CN103113308B - Method for preparing dihydropyrimidinone derivative - Google Patents
Method for preparing dihydropyrimidinone derivative Download PDFInfo
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- CN103113308B CN103113308B CN201310029167.6A CN201310029167A CN103113308B CN 103113308 B CN103113308 B CN 103113308B CN 201310029167 A CN201310029167 A CN 201310029167A CN 103113308 B CN103113308 B CN 103113308B
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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
Technical field
The present invention relates to a kind of method of preparing dihydro-pyrimidin ketone derivatives.
Background technology
Dihydro-pyrimidin ketone derivatives is a kind of heterocycle molecule with important biomolecule activity, can be used as fine chemical product and medical important intermediate; Research has been found that dihydro-pyrimidin ketone derivatives has numerous pharmacologically actives, referring to (
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;
eur.J. Med. Chem. 2010,
45, 367).The example that has wherein developed into medicine be (
s)-Monastrol, (
s)-L-771688 and (
s)-SQ 32926 etc., referring to (
chem. Biol., 2002,
9, 989;
j. Med. Chem., 2000,
43, 2703;
nat. Med., 2002,
8, 825;
j.Med. Chem., 1991,
34, 806.).
Taking acetylacetic ester, aldehyde and urea as raw material, by Biginelli method synthesizing dihydro pyrimidone derivatives be the most classical (
gazz. Chim. Ital. 1893,
23, 360), have recently and got many bibliographical informations and manyly prepare novel dihydropyrimidinonesand derivative with the reaction that other replaces acetylacetic ester to participate in Biginelli type containing active methylene compound, referring to (
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. 2009,
74, 3141;
chem. Commun. 2009, 2768).Due to higher biological activity of having of polysubstituted dihydro-pyrimidin ketone derivatives, and often can serve as the important intermediate of organic synthesis, the therefore further efficient preparation method of development of new dihydro-pyrimidin ketone derivatives, significant to new medicament screen etc.
Summary of the invention
The object of this invention is to provide a kind of reaction temperature and, the easy and simple to handle method of preparing dihydro-pyrimidin ketone derivatives.
The method of preparing dihydro-pyrimidin ketone derivatives of the present invention, its preparation process is with taking iodine as catalyzer, in organic solvent, first make at room temperature stirring reaction 30 minutes of 1-alkyl urea and aromatic aldehyde, then add alkanoic stirring and refluxing reaction 5～15 hours, obtain dihydro-pyrimidin ketone derivatives through purge process, the mol ratio between said 1-alkyl urea, aromatic aldehyde, alkanoic and iodine is 1:1～1.5:1:0.01～0.1;
Reaction formula is:
；
In formula: R
1be selected from C
1～C
4alkyl, R
2be selected from C
1～C
8alkyl or aryl, R
3be selected from H, halogen, nitro, cyano group, trifluoromethyl, C
1～C
4alkyl or C
1～C
4alkoxyl group.Described organic solvent is acetonitrile, tetrahydrofuran (THF), toluene, dimethylbenzene, 1,2-ethylene dichloride or Isosorbide-5-Nitrae-dioxane.
The present invention, compared with existing synthetic method, has the following advantages:
1) reaction conditions gentleness;
2) reaction highly versatile;
3) feed intake and aftertreatment all very simple;
4) do not need metal catalytic, adopt the group of compatible more substituting group, especially acid sensitivity of catalysis of iodine energy.
Specific implementation method
Following examples will contribute to understand the present invention, but be not limited to content of the present invention:
Embodiment 1
Paranitrobenzaldehyde (15 mmole), 1-MU (10 mmole) and iodine (1 mmole) are dissolved in acetonitrile (20 milliliters), after abundant stirring reaction 30 minutes, add phenylacetic aldehyde (10 mmole), heating reflux reaction 10 hours, react complete, dilute by ethyl acetate, through hypo solution washing, washing, the dry also decompression and solvent recovery of organic phase is concentrated into dry, concentrated mixture passes through purification by silica gel column chromatography, obtain 1-methyl-4-(4-nitrophenyl of yellow solid)-5-phenyl-3, 4-dihydro-pyrimidin-2(1 hydrogen)-one, productive rate 72%, product physical data is fusing point 186-188
oc, IR (neat)
ν3250,1682,1651,1519,1497,1455,1403,1270,818,736,732,700 cm
-1,
1h 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.
13c 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
17h
15n
3o
3): 309.1113, found:309.1111.
Embodiment 2
To cyanobenzaldehyde (12 mmole), 1-MU (10 mmole) and iodine (0.8 mmole) are dissolved in acetonitrile (15 milliliters), after abundant stirring reaction 30 minutes, add phenylacetic aldehyde (10 mmole), heating reflux reaction 12 hours, react complete, dilute by ethyl acetate, through hypo solution washing, washing, the dry also decompression and solvent recovery of organic phase is concentrated into dry, concentrated mixture passes through purification by silica gel column chromatography, obtain 1-methyl-4-(4-cyano-phenyl of white solid)-5-phenyl-3, 4-dihydro-pyrimidin-2(1 hydrogen)-one, productive rate 68%, product physical data is fusing point 113-115
oc, IR (neat)
ν3249,2925,2228,1679,1603,1498,1456,1404,1327,1269,1108,765,731,694,587 cm
-1,
1h 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.
13c 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. HRMS (EI): m/z calcd for (C
18h
15n
3o): 289.1215, found:289.1225.
Embodiment 3
P-bromobenzaldehyde (10 mmole), 1-MU (10 mmole) and iodine (1 mmole) are dissolved in toluene (20 milliliters), after abundant stirring reaction 30 minutes, add phenylacetic aldehyde (10 mmole), heating reflux reaction 12 hours, react complete, dilute by ethyl acetate, through hypo solution washing, washing, the dry also decompression and solvent recovery of organic phase is concentrated into dry, concentrated mixture passes through purification by silica gel column chromatography, obtain 1-methyl-4-(4-bromophenyl of yellow solid)-5-phenyl-3, 4-dihydro-pyrimidin-2(1 hydrogen)-one, productive rate 58%, product physical data is fusing point 170-172
oc, IR (neat)
ν3265,1673,1485,1455,1405,1325,1266,1003,754,730,694 cm
-1,
1h 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.
13c 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
17h
15brN
2o): 342.0368, found:340.0211.
Embodiment 4
Paranitrobenzaldehyde (15 mmole), 1-MU (10 mmole) and iodine (1 mmole) are dissolved in ethylene dichloride (20 milliliters), after abundant stirring reaction 30 minutes, add n-hexyl aldehyde (10 mmole), heating reflux reaction 12 hours, react complete, dilute by ethyl acetate, through hypo solution washing, washing, the dry also decompression and solvent recovery of organic phase is concentrated into dry, concentrated mixture passes through purification by silica gel column chromatography, obtain 1-methyl-4-(4-nitrophenyl of yellow solid)-5-butyl-3, 4-dihydro-pyrimidin-2(1 hydrogen)-one, productive rate 65%, product physical data is fusing point 121-123
oc, IR (neat)
ν3258,2956,2929,2869,1673,1596,1520,1465,1396,1346,1310,1268,1108,1036,855,754,697 cm
-1,
1h 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.
13c NMR (100 MHz, CDCl
3) δ 153.20,149.87,147.61,127.81,125.17,124.05,112.71,58.95,34.27,29.88,29.14,22.10,13.74 ppm. HRMS (EI): m/z calcd for (C
15h
19n
3o
3): 289.1426, found:289.1421.
Embodiment 5
Paranitrobenzaldehyde (11 mmole), 1-ethyl carbamide (10 mmole) and iodine (1 mmole) are dissolved in acetonitrile (20 milliliters), after abundant stirring reaction 30 minutes, add phenylacetic aldehyde (10 mmole), heating reflux reaction 12 hours, react complete, dilute by ethyl acetate, through hypo solution washing, washing, the dry also decompression and solvent recovery of organic phase is concentrated into dry, concentrated mixture passes through purification by silica gel column chromatography, obtain 1-ethyl-4-(4-nitrophenyl of yellow solid)-5-phenyl-3, 4-dihydro-pyrimidin-2(1 hydrogen)-one, productive rate 69%, product physical data is fusing point 182-184
oc, IR (neat)
ν3299,2932,1678,1598,1520,1497,1453,1347,1271,1236,1121,817,757,731,699 cm
-1,
1h 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.
13c 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. HRMS (EI): m/z calcd for (C
18h
17n
3o
3): 323.1270, found:323.1270.
Claims (2)
1. prepare the method for dihydro-pyrimidin ketone derivatives for one kind, its preparation process is taking iodine as catalyzer, in organic solvent, first make at room temperature stirring reaction 30 minutes of 1-alkyl urea and aromatic aldehyde, then add alkanoic stirring and refluxing reaction 5～15 hours, obtain dihydro-pyrimidin ketone derivatives through purge process, the mol ratio between said 1-alkyl urea, aromatic aldehyde, alkanoic and iodine is 1:1～1.5:1:0.01～0.1;
Reaction formula is:
；
In formula: R
1be selected from C
1～C
4alkyl, R
2be selected from C
1～C
8alkyl or aryl, R
3be selected from H, halogen, nitro, cyano group, trifluoromethyl, C
1～C
4alkyl or C
1～C
4alkoxyl group.
2. the method for preparing dihydro-pyrimidin ketone derivatives according to claim 1, is characterized in that described organic solvent is acetonitrile, tetrahydrofuran (THF), toluene, dimethylbenzene, 1,2-ethylene dichloride or Isosorbide-5-Nitrae-dioxane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501416A (en) * | 2017-08-25 | 2017-12-22 | 东华大学 | A kind of method that cellulose dihydropyrimidinone derivative is prepared based on multicomponent click chemistry |
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| HUE048503T2 (en) * | 2014-12-12 | 2020-07-28 | Japan Tobacco Inc | Dihydropyrimidine-2-one compounds and medicinal uses thereof |
| CN105233870A (en) * | 2015-09-24 | 2016-01-13 | 齐鲁工业大学 | Pyridine ethylene coordination polymers capable of catalyzing dihydropyrimidinones synthesis |
| CN105153240A (en) * | 2015-10-08 | 2015-12-16 | 齐鲁工业大学 | Research of pyridine oxadiazole complex in catalyzing dihydropyrimidones |
| KR20200126973A (en) | 2018-02-28 | 2020-11-09 | 니뽄 다바코 산교 가부시키가이샤 | 4-methyldihydropyrimidinone compound and its pharmaceutical use |
| CN110551089B (en) * | 2018-05-31 | 2022-11-22 | 中国科学院上海有机化学研究所 | Preparation method of (R) - (-) -massoialactone |
| CN110041231B (en) * | 2019-05-21 | 2021-04-09 | 东华理工大学 | Preparation method of N, O-acetal compound |
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| CN101323597A (en) * | 2007-06-11 | 2008-12-17 | 安徽省庆云医药化工有限公司 | Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amido) pyrimidine-5-formaldehyde |
| CN102408380A (en) * | 2011-12-22 | 2012-04-11 | 浙江大学 | 5-aminopyrimidine-thione compounds and preparation method thereof |
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| CN101323597A (en) * | 2007-06-11 | 2008-12-17 | 安徽省庆云医药化工有限公司 | Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amido) pyrimidine-5-formaldehyde |
| CN102408380A (en) * | 2011-12-22 | 2012-04-11 | 浙江大学 | 5-aminopyrimidine-thione compounds and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 《Bronsted Base-Catalyzed One-Pot Three-Component Biginelli-Type Reaction: An Efficient Synthesis of 4,5,6-Triaryl-3,4- dihydropyrimidin-2(1H)-one and Mechanistic Study》;Zhi-Liang Shen,等;《J. Org. Chem.》;20100119;第75卷(第4期);第1162-1167页 * |
| Zhi-Liang Shen,等.《Bronsted Base-Catalyzed One-Pot Three-Component Biginelli-Type Reaction: An Efficient Synthesis of 4,5,6-Triaryl-3,4- dihydropyrimidin-2(1H)-one and Mechanistic Study》.《J. Org. Chem.》.2010,第75卷(第4期),第1162-1167页. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501416A (en) * | 2017-08-25 | 2017-12-22 | 东华大学 | A kind of method that cellulose dihydropyrimidinone derivative is prepared based on multicomponent click chemistry |
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