis of derivatives of 4-hydrazinophenol and 4-hydrazino-1-naphthol in gram quantities.

A solution of phenol-containing starting material (5.31 mmol) and 8.0 mg of NaH (0.27 mmol, 80% purity) in 10 ml of tetrahydrofuran in a round-bottom flask with a volume of 50 ml was cooled to -5 ... 0 ° C and the unoccupied liquid was purged flask volume with inert gas or nitrogen. A portion of the azodicarboxylate (5.57 mmol) was added with stirring at room temperature. In the course of the process, the reaction mass changed color from yellow to dark orange, after which the stirring of the reaction in the flask was continued for another 1.5 hours. The solvent was evaporated and the reaction mass was extracted into CH ₂ Cl ₂ / saturated NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ , the solution was filtered to remove the formed crystalline hydrate, the solvent was evaporated, re-evaporated with toluene, the resulting residue was dried in vacuum. The product was dissolved in chloroform and applied to a silica gel column, eluted with chloroform. The purified product was obtained in the form of colorless solid crystals.

Example 2. Diisopropyl ether of 1- (4-hydroxyphenyl) hydrazinyl-1,2-dicarboxylate (1b)

The product was obtained in the form of colorless crystals according to the general preparation method (Example 1) from 0.500 g of phenol and 1.095 ml of diisopropylazoxycarboxylate in an amount of 1.416 g (Yield: 90%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.71 & 9.37 (2 × br.s, 1H, NH (2 conformers)), 9.37-9.71 (br.s, 1H , OH), 7.13 (d, J = 8.7 Hz, 2H, CH-2 & CH-6), 6.72 (d, J = 8.8 Hz, 2H, CH-3 & CH-5 ), 4.82 (2 x sept, J = 6.1 Hz, 2H, CH (i-Pr)), 1.21 & 1.18 (2 x d, 12H, Me (i-Pr)).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 155.71 (s, C4), 155.55 (2 × s, CO-NH), 154.25 (s, CO-N), 133.9 (s, C1), 125.98 (br.s, C2 & C6), 114.9 (s, C3 & C5), 69.36 & 68.34 (2 × s, C (i-Pr)), 21.87 & 21.77 (2xs, Me (i-Pr)).

Mass Spectrum C ₁₄ H ₂₀ N ₂ O ₅ (m / z): calculated for [M + H] ⁺ 297.1445, found 297.1442; calculated for [M + Na] ⁺ 319.1264, found 319.1256; calculated for [M + K] ⁺ 335.1004, found 335.0998.

Example 3. Di-tert-butyl ester of 1- (4-hydroxyphenyl) hydrazinyl-1,2-dicarboxylate (1c)

The product was obtained in the form of colorless crystals according to the general preparation method (Example 1) from 0.500 g of phenol and 1.284 g of di-tert-butylazoxycarboxylate in an amount of 1.551 g (Yield: 90%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.47 & 9.37 & 9.06 (3 × br.s, 1H, NH + OH (2 conformers)), 7.09 (d, J = 8.7 Hz, 2H, CH-2 & CH-6), 6.69 (d, J = 8.8 Hz, 2H, CH-3 & CH-5), 1.42 & 1.39 (2 X s, 18H, Me (t-Bu)).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 155.60 (s, C4), 155.53 (s, CO-NH), 154.00 (s, CO-N), 134.67 (s , C1), 126.49 (s, C2 & C6), 114.9 (br.s, C3 & C5), 80.75 & 79.96 (2 × s, C (t-Bu)), 28, 54 & 28.30 (2x, Me (t-Bu)).

Mass Spectrum C ₁₆ H ₂₄ N ₂ O ₅ (m / z): calculated for [M + H] ⁺ 325.1758, found 325.1763; calculated for [M + Na] ⁺ 347.1577, found 347.1577; calculated for [M + K] ⁺ 363.1317, found 363.1315.

Example 4. Di-tert-butyl ester of 1- (4-hydroxy-2,5-dimethylphenyl) hydrazinyl-1,2-dicarboxylate (2c)

The product was obtained in the form of colorless crystals according to the general preparation method (Example 1) from 0.650 g of 2,4-dimethylphenol and 1.284 g of di-tert-butylazoxycarboxylate in an amount of 1.797 g (Yield: 93%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.46 & 9.39 (2 × br.s, 1H, NH (2 conformers)), 9.20 (s, 1H, OH), 7, 00 (s, 1H, CH-5), 6.55 (s, 1H, CH-2), 2.09 & 2.04 (2 × br.s, 6H, 2 × Me), 1.42 & 1 , 31 (2 × s, 18H, Me (t-Bu)).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 155.07 (s, CO-NH), 154.22 (s, CO-N), 153.64 (s, C4), 133.66 (s , C2), 132.53 (s, C1), 129.27 (s, C6), 128.93 (s, C5), 115.51 (s, C3), 79.85 & 79.24 (2 × c, C (t-Bu)), 28.07 & 27.83 (2 × c, Me (t-Bu)), 17.13 (a, 2-Me), 15.53 (a, 5-Me ).

Mass Spectrum C ₁₆ H ₂₄ N ₂ O ₅ (m / z): calculated for [M + H] ⁺ 353.2071, found 353.2073; calculated for [M + Na] ⁺ 375.1890, found 375.1891.

Example 5. Di-tert-butyl ester of 1- (4-hydroxynaphth-1-yl) hydrazino-1,2-dicarboxylate (3c)

The product was obtained from 0.775 g of 1-naphthol and 1.284 g of di-tert-butylazoxycarboxylate according to the general preparation method (Example 1). After extraction, the reaction mixture was loaded onto a silica gel column and eluted in a chloroform-ethanol system (97%: 3% by volume). The fractions containing the target product were evaporated in vacuo, as a result of which 1.646 g of 3c was isolated in the form of a viscous beige liquid (80% yield).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.90-9.70 (br.s, 2H, NH + OH), 8.29 (dd, J = 0.8 Hz, J = 9, 0 Hz, 1H, CH-8), 8.05 (d, J = 8.2 Hz, 1H, CH-5), 7.62-7.52 (m, 3H, CH-6 + CH-7 + CH-8), 7.43 (d, 1H, J = 7.3 Hz, CH-3), 7.34 (d, 1H, J = 7.3 Hz, CH-2), 1.47 and 1 , 26 (2 × s, 18H, Me (t-Bu)).

Mass spectrum C ₂₀ H ₂₆ N ₂ O ₅ (m / z): calculated [M + Na] ⁺ 397.1734, found 397.1740.

Example 6. N, N '- (4-hydroxynaphthal-1,3-diyl) -bis- (hydrazino-1,2-dicarboxylate) tetra-tert-butyl ester (4c)

The product was obtained from 0.383 g of 1-naphthol (2.66 mmol) according to the general preparation method (Example 1). After extraction, the reaction mixture was loaded onto a silica gel column and eluted in chloroform. The fractions containing the target product as indicated by TLC were evaporated in vacuo to give 1.350 g in 4 s as a yellow viscous liquid (84% yield).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.94-9.29 (m, 3H, 2 × NH + OH), 8.22 (d, J = 7.5 Hz, 1H, CH- 5), 8.01 (s, 1H, CH-3), 7.54 (m, 3H, CH-6 + CH-7 + CH-8), 1.46 and 1.43 and 1.40 and 1 , 30 and 1.22 (5 × s, 36H, Me (t-Bu) (2 conformers)).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 158.25 (s, CO-NH), 155.38 (s, CO-NH) 154.14 (s, CO-N), 153.59 ( s, CO-N), 148.35 (s, C1), 130.45 (s, C4), 126.79 (s, C5), 124.91 (s, C6), 123.32 (s, C7 ), 122.68 (s, C8), 122.08 (s, C10), 121.69 (s, C9), 81.22 and 80.35 and 79.47 and 78.82 (4 × s, C (t-Bu)), 28.08 and 27.91 and 27.66 (3 × s, Me (t-Bu)).

Mass Spectrum C ₃₀ H ₄₄ N ₄ O ₉ (m / z): calculated [M + Na] ⁺ 627.3000, found 627.3003; calculated [M + K] ⁺ 643.2740, found 643.2739.

Example 7. General method for the synthesis of 4-substituted derivatives of 2-hydrazino-1-naphthol and 5-substituted derivatives of 7-hydrazino-8-hydroxyquinoline

A solution of 0.100 di-tert-butyl azodicarboxylate (0.43 mmol) and 5.9 mg of sodium hydride (0.20 mmol, 80% pure) were mixed with the corresponding amount of the substituted phenol-containing starting material (0.39 mmol) in 3 ml of tetrahydrofuran , was stirred at room temperature for 6 hours. The conversion was monitored by TLC and stirred for an additional 12 hours if necessary. At the end of the reaction, the solvent was evaporated, the reaction mass was extracted into CH ₂ Cl ₂ / saturated NaHCO ₃ solution, the organic layer was dried over Na ₂ SO ₄ , the solvent was evaporated, the residue was dissolved in CHCl ₃ and applied to a silica gel column, the target fractions were evaporated in vacuum.

Example 8. Di-tert-butyl ester of 1- (4-chloro-1-hydroxynaphth-2-yl) hydrazinyl-1,2-dicarboxylate (5c)

The product was obtained from 0.070 g of 4-chloro-1-naphthol (0.39 mmol) according to the general preparation method (Example 7.). After extraction, the reaction mass was washed with CCl _4. The residue containing the target product was additionally dried in a vacuum, as a result of which 0.153 g of 6s was obtained in the form of a milky white solid residue (Yield 95%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.96 (br.s, 1H, NH), 9.70 (br.s, 1H, OH), 8.29 (dd, J = 0, 8 Hz, J = 9.0 Hz, 1H, CH-8), 8.09 (d, J = 8.2 Hz, 1H, CH-5), 7.71 (dd, J = 6.9 Hz, J = 8.2 Hz, J = 1.0 Hz, 1H, CH-6), 7.63 (dd, 1H, J = 6.9 Hz, J = 9.0 Hz, J = 1.0 Hz, CH-7), 7.43 (s, 1H, CH-3), 1.44 and 1.30 (2 × s, 18H, Me (t-Bu)).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 157.57 (s, CO-NH), 153.38 (s, CO-N), 148.65 (s, C8), 130.17 (s , C9), 128.34 (s, C6), 128.10 (s, C10), 126.59 (s, C7), 126.43 (s, C5), 125.83 (s, C4), 123 , 48 (s, C), 123.27 (s, C8), 119.65 (s, C2), 81.53 and 81.46 (2 × s, C (t-Bu)), 27.87 and 27.69 (2 × s, Me (t-Bu)).

Mass Spectrum C ₂₀ H ₂₅ ClN ₂ O ₅ (m / z): calculated [M + NH ₄ ] ⁺ 426.1790, found 426.1797; calculated [M + Na] ⁺ 431.1344, found 431.1350; calculated [M + K] ⁺ 447.1084, found 447.1089.

Example 9. Di-tert-butyl ester of 1- (5-fluoro-8-hydroxyquinolin-7-yl) hydrazino-1,2-dicarboxylate (7c)

The product was obtained from 0.064 g of 5-fluoro-8-hydroxyquinoline (0.39 mmol) according to the general preparation method (Example 7.). After extraction, the reaction mixture was loaded onto a silica gel column and eluted in a CCl ₄ : dioxane (9: 1) system with the addition of 1% acetic acid. The fractions containing the target product were evaporated in vacuo, as a result of which 0.108 g of 8c was isolated as a light green solid (Yield 70%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.95 (br.s, 2H, NH + OH), 8.86 (d, J = 4.2 Hz, 1H, CH-2), 8 , 25 (d, J = 8.4 Hz, 1H, CH-4), 7.47 (s, 1H, CH-6), 7.31 (dd, J = 8.4 Hz, J = 4.2 Hz, 1H, CH-3), 1.42 and 1.40 (2 × br s, 18H, Me (t-Bu)).

Mass spectrum C ₁₉ H ₂₄ FN ₃ O ₅ (m / z): calculated [M + H] ⁺ 394.1773, found 394.1764.

Example 10. Di-tert-butyl ester of 1- (5-chloro-8-hydroxyquinolin-7-yl) hydrazino-1,2-dicarboxylate (8c)

The product was obtained from 0.071 g of 5-chloro-8-hydroxyquinoline (0.39 mmol) according to the general preparation method (Example 7.). After extraction, the reaction mixture was loaded onto a silica gel column and eluted in the CCl ₄ : dioxane (9: 1) system with the addition of 1% (v / v) acetic acid. The fractions containing the target product were evaporated in vacuo, as a result of which 0.156 g of 6s was isolated as a beige solid (Yield 97%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.92-9.38 (br.s, 2H, NH + OH), 8.86 (dd, J = 1.0 Hz, J = 4, 1 Hz, 1H, CH-2), 8.40 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H, CH-4), 7.64 (dd, J = 8.4 Hz, J = 4.2 Hz, 1H, CH-3), 7.56 (s, 1H, CH-6), 1.42 and 1.39 (2 × br s, 18H, Me (t-Bu)) ...

¹³ C NMR (DMSO-d ₆ , δ, Hz): 155.74 (s, CO-NH), 153.31 (s, CO-N), 148.65 (s, C2), 140.25 (s , C9), 132.31 (s, C4), 127.03 (br.s, C5 + C7), 125.94 (s, C8), 125.06 (s, C6), 122.75 (s, C3), 115 (s, C10), 80.89 and 80.24 (2 × s, C (t-Bu)), 28.50 and 28.28 (2 × s, Me (t-Bu)).

Mass Spectrum C ₁₉ H ₂₄ ClN ₃ O ₅ (m / z): calculated [M + H] ⁺ 410.1477, found 410.1480; calculated [M + Na] ⁺ 432.1297, found 432.1302.

Example 11. General method for the synthesis of derivatives of 7-hydrazino-8-hydroxyquinoline

To a solution containing 2 g of 8-hydroxyquinoline (13.8 mmol) and 21 mg of sodium hydride (0.69 mmol, 80% purity) in 40 ml of solvent was added a portion of azodicarboxylate (14.47 mmol) with stirring at room temperature. The reaction mixture was stirred at room temperature from 30 to 180 min until the end of the reaction (the progress of the reaction was monitored according to the data of thin layer chromatography). The solvent was evaporated in vacuo, the reaction mass was extracted into CH ₂ Cl ₂ / saturated aqueous NaHCO ₃ solution. The organic phase was additionally dried over Na ₂ SO ₄ , filtered to remove the formed crystalline hydrate and evaporated from the solvent, re-evaporated with toluene.

Example 12. 1- (8-hydroxyquinolin-7-yl) hydrazinyl-1,2-dicarboxylate diisopropyl ester (6b)

The product was obtained as a milky white solid based on the general procedure (Example 11) from 2.925 g of diisopropyl azodicarboxylate in an amount of 4.773 g (Yield: 99.7%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.91 (2 × br s, 1H, NH), 9.47 (2 × br s, 1H, OH), 8.87 (dd, J = 1.6 Hz, J = 4.2 Hz, 1H, CH-2), 8.31 (dd, J = 1.5 Hz, J = 8.3 Hz, 1H, CH-4), 7, 56 (dd, J = 4.2 Hz, J = 8.3 Hz, 1H, CH-3), 7.52 (d, J = 8.8 Hz, 1H, CH-6), 7.38 (d , J = 8.8 Hz, 1H, CH-5), 4.85 (sept, 2H, J = 6.2, CH (i-Pr)), 1.21 (d, 12H, Me (i-Pr )).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 156.87 and 154.59 (2 × s, CO-NH (2 conformers)), 148.89 (s, C2), 148.68 (s, CO-N), 138.1 (s, C9), 136.38 (s, C4), 128.17 (s, C8), 127.48 (2 × s, C5 and C10), 126.03 (s , C7), 122.46 (s, C3), 117.37 (s, C6), 69.98 and 69.00 (2 × s, C (i-Pr)), 22.32 and 22.25 ( 2 × c, Me (i-Pr)).

¹⁵ N NMR (DMSO-d ₆ , δ, Hz): 297.94 (s, N1), 119.18 (s, NH-CO).

Mass spectrum C ₁₇ H ₂₁ N ₃ O ₅ (m / z): calculated [M + H] ⁺ 348.1554, found 348.1562.

Example 13. Di-tert-butyl ester of 1- (8-hydroxyquinolin-7-yl) hydrazinyl-1,2-dicarboxylate (6c)

The product was obtained as a milky white solid starting from the general procedure (Example 11) from 3.173 g of di-tert-butyl azodicarboxylate in an amount of 5.170 g (Yield 99.9%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.73 (2 × br s, 1H, NH), 9.35 (2 × br s, 1H, OH), 8.86 (dd, J = 2.5 Hz, J = 4.2 Hz, 1H, CH-2), 8.50 (d, J = 8.4 Hz, 1H, CH-4), 7.61 (dd, J = 8 , 6 Hz, J = 4.1 Hz, 1H, CH-3), 7.51 (d, J = 8.2 Hz, 1H, CH-6), 7.08 (d, J = 8.2 Hz , 1H, CH-5), 1.46 and 1.41 and 1.19 (3 × br.s, 18H, Me (t-Bu) (2 conformers)).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 155.27 and 154.00 (s, CO-NH (conformers)), 153.16 (s, CO-N), 148.11 (s, C2 ), 138.14 (s, C9), 132.30 (s, C4), 129.30 (s, C10), 126.96 (s, C8), 126.35 (s, C5), 125.87 (s, C7), 121.82 (s, C3), 110.39 (s, C6), 80.55 and 80.12 and 79.63 (3 × c, C (t-Bu) (2 conformers) , 28.02 and 27.74 (2 × s, Me (t-Bu) (2 conformers)).

¹⁵ N NMR (DMSO-d ₆ , δ, Hz): 299.3 (s, N1), 245.5 (s, NH-CO), 111.2 (s, N-CO).

Mass spectrum C ₁₉ H ₂₅ N ₃ O ₅ (m / z): calculated [M + H] ⁺ 376.1867, found 376.1867.

Example 14 7- (1,2-Bis (tert-butoxycarbonyl) hydrazinyl) -8-hydroxyquinoline N-oxide (9c)

Method 1: The product was obtained as a cream-colored solid based on the general synthesis method (Example 11) from 0.437 g of starting 8-hydroxyquinoline N-oxide 0.705 and 0.948 g di-tert-butyl azodicarboxylate (Yield: 83%).

Method 2: A solution of 0.300 g of meta-chloroperbenzoic acid (1.73 mmol) in 2 ml of methylene chloride was added in portions to a solution cooled to ~ 0 ° C with 0.500 g with 7c (1.33 mmol) in 5 ml of methylene chloride. The reaction was stirred at room temperature for 5 h, the progress of the process was monitored by TLC. Upon completion of the reaction, the mixture was extracted into CH ₂ Cl ₂ / saturated NaHCO ₃ solution, the organic layer was dried over Na ₂ SO ₄ , the solution was filtered from the formed crystalline hydrate, the solvent was evaporated, the residue was dissolved in CHCl ₃ and applied to a chromatographic column with silica gel. The product was isolated by column chromatography in a gradient of ethanol in chloroform (0 → 6% alcohol by volume), the target fractions were evaporated in vacuum, yielding 0.481 g (92%) of a beige solid.

¹ H NMR (DMSO-d ₆ , δ, Hz): 8.27 (d, J = 5.8 Hz, 1H, CH-2), 8.20 (br.s, 1H, NH), 8.50 (d, J = 5.9 Hz, 1H, CH-4), 7.60 (d, J = 8.3 Hz, 1H, CH-6), 7.29 (dd, J = 8.7 Hz, J = 6.1 Hz, 1H, CH-3), 7.01 (d, J = 8.5 Hz, 1H, CH-5), 1.46 and 1.45 and 1.35 (3 × br. s, 18H, Me (t-Bu) (2 conformers)).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 155.60 (s, CO-NH), 154.53 (s, CO-N), 154.21 (s, C2), 138.1 (s , C9), 134.71 (s, C4), 130.17 (s, C7), 129.69 (s, C10), 128.59 (s C8), 126.44 (s, C5), 120, 88 (s, C3), 114.25 (s, C6), 80.80 and 81.96 (2 × s, C (t-Bu)), 28.33 and 28.19 (2 × s, Me ( t-Bu) (2 conformers)).

Mass Spectrum C ₁₉ H ₂₅ N ₃ O ₆ (m / z): calculated [M — O + H] ⁺ 376.1867, found 376.1867; calculated [M + H] ⁺ 392.1816, found 392.1813; calculated [M + Na] ⁺ 414.1636, found 414.1628; calculated [M + H] ⁺ 430.1375, found 430.1374.

Example 15. General method for producing hydrazine derivatives of phenol-containing aromatic compounds.

, количество: 10 гранул) помещали в колбу с навеской Вос-защищенного гидразинового производного (1,33 ммоль) в хлористом метилене (15 мл), после чего добавляли 0,246 мл перегнанного эфирата трифтористого бора (2,00 ммоль) при комнатной температуре, закрывали хлоркальциевой трубкой или другим приспособлением, регулирующим давление в реакционном сосуде, и оставляли перемешиваться при темературе 20-40°С. В течение 5-40 мин. наблюдали выделение газов из реакционной массы, и по завершении данного процесса в реакционную массу добавляли МеОН (10 мл) и переносили в другую чистую колбу. Растворители и избыток исходного эфирата трифтористого бора упаривали в вакууме и переупаривали с метанолом, в результате чего получали целевой незамещенный ароматический гидразин.Molecular Sieve Serving (Pore Size: 4

, amount: 10 granules) was placed in a flask with a weighed amount of Boc-protected hydrazine derivative (1.33 mmol) in methylene chloride (15 ml), after which 0.246 ml of distilled boron trifluoride etherate (2.00 mmol) was added at room temperature, closed calcium chloride tube or other device that regulates the pressure in the reaction vessel, and left stirring at a temperature of 20-40 ° C. Within 5-40 minutes. gas evolution from the reaction mass was observed, and upon completion of this process, MeOH (10 ml) was added to the reaction mass and transferred to another clean flask. The solvents and the excess of the starting boron trifluoride etherate were evaporated in vacuum and re-evaporated with methanol, as a result of which the target unsubstituted aromatic hydrazine was obtained.

Example 16. 4-Hydroxyphenylhydrazine (1d)

The product was obtained from 0.43 g of substance 1 s (1.33 mmol) according to the general preparation method (Example 15.) in an amount of 0.164 g in the form of a colorless solid precipitate (Yield 99%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.69 (br.s, 3H, NH + NH ₂ (one of two) + OH), 7.18 (d, J = 8.8 Hz, 2H, CH-3 + CH-5), 7.08 (t (equal intensity), J _{H, 15N} = 51.1 Hz, 1H, NH ₂ ), 6.90 (d, J = 8.8 Hz, 2H, CH-2 + CH-6).

¹³ C NMR (DMSO-d ₆ , δ, Hz): 157.26 (s, C4), 124.31 (s, C3 + C5), 122.10 (s, C1), 116.16 (s, C2 + C6).

Mass spectrum C ₆ H ₈ N ₂ O (m / z): calculated for [M + H] ⁺ 125.0709, found 125.0713.

Example 17 7-Hydrazino-8-hydroxyquinoline (6d)

The product was obtained from 0.5 g of substance 7c (1.33 mmol) according to the general method of preparation (Example 15.) in an amount of 0.590 g in the form of a solid dark crimson precipitate (Yield 98%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 10.63 (br.s, 2H, NH + OH), 8.95 (d, J = 4.5 Hz, 1H, CH-2), 8 , 80 (d, J = 8.4 Hz, 1H, CH-4), 7.76 (dd, J = 4.5 Hz, J = 8.5 Hz, 1H, CH-3), 7.52 ( d, J = 8.3 Hz, C5), 7.52 (d, J = 8.3 Hz, C6).

Mass spectrum C ₉ H ₉ N ₃ O (m / z): calculated for [M + H] ⁺ 176.0818, found 176.0820.

Example 18. General method of obtaining hydrochlorides of hydrazine derivatives of phenol-containing aromatic compounds.

A weighed portion of the Boc-protected hydrazine derivative (1.33 mmol) was dissolved in 5 ml of dioxane in a round-bottomed flask at room temperature and 2 ml of an aqueous solution of hydrochloric acid (33-37%) was added, closed with a calcium chloride tube or other device that regulates the pressure in the reaction vessel , and left stirring at a temperature of 20-40 ° C. The solvents and excess acid were evaporated in vacuum and re-evaporated with methanol, as a result of which the target unsubstituted aromatic hydrazine was obtained in the form of its hydrochloride salt with a variable composition of from one to two HCl molecules per ariometic hydrazine molecule.

Example 19 7-Hydrazino-8-hydroxyquinoline hydrochloride (6e)

The product was obtained from 1,000 g of substance 7 s (2.66 mmol) according to the general method of preparation (Example 18.) in an amount of 1.180 g in the form of a solid dark crimson precipitate (Yield 97%).

¹ H NMR (DMSO-d ₆ , δ, Hz): 9.50 (br.s, 3H, NH + OH + HCl), 8.97 (d, J = 4.4 Hz, 1H, CH-2) , 8.83 (d, J = 8.2 Hz, 1H, CH-4), 7.78 (dd, J = 4.4 Hz, J = 8.3 Hz, 1H, CH-3), 7, 55 (d, J = 8.2 Hz, C5), 7.54 (d, J = 8.3 Hz, C6).

Mass spectrum C ₉ H ₁₀ N ₃ OCl (m / z): calculated for [M + H-Cl] ⁺ 176.0818, found 176.0822.

Claims (6)

A method of obtaining substituted and unsubstituted phenol-containing hydrazine-N, N'-dicarboxylates using the hydrazination reaction of substituted and unsubstituted phenols with one- and bicyclic condensed structures (1-naphthols, quinolin-8-ols) with azodicarboxylate esters in the presence of a basic catalyst at room temperature at inert solvents with the possibility of subsequent deblocking of N-carboxylate residues in particular cases of Boc-substituted hydrazine derivatives to form N-unsubstituted phenol-containing hydrazines of the general formula

where X represents CH, N, N ⁺ -O ^- in a fixed position or absent in the absence of a cycle; R is —H, —COOEt, —COOi — Pr, —COOt — Bu; R 'is —H, —Me, —Cl, —F; Z represents nHCl (n = 1-2) when R = H.

Images