CN102285967A - 2-arylmethylmercapto-6-(tetrahydroquinoline-1-methyl)-4-pyrimidone derivatives, and preparation method and use thereof - Google Patents

2-arylmethylmercapto-6-(tetrahydroquinoline-1-methyl)-4-pyrimidone derivatives, and preparation method and use thereof Download PDF

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CN102285967A
CN102285967A CN2011101510120A CN201110151012A CN102285967A CN 102285967 A CN102285967 A CN 102285967A CN 2011101510120 A CN2011101510120 A CN 2011101510120A CN 201110151012 A CN201110151012 A CN 201110151012A CN 102285967 A CN102285967 A CN 102285967A
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methyl
quinoline
tetrahydroquinoline
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chloroacetophenone
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刘新泳
张静
展鹏
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Shandong University
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Abstract

The invention discloses 2-[(substitutedphenylamino)carbonylmethylmercapto]-6-(2,6-dichlorobenzyl)-3H-pyrimidine-4-one derivatives. The general structural formula of the derivatives is shown below. In the general structural formula, R1 may be H, methyl or ethyl; R2 may be 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, benzyl bromide, 4-methyl benzyl chloride, 4-chlorobenzyl chloride, 4-nitrobenzyl chloride, p-cyanobenzyl chloride, alpha-chloro-4-methoxytoluene or 4-fluorobenzyl chloride. The invention also relates to the preparation method of the compounds and the use of the compounds as human immunodeficiency virus (HIV) inhibitors.

Description

2-arylmethylthio-6- (tetrahydroquinoline-1-methyl) -4-pyrimidone derivative and preparation method and application thereof
Technical Field
The invention relates to a derivative and a preparation method thereof, in particular to a 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidine-4-ketone derivative and a preparation method and application thereof, belonging to the technical field of organic compound synthesis and medical application.
Background
Acquired Immune Deficiency Syndrome (AIDS) is an infectious disease caused by Human Immunodeficiency Virus (HIV), and seriously affects the life health of human beings. HIV is a retrovirus and the important role of reverse transcriptase in the viral life cycle makes it an important target for antiviral therapy. Reverse transcriptase inhibitors fall into two classes: nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are of great interest because of their high potency, low toxicity, high selectivity, and the like. But the spreading of drug-resistant strains causes the drugs to lose clinical potency rapidly. Therefore, the research and development of novel, highly effective, low-toxicity, broad-spectrum drug-resistant NNRTIs is one of the important directions of the current anti-HIV drug research.
There are over 50 classes of NNRTIs reported in the literature, of which Dihydroalkoxybenzylpyrimidinone (DABOs) derivatives are the more typical class. The DABO derivatives can improve the flexibility of molecular conformation and the position adaptability in a target spot, and are beneficial to improving the activity of the compound. We summarize the results of previous research on DABOs and find that 2-thio-DABO analogues significantly improve the anti-HIV-1 RT activity, and become a class of NNRTIs with development prospects. Up to now, S-DABOs pyrimidine mother ring is used as basic skeleton, for C2-，C3-，C4-，C5-，C6-After a series of structural modifications, a plurality of high-activity S-DABOs derivatives have been discovered and subjected to structure-activity relationship (SAR) research.
Therefore, the S-DABOs pyrimidine mother ring is used as a basic framework, and effective information of the structure-activity relationship of a lead compound is utilized to structurally modify the 6-site side chain, so that the method has important significance for finding broad-spectrum efficient anti-HIV drugs.
Disclosure of Invention
The invention aims to provide 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidine-4-ketone derivatives and a preparation method thereof, and also provides application of the compounds.
The technical scheme of the invention is as follows:
1.5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives
The 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidine-4-ketone derivative has the following structural general formula I:
Figure BDA0000066638180000011
wherein,
R1comprises the following steps: H. methyl or ethyl;
R2comprises the following steps: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitrochlorobenzyl, p-cyanochlorobenzyl, p-methoxychlorobenzyl or p-fluorobenzyl chloride.
Preferably, the compound of formula I above is one of the following:
Figure BDA0000066638180000021
Figure BDA0000066638180000031
Figure BDA0000066638180000041
Figure BDA0000066638180000051
the synthetic route for 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives is as follows:
Figure BDA0000066638180000052
reagent: (i) k2CO3Toluene, refluxing for 24h, 90 ℃; (ii) 15% NaOH, 15 h; (iii) MgCl2，Et3N，CH3CN，R1CH(CO2Et)(CO2K) N, N-carbonyl diimidazole, stirring at room temperature overnight, and refluxing for 2 hours; (iv) thiourea, EtONa, under reflux for 6-12 hours; (v) substituted halobenzyl and substituted alpha-haloacetophenone, potassium carbonate (K)2CO3) N, N-Dimethylformamide (DMF) at room temperature for 12 hours.
3. Preparation method of intermediate 1, 2, 3, 4-tetrahydroquinoline-1-acetic acid
30.37mmol of 1, 2, 3, 4-tetrahydroquinoline and K2CO360.78mmol is put into 80mL toluene, 29.94mmol of bromoethyl acetate is dropped into the mixture under the stirring condition, the mixture reacts for 24 hours under the condition of 90 ℃, and the TLC detection reaction is carried out; after the reaction, cooling the reaction liquid to room temperature, filtering, distilling under reduced pressure, extracting the residual liquid with chloroform for three times, and washing with brine; drying with anhydrous magnesium sulfate to obtain crude product, and purifying with ethyl acetate-petroleum ether column chromatography at volume ratio of 1: 4 to obtain brown oily pure product. Directly adding into 1mol/L NaOH aqueous solution without purification, refluxing for 12h, cooling, dripping into 1mol/LHCl to generate brown precipitate, filtering, and drying to obtain crude product.
1, 2, 3, 4-tetrahydroquinoline-1-acetic acid (3), brown solid, yield 46.5%, mp: 45-46 ℃ (dec) ms (esi): m/z192.31(M +1).
4. Preparation of beta-keto esters (4a-c)
0.5mol of substituted diethyl malonate is placed in 800mL of anhydrous acetonitrile, and 0.595mol of anhydrous MgCl is sequentially added2，0.717mol Et3N, stirring for 2 hours at room temperature; 0.25mol of 1, 2, 3, 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N, N-carbonyldiimidazole are put into 300mL of acetonitrile to react for 15 minutes, and then the reaction mixture is poured into substituted diethyl malonate, anhydrous MgCl2，Et3N in the mixed solution; stirring at room temperature overnight, heating and refluxing for 2h, and tracking by TLC until the reaction is complete; dropwise adding 150mL of HCl with the mass concentration of 13% in an ice bath environment, stirring for 10min after dropwise adding, taking out organic layers by layers, evaporating to dryness, and adding 150mL of ethyl acetate; the mixed solution of ethyl acetate is firstly added with NaHCO3Washed three times, 150ml each time, then washed three times with NaCl solution, 150ml each time, then anhydrous MgSO4Drying, and distilling under reduced pressure to obtain crude beta-keto ester (4a-c), which is directly used in the next step without purification.
Ethyl 3-oxo-4- (1- (1, 2, 3, 4-tetrahydroquinoline)) butyrate (4 a): yellow clear oil, yield: 15.1%, MS (ESI): m/z 262.30(M +1).
Ethyl 2-methyl-3-oxo-4- (1- (1, 2, 3, 4-tetrahydroquinoline)) butyrate (4 b): yellow clear oil, yield: 12.1%, MS (ESI): m/z 276.41(M +1).
Ethyl 2-ethyl-3-oxo-4- (1- (1, 2, 3, 4-tetrahydroquinoline)) butanoate (4 c): yellow clear oil, yield: 10.7%, MS (ESI): m/z 290.33(M +1).
Synthesis of 5.5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one
Adding 0.3mol of sodium into 100mL of absolute ethyl alcohol in batches in a dry reaction bottle, adding 0.225mol of thiourea into the reaction bottle at a time when the sodium is dissolved and cooled, then adding 0.15mol of a crude product beta-keto ester 4a-c, heating and refluxing the mixture, stopping heating after TLC (thin layer chromatography) tracks until a raw material point of the beta-keto ester disappears, evaporating the solvent under reduced pressure after cooling, dissolving the residue into 100mL of water, filtering, and adjusting the pH value to 4 by using 1mol/L of hydrochloric acid and glacial acetic acid to generate white precipitate; filtering, washing the filter cake with glacial ethanol and glacial ethyl ether to obtain 5a-c white solid; can be directly used in the next step without purification (containing more than 90% of pure product).
6- (1, 2, 3, 4-tetrahydroquinolinylmethyl) -2-mercapto-4 (3H) pyrimidinone (5 a): white solid, yield: 67.1%, mp: 238 deg.C and 240 deg.C (dec).1H NMR(DMSO-d6，ppm)δ：12.41(s，1H，N3H)，12.37(s，1H，N1H)，6.35-6.95(m，4H，quinoline-H)，5.41(s，1H，C5-H)，4.19(s，2H，NCH2)3.31-3.33(m，2H，quinoline-H2)，2.71-2.73(m，2H，quinoline-H4)，1.89-1.90(m，2H，quinoline-H3)；ESI-MS：m/z 274.09(M+1)。
6- (1, 2, 3, 4-tetrahydroquinolinylmethyl) -2-mercapto-5-methyl-4 (3H) pyrimidinone (5 b): white solid, yield: 70.3%, mp: 227 ℃ to 228 ℃ (dec).1H NMR(DMSO-d6，ppm)δ：12.01(s，1H，N3H)，11.99(s，1H，N1H)，6.57-6.99(m，4H，quinoline-H)，5.41(s，1H，C5-H)，4.21(s，2H，NCH2)3.15-3.17(m，2H，quinoline-H2)，2.68-2.70(m，2H，quinoline-H4)，1.86-1.88(m，2H，quinoline-H3)，1.79(s，3H，C5-CH3).ESI-MS：m/z 288.11(M+1).C15H17N3OS(287.38)。
6- (1, 2, 3, 4-tetrahydroquinolinylmethyl) -2-mercapto-5-ethyl-4 (3H) pyrimidinone (5 c): white solid, yield: 69.7%, mp: 210 deg.C and 211 deg.C (dec).1H NMR(DMSO-d6，ppm)δ：12.03(s，1H，N3H)，12.01(s，1H，N1H)，6.45-6.97(m，4H，quinoline-H)，4.20(s，2H，NCH2)3.30-3.37(m，2H，quinoline-H2)，2.37-2.45(m，2H，quinoline-H4)，2.28-2.31(q，2H，J＝7.2Hz，C5-CH2CH3)，1.68-1.79(m，2H，quinoline-H3)，1.79(s，3H，C5-CH3)，1.62-1.71(m，2H，quinolineH3)，1.05(t，3H，J＝7.2Hz，C5-CH2CH3).ESI-MS：m/z302.12(M+1)。
Process for the preparation of 6.5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives
And (2) performing alkylation reaction on the intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidine-4-ketone and each substituted halobenzyl and substituted alpha-halogenated acetophenone, and then performing recrystallization and purification to obtain the derivative 6 of the 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidine-4-ketone derivative, wherein the substituent is selected from the following groups: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitrobenzyl chloride, p-cyanoborobenzyl, p-methoxybenzyl chloride or p-fluorobenzyl chloride, and the target compound 6a1-6c14 is obtained, and the structure is shown in Table 1.
Preferred operating steps are provided below:
reacting 5-alkyl-6arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a-c) (2mmol) and K2CO3(2.2mmol) is placed in a reaction bottle, anhydrous Dimethylformamide (DMF) is added, after stirring for 30min at room temperature, 2.0mmol of substituent (substituted chloroacetanilide or substituted chlorobenzyl) is added, stirring is carried out at room temperature, TLC (thin layer chromatography) is carried out until the raw material point disappears, and the reaction is stopped; adding ice water to generate white precipitate; filtering, and recrystallizing with EtOH or EtOH-DMF mixed solvent to obtain target compound; the target compounds 6a1-6c14 (see Table 1) were obtained.
7.5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives pharmaceutical composition
An anti-HIV-1 pharmaceutical composition comprises the 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidine-4-ketone derivative and pharmaceutical excipients, and is prepared into medicines of different dosage forms.
8.5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives and their use
The 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidine-4-ketone derivative can be used as an HIV-1 non-nucleoside inhibitor. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.
The invention is based on molecular simulation, C2-By substituting halobenzyl and substituted alpha-haloacetophenone by active groups, in C6-1, 2, 3, 4-tetrahydroquinoline-1-methyl with stronger flexibility is introduced into the side chain to increase the hydrophobic and hydrogen bond interaction between inhibitor molecules and surrounding amino acid residues, so as to synthesize a series of 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl]-3H-pyrimidin-4-one derivatives. The series of compounds have high anti-HIV activity and low cytotoxicity, and have further medicinal development value.
The specific implementation mode is as follows:
the invention is further illustrated by the following examples, all of the target compounds being numbered as in Table 1. The percentage numbers are all mass percentages.
EXAMPLE 1 Synthesis of intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one
Preparation of intermediate 1, 2, 3, 4-tetrahydroquinoline-1-acetic acid
30.37mmol of 1, 2, 3, 4-tetrahydroquinoline and K2CO360.78mmol is put into 80mL toluene, 29.94mmol of bromoethyl acetate is dropped into the mixture under the stirring condition, the mixture reacts for 24 hours under the condition of 90 ℃, and the TLC detection reaction is carried out; after the reaction, cooling the reaction liquid to room temperature, filtering, distilling under reduced pressure, extracting the residual liquid with chloroform for three times, and washing with brine; drying with anhydrous magnesium sulfate to obtain crude product, and purifying with ethyl acetate-petroleum ether column chromatography at volume ratio of 1: 4 to obtain brown oily pure product. Directly adding into 1mol/L NaOH aqueous solution without purification, refluxing for 12h, cooling, dripping into 1mol/LHCl to generate brown precipitate, filtering, and drying to obtain crude product.
1, 2, 3, 4-tetrahydroquinoline-1-acetic acid (3), brown solid, yield 46.5%, mp: 45-46 ℃ (dec) ms (esi): m/z192.31(M +1).
Preparation of beta-keto esters (4a-c)
0.5mol of substituted diethyl malonate is placed in 800mL of anhydrous acetonitrile, and 0.595mol of anhydrous MgCl is sequentially added2，0.717mol Et3N, stirring for 2 hours at room temperature; 0.25mol of 1, 2, 3, 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N, N-carbonyldiimidazole are put into 300mL of acetonitrile to react for 15 minutes, and then the reaction mixture is poured into substituted diethyl malonate, anhydrous MgCl2，Et3N in the mixed solution; stirring at room temperature overnight, heating and refluxing for 2h, and tracking by TLC until the reaction is complete; dropwise adding 150mL of HCl with the mass concentration of 13% in an ice bath environment, stirring for 10min after dropwise adding, taking out organic layers by layers, evaporating to dryness, and adding 150mL of ethyl acetate; the mixed solution of ethyl acetate is firstly added with NaHCO3Washing three150ml each time, and washed three times with 150ml each time of NaCl solution, followed by anhydrous MgSO4Drying, and distilling under reduced pressure to obtain crude beta-keto ester (4a-c), which is directly used in the next step without purification.
Ethyl 3-oxo-4- (1- (1, 2, 3, 4-tetrahydroquinoline)) butyrate (4 a): yellow clear oil, yield: 15.1%, MS (ESI): m/z 262.30(M +1).
Ethyl 2-methyl-3-oxo-4- (1- (1, 2, 3, 4-tetrahydroquinoline)) butyrate (4 b): yellow clear oil, yield: 12.1%, MS (ESI): m/z 276.41(M +1).
Ethyl 2-ethyl-3-oxo-4- (1- (1, 2, 3, 4-tetrahydroquinoline)) butanoate (4 c): yellow clear oil, yield: 10.7%, MS (ESI): m/z 290.33(M +1).
Synthesis of 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one:
sodium (6.9g, 0.3mol) was added in portions to 100mL of anhydrous ethanol, thiourea (17.1g, 0.225mol) was added in one portion after the sodium was dissolved and cooled, then the crude product β -keto ester 4a-c (0.15mol) was added, the mixture was heated under reflux, the heating was stopped after the TLC tracking until the β -keto ester starting point disappeared, the solvent was distilled off under reduced pressure after cooling, the residue was dissolved in water (100mL), filtered, and adjusted to PH 4 with 1mol/L hydrochloric acid, glacial acetic acid, and a white precipitate was generated. Filtering, washing the filter cake with glacial ethanol and glacial ethyl ether to obtain 5a-c white solid. Can be directly used in the next step without purification (containing more than 90% of pure product).
6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl]-2-mercapto-4 (3H) pyrimidinone (5 a): white solid, yield: 67.1%, mp: 238 deg.C and 240 deg.C (dec).1H NMR(DMSO-d6，ppm)δ：12.41(s，1H，N3H)，12.37(s，1H，N1H)，6.35-6.95(m，4H，quinoline-H)，5.41(s，1H，C5-H)，4.19(s，2H，NCH2)3.31-3.33(m，2H，quinoline-H2)，2.71-2.73(m，2H，quinoline-H4)，1.89-1.90(m，2H，quinoline-H3)；ESI-MS：m/z 274.09(M+1)。6-[(1，2，3, 4-tetrahydroquinoline) -1-methyl]-2-mercapto-5-methyl-4 (3H) pyrimidinone (5 b): white solid, yield: 70.3%, mp: 227 ℃ to 228 ℃ (dec).1H NMR(DMSO-d6，ppm)δ：12.01(s，1H，N3H)，11.99(s，1H，N1H)，6.57-6.99(m，4H，quinoline-H)，5.41(s，1H，C5-H)，4.21(s，2H，NCH2)3.15-3.17(m，2H，quinoline-H2)，2.68-2.70(m，2H，quinoline-H4)，1.86-1.88(m，2H，quinoline-H3)，1.79(s，3H，C5-CH3).ESI-MS：m/z 288.11(M+1).C15H17N3OS(287.38)。
6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl]-2-mercapto-5-ethyl-4 (3H) pyrimidinone (5 c): white solid, yield: 69.7%, mp: 210 deg.C and 211 deg.C (dec).1H NMR(DMSO-d6，ppm)δ：12.03(s，1H，N3H)，12.01(s，1H，N1H)，6.45-6.97(m，4H，quinoline-H)，4.20(s，2H，NCH2)3.30-3.37(m，2H，quinoline-H2)，2.37-2.45(m，2H， quinoline-H4)，2.28-2.31(q，2H，J＝7.2Hz，C5-CH2CH3)，1.68-1.79(m，2H，quinoline-H3)，1.79(s，3H，C5-CH3)，1.62-1.71(m，2H，quinolineH3)，1.05(t，3H，J＝7.2Hz，C5-CH2CH3).ESI-MS：m/z302.12(M+1)。
Example 22-Phenylcarbonylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a1)
The reaction mixture of 6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a) (2mmol) and K2CO3(2.2mmol) is placed in a reaction bottle, anhydrous DMF is added, after stirring for 30min at room temperature, substituent 2-bromoacetophenone (2.0mmol) is added, stirring is carried out at room temperature, TLC tracking is carried out until the raw material point disappears, and the reaction is stopped. Ice water was added and a white precipitate formed. Filtering, and recrystallizing by using EtOH or EtOH-DMF mixed solvent to obtain the yield of the target compound: 48.6%, mp: 160 ℃ and 163 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.72(s，1H，NH)，8.04(d，2H，J＝7.8Hz，PhH)，7.69(t，1H，J1＝7.8Hz，J2＝15.6Hz，PhH)，7.58(t，2H，J1＝7.8Hz，J2＝15.6Hz，PhH)，6.23-6.86(m，4H，quinoline-H)，5.86(s，1H，C5-H)，4.77(s，2H，SCH2)，3.99(s，2H，NCH2)，3.24-3.26(m，2H，quinoline-H2)，2.61-2.63(m，2H，quinoline-H4)，1.75-1.77(m，2H，quinoline-H3).IR(KBr，cm-1)v3315(NH)，2945，2846(CH2)，1703(C＝O)，1654(C＝O)，1598，1575，1541，1499(aryl)，1239(C-N)，1204(C-N).ESI-MS：m/z 392.47(M+1).C22H21N3O2S(391.49).
example 32- [ (4-Methylphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a2)
The preparation was carried out as in example 2, except that the substituent was p-methyl-2-chloroacetophenone.
The product 2- [ (4-methylphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a2) was obtained in 54.1% yield, mp: 165 ℃ and 166 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.68(s，1H，NH)，7.93(d，2H，J＝7.8Hz，PhH)，7.36(d，2H，J＝7.8Hz，PhH)，6.24-6.87(m，4H，quinoline-H)，5.87(s，1H，C5-H)，4.74(s，2H，SCH2)，4.02(s，2H，NCH2)，3.26-3.31(m，2H，quinoline-H2)，2.71-2.73(m，2H，quinoline-H4)，2.39(s，3H，PhCH3)，1.76-1.78(m，2H，quinoline-H3).IR(KBr，cm-1)v 3421(NH)，2927，2841(CH3，CH2)，1675(C＝O)，1655(C＝O)，1602，1538，1506，1459(aryl)，1315(C-N)，1200(C-N).ESI-MS：m/z 406.47(M+1).C23H23N3O2S(405.51).
example 42- [ (4-chlorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a3)
The preparation is as in example 2 except that the substituent is p-chloro-2-chloroacetophenone.
The product obtained, 2- [ (4-chlorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a3), was 37.9% in yield, mp: 193 ℃ and 195 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.79(s，1H，NH)，8.05(d，2H，J＝8.4Hz，PhH)，7.64(d，2H，J＝8.4Hz，PhH)，6.22-6.86(m，4H，quinoline-H)，5.87(s，1H，C5-H)，4.75(s，2H，SCH2)，3.99(s，2H，NCH2)，3.25-3.33(m，2H，quinoline-H2)，2.62-2.64(m，2H，quinoline-H4)，1.76-1.78(m，2H，quinoline-H3).IR(KBr，cm-1)v 3522(NH)，2927，2843(CH2)，1690(C＝O)，1656(C＝O)，1600，1587，1545，1503(aryl)，1310(C-N)，1195(C-N).ESI-MS：m/z 426.87(M+1).C22H20ClN3O2S(425.93).
example 52- [ (4-Nitrophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a4)
The preparation method was the same as example 2, except that the substituent was p-nitro-2-chloroacetophenone.
The product 2- [ (4-nitrophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a4) was obtained in 45.1% yield, mp: 215 ℃ and 216 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.37(s，1H，NH)，8.27(d，2H，J＝8.4Hz，PhH)，8.03(d，2H，J＝8.4Hz，PhH)，6.35-6.95(m，4H，quinoline-H)，5.41(s，1H，C5-H)，4.65(s，2H，SCH2)，4.19(s，2H，NCH2)，3.32-3.34(m，2H，quinoline-H2)，2.71-2.73(m，2H，quinoline-H4)，1.89-1.90(m，2H，quinoline-H3).IR(KBr，cm-1)v 3405(NH)，2923，2856(CH2)，1703(C＝O)，1640(C＝O)，1579，1508，1458(aryl)，1308(C-N)，1185(C-N).ESI-MS：m/z 437.51(M+1).C22H20N4O4S(436.48).
example 62- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a5)
The preparation was as in example 2, except that the substituent was p-cyano-2-chloroacetophenone.
The product 2- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a5) was obtained in 43.3% yield, mp: 174 deg.C and 175 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.73(s，1H，NH)，7.67-7.98(m，4H，PhH)，6.73-7.01(m，4H，quinoline-H)，5.41(s，1H，C5-H)，4.66(s，2H，SCH2)，4.12(s，2H，NCH2)，3.27-3.31(m，2H，quinoline-H2)，2.41-2.53(m，2H，quinoline-H4)，1.79-1.90(m，2H，quinoline-H3).IR(KBr，cm-1)v3391(NH)，2925，2848(CH2)，2229(C≡N)，1662(C＝O)，1601(C＝O)，1581，1504，1458(aryl)，1272(C-N)，1198(C-N).ESI-MS：m/z 417.52(M+1).C23H20N4O2S(416.50).
example 72- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a6)
The preparation was as in example 2, except that the substituent was p-cyano-2-chloroacetophenone.
The product 2- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a6) was obtained in 39.1% yield, mp: 163 ℃ and 165 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.72(s，1H，NH)，8.02(d，2H，J＝8.4Hz，PhH)，7.07(d，2H，J＝8.4Hz，PhH)，6.28-6.87(m，4H，quinoline-H)，5.82(s，1H，C5-H)，4.69(s，2H，SCH2)，4.03(s，2H，NCH2)，3.85(s，3H，PhOCH3).3.28-3.38(m，2H，quinoline-H2)，2.63-2.65(m，2H，quinoline-H4)，1.78-1.80(m，2H，quinoline-H3).1R(KBr，cm-1)v 3416(NH)，2931，2838(CH3，CH2)，1656(C＝O)，1610(C＝O)，1599，1574，1535，1507(aryl)，1259(C-N)，1172(C-N).ESI-MS：m/z 422.54(M+1).C23H23N3O3S(421.51).
example 82- [ (4-fluorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a7)
The preparation method was the same as example 2, except that the substituent was p-fluoro-2-chloroacetophenone.
The product 2- [ (4-fluorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a7) was obtained in 47.1% yield, mp: 180 ℃ and 181 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.73(s，1H，NH)，8.10-8.13(m，2H，PhH)，7.37-7.40(m，2H，PhH)，6.23-6.86(m，4H，quinoline-H)，5.85(s，1H，C5-H)，4.74(s，2H，SCH2)，4.19(s，2H，NCH2)3.26-3.33(m，2H，quinoline-H2)，2.62-2.64(m，2H，quinoline-H4)，1.77-1.81(m，2H，quinoline-H3).IR(KBr，cm-1)v 3318(NH)，2940，2852(CH2)，1702(C＝O)，1655(C＝O)，1597，1575，1539，1502(aryl)，1220(C-N)，1154(C-N).ESI-MS：m/z 410.49(M+1).C22H20FN3O2S(409.48).
example 92-Phenylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a8)
The procedure is as in example 2, except that the substituent is benzyl bromide.
The product 2-phenylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a8) was obtained in 49.6% yield, mp: 200 ℃ and 203 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.70(s，1H，NH)，7.39(d，2H，J＝7.2Hz，PhH)，7.30(t，1H，J1＝7.2Hz，J2＝14.4Hz，PhH)，7.26(t，2H，J1＝7.2Hz，J2＝14.4Hz，，PhH)，6.35-6.90(m，4H，quinoline-H)，5.84(s，1H，C5-H)，4.38(s，2H，SCH2)，4.29(s，2H，NCH2)，3.42-3.44(m，2H，quinoline-H2)，2.70-2.72(m，2H，quinoline-H4)，1.90-1.92(m，2H，quinoline-H3).IR(KBr，cm-1)v3426(NH)，2928，2844(CH2)，1656(C＝O)，1602，1574，1547，1508(aryl)，1310(C-N)，1246(C-N).ESI-MS：m/z 364.57(M+1).C21H21N3OS(363.48).
example 102- [ (4-Methylphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a9)
The procedure is as in example 2, except that the substituent is p-methylbenzyl chloride.
The product 2- [ (4-methylphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a9) was obtained in 53.2% yield, mp: 185 deg.C and 186 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.60(s，1H，NH)，7.27(d，2H，J＝7.8Hz，PhH)，7.10(d，2H，J＝7.8Hz，PhH)，6.34-6.91(m，4H，quinoline-H)，5.89(s，1H，C5-H)，4.33(s，2H，SCH2)，4.28(s，2H，NCH2)，3.41-3.44(m，2H，quinoline-H2)，2.70-2.73(m，2H，quinoline-H4)，2.27(s，3H，PhCH3)，1.90-1.91(m，2H，quinoline-H3).IR(KBr，cm-1)v 3418(NH)，2921，2849(CH3，CH2)，1651(C＝O)，1602，1579，1534，1508(aryl)，1310(C-N)，1194(C-N).ESI-MS：m/z 378.57(M+1).C22H23N3OS(377.50).
example 112- [ (4-chlorophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a10)
The procedure is as in example 2, except that the substituent is p-chlorobenzyl chloride.
The product obtained, 2- [ (4-chlorophenyl) methylsulfanyl ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a10), was 57.9% yield, mp: 190 ℃ and 193 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.65(s，1H，NH)，7.41(d，2H，J＝8.4Hz，PhH)，7.33(d，2H，J＝8.4Hz，PhH)，6.33-6.90(m，4H，quinoline-H)，5.90(s，1H，C5-H)，4.36(s，2H，SCH2)，4.28(s，2H，NCH2)，3.41-3.44(m，2H，quinoline-H2)，2.70-2.72(m，2H，quinoline-H4)，1.88-1.92(m，2H，quinoline-H3).IR(KBr，cm-1)v 3413(NH)，2921，2850(CH2)，1648(C＝O)，1602，1581，1535(aryl)，1310(C-N)，1194(C-N).ESI-MS：m/z 398.74(M+1).C21H20ClN3OS(397.92).
example 122- [ (4-Nitrophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a11)
The procedure is as in example 2, except that the substituent is p-nitrobenzyl chloride.
The product 2- [ (4-nitrophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a11) was obtained in 51.5% yield, mp: 180 ℃ and 182 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.70(s，1H，NH)，8.13(d，2H，J＝8.4Hz，PhH)，7.66(d，2H，J＝8.4Hz，PhH)，6.30-6.89(m，4H，quinoline-H)，5.90(s，1H，C5-H)，4.47(s，2H，SCH2)，4.28(s， 2H，NCH2)，3.39-3.43(m，2H，quinoline-H2)，2.68-2.71(m，2H，quinoline-H4)，1.87-1.91(m，2H，quinoline-H3).IR(KBr，cm-1)v 3370(NH)，2930，2841(CH2)，1660(C＝O)，1600，1583，1518(aryl)，1310(C-N)，1240(C-N).ESI-MS：m/z 409.51(M+1).C21H20N4O3S(408.47).
example 132- [ (4-cyanophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a12)
The procedure is as in example 2, except that the substituent is p-cyanobenzyl chloride.
The product 2- [ (4-cyanophenyl) methylsulfanyl ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a12) was obtained in 54.0% yield, mp: 186 ℃ and 188 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.71(s，1H，NH)，7.73(d，2H，J＝7.8Hz，PhH)，7.59(d，2H，J＝7.8Hz，PhH)，6.30-6.90(m，4H，quinoline-H)，5.90(s，1H，C5-H)，4.43(s，2H，SCH2)，4.27(s，2H，NCH2)，3.38-3.40(m，2H，quinoline-H2)，2.69-2.71(m，2H，quinoline-H4)，1.87-1.91(m，2H，quinoline-H3).IR(KBr，cm-1)v 3419(NH)，2927，2840(CH2)，2227(C≡N)，1656(C＝O)，1601，1581，1533，1504(aryl)，1311(C-N)，1235(C-N).ESI-MS：m/z 389.52(M+1).C22H20N4OS(388.49).
example 142- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a13)
The procedure is as in example 2, except that the substituent is p-methoxybenzyl chloride.
The product 2- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a13) was obtained in 48.7% yield, mp: 194 ℃ and 196 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.60(s，1H，NH)，7.31(d，2H，J＝9.0Hz，PhH)，6.91(d，2H，J＝9.0Hz，PhH)，6.35-6.84(m，4H，quinoline-H)，5.89(s，1H，C5-H)，4.32(s，2H，SCH2)，4.29(s，2H，NCH2)，3.72(s，3H，PhOCH3)，3.42-3.45(m，2H，quinoline-H2)，2.70-2.73(m，2H，quinoline-H4)，1.89-1.93(m，2H，quinoline-H3).1R(KBr，cm-1)v 3426(NH)，2928，2835(CH3，CH2)，1649(C＝O)，1603，1579，1534，1510(aryl)，1311(C-N)，1246(C-N).ESI-MS：m/z 394.53(M+1).C22H23N3O2S(393.50).
example 152- [ (4-fluorophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a14)
The procedure is as in example 2, except that the substituent is p-fluorobenzyl chloride.
The product 2- [ (4-fluorophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6a14) was obtained in 53.9% yield, mp: 203 ℃ and 205 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.66(s，1H，NH)，7.31(d，2H，J＝9.0Hz，PhH)，6.91(d，2H，J＝9.0Hz，PhH)，6.35-6.84(m，4H，quinoline-H)，5.89(s，1H，C5-H)，4.36(s，2H，SCH2)，4.29(s，2H，NCH2)，3.41-3.43(m，2H，quinoline-H2)，2.70-2.72(m，2H，quinoline-H4)，1.90-1.91(m，2H，quinoline-H3).IR(KBr，cm-1)v 3319(NH)，2923，2844(CH2)，1649(C＝O)，1600，1577，1545，1508(aryl)，1313(C-N)，1229(C-N).ESI-MS：m/z 382.49(M+1).C21H20FN3OS(381.47).
example 165-methyl-2-benzenecarbonylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b1)
The preparation method was the same as example 2, except that the parent nucleus was 5b and the substituent was 2-bromoacetophenone.
The product 5-methyl-2-phenylcarbonylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b1) was obtained in 45.4% yield, mp: 188 ℃ and 189 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.77(s，1H，NH)，7.86(d，2H，J＝7.8Hz，PhH)，7.69(t，1H，J1＝7.8Hz，J2＝15.6Hz，PhH)，7.54(t，2H，J1＝7.8Hz，J2＝15.6Hz，，PhH)，6.29-6.82(m，4H，quinoline-H)，4.61(s，2H，SCH2)，4.21(s，2H，NCH2)，3.16-3.18(m，2H，quinoline-H2)，2.43-2.45(m，2H，quinoline-H4)，1.95(s，3H，C5CH3)，1.60-1.61(m，2H，quinoline-H3).IR(KBr，cm-1)v3420(NH)，2922，2842(CH3，CH2)，1682(C＝O)，1637(C＝O)，1601，1572，1506，1449(aryl)，1262(C-N)，1194(C-N).ESI-MS：m/z 406.47(M+1).C23H23N3O2S(405.51).
example 175-methyl-2- [ (4-methylphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b2)
The preparation method was the same as example 2, except that the parent nucleus was 5b and the substituent was p-methyl-2-chloroacetophenone.
The product 5-methyl-2- [ (4-methylphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b2) was obtained in 52.3% yield, mp: 203 ℃ and 204 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.71(s，1H，NH)，7.76(d，2H，J＝8.4Hz，PhH)，7.31(d，2H，J＝8.4Hz，PhH)，6.31-6.83(m，4H，quinoline-H)，4.56(s，2H，SCH2)，4.21(s，2H，NCH2)，3.16-3.18(m，2H，quinoline-H2)，2.39(s，3H，PhCH3)，2.47-2.50(m，2H，quinoline-H4)，1.95(s，3H，C5-CH3)，1.62-1.66(m，2H，quinoline-H3).IR(KBr，cm-1)v 3428(NH)，2940，2920，2832(CH3，CH2)，1704(C＝O)，1633(C＝O)，1603，1571，1550，1505(aryl)，1265(C-N)，1198(C-N).ESI-MS：m/z 420.74(M+1).C24H25N3O2S(419.54).
example 185-methyl-2- [ (4-chlorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b3)
The preparation method was the same as example 2, except that the core was 5b and the substituent was p-chloro-2-chloroacetophenone.
The product 5-methyl-2- [ (4-chlorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3 h-pyrimidin-4-one (6b3) was obtained in 36.7% yield, mp: 187 ℃ and 188 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.79(s，1H，NH)，7.85(d，2H，J＝8.4Hz，PhH)，7.58(d，2H，J＝8.4Hz，PhH)，6.28-6.81(m，4H，quinoline-H)，4.58(s，2H，SCH2)，4.20(s，2H，NCH2)，3.15-3.17(m，2H，quinoline-H2)，2.43-2.50(m，2H，quinoline-H4)，1.95(s，3H，C5-CH3)，1.62-1.68(m，2H，quinoline-H3).IR(KBr，cm-1)v 3434(NH)，2929，2842(CH3，CH2)，1681(C＝O)，1637(C＝O)，1600，1587，1550，1504(aryl)，1256(C-N)，1193(C-N).ESI-MS：m/z 440.87(M+1).C23H22ClN3O2S(439.96).
example 195-methyl-2- [ (4-nitrophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b4)
The preparation method is the same as example 2, except that the parent nucleus is 5b, and the substituent is p-nitro-2-chloroacetophenone.
The product 5-methyl-2- [ (4-nitrophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b4) was obtained in 39.1% yield, mp: 189 (dec) 190 deg.C
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.81(s，1H，NH)，8.27(d，2H，J＝7.8Hz，PhH)，8.09(d，2H，J＝7.8Hz，PhH)，6.28-6.79(m，4H，quinoline-H)，4.65(s，2H，SCH2)，4.18(s，2H，NCH2)，3.40-3.43(m，2H，quinoline-H2)，2.50-2.51(m，2H，quinoline-H4)，1.89-1.94(m，2H，quinoline-H3)，1.620(s， 3H，C5-CH3).IR(KBr，cm-1)v 3406(NH)，2918，2842(CH3，CH2)，1696(C＝O)，1641(C＝O)，1602，1524，1505，1458(aryl)，1344(C-N)，1189(C-N).ESI-MS：m/z 451.43(M+1).C23H22N4O4S(450.51).
example 205-methyl-2- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b5)
The preparation method was the same as example 2, except that the core was 5b and the substituent was p-cyano-2-chloroacetophenone.
The product 5-methyl-2- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b5) was obtained in 36.6% yield, mp: 179 ℃ and 180 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.73(s，1H，NH)，7.63-7.96(m，4H，PhH)，6.30-6.80(m，4H，quinoline-H)，4.62(s，2H，SCH2)，4.19(s，2H，NCH2)，3.14-3.23(m，2H，quinoline-H2)，2.44-2.50(m，2H，quinoline-H4)，1.94(s，3H，C5-CH3)，1.62-1.78(m，2H，quinoline-H3).IR(KBr，cm-1)v3442(NH)，2919，2840(CH3，CH2)，2231(C≡N)，1690(C＝O)，1643(C＝O)，1602，1544，1505(aryl)，1267(C-N)，1195(C-N).ESI-MS：m/z 431.59(M+1).C24H22N4O2S(430.52).
example 215-methyl-2- [ (4-methoxyphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b6)
The preparation method is the same as example 2, except that the parent nucleus is 5b, and the substituent is p-methoxy-2-chloroacetophenone.
The product 5-methyl-2- [ (4-methoxyphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b6) was obtained in 38.9% yield, mp: 210 deg.C and 211 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.72(s，1H，NH)，7.83(d，2H，J＝8.4Hz，PhH)，7.03(d，2H，J＝8.4Hz，PhH)，6.31-6.83(m，4H，quinoline-H)，4.54(s，2H，SCH2)，4.23(s，2H，NCH2)，3.86(s，3H，PhOCH3)，3.20-3.22(m，2H，quinoline-H2)，2.47-2.50(m，2H，quinoline-H4)，1.95(s，3H，C5-CH3)，1.64-1.66(m，2H，quinoline-H3).IR(KBr，cm-1)v 3225(NH)，2932，2839(CH3，CH2)，1667(C＝O)，1646(C＝O)，1599，1574，1546，1502(aryl)，1266(C-N)，1165(C-N).ESI-MS：m/z436.71(M+1).C24H25N3O3S(435.54).
example 225-methyl-2- [ (4-fluorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b7)
The preparation method was the same as example 2, except that the parent nucleus was 5b and the substituent was p-fluoro-2-chloroacetophenone.
The product 5-methyl-2- [ (4-fluorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b7) was obtained in 47.6% yield, mp: 179 ℃ and 180 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.73(s，1H，NH)，7.90-7.93(m，2H，PhH)，7.33-7.36(m，2H，PhH)，6.29-6.81(m，4H，quinoline-H)，4.58(s，2H，SCH2)，4.21(s，2H，NCH2)，3.16-3.18(m，2H，quinoline-H2)，2.43-2.45(m，2H，quinoline-H4)，1.95(s，3H，C5-CH3)，1.61-1.63(m，2H，quinoline-H3).IR(KBr，cm-1)v 3467(NH)，2951，2893，2845(CH3，CH2)，1703(C＝O)，1654(C＝O)，1600，1575，1551，1508(aryl)，1263(C-N)，1195(C-N).ESI-MS：m/z 424.56(M+1).C23H22FN3O2S(423.50).
example 235-methyl-2-phenylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b8)
The preparation method is the same as example 2, except that the parent nucleus is 5b and the substituent is benzyl bromide.
The product 5-methyl-2-phenylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b8) was obtained in 51.7% yield, mp: 224 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.63(s，1H，NH)，7.20(d，2H，J＝7.2Hz，PhH)，7.17(t，1H，J1＝7.2Hz，J2＝14.4Hz，PhH)，7.14(t，2H，J1＝7.2Hz，J2＝14.4Hz，，PhH)，6.42-6.90(m，4H，quinoline-H)，4.39(s，2H，SCH2)，4.15(s，2H，NCH2)，3.43-3.45(m，2H，quinoline-H2)，2.61-2.63(m，2H，quinoline-H4)，1.98(s，3H，C5-CH3)，1.84-1.86(m，2H，quinoline-H3).IR(KBr，cm-1)v3427(NH)，2942，2838(CH3，CH2)，1640(C＝O)，1602，1573，1554，1508(aryl)，1264(C-N)，1197(C-N).ESI-MS：m/z 378.56(M+1).C22H23N3OS(377.50).
example 245-methyl-2- [ (4-methylphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b9)
The preparation method was the same as example 2, except that the parent nucleus was 5b and the substituent was p-methylbenzyl chloride.
The product 5-methyl-2- [ (4-methylphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b9) was obtained in 35.0% yield, mp: 223 ℃ to 225 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.35(s，1H，NH)，7.01(d，2H，J＝7.8Hz，PhH)，6.96(d，2H，J＝7.8Hz，PhH)，6.58-6.61(m，4H，quinoline-H)，4.22(s，2H，SCH2)，4.12(s，2H，NCH2)，3.43-3.45(m，2H，quinolineH2)，2.61-2.63(m，2H，quinoline-H4)，2.24(s，3H，PhCH3)，1.97(s，3H，C5-CH3)，1.84-1.86(m，2H，quinoline-H3).IR(KBr，cm-1)v 3334(NH)，2926，2853(CH3，CH2)，1683(C＝O)，16001，1538，1497(aryl)，1239(C-N)，1190(C-N).ESI-MS：m/z 392.53(M+1).C23H25N3OS(391.53).
example 255-methyl-2- [ (4-chlorophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b10)
The procedure is as in example 2, except that the core is 5b and the substituent is p-chlorobenzyl chloride.
The product obtained, 5-methyl-2- [ (4-chlorophenyl) methylsulfanyl ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b10), was found in 56.3% yield, mp: 220 ℃ and 222 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.64(s，1H，NH)，7.15(d，2H，J＝7.8Hz，PhH)，7.11(d，2H，J＝7.8Hz，PhH)，6.40-6.91(m，4H，quinolineH)，4.38(s，2H，SCH2)，4.17(s，2H，NCH2)，3.41-3.43(m，2H，quinolineH2)，2.60-2.62(m，2H，quinolineH4)，1.98(s，3H，C5CH3)，1.82-1.86(m，2H，quinolineH3).IR(KBr，cm-1)v 3426(NH)，2941，2840(CH3，CH2)，1641(C＝O)，1601，1573，1554，1507(aryl)，1265(C-N)，1197(C-N).ESI-MS：m/z 412.56(M+1).C22H22ClN3OS(411.95).
example 265-methyl-2- [ (4-nitrophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b11)
The preparation method is the same as example 2, except that the parent nucleus is 5b, and the substituent is p-nitrobenzyl chloride.
The product 5-methyl-2- [ (4-nitrophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b11) was obtained in 52.9% yield, mp: 209 ℃ and 210 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.69(s，1H，NH)，7.93(d，2H，J＝8.4Hz，PhH)，7.34(d，2H，J＝8.4Hz，PhH)，6.39-6.91(m，4H，quinoline-H)，4.39(s，2H，SCH2)，4.32(s，2H，NCH2)，3.39-3.40(m，2H，quinoline-H2)，2.57-2.59(m，2H，quinoline-H4)，1.98(s，3H，C5-CH3)，1.80-1.84(m，2H，quinoline-H3).IR(KBr，cm-1)v 3334(NH)，2936，2842(CH3，CH2)，1643(C＝O)，1599，1573，1516 (aryl)，1344(C-N)，1263(C-N).ESI-MS：m/z 423.57(M+1).C22H22N4O3S(422.50).
example 275-methyl-2- [ (4-cyanophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b12)
The procedure is as in example 2, except that the core is 5b and the substituent is p-cyanobenzyl chloride.
The product 5-methyl-2- [ (4-cyanophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b12) was obtained in 50.4% yield, mp: 195 ℃ and 197 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.70(s，1H，NH)，7.54(d，2H，J＝7.8Hz，PhH)，7.27(d，2H，J＝7.8Hz，PhH)，6.40-6.90(m，4H，quinoline-H)，4.38(s，2H，SCH2)，4.25(s，2H，NCH2)，3.37-3.39(m，2H，quinoline-H2)，2.57-2.59(m，2H，quinoline-H4)，1.98(s，3H，C5-CH3)，1.80-1.84(m，2H，quinoline-H3).IR(KBr，cm-1)v 3433(NH)，2935，2842(CH3，CH2)，2225(C≡N)，1642(C＝O)，1601，1572，1541，1505(aryl)，1260(C-N)，1196(C-N).ESI-MS：m/z 403.57(M+1).C23H22N4OS(402.51).
example 285-methyl-2- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b13)
The preparation method was the same as example 2, except that the core was 5b and the substituent was p-methoxybenzyl chloride.
The product 5-methyl-2- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b13) was obtained in 39.8% yield, mp: 180 ℃ and 182 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.59(s，1H，NH)，7.05(d，2H，J＝8.4Hz，PhH)，6.91(d，2H，J＝8.4Hz，PhH)，6.41-6.84(m，4H，quinoline-H)，4.38(s，2H，SCH2)，4.10(s，2H，NCH2)，3.68(s，3H，PhOCH3)，3.44-3.47(m，2H，quinoline-H2)，2.62-2.64(m，2H，quinoline-H4)，1.98(s，3H，C5-CH3)，1.85-1.89(m，2H，quinoline-H3).IR(KBr，cm-1)v 3413(NH)，2928，2833(CH3，CH2)，1641(C＝O)，1601，1571，1545，1511(aryl)，1253(C-N)，1198(C-N).ESI-MS：m/z 408.57(M+1).C23H25N3O2S(407.53).
example 295-methyl-2- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b14)
The preparation method was the same as example 2, except that the core was 5b and the substituent was p-methoxybenzyl chloride.
The product 5-methyl-2- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6b14) was obtained in 55.8% yield, mp: 215 at 217 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.63(s，1H，NH)，7.14(m，2H，PhH)，6.93(m，2H，PhH)，6.41-6.90(m，4H，quinoline-H)，4.38(s，2H，SCH2)，4.16(s，2H，NCH2)，3.42-3.44(m，2H，quinoline-H2)，2.61-2.63(m，2H，quinoline-H4)，1.98(s，3H，C5-CH3)，1.83-1.87(m，2H，quinoline-H3).IR(KBr，cm-1)v 3459(NH)，2939，2840(CH3，CH2)，1641(C＝O)，1601，1573，1554，1508(aryl)，1265(C-N)，1222(C-N).ESI-MS：m/z 396.53(M+1).C22H22FN3OS(395.49).
example 305-Ethyl-2-benzenecarbonylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c1)
The preparation method was the same as example 2, except that the parent nucleus was 5c and the substituent was 2-bromoacetophenone.
The product 5-ethyl-2-phenylcarbonylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c1) was obtained in 47.5% yield, mp: 193 ℃ and 194 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.77(s，1H，NH)，7.85(d，2H，J＝7.8Hz，PhH)，7.68(t，1H，J1＝7.8Hz，J2＝15.6Hz，PhH)，7.53(t，2H，J1＝7.8Hz，J2＝15.6Hz，PhH)，6.32-6.82(m，4H，quinoline-H)，4.60(s，2H，SCH2)，4.24(s，2H，NCH2)，3.16-3.18(m，2H，quinoline-H2)，2.45-2.50(m，2H，quinoline-H4)，2.43(q，2H，J＝7.8Hz，C5-CH2CH3)，1.60-1.63(m，2H，quinoline-H3)，1.05(t，3H，J＝7.8Hz，C5-CH2CH3).IR(KBr，cm-1)v 3462(NH)，2931，2840(CH3，CH2)，1682(C＝O)，1633(C＝O)，1599，1573，1507，1448(aryl)，1254(C-N)，1195(C-N).ESI-MS：m/z 420.21(M+1).C24H25N3O2S(419.54).
example 315-Ethyl-2- [ (4-methylphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c2)
The preparation method was the same as example 2, except that the parent nucleus was 5c and the substituent was p-methyl-2-bromoacetophenone.
The product 5-ethyl-2- [ (4-methylphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c2) was obtained in 57.1% yield, mp: 185 ℃ and 187 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.76(s，1H，NH)，7.74(d，2H，J＝8.4Hz，PhH)，7.32(d，2H，J＝8.4Hz，PhH)，6.33-6.83(m，4H，quinoline-H)，4.56(s，2H，SCH2)，4.24(s，2H，NCH2)，3.16-3.18(m，2H，quinoline-H2)，2.45-2.50(m，2H，quinoline-H4)，2.42(q，2H，J＝7.2Hz，C5-CH2CH3)，2.39(s，3H，PhCH3)，1.62-1.65(m，2H，quinoline-H3)，1.02(t，3H，J＝7.2Hz，C5-CH2CH3).IR(KBr，cm-1)v 3437(NH)，2929，2842(CH3，CH2)，1677(C＝O)，1639(C＝O)，1602，1572，1505，1456(aryl)，1254(C-N)，1193(C-N).ESI-MS：m/z 434.57(M+1).C25H27N3O2S(433.18)
example 325-Ethyl-2- [ (4-chlorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c3)
The preparation method was the same as example 2, except that the parent nucleus was 5c and the substituent was p-chloro-2-bromoacetophenone.
The product 5-ethyl-2- [ (4-chlorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c3) was obtained in 39.2% yield, mp: 190 ℃ to 192 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.48(s，1H，NH)，7.84(d，2H，J＝8.4Hz，PhH)，7.57(d，2H，J＝8.4Hz，PhH)，6.31-7.01(m，4H，quinoline-H)，4.57(s，2H，SCH2)，4.24(s，2H，NCH2)，3.24-3.33(m，2H，quinoline-H2)，2.67-2.71(m，2H，quinoline-H4)，2.31(q，2H，J＝7.2Hz，C5-CH2CH3)，1.87-1.91(m，2H，quinoline-H3)，1.06(t，3H，J＝7.2Hz，C5-CH2CH3).IR(KBr，cm-1)v 3566(NH)，2962，2930，2868(CH3，CH2)，1686(C＝O)，1640(C＝O)，1601，1571，1536，1506(aryl)，1254(C-N)，1191(C-N).ESI-MS：m/z 454.43(M+1).C24H24ClN3O2S(454.13)
example 335-Ethyl-2- [ (4-nitrophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c4)
The preparation method was the same as example 2, except that the parent nucleus was 5c and the substituent was p-nitro-2-bromoacetophenone.
The product 5-ethyl-2- [ (4-nitrophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c4) was obtained in 43.7% yield, mp: 191 and 192 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.78(s，1H，NH)，8.27(d，2H，J＝7.8Hz，PhH)，8.04(d，2H，J＝7.8Hz，PhH)，6.32-7.01(m，4H，quinoline-H)，4.64(s，2H，SCH2)，4.23(s，2H，NCH2)，3.32-3.34 (m，2H，quinoline-H2)，2.71-2.73(m，2H，quinoline-H4)，2.43(q，2H，J＝7.8Hz，C5-CH2CH3)，1.89-1.90(m，2H，quinoline-H3)，1.07(t，3H，J＝7.8Hz，C5-CH2CH3).IR(KBr，cm-1)v 3467(NH)，2930，2869(CH3，CH2)，1693(C＝O)，1640(C＝O)，1601，1571，1536，1506(aryl)，1344(C-N)，1189(C-N).ESI-MS：m/z 465.55(M+1).C24H24N4O4S(464.15)
example 345-Ethyl-2- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c5)
The preparation method was the same as example 2, except that the parent nucleus was 5c and the substituent was p-cyano-2-bromoacetophenone.
The product 5-ethyl-2- [ (4-cyanophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c5) was obtained in 49.6% yield, mp: 192 ℃ to 194 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.80(s，1H，NH)，7.60-7.96(m，4H，PhH)，6.36-6.80(m，4H，quinoline-H)，4.61(s，2H，SCH2)，4.31(s，2H，NCH2)，3.33-3.42(m，2H，quinoline-H2)，2.43-2.51(m，2H，quinoline-H4)，2.39(q，2H，J＝7.2Hz，C5-CH2CH3)，1.60-1.61(m，2H，quinoline-H3)，1.02(t，3H，J＝7.2Hz，C5-CH2CH3).IR(KBr，cm-1)v 3343(NH)，2937，2869(CH3，CH2)，2230(C≡N)，1688(C＝O)，1640(C＝O)，1601，1542，1506(aryl)，1251(C-N)，1195(C-N).ESI-MS：m/z 445.54(M+1).C25H24N4O2S(444.16)
example 355-Ethyl-2- [ (4-methoxyphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c6)
The preparation method was the same as example 2, except that the parent nucleus was 5c and the substituent was p-methoxy-2-bromoacetophenone. The product 5-ethyl-2- [ (4-methoxyphenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c6) was obtained in 39.1% yield, mp: 196 ℃ 198 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.75(s，1H，NH)，7.82(d，2H，J＝8.4Hz，PhH)，7.02(d，2H，J＝8.4Hz，PhH)，6.33-6.83(m，4H，quinoline-H)，4.53(s，2H，SCH2)，4.24(s，2H，NCH2)，3.86(s，3H，PhOCH3).3.14-3.19(m，2H，quinoline-H2)，2.45-2.50(m，2H，quinoline-H4)，2.27-2.31(q，2H，J＝7.2Hz，C5-CH2CH3)，1.88-1.90(m，2H，quinoline-H3)，1.05(t，3H，J＝7.2Hz，C5-CH2CH3).IR(KBr，cm-1)v 3476(NH)，2932，2839(CH3，CH2)，1667(C＝O)，1642(C＝O)，1599，1564，1541，1504(aryl)，1264(C-N)，1166(C-N).ESI-MS：m/z 450.34(M+1).C25H27N3O3S(449.18).
example 365-Ethyl-2- [ (4-fluorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c7)
The preparation method was the same as example 2, except that the parent nucleus was 5c and the substituent was p-fluoro-2-bromoacetophenone.
The product 5-ethyl-2- [ (4-fluorophenyl) carbonylmethylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c7) was obtained in 49.3% yield, mp: 192 ℃ 193 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.84(s，1H，NH)，7.90-7.92(m，2H，PhH)，7.32-7.35(m，2H，PhH)，6.32-6.82(m，4H，quinoline-H)，4.58(s，2H，SCH2)，4.24(s，2H，NCH2)，3.33-3.44(m，2H，quinoline-H2)，2.39-2.50(m，2H，quinoline-H4)，2.28-2.31(q，2H，J＝7.2Hz，C5-CH2CH3)，1.62-1.71(m，2H，quinoline-H3)，1.05(t，3H，J＝7.2Hz，C5-CH2CH3).IR(KBr，cm-1)v 3466(NH)，2933，2840(CH3，CH2)，1680(C＝O)，1638(C＝O)，1598，1574，1547，1506(aryl)，1253(C-N)，1196(C-N).ESI-MS：m/z 438.56(M+1).C24H24FN3O2S(437.16).
example 375-Ethyl-2-phenylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c8)
The preparation is as in example 2, except that the core is 5c and the substituent is benzyl bromide.
The product 5-ethyl-2-phenylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c8) was obtained in 46.9% yield, mp: 224 deg.C and 226 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.62(s，1H，NH)，7.20(d，2H，J＝7.2Hz，PhH)，7.18(t，1H，J1＝7.2Hz，J2＝14.4Hz，PhH)，7.14(t，2H，J1＝7.2Hz，J2＝14.4Hz，PhH)，6.34-6.91(m，4H，quinoline-H)，4.42(s，2H，SCH2)，4.14(s，2H，NCH2)，3.42-3.44(m，2H，quinoline-H2)，2.61-2.63(m，2H，quinoline-H4)，2.46-2.51(q，2H，J＝7.8Hz，C5-CH2CH3)，1.84-1.86(m，2H，quinoline-H3)，1.06(t，3H，J＝7.8Hz，C5-CH2CH3).IR(KBr，cm-1)v 3361(NH)，2932，2840(CH3，CH2)，1635(C＝O)，1600，1570，1549，1508(aryl)，1252(C-N)，1197(C-N).ESI-MS：m/z 392.37(M+1).C23H25N3OS(391.53).
example 385-Ethyl-2- [ (4-methylphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c9)
The procedure is as in example 2, except that the core is 5c and the substituent is p-methylbenzyl chloride.
The product 5-ethyl-2- [ (4-methylphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c9) was obtained in 47.2% yield, mp: 218 deg.C and 221 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.60(s，1H，NH)，7.00(d，2H，J＝8.4Hz，PhH)，6.97(d，2H，J＝8.4Hz，PhH)，6.43-6.90(m，4H，quinoline-H)，4.41(s，2H，SCH2)，4.09(s，2H，NCH2)，3.42-3.44(m，2H，quinoline-H2)，2.61-2.64(m，2H，quinoline-H4)，2.46-2.51(q，2H，J＝7.8Hz，C5-CH2CH3)，2.22(s，3H，PhCH3)，1.84-1.88(m，2H，quinoline-H3)，1.07(t，3H，J＝7.8Hz，C5-CH2CH3).IR(KBr，cm-1)v 3422(NH)，2930，2838，2796(CH3，CH2)，1634(C＝O)，1600，1569，1546，1507(aryl)，1251(C-N)，1197(C-N).ESI-MS：m/z 406.59(M+1).C24H27N3OS(405.56).
example 395-Ethyl-2- [ (4-chlorophenyl) methylsulfanyl ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c10)
The procedure is as in example 2, except that the core is 5c and the substituent is p-chlorobenzyl chloride.
The product 5-ethyl-2- [ (4-chlorophenyl) methylsulfanyl ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c10) was obtained in 49.7% yield, mp: 227 ℃ to 229 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.65(s，1H，NH)，7.15(d，2H，J＝8.4Hz，PhH)，7.11(d，2H，J＝8.4Hz，PhH)，6.42-6.91(m，4H，quinoline-H)，4.41(s，2H，SCH2)，4.16(s，2H，NCH2)，3.40-3.42(m，2H，quinoline-H2)，2.60-2.62(m，2H，quinoline-H4)，2.47-2.50(q，2H，J＝7.8Hz，C5-CH2CH3)，1.83-1.85(m，2H，quinoline-H3)，1.06(t，3H，J＝7.8Hz，C5-CH2CH3).IR(KBr，cm-1)v 3326(NH)，2932，2840(CH3，CH2)，1636(C＝O)，1600，1570，1546，1507(aryl)，1251(C-N)，1197(C-N).ESI-MS：m/z 426.74(M+1).C23H24ClN3OS(425.97).
example 405-Ethyl-2- [ (4-nitrophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c11)
The preparation method was the same as example 2, except that the core was 5c and the substituent was p-nitrobenzyl chloride.
The product 5-ethyl-2- [ (4-nitrophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c11) was obtained in 45.1% yield, mp: 195 ℃ and 197 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.71(s，1H，NH)，7.93(d，2H，J＝8.4Hz，PhH)，7.34(d，2H，J＝8.4Hz，PhH)，6.42-6.91(m，4H，quinoline-H)，4.42(s，2H，SCH2)，4.31(s，2H，NCH2)，3.37-3.39(m，2H，quinoline-H2)，2.56-2.58(m，2H，quinoline-H4)，2.50(q，2H，J＝7.2Hz，C5-CH2CH3)，1.80-1.82(m，2H，quinoline-H3)，1.07(t，3H，J＝7.2Hz，C5-CH2CH3).IR(KBr，cm-1)v 3434(NH)，2931，2840(CH3，CH2)，1641(C＝O)，1600，1571，1519(aryl)，1250(C-N)，1196(C-N).ESI-MS：m/z 437.47(M+1).C23H24ClN4O3S(436.53).
example 415-Ethyl-2- [ (4-cyanophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c12)
The procedure is as in example 2, except that the core is 5c and the substituent is p-cyanobenzyl chloride.
The product 5-ethyl-2- [ (4-cyanophenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c12) was obtained in 45.2% yield, mp: 195 deg.C and 196 deg.C (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.70(s，1H，NH)，7.54(d，2H，J＝8.4Hz，PhH)，7.27(d，2H，J＝8.4Hz，PhH)，6.42-6.91(m，4H，quinoline-H)，4.41(s，2H，SCH2)，4.24(s，2H，NCH2)，3.36-3.38(m，2H，quinoline-H2)，2.57-2.59(m，2H，quinoline-H4)，2.50(q，2H，J＝7.8Hz，C5-CH2CH3)，1.80-1.83(m，2H，quinoline-H3)，1.07(t，3H，J＝7.8Hz，C5-CH2CH3).IR(KBr，cm-1)v 3411(NH)，2932，2840(CH3，CH2)，2227(C≡N)，1640(C＝O)，1601，1571，1542，1503(aryl)，1251(C-N)，1195(C-N).ESI-MS：m/z 417.62(M+1).C24H24N4OS(416.54).
example 425-Ethyl-2- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c13)
The preparation method was the same as example 2, except that the core was 5c and the substituent was p-methoxybenzyl chloride.
The product 5-ethyl-2- [ (4-methoxyphenyl) methylthio ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c13) was obtained in 48.7% yield, mp: 187 ℃ and 188 ℃ (dec).
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.58(s，1H，NH)，7.04(d，2H，J＝8.4Hz，PhH)，6.91(d，2H，J＝8.4Hz，PhH)，6.43-6.84(m，4H，quinoline-H)，4.32(s，2H，SCH2)，4.41(s，2H，NCH2)，3.68(s，3H，PhOCH3)，3.45-3.47(m，2H，quinoline-H2)，2.62-2.64(m，2H，quinoline-H4)，2.50(q，2H，J＝8.4Hz，C5-CH2CH3)，1.86-1.88(m，2H，quinoline-H3)，1.06(t，3H，J＝8.4Hz，C5-CH2CH3).IR(KBr，cm-1)v 3434(NH)，2930，2833，2763(CH3，CH2)，1637(C＝O)，1600，1569，1544，1509(aryl)，1251(C-N)，1197(C-N).ESI-MS：m/z 422.34(M+1).C24H27N3O2S(421.56).
example 435-Ethyl-2- [ (4-fluorophenyl) methylsulfanyl ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c14)
The preparation method was the same as example 2, except that the core was 5c and the substituent was p-fluorobenzyl chloride.
The product 5-ethyl-2- [ (4-fluorophenyl) methylsulfanyl ] -6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one (6c14) was obtained in 59.7% yield, mp: 224 + 227 deg.C (dec)
Product spectral analysis data:
1H NMR(DMSO-d6，ppm)δ：12.63(s，1H，NH)，7.12(d，2H，J＝8.4Hz，PhH)，6.93(d，2H，J＝8.4Hz，PhH)，6.43-6.90(m，4H，quinoline-H)，4.42(s，2H，SCH2)，4.15(s，2H，NCH2)，3.42-3.44(m，2H，quinoline-H2)，2.60-2.63(m，2H，quinoline-H4)，2.51(q，2H，J＝7.2Hz，C5-CH2CH3)，1.84-1.86(m，2H，quinoline-H3)，1.07(t，3H，J＝7.2Hz，C5-CH2CH3).IR(KBr，cm-1)v 3359(NH)，2932，2841(CH3，CH2)，1636(C＝O)，1600，1570，1547，1508(aryl)，1251(C-N)，1221(C-N). ESI-MS：m/z 410.29(M+1).C23H24FN3OS(409.52).
example 44: anti-HIV cellular activity screening assay
Description of terms:
MTT method: thiazole blue method;
MT-4: human acute lymphoblast cells;
CCID 50: half of the infection amount of the cells in culture;
DMSO, DMSO: dimethyl sulfoxide;
EC50: concentration of compound that protects 50% of HIV-1 infected MT-4 cells from cytopathic effects;
CC50: (ii) concentration of compound that causes lesions in 50% of cells not infected with HIV-1;
and (3) SI: coefficient of selectivity, i.e. CC50/EC50(HIV-1IIIB) The ratio of (A) to (B);
HIV-1(IIIB): HIV-1 Virus strains IIIBThe subtype;
HIV-2 (ROD): the HIV-2 strain is the ROD subtype.
Compound anti-HIV activity assay using thiazole blue method (MTT method): on a 96-well cell culture plate, 50uL of 1X 10-containing solution was added4Adding 20uL of culture solution of MT-4 cells (human acute lymphoblasts) into HIV-1 (III)B) Or MT-4 cell suspension of HIV-2(ROD) (100 times the infection amount of CCID50 in cell culture per ml), then adding test compound solutions of different concentrations (3 wells) to each well, after incubation at 37 ℃ for a certain period of time (5 days), adding 20uL (5mg/ml) of MTT solution to each well, followed byCulturing for 2 hours, adding a solution of dimethyl sulfoxide (DMSO), measuring the absorbance at 540nm on a microplate reader, and calculating the cell proliferation rate P% of the compound under different concentrations. Blank set at the same time, from which the concentration (EC) required for a compound to protect 50% of cells from HIV-induced cytopathic effects was calculated50)。
Determination of toxicity of the compounds: in uninfected MT-4 cells, the concentration of compound that causes cytopathic effect in 50% of uninfected cells, i.e., the toxic concentration (CC) was determined by MTT assay, in parallel with the test for anti-HIV activity of the compound50)。
Calculation of selection index: SI ═ CC50/EC50。
The 42 compounds 6a1-6c14 synthesized above were subjected to anti-HIV-1 (III)B) And HIV-2(ROD) activity screen, whose activity and toxicity data are listed in table 2, in which clinically used nucleoside reverse transcriptase inhibitors Nevirapine (NVP), Delavirdine (DLV), Efavirenz (EFV) and zidovudine (AZT) were used as positive controls. As can be seen from the table, the compounds have no inhibitory effect on HIV-2(ROD), but do not have inhibitory effect on HIV-1 (III)B) Shows certain inhibitory activity, wherein two compounds with the best activity 6c1 (EC)50＝0.24±0.05μM，CC50297.95, SI 1218) and 6c6 (EC)50＝0.38+0.13μM，CC50> 61.84. mu.M, SI > 164). Can be used as a lead compound for resisting HIV.
TABLE 2 anti-HIV-1 (III) Compounds 6a1-6c14B) And activity and toxicity of HIV-2(ROD) (MT-4 cells)
Figure BDA0000066638180000211
Figure BDA0000066638180000221
Figure BDA0000066638180000231

Claims (6)

1.5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives of the general structural formula (I) are as follows:
Figure FDA0000066638170000011
wherein,
R1comprises the following steps: H. methyl or ethyl;
R2comprises the following steps: 2-bromoacetophenone, p-methyl-2-Chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitrochlorobenzyl, p-cyanochlorobenzyl, p-methoxychlorobenzyl or p-fluorobenzyl chloride.
2. A 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivative according to claim 1, characterized by being one of the following compounds:
Figure FDA0000066638170000012
Figure FDA0000066638170000021
Figure FDA0000066638170000031
Figure FDA0000066638170000041
3. a process for the preparation of 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives as claimed in claim 1, which comprises the following steps:
the synthetic route is as follows:
Figure FDA0000066638170000051
reagent: (i) k2CO3Toluene, refluxing for 24h, 90 ℃; (ii) 15% NaOH, 15 h; (ii)i)MgCl2，Et3N，CH3CN，R1CH(CO2Et)(CO2K) N, N-carbonyl diimidazole, stirring at room temperature overnight, and refluxing for 2 hours; (iv) thiourea, EtONa, under reflux for 6-12 hours; (v) substituted halobenzyl and substituted alpha-haloacetophenone, potassium carbonate (K)2CO3) N, N-Dimethylformamide (DMF) at room temperature for 12 hours;
2mmol of 6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a, 5b, 5c) and 2.2mmol of K2CO3Placing the mixture into a reaction bottle, adding anhydrous dimethylformamide, stirring at room temperature for 30min, adding 2.0mmol of substituent, stirring at room temperature, tracking by TLC until the raw material point disappears, and stopping reaction; adding ice water to generate white precipitate; filtering, and recrystallizing with EtOH or EtOH-DMF mixed solvent to obtain target compound (6a1-6c 14);
wherein the substituents are: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitrochlorobenzyl, p-cyanochlorobenzyl, p-methoxychlorobenzyl or p-fluorobenzyl chloride.
4. A process for producing 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives as claimed in claim 3, wherein the intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a, 5b, 5c) is produced by the following steps:
30.37mmol of 1, 2, 3, 4-tetrahydroquinoline and K2CO360.78mmol is put into 80mL toluene, 29.94mmol of bromoethyl acetate is dropped into the mixture under the stirring condition, the mixture reacts for 24 hours under the condition of 90 ℃, and the TLC detection reaction is carried out; after the reaction, cooling the reaction liquid to room temperature, filtering, distilling under reduced pressure, extracting the residual liquid with chloroform for three times, and washing with brine; drying with anhydrous magnesium sulfate to obtain oily crude product, purifying with ethyl acetate-petroleum ether column chromatography at volume ratio of 1: 4 to obtain brown oily pure product, directly adding into 1mol/L NaOH aqueous solution, refluxing for 12 hr, cooling, dripping into 1mol/LHCl, and dischargingBrown precipitate, filtering and drying to obtain a crude product;
0.5mol of substituted diethyl malonate is placed in 800mL of anhydrous acetonitrile, and 0.595mol of anhydrous MgCl is sequentially added2，0.717mol Et3N, stirring for 2 hours at room temperature; 0.25mol of 1, 2, 3, 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N, N-carbonyldiimidazole are put into 300mL of acetonitrile to react for 15 minutes, and then the reaction mixture is poured into substituted diethyl malonate, anhydrous MgCl2，Et3N in the mixed solution; stirring at room temperature overnight, heating and refluxing for 2h, and tracking by TLC until the reaction is complete; dropwise adding 150mL of HCl with the mass concentration of 13% in an ice bath environment, stirring for 10min after dropwise adding, taking out organic layers by layers, evaporating to dryness, and adding 150mL of ethyl acetate; the mixed solution of ethyl acetate is firstly added with NaHCO3Washed three times, 150ml each time, then washed three times with NaCl solution, 150ml each time, then anhydrous MgSO4Drying, distilling under reduced pressure to obtain crude beta-keto ester (4a-c), and directly using in the next step without purification;
adding 0.3mol of sodium into 100mL of absolute ethyl alcohol in batches, adding 0.225mol of thiourea at one time when the sodium is dissolved and cooled, then adding 0.15mol of a crude product beta-keto ester (4a-c), heating and refluxing the mixture, stopping heating after TLC (thin layer chromatography) tracks until a beta-keto ester raw material point disappears, evaporating the solvent under reduced pressure after cooling, dissolving the residue into 100mL of water, filtering, adjusting the pH to 4 by using 1mol/L of hydrochloric acid and glacial acetic acid, and generating white precipitate; filtering, washing the filter cake with glacial ethanol and glacial ethyl ether to obtain (5a-c) white solid; can be directly used in the next step without purification (containing more than 90% of pure product).
5. Use of 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives according to claim 1 or 2 for the preparation of a medicament for the treatment of HIV-1 inhibitors.
6. An anti-HIV pharmaceutical composition, characterized in that 5-alkyl-2-arylmethylthio-6- [ (1, 2, 3, 4-tetrahydroquinoline) -1-methyl ] -3H-pyrimidin-4-one derivatives according to claim 1 or 2 and pharmaceutical excipients are used for preparing pharmaceutical preparations in different dosage forms.
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