CN110818710B - Benzodiazepine compound and preparation method thereof - Google Patents
Benzodiazepine compound and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a benzodiazepine compound and a preparation method thereof. The series of benzodiazepine compounds provided by the invention have novel structures and certain drug potential, and have positive significance when being used for development of new drugs. The invention provides a preparation method of a benzodiazepine compound, which is characterized in that a benzodiazepine compound with an N-heterocyclic bridged seven-membered ring structure is prepared by taking an N-heterocyclic bridged benzimidazole salt as a raw material and utilizing inherent water in an organic solvent to perform a ring opening-ring expansion reaction under the action of a catalyst. The method has the advantages of mild conditions, no need of solvent treatment, simple steps, good regioselectivity and high atom economy.
Description
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to a benzodiazepine compound and a preparation method thereof.
Background
The nitrogen heterocyclic bridged 1, 5-benzodiazepine compound is an important drug molecule with anti-HIV and anti-mental disease effects, and the traditional synthetic method of the drug mainly comprises the step of preparing the 1, 5-benzodiazepine compound through amino C-N bond coupling reaction. However, this type of method has a problem of regioselectivity, or a problem of more steps.
Taking pyridine ring bridged compounds as an example, there are two main methods for preparing the compounds at present:
the method A has fewer preparation steps, but the regioselectivity is difficult to control, for example, the first step has a problem of self-reaction or C-N bond coupling position selectivity, and the second step has a problem of C-N bond coupling position selectivity.
Method B has better regioselectivity but more steps.
Disclosure of Invention
The invention aims to provide a benzodiazepine compound and a preparation method thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a benzodiazepine compound which has a structure shown in a formula I:
wherein R is1And R2Independently hydrogen, alkyl, aryl, halogen, nitro or alkoxy; r3Is a saturated aliphatic chain, an unsaturated aliphatic chain or an aryl group; ar is an azaaromatic ring and comprises a pyridine ring, a quinoline ring or a pyrazine ring.
Preferably, the benzodiazepine compound comprises the following structure:
the invention provides a preparation method of a benzodiazepine compound in the technical scheme, which comprises the following steps:
mixing the nitrogen heterocyclic ring bridged benzimidazole salt, a catalyst and an organic solvent, and carrying out ring opening-ring expansion reaction to obtain a benzodiazepine compound;
the nitrogen heterocyclic ring bridged benzimidazole salt has a structure shown in a formula II:
wherein, X is Cl, Br or I.
Preferably, the catalyst is silver oxide or silver carbonate.
Preferably, the molar ratio of the nitrogen heterocyclic bridged benzimidazole salt to the catalyst is 0.5: 1.0-3.0.
Preferably, the organic solvent includes dimethyl sulfoxide, methanol, ethanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, toluene, 1, 4-dioxane, dichloromethane, tetrahydrofuran, nitrogen heterocycle, ethyl acetate, petroleum ether, chloroform, acetone, or diethyl ether.
Preferably, the dosage ratio of the nitrogen heterocyclic bridged benzimidazole salt to the organic solvent is 0.5mmol:2 mL.
Preferably, the temperature of the ring opening-ring expanding reaction is 50-150 ℃ and the time is 6-48 h.
Preferably, the ring opening-ring expanding reaction is carried out under the condition of stirring, and the rotating speed of the stirring is 200-500 r/min.
Preferably, after the ring opening-ring expanding reaction is completed, the method further comprises: and sequentially extracting, rotary evaporating and separating the obtained materials.
The invention provides a benzodiazepine compound, which has a novel structure and certain drug potential, and has positive significance when being used for developing new drugs.
The invention provides a preparation method of a benzodiazepine compound, which is characterized in that a benzodiazepine compound with an N-heterocyclic bridged seven-membered ring structure is prepared by taking an N-heterocyclic bridged benzimidazole salt as a raw material and carrying out a ring opening-ring expansion reaction under the action of a catalyst by using untreated water in an organic solvent.
The method has the advantages of mild conditions, no need of solvent treatment, simple steps, good regioselectivity and high atom economy.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the product prepared in example 1;
FIG. 2 is a nuclear magnetic carbon spectrum of the product prepared in example 1;
FIG. 3 is a nuclear magnetic hydrogen spectrum of the product prepared in example 2;
FIG. 4 is a nuclear magnetic carbon spectrum of the product prepared in example 2;
FIG. 5 is a nuclear magnetic hydrogen spectrum of the product prepared in example 3;
FIG. 6 is a nuclear magnetic carbon spectrum of the product prepared in example 3;
FIG. 7 is a nuclear magnetic hydrogen spectrum of the product produced in example 4;
FIG. 8 is a nuclear magnetic carbon spectrum of the product prepared in example 4;
FIG. 9 is a nuclear magnetic hydrogen spectrum of the product produced in example 5;
FIG. 10 is a nuclear magnetic carbon spectrum of the product prepared in example 5;
FIG. 11 is a nuclear magnetic hydrogen spectrum of the product produced in example 6;
FIG. 12 is a nuclear magnetic carbon spectrum of the product prepared in example 6;
FIG. 13 is a nuclear magnetic hydrogen spectrum of the product produced in example 7;
FIG. 14 is a nuclear magnetic carbon spectrum of the product prepared in example 7;
FIG. 15 is a nuclear magnetic hydrogen spectrum of the product produced in example 8;
FIG. 16 is a nuclear magnetic carbon spectrum of the product prepared in example 8;
FIG. 17 is a nuclear magnetic hydrogen spectrum of the product produced in example 9;
FIG. 18 is a nuclear magnetic carbon spectrum of the product prepared in example 9;
FIG. 19 is a nuclear magnetic hydrogen spectrum of the product produced in example 10;
FIG. 20 is a nuclear magnetic carbon spectrum of the product prepared in example 10;
FIG. 21 is a nuclear magnetic hydrogen spectrum of the product produced in example 11;
FIG. 22 is a nuclear magnetic carbon spectrum of the product prepared in example 11.
Detailed Description
The invention provides a benzodiazepine compound which has a structure shown in a formula I:
wherein R is1And R2Independently hydrogen, alkyl, aryl, halogen, nitro or alkoxy; r3Is a saturated aliphatic chain, an unsaturated aliphatic chain or an aryl group; ar is an azaaromatic ring and comprises a pyridine ring, a quinoline ring or a pyrazine ring.
In the present invention, said R1Preferably including methyl, carbomethoxy, 4, 5-dimethyl, methoxy, chloro, bromoA group; the R is2Preferably indazolyl, pyrazolyl, methyl, 2-bromo, 4-bromo, N-alkynyl, 2-methyl, 3-methylpyridine, 4-methyl, 2-fluoro, acetyl, trifluoromethyl, 3-iodo, 2-chloro, 3-fluoro, morpholinyl;
the R is3Preferably, nPr (n-propyl), methyl, propynyl, iPr (isopropyl), nBu (n-butyl), ethylphenyl, n-phenylpropyl are included.
The invention provides a preparation method of a benzodiazepine compound in the technical scheme, which comprises the following steps:
mixing the nitrogen heterocyclic ring bridged benzimidazole salt, a catalyst and an organic solvent, and carrying out ring opening-ring expansion reaction to obtain a benzodiazepine compound;
the nitrogen heterocyclic ring bridged benzimidazole salt has a structure shown in a formula II:
wherein, X is Cl, Br or I.
In the present invention, unless otherwise specified, the starting materials for the preparation are commercially available or prepared according to a conventional method, which are well known to those skilled in the art.
The invention mixes nitrogen heterocyclic ring bridged benzimidazole salt, catalyst and organic solvent. In the present invention, the catalyst is preferably silver oxide or silver carbonate; the mole ratio of the nitrogen heterocyclic ring bridged benzimidazole salt to the catalyst is preferably 0.5: 1.0-3.0, and more preferably 0.5: 1.5-2.5.
In the present invention, the organic solvent preferably includes dimethyl sulfoxide, methanol, ethanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, toluene, 1, 4-dioxane, dichloromethane, tetrahydrofuran, nitrogen heterocycle, ethyl acetate, petroleum ether, chloroform, acetone or diethyl ether, and the amount ratio of the nitrogen heterocycle bridged benzimidazole salt to the organic solvent is preferably 0.5mmol:2 mL. In the invention, the organic solvent can be directly used in the ring opening-ring expanding reaction process without any treatment, and the invention utilizes untreated water (mainly water vapor from air) in an polar solvent to carry out the hydrolysis ring opening reaction of the nitrogen heterocyclic ring bridged benzimidazole salt.
The mixing process is not particularly limited in the present invention, and the raw materials can be uniformly mixed by selecting a process known to those skilled in the art.
After the mixing is finished, the ring opening-ring expanding reaction is carried out to obtain the benzodiazepine compound. In the invention, the temperature of the ring opening-ring expanding reaction is preferably 50-150 ℃, more preferably 50-150 ℃, and the time is preferably 6-48 h, more preferably 10-30 h, and further preferably 15-25 h; the ring opening-ring expanding reaction is preferably carried out under the condition of stirring, and the rotating speed of the stirring is preferably 200-500 r/min, more preferably 250-400 r/min, and further preferably 300-350 r/min.
In the ring opening-ring expansion reaction process, under the condition that silver oxide or silver carbonate provides an alkaline environment, nitrogen heterocyclic bridged benzimidazole salt and a small amount of inherent water in an organic solvent undergo hydrolysis ring opening reaction, then the aldehyde group and pyridine ring of the generated ring opening product undergo C-H activation under the catalytic action of the silver oxide or silver carbonate, and ring expansion is carried out to obtain the benzodiazepine compound.
Taking pyridine bridged benzimidazole iodine n-propane salt as an example, the process of the ring opening-ring expansion reaction is as follows:
in the present invention, after the ring opening-expanding reaction is completed, it is preferable to further include: and sequentially extracting, rotary evaporating and separating the obtained materials. In the invention, the reagents used for extraction are preferably dichloromethane and saturated saline solution, and the volume ratio of the dichloromethane to the saturated saline solution is preferably 1: 1, the number of times of extraction is preferably 3; after the extraction was completed, the obtained dichloromethane phase was subjected to rotary evaporation, then the dichloromethane phase was removed, and the residue was subjected to thin layer chromatography column separation. The process of the present invention for the rotary evaporation and thin layer chromatography is not particularly limited, and may be any process known in the art.
In the invention, the structural formulas of the preparation raw materials of the benzodiazepine compound and the corresponding product are shown in table 1.
TABLE 1 preparation of benzodiazepine compounds of the present invention and their corresponding product structures
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Mixing 0.5mmol of pyridine bridged benzimidazole iodine n-propane salt, 1.5mmol of silver oxide and 2mL of dimethyl sulfoxide, stirring for 24 hours at 150 ℃, rotating at 300r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and 50mL of saturated saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 6-propyl-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diazepin-5-one, wherein the yield reaches 70%.
Performing nuclear magnetism characterization on the prepared product, wherein the obtained spectrogram is shown in a figure 1-2, and the obtained data is as follows:
1H NMR(400MHz,CDCl3):δ8.24(dd,J＝4.8Hz,J＝1.6Hz,1H),8.21(dd,J＝7.6Hz,J＝2.0Hz,1H),7.28(dd,J＝8.0Hz,J＝4.0Hz,1H),7.17-7.10(m,2H),7.04-7.02(m,1H),6.99(dd,J＝7.6Hz,J＝4.8Hz,1H),6.95(s,1H),4.08(t,J＝7.2Hz,2H),1.72-1.63(m,2H),0.94(t,J＝7.2Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ167.36,160.50,150.61,142.17,141.69,133.05,126.29,124.56,124.42,121.13,119.21,118.41,51.28,21.06,11.12,ppm；HRMS(ESI)m/z calcd for C15H15N3O[M+H]+254.1293,found 254.1297.
the reaction sequence of this example is as follows:
example 2
Mixing 0.5mmol of 6-pyrazolyl pyridine bridged benzimidazole iodine n-propane salt, 1.5mmol of silver carbonate and 2mL of acetonitrile, stirring at 80 ℃ for 48H at the rotating speed of 500r/min, carrying out ring opening-ring expansion reaction, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline after the reaction is finished, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 6-propyl-2- (1H-pyrazolyl) -6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diazepin-5-one with the yield of 74%.
Performing nuclear magnetism characterization on the prepared product, wherein the obtained spectrogram is shown in figures 3-4, and the obtained data is as follows:
1H NMR(400MHz,CDCl3):δ8.44(d,J＝2.8Hz,1H),8.29(d,J＝8.4Hz,1H),7.72(s,1H),7.57(d,J＝8.0Hz,1H),7.20(d,J＝7.6Hz,1H),7.14-7.07(m,2H),7.01-6.99(m,1H),6.51(d,J＝8.8Hz,1H),6.42(s,1H),4.04(t,J＝7.2Hz,2H),1.68-1.58(m,2H),0.89(t,J＝7.6Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ166.95,159.30,151.51,145.12,142.82,140.89,132.99,127.42,126.21,124.79,124.47,121.02,115.74,108.27,106.35,51.16,21.07,11.13,ppm；HRMS(ESI)m/z calcd for C18H17N5O[M+H]+320.1511,found 304.1524.
the reaction sequence of this example is as follows:
example 3
Mixing 5 mmol-bromopyridine bridged benzimidazole iodine n-propane salt with 3.0mmol of silver carbonate and 2mL of tetrahydrofuran, stirring for 24H at 70 ℃ at the rotation speed of 400r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and 50mL of saturated saline, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 6-propyl-5-bromo-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diazepin-5-one, wherein the highest yield reaches 76%.
Performing nuclear magnetism characterization on the prepared product, wherein the obtained spectrogram is shown in figures 5-6, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.26(d,J＝2.4Hz,1H),8.23(d,J＝2.4Hz,1H),7.25-7.22(m,1H),7.16-7.09(m,2H),6.99-6.97(m,1H),6.59(s,1H),4.04(t,J＝7.2Hz,2H),1.67-1.58(m,2H),0.90(t,J＝7.6Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ166.10,159.03,151.25,144.02,141.05,132.76,126.52,124.94,124.57,121.18,120.41,113.17,51.42,21.00,11.10,ppm；HRMS(ESI)m/z calcd for C15H14BrN3O[M+H]+332.0398,found 332.0400.
the reaction sequence of this example is as follows:
example 4
Mixing 0.5mmol of pyridine bridged benzimidazole iodomethane salt, 2.0mmol of silver carbonate and 2mL of tetrahydrofuran, stirring for 24 hours at 70 ℃, rotating at 400r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 6-methyl-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diazepin-5-one, wherein the highest yield reaches 70%.
Performing nuclear magnetism characterization on the prepared product, wherein the obtained spectrogram is shown in figures 7-8, and the obtained data is as follows:
1H NMR(400MHz,CDCl3):δ8.23-8.20(m,2H),7.18(dd,J＝7.6Hz,J＝1.6Hz,1H),7.15-7.07(m,2H),6.99-6.95(m,2H),6.87(s,1H),3.52(s,3H),ppm；13C NMR(100MHz,CDCl3):δ167.49,160.31,150.94,142.34,139.91,134.53,126.11,124.58,123.19,120.82,118.29,38.05,ppm；HRMS(ESI)m/ zcalcd for C13H11N3O[M+H]+226.0980,found 226.0978.
the reaction sequence of this example is as follows:
example 5
Mixing 0.5mmol of pyridine bridged benzimidazole bromopropenyl salt, 1.5mmol of silver carbonate and 2mL of tetrahydrofuran, stirring for 24 hours at 70 ℃, rotating at 500r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 6-allyl-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diazepin-5-one, wherein the highest yield reaches 65%.
Performing nuclear magnetic characterization on the prepared product, wherein the obtained spectrogram is shown in figures 9-10, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.22(dd,J＝4.8Hz,J＝2.0Hz,1H),8.18(dd,J＝8.0Hz,J＝2.0Hz,1H),7.36-7.31(m,1H),7.12-7.07(m,2H),7.00-6.97(m,2H),6.58(s,1H),6.95(s,1H),6.07-5.97(m,1H),5.35-5.30(m,1H),5.25-5.21(m,1H),4.62(dt,J＝5.2Hz,J＝2.0Hz,2H),ppm；13C NMR(100MHz,CDCl3):δ167.05,160.30,150.91,142.24,140.63,133.77,133.56,126.36,124.55,123.78,120.95,118.84,118.49,116.87,53.26,ppm；HRMS(ESI)m/z calcd for C15H13N3O[M+H]+252.1137,found 252.1136.
the reaction sequence of this example is as follows:
example 6
Mixing 0.5mmol of pyridine bridged benzimidazole benzyl bromide salt, 2.2mmol of silver carbonate and 2mL of tetrahydrofuran, stirring for 24 hours at 70 ℃, rotating at 300r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 6-benzyl-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diazepin-5-one, wherein the highest yield reaches 62%.
Performing nuclear magnetic characterization on the prepared product, wherein the obtained spectrogram is shown in figures 11-12, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.23(d,J＝5.6Hz,2H),7.33(d,J＝7.6Hz,2H),7.30-7.24(m,2H),7.21-7.18(m,2H),7.14-6.95(m,5H),5.27(s,2H),ppm；13C NMR(100MHz,CDCl3):δ167.63,160.67,150.94,142.44,141.12,137.27,133.43,128.58,127.11,126.97,126.47,124.52,124.00,121.09,118.82,118.43,53.88,ppm；HRMS(ESI)m/z calcd for C19H15N3O[M+H]+302.1293,found 302.1293.
the reaction sequence of this example is as follows:
example 7
Mixing 0.5mmol of quinoline bridged benzimidazole iodopropane salt, 1.5mmol of silver carbonate and 2mL of tetrahydrofuran, stirring for 24H at 70 ℃, rotating at 500r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain the 11-propyl-6, 11-dihydro-12H-benzo [2,3] [1,4] diazepine [5,6-b ] quinoline-12-ketone with the highest yield reaching 82%.
Performing nuclear magnetic characterization on the prepared product, wherein the obtained spectrogram is shown in figures 13-14, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.73(s,1H),7.77(t,J＝8.4Hz,2H),7.67-7.63(m,1H),7.39-7.35(m,1H),7.29(d,J＝7.6Hz,1H),7.15-7.08(m,4H),4.13(t,J＝7.6Hz,2H),1.75-1.66(m,2H),0.95(t,J＝7.6Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ166.67,158.80,147.86,144.07,140.31,133.09,132.01,128.85,126.55,126.46,125.56,124.92,124.68,124.25,121.60,120.67,51.57,21.14,11.17,ppm；HRMS(ESI)m/z calcd for C19H17N3O[M+H]+304.1450,found 304.1457.
the reaction sequence of this example is as follows:
example 8
Mixing 0.5mmol of pyrazine bridged benzimidazole iodopropane salt, 2.0mmol of silver carbonate and 2mL of dimethyl sulfoxide, stirring for 30H at 150 ℃, rotating at 400r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatographic column separation on the residue to obtain 10-propyl-5, 10-dihydro-11H-benzo [ b ] pyrazine [2,3-e ] [1,4] diazepin-11-one with the highest yield reaching 71%.
Performing nuclear magnetic characterization on the prepared product, wherein the obtained spectrogram is shown in figures 15-16, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.33(s,1H),8.12(s,1H),7.28(d,J＝8.0Hz,1H),7.19-7.09(m,2H),7.02(d,J＝7.6Hz,1H),6.68-6.57(m,1H),4.07(t,J＝7.6Hz,2H),1.68-1.59(m,2H),0.89(t,J＝7.2Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ165.18,157.07,143.40,140.54,139.55,136.10,132.97,126.54,125.28,125.02,121.25,51.52,20.96,11.11,ppm；HRMS(ESI)m/z calcd for C14H14N4O[M+H]+255.1246,found 255.1245.
the reaction sequence of this example is as follows:
example 9
Mixing 0.5mmol of pyridine bridged 5-nitrobenzimidazole iodopropane salt, 2.0mmol of silver oxide and 2mL of dimethyl sulfoxide, stirring for 30H at 150 ℃, rotating at 400r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain the 8-nitro-6-propyl-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diazepin-5-one with the highest yield reaching 77%.
Performing nuclear magnetic characterization on the prepared product, wherein the obtained spectrogram is shown in figures 17-18, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.58(d,J＝4.8Hz,1H),8.21(d,J＝9.2Hz,1H),8.15(d,J＝7.6Hz,1H),8.10(dd,J＝8.8Hz,J＝2.0Hz,1H),7.94-7.89(m,2H),7.33-7.30(m,1H),3.98(t,J＝7.6Hz,2H),1.92-1.83(m,2H),1.05(t,J＝7.2Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ153.08,149.47,148.19,143.38,138.58,132.60,129.79,122.08,118.35,117.80,112.75,103.21,43.20,21.48,11.32,ppm；HRMS(ESI)m/z calcd for C15H14N4O3[M+H]+299.1144,found 299.1151.
the reaction sequence of this example is as follows:
example 10
Mixing 0.5mmol of pyridine bridged 5-bromobenzimidazoliodopropane salt, 2.0mmol of silver oxide and 2mL of dimethyl sulfoxide, stirring for 30 hours at 150 ℃, rotating at 400r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 8-bromo-6-propyl-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diaza-5-one with the highest yield reaching 72%.
Performing nuclear magnetic characterization on the prepared product, wherein the obtained spectrogram is shown in figures 19-20, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.22(dd,J＝4.8Hz,J＝2.0Hz,1H),8.18(dd,J＝8.0Hz,J＝1.6Hz,1H),7.36(d,J＝2.0Hz,1H),7.20(dd,J＝8.4Hz,J＝2.0Hz,1H),6.99(dd,J＝7.6Hz,J＝4.8Hz,1H),6.88(d,J＝8.4Hz,1H),6.71(s,1H),4.02(t,J＝7.2Hz,2H),1.70-1.61(m,2H),0.92(t,J＝7.2Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ167.00,159.96,150.74,142.34,140.77,134.43,129.11,127.31,122.38,118.95,118.70,116.80,51.46,21.04,11.09,ppm；HRMS(ESI)m/z calcd for C15H14BrN3O[M+H]+332.0398,found 332.0403.
the reaction sequence of this example is as follows:
example 11
Mixing 0.5mmol of pyridine bridged 4-bromobenzimidazoliodopropane salt, 2.0mmol of silver oxide and 2mL of dimethyl sulfoxide, stirring for 30 hours at 150 ℃, rotating at 400r/min, carrying out ring opening-ring expansion reaction, after the reaction is finished, extracting the obtained product for 3 times by using a mixture of 50mL of dichloromethane and saturated 50mL of saline solution, carrying out rotary evaporation on the obtained dichloromethane phase, removing the dichloromethane phase, and carrying out thin-layer chromatography column separation on the residue to obtain 9-bromo-6-propyl-6, 11-dihydro-5H-benzo [ b ] pyridine [2,3-e ] [1,4] diaza-5-one with the highest yield of 85%.
Performing nuclear magnetic characterization on the prepared product, wherein the obtained spectrogram is shown in figures 21-22, and the obtained data are as follows:
1H NMR(400MHz,CDCl3):δ8.22(dd,J＝4.8Hz,J＝1.6Hz,1H),8.18(dd,J＝8.0Hz,J＝2.0Hz,1H),7.23(dd,J＝8.8Hz,J＝2.4Hz,1H),7.18(d,J＝2.4Hz,1H),7.09(d,J＝8.4Hz,1H),7.01(dd,J＝8.0Hz,J＝4.8Hz,1H),6.69(s,1H),4.02(t,J＝7.2Hz,2H),1.67-1.58(m,2H),0.90(t,J＝7.6Hz,3H),ppm；13C NMR(100MHz,CDCl3):δ166.94,159.76,150.68,142.89,142.32,132.20,127.58,125.75,123.98,119.11,118.91,118.82,51.31,20.97,11.09,ppm；HRMS(ESI)m/z calcd for C15H14BrN3O[M+H]+332.0398,found 332.0398.
the reaction sequence of this example is as follows:
the embodiments show that the benzodiazepine compound and the preparation method thereof are provided, and the series of benzodiazepine compounds have novel structures and certain drug potential, and have positive significance when being used for development of new drugs. The invention provides a preparation method of a benzodiazepine compound, which is characterized in that a benzodiazepine compound with an N-heterocyclic bridged seven-membered ring structure is prepared by taking an N-heterocyclic bridged benzimidazole salt as a raw material and carrying out hydrolytic ring-opening-ring-expansion reaction on inherent water in an organic solvent under the action of a catalyst. The method has the advantages of mild conditions, no need of solvent treatment, simple steps, good regioselectivity and high atom economy.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. A preparation method of a benzodiazepine compound is characterized by comprising the following steps:
mixing the nitrogen heterocyclic ring bridged benzimidazole salt, a catalyst and an organic solvent, and carrying out ring opening-ring expansion reaction to obtain a benzodiazepine compound;
the nitrogen heterocyclic ring bridged benzimidazole salt has a structure shown in a formula II:
wherein X is Cl, Br or I;
R1and R2Independently hydrogen, alkyl, aryl, halogen, nitro or alkoxy; r3Is a saturated aliphatic chain, an unsaturated aliphatic chain or an aryl group; ar is a pyridine ring;
the catalyst is silver oxide or silver carbonate;
the benzodiazepine compound has a structure shown in a formula I:
wherein R is1And R2Independently hydrogen, alkyl, aryl, halogen, nitro or alkoxy; r3Is a saturated aliphatic chain, an unsaturated aliphatic chain or an aryl group; and Ar is a pyridine ring.
2. The preparation method according to claim 1, wherein the molar ratio of the nitrogen heterocyclic bridged benzimidazole salt to the catalyst is 0.5: 1.0-3.0.
3. The method according to claim 1, wherein the organic solvent is dimethyl sulfoxide, methanol, ethanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, toluene, 1, 4-dioxane, dichloromethane, tetrahydrofuran, ethyl acetate, petroleum ether, chloroform, acetone, or diethyl ether.
4. The preparation method according to claim 1 or 3, wherein the amount ratio of the nitrogen heterocyclic bridged benzimidazole salt to the organic solvent is 0.5mmol:2 mL.
5. The preparation method according to claim 1, wherein the temperature of the ring opening-ring expanding reaction is 50-150 ℃ and the time is 6-48 h.
6. The preparation method according to claim 5, wherein the ring opening-ring expanding reaction is carried out under stirring conditions, and the rotation speed of the stirring is 200-500 r/min.
7. The method according to claim 6, further comprising, after the ring-opening-ring-expanding reaction is completed: and sequentially extracting, rotary evaporating and separating the obtained materials.
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