CN113121460A - Polycyclic fused 1, 5-benzodiazepine compound and preparation method thereof - Google Patents
Polycyclic fused 1, 5-benzodiazepine compound and preparation method thereof Download PDFInfo
- Publication number
- CN113121460A CN113121460A CN202110542446.7A CN202110542446A CN113121460A CN 113121460 A CN113121460 A CN 113121460A CN 202110542446 A CN202110542446 A CN 202110542446A CN 113121460 A CN113121460 A CN 113121460A
- Authority
- CN
- China
- Prior art keywords
- compound
- benzodiazepine
- polycyclic fused
- formula
- phenylenediamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the technical field of chemical synthesis, and particularly discloses a polycyclic fused 1, 5-benzodiazepine compound and a preparation method thereof. The structure of the 1, 5-benzodiazepine compound is shown as a formula (I) or a formula (II). The compound is prepared by using substituted o-phenylenediamine, diketone compounds and ester compounds as raw materials through nucleophilic addition reaction and carbon-carbon cross coupling reaction. The invention provides a novel, mild and green one-pot method for preparing a 1, 5-benzodiazepine compound, and the prepared compound structurally contains an alkoxycarbonyl methyl (-CH)2COOR) polycyclic condensed compound, the introduction of the structure is expected to effectively improve the biological activity of the medicine, provides a foundation for researching a novel medicine with high physiological activity, has very important value for expanding the application of the 1, 5-benzodiazepine compound in the fields of medicine and industrial production, and has extremely high popularization value.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a polycyclic fused 1, 5-benzodiazepine compound and a preparation method thereof.
Background
The 1, 5-benzodiazepine is an important benzo seven-membered nitrogen-containing heterocyclic compound with a privileged structure, is a skeleton of a plurality of natural products and drug molecules, has various biological activities, and is a valuable lead compound in the development of new drugs. The most representative drugs such as clozapine, olanzapine, etc. have been clinically used as specific drugs for the treatment of schizophrenia and epilepsy. Researchers also find that 1, 5-benzodiazepine compounds have good curative effects on cancers, cardiovascular diseases and the like, and some compounds also have activity of inhibiting bacteria and fungi. More particularly, the polycyclic split or fused 1, 5-benzodiazepine compound has strong inhibitory effect on HIV-1 viral protease of AIDS and Hepatitis C Virus (HCV), so the polycyclic fused 1, 5-benzodiazepine is an important drug molecule.
Because of its wide application prospects in the medical field and industrial production, the design and synthesis of 1, 5-benzodiazepine compounds are receiving more and more attention from researchers, and therefore, the synthesis of 1, 5-benzodiazepine compounds with novel structures is of great importance in the development of anxiolytic, anticonvulsant, antifungal, anticancer or anti-AIDS drugs. And the existing method for synthesizing the 1, 5-benzodiazepine compound is complicated and cannot realize industrial production. Therefore, there is also a need to develop a novel, mild, and green process for the synthesis of important 1, 5-benzodiazepines.
Disclosure of Invention
In order to enrich the types of 1, 5-benzodiazepine compounds and solve the problem that the method for synthesizing the 1, 5-benzodiazepine compounds in the prior art is complex, the invention provides a polycyclic fused 1, 5-benzodiazepine compound and a preparation method thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
in one aspect, the invention provides a polycyclic fused 1, 5-benzodiazepine compound having a structure represented by formula (I) or formula (ii):
wherein R is1、R2Is H, methyl, ethyl, propyl or halogenA peptide;
R3is H, methyl or ethyl; r4Is methyl, ethyl or propyl;
n is 1 or 2.
Compared with the prior art, the invention provides a 1, 5-benzodiazepine compound with a novel structure, which is a polycyclic condensed benzodiazepine compound, and the structure of the compound is introduced with an alkoxycarbonyl methyl (-CH)2COOR)，-CH2COOR is a pharmaceutical active group, and after being introduced into the structure of the benzodiazepine compound, the liposolubility of the benzodiazepine compound in a living body can be increased, so that the pharmacological activity of the benzodiazepine compound is increased, therefore, the invention not only enriches the types of the 1, 5-benzodiazepine compound, but also provides a new compound for developing anti-AIDS or anti-hepatitis C drugs, has very important significance for researching the activity of the compound and expanding the application of the compound in the medical field and industrial production, and provides a foundation for researching a novel drug with high physiological activity.
Optionally, the halogen is Cl or Br.
On the other hand, the invention also provides a preparation method of the polycyclic fused 1, 5-benzodiazepine compound, which is characterized in that the polycyclic fused 1, 5-benzodiazepine compound is prepared by using the substituted o-phenylenediamine shown in the formula (III), the diketone compound and the ester compound shown in the formula (IV) as raw materials through nucleophilic addition reaction and carbon-carbon cross coupling reaction;
wherein R is5Is ethynyl,
When the compound shown in the formula (I) is prepared, the structure of the diketone compound is shown as the formula (V):
when the compound shown in the formula (II) is prepared, the structure of the diketone compound is shown as the formula (VI):
wherein n is 1 or 2.
There are many reports on the synthesis method of 1, 5-benzodiazepine compounds, and most of the conventional methods for synthesizing 1, 5-benzodiazepine compounds utilize the condensation reaction of o-phenylenediamine and α, β -unsaturated carbonyl compounds or 1, 3-dicarbonyl compounds (or ketones); or carbon-nitrogen double bonds and carbon-carbon double bonds are built in molecules to form an active intermediate with an enamine-imine structure to synthesize the 1, 5-benzodiazepine compound. The synthesis of 1, 5-benzodiazepine compounds by intramolecular enamine-enamine self-cyclization has not been reported. The invention firstly utilizes the synthesis method of intramolecular enamine-enamine self-cyclization to synthesize the fused structure containing-CH which is not reported in literature2The 1, 5-benzodiazepine compound of COOR has important value for expanding the application of the 1, 5-benzodiazepine compound in the fields of medicine and industrial production.
Preferably, the method for preparing the polycyclic fused 1, 5-benzodiazepine compound comprises the following steps:
adding the substituted o-phenylenediamine and the diketone compound into an organic solvent, uniformly mixing, reacting at 50-110 ℃ for 2-4h, adding the ester compound and an acid catalyst, uniformly mixing, reacting at 10-30 ℃ for 3-8h to obtain a polycyclic fused 1, 5-benzodiazepine compound, wherein the reaction equation is as follows:
in the above reaction, when R is5In the case of ethynyl, R3Is H; when R is5Is composed of
When R is3is-CH3(ii) a When R is5Is composed of
When R is3is-CH2CH3。
Ester compounds as
For example, the reaction mechanism of the synthesis process of the polycyclic fused 1, 5-benzodiazepine compound provided by the present invention is as follows:
one amino group of substituted o-phenylenediamine is used as a nucleophilic reagent to attack one carbonyl carbon in 5, 5-dimethylcyclohexane-1, 3-diketone, a nucleophilic addition reaction is carried out to remove one molecule of water to obtain an enamine type intermediate product 5a, the other amino group of the intermediate product 5a and a carbonyl group activated by cerous chloride in acetyl ethyl acetate are subjected to a nucleophilic addition reaction to remove one molecule of water to obtain an active intermediate 6aa of an enamine-enamine structure, then the intermediate 6aa is subjected to intramolecular cyclization to obtain an intermediate 7aa, and the intermediate 7aa is subjected to intramolecular proton transfer to obtain a target product 4 aa.
The invention synthesizes the polycyclic fused 1, 5-benzodiazepine compound with a novel structure by a one-pot method, reduces the steps of separating and purifying intermediates, has simple steps and convenient operation, is more suitable for industrial large-scale production and application, and has higher yield and purity, the yield can reach more than 80 percent, and the purity can reach 95-98 percent.
Preferably, the mass ratio of the substituted o-phenylenediamine to the diketone compound to the ester compound is 1:0.8-1: 1-2.
More preferably, the mass ratio of the substituted o-phenylenediamine, the diketone compound and the ester compound is 1:0.9: 1.2.
The preferable ratio of the reaction substances can ensure that the forward progress of the reaction is promoted under the condition of small using amount, and the yield of the target product is improved.
Preferably, the mass ratio of the acid catalyst to the substituted o-phenylenediamine is from 0.1 to 0.2: 1.
More preferably, the mass ratio of the acid catalyst to the substituted o-phenylenediamine is 0.1: 1.
Preferably, the acid catalyst is at least one of cerium trichloride, glacial acetic acid, mandelic acid or p-toluenesulfonic acid.
More preferably, the acid catalyst is cerium trichloride.
The optimized acid catalyst can ensure that the reaction activity is improved to the maximum extent on the premise of the minimum dosage of the catalyst, the carbon-carbon coupling reaction is promoted, and the reaction rate and the product yield are improved; the dosage is too small, and the catalytic effect is not obvious; the use amount is excessive, the yield is not obviously improved, and the waste of the catalyst and the reduction of the purity of the product are caused.
Preferably, the organic solvent is at least one of absolute methanol, absolute ethanol, 1, 2-dichloroethane, acetonitrile or toluene.
More preferably, the organic solvent is absolute ethanol.
The method has the advantages that the absolute ethyl alcohol is selected as a reaction solvent, the nucleophilic addition reaction and the intramolecular cyclization reaction can be better promoted, the reaction rate is improved, the side reaction is reduced, and compared with other organic solvents, the absolute ethyl alcohol is more environment-friendly.
Preferably, the mass ratio of the organic solvent to the substituted o-phenylenediamine is 2-8: 1.
The preferable amount of the organic solvent can fully dissolve the substituted o-phenylenediamine and the diketone compound, promote the reaction, improve the yield of the intermediate product, simultaneously ensure that the intermediate product and the ester compound can be fully dissolved during the reaction, ensure that the target product is easy to separate out after being generated, and improve the yield of the target product.
Preferably, the reaction temperature of the substituted o-phenylenediamine and the diketone compound to form the intermediate is the reflux temperature of the organic solvent.
More preferably, when the organic solvent is absolute ethanol, the reaction temperature of the substituted o-phenylenediamine and the diketone compound is the reflux temperature of the absolute ethanol.
The reaction of the intermediate product with the ester compound of formula (IV) is a key step in the synthesis of the polycyclic fused 1, 5-benzodiazepine compound.
Preferably, the reaction of the intermediate product with the ester compound of formula (IV) is carried out at a reaction temperature of 20 to 25 ℃ for the synthesis of the polycyclic fused 1, 5-benzodiazepine compound.
If the reaction temperature is lowered, a longer reaction time is required or the reaction does not occur; increasing the reaction temperature leads to side reactions and a decrease in the yield and purity of the desired product. The optimal reaction temperature can ensure the yield of the target product on the premise of reducing side reactions to the maximum extent.
The invention provides a novel, mild and green one-pot method for preparing a 1, 5-benzodiazepine compound, and the prepared compound structurally contains an alkoxycarbonyl methyl (-CH)2COOR) polycyclic condensed compound, the introduction of the structure is expected to effectively improve the biological activity of the medicine, provides a foundation for researching a novel medicine with high physiological activity, has very important value for expanding the application of the 1, 5-benzodiazepine compound in the fields of medicine and industrial production, and has extremely high popularization value.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In order to better illustrate the invention, the following examples are given by way of further illustration.
Example 1
Preparation of ethyl 2- (7, 10-dimethyl-1-oxo-1, 2,3,4,9, 10-hexahydrobenzo [ b ] cyclopenta [ e ] [1,4] diazepin-10-yl) acetate:
taking a 50mL clean reaction bottle, adding 1.22g of 4-methyl o-phenylenediamine, 0.882g of 1, 3-cyclopentanedione and 3mL of absolute ethyl alcohol, stirring for dissolving, reacting for 2.5h under a reflux condition, cooling to room temperature, adding 1.56g of ethyl acetoacetate and 0.37g of cerium trichloride into the reaction bottle, continuing to react for 4.0h at 15 ℃, after the reaction is finished, precipitating a solid in an ice bath, performing vacuum filtration, washing with absolute ethyl alcohol to obtain 281mg of a gray solid, wherein the yield is 90%, the purity is 98%, the melting point is 216-218 ℃, and the reaction equation is as follows.
IR(KBr,cm-1)：3321,3237,2978,1711,1618,1561。
1H NMR(400MHz,DMSO-d6,TMS):δ1.14(3H,t,J＝7.0Hz,Me),1.41(3H,s,Me),2.16(3H,s,Me),2.21(2H,m,CH2),2.57(2H,m,CH2),2.71(1H,d,J＝14.3Hz,1/2CH2),2.76(1H,d,J＝14.2Hz,1/2CH2),3.93(2H,q,J＝7.1Hz,CH2),4.92(1H,s,NH),6.62(1H,d,J＝8.0Hz,Ph),6.75(1H,s,Ph),6.87(1H,d,J＝8.1Hz,Ph),9.44(1H,s,NH)。
13C NMR(100MHz,DMSO-d6,TMS):δ14.44,20.79,26.91,33.82,44.40,57.84,59.99,116.41,119.60,122.05,123.58,130.30,132.05,136.85,165.75,171.06,200.14。
ESI-MS：C18H22N2O3 314，found 315(M+1)。
Elemental analysis (%): c18H22N2O3:C 68.77,H 7.05,N 8.91；found:C 68.79,H 7.04,N 8.91。
Examples 2 to 4
The preparation of ethyl 2- (7, 10-dimethyl-1-oxo-1, 2,3,4,9, 10-hexahydrobenzo [ b ] cyclopenta [ e ] [1,4] diazepin-10-yl) acetate in examples 2-4 was carried out in the same manner as in example 1, and the specific reaction conditions are shown in Table 1.
Table 1 examples 2-4 reaction conditions
The purity of the products prepared in examples 2-4 can reach 95-98%.
Example 5
Preparation of ethyl 2- (2,2, 11-trimethyl-1-oxo-2, 3,4,5,10, 11-hexahydro-1H-dibenzo [ b, e ] [1,4] diazepin-11-yl) acetate:
adding 1.08g of o-phenylenediamine, 1.26g of 5, 5-dimethylcyclohexane-1, 3-dione and 3mL of absolute ethyl alcohol into a 50mL clean reaction bottle, reacting for 3h under a reflux condition (first reaction temperature), cooling to room temperature, adding 1.56g of ethyl acetoacetate and 0.37g of cerium trichloride into the reaction bottle, continuing to react for 5h at 20 ℃ (second reaction temperature), separating out a white solid after the reaction is finished in an ice bath, performing vacuum filtration, washing with absolute ethyl alcohol to obtain 274mg of the white solid, wherein the yield is 82%, the purity is 98%, the melting point is 176-.
IR(KBr,cm-1)：3352,3307,2949,1725,1625,1539。
1H NMR(400MHz,DMSO-d6,TMS):δ1.02(3H,s,Me),1.05(3H,s,Me),1.13(3H,t,J＝7.1Hz,Me),1.44(3H,s,Me),2.06(2H,s,CH2),2.47(2H,s,CH2),2.89(1H,d,J＝14.7Hz,1/2CH2),2.99(1H,d,J＝14.6Hz,1/2CH2),3.93(2H,q,J＝6.8Hz,CH2),4.86(1H,s,NH),6.80-6.82(2H,m,Ph),6.93-6.95(1H,m,Ph),6.98-7.00(1H,m,Ph),8.61(1H,s,NH)。
13C NMR(100MHz,DMSO-d6,TMS):δ14.53,27.85,28.25,28.82,30.51,44.49,46.01,51.71,59.76,60.30,113.33,119.94,121.56,122.56,123.29,133.72,137.80,153.25,171.38,194.43。
ESI-MS：C20H26N2O3 342，found 343(M+1)。
Elemental analysis (%): c20H26N2O3:C 70.15,H 7.65,N 8.18；found:C 70.16,H 7.63,N 8.19。
Example 6
Preparation of ethyl 2- (7-bromo-1-oxo-1, 2,3,4,9, 10-hexahydrobenzo [ b ] cyclopenta [ e ] [1,4] diazepin-10-yl) acetate:
taking a 50mL clean reaction bottle, adding 1.85g of 4-bromine o-phenylenediamine, 0.882g of 1, 3-cyclopentanedione and 3mL of anhydrous ethanol, stirring for dissolving, reacting for 3h under a reflux condition, cooling to room temperature, adding 1.176g of ethyl propiolate and 0.37g of cerium trichloride into the reaction bottle, continuing to react for 5.2h at 25 ℃, separating out solid after the reaction is finished, carrying out vacuum filtration and washing with anhydrous ethanol to obtain 290mg of gray solid, the yield is 89%, the purity is 98%, the melting point is 260-phase 262 ℃, and the reaction equation is as follows.
IR(KBr,cm-1)：3371,3261,2956,1711,1618,1539。
1H NMR(400MHz,DMSO-d6,TMS):δ1.19(3H,t,J＝7.1Hz,Me),2.17(1H,dd,J＝14.2,9.6Hz,1/2CH2),2.27(2H,m,CH2),2.31(1H,d,J＝14.2,4.4Hz,1/2CH2),2.62(2H,m,CH2),4.03(2H,q,J＝7.2Hz,CH2),4.28(1H,m,J＝9.3Hz,CH),5.83(1H,d,J＝4.7Hz,NH),6.93-6.94(2H,m,Ph),6.99(1H,s,Ph),9.73(1H,s,NH)。
13C NMR(100MHz,DMSO-d6,TMS):δ14.42,26.83,33.29,42.04,50.71,60.55,115.25,121.97,123.53,125.11,131.48,139.13,166.85,171.03,199.58。
ESI-MS：C16H17BrN2O3 364,found 365(M+1)。
Elemental analysis (%): c16H17BrN2O3:C 52.62,H 4.69,N 7.67；found:C 52.63,H 4.70,N 7.66。
Example 7
Preparation of ethyl 2- (8-chloro-1-oxo-2, 3,4,5,10, 11-hexahydro-1H-dibenzo [ b, e ] [1,4] diazepin-11-yl) acetate:
taking a 50mL clean reaction bottle, adding 1.42g of 4-chloro-o-phenylenediamine, 1.008g of 1, 3-cyclohexanedione and 3mL of anhydrous ethanol, stirring for dissolving, reacting for 3.5h under confluent conditions, cooling to room temperature, adding 1.166g of ethyl propiolate and 0.37g of cerium trichloride into the reaction bottle, continuing to react for 5.3h at 30 ℃, after the reaction is finished, precipitating a solid in an ice bath, performing vacuum filtration, washing with anhydrous ethanol to obtain 240mg of a white solid, wherein the yield is 79%, the purity is 98%, the melting point is 194-196 ℃, and the reaction equation is as follows.
IR(KBr,cm-1)：3293,3231,2949,1725,1618,1525。
1H NMR((400MHz,DMSO-d6,TMS):δ1.11(3H,t,J＝7.1Hz,Me),1.86(2H,m,CH2),2.10(1H,dd,J＝16.1,11.1Hz,1/2CH2),2.27(2H,m,CH2),2.35(1H,dd,J＝16.2,4.0Hz,1/2CH2),2.59(2H,m,CH2),4.00(2H,q,J＝7.2Hz,CH2),4.65(1H,m,J＝8.6Hz,CH),5.50(1H,d,J＝6.4Hz,NH),7.04(1H,s,Ph),7.27(1H,d,J＝8.8Hz,Ph),7.36(1H,d,J＝13.4Hz,Ph),9.30(1H,s,NH)。
13C NMR(100MHz,DMSO-d6,TMS):δ14.57,18.98,21.45,27.86,36.68,38.60,56.52,60.15,112.41,114.65,115.99,121.38,132.08,134.72,147.66,154.78,173.48,196.10。
ESI-MS：C17H19ClN2O3 334,found 335(M+1)。
Elemental analysis (%): c17H19ClN2O3:C 60.99,H 5.72,N 8.37；found:C 60.98,H 5.74,N 8.36。
Example 8
Preparation of propyl 2- (3,3, 11-trimethyl-1-oxo-2, 3,4,5,10, 11-hexahydro-1H-dibenzo [ b, e ] [1,4] diazepin-11-yl) acetate:
taking a 50mL clean reaction bottle, adding 1.08g of o-phenylenediamine, 1.26g of 5, 5-dimethylcyclohexane-1, 3-dione and 3mL of absolute ethyl alcohol, stirring to dissolve, reacting for 3h under confluence conditions, cooling to room temperature, adding 1.728g of propyl acetoacetate and 0.37g of cerium trichloride into the reaction bottle, continuing to react for 5.1h at 30 ℃, after the reaction is finished, precipitating a solid by ice bath, performing vacuum filtration, washing with absolute ethyl alcohol to obtain 238mg of white solid, wherein the yield is 83%, the purity is 98%, and the melting point is 162-164 ℃, and the reaction equation is as follows.
IR(KBr,cm-1)：3365,3307,2964,1711,1611,1532。
1H NMR((400MHz,DMSO-d6,TMS):(400MHz,DMSO-d6,TMS):δ0.85(3H,t,J＝7.4Hz,Me),1.02(3H,s,CH3),1.05(3H,s,CH3),1.45(3H,s,CH3),1.53(2H,m,J＝7.0Hz,CH2),2.06(2H,s,CH2),2.47(2H,s,CH2),2.92(1H,d,J＝14.7Hz,1/2CH2),3.01(1H,d,J＝14.7Hz,1/2CH2),3.85(2H,t,J＝6.6Hz,CH2),4.84(1H,s,NH),6.80(2H,m,Ph),6.93(1H,m,Ph),7.00(1H,m,Ph),8.60(1H,s,NH)。
13C NMR(100MHz,DMSO-d6,TMS):δ10.80,21.95,27.86,28.31,28.84,30.52,44.44,46.07,51.76,60.30,65.34,113.39,119.98,121.58,122.56,123.33,133.77,137.84,153.27,171.50,194.44。
ESI-MS：C21H28N2O3 356,found 357(M+1)。
Elemental analysis (%): c21H28N2O3:C 70.76,H 7.92,N 7.86；found:C 70.78,H 7.94,N 7.85。
Example 9
Preparation of ethyl 2- (3,3,7,8, 11-pentamethyl-1-oxo-2, 3,4,5,10, 11-hexahydro-1H-dibenzo [ b, e ] [1,4] diazepin-11-yl) acetate:
taking a 50mL clean reaction bottle, adding 1.36g of 4, 5-dimethyl-1, 2-phenylenediamine, 1.26g of 5, 5-dimethylcyclohexane-1, 3-diketone and 3mL of absolute ethyl alcohol, stirring and dissolving, reacting for 2.8h under a confluence condition, cooling to room temperature, adding 1.56g of ethyl acetoacetate and 0.37g of cerium trichloride into the reaction bottle, continuing to react for 4.8h at 30 ℃, after the reaction is finished, precipitating a solid in an ice bath, carrying out vacuum filtration and washing with absolute ethyl alcohol to obtain 278mg of a white solid, wherein the yield is 86%, the purity is 98%, the melting point is 156-158 ℃, and the reaction equation is as follows.
IR(KBr,cm-1)：3293,3242,2956,1725,1625。
1H NMR((400MHz,DMSO-d6,TMS):(400MHz,DMSO-d6,TMS):δ1.01(3H,s,Me),1.02(3H,s,Me),1.14(3H,t,J＝7.1Hz,Me),1.42(3H,s,Me),2.03(2H,s,CH2),2.08(3H,s,Me),2.08(3H,s,Me),2.42(2H,s,CH2),2.83(1H,d,J＝14.6Hz,1/2CH2),2.95(1H,d,J＝14.7Hz,1/2CH2),3.95(2H,q,J＝7.0Hz,CH2),4.81(1H,s,NH),6.69(1H,s,Ph),6.75(1H,s,Ph),8.49(1H,s,NH)。
13C NMR(100MHz,DMSO-d6,TMS):δ14.56,19.14,19.26,27.79,28.36,28.54,30.50,44.24,46.02,51.80,59.81,60.47,113.21,121.01,123.70,129.04,130.96,131.40,135.50,153.51,171.58,194.22。
ESI-MS：C22H30N2O3 370,found 371(M+1)。
Elemental analysis (%): c22H30N2O3:C 71.32,H 8.16,N 7.56；found:C 71.34,H 8.14,N 7.55。
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A polycyclic fused 1, 5-benzodiazepine compound having the structure shown in formula (I) or formula (II):
wherein R is1、R2Is H, methyl, ethyl, propyl or halogen;
R3is H, methyl or ethyl; r4Is methyl, ethyl or propyl;
n is 1 or 2.
2. The polycyclic fused 1, 5-benzodiazepine compound of claim 1, wherein said halogen is Cl or Br.
3. A method for preparing a polycyclic fused 1, 5-benzodiazepine compound according to claim 1 or 2, characterized in that the polycyclic fused 1, 5-benzodiazepine compound is prepared by a nucleophilic addition reaction and a carbon-carbon cross-coupling reaction using a substituted o-phenylenediamine represented by formula (III), a diketone compound and an ester compound represented by formula (IV) as raw materials;
wherein R is5Is ethynyl,
Or
When the compound shown in the formula (I) is prepared, the structure of the diketone compound is shown as the formula (V):
when the compound shown in the formula (II) is prepared, the structure of the diketone compound is shown as the formula (VI):
4. a method of preparing a polycyclic fused 1, 5-benzodiazepine compound of claim 3, comprising the steps of:
adding the substituted o-phenylenediamine and the diketone compound into an organic solvent, uniformly mixing, reacting for 2-4h at 50-110 ℃, adding the ester compound and an acid catalyst, uniformly mixing, and reacting for 3-8h at 10-30 ℃ to obtain the polycyclic fused 1, 5-benzodiazepine compound.
5. The method for producing a polycyclic fused 1, 5-benzodiazepine compound according to claim 4, wherein the substance ratio of said substituted o-phenylenediamine, said diketone compound and said ester compound is 1:0.8 to 1:1 to 2; and/or
The mass ratio of the acid catalyst to the substituted o-phenylenediamine is 0.1-0.2: 1.
6. The method for producing a polycyclic fused 1, 5-benzodiazepine compound according to claim 5, wherein the substance ratio of said substituted o-phenylenediamine, said diketone compound and said ester compound is 1:0.9: 1.2; and/or
The mass ratio of the acid catalyst to the substituted o-phenylenediamine is 0.1: 1.
7. The method for producing a polycyclic fused 1, 5-benzodiazepine compound according to any one of claims 4 to 6, wherein said acid catalyst is at least one of cerium trichloride, glacial acetic acid, mandelic acid, or p-toluenesulfonic acid.
8. The method of claim 7, wherein the acid catalyst is cerium trichloride.
9. The method of claim 4, wherein the organic solvent is at least one of absolute methanol, absolute ethanol, 1, 2-dichloroethane, acetonitrile, or toluene.
10. The method for producing a polycyclic fused 1, 5-benzodiazepine compound according to claim 4 or 9, wherein the mass ratio of said organic solvent to said substituted o-phenylenediamine is 2-8: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110542446.7A CN113121460B (en) | 2021-05-18 | 2021-05-18 | Polycyclic fused 1, 5-benzodiazepine compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110542446.7A CN113121460B (en) | 2021-05-18 | 2021-05-18 | Polycyclic fused 1, 5-benzodiazepine compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113121460A true CN113121460A (en) | 2021-07-16 |
| CN113121460B CN113121460B (en) | 2022-08-30 |
Family
ID=76782278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110542446.7A Active CN113121460B (en) | 2021-05-18 | 2021-05-18 | Polycyclic fused 1, 5-benzodiazepine compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113121460B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276304A (en) * | 2021-10-09 | 2022-04-05 | 南京苏亦欣医药科技有限公司 | A method for preparing 1, 5-benzodiazepine derivative as medicinal intermediate containing fused ring |
-
2021
- 2021-05-18 CN CN202110542446.7A patent/CN113121460B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| 李静等: "三组分串联反应一锅合成多环稠合的1,5-苯并二氮杂䓬化合物", 《有机化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276304A (en) * | 2021-10-09 | 2022-04-05 | 南京苏亦欣医药科技有限公司 | A method for preparing 1, 5-benzodiazepine derivative as medicinal intermediate containing fused ring |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113121460B (en) | 2022-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101792438B (en) | Method for synthesizing 1-substituted-1,2,3-tolyltriazole | |
| CN109293574A (en) | A kind of dehydroabietic acid aryl amine benzimidizole derivatives with anti-tumor activity and its preparation method and application | |
| CN111269228B (en) | Preparation method of indolizine ring-1, 2-diketone and derivative thereof with fluorescence activity | |
| CN113121460B (en) | Polycyclic fused 1, 5-benzodiazepine compound and preparation method thereof | |
| CN109912520B (en) | 1, 5-benzodiazepine compound and preparation method thereof | |
| CN110028518B (en) | Method for preparing medical intermediate pyrano [2, 3-d ] pyrimidone derivative through catalysis | |
| CN101941971B (en) | Method for synthesizing evodiamine | |
| CN108864089B (en) | Indolopyridone drug molecule and preparation method and application thereof | |
| CN115093372B (en) | Synthesis method of imidazole derivative | |
| CN113912609B (en) | Preparation method of natural alkaloid tryptanthrin and derivatives thereof | |
| CN112094240B (en) | Method for synthesizing quinazoline-2, 4(1H,3H) -diketone compound | |
| CN108191736B (en) | 2, 3-disubstituted indole derivatives and preparation method thereof | |
| CN113717135A (en) | Synthesis method of carbonyl substituted benzodihydropyran and benzodihydropyran compound | |
| CN109206430B (en) | Thiourea catalytic synthesis of nitrogen-containing ternary polycyclic chiral compound and application thereof | |
| CN113845481B (en) | Synthesis method of 4, 4-dimethyl-4, 5-dihydropyridazin-3-one | |
| Liu et al. | Cp* Rh (iii)-catalyzed regioselective cyclization of aromatic amides with allenes | |
| CN112480016B (en) | (E) -1-acyl-1- (3-quinoxalinone) methyl ketoxime and synthesis method thereof | |
| CN103254108B (en) | Preparation method of multifunctional pyrrole and pyrrolo [3,4-C ] quinoline | |
| CN112500393B (en) | C2-sulfonylamino indole derivative and preparation method thereof | |
| Wang et al. | Liquid-phase parallel synthesis of 2-aryl-5-methoxylcarbonyl-dihydropyrones using soluble polymer support | |
| CN112358447B (en) | Synthesis method of 7-fluoroisoquinoline-1-carboxylic acid | |
| CN115108985B (en) | Synthesis method of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione | |
| CN109942584B (en) | Method for synthesizing Becrabavir intermediate | |
| CN110698533B (en) | Ursolic acid indoquinone derivative and preparation method and application thereof | |
| CN108794470B (en) | 6-hydrazino-1H-pyrazolo [3,4-b ] pyridine and synthesis method of downstream product thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |