CN112574220A - Chiral 1, 4-benzodiazepine-2-ketone spiroheterocyclic compound and preparation method thereof - Google Patents

Chiral 1, 4-benzodiazepine-2-ketone spiroheterocyclic compound and preparation method thereof Download PDF

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CN112574220A
CN112574220A CN202011442438.7A CN202011442438A CN112574220A CN 112574220 A CN112574220 A CN 112574220A CN 202011442438 A CN202011442438 A CN 202011442438A CN 112574220 A CN112574220 A CN 112574220A
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benzodiazepine
acid
chiral
ketospiro
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CN112574220B (en
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赵洪武
范晓祖
吴慧慧
汤喆
毕晓帆
张恒
蔡璐羽
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Beijing University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Chiral 1, 4-benzodiazepine
Figure DDA0002822871660000011
A (E) -2-ketone spiro-heterocyclic compound and a preparation method thereof, belonging to the technical field of compound preparation. In particular to 3-amino-1, 4-benzodiazepine under the catalytic action of an additive
Figure DDA0002822871660000012
Reacting imine ylide generated in situ by the-2-ketone and the aldehyde with the azodicarboxylic acid derivative at room temperature to obtain a product. The preparation method is efficient and simple, simple to operate, mild in reaction conditions, good in substrate universality and simple in post-treatment, and most of synthesized target substances have high yield. The chiral 1, 4-benzodiazepine has a new and high efficiency and has potential biological activity and medicinal value

Description

Chiral 1, 4-benzodiazepine-2-ketone spiroheterocyclic compound and preparation method thereof
Technical Field
The invention relates to chiral 1, 4-benzodiazepine
Figure BDA0002822871650000012
A (E) -2-ketone spiro-heterocyclic compound and a preparation method thereof, belonging to the technical field of compound preparation.
Background
1, 4-benzodiazepines
Figure BDA0002822871650000013
The-2-ketone has thermodynamically stable conformation chirality, has unique spatial structure and chemical structure, is an advantageous drug skeleton, and various derivatives thereof have wide biological activities and medicinal values, such as biological activities of sedation, hypnosis, antidepressant, senile dementia resistance, antitumor, HIV resistance, malaria resistance and the like. Currently, 1, 4-benzodiazepines
Figure BDA0002822871650000014
Chemical modification and structural modification of 2-ketones focus mainly on the following two aspects: 1. in the benzene ring and dinitrogen
Figure BDA0002822871650000015
Introducing different functional groups and substituents on the heterocyclic ring; 2. in the presence of dinitrogen
Figure BDA0002822871650000016
Various complex fused heterocyclic ring systems are constructed on the heterocyclic ring. In contrast, with 1, 4-benzodiazepines
Figure BDA0002822871650000017
The construction research of chiral spiro system with-2-ketone skeleton as parent structure has not been reported. Therefore, the design and development of novel, efficient, mild reaction conditions and easy-to-operate stereoselective cycloaddition reaction for constructing chiral 1, 4-benzodiazepines with complex and diverse structures
Figure BDA0002822871650000018
-2-ketospiro heterocyclic system, not only capable of enriching and developing 1, 4-benzodiazepine
Figure BDA0002822871650000019
Research on the methodology of organic synthesis of (E) -2-ketones, and development of novel chiral 1, 4-benzodiazepines
Figure BDA00028228716500000110
The (E) -2-ketospiro heterocyclic candidate drugs have very important significance.
The imine ylide is a high-activity and high-efficiency organic synthon with wide application, can perform high-efficiency, simple and stereoselective cycloaddition reaction with unsaturated systems with different chemical structures, and is used for constructing various spiro/fused heterocyclic systems with complex and various spatial structures and chemical structures. At present, the cycloaddition reaction of imine ylides based on aldehydes, ketones and isatin is more studied; in contrast, based on 1, 4-benzodiazepines
Figure BDA00028228716500000111
Few studies on the stereoselective cycloaddition reaction of (E) -2-ketimine ylide have been reported in the literature. The invention selects protonic acid as catalyst and uses 3-amino-1, 4-benzodiazepine
Figure BDA00028228716500000112
-imine ylides of in situ formation of 2-ketones and aldehydes, with derivatives of azodicarboxylic acids [3+2 ]]The cycloaddition reaction of (A) to synthesize novel chiral 1, 4-benzodiazepine with complex and various structures efficiently and high stereoselectivity
Figure BDA00028228716500000113
-2-ketospiro-heterocyclic compounds. The reaction has the characteristics of mild reaction conditions, simple operation, high chemical yield, high diastereomer selectivity and the like. The invention is selective [3+2 ] through three groups of discrete bodies]Cycloaddition reaction to construct 1, 4-benzodiazepine
Figure BDA00028228716500000114
The chemical skeleton structure of the target molecule is obvious in drug property structure, and has potential biological activity and medicinal value.
Disclosure of Invention
The invention aims to provide chiral 1, 4-benzodiazepine
Figure BDA0002822871650000022
A method for preparing (E) -2-ketospiro-heterocyclic compounds.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
chiral 1, 4-benzodiazepine
Figure BDA0002822871650000023
A method for preparing a (2-keto) spiroheterocyclic compound, said method comprising: with 3-amino-1, 4-benzodiazepines
Figure BDA0002822871650000024
Taking the (E) -2-ketone, the aldehyde and the azodicarboxylic acid derivative as reactants, adding an acidic or basic additive, and reacting in an organic solvent with the polarity of 2-7 at room temperature to obtain the product 1, 4-benzodiazepine
Figure BDA0002822871650000025
-2-ketospiro-heterocyclic compounds; preferably said 3-amino-1, 4-benzodiazepine
Figure BDA0002822871650000026
-the molar ratio of 2-ketone, aldehyde and azodicarboxylic acid compound is 1:3: 3;
the 1, 4-benzodiazepine
Figure BDA0002822871650000027
-the structural formula of the 2-ketospiro-heterocyclic compound is:
Figure BDA0002822871650000021
wherein R is1Is alkyl, benzyl or hydrogen; r2Is one of methoxyl, fluorine, chlorine, bromine, hydrogen, nitryl and alkyl; r3Is one of hydrogen, fluorine, chlorine, bromine, methoxyl, nitryl and alkyl; r4Is aryl or alkyl; r5Is ethoxycarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl.
The above aryl group means a naphthyl group, a pyridyl group, a phenyl group or a substituted phenyl group; the substituents on the above phenyl groups are selected from: one of methyl, methoxy, fluorine, chlorine, bromine, nitro or trifluoromethyl.
In the technical scheme, the organic solvent is tetrahydrofuran, dichloromethane, trichloromethane, 1, 2-dichloroethane, toluene, acetonitrile, N-dimethylformamide or methanol.
In the technical scheme, the additive is one or more of copper (II) trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, benzoic acid, acetic acid, stearic acid, toluene-4-sulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, 4-methylbenzoic acid, 2-aminobenzoic acid, terephthalic acid, phthalic acid, malonic acid, 2' -dihydroxybiphenyl, triethylamine, sodium carbonate and 4-dimethylaminopyridine.
In the technical scheme, the reaction time is 6-48 hours.
In the technical scheme, the dosage of the additive is 3-amino-1, 4-benzodiazepine
Figure BDA0002822871650000035
20% by mole of the 2-ketone compound.
In the above technical scheme, the reaction process comprises: weighing 3-amino-1, 4-benzodiazepine
Figure BDA0002822871650000036
Dissolving the (E) -2-ketone, the aldehyde, the azodicarboxylic acid compound and the additive in an organic solvent, and fully stirring the reaction mixed solution (monitoring the reaction by TLC) at room temperature until the reaction is finished, wherein the reaction is finished until the reaction is finished, and the reaction is finished
Figure BDA0002822871650000037
-complete consumption of the 2-ketimine ylide intermediate; finally, the reaction mixed solution is decompressed and concentrated, and the crude product is subjected to simple column chromatography to obtain the target product 1, 4-benzodiazepine
Figure BDA0002822871650000038
-2-ketospiro-heterocyclic compounds.
In the present invention, 3-amino-1, 4-benzodiazepine
Figure BDA0002822871650000039
The preparation method of the (E) -2-ketone compound belongs to the prior art, and the structural formula is shown as follows:
Figure BDA0002822871650000031
R1is alkyl, benzyl or hydrogen; r2Is one of methoxyl, fluorine, chlorine, bromine, hydrogen, nitryl and alkyl; r3Is one of hydrogen, fluorine, chlorine, bromine, methoxyl, nitryl and alkyl;
the preparation method of the aldehyde compound belongs to the prior art, and the structural formula of the aldehyde compound is as follows:
Figure BDA0002822871650000032
R4is aryl or alkyl;
the preparation method of the azodicarboxylic acid derivative belongs to the prior art, and the structural formula is as follows:
Figure BDA0002822871650000033
R5is ethoxycarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl.
The reaction process disclosed by the invention is as follows:
Figure BDA0002822871650000034
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention selects protonic acid and the like as catalysts and utilizes 3-amino-1, 4-benzodiazepine
Figure BDA00028228716500000310
-three components [3+2 ] of 2-ketone, aldehyde and azodicarboxylic acid derivative]The cycloaddition reaction stereoselectively constructs novel chiral 1, 4-benzodiazepine with complex and various structures
Figure BDA00028228716500000311
-2-ketospiro-heterocyclic compounds.
2. The synthesis method has the advantages of simple operation, mild reaction conditions and high diastereomer selectivity.
3. The method disclosed by the invention has the advantages of good substrate universality, high chemical yield and simple separation and purification.
4. The invention has low cost of the initial raw materials and no pollution.
5.1, 4-benzodiazepines constructed according to the invention
Figure BDA0002822871650000042
The (2-ketospiro-heterocyclic compound has a remarkable drug property structure and potential biological activity and medicinal value.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited to the following examples.
Example 1:
Figure BDA0002822871650000041
1a (30.0mg, 0.1mmol), 2a (46.9mg, 0.3mmol), 3a (60.7mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) are weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 8 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether-1/3-1/4) to obtain the target product 4aaa (53.5mg), and the yield is 84%.
Characterization and analysis of the target: a white solid; m.p. ═ 202.0-202.3 ℃;1H NMR(400MHz,CDCl3):δ8.05(s,1H),7.89-7.81(m,3H),7.66-7.62(m,3H),7.56-7.48(m,4H),7.47-7.43(m,2H),7.38(d,J＝8.8Hz,1H),7.29(s,1H),6.43(d,J＝10.0Hz,1H),4.91-4.85(m,1H),4.76-4.73(m,1H),4.05(d,J＝9.6Hz,1H),3.52(s,3H),1.19-1.13(m,6H),1.05-1.01(m,6H)ppm；13C NMR(100MHz,CDCl3):δ170.6,166.9,156.7,155.9,140.9,138.2,135.2,133.5,133.2,131.6,131.0,130.3,129.8,128.6,128.3,128.2,127.7,126.32,126.30,125.9,124.3,123.1,93.6,76.6,71.1,70.5,36.2,22.4,21.8,21.5ppm；HRMS(ESI)calculated for C35H34ClN5O5[M+H]+the theoretical calculation value is 640.2321, and the actual value is 640.2300.
Example 2:
Figure BDA0002822871650000051
1a (30.0mg, 0.1mmol), 2b (70.5mg, 0.3mmol), 3a (60.7mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) were weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 48 hours (detection reaction by TLC), and after the reaction was completed, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/3-1/4) to obtain the target product 4aba (51.3mg), with a yield of 71%.
Characterization and analysis of the target: a white solid; m.p. ═ 111.5-111.7 ℃;1H NMR(400MHz,CDCl3):δ8.45(d,J＝8.4Hz,1H),7.82(d,J＝8.0Hz,1H),7.77(d,J＝8.8Hz,1H),7.67-7.62(m,3H),7.61-7.52(m,4H),7.46(t,J＝7.6Hz,2H),7.38(d,J＝8.8Hz,1H),7.29(s,1H),6.80(d,J＝9.2Hz,1H),4.88-4.81(m,2H),4.02(d,J＝9.2Hz,1H),3.5(s,3H),1.31-1.27(m,4H),1.13(s,2H),1.06-1.02(m,6H)ppm；13C NMR(100MHz,CDCl3):δ170.6,166.8,156.6,155.6,140.9,138.2,134.9,134.6,132.5,131.6,131.1,131.0,130.2,129.8,128.6,128.4,128.1,128.0,127.9,127.7,127.1,124.5,124.2,123.1,93.5,77.0,71.3,70.5,36.2,21.8,21.5ppm；HRMS(ESI)calculated for C35H33BrClN5O5[M+H]+theoretical calculation 718.1426, found 718.1400.
Example 3:
Figure BDA0002822871650000052
1a (30.0mg, 0.1mmol), 2c (55.9mg, 0.3mmol), 3a (60.7mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) were weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 6 hours (detection reaction by TLC), and after the reaction was completed, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/3-1/4) to obtain the target product 4aca (53.1mg), with a yield of 79%.
Characterization and analysis of the target: a white solid; m.p. 173.8-174.2 ℃;1H NMR(400MHz,CDCl3):δ7.96(s,1H),7.76(d,J＝8.4Hz,1H),7.71(d,J＝8.8Hz,1H),7.64-7.58(m,3H),7.54-7.51(m,2H),7.44(t,J＝7.6Hz,2H),7.37(d,J＝8.8Hz,1H),7.29(s,1H),7.18-7.15(m,2H),6.39(d,J＝9.6Hz,1H),4.90-4.84(m,1H),4.77-4.71(m,1H),4.04(d,J＝9.6Hz,1H),3.94(s,3H),3.52(s,3H),1.19-1.12(m,6H),1.05-1.00(m,6H)ppm；13C NMR(100MHz,CDCl3):δ170.5,167.0,158.0,156.7,155.9,140.9,138.3,134.7,133.0,131.5,131.1,131.0,130.2,129.8,129.6,128.62,128.57,128.3,127.4,125.7,124.8,123.0,119.1,105.7,93.6,76.6,71.0,70.4,55.3,36.2,21.8,21.5ppm；HRMS(ESI)calculated for C36H36ClN5O6[M+H]+theoretical calculation 670.2427, found 670.2407.
Example 4:
Figure BDA0002822871650000061
1a (30.0mg, 0.1mmol), 2d (45.3mg, 0.3mmol), 3a (60.7mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) are weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 48 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether-1/3-1/4) to obtain the target product 4ada (37.3mg), and the yield is 59%.
Characterization and analysis of the target: a white solid; m.p. 197.2-197.7 ℃;1H NMR(400MHz,CDCl3):δ8.25(d,J＝8.4Hz,2H),7.78(d,J＝8.8Hz,2H),7.60-7.52(m,4H),7.44(t,J＝7.6Hz,2H),7.37(d,J＝8.8Hz,1H),7.26(s,1H),6.31(d,J＝9.6Hz,1H),4.89-4.83(m,1H),4.76-470(m,1H),3.93(d,J＝9.6Hz,1H),3.51(s,3H),1.15-1.14(m,6H),1.04-1.00(m,6H)ppm；13C NMR(100MHz,CDCl3):δ171.0,166.6,156.6，155.6，148.1，144.8，140.8，138.0，131.7，131.2，130.9，130.2，129.8，128.8，128.4,127.9,123.9,123.1,93.7,75.2,71.4,71.0,36.3,21.7,21.4ppm；HRMS(ESI)calculated for C31H31ClN6O7[M+H]+theoretical calculation 635.2016, found 635.1997.
Example 5:
Figure BDA0002822871650000071
1a (30.0mg, 0.1mmol), 2e (32.1mg, 0.3mmol), 3a (60.7mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) are weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 48 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether-1/1-1/2) to obtain the target product 4aea (51.0mg), and the yield is 86%.
Characterization and analysis of the target: a white solid; m.p. ═ 206.4-206.7 ℃;1H NMR(400MHz,CDCl3):δ8.48(d,J＝4.4Hz,1H),7.70(d,J＝4.0Hz,2H),7.59(d,J＝7.2Hz,2H),7.51-7.46(m,2H),7.40(t,J＝7.6Hz,2H),7.33(d,J＝8.8Hz,1H),7.24-7.21(m,2H),6.18(d,J＝9.2Hz,1H),5.48(d,J＝8.8Hz,1H),4.82-4.79(m,1H),4.57-4.54(m,1H),3.52(s,3H),1.01-0.97(m,6H),0.84-0.76(m,6H)ppm；13C NMR(100MHz,CDCl3):δ169.9,166.9,156.5,156.1,155.7,148.9,141.0,138.3,136.8,131.4,131.3,130.9,130.2,129.7,128.2,123.8,123.7,123.4,123.0,94.5,74.6,70.4,70.3,36.2,22.5,21.7,21.32,21.29ppm；HRMS(ESI)calculated for C30H31ClN6O5[M+H]+theoretical calculation 591.2117, found 591.2105.
Example 6:
Figure BDA0002822871650000072
1a (30.0mg, 0.1mmol), 2a (46.9mg, 0.3mmol), 3b (69.1mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) were weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 9 hours (detection reaction by TLC), and after the reaction was completed, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/3-1/4) to obtain the target product 4aab (63.8mg), with a yield of 96%.
Characterization and analysis of the target: a white solid; m.p. ═ 209.1 to 209.5 ℃;1H NMR(400MHz,CDCl3):δ8.06(s,1H),7.89-7.82(m,3H),7.64(d,J＝7.6Hz,3H),7.56-7.49(m,4H),7.46-7.43(m,2H),7.36(d,J＝8.8Hz,1H),7.27(s,1H),6.42(d,J＝9.2Hz,1H),4.02(d,J＝10.0Hz,1H),3.51(s,3H),1.32(d,J＝1.6Hz,18H)ppm；13C NMR(100MHz,CDCl3):δ170.3,167.0,155.9,155.1,141.1,138.5,135.8,133.5,133.3,131.4,131.3,131.0,130.3,129.8,128.6,128.3,128.1,127.8,126.3,125.9,124.4,123.2,93.2,82.6,81.5,75.8,36.3,28.3,27.9ppm；HRMS(ESI)calculated for C37H38ClN5O5[M+H]+theoretical calculation 668.2634, found 668.2614.
Example 7:
Figure BDA0002822871650000081
1b (26.5mg, 0.1mmol), 2f (36.0mg, 0.3mmol), 3b (69.1mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) are weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 30 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether-1/3-1/4) to obtain the target product 4bfb (58.2mg), and the yield is 97%.
Characterization and analysis of the target: a white solid; m.p. 185.9-186.3 ℃;1H NMR(400MHz,CDCl3):δ7.62(d,J＝7.2Hz,2H),7.54-7.47(m,2H),7.44-7.37(m,5H),7.31(d,J＝6.4Hz,1H),7.18(d,J＝8.0Hz,3H),6.20(d,J＝8.0Hz,1H),3.87(d,J＝9.6Hz,1H),3.52(s,3H),2.36(s,3H),1.25(s,18H)ppm；13C NMR(100MHz,CDCl3):δ171.5,167.3,155.8,155.0,142.4,139.2,138.1,135.7,131.0,130.9,130.8,130.4,129.9,129.2,128.0,126.6,123.1,121.4,93.2,82.2,81.0,75.5,36.2,28.2,27.8,21.2ppm；HRMS(ESI)calculated for C34H39N5O5[M+H]+theoretical calculation 598.3024, found 598.3004.
Example 8:
Figure BDA0002822871650000091
1b (26.5mg, 0.1mmol), 2a (46.9mg, 0.3mmol), 3b (69.1mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) are weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 24 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether-1/3-1/4) to obtain the target product 4bab (57.1mg), with the yield of 90%.
Characterization and analysis of the target: a white solid; m.p. 188.4-188.7 ℃;1H NMR(400MHz,CDCl3):δ8.06(s,1H),7.89-7.82(m,3H),7.66-7.64(m,3H),7.56-7.49(m,4H),7.42(t,J＝7.6Hz,3H),7.34(d,J＝6.4Hz,1H),7.19(s,1H),6.41(s,1H),4.01(d,J＝9.6Hz,1H),3.54(s,3H),1.30(s,18H)ppm；13C NMR(100MHz,CDCl3):δ171.6,167.2,156.0,155.0,142.5,139.2,136.0,133.5,133.3,131.1,131.0,130.8,130.4,129.9,128.5,128.1,128.0,127.8,126.21,126.20,125.9,124.5,123.1,121.6,93.3,82.4,81.2,75.8,36.3,28.3,27.9ppm；HRMS(ESI)calculated for C37H39N5O5[M+H]+theory of the inventionCalculated 634.3024, found 634.3002.
Example 9:
Figure BDA0002822871650000092
1b (26.5mg, 0.1mmol), 2g (42.2mg, 0.3mmol), 3b (69.1mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) are weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 30 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether-1/3-1/4) to obtain the target product 4bgb (60.8mg), and the yield is 98%.
Characterization and analysis of the target: a white solid; m.p. ═ 178.3-178.6 ℃;1H NMR(400MHz,CDCl3):δ7.60(d,J＝7.2Hz,2H),7.54-7.47(m,4H),7.39(t,J＝7.6Hz,3H),7.32-7.28(m,3H),7.17(s,1H),6.23(d,J＝8.8Hz,1H),3.84(d,J＝9.6Hz,1H),3.52(s,3H),1.28(s,18H)ppm；13C NMR(100MHz,CDCl3):δ171.7,167.1,155.7,154.8,142.4,140.6,139.1,134.6,131.1,130.8,130.3,130.0,129.0,128.6,128.0,126.4,125.4,124.9,123.2,121.5,93.3,82.7,81.5,75.0,36.3,28.2,27.7ppm；HRMS(ESI)calculated for C33H36ClN5O5[M+H]+theoretical calculation 618.2478, found 618.2457.
Example 10:
Figure BDA0002822871650000101
1b (26.5mg, 0.1mmol), 2c (55.9mg, 0.3mmol), 3b (69.1mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) are weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 24 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether-1/3-1/4) to obtain the target product 4bcb (64.9mg), and the yield is 98%.
Characterization and analysis of the target: a white solid; m.p. ═ 180.0-180.3 ℃;1H NMR(400MHz,CDCl3):δ7.96(s,1H),7.76(d,J＝8.4,1H),7.71(d,J＝9.6,1H),7.66-7.58(m,3H),7.55-7.48(m,2H),7.41(t,J＝7.6Hz,3H),7.33(d,J＝6.0Hz,1H),7.18-7.15(m,3H),6.38(d,J＝7.6Hz,1H),3.99(d,J＝9.6Hz,1H),3.93(s,3H),3.54(s,3H),1.29(s,18H)ppm；13C NMR(100MHz,CDCl3):δ171.5,167.3,157.9,155.9,155.1,142.5,139.2,134.6,133.7,131.02,130.97,130.8,130.4,129.9,129.6,128.7,128.0,127.3,125.7,125.1,123.1,121.5,119.1,105.7,93.2,82.3,81.2,75.8,55.3,36.3,28.3,27.9ppm；HRMS(ESI)calculated for C38H41N5O6[M+H]+theoretical calculation 664.3130, found 664.3104.
Example 11:
Figure BDA0002822871650000111
1c (29.7mg, 0.1mmol), 2a (46.9mg, 0.3mmol), 3b (69.1mg, 0.3mmol) and benzoic acid (2.4mg, 0.02mmol) were weighed and dissolved in 1mL tetrahydrofuran, stirred at room temperature for 48 hours (detection reaction by TLC), and after the reaction was completed, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/3-1/4) to obtain the target product 4cab (53.5mg), with a yield of 97%.
Characterization and analysis of the target: a white solid; m.p. 166.3-166.8 ℃;1H NMR(400MHz,CDCl3):δ8.03(s,1H),7.88-7.81(m,3H),7.69-7.61(m,3H),7.51-7.48(m,2H),7.20(s,2H),7.09(t,J＝8.4Hz,2H),7.02(s,1H),6.38(s,1H),4.00(d,J＝10.0Hz,1H),3.52(s,3H),2.45(s,3H),1.30(s,18H)ppm；13C NMR(100MHz,CDCl3):δ170.3,167.2,164.7(d,JC,F＝251.0Hz),156.0,155.1,142.4,141.8,135.9,135.3,133.4,133.3,132.5(d,JC,F＝9.0Hz),130.6,128.5,128.1,127.7,127.2,126.23,126.21,125.8,124.4,124.2,122.0,115.1(d,JC,F＝22.0Hz),93.2,82.2,81.3,75.8,36.3,28.3,27.8,21.6ppm；HRMS(ESI)calculated for C38H40FN5O5[M+H]+theoretical calculation 666.3086, found 666.3062.
From the above results, it can be seen that the preparation method disclosed by the present invention has mild reaction conditions, simple post-treatment, and excellent yields of most of the synthesized targets.

Claims (8)

1. Chiral 1, 4-benzodiazepine
Figure FDA0002822871640000011
-2-ketospiro-heterocyclic compounds of the formula:
Figure FDA0002822871640000012
wherein R is1Is alkyl, benzyl or hydrogen; r2Is one of methoxyl, fluorine, chlorine, bromine, hydrogen, nitryl and alkyl; r3Is one of hydrogen, fluorine, chlorine, bromine, methoxyl, nitryl and alkyl; r4Is aryl or alkyl; r5Is ethoxycarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl.
The above aryl group means a naphthyl group, a pyridyl group, a phenyl group or a substituted phenyl group; the substituents on the above phenyl groups are selected from: one of methyl, methoxy, fluorine, chlorine, bromine, nitro or trifluoromethyl.
2. Preparation of a chiral 1, 4-benzodiazepine according to claim 1
Figure FDA0002822871640000013
The preparation method of the (E) -2-ketospiro heterocyclic compound is characterized in that the reaction process comprises the following steps: weighing 3-amino-1, 4-benzodiazepine
Figure FDA0002822871640000014
Dissolving the (2-ketone), the aldehyde, the azodicarboxylic acid compound and the additive in an organic solvent, fully stirring the reaction mixed solution at room temperature, and monitoring the reaction by TLC until the 1, 4-benzodiazepine is obtained
Figure FDA0002822871640000015
-complete consumption of the 2-ketimine ylide intermediate; and finally, carrying out reduced pressure concentration on the reaction mixed solution, carrying out simple column chromatography on the crude product to obtain a target product, wherein the eluent is selected from petroleum ether/ethyl acetate mixed solution with the volume ratio of 4: 1-3: 1.
3. A chiral 1, 4-benzodiazepine according to claim 2
Figure FDA0002822871640000016
-2-ketospiro-heterocyclic compound, characterized in that the 3-amino-1, 4-benzodiazepine
Figure FDA0002822871640000017
The molar ratio of the (E) -2-ketone, the aldehyde and the azodicarboxylic acid compound is 1:3: 3.
4. A chiral 1, 4-benzodiazepine according to claim 2
Figure FDA0002822871640000018
The preparation method of the (E) -2-ketospiro heterocyclic compound is characterized in that the organic solvent is tetrahydrofuran, dichloromethane, trichloromethane, 1, 2-dichloroethane, toluene, acetonitrile, N-dimethylformamide or methanol.
5. A chiral 1, 4-benzodiazepine according to claim 2
Figure FDA0002822871640000019
-2-ketospiro-heterocyclic compound, characterized in that said additive is selected from: copper (II) trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, benzoic acid, acetic acid, stearic acid, toluene-4-sulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, 4-methylbenzoic acid, 2-aminobenzoic acid, terephthalic acid, phthalic acid, malonic acid, 2' -dihydroxybiphenyl, triethylamine, sodium carbonate, 4-One or more of dimethylamino pyridine.
6. A chiral 1, 4-benzodiazepine according to claim 2
Figure FDA00028228716400000110
-2-ketospiro-heterocyclic compound, characterized in that the reaction time is 6 hours to 48 hours.
7. A chiral 1, 4-benzodiazepine according to claim 2
Figure FDA00028228716400000111
-2-ketospiro-heterocyclic compound, characterized in that the additive is used in an amount of 3-amino-1, 4-benzodiazepine
Figure FDA00028228716400000112
-20% of moles of 2-ketone.
8. A chiral 1, 4-benzodiazepine according to claim 2
Figure FDA00028228716400000113
A process for producing a (E) -2-ketospiro-heterocyclic compound,
3-amino-1, 4-benzodiazepines
Figure FDA0002822871640000021
2-ketone compounds having the structural formula:
Figure FDA0002822871640000022
R1is alkyl, benzyl or hydrogen; r2Is one of methoxyl, fluorine, chlorine, bromine, hydrogen, nitryl and alkyl; r3Is one of hydrogen, fluorine, chlorine, bromine, methoxyl, nitryl and alkyl;
the aldehyde compound has the following structural formula:
Figure FDA0002822871640000023
R4is aryl or alkyl;
the structural formula of the azo compound is shown as follows:
Figure FDA0002822871640000024
R5is ethoxycarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl.
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