CN111995587B - 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound and synthesis method and application thereof - Google Patents

1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound and synthesis method and application thereof Download PDF

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CN111995587B
CN111995587B CN202010700088.3A CN202010700088A CN111995587B CN 111995587 B CN111995587 B CN 111995587B CN 202010700088 A CN202010700088 A CN 202010700088A CN 111995587 B CN111995587 B CN 111995587B
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孙智华
王圆圆
戴伊如
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Abstract

The invention belongs to the field of organic synthesis and medicines, and particularly relates to a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound, and a synthesis method and application thereof. R 1 Is hydrogen or chlorine, R 2 Is hydrogen, methyl, methoxy or fluorine, R 3 Is nitrophenyl, (2-trifluoromethyl-5-Cl) piperidinyl, phenyl, methoxyphenyl, methylphenyl, 2-trifluoromethylphenyl or C2-C8 alkyl or cycloalkyl, R 4 Is hydrogen or methyl, and X is O or S. The compound is a novel compound with a non-peptide structure, has a good inhibition effect on cancer cells, has a broad-spectrum effect, particularly has a good inhibition activity on liver cancer cells, and has good market prospect and application prospect.

Description

1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound and synthesis method and application thereof
Technical Field
The invention belongs to the field of organic synthesis and medicines, and particularly relates to a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound, and a synthesis method and application thereof.
Background
Quinazolinones and their derivatives are widely used in the medical field due to their structural variability and broad spectrum of biological activity. CN 106632092A shows that 4-quinazoline derivatives and 2, 4-quinazoline derivatives can be used for DHQA drugs and antibacterial agents. An important 4-dihydro-2 (1H) -quinazolinone derivative was first mentioned in DE2702530A1 by Sumitomo chemical Co., ltd in 1976. The prior art shows that derivatives with different substituents in the 3-and 4-positions are good Na + /Ca 2+ Ion exchange inhibitors useful in the treatment of ischemic heart disease; CN 101255138A discloses derivatives having a 3,4-substituted 2 (1H) -quinazoline structure with anticoccidial activity 7 or inhibitory effect on HIV infection. However, to date, no 3,4-dihydro-2 (3H) -quinazolinone has been reported. Based on this fact, we synthesized a series of compounds with the following frameworks, enriching the compound library. And further research the anti-tumor effectiveness of the composition.
Disclosure of Invention
The invention aims to solve the technical problem of providing a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound and a synthesis method and application thereof.
The invention is realized by the following technical scheme:
a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound having the following structural formula:
Figure BDA0002592696950000021
wherein R is 1 Is hydrogen or chlorine, R 2 Is hydrogen, methyl, methoxy or fluorine, R 3 Is nitrophenyl, (2-trifluoromethyl-5-Cl) piperidinyl, phenyl, methoxyphenyl, trifluoromethylphenyl, or C2-C8 alkyl, R 4 Is hydrogen or methyl, and X is selected from O or S.
Preferably, R 1 Is hydrogen or 6-chloro.
Preferably, R 2 Hydrogen, or methyl, methoxy or chlorine at the 2-or 4-position.
Preferably, R 1 Is hydrogen or 6-chloro, R 2 Is hydrogen, 2-fluoro or 4-fluoro, R 3 Is (2-trifluoromethyl-5-chloro) piperidyl, 2-trifluoromethylphenyl, cyclohexyl, R 4 Is hydrogen or methyl, and X is O.
Preferably, R 3 Is 2-nitrophenyl, (2-trifluoromethyl-5-chloro) piperidinyl, phenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, ethyl, isobutyl, isopentyl, cyclopropanemethyl, cyclohexane methyl, or cyclopentanopropyl.
More preferably, the compound is: (1) R 1 Is chlorine, R 2 Is fluorine, R 3 Is (2-trifluoromethyl-5-Cl) piperidinyl or cyclohexanyl, R 4 Is hydrogen, X is O; or,
(2)R 1 is chlorine, R 2 Is 2-fluoro, R 3 Is 2-trifluoromethylphenyl, R 4 Is hydrogen or methyl, X is O; or,
(3)R 1 is 6-chloro, R 2 Is hydrogen, R 3 Is 2-trifluoromethylphenyl, R 4 Is hydrogen and X is O.
In a preferred embodiment of the present invention, R is 1 Is 6-chloro, R 2 Is 2-fluoro, R 3 Is (2-trifluoromethyl-5-chloro) piperidinyl or cyclohexanyl, R 4 Is hydrogen and X is O.
In another preferred embodiment of the present invention, R 1 Is 6-chloro, R 2 Is 2-fluoro, R 3 Is trifluoromethyl-phenyl or cyclohexyl, R 4 Is hydrogen or methyl, and X is O.
In another preferred embodiment of the present invention, R 1 Is 6-chloro, R 2 Is hydrogen, R 3 Is trifluoromethyl-phenyl or cyclohexyl, R 4 Is hydrogen and X is O.
The synthesis method of the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound comprises the following steps:
(1) Taking the compound 1 as an initial raw material, and carrying out a Grignard reaction with the compound 1' to obtain a compound 2; the compound 1 is 2-nitrobenzaldehyde or chlorine substituted 2-nitrobenzaldehyde; preferably 2-nitrobenzaldehyde or 5-chloro-2-nitrobenzaldehyde; the compound 1' is bromobenzene or substituted bromobenzene substituted at 2-position or 4-position; the substituted bromobenzene is selected from 2-fluorobromobenzene, 4-fluorobromobenzene, 2-methylbromobenzene or 2-methoxybromobenzene.
(2) Carrying out oxidation reaction on the compound 2 to obtain a compound 3;
preferably, the compound 2 is added into an organic solvent, and chromium trioxide pyridine hydrochloride (PCC) is added to react to obtain a compound 3;
(3) Reducing nitro group of the compound 3 to obtain a compound 4;
preferably, the reduction reaction is carried out with iron powder;
(4) Respectively using (S) - (-) -tertiary butyl sulfinamide and (R) - (+) -tertiary butyl sulfinamide as chiral inducers in an organic solvent, and obtaining a compound 5 through microwave reaction;
(5) The sulfinamide is reduced by diisobutylaluminum hydride to prepare chiral sulfinyl amine compound 6;
(6) Sulfinyl is removed with HCl/MeOH to give chiral diamine compound 7;
(7) The compound 7 and a nitro-substituted benzene ring are subjected to Buchwald-Hartwig coupling to generate a compound 8 of which the R3 substituent is nitrophenyl, or the compound 7 and 2-methylbenzeneboronic acid, 2-methoxybenzeneboronic acid, 2-trifluoromethylphenylboronic acid or 2-chloro-5- (trifluoromethyl) pyridine-4-boronic acid are subjected to Chan-Lam-Evans coupling to generate a compound 8 of which the R3 substituent is methyl, methoxy or trifluoromethyl-substituted phenyl unsubstituted phenyl, or the compound 7 and the compound 7 are subjected to reaction to generate a compound 8 (8 f 3) of which the R3 substituent is pyridine substituent, or the compound 7 and aldehyde or ketone or sodium triacetoxyborohydride are subjected to reaction to generate a compound 8 of which the R3 substituent is an alkyl chain or a ring, wherein the aldehyde comprises acetaldehyde, isobutyraldehyde, isovaleraldehyde, cyclopropane formaldehyde, cyclohexane formaldehyde and cyclopentane formaldehyde, and the ketone is cyclohexanone;
(8) Adding the compound 8 and triethylamine into an organic solvent, and treating with bis (trichloromethyl) carbonate in an ice-water bath to obtain a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X = O and R4= H;
or adding the compound 8 and triethylamine into an organic solvent, and treating with bis (trichloromethyl) carbonate in an ice-water bath to obtain a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X = O and R4= H; reacting with NaH organic solvent at-10-5 ℃ under the protection of nitrogen or inert gas, and then adding methyl iodide for treatment to obtain X = O and R4= CH 3 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds;
or adding the compound 8 and triethylamine into an organic solvent, and treating with bis (trichloromethyl) carbonate in an ice-water bath to obtain a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X = O and R4= H; reuse of P 4 S 10 And xylene further treatment to change O to S to give a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with R4= H, X = S;
or adding the compound 8 and triethylamine into an organic solvent, treating with bis (trichloromethyl) carbonate in an ice-water bath, and then treating with P 4 S 10 And xylene further treatment to change O to S to give a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with R4= H, X = S; under the protection of nitrogen or inert gas, reacting the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with R4= H and X = S with NaH in an organic solvent at-10-5 ℃, and adding methyl iodide for treatment to obtain X = O and R4= CH 3 1,4-Disubstituted 3, 4-dihydro-2 (3H) -quinazolinones.
R of Compound 1 1 Is hydrogen or chlorine; r of Compound 1 2 Is methyl, methoxy or fluorine.
Preferably, R of Compound 1 1 R of compound 2 being hydrogen or chlorine 2 Hydrogen, methyl at position 2 or 4, methoxy at position 2 or 4, or chlorine at position 2 or 4.
Preferably, compound 1 is 5-chloro-2-nitrobenzaldehyde or 2-nitrobenzaldehyde.
Preferably, compound 1' is bromobenzene, 2-methyl-bromobenzene, 4-methyl-bromobenzene, 2-methoxy-bromobenzene, 4-methoxy-bromobenzene, 2-fluoro-bromobenzene or 4-fluoro-bromobenzene.
Preferably, the aldehyde in step 7 is acetaldehyde, isobutyraldehyde, isovaleraldehyde, cyclopropane formaldehyde, cyclohexane formaldehyde or cyclopentane formaldehyde; the ketone is cyclohexanone, 2-methyl benzene boric acid or 2-methoxy benzene boric acid or 2-trifluoromethyl benzene boric acid or 2-chlorine-5- (trifluoromethyl) pyridine-4-boric acid.
Figure BDA0002592696950000051
The aldehyde or ketone in the step (7) is as follows:
Figure BDA0002592696950000052
adding magnesium and iodine into an organic solvent under the condition of nitrogen protection in the Grignard reaction in the step (1), heating to 70-80 ℃, adding 2-methyl bromobenzene after the reaction liquid becomes colorless and transparent (activated), reacting for 1-3 hours, cooling to 25-35 ℃, adding a small amount of reaction liquid into the organic solvent containing 5-chloro-2-nitrobenzaldehyde or 2-nitrobenzaldehyde for many times, reacting for 1-3 hours at 25-35 ℃ under the condition of nitrogen protection, quenching with water, extracting, washing an organic layer with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, rotary steaming, and purifying to obtain a white solid, namely a compound 2.
In the step (1), the halogen in the grignard reaction is iodine, and the molar ratio of the compound 1, the compound 1', magnesium and iodine is 1:1 to 2: 1.05-1.1: 0.05; preferably 1:1 to 2: 1.05-1.1: 0.05.
in the step (1), the dosage ratio of magnesium to the organic solvent is 0.6-1.2mol/L.
In the reaction system in the step (1), the concentration of the compound 1 or the compound 1' is 0.5-1.0mol/L.
In the step (1), the organic solvent is tetrahydrofuran or anhydrous ether.
In the step (2), the molar ratio of the compound 2 to the PCC is 1:1 to 1.5, the reaction time is 3 to 5 hours, and the reaction temperature is 25 to 35 ℃.
In the step (2), the concentration of the compound 2 in the organic solvent is 0.2-0.3 mol/L, and the organic solvent is dichloromethane or anhydrous ether.
In the step (2), the chromic trioxide pyridine hydrochloride (PCC) is dichloromethane (20 mL) solution of PCC with the concentration of PCC being 0.2-0.6mol/L.
In the step (3), the compound 3 and iron powder are added into a mixed solvent, the mixture reacts for 0.5 to 1 hour at the temperature of 40 to 60 ℃, hydrochloric acid is added, the reaction is continued for 1 to 3 hours, and the light yellow solid, namely the compound 4, is obtained after filtration, washing, extraction, drying, rotary evaporation and purification.
In the step (3), the molar ratio of the compound 3 to the iron powder is 1:15 to 25.
In the step (3), the mixed solvent is an organic solvent and water according to a volume ratio of 1:0.5-5 of a mixture. The organic solvent is any one of ethanol, methanol or isopropanol.
In the step (3), the concentration of the compound 3 in the mixed solvent is 0.2-0.5mol/L.
In the step (3), the concentration of the hydrochloric acid is 10-15mol/L, and the volume ratio of the hydrochloric acid to the mixed solvent is 1:12-18.
In the step (4), the compound 4 and tert-butyl sulfenamide are added into an organic solvent, and the mixture is reacted in a microwave reaction tube, washed by water, filtered, washed by ethyl acetate, dried by anhydrous sodium sulfate, rotary evaporated and purified to obtain a yellow solid, namely the compound 5.
In the step (4), the molar ratio of the compound 4 to the tert-butyl sulfenamide is 1. The reaction time is 1.5 to 3 hours, the reaction temperature is 115 ℃ to 200 ℃, and the preferable temperature is 118 ℃.
In the step (4), the organic solvent is tetraethyl titanate or tetraisopropyl titanate, and the concentration of the compound 4 in the organic solvent is 0.2-1mol/L.
In the step (5), the organic solvent containing the compound 5 is cooled to-85 to-70 ℃ under the protection of nitrogen, the organic solvent containing diisobutylaluminum hydride is slowly added, the reaction is continued for 1.5 to 3 hours at-85 to-70 ℃, and the mixture is quenched, extracted, filtered, rotary evaporated and purified to obtain a light yellow solid, namely the compound 6.
The concentration of the organic solvent containing the compound 5 is 0.2-0.5mol/L, and the organic solvent is tetrahydrofuran, dichloromethane or 1, 2-dichloroethane.
The concentration of the organic solvent containing diisobutylaluminum hydride is 1-2mol/L. The organic solvent is tetrahydrofuran, dichloromethane or toluene.
The molar ratio of the compound 5 to the diisobutylaluminum hydride is 1:2.5 to 3.5.
In the step (6), under the protection of nitrogen, the compound 6 and methanol are added into an organic solvent, and under the ice bath condition, a dioxane solution of hydrogen chloride is slowly dripped into the organic solvent to react for 1.5 to 4 hours at the temperature of between 15 and 35 ℃. Performing rotary evaporation, adding water for dissolution, extracting with ethyl acetate, adjusting the pH value of a water layer to 8-9 with ammonia water, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, performing rotary evaporation, and purifying to obtain a light yellow oily substance, namely a chiral diamine compound 7, wherein the reaction time is preferably 2 hours, and the molar ratio of the compound 6 to hydrogen chloride is 1:2.5 to 3.5, preferably 1:3.0, the solid-to-liquid ratio of the compound 6 to the methanol is 1mol:2 to 3L, the organic solvent is any one of 1, 4-dioxane, dichloromethane or 1, 2-dichloroethane, and the concentration of the hydrogen chloride in the dioxane solution of the hydrogen chloride is 1.8 to 2.6mol/L.
In step (7), buchwald-Hartwig coupling: adding the compound 7, 2-bromonitrobenzene, (+ -) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl and inorganic base into an organic solvent, reacting under the protection of nitrogen, performing suction filtration, washing, drying, rotary evaporation and purification to obtain a light yellow solid compound 8.
The compounds 7, 2-bromonitrobenzene, (+ -) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, CS 2 CO 3 1 to 1.5:0.5 to 1.0:1.5 to 2.5.
The reaction time is 6-8 hours, and the reaction temperature is 65-80 ℃.
The organic solvent is any one of toluene, xylene, dimethylformamide, dichloromethane, 1, 2-dichloroethane or tetrahydrofuran, and is preferably toluene.
The concentration of the compound 7 in the organic solvent is 0.2-0.3 mol/L.
The base is cesium carbonate, potassium carbonate or potassium phosphate.
In step (7), chan-Lam-Evans coupling: adding aryl boric acid compounds such as 7, 2-methyl phenylboronic acid, 2-methoxy phenylboronic acid, 2-trifluoromethyl phenylboronic acid or 2-chloro-5- (trifluoromethyl) pyridine-4-boric acid and triethylamine into an organic solvent, dissolving, and adding copper acetate for reaction. After the reaction is finished, the mixture is quenched by saturated sodium bicarbonate solution, extracted by ethyl acetate, rotary evaporated and purified to obtain a light yellow oily compound 8. The molar ratio of the compound 7 to the 2-methyl phenylboronic acid to the triethylamine to the copper acetate is 1.2-2: 2 to 3:0.4 to 0.8. The reaction time is 8-12 h, and the reaction temperature is 15-35 ℃. The organic solvent is any one of toluene, dichloromethane, 1, 2-dichloroethane or tetrahydrofuran. The concentration of the compound 7 in the organic solvent is 0.2-0.3 mol/L.
In step (7), reaction of aniline with aldehyde or ketone and sodium triacetoxyborohydride: adding ketone compounds such as compound 7, acetaldehyde, isobutyraldehyde, isovaleraldehyde, cyclopropane formaldehyde, cyclohexanone, cyclohexane formaldehyde, cyclopentane formaldehyde and the like into an organic solvent, and reacting for 1-3 hours at 15-35 ℃; then adding sodium triacetoxyborohydride, reacting for 1-3 hours at 15-35 ℃, washing, extracting, drying, rotary evaporating and purifying to obtain a compound 8. The organic solvent is any one of dichloromethane, toluene, 1, 2-dichloroethane or tetrahydrofuran, and dichloromethane is preferred. The concentration of the organic solvent compound 7 is 0.15 to 0.25mol/L, preferably 0.2mol/L. The molar ratio of the compound 7 to cyclopentanone to sodium triacetoxyborohydride is 1:1 to 2:1 to 1.2.
In the step (8), the organic solvent is any one of dichloromethane, toluene, 1, 2-dichloroethane or tetrahydrofuran.
In the step (8), when the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X = O and R4= H is synthesized, the concentration of the compound 8 in the organic solvent is 0.02 to 0.1mol/L. Preferably, the molar ratio of the compound 8 to the triethylamine to the bis (trichloromethyl) carbonate is 1: 1.2-1.8: 1 to 1.5.
In step (8), with P 4 S 10 When the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X = O is further processed, the molar ratio of the two compounds is 1-1.2: 1;
in the step (8), R is treated with NaH and methyl iodide 4 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds of H, R 4 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound of H, naH and methyl iodide in a molar ratio of 1.9-2: 1:1.
the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound has good inhibitory effect on tumor cells, and is used in RPM1 1640 culture medium for leukemia cells (K562), lung cancer cells (A549) and liver cancer cells (BEL 7402); pancreatic cancer cells (SW 1990) and glioma cells (U251) have strong inhibitory effect, and can be used for preparing antitumor drugs. In particular to the application in the preparation of drugs for treating leukemia, lung cancer, liver cancer, pancreatic cancer cells or glioma.
The invention has the beneficial effects that: the invention carries out structural design and extension modification based on a chiral 1, 4-disubstituted-3, 4-dihydro-2 (3H) -quinazolinone skeleton structure. The (S) - (-) -tert-butyl imido amide is used as a chiral inducer, and after aromatic amine compounds are formed through three synthetic routes, a series of novel quinazolinone derivatives are obtained and antitumor activity tests are performed. The quinazolinone derivative has good inhibition effect on 5 different cancer cells, has broad spectrum effect, and particularly has good inhibition activity on liver cancer cells. The compound is completely different from other inhibitors, is a novel compound with a non-peptide structure, can be regarded as a novel compound worthy of exploration, and has good market prospect and application prospect.
Detailed Description
In specific embodiments all chemicals were purchased from either Annaige reagent or Aladdin reagent. All reagents were subjected to strictly anhydrous treatment prior to use. The column used for purification was 200-300 mesh silica gel. The reaction was monitored by NMR or Thin Layer Chromatography (TLC) using a magnetic stirring apparatus (UV irradiation 254nm or iodine jar development).
23 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds of the examples of the invention are shown in Table 1.
TABLE 1 all 23 Final Compounds
Figure BDA0002592696950000091
Figure BDA0002592696950000101
The structural formula is as follows:
Figure BDA0002592696950000102
Figure BDA0002592696950000111
the structure of intermediate compound 7 is as follows:
Figure BDA0002592696950000112
7a, 7b, 7c, 7d, 7e, 7f were used to prepare 9a, 9b 1-9 b2, 9c 1-9 c2, 9d, 9e, 9f 1-9 f16, respectively.
The following will describe the preparation of compounds 9f2, 9f9 and 9f15 by way of example. The above compounds can be prepared by selecting the starting materials for the reaction by those skilled in the art according to the descriptions of the specification and examples.
EXAMPLE 1 Compound 2a
Figure BDA0002592696950000121
Magnesium (0.4g, 17.8mmol) was added to tetrahydrofuran THF (20 mL) under nitrogen, and an additional iodine pellet (0.2 mm diameter, ca. 10 mg) was added and heated to 70 ℃. Then, 2-methylbromobenzene (3g, 17.5 mmol) was added and reacted at 70 ℃ for 1 hour. Thereafter, the solution was transferred to a THF solution (20 mL) of 2-nitrobenzaldehyde (2.65g, 17.5 mmol) and reacted at room temperature for 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed using a rotary evaporator. The crude product obtained was purified by silica gel column chromatography. The product was obtained in 3.6g (14.8 mmol) in 85% yield as a white solid.
EXAMPLE 2 Compound 3a example
Compound 3a
Figure BDA0002592696950000122
A solution of chromium trioxide pyridine hydrochloride (PCC) (90 mmol) in methylene chloride (20 mL) was added dropwise to a solution of compound 2a (3.6 g,14.8 mmol) in methylene chloride (50 mL) at room temperature, the mixture was stirred at room temperature for 5 hours, the reaction solution was filtered through celite, washed with ether, and the solvent was removed by rotary evaporator. The crude product was purified by silica gel column chromatography to give the product 3.2g (13.2 mmol) in 90% yield as a pale yellow solid.
EXAMPLE 3 Compound 4 example
Compound 4a
Figure BDA0002592696950000123
Compound 3a (3 g,12.4 mmol), ethanol (15 mL), water (15 mL) and iron powder (14 g, 249 mmol) were mixed and heated at 40 ℃ for 30 minutes, followed by addition of hydrochloric acid (2mL, 12mol/L) and reaction at room temperature for 2 hours. The solution was filtered through celite and washed with saturated sodium bicarbonate. After extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. The product was obtained as 2.5g (12 mmol) in 95% yield as a pale yellow solid.
EXAMPLE 4 Compound 5 example
Compound 5a
Figure BDA0002592696950000131
Compound 4a (3.5g, 17.8mmol) and (S) - (-) -tert-butylsulfinamide (3.2g, 27mmol) were added to 20mL of tetraethyltitanate in a microwave reaction tube at 118 ℃. After 2 hours, quench with water, filter through celite, and extract with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. Product 3.3g (11 mmol) was obtained as a yellow solid in 62% yield.
EXAMPLE 5 Compound 6 example
Compound 6a
Figure BDA0002592696950000132
Under nitrogen protection, compound 5a (2.85g, 9.5 mmol) was added to anhydrous THF (25 mL), cooled to-78 deg.C, then diisobutylaluminum hydride (19mL, 1.5mol/L THF) was added slowly and stirred at-78 deg.C for 2h. The reaction solution was quenched with saturated sodium chloride and extracted with ethyl acetate, followed by suction filtration with celite. The crude product obtained was purified by silica gel column chromatography. Product 2.3g (7.9 mmol) was obtained in 82% yield as a pale yellow solid.
EXAMPLE 6 Compound 7 example
Compound 7a
Figure BDA0002592696950000141
Under nitrogen protection, compound 6a (2.4 g,7.9 mmol) and methanol (20 mL) were added to 20mL dioxane solvent. The reaction was cooled to 0 deg.C, a solution of hydrogen chloride in dioxane (10.3 mL,2.3 mol/L) was slowly added and reacted at 0 deg.C for 2 hours. The mixture was then concentrated by rotary evaporator and water was added and extracted with ethyl acetate. The aqueous layer was made basic (pH = about 8) with ammonia and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. 1.1g (5.5 mmol) of the product are obtained in 70% yield as a pale yellow oil.
EXAMPLE 7 Compound 8 example
Compound 8b1
Figure BDA0002592696950000142
Under a nitrogen atmosphere, compound 7a (488mg, 2.3mmol), 2-bromonitrobenzene (465 mg,2.3 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (1.1g, 1.84mmol) and cesium carbonate (1.5g, 4.6 mmol) were added to 10ml of toluene and reacted at 70 ℃ for 8 hours. The reaction solution was filtered through celite, and washed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. The product was obtained in 0.513g (1.5 mmol) in 67% yield as a pale yellow solid.
EXAMPLE 8 Compound 8b2
Figure BDA0002592696950000151
Compound 7a (488mg, 2.3mmol), 2-trifluoromethylphenylboronic acid (449mg, 3.68mmol), and triethylamine (580mg, 5.75mmol) were addedTo 10mL CH 2 Cl 2 In (1). Then, copper acetate (276 mg, 1.38 mmol) was added thereto, and the reaction was carried out at room temperature for 10 hours. After quenching with saturated sodium bicarbonate solution, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. 0.549g (7.9 mmol) of product was obtained in 67% yield as a pale yellow oil.
EXAMPLE 9 Compound 8f3
Figure BDA0002592696950000152
Compound 7f (500mg, 2mmol), 2-chloro-4-iodo-5- (trifluoromethyl) pyridine (620mg, 2mmol), (+ -) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (1.1g, 1.7 mmol), CS 2 CO 3 (1.4 g, 4.2 mmol) and toluene (10 mL) were added to a three-necked flask with a condenser and reacted at 70 ℃ for 8h under nitrogen. After the reaction is finished, the mixture is filtered by diatomite in a suction way, washed by ethyl acetate and then removed from the solvent by a rotary evaporator to obtain a crude product. The crude product was purified by column chromatography. The product was a pale yellow solid with a mass of 560mg (1.3 mmol) and a yield of 65%.
EXAMPLE 10 Compound 8f15
Figure BDA0002592696950000161
Compound 7a (0.577g, 2.3mmol) and cyclohexanecarboxaldehyde (336mg, 4mmol) were added to methylene chloride (20 mL) and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (1.0 g,4.8 mmol) was then added and the reaction was continued for 1 hour. After the reaction was completed, the mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. The product was obtained in 0.575g (1.7 mmol) as a 72% yield pale yellow oil.
EXAMPLE 11 Compound 9 example
Compound 9f15
Figure BDA0002592696950000162
Compound 8f15 (167mg, 0.5mmol) and triethylamine (100mg, 0.9mmol) were added to 10mL of dichloromethane. After the solution was cooled to 0 ℃, bis (trichloromethyl) carbonate (190 mg, 0.6 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. Product 0.127 g (0.335 mmol) was obtained in 68% yield as a white solid.
The same synthetic method, 9b1 and 9b2 were prepared from 8b1 and 8b2, respectively.
EXAMPLE 12 Compound 9f1
Figure BDA0002592696950000171
Compound 8f1 (186mg, 0.5 mmol) and triethylamine (100mg, 0.9 mmol) were added to 10mL of dichloromethane. The solution was cooled to 0 ℃ and bis (trichloromethyl) carbonate (190 mg, 0.6 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. Product 0.150 g (0.36 mmol) was obtained in 72% yield as a white solid.
Compound 8f1 was prepared by the same method as that for 8b1 obtained in examples 1 to 7, except that 2-fluorobromobenzene in example 1 was replaced with 2-fluoro-bromobenzene and 5-chloro-2-nitrobenzaldehyde was used in place of 2-nitrobenzaldehyde in example 1.
EXAMPLE 13 Compound 9f2
Figure BDA0002592696950000181
The compound 9f1 (199mg, 0.5mmol) and P 4 S 10 (780 mg, 0.5mmol) was added to 10mL of xylene, and reacted at 140 ℃ for 5 hours. Then, 0.5mL of ammonia water was added thereto, and the reaction was carried out at 80 ℃ for 1 hour. After the reaction, the reaction solution was quenched with saturated sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. Product 0.245 g (0.32 mmol) was obtained in 64% yield as a yellow solid.
EXAMPLE 14 Compound 9f6
Figure BDA0002592696950000182
Compound 8f6 (197mg, 0.5 mmol) and triethylamine (100mg, 0.9 mmol) were added to 10mL of dichloromethane. The solution was cooled to 0 ℃ and bis (trichloromethyl) carbonate (190 mg, 0.6 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. The product was obtained in 0.150 g (0.35 mmol) in 70% yield as a white solid.
8f6 is prepared by the same method as 8b2 except that the methyl-substituted diamine compound 7b is replaced with the chlorine or fluorine-substituted diamine compound 7 f.
EXAMPLE 15 Compound 9f9
Figure BDA0002592696950000191
Compound 9f6 (211mg, 0.5 mmol) and sodium hydride (6 mg,0.24 mmol) were added to THF (5 mL) under nitrogen protection and reacted at 0 ℃ for 1 hour. Methyl iodide (34mg, 0.24mmol) was then added and the reaction continued at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product obtained was purified by silica gel column chromatography. Product 0.178 g (0.24 mmol) was obtained in 48% yield as a white solid.
Example 16 in vitro antitumor Activity assay
The main reagents are as follows: MTT (tetramethylazocycloblue); DMSO (dimethyl sulfoxide); RPM1 1640 medium; DMEM medium. MTT (Tetramethyltetrazolium blue) was purchased from Fluka (Missouri, USA).
The main test cells: lung cancer cell A549, leukemia cell K562, glioma cell U251, liver cancer cell BEL7402, pancreatic cancer cell SW1990 and human liver cell L02 were purchased from Shanghai Biochemical and cell biology institute cell banks of Chinese academy of sciences.
1. Cell dosing experiments: leukemia cells (K562), lung cancer cells (A549) and liver cancer cells (BEL 7402) in RPM1 1640 medium; pancreatic cancer cells (SW 1990) and glioma cells (U251) were cultured in DMEM. Cells were incubated at 37 ℃ and 5% CO 2 Culturing in an incubator. After 24h, the drugs were added as designed. Hepatocytes (L02) were incubated in the drug-containing DMSO solutions for 20, 40, and 80 hours, respectively.
2. Cell activity assay: dissolving the experimental drug in DMSO, diluting with culture medium to appropriate concentration, each concentration is 5 multiple wells, adding the drug, placing 96-well culture plate at 37 deg.C, and 5% CO 2 After 48 hours of incubation in an incubator, 10. Mu.L of MTT (final concentration 0.5 g/L) was added to each well, the mixture was left at 37 ℃ for 4 to 6 hours, the supernatant was aspirated, and 100. Mu.L of DMSO was added to each well to dissolve the crystals sufficiently. Untreated cells were used as a control with 100% activity and cells without added MTT were used as a blank. Finally, the absorbance (o.d. value) at 570nm of each well was measured with an automatic microplate reader (EL 800, BIO-TEK Instruments inc., usa). Statistical analysis was performed using SPSS software to calculate the median lethality IC 50 。
TABLE 2 inhibitory Effect on cancer cells 16 Compounds
Figure BDA0002592696950000201
Figure BDA0002592696950000211
The anti-activity test aiming at 5 tumor cells comprises lung cancer cells A549, leukemia cells K562, glioma cells U251, liver cancer cells BEL7402 and pancreatic cancer cells SW1990. We tested the antitumor cell efficacy of the first 18 compounds and found that compounds with R3 as the alkyl substituent showed good activity. When human hepatocytes L02 cells were used for cytotoxicity tests, no significant decrease in cells was observed after 80h when human hepatocytes L02 were each exposed to the first five compounds (9 f6, 9f14, 9f3, 9f4, 9 e) with optimal tumor cell inhibition, indicating good safety.
Table 2 shows 16 compounds with better cancer cell inhibitory effect. Among these compounds, compound 9f6, compound 9e, compound 9f14, compound 9f3 and compound 9f9 showed a broad spectrum of antitumor activity, IC 50 Both less than 50. Mu.M, wherein the IC of both compounds 50 Less than 20. Mu.M. R is 3 9f3 with 2-chloro-5-trifluoromethylpyridine as substituent shows the best anticancer activity on all 5 tumor cell lines and IC of A549 50 IC value of 7.386. Mu.M for K562 50 IC with value of 11.506 μ M for U251 50 32.860 μ M, 13.800 μ M for BEL7402 and 28.261 μ M for SW1990. R 3 9f14, with the substituent 1-cyclohexyl, showed the second best anticancer activity, IC for A549 50 IC value of 5.920. Mu.M for K562 50 IC value of 14.420 μ M for U251 50 IC at 14.370 μ M for BEL7402 50 IC 13.370 μ M and 1990 SW 50 It was 29.462. Mu.M. Among the five cells, the scaffold analog synthesized here had the best inhibitory effect on a 549. In particular for this liver cancer, IC of 9f14 and 9f3 50 The value is less than 10. Mu.M. All of these compounds are structurally novel for anticancer agents.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that are not thought of through the inventive work should be included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.

Claims (2)

1. A1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound having the structural formula:
Figure DEST_PATH_IMAGE001
wherein R is 1 Is 6-chloro, R 2 Is 2-fluoro, R 3 Is cyclohexane radical, R 4 Is hydrogen and X is O.
2. Use of the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds according to claim 1 for the preparation of a medicament for the treatment of leukemia, lung cancer, liver cancer, pancreatic cancer cells or glioma.
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