CN103113308A - Method for preparing dihydropyrimidinone derivative - Google Patents

Abstract

The invention discloses a method for preparing a dihydropyrimidinone derivative. The method comprises the following steps of: taking iodine as a catalyst, stirring and reacting 1-alkyl urea and aromatic aldehyde in an organic solvent at room temperature for 30 minutes, adding fatty aldehyde for stirring, refluxing and reacting for 5-15 hours, and purifying to obtain the dihydropyrimidinone derivative. The method is mild in reaction conditions, simple in process and convenient to operate; and the obtained dihydropyrimidinone derivative has potential high biological activity and can serve as an organic synthesis intermediate.

Description

A method for preparing dihydropyrimidinone derivatives

technical field

The invention relates to a method for preparing dihydropyrimidinone derivatives.

Background technique

Dihydropyrimidone derivatives are heterocyclic molecules with important biological activities, which can be used as important intermediates in fine chemical products and medicines; studies have found that dihydropyrimidone derivatives have many pharmacological activities, see ( Eur. J. Med. Chem. 2000 , 35 , 1043; Science , 1999 , 286 , 971; J. Med. Chem. , 1995 , 38 , 119; Molecules 2000 , 5 , 227; Molecules 1998 , 3 , 1 ; . Chem. 2010 , 45 , 367). Examples of which have been developed into drugs are ( S )-Monastrol, ( S )-L-771688 and ( S )-SQ 32926, etc., see ( Chem. Biol ., 2002, 9 , 989; J. Med. Chem. , 2000, 43 , 2703; Nat. Med. , 2002, 8 , 825; J. Med. Chem. , 1991, 34 , 806.).

Using acetoacetate, aldehyde and urea as raw materials, the synthesis of dihydropyrimidinone derivatives by the Biginelli method is the most classic ( Gazz. Chim. Ital. 1893 , 23 , 360 ). Active methylene compounds instead of acetoacetate participate in Biginelli-type reactions to prepare novel dihydropyrimidinone derivatives, see ( Tetrahedron Lett. 2003 , 44 , 4559; Tetrahedron Lett. 2004 , 45 , 7951; Helv. Chim . Acta 2005 , 88 , 2996; Tetrahedron 2007 , 63 , 1981; Tetrahedron Lett. 2009 , 50 , 1622; Chem . Commun. 2007 , 2932 ; J. Org . Chem. 2768). Since the multi-substituted dihydropyrimidinone derivatives have high biological activity and can often be used as important intermediates in organic synthesis, further development of efficient preparation methods for novel dihydropyrimidinone derivatives will be useful for new drug screening and the like. Significance.

Contents of the invention

The object of the present invention is to provide a method for preparing dihydropyrimidinone derivatives with mild reaction and easy operation.

In the method for preparing dihydropyrimidinone derivatives of the present invention, the preparation process is to use iodine as a catalyst, first make 1-alkylurea and aromatic aldehyde stir and react at room temperature for 30 minutes in an organic solvent, and then add aliphatic aldehyde and stir Refluxing reaction for 5-15 hours, after purification process to obtain dihydropyrimidinone derivatives, the molar ratio between said 1-alkylurea, aromatic aldehyde, fatty aldehyde and iodine is 1:1～1.5:1:0.01～ 0.1;

The reaction formula is:

；

;

In the formula: R ¹ is selected from C ₁ ~ C ₄ alkyl, R ² is selected from C ₁ ~ C ₈ alkyl or aryl, R ³ is selected from H, halogen, nitro, cyano, trifluoromethyl , C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. The organic solvent is acetonitrile, tetrahydrofuran, toluene, xylene, 1,2-dichloroethane or 1,4-dioxane.

Compared with existing synthetic methods, the present invention has the following advantages:

1) Mild reaction conditions;

2) Strong versatility of response;

3) Feeding and post-processing are very simple;

4) It does not require metal catalysis, and the use of iodine catalysis can accommodate more substituents, especially acid-sensitive groups.

Specific implementation method

The following examples will help to understand the present invention, but are not limited to the content of the present invention:

Example 1

Dissolve p-nitrobenzaldehyde (15 mmoles), 1-methylurea (10 mmoles) and iodine (1 mmoles) in acetonitrile (20 milliliters), and after fully stirring for 30 minutes, add phenylacetaldehyde (10 millimoles), heated to reflux for 10 hours, the reaction was completed, diluted with ethyl acetate, washed with sodium thiosulfate solution, washed with water, dried the organic phase and recovered the solvent under reduced pressure and concentrated to dryness, and the concentrated mixture was purified by silica gel column chromatography , to obtain 1-methyl-4-(4-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1hydrogen)-one as a yellow solid in 72% yield; product physical data Melting point 186-188 ^o C; IR(neat) ν 3250, 1682, 1651, 1519, 1497, 1455, 1403, 1270, 818, 736, 732, 700 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ =8.13 (d, J = 8.7 Hz, 2 H), 7.46 (d, J = 8.7 Hz, 2 H), 7.26-7.12 (m, 5 H), 6.55 (s, 1 H), 6.14 (s, 1 H), 5.60 (d, J = 2.6 Hz, 1 H), 3.20 (s, 3 H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ= 153.24, 149.21, 147.53, 135.30, 128.78, 127.95, 127.65, 127.06, 124.86, 124.21, 112.81, 57.34, 34.79 ppm. HRMS (EI): m/z calcd for (C ₁₇ H ₁₅ N ₃ O ₃ ): 309.1113; found: 309.1111.

Example 2

Dissolve p-cyanobenzaldehyde (12 mmoles), 1-methylurea (10 mmoles) and iodine (0.8 mmoles) in acetonitrile (15 milliliters), and after fully stirring for 30 minutes, add phenylacetaldehyde (10 millimoles), heated to reflux for 12 hours, the reaction was completed, diluted with ethyl acetate, washed with sodium thiosulfate solution, washed with water, dried the organic phase and recovered the solvent under reduced pressure and concentrated to dryness, and the concentrated mixture was purified by silica gel column chromatography , to obtain 1-methyl-4-(4-cyanophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1hydrogen)-one as a white solid in a yield of 68%; product physical data IR(neat) ν 3249, ²⁹²⁵ , 2228, 1679, 1603, 1498, 1456, 1404, 1327, 1269, 1108, 765, 731, 694, 587 cm ^-1 ; ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 7.55 (d, J = 7.2 Hz, 2 H), 7.38 (d, J = 7.9 Hz, 2 H), 7.26-7.19 (m, 2 H), 7.14 (dd, J = 17.6 , 7.4 Hz, 3 H), 6.53 (s, 1 H), 6.08 (br, 1 H), 5.52 (s, 1 H), 3.17 (s, 3 H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.26, 147.33, 135.37, 132.72, 128.72, 127.90, 127.47, 126.96, 124.81, 118.44, 112.77, _{111.83 ,} 57.50, _34.72 ppm. : 289.1215; found: 289.1225.

Example 3

Dissolve p-bromobenzaldehyde (10 mmol), 1-methylurea (10 mmol) and iodine (1 mmol) in toluene (20 ml), stir the reaction for 30 minutes, then add phenylacetaldehyde (10 mmol mol), heated to reflux for 12 hours, the reaction was completed, diluted with ethyl acetate, washed with sodium thiosulfate solution, washed with water, dried the organic phase and recovered the solvent under reduced pressure and concentrated to dryness, the concentrated mixture was purified by silica gel column chromatography, 1-Methyl-4-(4-bromophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1hydrogen)-one was obtained as a yellow solid in a yield of 58%; the physical data of the product are melting points 170-172 ^o C; IR(neat) ν 3265, 1673, 1485, 1455, 1405, 1325, 1266, 1003, 754, 730, 694 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ =7.41 ( d, J = 8.3 Hz, 2 H), 7.25-7.19 (m, 2 H), 7.15 (t, J = 7.8 Hz, 5 H), 6.52 (s, 1 H), 5.56 (s, 1 H), 5.43 (d, J = 2.1 Hz, 1 H), 3.19 (s, 3 H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ =153.29, 141.39, 135.71, 132.00, 128.59, 128.47, 127.51, 126.75, 124.85, 121.93, 113.30, 57.46, 34.69 ppm. HRMS (EI): m/z calcd for (C ₁₇ H ₁₅ BrN ₂ O): 342.0368; found: 340.0211.

Example 4

Dissolve p-nitrobenzaldehyde (15 mmol), 1-methylurea (10 mmol) and iodine (1 mmol) in dichloroethane (20 ml), stir the reaction for 30 minutes, then add n-hexanal (10 mmol), heated to reflux reaction for 12 hours, the reaction was completed, diluted with ethyl acetate, washed with sodium thiosulfate solution, washed with water, dried the organic phase and recovered the solvent under reduced pressure and concentrated to dryness, and the concentrated mixture was passed through a silica gel column layer Analysis and purification, 1-methyl-4-(4-nitrophenyl)-5-butyl-3,4-dihydropyrimidin-2(1hydrogen)-one was obtained as a yellow solid with a yield of 65%; the product Physical data are melting point 121-123 ^o C; IR (neat) ν 3258, 2956, 2929, 2869, 1673, 1596, 1520, 1465, 1396, 1346, 1310, 1268, 1108, 1036, 855, 754, 697 cm ^{- 1} ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 8.6 Hz, 2 H), 7.45 (d, J = 8.6 Hz, 2 H), 5.80 (s, 1 H), 5.37 (s , 1 H), 5.02 (s, 1 H), 3.07 (s, 3 H), 1.72 (d, J = 4.5 Hz, 2 H), 1.35-1.18 (m, 4 H), 0.83 (t, J = 6.9 Hz, 3 H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.20, 149.87, 147.61, 127.81, 125.17, 124.05, 112.71, 58.95, 34.27, 29.88, 29.14, 213.10 ppm MS : m/z calcd for (C ₁₅ H ₁₉ N ₃ O ₃ ): 289.1426; found: 289.1421.

Example 5

Dissolve p-nitrobenzaldehyde (11 mmoles), 1-ethylurea (10 mmoles) and iodine (1 mmoles) in acetonitrile (20 milliliters), and after fully stirring for 30 minutes, add phenylacetaldehyde (10 millimoles), heated to reflux for 12 hours, the reaction was completed, diluted with ethyl acetate, washed with sodium thiosulfate solution, washed with water, dried the organic phase and recovered the solvent under reduced pressure and concentrated to dryness, and the concentrated mixture was purified by silica gel column chromatography , to obtain 1-ethyl-4-(4-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1hydrogen)-one as a yellow solid in a yield of 69%; product physical data IR ( ^neat ) ν 3299, 2932, 1678, 1598, 1520, 1497, 1453, 1347, 1271, 1236, 1121, 817, 757, 731, 699 cm ^-1 ; ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 8.14 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 7.4 Hz, 2 H), 7.17 (m, 3 H), 6.58 (s, 1 H), 5.97 (s, 1 H), 5.58 (s, 1 H), 3.63 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.75, 149.32, 147.49, 135.46, 128.75, 127.61, 126.99, 126.53, 124.80, 113.05, 57.12, 42.17, 14.43 ppm for m (dMS/zEpm) ₁₈ H ₁₇ N ₃ O ₃ ): 323.1270; found: 323.1270.

Claims (2)

1. A method for preparing dihydropyrimidinone derivatives, its preparation process is to use iodine as a catalyst, first make 1-alkylurea and aromatic aldehyde in an organic solvent and stir and react at room temperature for 30 minutes, then add aliphatic aldehyde and stir Refluxing reaction for 5-15 hours, after purification process to obtain dihydropyrimidinone derivatives, the molar ratio between said 1-alkylurea, aromatic aldehyde, fatty aldehyde and iodine is 1:1～1.5:1:0.01～ 0.1; The reaction formula is: ; In the formula: R ¹ is selected from C ₁ ~ C ₄ alkyl, R ² is selected from C ₁ ~ C ₈ alkyl or aryl, R ³ is selected from H, halogen, nitro, cyano, trifluoromethyl , C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. 2. The method for preparing dihydropyrimidinone derivatives according to claim 1, wherein said organic solvent is acetonitrile, tetrahydrofuran, toluene, xylene, 1,2-dichloroethane or 1,4- Dioxane.