RU2567757C1 - METHOD OF PRODUCING ALKYL 2-SUBSTITUTED 6H-BENZOTHIENO[2,3,4-ij]-2,7-NAPHTHYRIDINE-5-CARBOXYLATES - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing alkyl 2-substituted 6H-benzothieno[2,3,4-ij]-2,7-naphthyridine-5-carboxylates of general formula 1

, where 1a Ar=Ph, R=H, R′=Et; 1b Ar=4-CH₃O-C₆H₄, R=CH₃, R'=Et; 1c Ar=4-CH₃-C₆H₄, R=CH₃, R'=Am; 1d Ar=4-CH₃-C₆H₄, R=CH₃O, R'=Et; 1e Ar=Ph, R=H, R'=Am, which can be used as potentially biologically active substances and semi-products for synthesis of novel heterocyclic systems. The method of producing alkyl 2-substituted 6H-benzothieno[2,3,4-ij]-2,7-naphthyridine-5-carboxylates of general formula I includes forming a heterocyclic system of 6H-benzothieno[2,3,4-ij]-2,7-naphthyridine as a result of thermal decomposition of the azido group of alkyl 3-azidothieno[2,3-b]pyridine-2-carboxylates and intramolecular cyclisation of the formed nitrene; the reaction is carried out while boiling said compounds in chlorobenzene for 30-60 minutes.

EFFECT: high output.

3 tbl, 6 ex

Description

The invention relates to the field of organic chemistry - the synthesis of heterocyclic compounds - derivatives of 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridines.

The invention relates to the development of a method for producing alkyl 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylates of the general formula 1,

Where

1a Ar = Ph, R = H, R ′ = Et; 1b Ar = 4-CH ₃ O-C ₆ H ₄ , R = CH ₃ , R ′ = Et;

1c Ar = 4-CH ₃ -C ₆ H ₄ , R = CH ₃ , R ′ = Am;

1 g Ar = 4-CH ₃ -C ₆ H ₄ , R = CH ₃ O, R ′ = Et;

1d Ar = Ph, R = H, R ′ = Am,

which can find application as potential biologically active substances and intermediates for the synthesis of new heterocyclic systems.

The thermal decomposition of aromatic azides is one of the widely used methods for the formation of condensed systems containing five-, six-, or seven-membered azaheterocycles in organic synthesis. This technique was used to obtain the pyrrole ring in heterocyclic systems such as indolopyridocarbazolones [H.V. Dang, W. Knobloch, N.S. Habib, T. Kappe, W. Stadlbauer, J. Heterocyclic Chem., 2005, 42, 85-91], carbazoles [H. Jian, J.M. Tour, J. Org. Chem., 2003, 68, 5091-5103], indoloisoquinolines [M Béres, G. Timári, G. Hajos, Tetrahedron Lett., 2002, 43, 6035-6038], including the alkaloids Cryptotackieine and Cryptosanguinolentine [P.M. Fresneda, P. Molina, S. Delgado, Tetrahedron, 2001, 57, 6197-6202; P.M. Fresneda, P. Molina, S. Delgado, Tetrahedron Lett., 1999, 40, 7275-7278], pyridazino [3,4] indoles [Z. Riedl, K. Monsieurs, G. Krajsovszky, P. Dunkel, B.U. W. Maes, P. Tapolcsányi, O. Egyed, S. Boros, P. Mátyus, L. Pieters, G.L. F. Lemiére, G. Hajos, Tetrahedron, 2006, 62, 121-129; P. Tapolcsányi, G. Krajsovszky, R. Ando, P. Lipcsey, G. Horváth, P. Mátyus, Z. Riedl, G. Hajos, B.U. W. Maes, G.L. F. Lemiére, Tetrahedron, 2002, 58, 10137-10143].

The thermal decomposition of azides is also used to close the seven-membered ring in annelated azepines [G. Broggini, G. Molteni, G. Zecchi, Synthesis, 1995, 647-648; E. Beccalli, G. Broggini, G. Paladino, T. Pilati and G. Pontremoli, Tetrahedron Asym. 2004, 15, 687-692; G. Broggini, L. Garanti, G. Molteni and T. Pilati, Tetrahedron Asym., 2001, 12, 1201-1206; V. Santagada, E. Perissutti, F. Fiorino, B. Vivenzio and G. Caliendo, Tetrahedron Lett. 2001, 42, 2397-2400].

Closest to the claimed method is a method of forming a six-membered azaheterocycle, based on the intramolecular cyclization of nitrene during thermolysis or thermophotolysis of the azido group, used in the synthesis of such natural compounds as pyridoacridine alkaloids and their analogues [N.M. Ali, Sh. K. Chattopadhyay, A. McKillop, R. M. Perret-Gentil, T. Ozturk and R.A. Rebelo, Chem. Soc. Chem. Commun., 1992, 1453-1454; G. Gellerman, A. Rudi and Y. Kashman, Tetrahedron Lett., 1992, 33, 38, 5577-5580; Ciufolini, M.A .; Shen, Y. - C .; Tetrahedron Lett., 1995, 36, 27, 4709-4712].

The objective of the invention is to develop a method for producing alkyl 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylates.

The technical result is the formation of a new previously undescribed heterocyclic system - 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine - as a result of thermal decomposition of the azido group of alkyl 3-azidothieno [2,3-6] pyridin-2-carboxylates and intramolecular cyclization of the formed nitrene.

The technical result is achieved by the fact that in the method for producing alkyl 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylates of the general formula I,

Where

1a Ar = Ph, R = H, R ′ = Et; 1b Ar = 4-CH ₃ O — C ₆ H ₄ , R = CH ₃ , R ′ = Et;

1c Ar = 4-CH ₃ -C ₆ H ₄ , R = CH ₃ , R ′ = Am;

1 g Ar = 4-CH ₃ -C ₆ H ₄ , R = CH ₃ O, R ′ = Et;

1d Ar = Ph, R = H, R ′ = Am,

comprising the formation of a heterocyclic system of 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine as a result of thermal decomposition of the azido group of the alkyl 3-azidothieno [2,3-b] pyridine-2-carboxylates and intramolecular cyclization of the formed nitrene; the reaction is carried out by boiling these compounds in chlorobenzene for 30-60 minutes

In the proposed method for the preparation of derivatives of 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridines I, the synthesized readily available alkyl 3-azidothieno [2,3-b] pyridin-2- carboxylates 2a-d, which are obtained as a result of sequential diazotization and azidation reactions of the corresponding 3-aminothieno [2,3-b] pyridine-2-carboxylates 3a-d according to a procedure similar to that given in [E.A. Kanishcheva, V.K. Vasilin, D.R. Kasimova, T.A. Stroganova, G.D. Krapivin, CHC, 2012, 12, 2005-2008].

The choice of a high boiling aromatic hydrocarbon (chlorobenzene) as a solvent allows one to achieve the temperature necessary for the thermal decomposition of the azido group, and also contributes to a good dissolution of the starting materials.

All of the above helps the reaction, minimizes undesirable side reactions and achieves complete conversion of the starting materials 2a-d to alkyl 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylates 1a -d for 30-60 minutes without significant resinification of the starting materials and reaction products, which in turn reduces losses during purification and contributes to high yields of target products.

Based on the obtained experimental data, it was found that, during thermal decomposition of azides 2a-d upon boiling in chlorobenzene, the yields of alkyl 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylates 1a-d reach 49-57%, and the duration of the process is from 30 to 60 minutes

Thus, the set of essential features set forth in the claims, allows to achieve the desired technical result.

The individuality and structure of the synthesized compounds 1a-d were confirmed by ¹ H and ¹³ C NMR spectroscopy and elemental analysis.

The starting alkyl 3-azidothieno [2,3-b] pyridines 2a-d were obtained by sequential diazotization and azidation reactions of the corresponding alkyl 3-aminothieno [2,3-b] pyridin-2-carboxamides 3a-d with yields from 90 to 93% Physico-chemical characteristics of compounds 2a-e are given in table 1.

Below are the methods for the synthesis of starting azides 2a-d and examples of the implementation of the proposed method for the production of alkyl 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylates Ia-d.

Example 1

Synthesis of alkyl 3-azidothieno [2,3-b] pyridine-2-carboxylates (2a-d) (general procedure)

To a solution of 10 mmol of compound 3a-d in 75 ml of CH ₃ COOH, 0.52 ml (10 mmol) of H ₂ SO _{4 was} added with stirring. The mixture is cooled to 7-10 ° C, a solution of 1.02 g (15 mmol) of NaNO ₂ in 2 ml of water is added, stirred for 15 minutes, the excess HNO _{2 is} neutralized with urea and a solution of 0.96 g (15 mmol) of NaN ₃ in 2 is added ml of water. After 30 minutes, the mass is poured into 200 ml of water, the precipitate formed is filtered off, washed thoroughly with water and dried in a vacuum desiccator. The yields of azides 2a-d are 90-93%. Since azides 2 are very unstable compounds, they are used in the next step without further purification.

The melting point and spectral characteristics of the products 2a-e are shown in table 1.

Example 2. Synthesis of ethyl 2-phenyl-6H-benzo [c] thieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylate (1a)

A solution of 1.2 g (3 mmol) of azide 2a in 100 ml of anhydrous chlorobenzene is boiled for 30 minutes until gas evolution ceases and the starting material is completely consumed. Then the reaction mixture is evaporated under reduced pressure to 1/3 of the original volume. The hot solution is diluted with 10-15 ml of petroleum ether (fraction 70-100) and left to crystallize. The precipitated crystals are separated by filtration, washed with petroleum ether and recrystallized from DMF, to obtain 0.64 g (57%) of compound 1a in the form of a yellow powder with T pl. 202-203 ° C. Physico-chemical characteristics and spectral data are shown in tables 2 and 3.

Example 3. Synthesis of ethyl 8-methyl-2- (4-methoxyphenyl) -6H-benzo [c] thieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylate (1b)

Obtained by the method similar to that described in example 2, from 1.33 g (3 mmol) of compound 2b. The reaction time is 60 minutes. The yield of product 1b in the form of bright yellow crystals is 0.66 g (53%). T pl. and spectral data are shown in tables 2 and 3.

Example 4. Synthesis of amyl 8-methyl-2- (4-methylphenyl) -6H-benzo [c] thieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylate (1c)

Obtained by a method similar to that described in example 2 from 1.41 g (3 mmol) of compound 2B. The reaction time is 45 minutes. The yield of product 1c in the form of a bright yellow powder is 0.68 g (51%). T pl. and spectral data are shown in tables 2 and 3.

Example 5. Synthesis of ethyl 2- (4-methylphenyl) -8-methoxy-6H-benzo [c] thieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylate (1 g)

Obtained by a method similar to that described in example 2 from 1.33 g (3 mmol) of compound 2g. The reaction time is 50 minutes. The yield of product 1 g in the form of bright yellow crystals is 0.71 g (57%). T pl. and spectral data are shown in tables 2 and 3.

Example 6. Synthesis of amyl 2-phenyl-6H-benzo [c] thieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylate (1e)

Obtained by a method similar to that described in example 2 from 1.32 g (3 mmol) of compound 2d. The reaction time is 35 minutes. The yield of product 1d in the form of bright yellow crystals is 0.61 g (49%). T pl. and spectral data are shown in tables 2 and 3.

Claims (1)

The method of producing alkyl 2-substituted 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine-5-carboxylates of the general formula I,

Where
1a Ar = Ph, R = H, R ′ = Et; 1b Ar = 4-CH ₃ O-C ₆ H ₄ , R = CH ₃ , R ′ = Et;
1c Ar = 4-CH ₃ -C ₆ H ₄ , R = CH ₃ , R ′ = Am;
1 g Ar = 4-CH ₃ -C ₆ H ₄ , R = CH ₃ O, R ′ = Et;
1d Ar = Ph, R = H, R ′ = Am,
comprising the formation of a heterocyclic system of 6H-benzothieno [2,3,4-ij] -2,7-naphthyridine as a result of thermal decomposition of the azido group of the alkyl 3-azidothieno [2,3-b] pyridine-2-carboxylates and intramolecular cyclization of the formed nitrene; the reaction is carried out by boiling these compounds in chlorobenzene for 30-60 minutes