CN111995587A - 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound and synthetic method and application thereof - Google Patents
1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound and synthetic method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
- C07D239/82—Oxygen atoms with an aryl radical attached in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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. R1Is hydrogen or chlorine, R2Is hydrogen, methyl, methoxy or fluorine, R3Is nitrophenyl, (2-trifluoromethyl-5-Cl) piperidyl, phenyl, methoxyphenyl, methylphenyl, 2-trifluoromethylphenyl or C2-C8 alkyl or cycloalkyl, R4Is hydrogen or methyl, and X is O or S. The compound is a novel compound having a non-peptide structure, and is useful for cancer cellsHas good inhibition effect, broad spectrum effect, particularly good inhibition activity on liver cancer cells, and good market prospect and application prospect.
Description
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. Demonstration of 4-quinazoline derivatives in CN 106632092AThe biological and 2, 4-quinazoline derivatives can be used for DHQA drugs and antibacterial. 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+/Ca2+Ion exchange inhibitors useful in the treatment of ischemic heart disease; CN 101255138A discloses derivatives with 3, 4-substituted 2(1H) -quinazoline structure, having anticoccidial activity 7 or having 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:
wherein R is1Is hydrogen or chlorine, R2Is hydrogen, methyl, methoxy or fluorine, R3Is nitrophenyl, (2-trifluoromethyl-5-Cl) piperidyl, phenyl, methoxyphenyl, trifluoromethylphenyl or C2-C8 alkyl, R4Is hydrogen or methyl, and X is selected from O or S.
Preferably, R1Is hydrogen or 6-chloro.
Preferably, R2Hydrogen, or methyl, methoxy or chlorine at the 2-or 4-position.
Preferably, R1Is hydrogen or 6-chloro, R2Is hydrogen, 2-fluoro or 4-fluoro, R3Is (2-trifluoromethyl-5-chloro) piperidyl, 2-trifluoromethylphenyl, cyclohexyl, R4Is hydrogen or methylAnd X is O.
Preferably, R3Is 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) r1Is chlorine, R2Is fluorine, R3Is (2-trifluoromethyl-5-Cl) piperidinyl or cyclohexanyl, R4Is hydrogen, X is O; alternatively, the first and second electrodes may be,
(2)R1is chlorine, R2Is 2-fluoro, R3Is 2-trifluoromethylphenyl, R4Is hydrogen or methyl, X is O; alternatively, the first and second electrodes may be,
(3)R1is 6-chloro, R2Is hydrogen, R3Is 2-trifluoromethylphenyl, R4Is hydrogen and X is O.
In a preferred embodiment of the present invention, R is1Is 6-chloro, R2Is 2-fluoro, R3Is (2-trifluoromethyl-5-chloro) piperidinyl or cyclohexanyl radical, R4Is hydrogen and X is O.
In another preferred embodiment of the present invention, R1Is 6-chloro, R2Is 2-fluoro, R3Is trifluoromethyl-phenyl or cyclohexyl, R4Is hydrogen or methyl, and X is O.
In another preferred embodiment of the present invention, R1Is 6-chloro, R2Is hydrogen, R3Is trifluoromethyl-phenyl or cyclohexyl, R4Is 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) removing sulfinyl with HCl/MeOH to obtain 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 substituent R3 is nitrophenyl, or the compound 7 and 2-methylphenylboronic acid, 2-methoxyphenylboronic 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 substituent R3 is methyl, methoxy or trifluoromethyl-substituted phenyl and is not substituted by phenyl, or the compound 7 and the compound 7 are subjected to reaction to generate a compound 8(8f3) of which the substituent R3 is pyridine substituent, or the compound 7 and aldehyde or ketone and sodium triacetoxyborohydride are subjected to reaction to generate a compound 8 of which the substituent R3 is an alkyl chain or a ring, 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 the mixture with bis (trichloromethyl) carbonate in an ice-water bath to obtain a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X being O, R4 being H;
or adding the compound 8 and triethylamine into an organic solvent, and treating the mixture with bis (trichloromethyl) carbonate in an ice-water bath to obtain a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X being O, R4 being H; then in nitrogen or inert gasReacting with NaH organic solvent at-10-5 ℃ under protection, and then adding methyl iodide for treatment to obtain X-O, R4-CH31, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds;
or adding the compound 8 and triethylamine into an organic solvent, and treating the mixture with bis (trichloromethyl) carbonate in an ice-water bath to obtain a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound with X being O, R4 being H; reuse of P4S10And xylene further treatment to change O to S, to give a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound 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 P4S10And xylene further treatment to change O to S, to give a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound R4 ═ H, X ═ S; under the protection of nitrogen or inert gas, reacting the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound of R4 ═ H, X ═ S with NaH in an organic solvent at-10 to 5 ℃, and then adding methyl iodide for treatment to obtain X ═ O, R4 ═ CH31, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds.
R of Compound 11Is hydrogen or chlorine; r of Compound 12Is methyl, methoxy or fluorine.
Preferably, R of Compound 11R of compound 2 being hydrogen or chlorine2Hydrogen, 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.
The aldehyde or ketone in the step (7) is as follows:
adding magnesium and iodine into an organic solvent under the condition of nitrogen protection in the step (1), heating to 70-80 ℃, adding 2-methyl bromobenzene after a reaction liquid becomes colorless and transparent (activated), reacting for 1-3 hours, cooling to 25-35 ℃, adding a small amount of the 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: 1-2: 1.05-1.1: 0.05; preferably 1: 1-2: 1.05-1.1: 0.05.
in the step (1), the dosage ratio of magnesium to the organic solvent is 0.6-1.2 mol/L.
In the reaction system in the step (1), the concentration of the compound 1 or the compound 1' is 0.5-1.0 mol/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: 1-1.5, the reaction time is 3-5 hours, and the reaction temperature is 25-35 ℃.
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 chromium trioxide pyridine hydrochloride (PCC) is a dichloromethane (20mL) solution of PCC, wherein the concentration of PCC is 0.2-0.6 mol/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 0.2-0.5 mol/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: 1-2. The reaction time is 1.5-3 hours, the reaction temperature is 115-200 ℃, 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 0.2-1 mol/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 1-2 mol/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, adding the compound 6 and methanol into an organic solvent, slowly dropping a dioxane solution of hydrogen chloride under the ice bath condition, and reacting for 1.5-4 hours at 15-35 ℃. Performing rotary evaporation, dissolving in water, extracting with ethyl acetate, adjusting the pH 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: 2.5-3.5, preferably 1: 3.0, the solid-to-liquid ratio of the compound 6 to the methanol is 1 mol: 2-3L, wherein the organic solvent is any one of 1, 4-dioxane, dichloromethane or 1, 2-dichloroethane, and the concentration of hydrogen chloride in the dioxane solution of the hydrogen chloride is 1.8-2.6 mol/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 are 7, 2-bromonitrobenzene, (+ -) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl and CS2CO3In a molar ratio of 1:1 to 1.5: 0.5-1.0: 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 the like and triethylamine into an organic solvent, dissolving, and then 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: 1.2-2: 2-3: 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 the step (7), aniline reacts with aldehyde or ketone and sodium triacetoxyborohydride: adding ketone compounds such as a 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 ℃; and then adding sodium triacetoxyborohydride, reacting for 1-3 hours at 15-35 ℃, washing, extracting, drying, rotary steaming 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 0.2 mol/L. The molar ratio of the compound 7 to cyclopentanone to sodium triacetoxyborohydride is 1: 1-2: 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 being O, R4 being H is synthesized, the concentration of the compound 8 in the organic solvent is 0.02 to 0.1 mol/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 P4S10When 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 iodide4When 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds of ═ H, R4The molar ratio of the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound as H to NaH to methyl iodide is 1.9-2: 1:1.
the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound has good inhibition effect on tumor cells, and is used for leukemia cells (K562), lung cancer cells (A549) and liver cancer cells (BEL7402) in RPM 11640 culture medium; pancreatic cancer cells (SW1990) 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. 200-300 mesh silica gel was used for the purification column. The reaction was monitored by NMR or Thin Layer Chromatography (TLC) using a magnetic stirring apparatus (UV irradiation 254nm or iodine jar development).
The 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
The structural formula is as follows:
the structure of intermediate compound 7 is as follows:
7a, 7b, 7c, 7d, 7e and 7f are respectively used for preparing 9a, 9b 1-9 b2, 9c 1-9 c2, 9d, 9e and 9f 1-9 f 16.
The preparation of the compounds 9f2, 9f9 and 9f15 is described below 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
Magnesium (0.4g, 17.8mmol) was added to tetrahydrofuran THF (20mL) under nitrogen protection, followed by an additional dose of iodine (0.2 mm diameter, ca. 10mg) and heating to 70 ℃. Then 2-methylbromobenzene (3g, 17.5mmol) was added and reacted at 70 ℃ for 1 hour. Thereafter, the solution was transferred to a THF solution (20mL) of 2-nitrobenzaldehyde (2.65g, 17.5mmol) 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 (14.8mmol) in 85% yield as a white solid.
EXAMPLE 2 Compound 3a example
Compound 3a
A solution of chromium trioxide pyridine hydrochloride (PCC) (90mmol) in dichloromethane (20mL) was added dropwise to a solution of compound 2a (3.6g, 14.8mmol) in dichloromethane (50mL) at room temperature, the mixture was stirred at room temperature for 5h, 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 (13.2mmol) in 90% yield as a pale yellow solid.
EXAMPLE 3 Compound 4 example
Compound 4a
Compound 3a (3g, 12.4mmol), ethanol (15mL), water (15mL) and iron powder (14g, 249mmol) 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 (12mmol) in 95% yield as a pale yellow solid.
EXAMPLE 4 Compound 5 example
Compound 5a
Compound 4a (3.5g, 17.8mmol) and (S) - (-) -tert-butylsulfinamide (3.2g, 27mmol) were added to 20mL tetraethyltitanate in a microwave reaction tube at 118 deg.C. 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 concentration on a rotary evaporator. The crude product obtained was purified by silica gel column chromatography. The product was obtained as 3.3g (11mmol), 62% yield, yellow solid.
EXAMPLE 5 Compound 6 example
Compound 6a
Compound 5a (2.85g, 9.5mmol) was added to anhydrous THF (25mL) under nitrogen protection, cooled to-78 deg.C, then diisobutylaluminum hydride (19mL, 1.5mol/L THF) was added slowly and stirred at-78 deg.C for 2 h. 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. The product was obtained in 2.3g (7.9mmol) in 82% yield as a pale yellow solid.
EXAMPLE 6 Compound 7 example
Compound 7a
Under nitrogen protection, compound 6a (2.4g, 7.9mmol) and methanol (20mL) were added to 20mL dioxane solvent. The reaction was cooled to 0 deg.C, a solution of hydrogen chloride in dioxane (10.3mL, 2.3mol/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 alkaline (pH 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 (5.5mmol) of the product are obtained in 70% yield as a pale yellow oil.
EXAMPLE 7 Compound 8 example
Compound 8b1
Compound 7a (488mg, 2.3mmol), 2-bromonitrobenzene (465mg, 2.3mmol), 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (1.1g, 1.84mmol) and cesium carbonate (1.5g, 4.6mmol) were added to 10mL of toluene under nitrogen protection 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 (1.5mmol) in 67% yield as a pale yellow solid.
EXAMPLE 8 Compound 8b2
Compound 7a (488mg, 2.3mmol), 2-trifluoromethylphenylboronic acid (449mg, 3.68mmol), and triethylamine (580mg, 5.75mmol) were added to 10mL of CH2Cl2In (1). Then, copper acetate (276mg, 1.38mmol) 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 (7.9mmol) of product was obtained in 67% yield as a pale yellow oil.
EXAMPLE 9 Compound 8f3
Compound 7f (500mg, 2mmol), 2-chloro-4-iodo-5- (trifluoromethyl) pyridine (620mg, 2mmol), (+ -) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (1.1g, 1.7mmol), CS2CO3(1.4g, 4.2mmol) and toluene (10mL) were added to a three-necked flask with a condenser and reacted at 70 ℃ for 8h under nitrogen. After the reaction is finished, filtering with diatomite, washing with ethyl acetate, and removing 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 (1.3mmol) and a yield of 65%.
EXAMPLE 10 Compound 8f15
Compound 7a (0.577g, 2.3mmol) and cyclohexanecarboxaldehyde (336mg, 4mmol) were added to dichloromethane (20mL) and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (1.0g, 4.8mmol) 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 (1.7mmol) as a 72% yield pale yellow oil.
EXAMPLE 11 Compound 9 example
Compound 9f15
Compound 8f15(167mg, 0.5mmol) and triethylamine (100mg, 0.9mmol) were added to 10mL of dichloromethane. The solution was cooled to 0 ℃ and bis (trichloromethyl) carbonate (190mg, 0.6mmol) 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 (0.335mmol) was obtained in 68% yield as a white solid.
The same synthetic method was used to prepare 9b1 and 9b2 from 8b1 and 8b2, respectively.
EXAMPLE 12 Compound 9f1
Compound 8f1(186mg, 0.5mmol) and triethylamine (100mg, 0.9mmol) were added to 10mL of dichloromethane. The solution was cooled to 0 ℃ and bis (trichloromethyl) carbonate (190mg, 0.6mmol) 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 (0.36mmol) was obtained in 72% yield as a white solid.
Compound 8f1 was prepared according to the same method as 8b1 obtained in examples 1 to 7, except that 2-bromobenzene in example 1 was replaced with 2-fluoro-bromobenzene, and 2-nitrobenzaldehyde in example 1 was replaced with 5-chloro-2-nitrobenzaldehyde.
EXAMPLE 13 Compound 9f2
Compound 9f1(199mg, 0.5mmol) and P4S10(780mg, 0.5mmol) was added to 10mL of xylene and reacted at 140 ℃ for 5 hours. Then, 0.5mL of aqueous ammonia was added thereto, and the mixture was reacted 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. The product was obtained in 0.245 g (0.32mmol) in 64% yield as a yellow solid.
EXAMPLE 14 Compound 9f6
Compound 8f6(197mg, 0.5mmol) and triethylamine (100mg, 0.9mmol) were added to 10mL of dichloromethane. The solution was cooled to 0 ℃ and bis (trichloromethyl) carbonate (190mg, 0.6mmol) 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 (0.35mmol) 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
Compound 9f6(211mg, 0.5mmol) and sodium hydride (6mg, 0.24mmol) were added to THF (5mL) under nitrogen protection and reacted at 0 ℃ for 1 hour. Methyl iodide (34mg, 0.24mmol) was then added and the reaction was 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 (0.24mmol) was obtained in 48% yield as a white solid.
Example 16 in vitro antitumor Activity assay
The main reagents are as follows: MTT (tetramethylazodicarbonyl blue); DMSO (dimethyl sulfoxide); RPM 11640 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: RPM 11640 medium for leukemia cells (K562), lung cancer cells (a549), and liver cancer cells (BEL 7402); pancreatic cancer cells (SW1990) and glioma cells (U251) were cultured in DMEM. The cells were incubated at 37 ℃ with 5% CO2Culturing 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, and diluting with culture medium to obtain the final productConcentration, each concentration is 5 multiple wells, the medicated 96-well culture plate is placed at 37 ℃ and 5% CO2After 48 hours of incubation in an incubator, 10. mu.L of MTT (final concentration: 0.5g/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 (EL800, BIO-TEK Instruments inc., usa). Statistical analysis was performed using SPSS software to calculate the median lethality IC50。
TABLE 2 inhibitory Effect on cancer cells 16 Compounds
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 SW 1990. 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 hepatocyte L02 cells were used for cytotoxicity test, no significant cytoreduction was observed after 80h when human hepatocyte L02 was reacted with the first five compounds (9f6, 9f14, 9f3, 9f4, 9e) having optimal tumor cell inhibitory effect, respectively, indicating that they have 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, IC50Both less than 50. mu.M, wherein the IC of both compounds50Less than 20. mu.M. R39f3 with 2-chloro-5-trifluoromethylpyridine as substituent showed the best anticancer activity on all 5 tumor cell lines and IC of A54950IC value of 7.386 μ M for K56250IC with value of 11.506 μ M for U2515032.860 μ M, 13.800 μ M for BEL7402 and 28.261 μ M for SW 1990. R39f14 with 1-cyclohexyl substituent showed the second best anticancer activity, IC for A54950IC value of 5.920 μ M for K56250IC with value of 14.420 μ M for U25150IC at 14.370 μ M for BEL740250IC 13.370 μ M and 1990 SW5029.462 μ M. Among the five cells, the scaffold analogs synthesized here were the most effective in inhibiting a 549. Particularly for this liver cancer, IC of 9f14 and 9f350The 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 (9)
1. A1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound, characterized in that it has the structural formula:
wherein R is1Is hydrogen or chlorine, R2Is hydrogen, methyl, methoxy or fluorine, R3Is nitrophenyl, (2-trifluoromethyl-5-Cl) piperidyl, phenyl, methoxyphenyl, methylphenyl, 2-trifluoromethylphenyl or C2-C8 alkyl or cycloalkyl, R4Is hydrogen or methyl, and X is O or S.
2. The 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds of claim 1, wherein R is1Is hydrogen or 6-chloro; r2Is hydrogen, or R2Is 2-or 4-methyl, methoxy or chlorine; r3Is 2-nitrePhenylphenyl, (2-trifluoromethyl-5-Cl) piperidinyl, phenyl, 2-methoxyphenyl, 2-methylphenyl, 2-trifluoromethylphenyl, ethyl, isobutyl, isopentyl, cyclopropanemethyl, cyclohexane methyl, or cyclopentanepropyl.
3. The 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds of claim 1, wherein R is1Is hydrogen or 6-chloro, R2Is hydrogen, 2-fluoro or 4-fluoro, R3Is (2-trifluoromethyl-5-chloro) piperidinyl, 2-trifluoromethylphenyl, isopentyl, cyclopentane-n-propyl or cyclohexane, R4Is hydrogen or methyl, and X is O.
4. The 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound of claim 1, wherein said compound is: (1) r1Is 6-chloro, R2Is 2-fluoro, R3Is (2-trifluoromethyl-5-chloro) piperidinyl, cyclohexanyl, isopentyl, cyclopentane-n-propyl or ethyl, R4Is hydrogen, X is O; alternatively, the first and second electrodes may be,
(2)R1is 6-chloro, R2Is 2-fluoro, R3When it is 2-trifluoromethylphenyl, R4Is hydrogen and X is S; alternatively, the first and second electrodes may be,
(3)R1is 6-chloro, R2Is hydrogen, R3Is 2-trifluoromethylphenyl, R4Is hydrogen, X is O; alternatively, the first and second electrodes may be,
(4)R1is hydrogen, R2Is hydrogen, R3Is phenyl, R4Is hydrogen, X is O; or, (5) R1Is hydrogen, R2Is 2-methyl, R3Is 2-trifluoromethylphenyl or 2-nitrophenyl, R4Is hydrogen, X is O; alternatively, the first and second electrodes may be,
(6)R1is 6-chloro, R2Is 2-fluoro, R3Is 2-trifluoromethylphenyl, R4Is hydrogen or methyl, and X is O.
5. The method for preparing a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound according to any one of claims 1 to 4, comprising the steps of:
(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;
(2) carrying out oxidation reaction on the compound 2 to obtain a compound 3;
(3) reducing nitro group of the compound 3 to obtain a compound 4;
(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) removing sulfinyl with HCl/MeOH to obtain chiral diamine compound 7;
(7) the compound 7 and a nitro-substituted benzene ring are subjected to Buchwald-Hartwig coupling to generate R3Compound 8 with substituent being 2-nitrophenyl or compound 7 is coupled with 2-methylphenylboronic acid, 2-methoxyphenylboronic acid, 2-trifluoromethylphenylboronic acid or 2-chloro-5- (trifluoromethyl) pyridine-4-boronic acid through Chan-Lam-Evans to generate R3The compound 8 with the substituent of phenyl, 2-methoxyphenyl and 2-trifluoromethylphenyl, or the 2-chloro-4-iodo-5- (trifluoromethyl) pyridine reacts with the compound 7 to generate R3The compound 8 with substituent group being (2-trifluoromethyl-5-chloro) piperidyl or the compound 7 reacts with aldehyde or ketone and sodium triacetoxyborohydride to generate R3A compound 8 with a substituent of ethyl, isobutyl, isoamyl, cyclopropanemethyl, cyclohexane methyl or cyclopentane propyl, wherein the aldehyde comprises acetaldehyde, isobutyraldehyde, isovaleraldehyde, cyclopropane formaldehyde, cyclohexane alkyl formaldehyde and cyclopentane formaldehyde, and the ketone is cyclohexanone;
(8) adding the compound 8 and triethylamine into an organic solvent, and treating the mixture with bis (trichloromethyl) carbonate in an ice-water bath to obtain the compound X-O, R41, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds;
alternatively, compound 8 and triethylamine were added to an organic solvent, and treated with bis (trichloromethyl) carbonate in an ice-water bath to give X ═ O, R41, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds; reacting with NaH in an organic solvent at the temperature of-10-5 ℃ under the protection of nitrogen or inert gas, and then adding methyl iodide for treatment to obtain X (O, R)4＝CH31, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds;
alternatively, compound 8 and triethylamine were added to an organic solvent, and treated with bis (trichloromethyl) carbonate in an ice-water bath to give X ═ O, R41, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds; reuse of P4S10And further treatment with xylene to convert O to S to give R41, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds of formula (i) 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 P4S10And further treatment with xylene to convert O to S to give R41, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds of formula (i) H, X ═ S; then under the protection of nitrogen or inert gas, R4Reacting 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound of H, X ═ S with NaH in an organic solvent at-10 to 5 ℃, and then adding methyl iodide for treatment to obtain X ═ O, R4＝CH31, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds.
6. The method for preparing a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound according to claim 5, wherein the halogen in the grignard reaction in step (1) is iodine, and the molar ratio of compound 1, compound 1', magnesium to iodine is 1: 1-2: 1.05-1.1: 0.05;
step (2), adding the compound 2 into an organic solvent, and then adding chromium trioxide pyridine hydrochloride to react to obtain a compound 3;
step (3), adding the compound 3 and iron powder into the mixed solvent, reacting for 0.5-1h at 40-60 ℃, adding hydrochloric acid, and continuing to react for 1-3 h; the mixed solvent is an organic solvent and water according to a volume ratio of 1: 0.5-5 of a mixture;
in the step (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;
in the step (6), under the protection of nitrogen, adding the compound 6 and methanol into an organic solvent, slowly dropping a dioxane solution of hydrogen chloride under the ice bath condition, and reacting for 1.5-4 hours at 15-35 ℃.
7. The process for preparing 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds according to claim 5, wherein R of Compound 11R of compound 2 being hydrogen or chlorine2Hydrogen, methyl at position 2 or 4, methoxy at position 2 or 4, or chlorine at position 2 or 4; compound 1' is bromobenzene, 2-methyl-bromobenzene, 4-methyl-bromobenzene, 2-methoxy-bromobenzene, 4-methoxy-bromobenzene, 2-fluoro-bromobenzene or 4-fluoro-bromobenzene; the compound 7' is acetaldehyde, isobutyraldehyde, isovaleraldehyde, cyclopropane formaldehyde, cyclohexanone, cyclohexane formaldehyde or cyclopentane formaldehyde, 2-methyl benzene boric acid or 2-methoxy benzene boric acid or 2-trifluoromethyl benzene boric acid or 2-chloro-5- (trifluoromethyl) pyridine-4-boric acid.
8. The use of a1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compound according to any of claims 1 to 4 for the preparation of a medicament for the treatment of cancer.
9. Use of the 1, 4-disubstituted 3, 4-dihydro-2 (3H) -quinazolinone compounds according to any of claims 1 to 4 for the preparation of a medicament for the treatment of leukemia, lung cancer, liver cancer, pancreatic cancer cells or glioma.
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