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Preparation method of 3, 4-dihydropyrimidine-2-ketone derivative through high-efficient catalyzation of ethyl alcohol promoted titanocene dichloride

A technology of titanocene dichloride and dihydropyrimidine, which is applied in the field of efficient preparation of 3,4-dihydropyrimidin-2-one derivatives, and can solve complex catalyst preparation process, tedious experimental process, narrow substrate application range, etc. problems, to achieve the effect of stable air, less dosage, and simple operation

Active Publication Date: 2017-05-10
SHAANXI NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are always some places that need to be further improved in the existing methods, such as the use of strong acids or highly toxic catalysts, cumbersome and complicated experimental procedures, lack of universality, and too severe reaction conditions, etc. Specifically, Liu-Zhu Gong et al. As a catalyst, BINOL-chiral phosphoric acid can effectively catalyze the reaction of aldehyde, β-diketone and urea to synthesize 3,4-dihydropyrimidin-2-one derivatives with a yield of 54% to 95%. However, in this reaction The time is too long, the preparation process of the catalyst is complicated and the dosage is large, the applicable scope of the substrate is narrow, and the reaction requires toxic organic solvents

Method used

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  • Preparation method of 3, 4-dihydropyrimidine-2-ketone derivative through high-efficient catalyzation of ethyl alcohol promoted titanocene dichloride
  • Preparation method of 3, 4-dihydropyrimidine-2-ketone derivative through high-efficient catalyzation of ethyl alcohol promoted titanocene dichloride
  • Preparation method of 3, 4-dihydropyrimidine-2-ketone derivative through high-efficient catalyzation of ethyl alcohol promoted titanocene dichloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Preparation of 5-ethoxyformyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2-one of the following structural formula

[0013]

[0014] Add 0.0250 g (0.1 mmol) titanocene dichloride, 102 μL (1 mmol) benzaldehyde, 128 μL (1 mmol) ethyl acetoacetate, 0.120 g (2 mmol) urea, 4 mL ethanol to a 50 mL Shrek tube, and stir at 70 °C Reacted for 10 hours, stopped the reaction, added 15mL of dichloromethane, removed the dichloromethane by rotary evaporation, separated with a silica gel column (the eluent was a mixture of ethyl acetate and sherwood oil in a volume ratio of 1:1), and obtained 5- Ethoxyformyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2-one, its yield is 93%, and the spectral data of the product are: 1 H NMR (400MHz, DMSO) δ9.19(s,1H),7.74(s,1H),7.34–7.29(m,2H),7.24(d,J=6.9Hz,3H),5.15(d,J= 3.1Hz, 1H), 3.98(q, J=7.1Hz, 2H), 2.25(s, 3H), 1.09(t, J=7.1Hz, 3H); 13 C NMR (101 MHz, DMSO) δ 165.39, 152.26, 148.38, 144.92, 128.42, 127.30, 126.31, 99.35, 59.31, 54.06, 17.83, 14.09....

Embodiment 2

[0020] Preparation of 4-(4-chlorophenyl)-5-ethoxyformyl-6-methyl-3,4-dihydropyrimidin-2-one of the following structural formula

[0021]

[0022] In Example 1, the benzaldehyde used is replaced with equimolar 4-chlorobenzaldehyde, and other steps are the same as in Example 1 to obtain 4-(4-chlorophenyl)-5-ethoxyformyl-6-methanol Base-3,4-dihydropyrimidin-2-one, its yield is 81%, and the spectral data of product is: 1 H NMR (400MHz, DMSO) δ9.29(s, 1H), 7.81(s, 1H), 7.37(d, J=8.3Hz, 2H), 7.28(d, J=8.3Hz, 2H), 5.19(d , J=2.4Hz, 1H), 3.98(dd, J=12.4, 6.5Hz, 2H), 2.28(s, 3H), 1.08(t, J=7.0Hz, 3H); 13 C NMR (101 MHz, DMSO) δ 165.31, 152.22, 148.76, 143.88, 131.98, 128.38 (d, J=14.7 Hz), 99.04, 59.36, 53.63, 17.91, 14.11.

Embodiment 3

[0024] Preparation of 4-(4-bromophenyl)-5-ethoxyformyl-6-methyl-3,4-dihydropyrimidin-2-one of the following structural formula

[0025]

[0026] In Example 1, the benzaldehyde used is replaced with equimolar 4-bromobenzaldehyde, and other steps are the same as in Example 1 to obtain 4-(4-bromophenyl)-5-ethoxyformyl-6-methanol Base-3,4-dihydropyrimidin-2-one, its yield is 90%, and the spectral data of product is: 1 H NMR (400MHz, DMSO) δ9.30(s, 1H), 7.81(s, 1H), 7.51(d, J=8.0Hz, 2H), 7.23(d, J=8.2Hz, 2H), 5.17(d ,J=12.4Hz,1H),3.98(dd,J=13.2,6.4Hz,2H),2.28(s,3H),1.08(t,J=6.9Hz,3H); 13 C NMR (101 MHz, DMSO) δ 165.30, 152.24, 148.75, 144.29, 131.38, 128.68, 120.48, 99.00, 59.38, 53.71, 17.94, 14.13.

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Abstract

The invention discloses a preparation method of 3, 4-dihydropyrimidine-2-ketone derivative through high-efficient catalyzation of ethyl alcohol promoted titanocene dichloride. The method takes aromatic aldehyde, beta-diketone and urea as raw material, takes ethanol as solvent and accelerant, and takes titanocene dichloride as catalyst; under the synergistic promotion effect of ethanol, titanocene dichloride can efficiently prepare 3, 4-dihydropyrimidine-2-ketone derivative with high yield. The catalyst is less in dosage, low in price, toxic free, stable in air; the reaction condition is gentle, time is short, and operation is simple, and atom economy is high; after finishing the reaction, the 3, 4-dihydropyrimidine-2-ketone derivative can be obtained through performing simple column chromatography isolation on products, thus the preparation method opens a new low-cost, green and high-efficient way for the preparation of the 3, 4-dihydropyrimidine-2-ketone derivative, and has an extensive application prospect.

Description

technical field [0001] The invention relates to a method for efficiently preparing 3,4-dihydropyrimidin-2-one derivatives through ethanol-catalyzed reaction of aromatic aldehyde, β-diketone and urea by promoting titanocene dichloride. Background technique [0002] 3,4-dihydropyrimidin-2-one derivatives have a wide range of pharmacological activities, such as calcium antagonists, antihypertensive agents, etc., in anti-allergy, anti-cancer, anti-tumor, anti-inflammatory, anti-hypertensive, Microbial and antifungal aspects show good activity. For example, the Eg5 inhibitor (monastrol) with sustained release effect, the drug MAL3-101 with anticancer effect, and the guanidine alkaloid (Batzelladine B) with strong antiviral, antifungal and anticancer activities, etc. 3,4-Dihydropyrimidin-2-one derivatives. [0003] At present, the catalysts used to prepare 3,4-dihydropyrimidin-2-one derivatives are CoCl·6H 2 O, NiCl 2 ·6H 2 O, ionic liquid, indium tribromide, solid acid, etc....

Claims

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Application Information

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IPC IPC(8): C07D239/22
CPCC07D239/22
Inventor 高子伟郑绍华罗艳龙张伟强徐珊杨明明孙华明张国防
Owner SHAANXI NORMAL UNIV
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