Method of obtaining 2-oxo-4-cyano-1,2-dihydropyridine-3-carboxamides

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining 2-oxo-4cyano-1,2-dihydropyridine-3-carboxamides of general formula , where R1+R2=(CH2)4, (CH2)5, (CH2)6, (CH2)2CH(CH3)CH2, (CH2)2CH[C(CH3)3]CH2, which lies in the following: respective 4-oxoalkane-1,1,2,2-tetracarbonitryl is dissolved in inert organic solvent, 25 mmole of water per 1 mmole of initial component are added, after which reaction mass is heated for 1.5-2 hours at 75-80°C until target product is formed.

EFFECT: described is method of obtaining novel compounds, which can find application as medications for prevention and treatment of pellagra, hyperlipemia, spasm of peripheral vessels, stenocardia, as well as central nervous system stimulators.

 

The invention relates to the field of organic chemistry, in particular to the field of production of functionally substituted 1H-pyrid-2-ones, particularly to obtain 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamido

where R1+R2=(CH2)4, (CH2)5, (CH2)6, (CH2)2CH(CH3)CH2, (CH2)2CH[C(CH3)3]CH2that may find application as pharmaceuticals for the prevention and treatment of pellagra, hyperlipidemia, spasm of peripheral vessels, angina, as well as stimulating the Central nervous system.

Known methods for producing substituted 2-oxo-1,2-dihydropyridines-3-carboxamides by reacting substituted aldehydes and ketones with methylene-active compounds, which are malongane [New Cardiotonic Agents Related to Amrinone: Synthesis of 1,2-Dihydro-5-arylpyridin-2-on. Gomez-Parra, V.; Carmen Gomez, M. del; Sanchez, Felix; Stefani, V.; Archiv der Pharmazie (Weinheim, Germany); vol.325; nb.8; (1992); p.483-490; FeCl3-Promoted [3+3] Cycloaddition: Efficient Preparation of 1,2-Dihydro-2-oxo-3-pyridinecarboxylate and 1,2-Dihydro-2-oxo-3-pyridinecarboxamide. Derivatives Li, Shuheng; Wang, Shaozhong; Journal of Heterocyclic Chemistry; vol.45; nb.6; (2008); p.1875-1878] and cyanoacetamide [Rapid microwave-assisted solution phase synthesis of substituted 2-pyridone libraries. Gorobets, Nikolay Yu.; Yousefi, Behrooz H.; Belaj, Feminand; Kappe, C.Oliver; Tetrahedron; vol.60; nb.39; (2004); p.8633-

8644].

Similar transformations are observed in the interaction of 3-dimethylamino--(4-pyridinyl)-2-propen-1-ylidenemethyl chloride with sodium hydroxide [US 4264609 A61K 31/44; A61K 31/4409; A61P 9/04; C07D 213/53; C07D 213/82; C07D 213/84; C07D 213/85; (IPC1-7): A61K 31/44; C07D 213/53. N-[3-Dimethylamino-2-(4-pyridinyl)-2-propenylidene]-N-methylmethaniminium chloride hydrochloride, its use in preparing 5-(cyano or carbamyl)-[3,4'-bipyridin]-6(1H)-one and its use as a cardiotonic].

Also known is a method of obtaining 4-amino-6-hydroxy-2-oxo-1,2-dihydropyridines-3-carboxamide in the intramolecular cyclization of 3-amino-2-CANopen-2-endemica (dimer of malononitrile) under the action of concentrated hydrochloric acid [Synthesen mit Nitrilen. Junek; Schmidt; Monatshefte flier Chemie; vol.98; nb.3; (1967); p.1097].

To obtain 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide authors [4-Hidroxy-2-quinolones. 4. Selection of the optimum path for synthesis of N-R-substituted 4-hydroxy-2-quinolone-3-carboxylic acid avides. Ukrainets, I.V.; Bezuglyi, P.A.; Treskach, V.I.; Turov, A.V.; Chemistry of Heterocyclic Compounds (New York, NY, United States); vol.28; nb.5; (1992); p.538-540] also used an intramolecular cyclization. The catalyst in this case are different grounds, and as the parent compound is ethyl 2-(3-ethoxy-3-oxopropyl)benzoate.

2-Oxo-1,2-dihydropyridin-3-carboxamide you can get and decomposition of more complex structure of compounds. Thus, the authors of [Acetals of lactams and acid amides. 40. Synthesis and hydrolytic cleavage of one-ring and two rings derivatives of 4-pyrimidinone. Granik, V.G.; Grizik, S.I.; Kiselev, S.S.; Chistyakov, V.V.; Anisimova, O.S.; Solov'eva, N.P.; Chemistry of Heterocyclic Compounds (New York, NY, United States); vol.20; nb.4; (1984); p.434-439] managed to get 4 benzylamino-2-oxo-1,2-dihydropyridines-3-carboxamide in the decyclization of boiling 1 benzil the Rideau[4,3-d]pyrimidine-4,5(1H,6N)-dione with ethylene glycol with a small amount of water in for 5 hours.

When attempting to obtain a silver salt tetracyanoethylene acetone authors [Koordinationspolymere aus Silber (1)- und Kupfer (1)-Ionen und einem anionischen Acetonyl-Derivat von Tetracyanethylen. Carlucci, Lucia; Ciani, Gianfranco; Proserpio, Davide M.; Sironi, Angelo; Angewandte Chemie; vol.108; nb.10; (1996); p.1170-1172] failed to allocate 6-methyl-2-oxo-1,2-dihydropyridines-3,4-dicarboxamide. The reaction was carried out in a mixture of acetone-water when using tetracyanoethylene and silver triflate.

A method of obtaining derivatives of 3-carbarnoyl-2-pyridone by boiling ketones with amines and subsequent addition of diethylethoxymethylenemalonate (dimethylethoxysilane) [EN 2392271 C07D 213/82; C07D 213/85; C07D 215/54; C07D 215/56; C07D 221/16; C07D 401/06; C07D 401/12; C07D 405/06; C07D 405/12; C07D 409/12; C07D 413/12; C07D 417/12; C07D 491/052; C07D 495/04; A61K 31/4365; A61K 31/4412; A61K 31/4439; A61K 31/455; A61K 31/55; A61K 31/5377; A61K 31/496; A61K 31/506; A61K 31/517; A61K 31/5375; A61K 31/452; A61P 17/00. 20;06.2010].

A method of obtaining N-benzyl-N-phenyl-4,6-dimethyl-2-chloropyridin-3-carboxamide, showing astragulus activity during 4-4,5 hours by stirring at a room temperature solution of the acid chloride 4-methyl-2,6-dichloro-picatinney acid, N-benzylaniline and triethylamine in anhydrous benzene [EN 2408582, C07D 213/82; A01N 43/40; A01P 21/00 10.01.2011].

The main drawback of all the above methods is that they do not allow to obtain 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamide.

The objective of the invention is one which by the development of a method of obtaining a previously unknown alkyl substituted 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamido, which can find application as pharmaceuticals for the prevention and treatment of pellagra, hyperlipidemia, spasm of peripheral vessels, angina, as well as stimulants of the Central nervous system.

The technical result is to develop a method of obtaining not previously described in the literature 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamide.

The technical result is achieved in that a method of obtaining 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamido General formula (1)

where R1+R2=(CH2)4, (CH2)5, (CH2)6, (CH2)2CH(CH3)CH2, (CH2)2CH[C(CH3)3]CH2,

according to the invention is characterized by the fact that the corresponding 4-oxolan-1,1,2,2-tetracarboxylic dissolved in an inert organic solvent, is added 25 mmol of water per 1 mmol of the source component, after which the reaction mass is heated for 1.5-2 hours at 75-80°C before the formation of the target product.

Comparative analysis of the proposed solutions with known shows that the means of obtaining 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamido not described in literature. The starting components used 4-oxolan-1,1,2,2-tetracarboxylate, and as a reagent - water, which increases ekologiczne the ü and availability of this method.

The invention is represented in the examples:

Example 1. The method of obtaining 2-oxo-4-cyano-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

1.5 g (7 mmol) of 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylate dissolved in 3 ml of cyclohexanone. Then the reaction mass was added 3.2 ml (178 mmol) of water, after which the mixture is stirred for 1.5-2 hours at 75-80°C and the precipitate discarded. The reaction mass is then cooled, the precipitated precipitate 2-oxo-4-cyano-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide was filtered and washed with 5 ml of ethyl acetate. Control over the completeness of the reaction is carried out by thin layer chromatography on Silufol UV-254 plates, the manifestation takes place under UV light, iodine vapours and thermal decomposition. Yield 59%, TPL 237-238°C (decomp.). An NMR spectrum1H (DMSO-d6), δ, ppm; J, Hz: 12.85 (1H, NH), 9.03 (1H, CONH2), 7.79 (1H, J=2.9 CONH2), 2.64-2.61 m (2H, CH2), 2.59-2.56 m (2H, CH2), 1.75-1.69 (m 4N, (CH2)2). Range of IR, cm-1: 1669 (C=O), 2225 (C≡N), 3190-3300 (NH), 3371 (NH), 3480 (NH). Mass spectrum, m/z (IRel., %): 217(69).

Example 2. The method of obtaining 2-oxo-4-cyano-2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridine-3-carboxamide

The method is similar to method 1, instead of 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylate is 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylic. The yield was 73%, TPL 250-251°C (decomp.). An NMR spectrum1H (DMSO-d6), δ, MD.; J, Hz: 12.98 (1H, NH), 8.98 (1H, CONH2), 7.73 (1H, CONH2), 2.87-2.85 m (4H, (CH2)2), 1.80-1.73 m (2H, CH2), 1.63-1.53 (m 4N, (CH2)2). Range of IR, cm-1: 1682 (C=O), 2222 (C≡N), 3180 (NH), 3325 (NH). Mass spectrum, m/z (IRel., %): 231 (40).

Example 3. The method of obtaining 2-oxo-4-cyano-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxamide

The method is similar to method 1, instead of 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylate is 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylic. Yield 71%, TPL 258-259°C (decomp.). An NMR spectrum1H (DMSO-d6), δ, ppm; J, Hz: 12.98 (1H, NH), 8.99 (1H, CONH2), 7.72 (1H, CONH2), 2.87-2.83 m (4H, (CH2)2), 2.53-2.51 (m 2H, CH2), 1.81-1.74 m (6H, (CH2)3). Range of IR, cm-1: 1677 (C=O), 2183 (C≡N), 3163 (NH), 3325 (NH). Mass spectrum, m/z (IRel., %): 245 (2).

Example 4. The way to obtain 6-methyl-2-oxo-4-cyano-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

The method is similar to method 1, instead of 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylate used 1-(5-methyl-2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylic. Yield 62%, TPL 244-245°C (decomp.). An NMR spectrum1H (DMSO-d6), δ, ppm; J, Hz: 12.86 (1H, NH), 9.02 (1H, CONH2), 7.77 (1H, J=2.92 CONH2), 2.76-2.70 DD (1H,3J=16.3,4J=5.1 CH), 2.69-2.65 (m 2H, CH2), 2.16-2.09 DD (1H,3J=16.3,4J=10.3 CH2), 1.83-1.76 (m 2H, CH2), 1.38-1.28 m (1H, CH2), 1.04 (3H, J=6.5 CH3). Range of IR, cm-1 : 1688 (C=O), 2220 (C≡N), 3248 (NH), 3372 (NH), 3464 (NH). Mass spectrum, m/z (IRel., %): 231 (9).

Example 5. The way to obtain 6-tert-butyl-2-oxo-4-cyano-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

The method is similar to method 1, instead of 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarbonyl used 1-(5-tert-butyl-2-oxocyclohexyl)ethane-1,1,2,2-tetracarboxylic. Yield 65%, TPL 268-269°C (decomp.). An NMR spectrum1H (DMSO-d6), δ, ppm; J, Hz: 12.85 (1H, NH), 9.02 (1H, CONH2), 7.76 (1H, J=2.6 CONH2), 2.72 (3H, J=3.3V CHCH2), 2.28-2.19 m (1H, CH2), 1.96-1.92 m (1H, CH2), 1.45-1.37 m (1H, CH2), 1.29-1.21 m (1H, CH2), 0.93 (9H, C(CH3)3). Range of IR, cm-1: 1678 (C=O), 2223 (C≡N), 3240 (NH), 3369 (NH), 3458 (NH). Mass spectrum, m/z (IRel., %): 273 (16).

Thus, the proposed method allows to obtain not described in the literature 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamide, which may find application as pharmaceuticals for the prevention and treatment of pellagra, hyperlipidemia, spasm of peripheral vessels, angina, as well as stimulants of the Central nervous system.

The method of obtaining 2-oxo-4-cyano-1,2-dihydropyridines-3-carboxamido General formula (1)

where R1+R2=(CH2)4, (CH2)5, (CH2)6, (CH2)2CH(CH3)CH2, (CH2)2CH[C(CH3)3]CH2characterized in that that the corresponding 4-oxolan-1,1,2,2-tetracarboxylic dissolved in an inert organic solvent, is added 25 mmol of water per 1 mmol of the source component, after which the reaction mass is heated for 1.5-2 h at 75-80°C before the formation of the target product.



 

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