CN109053589A - The preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound - Google Patents

The preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound Download PDF

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CN109053589A
CN109053589A CN201811153808.8A CN201811153808A CN109053589A CN 109053589 A CN109053589 A CN 109053589A CN 201811153808 A CN201811153808 A CN 201811153808A CN 109053589 A CN109053589 A CN 109053589A
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tetrahydropyrimidin
reaction
class compound
imido grpup
propargylamine
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吕新
童涛
康红兰
李二飞
吴鑫
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Zhejiang Normal University CJNU
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Zhejiang Normal University CJNU
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    • 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

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Abstract

The present invention relates to a kind of preparation methods of 4- imido grpup tetrahydropyrimidin-2-ones class compound comprising following steps: (1) mixing propargylamine, isocyanates in solvent, carries out the first reaction, obtains mixture；(2) molecular sieve, catalyst, sulfonyl nitrine and organic base are sequentially added to the mixture, carries out the second reaction, obtains 4- imido grpup tetrahydropyrimidin-2-ones class compound.The preparation method raw material is cheap and easy to get, operation is convenient, yield is higher, can introduce a variety of substituent groups in different parts, and post-process more convenient, suitable industrial production.

Description

The preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound
Technical field
The present invention relates to a kind of preparation methods of 4- imido grpup tetrahydropyrimidin-2-ones compound.
Background technique
Pyrimidone structure is widely present in many natural products, synthetic drug and functional material molecule.Studies have shown that being permitted More pyrimidone derivatives have important biology and pharmacological activity, can be used for antineoplastic, antispasmodic, antiviral agent, decompression Medicine, calcium antagonist, ɑ1aAntagonist, herbicide etc..Wherein, 4- imino group pyrimid-2-one class compound due to contain imine structure, The specific biology of tool and pharmacological activity have potential purposes in biology, medicine and other fields.Research shows that introducing various substituent groups Can reduce Pyrimdinone drug first-pass metabolism and certain side effects, and improve its lipophilicity and stability.And according to human body generation It thanks to rule, often protects nitrogenous active group using acyl group or sulfonyl.Accordingly, with respect to exposed or alkyl substituted imine base class Like object, the 4- imino group tetrahydropyrimidin-2-ones class compound of N- sulfonyl protection may have better potential pharmacological properties.
At present in terms of synthesis pyrimid-2-one and dihydropyrimidine-2-keto derivative, there is good several method.Such as enamine ester It (is referred to: Merour J.Y., Synthesis specifique de with ɑ-cyanoacrylate condensation method pyrimidines.Formation conccurentielle de pyrimidines et de Triazepines.Heterocycl.Chem., 1982,19:1425), Biginelli reaction method (refer to: Quan Zhengjun, Evident, up to beautiful rosy clouds, king likes to deposit the study on the synthesis new development organic chemistry of .Biginelli 3,4- dihydropyrimidine-2-keto derivative, 2009,29:876-883.), α, β-unsaturation double carbonyl compound and (sulphur) urea derivative condensation method (Atwal is referred to, K.S.；Rovnyak,G.C.；O'Reilly,B.C.；Schwartz,J.Substituted 1,4- dihydropyrimidines.3.Synthesis of selectively functionalized 2-hetero-1,4- Dihydropyrimidines.J.Org.Chem.1989,54:5898-5907), miscellaneous Diels-Alder method etc..
And in terms of synthesizing 4- imino group pyrimid-2-one, only a small amount of report, such as by Baylis-Hillman addition product It sets out and (refers to Nag, S. through the synthesis of four steps；Pathak,R.；Kumar,M.；Shukla,P.K.；Batra,S.Synthesis and antibacterial evaluation of ureides of Baylis-Hillman Derivatives.Bioorg.Med.Chem.Lett.2016,16:3824-3828) and by 3- amino -2,2- difluoro propionitrile with Isocyanates, which sets out, (refers to Kosobokov, M.D. through the synthesis of two steps；Struchkova,M.I.；Arkhipov,D.E.； Korlyukov,A.A.；Dilman,A.D.Synthesis of fluorinated pyrimidinones.J.Fluor.Chem.2013,154:73-79).However, there are some disadvantages for these methods, as step is numerous It is trivial, condition is harsh, narrow application range or needs specific substrates.In synthesis 4- sulfonylimino tetrahydropyrimidin-2-ones class chemical combination object space Face, there has been no convenient effective routes to report.Therefore, develop efficient, simple and direct method synthesis containing the expected 4- sulphur for replacing structure - 2 ketone compounds of acylimino tetrahydropyrimidine have very important meaning.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of N- sulfonyl -4- imino group tetrahydropyrimidin-2-ones classes The preparation method of object is closed, which has the advantages that raw material is cheap and easy to get, easy to operate, yield is high.
The present invention provides a kind of preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound comprising following steps:
(1) propargylamine, isocyanates are mixed in solvent, carries out the first reaction, obtains mixture；
(2) molecular sieve, catalyst, sulfonyl nitrine and organic base are sequentially added to the mixture, carry out the second reaction, Obtain 4- imido grpup tetrahydropyrimidin-2-ones class compound.
Wherein, in step (1), the structural formula of the propargylamine isThe structural formula of the isocyanates is R3- NCO, the chemical formula of the sulfonyl nitrine are R4-SO2N3, wherein R1For one of hydrogen, phenethyl, benzyl, n-hexyl, R2For One of hydrogen, benzyl, phenethyl, normal-butyl, R3For phenyl, p-methylphenyl, tolyl, o-tolyl, p-methoxyphenyl, One of rubigan, chlorphenyl, naphthalene, benzyl, R4For p-methylphenyl, phenyl, rubigan, acetparaminosalol phenyl One of.
Wherein, solvent described in step (1) is acetonitrile or 1,2- dichloroethanes.
Wherein, the ratio of molecular sieve described in step (2) and propargylamine is (100mg~300mg): 1mmol.
Wherein, organic base is triethylamine, diisopropylethylamine, n,N-diisopropylethylamine, triethylene diamine in step (2) One of, the catalyst is one of cuprous iodide, cuprous bromide, cuprous cyanide.
Wherein, the propargylamine, isocyanates, sulfonyl nitrine, organic base, catalyst the ratio of amount of substance be 1.0:1.02:1.0:2.0:(0.1~0.2).
Wherein, in first reaction, temperature is 15 DEG C~35 DEG C, and the time is 2 hours~4 hours, first reaction It carries out under an inert atmosphere.
Wherein, in second reaction, temperature is 60 DEG C~80 DEG C, and the time is 3 hours~16 hours, second reaction It carries out under an inert atmosphere.
Wherein, further include the steps that one isolates and purifies after step (2).
Using propargylamine and sulfonyl nitrine as raw material, only with two steps, 4- sulfonylimino is prepared in the preparation method Tetrahydropyrimidin-2-ones class compound.The preparation method has the advantage that first, first reaction and the second reaction be It is completed in the same reaction unit, this makes the product of the first reaction without separating treatment, is directly entered the second reaction, existing Conducive to yield is improved, operating procedure is in turn simplified；Second, the yield of the reaction is higher (up to 65% or more), and passes through weight The higher product of purity can be obtained in crystallization purifying or column chromatography for separation (purity can reach 97% or more)；Third, related raw material It is cheap and easy to get with organic base, the use of additional solvent is also saved, cost is relatively low；4th, step is simple, easily operated, after Processing is easy, and reaction condition is mild, thus the preparation method can be applied to large-scale production.
Detailed description of the invention
Fig. 1 is the schematic diagram of the synthetic reaction formula of the 4- imido grpup tetrahydropyrimidin-2-ones class compound.
Fig. 2 is the obtained 4- imido grpup tetrahydropyrimidin-2-ones class compound of embodiment 11H NMR spectra.
Fig. 3 is the obtained 4- imido grpup tetrahydropyrimidin-2-ones class compound of embodiment 113C NMR spectra.
Fig. 4 is the obtained 4- imido grpup tetrahydropyrimidin-2-ones class compound of embodiment 21H NMR spectra.
Fig. 5 is the obtained 4- imido grpup tetrahydropyrimidin-2-ones class compound of embodiment 213C NMR spectra.
Fig. 6 is the obtained 4- imido grpup tetrahydropyrimidin-2-ones class compound of embodiment 31H NMR spectra.
Fig. 7 is the obtained 4- imido grpup tetrahydropyrimidin-2-ones class compound of embodiment 313C NMR spectra.
Specific embodiment
Below in conjunction with the attached drawing in embodiment of the present invention, the technical solution in embodiment of the present invention is carried out clear Chu is fully described by, it is clear that described embodiment is only some embodiments of the invention, rather than whole realities Apply mode.Based on the embodiment in the present invention, those of ordinary skill in the art institute without creative efforts The every other embodiment obtained, shall fall within the protection scope of the present invention.
The present invention provides a kind of preparation methods of 4- imido grpup tetrahydropyrimidin-2-ones class compound, which is characterized in that its The following steps are included:
S1 mixes propargylamine, isocyanates in solvent, carries out the first reaction, obtains mixture；
S2 sequentially adds molecular sieve, catalyst, sulfonyl nitrine and organic base to the mixture, carries out the second reaction, Obtain 4- imido grpup tetrahydropyrimidin-2-ones class compound.
In step sl, the structural formula of the propargylamine isWherein R1For in hydrogen, phenethyl, benzyl, n-hexyl One kind, R2For one of hydrogen, benzyl, phenethyl, normal-butyl.The structural formula of the isocyanates is R3- NCO, wherein R3For Phenyl, p-methylphenyl, tolyl, o-tolyl, p-methoxyphenyl, rubigan, chlorphenyl, naphthalene, one in benzyl Kind.
The solvent can be acetonitrile or 1,2- dichloroethanes.
Net reaction such as Fig. 1 of first reaction and the second reaction.In fact, the first reaction is that intermolecular addition is anti- It answers, it is therefore an objective to react both propargylamine and isocyanates first, obtain propargyl urea intermediate product.
In first reaction, temperature is 15 DEG C~35 DEG C, and the time is 2 hours~4 hours.First reaction is in inertia It is carried out under atmosphere.The inert atmosphere is nitrogen.Preferably, first reaction carries out under conditions of anhydrous and oxygen-free.
In step s 2, second reaction is intramolecular addition reaction.
The chemical formula of the sulfonyl nitrine is R4-SO2N3, wherein R4For p-methylphenyl, phenyl, rubigan, to acetyl One of aminophenyl.
The molecular sieve uses micropore partial size for 0.1 nanometer or more of molecular sieve (English is abbreviated as MS), it is preferred that micropore The molecular sieve that partial size is 0.1 nanometer~1 nanometer.The effect of the molecular sieve is the effect of catalyst.
The catalyst is one of cuprous iodide, cuprous bromide, cuprous cyanide.The ratio of the molecular sieve and propargylamine Example is (100mg~300mg): 1mmol.
The organic base role is the addition reaction promoted between propargylamine and isocyanates.The organic base is three Ethamine (English is abbreviated as TEA), diisopropylethylamine, N, one of N- diisopropylethylamine, triethylene diamine.
The propargylamine, isocyanates, sulfonyl nitrine, organic base, catalyst substance amount ratio be 1.0: 1.02:1.0:2.0:(0.1~0.2).
It is appreciated that for the ease of being added dropwise each reaction raw materials, the propargylamine, isocyanates, sulfonyl nitrine and organic Alkali can distinguish elder generation and mix with solvent such as acetonitrile, obtain the solution containing propargylamine, the solution containing isocyanates, nitrine containing sulfonyl Solution and solution containing organic base, then be separately added into.Wherein in step sl used in the solvent dosage and step The summation of the dosage of solvent used in rapid S2 is the dosage of the solvent.The dosage of the solvent and the ratio of propargylamine It can be (8~10) mL:1mmol.
In second reaction, temperature is 60 DEG C~80 DEG C, and the time is 3 hours~16 hours.Second reaction is lazy It is carried out under property atmosphere.The inert atmosphere is nitrogen atmosphere.
Further include the steps that one isolates and purifies upon step s 2.Specifically: the mixture that reaction obtains first is used into acetic acid Ethyl ester dilution, then saturated common salt is washed, and separates organic layer；It is dry with anhydrous sodium sulfate again, it is evaporated under reduced pressure with recycling design, and The solid that will be left behind is chromatographed using column and carries out separating-purifying, and final product is obtained.
Theoretical yield is calculated with raw material propargylamine, by the weight of the product actually obtained (after isolating and purifying) divided by reason By yield, the yield of product can be obtained.By the weight of the solid after isolating and purifying divided by the solid before isolating and purifying Weight is to get the purity for arriving product.
Below with specific embodiment to further illustrate the technical scheme of the present invention, but the present invention is not limited to following implementation Example.
Embodiment 1
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Methyl-N-(2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonami de。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.1.Wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL.Molecular sieve 100mg.Detailed process is as follows:
Equipped in stirrer 25mL reaction tube, logical nitrogen is first vacuumized, is added under anhydrous and oxygen-free environment and contains alkynes third The acetonitrile solution 1.5mL of amine 28mg (i.e. 0.5mmol) is slowly added dropwise containing to toluene diisocyanate 69mg's (i.e. 0.52mmol) Acetonitrile solution 1.5mL carries out the first reaction at room temperature, and the time is 3 hours, tracks to original using thin-layer chromatography (referred to as TLC) Expect fully reacting, is added in a nitrogen environmentMolecular sieve 100mg and cuprous iodide 10mg (i.e. 10mol%), add containing The acetonitrile solution 1.0mL of p-toluene sulfonyt azide 99mg (i.e. 0.5mmol), is finally slowly added dropwise containing triethylamine 101mg The acetonitrile solution 1.0mL of (1mmol) is warming up to 70 DEG C, carries out the second reaction, and the reaction time is 6 hours, and TLC tracks to centre Precursor reactant is complete, and reaction solution is evaporated under reduced pressure, and by silica gel post separation, obtains solid product 139mg.Yield is 78%, product Purity be 97%.
Nuclear magnetic resonance test also has been carried out to obtained product, has as a result seen Fig. 2 and Fig. 3.Specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 8.39 (s, 1H), 7.54 (d, J=8.1Hz, 2H), 7.21-7.16 (m, 4H), 6.91 (d, J=8.0Hz, 2H), 3.63 (td, J=6.7,2.9Hz, 2H), 2.88 (t, J=6.8Hz, 2H), 2.39 (s, 3H), 2.38(s,3H)；13C NMR(151MHz,CDCl3)δ168.2,154.1,142.8,139.7,138.7,132.5,129.8, 129.3,128.5,126.0,36.6,31.8,21.6,21.4。
By Fig. 2, Fig. 3 and above-mentioned data result as it can be seen that obtained product is
Embodiment 2
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4-Methyl- N-(2-oxo-3-(m-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonami de。
The mass ratio of the material of raw material is as follows: propargylamine: toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL. AdditionMolecular sieve 100mg, the time of the first reaction are 3 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 134mg, yield 75% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also has been carried out to obtained product, has as a result seen Fig. 4 and Fig. 5.Specific test data is as follows:
1H NMR(400MHz,CDCl3) δ 8.40 (s, 1H), 7.54 (d, J=8.1Hz, 2H), 7.30-7.27 (m, 1H), 7.22-7.15 (m, 3H), 6.84 (d, J=5.7Hz, 2H), 3.63 (td, J=6.7,2.9Hz, 2H), 2.88 (t, J=6.7Hz, 2H),2.39(s,3H),2.33(s,3H)；13C NMR(151MHz,CDCl3)δ168.0,154.0,142.8,139.8,139.0, 135.0,129.6,129.4,129.3,128.9,126.0,125.8,36.7,31.8,21.6,21.4。
By Fig. 4, Fig. 5 and above-mentioned data result as it can be seen that obtained product is
Embodiment 3
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4-Methyl- N-(2-oxo-3-(o-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonami de。
The mass ratio of the material of raw material is as follows: propargylamine: adjacent toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL. AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 8 hours.
Detailed process obtains solid product 127mg, yield 71% with embodiment 1, and the purity of product is 97%.
Nuclear magnetic resonance test also has been carried out to obtained product, has as a result seen Fig. 6 and Fig. 7.Specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 8.42 (s, 1H), 7.50 (d, J=8.2Hz, 2H), 7.29 (t, J=7.1Hz, 1H), 7.24-7.21 (m, 2H), 7.17 (d, J=8.1Hz, 2H), 6.97 (d, J=7.4Hz, 1H), 3.66-3.59 (m, 2H), 2.90–2.84(m,2H),2.37(s,3H),1.94(s,3H)；13C NMR(151MHz,CDCl3)δ167.8,153.5,142.8, 139.7,135.9,134.5,130.8,129.2,129.1,128.9,126.9,125.9,36.7,31.7,21.6,17.4。
By Fig. 6, Fig. 7 and above-mentioned data result as it can be seen that obtained product is
Embodiment 4
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Methyl-N-(2-oxo-3-phenyltetrahydropyrimidin-4(1H)-ylidene)benzenesulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine: phenyl isocyanate: p-toluene sulfonyt azide: triethylamine: cuprous iodide =1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 3 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 120mg, yield 70% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 8.39 (s, 1H), 7.52 (d, J=8.2Hz, 2H), 7.41-7.35 (m, 3H), (7.18 d, J=8.1Hz, 2H), 7.03 (dd, J=7.6,1.8Hz, 2H), 3.60 (td, J=6.8,2.8Hz, 2H), 2.85 (t, J=6.8Hz, 2H), 2.37 (s, 3H)；13C NMR(151MHz,CDCl3)δ168.2,153.9,142.8,139.7,135.3, 129.3,129.0,128.9,128.7,125.9,36.6,31.7,21.6。
Embodiment 5
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N- (3-(4-Methoxyphenyl)-2-oxotetrahydropyrimidin-4(1H)-ylidene)-4-methylbenzene sulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine: p-Methoxyphenyl isocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, and dosage is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 122mg, yield 65% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 8.39 (s, 1H), 7.55 (d, J=8.2Hz, 2H), 7.19 (d, J=8.1Hz, 2H), 6.96-6.92 (m, 2H), 6.91-6.87 (m, 2H), 3.82 (s, 3H), 3.61 (t, J=6.2Hz, 2H), 2.86 (t, J= 6.9Hz,2H),2.38(s,3H)；13C NMR(151MHz,CDCl3)δ168.4,159.5,154.2,142.8,139.7, 129.8,129.3,127.7,126.0,114.3,55.6,36.6,31.7,21.6。
Embodiment 6
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N- (3- (4-Chlorophenyl)-2-oxotetrahydropyrimidin-4(1H)-ylidene)-4-methylbenzenesu lfonamide。
The mass ratio of the material of raw material is as follows: propargylamine: chlorophenyl isocyanate: p-toluene sulfonyt azide: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL. AdditionMolecular sieve 100mg.The time of first reaction is 3 hours.The time of second reaction is 4 hours.
Detailed process obtains solid product 136mg, yield 72% with embodiment 1, and the purity of product is 98%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 8.41 (s, 1H), 7.54 (d, J=8.2Hz, 2H), 7.35 (d, J=8.6Hz, 2H), 7.21 (d, J=8.1Hz, 2H), 6.97 (d, J=8.6Hz, 2H), 3.66 (td, J=6.8,3.0Hz, 2H), 2.90 (t, J =6.8Hz, 2H), 2.39 (s, 3H)；13C NMR(151MHz,CDCl3)δ167.9,153.7,143.1,139.4,134.7, 133.6,130.3,129.40,129.35,126.0,36.7,31.7,21.6。
Embodiment 7
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Methyl-N-(3-(naphthalen-2-yl)-2-oxotetrahydropyrimidin-4(1H)-ylidene)benzenes ulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine: betanaphthyl isocyanates: to benzenesulfonyl azide: triethylamine: iodate is sub- Copper=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol, and solvent is acetonitrile, dosage 5mL.Add AddMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
For detailed process with embodiment 1, production obtains solid product 132mg, yield 67%, and the purity of product is 98%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,d6- DMSO) δ 8.77 (s, 1H), 7.98 (dd, J=12.5,8.3Hz, 2H), 7.58-7.50 (m, 3H), 7.41 (t, J=7.4Hz, 1H), 7.35 (d, J=7.1Hz, 1H), 7.23 (d, J=8.0Hz, 2H), 7.13 (d, J= 7.8Hz,2H),3.82–3.70(m,2H),3.08–3.00(m,1H),2.95–2.86(m,1H),2.32(s,3H)；13C NMR (151MHz,d6-DMSO)δ169.0,153.8,141.8,133.6,130.1,128.9,128.6,128.1,127.1,126.7, 126.1,125.44,125.35,122.3,36.4,31.0,20.9.
Embodiment 8
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N- (1-Benzyl-2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)-4- methylbenzenes ulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol, and solvent is acetonitrile, and dosage is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours.The time of second reaction is 6 hours.
Detailed process obtains solid product 186mg, yield 83% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3)δ1H NMR(600MHz,CDCl3) δ 7.50 (d, J=8.2Hz, 2H), 7.43- 7.33 (m, 5H), 7.23 (d, J=8.0Hz, 2H), 7.16 (d, J=8.1Hz, 2H), 7.05 (d, J=8.2Hz, 2H), 4.67 (s, 2H), 3.56 (t, J=6.6Hz, 2H), 3.47 (t, J=6.6Hz, 2H), 2.40 (s, 3H), 2.37 (s, 3H)；13C NMR (151MHz,CDCl3)δ165.8,152.7,142.9,139.3,138.4,136.0,134.0,129.7,129.2,129.1, 128.34,128.30,128.27,126.2,51.9,40.3,28.5,21.6,21.3。
Embodiment 9
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beIt is entitled 4-Methyl-N-(2-oxo-1-phenethyl-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene) benze nesulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, and dosage is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 201mg, yield 87% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(400MHz,CDCl3) δ 7.47 (d, J=8.3Hz, 2H), 7.33 (t, J=6.5Hz, 2H), 7.25-7.16 (m, 5H), 7.13 (d, J=8.1Hz, 2H), 6.96 (d, J=8.2Hz, 2H), 3.70 (t, J=7.1Hz, 2H), 3.42 (t, J= 6.6Hz, 2H), 3.31 (t, J=6.4Hz, 2H), 2.94 (t, J=7.1Hz, 2H), 2.37 (s, 3H), 2.35 (s, 3H)；13C NMR(151MHz,CDCl3)δ165.9,159.4,152.2,142.9,139.4,138.5,129.6,129.3,129.2, 129.0,128.9,127.0,126.2,114.3,55.6,51.1,42.2,34.1,28.4,21.6。
Embodiment 10
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N-(1-Butyl-2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)-4- methylbenzenesul fonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, and dosage is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 145mg, yield 70% with embodiment 1, and the purity of product is 97%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 7.48 (d, J=8.2Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 7.13 (d, J =8.1Hz, 2H), 6.98 (d, J=8.1Hz, 2H), 3.59 (t, J=6.2Hz, 2H), 3.53 (t, J=6.2Hz, 2H), 3.45 (t, J=7.3Hz, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 1.61-1.56 (m, 2H), 1.38-1.31 (m, 2H), 0.94 (t, J=7.4Hz, 3H)；13C NMR(151MHz,CDCl3)δ165.8,152.2,142.8,139.5,138.2,134.0,129.7, 129.2,128.3,126.2,48.6,41.1,29.6,28.6,21.6,21.3,20.1,13.9。
Embodiment 11
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle Are as follows: N- (3- (4-Methoxyphenyl) -2-oxo-1-phenethyltetrahydropyrimidin-4 (1H) - ylidene)-4-m ethylbenzenesulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: p-Methoxyphenyl isocyanate: p-toluene sulfonyt azide: three Ethamine: cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol, and solvent is acetonitrile, is used Amount is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 230mg, yield 96% with embodiment 1, and the purity of product is 98%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 7.49 (d, J=8.3Hz, 2H), 7.33 (t, J=7.4Hz, 2H), 7.27 (d, J =6.9Hz, 1H), 7.24-7.21 (m, 2H), 7.14 (d, J=8.0Hz, 2H), 7.02-6.96 (m, 2H), 6.93-6.88 (m, 2H), 3.82 (s, 3H), 3.70 (t, J=7.1Hz, 2H), 3.42 (t, J=6.7Hz, 2H), 3.30 (t, J=6.7Hz, 2H), 2.94 (t, J=7.1Hz, 2H), 2.35 (s, 3H)；13C NMR(151MHz,CDCl3)δ165.9,159.4,152.2,142.9, 139.4,138.5,129.6,129.3,129.2,128.93,128.92,127.0,126.2,114.3,55.6,51.1,42.2, 34.1,28.4,21.6。
Embodiment 12
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N-(3-(4-Chlorophenyl)-2-oxo-1-phenethyltetrahydropyrimidin-4(1H)-ylidene)-4- met hylbenzenesulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: chlorophenyl isocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, and dosage is 5mL.AdditionMolecular sieve 100mg, the time of the first reaction are 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 176mg, yield 73% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 7.51 (d, J=7.6Hz, 2H), 7.40-7.33 (m, 4H), 7.31-7.27 (m, 2H), 7.25-7.23 (m, 1H), 7.19 (d, J=7.5Hz, 2H), 7.04 (d, J=8.0Hz, 2H), 3.73 (t, J=6.5Hz, 2H), 3.50-3.41 (m, 2H), 3.38-3.29 (m, 2H), 2.97 (t, J=6.5Hz, 2H), 2.40 (s, 3H).
Embodiment 13
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N-(6-Benzyl-2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)-4- methylbenzenes ulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, and dosage is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 180mg, yield 80% with embodiment 1, and the purity of product is 98%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(400MHz,CDCl3) δ 8.38 (s, 1H), 7.43 (d, J=8.2Hz, 2H), 7.36-7.34 (m, 3H), 7.22-7.13 (m, 6H), 6.77 (d, J=8.2Hz, 2H), 4.10-3.91 (m, 1H), 3.01-2.87 (m, 3H), 2.79-2.72 (m,1H),2.39(s,3H),2.36(s,3H)；13C NMR(151MHz,CDCl3)δ167.6,153.4,142.7,139.6, 138.7,134.8,132.3,129.8,129.6,129.4,129.2,128.4,127.9,126.1,49.3,41.2,37.0, 21.6,21.3。
Embodiment 14
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4-Methyl-N-(2-oxo-6-phenethyl-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene) benze nesulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: to toluene diisocyanate: to benzenesulfonyl azide: triethylamine: iodine Change cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol, and solvent is acetonitrile, and dosage is 5mL。Molecular sieve dosage is 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 190mg, yield 82% with embodiment 1, and the purity of product is 98%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(400MHz,CDCl3) δ 8.48 (s, 1H), 7.57 (d, J=8.1Hz, 2H), 7.33 (t, J=7.3Hz, 2H), 7.26 (d, J=3.5Hz, 1H), 7.21-7.18 (m, 6H), 6.89 (d, J=8.1Hz, 2H), 3.74-3.66 (m, 1H), 2.96 (dd, J=16.4,4.7Hz, 1H), 2.82-2.67 (m, 3H), 2.39 (s, 3H), 2.38 (s, 3H), 2.08-1.93 (m, 2H)；13C NMR(151MHz,CDCl3)δ167.7,153.5,142.8,139.7,139.5,138.8,132.3,129.8, 129.3,129.0,128.5,128.4,126.8,126.1,47.0,37.4,36.2,31.4,21.6,21.4。
Embodiment 15
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle Are as follows: N- (6-Hexyl-2-oxo-3- (p-tolyl) tetrahydropyrimidin-4 (1H)-ylidene) -4- methylbenzenesu lfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, and dosage is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 143mg, yield 65% with embodiment 1, and the purity of product is 97%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(400MHz,CDCl3) δ 8.37 (s, 1H), 7.54 (d, J=8.2Hz, 2H), 7.21-7.16 (m, 4H), (6.89 d, J=8.2Hz, 2H), 3.78-3.71 (m, 1H), 2.93 (dd, J=16.3,4.5Hz, 1H), 1.72-1.62 (m, 1H), 2.39 (s, 3H), 2.38 (s, 3H), 1.67 (dd, J=14.8,7.8Hz, 2H), 1.36-1.27 (m, 8H), 0.91 (t, J =6.7Hz, 3H)；13C NMR(151MHz,CDCl3)δ168.0,153.6,142.8,139.8,138.7,132.4,129.8, 129.3,128.5,126.1,48.1,37.6,34.7,31.7,29.0,25.3,22.7,21.6,21.4,14.2。
Embodiment 16
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N- (3- Benzyl-2-oxo-1-phenethyltetrahydropyrimidin-4(1H)-ylidene)-4-methylbenzen esulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: benzyl isocyanate ester: to benzenesulfonyl azide: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL. AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 227mg, yield 98% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 7.65 (d, J=7.1Hz, 2H), 7.28-7.24 (m, 6H), 7.21-7.13 (m, 6H),4.98(s,2H),3.72–3.62(m,2H),3.29–3.19(m,2H),3.17–3.09(s,2H),2.94–2.85(s, 2H),2.42(s,3H)；13C NMR(151MHz,CDCl3)δ164.3,152.0,143.2,139.2,138.4,136.9, 129.4,128.89,128.86,128.7,128.4,127.4,126.9,126.6,51.1,46.2,41.9,34.0,28.0, 21.6。
Embodiment 17
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N- (2- Oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: benzenesulfonyl azide: triethylamine: cuprous iodide =1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol, and solvent is acetonitrile, dosage 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 4 hours.
Detailed process obtains solid product 139mg, yield 81% with embodiment 1, and the purity of product is 97%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 8.41 (s, 1H), 7.69-7.63 (m, 2H), 7.49 (t, J=7.4Hz, 1H), 7.39 (t, J=7.8Hz, 2H), 7.18 (d, J=8.1Hz, 2H), 6.91 (d, J=8.2Hz, 2H), 3.63-3.59 (m, 2H), 2.86 (t, J=6.7Hz, 2H), 2.37 (s, 3H)；13C NMR(151MHz,CDCl3)δ168.2,154.2,142.5,138.7, 132.5,132.1,129.7,128.7,128.5,125.9,36.6,31.7,21.3。
Embodiment 18
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: N-(4-(N-(2-Oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)sulfamoyl)phenyl) acet amide。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: acetparaminosalol benzenesulfonyl azide: three second Amine: cuprous iodide=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage For 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 5 hours.
Detailed process obtains solid product 138mg, yield 69% with embodiment 1, and the purity of product is 97.5%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,d6- DMSO) δ 10.24 (s, 1H), 8.61 (s, 1H), 7.65 (d, J=8.7Hz, 2H), 7.53 (d, J=8.7Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 6.96 (d, J=8.1Hz, 2H), 3.60 (td, J=6.8,3.2Hz, 2H), 2.80 (t, J=6.8Hz, 2H), 2.32 (s, 3H), 2.07 (s, 3H)；13C NMR(151MHz,d6-DMSO)δ168.9, 168.8,153.7,142.2,137.2,136.8,133.6,129.0,128.8,126.6,118.2,36.1,31.0,24.1, 20.7。
Embodiment 19
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Bromo-N-(2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonamid e。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: brosyl nitrine: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL. AdditionMolecular sieve 100mg.The time of first reaction is 4 hours, and the time of the second reaction is 4 hours.
Detailed process obtains solid product 180mg, yield 85% with same embodiment 1, and the purity of product is 98%.
Nuclear magnetic resonance test also is carried out to obtained product, specific test data is as follows:
1H NMR(600MHz,CDCl3) δ 8.33 (s, 1H), 7.55-7.47 (m, 4H), 7.20 (d, J=8.1Hz, 2H), 6.91 (d, J=8.2Hz, 2H), 3.65 (td, J=6.9,3.1Hz, 2H), 2.90 (t, J=6.9Hz, 2H), 2.39 (s, 3H)；13C NMR(151MHz,CDCl3)δ168.0,154.3,141.6,138.9,132.4,131.9,129.9,128.5,127.6, 126.9,36.7,31.7,21.4。
Embodiment 20
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Methyl-N-(2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonami de。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is 1,2- dichloroethanes, is used Amount is 5mL.AdditionMolecular sieve 100mg.The time of first reaction is 3 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 123mg, yield 69% with embodiment 1, and the purity of product is 97%.
Embodiment 21
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Methyl-N-(2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonami de。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: bromination Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL. AdditionMolecular sieve 100mg.The time of first reaction is 3 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 116mg, yield 65% with embodiment 1, and the purity of product is 97.5%.
Embodiment 22
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Methyl-N-(2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonami de。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: cyaniding Cuprous=1.0:1.02:1.0:2.0:0.1, wherein the dosage of propargylamine is 0.5mmol.Solvent is acetonitrile, dosage 5mL. AdditionMolecular sieve 100mg.The time of first reaction is 3 hours, and the time of the second reaction is 6 hours.
Detailed process obtains solid product 118mg, yield 66% with embodiment 1, and the purity of product is 97%.
Embodiment 23
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle are as follows: 4- Methyl-N-(2-oxo-3-(p-tolyl)tetrahydropyrimidin-4(1H)-ylidene)benzenesulfonami de。
The mass ratio of the material of raw material is as follows: propargylamine: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: iodate Cuprous=1.0:1.02:1.0:2.0:0.15, wherein the dosage of propargylamine is 10mmol.Solvent is acetonitrile, dosage 80mL. AdditionMolecular sieve 2.0g.The time of first reaction is 4 hours, time 16 hours of the second reaction.Detailed process is as follows:
Equipped in stirrer 250mL round-bottomed flask, logical nitrogen is first vacuumized, propargylamine is added under anhydrous and oxygen-free environment Solution is cooled to 0 DEG C, is slowly added dropwise to toluene diisocyanate 1.385g by the acetonitrile solution 30mL of 551mg (10mmol) The acetonitrile solution 20mL of (10.4mmol) is warming up to room temperature reaction 4 hours, and TLC tracks to raw material fully reacting.In nitrogen environment Lower additionMolecular sieve 2.0g and cuprous iodide 285mg (15mol%), adds p-toluene sulfonyt azide 1.970g The acetonitrile solution 15mL of (10mmol) is finally slowly added dropwise the acetonitrile solution 15mL of triethylamine 2.024g (20mmol), is warming up to 70 DEG C are reacted 16 hours, and it is complete that TLC tracks to intermediate reaction, and reaction solution is evaporated under reduced pressure, by silica gel post separation, consolidate Body product 2.427g, yield 68%, the purity of product are 97.5%.
This embodiment is the amplification test of embodiment 1, the results show that the amplification effect is good, it can industrialized production.
Embodiment 24
Synthesis 4- imido grpup tetrahydropyrimidin-2-ones class compound structural formula beTitle Are as follows: 4-Methyl-N- (2-oxo-1-phenethyl-3- (p-tolyl) tetrahydropyrimidin-4 (1H)- ylidene)benze nesulfonamide。
The mass ratio of the material of raw material is as follows: propargylamine substrate: to toluene diisocyanate: p-toluene sulfonyt azide: triethylamine: Cuprous iodide=1.0:1.02:1.0:2.0:0.15, wherein the dosage of propargylamine is 10mmol, and solvent is acetonitrile, and dosage is 80mL.AdditionMolecular sieve 2.0g.The time of first reaction is 4 hours, and the time of the second reaction is 16 hours.
Detailed process obtains solid product 3.698g, yield 80% with embodiment 23, and the purity of product is 97%.
This embodiment is the amplification test of embodiment 9, the results show that the amplification effect is good, it can industrialized production.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims (9)

1. a kind of preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound, which is characterized in that itself the following steps are included:
(1) propargylamine, isocyanates are mixed in solvent, carries out the first reaction, obtains mixture；
(2) molecular sieve, catalyst, sulfonyl nitrine and organic base are sequentially added to the mixture, carries out the second reaction, obtains 4- imido grpup tetrahydropyrimidin-2-ones class compound.
2. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, which is characterized in that In step (1), the structural formula of the propargylamine isThe structural formula of the isocyanates is R3- NCO, the sulfonyl The chemical formula of nitrine is R4-SO2N3, wherein R1For one of hydrogen, phenethyl, benzyl, n-hexyl, R2For hydrogen, benzyl, benzene second One of base, normal-butyl, R3For phenyl, p-methylphenyl, tolyl, o-tolyl, p-methoxyphenyl, rubigan, One of chlorphenyl, naphthalene, benzyl, R4For one of p-methylphenyl, phenyl, rubigan, acetparaminosalol phenyl.
3. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, which is characterized in that Solvent described in step (1) is acetonitrile or 1,2- dichloroethanes.
4. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, which is characterized in that The ratio of molecular sieve described in step (2) and propargylamine is (100mg~300mg): 1mmol.
5. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, which is characterized in that In step (2) organic base be one of triethylamine, diisopropylethylamine, n,N-diisopropylethylamine, triethylene diamine, it is described Catalyst is one of cuprous iodide, cuprous bromide, cuprous cyanide.
6. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, which is characterized in that The propargylamine, isocyanates, sulfonyl nitrine, organic base, catalyst substance amount ratio be 1.0:1.02:1.0: 2.0:(0.1~0.2).
7. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, which is characterized in that It is described first reaction in, temperature be 15 DEG C~35 DEG C, the time be 2 hours~4 hours, it is described first reaction under an inert atmosphere into Row.
8. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, which is characterized in that In second reaction, temperature is 60 DEG C~80 DEG C, and the time is 3 hours~16 hours, and second reaction is under an inert atmosphere It carries out.
9. the preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound according to claim 1, step (2) it After further include the steps that one isolates and purifies.
CN201811153808.8A 2018-09-30 2018-09-30 The preparation method of 4- imido grpup tetrahydropyrimidin-2-ones class compound Pending CN109053589A (en)

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CN103193715A (en) * 2013-03-28 2013-07-10 浙江大学 Preparation method of 5,6-dihydropyrimidone derivative

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EP0123402B1 (en) * 1983-03-25 1988-09-07 Fujisawa Pharmaceutical Co., Ltd. Pyrimidine derivatives, preparation thereof and use thereof
CN103193715A (en) * 2013-03-28 2013-07-10 浙江大学 Preparation method of 5,6-dihydropyrimidone derivative

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Application publication date: 20181221