CN107879989B - 3,4, 5-substituted benzodiazepine 2-one drug molecule with biological activity and preparation method thereof - Google Patents

3,4, 5-substituted benzodiazepine 2-one drug molecule with biological activity and preparation method thereof Download PDF

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CN107879989B
CN107879989B CN201711220444.6A CN201711220444A CN107879989B CN 107879989 B CN107879989 B CN 107879989B CN 201711220444 A CN201711220444 A CN 201711220444A CN 107879989 B CN107879989 B CN 107879989B
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biological activity
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substituted benzodiazepine
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CN107879989A (en
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占敏霞
莫宗成
黄鹤
梅小利
涂如霞
李恒华
吴书祎
侯茜茜
毛伸
胡娅伦
刘国锋
穆开蕊
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Chongqing Academy of Chinese Materia Medica
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Abstract

The invention discloses a 3,4, 5-substituted benzodiazepine 2-one drug molecule with bioactivity and a preparation method thereof, belonging to the technical field of medicine synthesis. The technical points of the invention are as follows:
Figure DDA0001486315180000011
wherein R is1Is methyl, pyridyl, phenyl or isopropyl, R2And R3Each independently selected from methyl, ethyl or phenyl. Compared with the prior art, the invention has the following beneficial effects: the invention has simple synthesis method and novel molecular structure, has the inhibition effect on leukemia cell strains K562 and breast cancer cells MCF-7, and is expected to be further popularized and applied.

Description

3,4, 5-substituted benzodiazepine 2-one drug molecule with biological activity and preparation method thereof
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a 3,4, 5-substituted benzodiazepine 2-one medicine molecule with bioactivity and a preparation method thereof.
Background
Tumor is the most common and serious disease that endangers human life directly in the world, and it refers to local lump formed by abnormal proliferation of cells of local tissues under the action of various tumorigenic factors, wherein malignant tumor is also called cancer. In recent years, the incidence of tumors is increasing continuously, and the tumors become common diseases seriously harming human health, and especially the fatality rate of malignant tumors is increasing to threaten human life. The world health organization estimates, based on the incidence of cancer, mortality and world population data in various regions of the world, that an average of over 50 billion people worldwide die of 690 million people who die of malignant tumors each year, and about 870 million new cases, of which nearly 60% die of lung cancer, gastric cancer, breast cancer, colorectal cancer, oral cancer, liver cancer, cervical cancer and esophageal cancer, are the second leading cause of death after cardiovascular diseases.
Benzodiazepines are used in a wide range of pharmaceutical applications, for example as anxiolytic, antiarrhythmic, antidiuretic hormone antagonists, HIV reverse transcriptase inhibitors and cholecystokinin antagonists. The research designs and synthesizes a series of 3,4, 5-substituted benzodiazepine 2-ketone compounds, and tests on the antitumor activity of the compounds find that the compounds have good inhibitory activity on cancer cells, so the compounds have potential application value in the aspect of antitumor development.
Disclosure of Invention
The invention solves the technical problem of providing a 3,4, 5-substituted benzodiazepine 2-ketone drug molecule with bioactivity and a preparation method thereof.
The molecular structure of the 3,4, 5-substituted benzodiazepine 2-ketone medicine with biological activity is shown as a formula I:
in the formula I, R1Is methyl, pyridyl, benzeneOr isopropyl radical, R2And R3Each independently selected from methyl, ethyl or phenyl.
The preparation method of the 3,4, 5-substituted benzodiazepine 2-ketone drug molecule with bioactivity is characterized by comprising the following specific steps:
A. after acylation of aniline with pivaloyl chloride, under the action of n-butyllithium with R1-CHO by addition reaction
Figure BDA0001486315170000021
B、
Figure BDA0001486315170000022
Oxidizing by oxidant to generate carbonyl group on its structure, and removing tert-butyryl under acidic condition to obtain
Figure BDA0001486315170000023
C、
Figure BDA0001486315170000024
Is reacted with dimethyl sulfate to generate
D、
Figure BDA0001486315170000026
And R2-NH2Generated by substitution reaction under alkaline condition
Figure BDA0001486315170000027
E、
Figure BDA0001486315170000028
Reacting with chloracetyl chloride to obtain
F. Compound (I)
Figure BDA00014863151700000210
And R3-I or dimethyl sulfate to obtain the compound
Figure BDA00014863151700000211
Further limiting, the specific process of step a is: adding aniline and triethylamine into anhydrous THF, slowly dripping pivaloyl chloride at room temperature, stirring for 2 hr, slowly dripping n-butyllithium solution, stirring for 30min, and adding R1Slowly dropwise adding an anhydrous THF (tetrahydrofuran) solution of-CHO (Chinese hamster ovary) into the reaction solution, heating to reflux reaction for 8h, monitoring by TLC (thin layer chromatography), adding 10% ammonium chloride to quench the reaction after the reaction is finished, extracting the reaction solution by ethyl acetate, and evaporating an organic phase to obtain the final product
Figure BDA00014863151700000212
The crude product is separated by column chromatography to obtain a pure product; wherein R is1Is pyridyl, phenyl or isopropyl.
Further limiting, the specific process of step B is: in the reaction flask, handle
Figure BDA0001486315170000031
Adding a metal oxidant into chloroform, heating to reflux temperature, reacting for 1-4 h, filtering and concentrating to obtain the product
Figure BDA0001486315170000032
Adding the product into mixed solution of concentrated hydrochloric acid and methanol, heating to reflux reaction for 3 hr, vacuum concentrating to remove methanol, and adjusting pH with saturated sodium carbonate solution>7, extracting the reaction solution by dichloromethane, combining organic phases and concentrating to obtain
Figure BDA0001486315170000033
The crude product is separated by column chromatography to obtain a pure product; the metal catalyst is MnO2、KMnO4Or BaMnO4。
Further limiting, the specific process of step C is: handle
Figure BDA0001486315170000034
Adding dimethyl sulfate and an alkaline compound into a reaction bottle, reacting for 3-8 h at 50 ℃, monitoring the reaction completion of raw materials by TLC (thin layer chromatography), cooling the reaction liquid to room temperature, adding ethyl acetate into the reaction liquid for dilution, then adding ammonia water, stirring for 20min, separating an organic phase, and concentrating to obtain the product
Figure BDA0001486315170000035
The alkaline compound is NaH, KOH or DBU.
Further limiting, the specific process of step D is: in the reaction flask, R2-NH2Adding the mixture into a hydrochloric acid solution, adding a certain amount of sodium chloride, slowly dropwise adding a sodium bicarbonate solution at room temperature to adjust the pH of the reaction solution to 7-8, and adding
Figure BDA0001486315170000036
Adjusting the pH value of the reaction solution to 9-10, monitoring the reaction of the raw materials by TLC (thin layer chromatography), cooling the reaction solution to room temperature, pouring the reaction solution into water, and performing suction filtration to obtain the productWherein R is2Is methyl, ethyl or phenyl.
Further limiting, the specific process of step E is: in the reaction flask, handleAdding NaH into a reaction solvent, slowly dropwise adding chloroacetyl chloride at room temperature, keeping the temperature for reacting for 2-10 h, adding ice water for quenching reaction, separating an organic phase, and concentrating to obtain the final product
Figure BDA0001486315170000042
The reaction solvent is DMF, THF or pyridine.
Further limiting, the specific process of step F is: in the reaction flask, handle
Figure BDA0001486315170000043
Adding LDA into dichloromethane, adding a certain amount of phosphoric acid, cooling to 0 deg.C, and slowly adding dropwise R3Controlling the reaction temperature to be not more than 10 ℃ in dichloromethane solution of-I or dimethyl sulfate, reacting for 2 hours at 0 ℃ after dropwise adding, monitoring the raw materials by TLC to react completely, adding ice water to quench the reaction after evaporating the solvent, and performing suction filtration to obtain a compound
Figure BDA0001486315170000044
Wherein R is3Is methyl, ethyl or phenyl.
Figure BDA0001486315170000045
Compared with the prior art, the invention at least has the following advantages and beneficial effects:
according to the invention, aniline is used as a raw material, a reaction route is designed, reaction conditions are screened, and 3,4, 5-substituted benzodiazepine 2-one drug molecules are synthesized for the first time. The drug molecular compound has good anti-tumor activity, has great potential in the field of anti-cancer drug development, has simple preparation process and easy control, and lays a foundation for the industrial production of the drug molecular compound.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Adding aniline (10g,0.107mol) and triethylamine (2g,0.02mol) into 50mL of anhydrous THF (tetrahydrofuran), slowly dropwise adding pivaloyl chloride (14.24g,0.118mol) at room temperature, stirring for 2h after dropwise adding, slowly dropwise adding n-butyl lithium (4.48g,0.07mol) solution, stirring for 30min after dropwise adding, slowly dropwise adding anhydrous THF solution dissolved with benzaldehyde (14.24g,0.118mol) into the reaction solution, heating to reflux reaction for 8h, monitoring by TLC, adding 15mL of 10% ammonium chloride to quench the reaction, and extracting the reaction solution with ethyl acetateEvaporating the organic phase to obtain
Figure BDA0001486315170000051
Then, the crude product of (1) was separated by column chromatography to obtain a pure product (19.7g, yield: 64.98%). MS (ESI) M/z 283.2(M + H)+)；HNMR:(CDCl3)δ7.34-7.38(m,8H,Ar-H),7.12(m,1H,Ar-H),6.55(s,1H，N-H),5.02(s,1H),1.85(s,9H).
Example 2
In the reaction flask, handle
Figure BDA0001486315170000052
(283mg,1.0mmol) and MnO2(26mg,0.3mmol) in chloroform, reacted at 40 ℃ for 4h, filtered and concentrated to give
Figure BDA0001486315170000053
Adding the product into mixed solution of concentrated hydrochloric acid and methanol (1:1), heating to reflux reaction for 3 hr, vacuum concentrating to remove methanol, and adjusting pH of the reaction solution with saturated sodium carbonate solution>7, extracting the reaction solution by dichloromethane, combining organic phases and concentrating to obtain
Figure BDA0001486315170000054
Then, the crude product of (5) was separated by column chromatography to obtain a pure product (132mg, yield: 67.1%). MS (ESI) M/z 197.1(M + H)+).HNMR:(CDCl3)δ7.78(m,2H,Ar-H),7.22-7.32(m,4H,Ar-H),7.06(d,H,Ar-H),6.81(d,1H,J＝8Hz,Ar-H),6.57(m,1H,Ar-H),5.88(s,2H,N-H).
Example 3
In the reaction flask, handle
Figure BDA0001486315170000061
(283mg,1.0mmol) and KMnO4(26mg,0.3mmol) in chloroform, refluxing for 3h, filtering and concentrating to obtain
Figure BDA0001486315170000062
Adding the product into mixed solution of concentrated hydrochloric acid and methanol (1:1), heating to reflux reaction for 3 hr, vacuum concentrating to remove methanol, dissolving with saturated sodium carbonateLiquid adjustment of reaction liquid pH>7, extracting the reaction solution by dichloromethane, combining organic phases and concentrating to obtain
Figure BDA0001486315170000063
Then, the crude product of (1) was separated by column chromatography to obtain a pure product (78.8mg, yield: 58.3%). MS (ESI) M/z:135.2(M + H)+).HNMR:(CDCl3)δ10.35(s,2H,NH),7.78(m,1H,Ar-H),7.24(m,1H,Ar-H),6.75-6.92(m,2H,Ar-H),2.5(s,3H,CH).
Example 4
In the reaction flask, handle
Figure BDA0001486315170000064
(284mg,1.0mmol) and BaMnO4(46mg,0.18mmol) in chloroform, reacted at 25 ℃ for 1h, filtered and concentrated to give
Figure BDA0001486315170000065
Adding the product into mixed solution of concentrated hydrochloric acid and methanol (1:1), heating to reflux reaction for 3 hr, vacuum concentrating to remove methanol, and adjusting pH of the reaction solution with saturated sodium carbonate solution>7, extracting the reaction solution by dichloromethane, combining organic phases and concentrating to obtain
Figure BDA0001486315170000066
Then, the crude product of (1) was separated by column chromatography to obtain a pure product (165mg, yield: 83%). MS (ESI) M/z 199.2(M + H)+).HNMR:(CDCl3)δ8.75-8.76(m,2H,Ar-H),7.44(d,2H,Ar-H),7.43(d,2H,Ar-H),6.75(d,1H,J＝8Hz,Ar-H),6.57-6.61(m,1H,Ar-H),6.32(brs,2H,NH).
Example 5
In the reaction flask, handle
Figure BDA0001486315170000071
(135mg,1mmol), dimethyl sulfate (101mg,0.8mmol) and NaH (19.2mg,0.8mmol) are added into a reaction bottle, the reaction is carried out for 5h at 50 ℃, TLC monitors that the raw materials are completely reacted, the reaction liquid is cooled to room temperature, 20mL of ethyl acetate is added into the reaction liquid for dilution, 10mL of ammonia water is added into the reaction liquid for stirring for 20min, the organic phase is separated and concentrated to obtain the compound
Figure BDA0001486315170000072
(75.4mg,yield:49.84％).MS(ESI)m/z:151.2(M+H+).HNMR:(DMSO-d6)δ11.61(s,1H,NH),7.38(s,2H,Ar-H),6.88(m,2H,Ar-H),4.54(m,1H),3.17(s,3H,CH),2.22(m,3H,CH).
Example 6
In the reaction flask, handle(198mg,1.0mmol), dimethyl sulfate (126mg,1.0mmol) and KOH (33.6mg,0.6mmol) are added into a reaction bottle and reacted for 8h at 50 ℃, TLC monitors that the raw materials are completely reacted, the reaction liquid is cooled to room temperature, 20mL of ethyl acetate is added into the reaction liquid for dilution, 10mL of ammonia water is added into the reaction liquid and stirred for 20min, and the organic phase is separated and concentrated to obtain the compound
Figure BDA0001486315170000074
(126mg,yield:58.89％).MS(ESI)m/z:214.3(M+H+).HNMR:(DMSO-d6)δ11.61(s,2H,NH),8.38(s,2H,Ar-H),7.54-7.58(m,4H,Ar-H),7.50(m,2H,Ar-H),5.41(s,1H,CH),3.32(m,3H,CH).
Example 7
In the reaction flask, handle
Figure BDA0001486315170000075
Adding (163mg,1.0mmol), dimethyl sulfate (76mg,0.6mmol) and DBU (45.6mg,0.3mmol) into a reaction flask, reacting at 50 ℃ for 3h, monitoring by TLC that the raw materials are completely reacted, cooling the reaction solution to room temperature, adding 20mL of ethyl acetate into the reaction solution for dilution, adding 10mL of ammonia water, stirring for 20min, separating the organic phase, and concentrating to obtain the final product
Figure BDA0001486315170000076
(128mg,yield:71.66％).MS(ESI)m/z:179.3(M+H+).HNMR:(DMSO-d6)δ11.46(s,2H,NH),7.33(m,1H,Ar-H),6.81(m,2H,Ar-H),6.55(m,1H,Ar-H),4.41(m,1H,CH),3.27(s,3H,CH),2.87(m,1H,CH),1.91(m,6H,CH).
Example 8
In a reaction flask, adding CH3NH2(62mg,2.0mmol) is added into 20mL of 10 percent hydrochloric acid solution, then 0.5eq of sodium chloride is added, sodium bicarbonate solution is slowly dripped under the condition of room temperature to adjust the pH of the reaction solution to 7-8, and then the mixture is added
Figure BDA0001486315170000081
(179mg,1.0mmol), adjusting the pH of the reaction solution to 9-10, monitoring the complete reaction of the raw materials by TLC, cooling the reaction solution, pouring the cooled reaction solution into water, and performing suction filtration to obtain the product
Figure BDA0001486315170000082
(160mg,yield:90.1％).MS(ESI)m/z:178.3(M+H+).HNMR:(DMSO-d6)δ11.46(s,2H,NH),8.99(m,1H,NH),6.86-7.02(m,4H,Ar-H),4.41(m,1H,CH),3.27(s,3H,CH),2.57(m,1H,CH),2.0(s,1H,NH),0.91(m,6H,CH).
Example 9
In a reaction flask, adding CH3CH2NH2(68mg,1.5mmol) is added into 20mL of 10 percent hydrochloric acid solution, then 0.5eq of sodium chloride is added, sodium bicarbonate solution is slowly dripped under the condition of room temperature to adjust the pH value of the reaction solution to 7-8, and then the solution is added
Figure BDA0001486315170000083
(240mg,1.0mmol), adjusting the pH of the reaction solution to 9-10, monitoring the complete reaction of the raw materials by TLC, cooling the reaction solution, pouring the cooled reaction solution into water, and performing suction filtration to obtain the product
Figure BDA0001486315170000084
(199mg,yield:87.9％).MS(ESI)m/z:227.1(M+H+).HNMR:(DMSO-d6)δ9.55(s,2H,NH),8.78(m,2H,Ar-H),6.76-7.07(m,6H,Ar-H),5.28(m,1H,CH),2.97(m,2H,CH),2.3(s,1H,NH),1.01(m,3H,CH).
Example 10
Adding aniline (168mg,1.8mmol) into 30mL of 10% hydrochloric acid solution in a reaction bottle, adding 0.5eq of sodium chloride, slowly dropwise adding sodium bicarbonate solution at room temperature to adjust the pH of the reaction solution to 7-8, and adding
Figure BDA0001486315170000085
(213mg,1.0mmol), readjustment of the reactionThe pH value of the solution is 9-10, TLC monitors that the raw materials are completely reacted, the reaction solution is cooled, poured into water and filtered to obtain the product
Figure BDA0001486315170000091
(181mg,yield:65.91％).MS(ESI)m/z:274.1(M+H+).HNMR:(DMSO-d6)δ10.55(s,2H,NH),7.23-7.33(m,6H,Ar-H),6.98(m,2H,Ar-H),6.70-6.82(m,5H,CH),5.99(s,1H,CH),4.28(s,1H,NH).
Example 11
In the reaction flask, handle
Figure BDA0001486315170000092
(274mg,1.0mmol) and NaH (24mg,1.0mmol) are added to THF 10mL, chloroacetyl chloride (203mg,1.8mmol) is slowly added dropwise at room temperature, reaction is carried out for 10h while maintaining the temperature, ice water is added to quench the reaction, ethyl acetate 10mL is extracted, an organic phase is separated, and concentration is carried out to obtain
Figure BDA0001486315170000093
(258mg,yield:82.1％).MS(ESI)m/z:314.1(M+H+).HNMR:(DMSO-d6)δ8.25(s,1H,NH),6.83-7.30(m,14H,Ar-H),5.28(s,1H,CH),4.35(m,2H,CH).
Example 12
In the reaction flask, handle
Figure BDA0001486315170000094
(178mg,1.0mmol) and NaH (20mg,0.8mmol) were added to DMF10mL, chloroacetyl chloride (168mg,1.5mmol) was slowly added dropwise at room temperature, the reaction was allowed to proceed for 6h, ice water was added to quench the reaction, ethyl acetate 10mL was extracted and the organic phase was separated and concentrated to give
Figure BDA0001486315170000095
(175mg,yield:80.6％).MS(ESI)m/z:218.1(M+H+).HNMR:(DMSO-d6)δ9.01(s,1H,NH),7.12-7.37(m,4H,Ar-H),3.89(t,1H,CH),3.35(m,2H,CH),2.45(m,1H,CH),2.15(m,3H,CH),1.66(m,6H,CH).
Example 13
In the reaction flask, handle
Figure BDA0001486315170000101
(228mg,1.0mmol) and NaH (20mg,0.8mmol) are added to pyridine 10mL, chloroacetyl chloride (168mg,1.5mmol) is slowly added dropwise at room temperature, reaction is carried out for 2h while maintaining the temperature, ice water is added to quench the reaction, ethyl acetate 10mL is extracted, an organic phase is separated, and concentration is carried out to obtain the final product
Figure BDA0001486315170000102
(227mg,yield:85.7％).MS(ESI)m/z:267.1(M+H+).HNMR:(DMSO-d6)δ9.37(brs,1H,NH),8.68(s,2H,Ar-H),7.54(d,1H,J＝8Hz,Ar-H),7.45(s,2H,Ar-H),7.20-7.27(m,3H,Ar-H),5.38(s,1H),3.53(m,2H),2.88(m,2H),1.08(m,3H).
Example 14
In the reaction flask, handle
Figure BDA0001486315170000103
(267mg,1.0mmol) and LDA (22mg,0.2mmol) are added into 15mL of dichloromethane, 1eq phosphoric acid is added, the reaction temperature is reduced to 0 ℃, dichloromethane solution dissolved with iodomethane (170mg,1.2mmol) is slowly dripped, the reaction temperature is controlled not to exceed 10 ℃, the dichloromethane solution is reacted for 2 hours at 0 ℃ after the dripping is finished, TLC monitors that the raw materials are completely reacted, ice water is added to quench the reaction after the solvent is evaporated, a large amount of solid is separated out, and the compound is obtained by suction filtration
Figure BDA0001486315170000104
(187mg,yield:66.4％).MS(ESI)m/z:281.1(M+H+).HNMR:(DMSO-d6)δ9.37(brs,1H,NH),8.68(s,2H,Ar-H),7.10-7.30(m,6H,Ar-H),5.38(s,1H),3.53(m,1H),2.48(m,2H),1.30(m,3H),1.08(m,3H).
Example 15
In the reaction flask, handle(267mg,1.0mmol) and LDA (22mg,0.2mmol) are added into 15mL of dichloromethane, 1eq phosphoric acid is added, the reaction temperature is reduced to 0 ℃, a dichloromethane solution dissolved with dimethyl sulfate (189mg,1.5mmol) is slowly dripped, the reaction temperature is controlled not to exceed 10 ℃, and after the dripping is finished, the dichloromethane solution is addedReacting at 0 deg.C for 2h, TLC monitoring the reaction of raw materials, evaporating solvent, adding ice water to quench reaction, precipitating a large amount of solid, and vacuum filtering to obtain compound
Figure BDA0001486315170000111
(168mg,yield:59.88％).MS(ESI)m/z:281.1(M+H+).
Example 16
In the reaction flask, handle
Figure BDA0001486315170000112
(267mg,1.0mmol) and LDA (22mg,0.2mmol) are added into 15mL of dichloromethane, 1eq phosphoric acid is added, the reaction temperature is reduced to 0 ℃, dichloromethane solution dissolved with iodobenzene (306mg,1.5mmol) is slowly dripped, the reaction temperature is controlled not to exceed 10 ℃, the mixture reacts for 2 hours at the temperature of 0 ℃ after the dripping is finished, TLC monitors that the raw materials completely react, ice water is added to quench the reaction after the solvent is evaporated, a large amount of solid is separated out, and the compound is obtained by suction filtration
Figure BDA0001486315170000113
(140mg,yield:47.61％).MS(ESI)m/z:294.2(M+H+).HNMR:(DMSO-d6)δ8.88(brs,1H,NH),7.14-7.33(m,9H,Ar-H),4.88(s,1H),3.85(m,1H),2.48(m,1H),2.38(s,3H),1.28(m,6H).
Example 17
In the reaction flask, handle(314mg,1.0mmol) and LDA (44mg,0.4mmol) are added into 15mL of dichloromethane, 1eq of phosphoric acid is added, the reaction temperature is reduced to 0 ℃, dichloromethane solution dissolved with iodoethane (234mg,1.5mmol) is slowly dripped, the reaction temperature is controlled not to exceed 10 ℃, the dichloromethane solution is reacted for 2 hours at the temperature of 0 ℃ after the dripping is finished, TLC monitors that the raw materials are completely reacted, ice water is added to quench the reaction after the solvent is evaporated, a large amount of solid is precipitated, and a compound (149mg, yield: 45.88%) is obtained by suction filtration+).HNMR:(DMSO-d6)δ9.18(brs,1H,NH),6.79-7.30(m,14H,Ar-H),5.58(s,1H),3.99(m,1H),2.08(m,2H),1.33(m,3H).
Example 18
The procedures of examples 1-17 were repeated except that different starting materials were used to obtain a series of compounds, as detailed in Table 1.
In the formula I, R1Is methyl, pyridyl, phenyl or isopropyl, R2And R3Each independently selected from methyl, ethyl or phenyl;
Figure BDA0001486315170000121
Figure BDA0001486315170000131
example 19
Antitumor Activity test
The anticancer activity of compounds 1-36 was measured by MTS method in human leukemia cell line K562 and breast cancer cell MCF-7, cells were added to 96-well cell culture plates at appropriate concentration, cultured for 24 hours, and cultured at 37 ℃ with 5% CO2Under these conditions, the compound was allowed to react for 72h at various concentrations, and then a mixture of MTS (final concentration 2mg/mL) and DMS (final concentration 30. mu.M) was added directly to the cell-containing medium. After 4h of action, cell viability was determined by its absorbance at 492nm of the metabolite acting on MTS. We chose to perform activity assays on this series of compounds at 40 μ M and 4 μ M concentrations and measure the inhibition of both cells.
Figure BDA0001486315170000132
Figure BDA0001486315170000141
Preliminary biological activity tests show that the compounds have a certain inhibiting effect on cancer cells in a human leukemia cell line K562 and a breast cancer cell MCF-7, wherein the compounds I-10, I-16 and I-30 have a remarkable inhibiting effect on MCF-7 tumor cell lines, the compounds I-18 and I-21 have good inhibiting effects on the two cells simultaneously, and the compounds I-25 and I-27 have good inhibiting effects on a K562 cell line.
In summary, the patent provides a 3,4, 5-substituted benzodiazepine 2-ketone compound with bioactivity, which is the first discovery of the application of the compound and has great research and development potential.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.

Claims (9)

1. The 3,4, 5-substituted benzodiazepine 2-ketone medicine molecule with bioactivity is characterized in that the molecular structure is as follows:
Figure FDA0002158040570000011
wherein R is1Is methyl, pyridyl, phenyl or isopropyl, R2And R3Each independently selected from methyl, ethyl or phenyl.
2. A method for preparing 3,4, 5-substituted benzodiazepine 2-one drug molecules with biological activity according to claim 1, characterized by comprising the following steps:
A. after acylation of aniline with pivaloyl chloride, under the action of n-butyllithium with R1-CHO by addition reaction
Figure FDA0002158040570000012
B、Oxidizing by oxidant to generate carbonyl group on its structure, and removing tert-butyryl under acidic condition to obtain
Figure FDA0002158040570000014
C、
Figure FDA0002158040570000015
Is reacted with dimethyl sulfate to generate
Figure FDA0002158040570000016
D、
Figure FDA0002158040570000017
And R2-NH2Generated by substitution reaction under alkaline condition
Figure FDA0002158040570000018
E、
Figure FDA0002158040570000019
Reacting with chloracetyl chloride to obtain
Figure FDA00021580405700000110
F. Compound (I)
Figure FDA0002158040570000021
And R3-I or dimethyl sulfate to obtain the compound
Figure FDA0002158040570000022
3. The method for preparing 3,4, 5-substituted benzodiazepine 2-one drug molecules with biological activity according to claim 2, characterized in that the specific process of step a is as follows: adding aniline and triethylamine into anhydrous THF, slowly dripping pivaloyl chloride at room temperature, stirring for 2 hr, slowly dripping n-butyllithium solution, stirring for 30 hrmin, dissolving R in the stalk1Slowly dropwise adding an anhydrous THF (tetrahydrofuran) solution of-CHO (Chinese hamster ovary) into the reaction solution, heating to reflux reaction for 8h, monitoring by TLC (thin layer chromatography), adding 10% ammonium chloride to quench the reaction after the reaction is finished, extracting the reaction solution by ethyl acetate, and evaporating an organic phase to obtain the final product
Figure FDA0002158040570000023
The crude product is separated by column chromatography to obtain a pure product; wherein R is1Is pyridyl, phenyl or isopropyl.
4. The method for preparing 3,4, 5-substituted benzodiazepine 2-one drug molecules with biological activity according to claim 2, characterized in that the specific process of step B is as follows: in the reaction flask, handle
Figure FDA0002158040570000024
Adding a metal oxidant into chloroform, reacting at the temperature of 25 ℃ to reflux temperature for 1-4 h, filtering and concentrating to obtain
Figure FDA0002158040570000025
Adding the product into mixed solution of concentrated hydrochloric acid and methanol, heating to reflux reaction for 3 hr, vacuum concentrating to remove methanol, and adjusting pH with saturated sodium carbonate solution>7, extracting the reaction solution by dichloromethane, combining organic phases and concentrating to obtain
Figure FDA0002158040570000026
The crude product is separated by column chromatography to obtain a pure product; the metal catalyst is MnO2、KMnO4Or BaMnO4。
5. The method for preparing 3,4, 5-substituted benzodiazepine 2-one drug molecules with biological activity according to claim 2, characterized in that the specific process of step C is as follows: : handleDimethyl sulfateAdding ester and an alkaline compound into a reaction bottle, reacting for 3-8 h at 50 ℃, monitoring the complete reaction of raw materials by TLC (thin layer chromatography), cooling the reaction liquid to room temperature, adding ethyl acetate into the reaction liquid for dilution, then adding ammonia water, stirring for 20min, separating an organic phase, and concentrating to obtain the productThe alkaline compound is NaH, KOH or DBU.
6. The method for preparing 3,4, 5-substituted benzodiazepine 2-one drug molecules with biological activity according to claim 2, characterized in that the specific process of step D is as follows: in the reaction flask, R2-NH2Adding the mixture into a hydrochloric acid solution, adding a certain amount of sodium chloride, slowly dropwise adding a sodium bicarbonate solution at room temperature to adjust the pH of the reaction solution to 7-8, and addingAdjusting the pH value of the reaction solution to 9-10, monitoring the reaction of the raw materials by TLC (thin layer chromatography), cooling the reaction solution to room temperature, pouring the reaction solution into water, and performing suction filtration to obtain the productWherein R is2Is methyl, ethyl or phenyl.
7. The method for preparing 3,4, 5-substituted benzodiazepine 2-one drug molecules with biological activity according to claim 2, characterized in that the specific process of step E is as follows: in the reaction flask, handleAdding NaH into a reaction solvent, slowly dropwise adding chloroacetyl chloride at room temperature, keeping the temperature for reacting for 2-10 h, adding ice water for quenching reaction, separating an organic phase, and concentrating to obtain the final product
Figure FDA0002158040570000035
The reaction solvent is DMF, THF or pyridine.
8. The method for preparing 3,4, 5-substituted benzodiazepine 2-one drug molecules with biological activity according to claim 2, characterized in that the specific process of step F is as follows: in the reaction flask, handle
Figure FDA0002158040570000036
Adding LDA into dichloromethane, adding a certain amount of phosphoric acid, cooling to 0 deg.C, and slowly adding dropwise R3Controlling the reaction temperature to be not more than 10 ℃ in dichloromethane solution of-I or dimethyl sulfate, reacting for 2 hours at 0 ℃ after dropwise adding, monitoring the raw materials by TLC to react completely, adding ice water to quench the reaction after evaporating the solvent, and performing suction filtration to obtain a compoundWherein R is3Is methyl, ethyl or phenyl.
9. The use of a 3,4, 5-substituted benzodiazepine 2-one drug molecule of claim 1 in the preparation of an anti-neoplastic drug.
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