RU2417995C1 - Method of producing 3-(2-substituted-1,3-oxazol-4-yl)pyridin-2(1h)-ones - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one derivatives of general formula 1,

, where 1a R=Br, R'=CH₂OCH₃, R"=CH₃; 1b R=H, R'=CH₂, R"=CH₃; 1c R=H, R¹=CH₂OCH₃, R"=Ph; 1d R=H, R'=CH₃, R"=Ph; 1e R=Br, R=CH₃, R" - fur-2-yl, which can be used as potential biologically active substances and intermediate products for synthesis of novel heterocyclic systems. The method of producing 3 -(2-substituted-1,3 -oxazol-4-yl)pyridin-2( 1 H)-ones of general formula I involves formation of a heterocyclic system of 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one as a result of base-catalysed regrouping of 3-acylamino-2-furfurylfuro[2,3-b]pyridines while boiling said compounds in ethanol for 4-20 hours with addition of 6-7 mmol of potassium hydroxide per 1 mol of the initial 3-acylamino-2-furfurylfuro[2,3-b]pyridine.

EFFECT: high yield.

1 cl, 2 tbl, 5 ex

Description

The invention relates to the field of organic chemistry - the synthesis of heterocyclic compounds - 3- (2-substituted-1,3-oxazol-4-yl) pyridin-2 (1H) -ones, containing an aliphatic, aromatic or heteroaromatic substituent at position 2 of the oxazole ring.

The invention relates to the development of a process for the preparation of 3- (1,3-oxazol-4-yl) pyridin-2 (1H) -one derivatives of the general formula 1,

where 1a R = Br, R ′ = CH ₂ OCH ₃ , R ″ = CH ₃ ;

1b R = H, R ′ = CH ₃ , R ″ = CH ₃ ;

1c R = H, R '= CH ₂ OCH ₃ , R''=Ph;

1g R = H, R '= CH ₃ , R''=Ph;

1d R = Br, R ′ = CH ₃ , R ″ = fur-2-yl,

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

Such structures are not described in the scientific literature, therefore, the proposed method of production has no analogues.

The technical result is the formation of a new heterocyclic system not previously described - 3- (1,3-oxazol-4-yl) pyridin-2 (1H) -one, containing in the position 2 of the oxazole ring an aliphatic, aromatic or heteroaromatic substituent, as a result of which is catalyzed by base rearrangements of the corresponding 3-acylamino-2-furfurylfuro [2,3-b] pyridines.

The technical result is achieved by the fact that in the method for producing 3- (2-substituted-1,3-oxazol-4-yl) pyridin-2 (1H) -ones of the general formula I,

where 1a R = Br, R ′ = CH ₂ OCH ₃ , R ″ = CH ₃ ;

1b R = H, R ′ = CH ₃ , R ″ = CH ₃ ;

1c R = H, R '= CH ₂ OCH ₃ , R''=Ph;

1g R = H, R '= CH ₃ , R''=Ph;

1d R = Br, R ′ = CH ₃ , R ″ = fur-2-yl,

including the formation of a heterocyclic system of 3- (1,3-oxazol-4-yl) pyridin-2 (1H) -one as a result of base-catalyzed rearrangement of 3-acylamino-2-furfurylfuro [2,3-b] pyridines; the reaction is carried out by boiling these compounds in ethanol for 4-20 hours with the addition of 6-7 mmol of potassium hydroxide per 1 mmol of the starting 3-acylamino-2-furfurylfuro [2,3-b] pyridine 2a-d.

In the proposed method for the preparation of derivatives of 3- (2-substituted-1,3-oxazol-4-yl) pyridin-2 (1H) -one I, synthetically readily available 3-N-acylamino-2-furfurylfuro [2] were used as starting compounds , 3-b] pyridines 2a-d, which are obtained by alkylation of 2-alkylfuran with alcohols of the 3-aminofuro [2,3-b] pyridine series according to a procedure similar to that described in [Butin AV; Smirnov S.K., Stroganova T.A .; Bender W .; Krapivin G..D. Simple route to 3- (2-indolyl) -1-propanones via a furan recyclization reaction // Tetrahedron, 2007, 63, 474-491].

The choice of ethanol as a solvent allows one to achieve a good dissolution of both starting materials and reaction products. The use of potassium hydroxide is explained by its good solubility in ethanol, which allows the reaction to be carried out in a homogeneous system.

All of the above contributes to the reaction and allows to achieve complete conversion of the starting materials to derivatives of 3- (1,3-oxazol-4-yl) pyridin-2 (1H) -one for 4-20 hours without tarring the starting materials and reaction products during process, which in turn reduces losses during cleaning and contributes to obtaining high yields of target products.

Based on the obtained experimental data, it was found that it is optimal to carry out the reaction when boiling in ethanol with the addition of 6-7 mmol of potassium hydroxide per 1 mmol of the starting 3-acylamino-2-furfurylfuro [2,3-b] pyridine 2a-d, since this in the case, the yields of 3- (2-substituted-1,3-oxazol-4-yl) pyridin-2 (1H) -ones 1a-d reach 65-73%, and the duration of the process is from 4 to 20 hours.

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

The identity and structure of the synthesized compounds I are confirmed by ¹ H NMR spectroscopy and elemental analysis.

The starting 3-acylamino-2-furfurylfuro [2,3-b] pyridines 2 a-d were obtained by alkylation of 2-methylfuran with alcohols of the 3-acylaminofuro [2,3-b] pyridine series in yields from 74 to 83%. Physico-chemical characteristics of compounds 2a-e are given in table 1.

The following are examples of the implementation of the proposed method for producing derivatives of 3- (2-substituted-1,3-oxazol-4-yl) pyridin-2 (1H) -one1.

Example 1

To a solution of furo [2,3-b] pyridine 2a (0.483 g, 1 mmol) in 20 ml of ethanol was added 0.4 g (7 mmol) of potassium hydroxide, and the resulting mixture was refluxed for 4 hours. At the end of the reaction, the mixture was diluted with 100 ml of ice water and acidified with diluted hydrochloric acid to pH ~ 7. The precipitate formed is filtered off, washed with water and dried in air. Recrystallization from ethyl acetate-petroleum ether gave 3-oxazolylpyridone 1a as a white powder in 67% yield. The melting point and spectral characteristics of the product are shown in table 2.

Example 2

The reaction is carried out under similar conditions using 0.34 g (6 mmol) of potassium hydroxide. The reaction time is 7 hours, the yield of the target product is 65%.

Example 3

The reaction is carried out under similar conditions using 0.56 g (0.01 mol) of potassium hydroxide. The reaction time is 4 hours, yield 66%.

Example 4

To a solution of furo [2,3-b] pyridine 2a (0.483 g, 1 mmol) in 20 ml of ethanol was added 0.4 g (7 mmol) of potassium hydroxide, and the resulting mixture was kept at a temperature of 50 ° C for 30 hours. At the end of the reaction, the mixture was diluted with 100 ml of ice water and acidified with diluted hydrochloric acid to pH ~ 7. The precipitate formed is filtered off, washed with water and dried in air. After recrystallization from ethyl acetate-petroleum ether, 3-oxazolylpyridone 1a is obtained in the form of a white powder in 60% yield.

Example 5

To a solution of furo [2,3-b] pyridine 2a (0.483 g, 1 mmol) in 20 ml of butanol was added 0.4 g (7 mmol) of potassium hydroxide, and the resulting mixture was kept at boiling for 3 hours. At the end of the reaction, the mixture is poured into 150 ml of water, acidified with dilute hydrochloric acid to pH ~ 7 and left overnight. The product is released as butanol evaporates. The resulting substance was separated by filtration, washed with water and recrystallized from a mixture of ethyl acetate - petroleum ether, passing a hot solution through a layer of silica gel. The yield of 3-oxazolylpyridone 1a as a white powder is 47%.

As follows from the above examples, the yield of the product is greatly influenced by the temperature of the process and the amount of potassium hydroxide used. At low temperatures, the conversion of furopyridine → oxazolylpyridone proceeds slowly, while an increase in temperature due to the use of a higher boiling solvent (butanol) leads to undesirable side reactions, which, due to large losses during purification, reduces the yield of the target product.

At the same time, the use of smaller amounts of potassium hydroxide in the reaction increases the duration of the process, which also causes a decrease in the yield of the target product due to side processes occurring during the reaction.

Thus, the best option is to carry out the reaction by boiling 3-acylaminofuro [2,3-b] pyridine 2a in ethanol in the presence of 7 mmol potassium hydroxide per 1 mmol of compound 2a, since in this case the yield of 5-bromo-4- (methoxymethyl) -6-methyl-3- {2-methyl-5 - [(5-methyl-2-furyl) (phenyl) methyl] -1,3-oxazol-4-yl} pyridin-2 (1H) -one (1a ) reaches 67%, and the duration of the process is 4 hours.

The inventive method obtained a number of 3-oxazolylpyridones 1b-d, for which table 2 shows the duration of the reaction, yields, melting points and spectral characteristics.

Claims (1)

The method of obtaining 3- (2-substituted-1,3-oxazol-4-yl) pyridin-2 (1H) -ones of the general formula I

where 1a R = Br, R '= CH ₂ OCH ₃ , R''= CH ₃ ;
1b R = H, R ′ = CR ₃ , R ″ = CH ₃ ;
1c R = H, R '= CH ₂ OCH ₃ , R''=Ph;
1g R = H, R '= CH ₃ , R''=Ph;
1d R = Br, R ′ = CH ₃ , R ″ = fur-2-yl,
including the formation of a heterocyclic system of 3- (1,3-oxazol-4-yl) pyridin-2 (1H) -one as a result of base-catalyzed rearrangement of 3-acylamino-2-furfurylfuro [2,3-b] pyridines and the reaction is carried out by boiling of these compounds in ethanol for 4-20 hours with the addition of 6-7 mmol of potassium hydroxide per 1 mmol of starting 3-acylamino-2-furfurylfuro [2,3-b] pyridine.