RU2547844C1 - Method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidine, represented by the general formula :

where X=O or S, Ar=3-nitrophenyl or 2-thienyl. The described method consists in the fact that at the first stage 5-brom-4-(2-thienyl)-2-(thio)morpholylpyrimidine is obtained by interaction with the excess of 2-thienyllithium in the absolute ether at first at a temperature from -20 to -25°C for not less than 1 hour, and then at room temperature for not less than 18 hours, a solution of a mixture of potassium hexacyonoferrate (III) and potassium hydroxide in water are added with further mixing for 4 hours at room temperature, the ether phase is separated and distilled and the obtained remaining part is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate-hexane, 1:3, with (het)arylboric acid and tetrakis(triphenyphosphine)palladium(0) in tetrahydrofurane, a water solution of potassium carbonate is added and the obtained mixture is irradiated by microwave radiation at 155°C for 20 minutes, the solvent is distilled under a reduced pressure, the obtained residual is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate - hexane, 1:2 with obtaining the target product.

EFFECT: claimed is the highly-efficient two-stage method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidines, which can have a wide spectrum of biological activity.

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Description

Technical field

The present invention relates to 2-thio (morpholyl) -4,5-di (get) aryl-substituted pyrimidines, which have a wide spectrum of biological activity, for example, herbicidal and antibacterial, regulate the activity of specific proteins, such as ATON-1, which affects transcription factors and participating in the formation of neurons, affect the epidermal growth factor (EGF), which stimulates cell growth and cell differentiation of the epithelial cover, can be used in the treatment of neurodegenerative diseases itivnyh disorders and Alzheimer's disease.

The prior art:

The main way to obtain 2-thio (morpholyl) -4,5-di (get) aryl-substituted pyrimidines (3) is the condensation of (thio) morpholylcarboxamidines (1) with 1,2- (get) aryl-3-dimethylaminopropenones (2) (Scheme 1) [WO 2012/055942. Alpha-7 nicotinic receptor fort he trtreatment of pain, a psychotic disorder, cognitive impaiment or alzheimer desease. / Dean D., Lightfoot A., Roomans S.]

The disadvantages of this method are: 1) the low availability of the starting (thio) morpholylcarboxamidines (1) and 1,2- (get) aryl-3-dimethylaminopropenones (2), as a result of which their preliminary laborious multi-stage synthesis is necessary; 2) a low total yield of the final 2-thio (morpholyl) -4,5-di (get) aryl-substituted pyrimidines (3), averaging 20-40%.

There is also a method for producing 2,4,5-tri (get) aryl-substituted pyrimidines (4) by direct modification of 2-chloro-4,5-di (get) aryl-substituted pyrimidines using palladium-catalyzed reactions as with secondary amines, with the formation of the corresponding 2 dialkyl substituted 4,5,6-tripyrimidines (5) or by cross-coupling according to Suzuki with (get) arylboric acids, with the formation of the corresponding 2,4,5,6-tetra (get) aryl substituted pyrimidines (6) in organic solvent (1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, acetonitrile) at 80-100 ° C (С EMA 2) [WO 2012/172043. Purine derivatives and their use as pharmaceuticals for prevention or treatment of bacterial infections. / Denis A., Gerusz V., Ledoussal B., Bonvin Y., Desroy N., Gold J., Moreau F., Oxoby M.]. The main disadvantage of this method is the long reaction time is 16-48 hours.

Thus, existing methods are multistage, require complex preliminary synthesis of the starting compounds and a long reaction time.

Object of the invention: to synthesize compounds with biological activity, from available raw materials, in mild conditions, with a high yield.

The problem is solved in that in the first stage receive 5-bromo-4- (2-thienyl) -2- (thio) morpholylpyrimidine (10a, b) by the interaction of 5-bromo-2- (thio) morpholylpyrimidine (7a, b) with an excess of 2-thienyllithium (8) in absolute ether, first at -20 ÷ -25 ° C for at least 1 hour, and then at room temperature for at least 18 hours, add a solution of a mixture of potassium hexacyanoferrate (III) and potassium hydroxide in water and not mix less than 4 hours at room temperature, the ether phase is separated and distilled off, and the obtained residue is subjected to chromatographic separation on silica gel When the ratio in the eluent ethyl acetate-hexane 1: 3,

and in the second stage, the obtained 5-bromo-4- (2-thienyl) -2- (thio) morpholylpyrimidine is mixed with (get) arylboric acid and tetrakis (tripheniphosphine) palladium (0) in tetrahydrofuran, an aqueous solution of potassium carbonate and the resulting mixture are added irradiated with microwave radiation at 155 ° C for 20 minutes, the solvent was distilled off under reduced pressure, the obtained residue was subjected to chromatographic separation on silica gel with an ethyl acetate-hexane ratio of 1: 2 in the eluent.

The reaction of 5-bromo-2- (thio) morpholylpyrimidine (7a, b) with an excess of 2-thienyllithium (8) in absolute ether is carried out in the temperature range of -20 ÷ -25 ° C for at least 1 hour, since an increase in temperature leads to decomposition of 2-thienyllithium (8) and a sharp decrease in the yield of intermediate 5-bromo-4- (2-thienyl) -2- (thio) morpholyl-1,2-dihydropyrimidine (9a, b), in turn, the temperature decreases below - 25 ° C leads to a significant increase in the reaction time. A reaction time of 1 hour -20 ÷ -25 ° C and at least 18 hours at room temperature is sufficient for the complete addition reaction to proceed, while its decrease at any temperature also leads to a decrease in the yield of intermediate 5-bromo-4- (2-thienyl ) -2- (thio) morpholyl-1,2-dihydropyrimidine (9a, b).

After the formation of 5-bromo-4- (2-thienyl) -2- (thio) morpholyl-1,2-dihydropyrimidine (9a, b), a solution of a mixture of potassium hexacyanoferrate (III) and potassium hydroxide in water is added to the reaction mixture and not stirred less than 4 hours at room temperature, since the reaction time less than 4 hours does not completely oxidize the intermediate 5-bromo-4- (2-thienyl) -2- (thio) morpholyl-1,2-dihydropyrimidine (9a, b) to the target 5-bromo-4- (2-thienyl) -2- (thio) morpholylpyrimidine (10a, b), i.e., leads to a decrease in its yield.

The isolation of the product (10a, b) is carried out by chromatographic separation on silica gel at a ratio of 1: 3 in ethyl acetate-hexane. An increase in this ratio in favor of hexane will lead to an unreasonable consumption of solvent, while with an increase in the proportion of ethyl acetate in the eluent, selective separation of the target product (10a, b) from side impurities does not occur.

After purification in the second stage, the reaction of 5-bromo-4- (2-thienyl) -2- (thio) morpholylpyrimidine (10a, b) with (get) arylboric acid (11 or 12) proceeds at 155 ° C for 20 minutes. This temperature is optimal. A time of 20 minutes is sufficient for the reaction to proceed, an increase in time does not significantly increase the yield of the target 5- (get) aryl-4- (2-thienyl) -2- (thio) morpholylpyrimidine (I), while a decrease in time of less than 20 minutes leads to to reduce the yield of product (I).

Isolation of product (I) is carried out by chromatographic separation on silica gel with an ethyl acetate-hexane ratio of 1: 2 in the eluent. An increase in this ratio in favor of hexane will lead to an unreasonable consumption of solvent, whereas with an increase in the proportion of ethyl acetate in the eluent, selective separation of the target product (I) from side impurities does not occur.

The analysis of intermediate and target compounds is carried out using NMR spectroscopy ( ¹ H and ¹³ C NMR spectra were measured on a Bruker AVANCE ^III -500 spectrometer (500 and 126 MHz) in a solution of CDCl ₃ , internal TMS standard). The complete assignment of ¹ H and ¹³ C signals was performed using a combination of 2D experiments ¹ H- ¹ H COSY, ¹ Н- ¹³ C HSQC / НМВС), gas chromatography / mass spectrometry (Gas chromatograph-mass spectrometer Agilent GC 7890А MS 5975С Inert XL EI / CI with quadrupole mass spectrometric detector) and elemental analysis on a Perkin-Elmer PE-2400 automated analyzer.

Example 1

An excess of 2-thienyl lithium (2) 405 mg (4.5 mmol) in 20 ml of absolute ether is added to a solution of 5-bromo-2-morpholylpyrimidine (7a) 732 mg (3 mmol) in absolute ether at -30 ° C. The reaction mixture was stirred at −20 ° C. for 1 hour, then cooling was stopped and stirring was continued for another 18 hours at room temperature. Then, a solution of a mixture of potassium hexacyanoferrate (III) 2 g (6 mmol) and potassium hydroxide 1 g (18 mmol) in 20 ml of water is added to the reaction mixture and it is stirred for 4 hours at room temperature. After that, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 3). The result is 5-bromo-4- (2-thienyl) -2-morpholylpyrimidine (10a) as a beige powder.

Yield 499 mg (51%).

Mp 122-124 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 3.77 (m, 4H, OCH ₂ ); 3.82 (m, 4H, NCH ₂ ); 7.15 (dd, 1H, H (4 ′), J = 5.1, 3.9); 7.52 (dd, 1H, H (5 ′), J = 5.1, 1.1); 8.33 (dd, 1H, H (3 ′), J = 3.9, 1.1); 8.40 (s, 1H, H (6)).

¹³ C NMR Spectrum (δ, ppm): 44.35 (NCH ₂ ); 66.73 (OCH ₂ ); 101.89 (C (5)); 127.99 (C (4 ′)); 130.46 (C (5 ′)); 131.00 (C (3 ′)); 142.37 (C (2 ′)); 155.72 (C (4)), 159.55 (C (2)); 161.38 (C (6)).

Elemental analysis for C ₁₂ H ₁₂ BrN ₃ OS:

Calculated (%): C, 44.18; H, 3.71; N, 12.88.

Found (%): C, 44.11; H, 3.70; N, 12.63.

GLC: t _R = 26.01 min. Mass spectrum: (EU, 70 eV), m / z (I _rel ,%): 325 [M] ⁺ (100) for ⁷⁹ Br, 327 [M] ⁺ (100) for ⁸¹ Br.

5-Bromo-2-morpholylpyrimidine 326 mg (1 mmol) (10a) is mixed with 3-nitrophenylboronic acid (11) 200 mg (1.2 mmol) and tetrakis (tripheniphosphine) palladium (0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution is added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave at 155 ° C (250 W) for 20 minutes. After that, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 2). The result is 5- (3-nitrophenyl) -4- (2-thienyl) -2-morpholylpyrimidine (13a) as a yellow powder. Yield 258 mg (70%).

Mp 172-174 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 3.82 (m, 4H, OCH ₂ ); 3.92 (m, 4H, NCH ₂ ); 6.71 (dd, 1H, H (3 ′), J = 3.8, 1.0); 6.85 (dd, 1H, H (4 ′), J = 5.0, 3.8); 7.38 (dd, 1H, H (5 ′), J = 5.0, 1.0); 7.61 (t, 1H, H (5 ″), J = 7.9); 7.66 (dt, 1H, H (6 ″), J = 7.7, 1.5); 8.20 (s, 1H, H (4)); 8.21 (t, 1H, H (2 ″), J = 1.9); 8.27 ((ddd, 1H, H (4 ″), J = 8.1, 2.1, 1.2).

¹³ C NMR Spectrum (δ, ppm): 44.28 (NCH ₂ ); 66.85 (OCH ₂ ); 118.25 (C (5)); 122.76 (C (4 ″)); 124.67 (C (2 ″)); 127.80 (C (4 ′)); 129.74 (C (5 ′)); 128.82, 129.86 (C (5 ″), C (3 ′)); 136.14 (C (6 ″)); 139.42 (C (1 ″)); 142.60 (C (2 ′)); 148.63 (C (3 ″)); 156.51 (C (6)); 159.30 (C (4)); 160.46 (C (2)).

Elemental analysis for C ₁₈ H ₁₆ N ₄ O ₃ S:

Calculated (%): C, 58.68; H, 4.38; N, 15.21.

Found (%): C, 58.75; H, 4.28; N, 15.41.

GLC: t _R = 33.99 min. Mass spectrum: (EU, 70 eV), m / z (I _rel ,%): 368 [M] ⁺ (100).

Example 2

An excess of 2-thienyl lithium (2) 405 mg (4.5 mmol) in 20 ml of absolute ether is added to a solution of 5-bromo-2-thiomorpholylpyrimidine (7b) 780 mg (3 mmol) in absolute ether at -30 ° C. The reaction mixture was stirred at −20 ° C. for 1 hour, then cooling was stopped and stirring was continued for another 18 hours at room temperature. Then, a solution of a mixture of potassium hexacyanoferrate (III) 2 g (6 mmol) and potassium hydroxide 1 g (18 mmol) in 20 ml of water is added to the reaction mixture and it is stirred for 4 hours at room temperature. After this, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 3). The result is 5-bromo-4- (2-thienyl) -2-thiomorpholylpyrimidine (10b) as a yellow powder.

Yield 709 mg (69%).

Mp 105-107 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 2.67 (m, 4H, SCH ₂ ); 4.16 (m, 4H, NCH ₂ ); 7.15 (dd, 1H, H (4 ′), J = 5.1, 3.9); 7.52 (dd, 1H, H (5 ′), J = 5.1, 1.1); 8.33 (dd, 1H, H (3 ′), J = 3.9, 1.1); 8.39 (s, 1H, H (6)).

¹³ C NMR spectrum (δ, ppm): 26.84 (SCH ₂ ); 46.64 (NCH ₂ ); 101.47 (C (5)); 128.00 (C (4 ′)); 130.43 (C (5 ′)); 130.95 (C (3 ′)); 142.45 (C (2 ′)); 155.78 (C (4)), 159.05 (C (2)); 161.46 (C (6)).

Elemental analysis for C ₁₂ H ₁₂ BrN ₃ S ₂ :

Calculated (%): C, 42.11; H, 3.53; N, 12.28.

Found (%): 42.01; H, 3.60; N, September 12.

GLC: t _R = 27.87 min. Mass spectrum: (EU, 70 eV), m / z ( _Irel ,%): 341 [M] ⁺ (100) for ⁷⁹ Br, 343 [M] ⁺ (100) for ⁸¹ Br.

5-Bromo-2-thiomorpholylpyrimidine 342 mg (1 mmol) (10b) is mixed with 3-nitrophenylboronic acid (11) 200 mg (1.2 mmol) and tetrakis (tripheniphosphine) palladium (0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution is added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave at 155 ° C (250 W) for 20 minutes. After that, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 2). The result is 5- (3-nitrophenyl) -4- (2-thienyl) -2-thiomorpholylpyrimidine (13b) as a pale yellow powder. Yield 258 mg (67%).

Mp 163-164 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 2.72 (m, 4H, SCH ₂ ); 4.25 (m, 4H, NCH ₂ ); 6.70 (dd, 1H, H (3 ′), J = 3.9, 1.1); 6.85 (dd, 1H, H (4 ′), J = 5.1, 3.9); 7.37 (dd, 1H, H (5 ′), J = 5.1, 1.1); 7.60 (t, 1H, H (5 ″), J = 7.9); 7.66 (dt, 1H, H (6 ″), J = 7.7, 1.5); 8.18 (s, 1H, H (6)); 8.21 (t, 1H, H (2 ″), J = 1.9); 8.27 (dd, 1H, H (4 ″), J = 8.1, 2.2, 1.2).

¹³ C NMR spectrum (δ, ppm): 27.00 (SCH ₂ ); 46.52 (NCH ₂ ); 117.90 (C (5)); 122.73 (C (4 ″)); 124.68 (C (2 ″)); 127.80 (C (4 ′)); 129.70 (C (5 ′)); 129.79, 129.80 (C (3 ′), C (5 ″)); 136.14 (C (6 ″)); 139.43 (C (1 ″)); 142.69 (C (2 ′)); 148.63 (C (3 ″)); 156.57 (C (4)); 159.35 (C (6)); 160.28 (C (2)).

Elemental analysis for C ₁₈ H ₁₆ N ₄ O ₃ S:

Calculated (%): C, 58.68; H, 4.38; N, 15.21.

Found (%): C, 58.75; H, 4.28; N, 15.41.

GLC: t _R = 39.13 min. Mass spectrum: (EU, 70 eV), m / z (I _rel ,%): 384 [M] ⁺ (100).

Example 3

An excess of 2-thienyl lithium (2) 405 mg (4.5 mmol) in 20 ml of absolute ether is added to a solution of 5-bromo-2-morpholylpyrimidine (7a) 732 mg (3 mmol) in absolute ether at -30 ° C. The reaction mixture was stirred at −20 ° C. for 1.2 hours, then cooling was stopped and stirring was continued for another 19 hours at room temperature. Then, a solution of a mixture of potassium hexacyanoferrate (III) 2 g (6 mmol) and potassium hydroxide 1 g (18 mmol) in 20 ml of water is added to the reaction mixture and it is stirred for 5 hours at room temperature. After that, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 3). The result is 5-bromo-4- (2-thienyl) -2- (thio) morpholylpyrimidine (10a) as a beige powder. Yield 514 mg (53%).

Mp 122-124 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 3.77 (m, 4H, OCH ₂ ); 3.82 (m, 4H, NCH ₂ ); 7.15 (dd, 1H, H (4 ′), J = 5.1, 3.9); 7.52 (dd, 1H, H (5 ′), J = 5.1, 1.1); 8.33 (dd, 1H, H (3 ′), J = 3.9, 1.1); 8.40 (s, 1H, H (6)).

¹³ C NMR Spectrum (δ, ppm): 44.35 (NCH ₂ ); 66.73 (OCH ₂ ); 101.89 (C (5)); 127.99 (C (4 ′)); 130.46 (C (5 ′)); 131.00 (C (3 ′)); 142.37 (C (2 ′)); 155.72 (C (4)), 159.55 (C (2)); 161.38 (C (6)).

Elemental analysis for C ₁₂ H ₁₂ BrN ₃ OS:

Calculated (%): C, 44.18; H, 3.71; N, 12.88.

Found (%): C, 44.11; H, 3.70; N, 12.63.

GLC: t _R = 26.01 min. Mass spectrum: (EU, 70 eV), m / z (I _rel ,%): 325 [M] ⁺ (100) for ⁷⁹ Br, 327 [M] ⁺ (100) for ⁸¹ Br.

5-Bromo-2-morpholylpyrimidine 326 mg (1 mmol) (10a) is mixed with 2-thienylboronic boric acid (12) 154 mg (1.2 mmol) and tetrakis (tripheniphosphine) palladium (0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution is added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave at 155 ° C (250 W) for 20 minutes. After that, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 2). The result is 4,5-di (2-thienyl) -2-morpholylpyrimidine (14a) as a pale yellow powder. Yield 264 mg (80%).

Mp 158-160 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 3.81 (m, 4H, OCH ₂ ); 3.90 (m, 4H, NCH ₂ ); 6.89 (dd, 1H, H (4 ′), J = 4.9, 3.8); 6.91 (dd, 1H, H (3 ′), J = 3.8, 1.3); 7.02 (dd, 1H, H (3 ″), J = 3.5, 1.2); 7.12 (dd, 1H, H (4 ″), J = 5.2, 3.5); 7.36 (dd, 1H, H (5 ′), J = 4.9, 1.3); 7.43 (dd, 1H, H (5 ″), J = 5.2, 1.2); 8.27 (s, 1H, H (6)).

¹³ C NMR Spectrum (δ, ppm): 44.28 (NCH ₂ ); 66.86 (OCH ₂ ); 112.82 (C (5)); 126.85 (C (5 ″)); 127.58 (C (4 ″)); 127.84 (C (4 ′)); 128.14 (C (3 ″)); 129.58 (C (5 ′)); 129.95 (C (3 ′)); 138.20 (C (2 ″)); 142.83 (C (2 ′)); 157.53 (C (4)); 160.31 (C (6)); 160.72 (C (2)).

Elemental analysis for C ₁₆ H ₁₅ N ₃ OS ₂ :

Calculated (%): C, 58.33; H, 4.59; N, 12.75.

Found (%): C, 58.45; H, 4.44; N, 12.79.

GLC: t _R = 28.72 min. Mass spectrum: (EU, 70 eV), m / z (I _rel ,%): 329 [M] ⁺ (100).

Example 4

An excess of 2-thienyl lithium (2) 405 mg (4.5 mmol) in 20 ml of absolute ether is added to a solution of 5-bromo-2-thiomorpholylpyrimidine (7b) 780 mg (3 mmol) in absolute ether at -30 ° C. The reaction mixture was stirred at −20 ° C. for 1.5 hours, then cooling was stopped and stirring was continued for another 18.5 hours at room temperature. Then, a solution of a mixture of potassium hexacyanoferrate (III) 2 g (6 mmol) and potassium hydroxide 1 g (18 mmol) in 20 ml of water is added to the reaction mixture and it is stirred for 4.5 hours at room temperature. After that, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 3). The result is 5-bromo-4- (2-thienyl) -2-thiomorpholylpyrimidine (10b) as a yellow powder. Yield 739 mg (72%).

Mp 105-107 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 2.67 (m, 4H, SCH ₂ ); 4.16 (m, 4H, NCH ₂ ); 7.15 (dd, 1H, H (4 ′), J = 5.1, 3.9); 7.52 (dd, 1H, H (5 ′), J = 5.1, 1.1); 8.33 (dd, 1H, H (3 ′), J = 3.9, 1.1); 8.39 (s, 1H, H (6)).

¹³ C NMR spectrum (δ, ppm): 26.84 (SCH ₂ ); 46.64 (NCH ₂ ); 101.47 (C (5)); 128.00 (C (4 ′)); 130.43 (C (5 ′)); 130.95 (C (3 ′)); 142.45 (C (2 ′)); 155.78 (C (4)), 159.05 (C (2)); 161.46 (C (6)).

Elemental analysis for C ₁₂ H ₁₂ BrN ₃ S ₂ :

Calculated (%): C, 42.11; H, 3.53; N, 12.28.

Found (%): 42.01; H, 3.60; N, September 12.

GLC: t _R = 27.87 min. Mass spectrum: (EU, 70 eV), m / z ( _Irel ,%): 341 [M] ⁺ (100) for ⁷⁹ Br, 343 [M] ⁺ (100) for ⁸¹ Br.

5-Bromo-2-thiomorpholylpyrimidine 342 mg (1 mmol) (10b) is mixed with 2-thienylboronic boric acid (12) 154 mg (1.2 mmol) and tetrakis (tripheniphosphine) palladium (0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution is added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave at 155 ° C (250 W) for 20 minutes. After that, the solvent was distilled off on a rotary evaporator under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate-hexane, 1: 2). The result is 4,5-di (2-thienyl) -2-thiomorpholylpyrimidine (14b) as a pale yellow powder. Yield 252 mg (73%).

Mp 149-152 ° C.

¹ H NMR Spectrum (δ, ppm, J / Hz): 2.71 (m, 4H, SCH ₂ ); 4.24 (m, 4H, NCH ₂ ); 6.88-6.90 (m, 2H, H (3 ′), H (4 ′)); 7.02 (dd, 1H, H (3 ″), J = 3.5, 1.1); 7.12 (dd, 1H, H (4 ″), J = 5.1, 3.5); 7.36 (m, 1H, H (5 ′)); 7.43 (dd, 1H, H (5 ″), J = 5.1.1.1); 8.25 (s, 1H, H (6)).

¹³ C NMR Spectrum (δ, ppm): 26.98 (SCH ₂ ); 46.53 (NCH ₂ ); 112.45 (C (5)); 126.84 (C (5 ″)); 127.59 (C (4 ″)); 127.86 (C (4 ′)); 128.15 (C (3 ″)); 129.57 (C (5 ′)); 129.91 (C (3 ′)); 138.24 (C (2 ″)); 142.93 (C (2 ′)); 157.59 (C (4)); 160.26 (C (2)); 160.39 (C (6)).

Elemental analysis for C ₁₆ H ₁₅ N ₃ S ₃ :

Calculated (%): C, 55.62; H, 4.38; N, 12.16.

Found (%): C, 55.41; H, 4.45; N, 12.27.

GLC: t _R = 31.03 min. Mass spectrum: (EU, 70 eV), m / z (I _rel ,%): 345 [M] ⁺ (100).

Thus, we have proposed a new effective method for producing 4,5-di (get) aryl-2- (thio) morpholylpyrimidines, which can be useful as antibacterial compounds, as well as for the treatment of neurodegenerative diseases, cognitive disorders and Alzheimer's disease.

The advantages of this method are:

1. The ease of variation of the substituents due to the high availability of commercially available (get) arylboric acids and the ease of preparation of organolithium compounds.

2. The mild conditions of the reactions and the speed of their implementation, including through the use of microwave radiation.

3. There are only two stages of production and high yields of target products, in contrast to multi-stage (at least 3 stages) described in the literature methods for producing similar products with yields of not more than 50%.

Claims (1)

The method of obtaining 5- (get) aryl-4- (2-thienyl) -2- (thio) morpholylpyrimidine of the general formula (I)

where X = O or S, Ar = 3-nitrophenyl or 2-thienyl,
consisting in the fact that in the first stage receive 5-bromo-4- (2-thienyl) -2- (thio) morpholylpyrimidine by the interaction of 5-bromo-2- (thio) morpholylpyrimidine with an excess of 2-thienyl lithium in absolute ether, first at -20 ÷ -25 ° C for at least 1 hour, and then at room temperature for at least 18 hours, add a solution of a mixture of potassium hexacyanoferrate (III) and potassium hydroxide in water and mix for at least 4 hours at room temperature, the ether phase is separated and distilled off, and the obtained residue is subjected to chromatographic separation on silica gel at a ratio in the eluent thylacetate - hexane 1: 3, and in the second stage, the obtained 5-bromo-4- (2-thienyl) -2- (thio) morpholylpyrimidine is mixed with (get) arylboric acid and tetrakis (tripheniphosphine) palladium (0) in tetrahydrofuran, add an aqueous solution of potassium carbonate and the resulting mixture was irradiated with microwave radiation at 155 ° C for 20 minutes, the solvent was distilled off under reduced pressure, the obtained residue was subjected to chromatographic separation on silica gel with an ethyl acetate-hexane ratio of 1: 2 in the eluent.