CN110201714B - Synthesis method and catalyst of dihydropyrimidinone compound - Google Patents
Synthesis method and catalyst of dihydropyrimidinone compound Download PDFInfo
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- CN110201714B CN110201714B CN201910600111.9A CN201910600111A CN110201714B CN 110201714 B CN110201714 B CN 110201714B CN 201910600111 A CN201910600111 A CN 201910600111A CN 110201714 B CN110201714 B CN 110201714B
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- 239000003054 catalyst Substances 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- -1 dihydropyrimidinone compound Chemical class 0.000 title claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 109
- 239000000741 silica gel Substances 0.000 claims abstract description 83
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 83
- 150000007524 organic acids Chemical class 0.000 claims abstract description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 23
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000004202 carbamide Substances 0.000 claims abstract description 15
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 15
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 13
- 238000005580 one pot reaction Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 11
- QGKGASXQTBQINX-UHFFFAOYSA-N 3,4-dihydro-1h-pyrimidin-2-one Chemical class O=C1NCC=CN1 QGKGASXQTBQINX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000003377 acid catalyst Substances 0.000 claims description 31
- 238000005406 washing Methods 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 230000007935 neutral effect Effects 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 4
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims description 4
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 4
- 229940014800 succinic anhydride Drugs 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 150000008064 anhydrides Chemical class 0.000 description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 2
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 2
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229910004261 CaF 2 Inorganic materials 0.000 description 1
- 229910002492 Ce(NO3)3·6H2O Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229910013684 LiClO 4 Inorganic materials 0.000 description 1
- 229910007926 ZrCl Inorganic materials 0.000 description 1
- 238000002479 acid--base titration Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0834—Compounds having one or more O-Si linkage
- C07F7/0836—Compounds with one or more Si-OH or Si-O-metal linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
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- Chemical Kinetics & Catalysis (AREA)
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing dihydropyrimidinone compounds and a catalyst, and mainly relates to the technical field of organic synthesis. The synthesis method comprises synthesizing dihydropyrimidinone compounds by taking ethyl acetoacetate, aromatic aldehyde and urea as raw materials, taking organic acid loaded by silica gel as a catalyst and ethanol as a solvent by a one-pot method. The invention has the beneficial effects that: the method for synthesizing dihydropyrimidinone compounds is mild in reaction conditions, simple to operate and environment-friendly.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing dihydropyrimidinones and a catalyst.
Background
Dihydropyrimidinones (DHPMs) are important pharmaceutical intermediates with biological and pharmacological activities such as antiviral, antitumor, antibacterial, and antihypertensive effects. In 1893, Biginelli synthesizes 3, 4-dihydropyrimidinone compounds by a one-pot method by taking concentrated hydrochloric acid as a catalyst and taking aromatic aldehyde, ethyl acetoacetate and urea as raw materials for the first time. Since then, many studies have been made on the selection of a catalyst, the extension of the range of reaction raw materials, the optimization of reaction conditions, and the like. The reaction is improved and developed in the aspects of reaction conditions, product diversity and the like. The catalyst can be selected from protonic acid such as sulfuric acid, phosphoric acid, hydrochloric acid, p-toluenesulfonic acid, acetic acid, etc.; lewis acids such as BF 3 ·OEt 2 /CuCl,Cu(OTf) 2 ,CuI,In(OTf) 3 ,La(OTf) 3 ,Yb(OTf) 3 ,Mn(OAc) 3 ·2H 2 O,LiClO 4 ,Ce(NO 3 ) 3 ·6H 2 O,FeCl 3 ·6H 2 O,NiCl 2 ·6H 2 O,ZnCl 2 ,ZrCl 4 ,ZrOCl 2 ·8H 2 O,Sr(OTf) 2 ,Bi(OTf) 3 ,CaF 2 ,Y(NO 3 ) 3 ·6H 2 O,SmI 2 Etc.; the used catalyst is generally high in price and easily causes pollution to the environment, and how to select a simple and effective catalyst to synthesize the dihydropyrimidinone compound becomes a research hotspot and difficulty of the reaction.
Disclosure of Invention
The invention aims to provide a method and a catalyst for synthesizing dihydropyrimidinones, and provides a method for synthesizing dihydropyrimidinones, which has the advantages of mild reaction conditions, simple operation and environmental protection.
In order to achieve the purpose, the invention is realized by the following technical scheme:
the silica gel catalyst for synthesizing dihydropyrimidinone compounds by a one-pot method is characterized by being prepared by the following steps:
s1, activating silica gel:
uniformly mixing concentrated sulfuric acid and concentrated nitric acid according to the volume ratio of 5:1, adding silica gel with the mass ratio of 1-1.5: 8 to the concentrated sulfuric acid, reacting for 24-48 hours at 120-160 ℃, cooling, filtering, washing with deionized water to be neutral, washing with methanol and dichloromethane respectively, and drying to obtain activated silica gel;
s2, preparation of amino functional silica gel:
adding 3-aminopropyltriethoxysilane and the activated silica gel into anhydrous toluene, wherein the ratio of the 3-aminopropyltriethoxysilane to the silica gel is 3-6 mmol/g, reacting for 24-48 hours at 120 ℃ under the protection of nitrogen, cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;
S3, preparation of a silica gel loaded organic acid catalyst:
adding anhydride and the amino-functionalized silica gel into dichloromethane, wherein the proportion of the anhydride to the amino-functionalized silica gel is 9-18 mmol/g, shaking at room temperature for 24-48 hours, filtering, washing with methanol and dichloromethane, and drying to obtain the silica gel-loaded organic acid catalyst.
Further, the silica gel catalyst for synthesizing dihydropyrimidinones by the one-pot method according to claim 1, characterized by comprising the following steps:
s1, activating silica gel:
uniformly mixing concentrated sulfuric acid and concentrated nitric acid according to the volume ratio of 5:1, adding silica gel with the mass ratio of 1-1.5: 8 to the concentrated sulfuric acid, reacting for 24 hours at 140 ℃, cooling, filtering, washing with deionized water to be neutral, washing with methanol and dichloromethane respectively, and drying to obtain activated silica gel;
s2, preparing amino functional silica gel:
adding 3-aminopropyltriethoxysilane and the activated silica gel into anhydrous toluene, wherein the ratio of the 3-aminopropyltriethoxysilane to the silica gel is 3mmol/g, reacting for 24 hours at 120 ℃ under the protection of nitrogen, cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;
S3, preparation of a silica gel loaded organic acid catalyst:
adding anhydride and the amino-functionalized silica gel into dichloromethane, wherein the proportion of the anhydride to the amino-functionalized silica gel is 9mmol/g, shaking for 24 hours at room temperature, filtering, washing with methanol and dichloromethane, and drying to obtain the silica gel supported organic acid catalyst.
Further, the silica gel used in the step S1 is 100-200 mesh silica gel, and the acid anhydride used in the step S3 is one of succinic anhydride and glutaric anhydride.
Further, when the catalyst is specifically applied, the catalyst is used for synthesizing dihydropyrimidinones by a one-pot method.
Further, in specific application, ethyl acetoacetate, aromatic aldehyde and urea are used as raw materials, and ethanol is used as a solvent.
In another aspect of the present invention, a method for synthesizing dihydropyrimidinones from ethyl acetoacetate, aromatic aldehyde and urea by a one-pot method using organic acid supported on silica gel as a catalyst and ethanol as a solvent is provided, wherein the organic acid supported on silica gel is the catalyst according to any one of claims 1 to 5.
Further, the amount of the organic acid catalyst supported on silica gel is determined in accordance with the carboxyl group-CO contained 2 H accounts for 6-10 mol% of the aromatic aldehyde.
Further, the molar ratio of the ethyl acetoacetate to the aromatic aldehyde to the urea is as follows: 1:1: 1.2-1.5.
Further, the aromatic aldehyde comprises any one or more of benzaldehyde, p-tolualdehyde, p-methoxybenzaldehyde, p-fluorobenzaldehyde, p-nitrobenzaldehyde, p-trifluoromethylbenzaldehyde, p-chlorobenzaldehyde, m-bromobenzaldehyde and o-bromobenzaldehyde.
Further, the method comprises the following steps:
adding ethyl acetoacetate, aromatic aldehyde, urea, an organic acid catalyst loaded by silica gel and an ethanol solvent into a reactor, heating and refluxing for 4-5 hours, cooling with ice water for crystallization, filtering to obtain a crude product, and then recrystallizing with ethanol to obtain the product;
the organic acid catalyst loaded by silica gel recovered in the recrystallization process is directly used for the synthesis reaction of the next cycle.
Compared with the prior art, the invention has the beneficial effects that:
compared with the prior literature, the method has the advantages that the yield of the dihydropyrimidinone compounds is improved by using the organic acid catalyst immobilized on silica gel, the use of inorganic strong acid, noble metal and other catalysts is avoided, the purification time of the product is shortened, the post-treatment operation is simplified, the environmental pollution is reduced, the cost is saved, and the method is favorable for large-scale production. The organic acid catalyst loaded by the silica gel can be recycled, so that the cost is saved.
Drawings
FIG. 1 shows the preparation of a silica gel supported organic acid catalyst.
FIG. 2 shows the synthesis of dihydropyrimidinones using organic acid loaded on silica gel as catalyst.
FIG. 3 is a schematic representation of the recycling of organic acid catalyst supported on silica gel.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and these equivalents also fall within the scope of the present application.
One) silica gel catalyst for synthesizing dihydropyrimidinone compounds by a one-pot method, which comprises the following specific steps:
1) activation of silica gel: uniformly mixing concentrated sulfuric acid and concentrated nitric acid according to the volume ratio of 5:1, adding a proper amount of silica gel (100-200 meshes), wherein the mass ratio of the silica gel to the concentrated sulfuric acid is 1-1.5:8, reacting at 140 ℃ for 24h, cooling, filtering, washing with deionized water to be neutral, washing with methanol and dichloromethane respectively, and drying to obtain the activated silica gel.
2) Preparation of amino-functionalized silica gel: adding 3-Aminopropyltriethoxysilane (APTS) and the activated silica gel into anhydrous toluene, wherein the ratio of the 3-aminopropyltriethoxysilane to the silica gel is 3mmol/g, reacting at 120 ℃ for 24 hours under the protection of nitrogen, cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel (APS).
3) Preparation of silica gel supported organic acid catalyst (as shown in fig. 1): adding an appropriate amount of acid anhydride and the amino-functionalized silica gel (APS) into dichloromethane, wherein the ratio of the acid anhydride to the amino-functionalized silica gel (APS) is 9mmol/g, shaking at room temperature for 24 hours, then filtering, washing with methanol and dichloromethane, and drying to obtain the silica gel supported organic acid catalyst. (the content of the organic acid supported by the silica gel was 0.8mmol/g as measured by acid-base titration reaction).
The anhydride is one of succinic anhydride or glutaric anhydride.
The concrete reflection formula is shown in attached figure 1.
Synthesis of di) dihydropyrimidinones
Adding raw materials of ethyl acetoacetate, aromatic aldehyde, urea, organic acid catalyst loaded by silica gel and an ethanol solvent into a reaction vessel, heating and refluxing for 4-5 hours, cooling with ice water for crystallization, filtering to obtain a crude product, and recrystallizing with ethanol to obtain the dihydropyrimidinone compound.
The molar ratio of the ethyl acetoacetate to the aromatic aldehyde to the urea is as follows: 1:1:1.2-1.5, preferably 1:1: 1.2.
The aromatic aldehyde is benzaldehyde, p-tolualdehyde, p-methoxybenzaldehyde, p-fluorobenzaldehyde, p-nitrobenzaldehyde, p-trifluoromethylbenzaldehyde, p-chlorobenzaldehyde, m-bromobenzaldehyde and o-bromobenzaldehyde (the yield of corresponding dihydropyrimidinone compounds is shown in table 1).
The concrete reflection formula is shown in the attached figure 2.
TABLE 1 Synthesis of dihydropyrimidinones using silica gel-supported organic acids as catalysts
III) recovery and use of organic acid catalyst loaded on silica gel
According to the invention, after the reaction, the target product is obtained by using ethanol for recrystallization, and the organic acid catalyst loaded on the silica gel obtained by filtering and recycling can be recycled. Table 2 shows the molar ratio of ethyl acetoacetate to benzaldehyde to urea: 1:1:1.2, the amount of organic acid catalyst supported on silica gel is 10 mol% (based on carboxyl-CO content) 2 H) and the catalyst was recovered and used after a reflux reaction for 5 hours. As can be seen from Table 2, the organic acid catalyst supported on silica gel was recovered and reused, and still had good catalytic activity.
The concrete reflection formula is shown in the attached figure 3.
TABLE 2 Recycling of silica gel-loaded organic acid catalysts
The foregoing is a further explanation of embodiments, and the following is illustrative:
example 1: silica gel catalyst
The method is used for synthesizing dihydropyrimidinones by a one-pot method, and the specific preparation method comprises the following steps:
1) activation of silica gel: adding 150mL of concentrated sulfuric acid and 30mL of concentrated nitric acid into a round-bottom flask, uniformly mixing, adding 25.0g of silica gel (180 meshes), reacting at 140 ℃ for 24 hours, cooling to room temperature, filtering, washing with deionized water to be neutral, washing with methanol and dichloromethane respectively, and drying to obtain the activated silica gel.
2) Preparation of amino-functionalized silica gel: 6.0g of the above activated silica gel and 18.0mmol of 3-Aminopropyltriethoxysilane (APTS) were added to 40mL of anhydrous toluene, reacted at 120 ℃ under nitrogen protection for 24 hours, cooled, filtered, washed with acetone and dichloromethane, and dried to obtain 6.4g of amino-functionalized silica gel (APS).
3) Preparation of silica gel supported organic acid catalyst: 2.0g of the above amino-functionalized silica gel (APS) and 18.0mmol of glutaric anhydride were added to 20ml of methylene chloride, shaken at room temperature for 24 hours, then filtered, washed with methanol and methylene chloride, and dried to obtain 2.15g of the silica gel-supported organic acid catalyst (II).
Example 2: synthesis of dihydropyrimidinones using the catalyst described in example 1
In a 50ml round bottom flask were charged ethyl acetoacetate (1.0mmol), p-methoxybenzaldehyde (1.0mmol) and urea (1.2mmol) as raw materials in this order, and 1.0g (carboxyl group-containing-CO) of the above silica gel-supported organic acid catalyst 2 H0.08 mmol) and 10ml of ethanol solvent, heating and refluxing for 5 hours, cooling and crystallizing with ice water, filtering to obtain a crude product, and then recrystallizing with ethanol to obtain the target product with the yield of 94 percent.
Example 3: silica gel catalyst
The method is used for synthesizing dihydropyrimidinones by a one-pot method, and the specific preparation method comprises the following steps: .
One), preparation of silica gel supported organic acid:
1) activation of silica gel: adding 75mL of concentrated sulfuric acid and 15mL of concentrated nitric acid into a round-bottom flask, uniformly mixing, adding 12.0g of silica gel (100 meshes), reacting at 140 ℃ for 24 hours, cooling to room temperature, filtering, washing with deionized water to be neutral, washing with methanol and dichloromethane respectively, and drying to obtain the activated silica gel.
2) Preparation of amino-functionalized silica gel: 4.0g of the above activated silica gel and 12.0mmol of 3-Aminopropyltriethoxysilane (APTS) were added to 25mL of anhydrous toluene, reacted at 120 ℃ under nitrogen protection for 24 hours, cooled, filtered, washed with acetone and dichloromethane, and dried to obtain 4.3g of amino-functionalized silica gel (APS).
3) Preparation of silica gel supported organic acid catalyst: 2.0g of the above amino-functionalized silica gel (APS) and 18.0mmol of succinic anhydride were added to 12ml of dichloromethane, shaken at room temperature for 24 hours, then filtered, washed with methanol and dichloromethane, and dried to obtain 2.16g of silica gel-supported organic acid catalyst (III).
Example 4: synthesis of dihydropyrimidinones using the catalyst described in example 3
In a 50ml round bottom flask, raw materials of ethyl acetoacetate (1.0mmol), p-chlorobenzaldehyde (1.0mmol) and urea (1.2mmol) were sequentially added, 0.75g of the above silica gel-supported organic acid catalyst (carboxyl group-containing-CO 2H 0.06.06 mmol) and 10ml of ethanol solvent, and the mixture was heated under reflux for 4 hours, cooled and crystallized with ice water, filtered to obtain a crude product, and then recrystallized with ethanol to obtain the objective product in 92% yield.
Claims (4)
1. The silica gel catalyst for synthesizing dihydropyrimidinone compounds by a one-pot method is characterized by being prepared by the following steps:
(1) activation of silica gel: adding 150mL of concentrated sulfuric acid and 30mL of concentrated nitric acid into a round-bottom flask, uniformly mixing, adding 25.0g of 180-mesh silica gel, reacting at 140 ℃ for 24h, cooling to room temperature, filtering, washing with deionized water to be neutral, then washing with methanol and dichloromethane respectively, and drying to obtain activated silica gel;
(2) preparation of amino-functionalized silica gel: adding 6.0g of activated silica gel and 18.0mmol of 3-aminopropyltriethoxysilane into 40mL of anhydrous toluene, reacting for 24 hours at 120 ℃ under the protection of nitrogen, cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;
(3) Preparation of silica gel supported organic acid catalyst: adding 2.0g of amino-functionalized silica gel and 18.0mmol of glutaric anhydride into 20ml of dichloromethane, shaking for 24 hours at room temperature, then filtering, washing with methanol and dichloromethane, and drying to obtain a silica gel-loaded organic acid catalyst;
2. the silica gel catalyst for synthesizing dihydropyrimidinone compounds by a one-pot method is characterized by being prepared by the following steps:
(1) activation of silica gel: adding 75mL of concentrated sulfuric acid and 15mL of concentrated nitric acid into a round-bottom flask, uniformly mixing, adding 12.0g of 100-mesh silica gel, reacting at 140 ℃ for 24h, cooling to room temperature, filtering, washing with deionized water to be neutral, then washing with methanol and dichloromethane respectively, and drying to obtain activated silica gel;
(2) preparation of amino-functionalized silica gel: adding 4.0g of activated silica gel and 12.0mmol of 3-aminopropyltriethoxysilane into 25mL of anhydrous toluene, reacting for 24 hours at 120 ℃ under the protection of nitrogen, cooling, filtering, washing with acetone and dichloromethane, and drying to obtain amino-functionalized silica gel;
(3) preparation of silica gel supported organic acid catalyst: 2.0g of amino-functionalized silica gel and 18.0mmol of succinic anhydride were added to 12ml of dichloromethane, shaken at room temperature for 24 hours, then filtered, washed with methanol and dichloromethane, and dried to obtain a silica gel-supported organic acid catalyst.
3. The synthesis method of the dihydropyrimidinone compound is synthesized by taking ethyl acetoacetate, aromatic aldehyde and urea as raw materials, and is characterized in that: adding raw materials of ethyl acetoacetate 1.0mmol, p-methoxybenzaldehyde 1.0mmol and urea 1.2mmol, the silica gel supported organic acid catalyst 1.0g and 10ml of ethanol solvent into a round-bottom flask in sequence, heating and refluxing for 5 hours, cooling and crystallizing with ice water, filtering to obtain a crude product, and then recrystallizing with ethanol to obtain the target product.
4. The synthesis method of the dihydropyrimidinone compound is synthesized by taking ethyl acetoacetate, aromatic aldehyde and urea as raw materials, and is characterized in that: adding raw materials of ethyl acetoacetate 1.0mmol, p-chlorobenzaldehyde 1.0mmol and urea 1.2mmol, a silica gel supported organic acid catalyst 0.75g of claim 2 and 10ml of ethanol solvent into a round-bottom flask in sequence, heating and refluxing for 4 hours, cooling with ice water for crystallization, filtering to obtain a crude product, and then recrystallizing with ethanol to obtain the target product.
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