CN110963996B - Indanazolol compound containing acetophenone substituent, preparation method and medical application thereof - Google Patents

Indanazolol compound containing acetophenone substituent, preparation method and medical application thereof Download PDF

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CN110963996B
CN110963996B CN201911350930.9A CN201911350930A CN110963996B CN 110963996 B CN110963996 B CN 110963996B CN 201911350930 A CN201911350930 A CN 201911350930A CN 110963996 B CN110963996 B CN 110963996B
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周成合
坦咖丹初·维加库玛·瑞迪
张园
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Abstract

The invention relates to an isatin alcohol compound containing acetophenone substituent, a preparation method and medical application thereof, wherein the isatin alcohol compound is shown as a general formulaIII and IV show that the compounds have certain inhibitory activity on gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing antibacterial and/or antifungal medicaments, have simple preparation raw materials, are cheap and easy to obtain, have short synthetic route and have important significance in the application of resisting infection.

Description

Indan azolol compound containing acetophenone substituent, preparation method and medical application thereof
Technical Field
The invention belongs to the field of chemical synthesis, relates to an isatin alcohol compound containing acetophenone substituent, and also relates to a preparation method and medical application of the compound.
Background
Microbial infections have become the greatest threat to human health. To date, a large number of antibiotics and synthetic drugs have been used to treat microbial infections. However, excessive reliance on these antimicrobial drugs has led to the emergence of multi-drug resistant bacteria, such as methicillin-resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis, vancomycin-resistant enterococcus faecium, which have rendered many traditional antibiotics and synthetic drugs ineffective. Therefore, the development of antibacterial agents having new structures has become urgent, and particularly, the development of antibacterial agents having high efficacy, low toxicity and low drug resistance has attracted extensive attention.
Isatin is a well-known pharmaceutical agent and is widely found in the brain, nerve endings and other fluid sites of humans and animals as a bioregulator. The versatility of isatin molecular structure makes it an ideal substrate in structural modification and structural derivation, and can exhibit a wide range of biological activities such as antibacterial, antifungal, anticancer, antidepressant, antispasmodic, anti-HIV, anti-inflammatory, etc. by binding to various active targets such as enzymes, receptors, etc. in vivo through non-covalent bonding forces (hydrogen bonding, metal ion coordination, ion-dipole interaction, pi-pi stacking, hydrophobic-hydrophobic interaction, and van der Waals force). Isatin derivative oxindole has been widely used in the synthesis of drug molecules, for example, the oxindole fragment-containing drugs SU-5416 and SU-11248 approved by the U.S. food and drug administration have been used in the treatment of gastrointestinal stromal tumors and advanced kidney cancers. Furthermore, thiazoline, thiazolinone, and the like generated by the cyclization of isatin can increase the antibacterial activity thereof. With the successive appearance of a plurality of drugs containing isatin structural fragments, the synthesis of isatin drug molecules and the research on the biological activity thereof increasingly become hot spots in the field of medicine research and development, mainly through carrying out structural modification on the basic skeleton of the isatin drug molecules and introducing different active groups, and the isatin drug with good pharmacokinetic property, low toxic and side effects and high biological activity is expected to be obtained.
The carfentrazol fragment is an important pharmacodynamic fragment widely existing in bioactive molecules. Many azole alcohols have been successfully developed in recent years and are widely used in clinical practice. For example, the triadimenol compounds fluconazole and voriconazole have very good curative effect when being used as first-line medicaments for treating fungal infection when being used for treating candida albicans and neococcal negative bacteria infection. Nitroimidazole azole compounds such as metronidazole, secnidazole and ornidazole have been used for many years to treat infectious diseases caused by anaerobic bacteria. There has been a great deal of interest in the development of antibacterial drugs such as triadimenol. In addition, the unique aromatic nitrogen heterocyclic structure of the azole ring enables the azole derivative to quickly and efficiently react with biological macromolecules such as proteins, enzymes, receptors and the like in organisms to play a good biological activity. Azole compounds have the advantages of high cure rate, good pharmacokinetic properties, high activity, low toxicity, and the like when used for treating infectious diseases. In recent years, the development of new compounds with new targets or multiple modes of action through the combination of oxazolol and other pharmacodynamic fragments has received much attention as a hydrogen bond donor capable of hydrogen bonding interactions with active molecules in the organism to improve the biological activity of drug molecules. Therefore, the modification of isatin molecular structure with the use of an oxazolol fragment in order to obtain an antibacterial drug with high efficacy and low toxicity has attracted our research interest.
Disclosure of Invention
In view of the above, the present invention aims to provide an isatinol compound and a pharmaceutically acceptable salt thereof; the second purpose of the invention is to provide a method for preparing the isatin alcohol compound and the medicinal salt thereof; the third object of the present invention is to provide a preparation containing the isatinozolol compound; the fourth purpose of the invention is to provide the application of the isatinol compound and the pharmaceutically acceptable salt thereof in preparing antibacterial and/or antifungal medicaments.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the isatin alcohol compound containing acetophenone substituent and the medicinal salt thereof is shown as general formulas III and IV:
Figure BDA0002334648820000021
in the formula, R 1 Hydrogen, alkyl; r 2 Hydrogen and nitro; r 3 Hydrogen and nitro; r 5 Hydrogen, halogen and alkyl.
Preferably, R 1 Hydrogen and methyl; r 2 Hydrogen and nitro; r 3 Hydrogen and nitro; r 5 Hydrogen, chlorine and methyl.
Preferably, it is any one of the following compounds:
Figure BDA0002334648820000022
Figure BDA0002334648820000031
more preferably, the isatin azole alcohol compound is III-1, III-2, III-3, III-4, III-5, III-6, IV-1, IV-2, IV-3, IV-4 and IV-6.
2. The preparation method of the isatin alcohol compound containing acetophenone substituent and the medicinal salt thereof,
a. preparation of pharmaceutically acceptable salts of isatin alcohol compounds shown as general formula I: azole compounds are dissolved in an organic solvent and undergo a ring-opening reaction with the isatin epoxide shown in the general formula VI under the action of alkali to prepare the medicinal salt of the isatin alcohol compounds shown in the general formula I;
Figure BDA0002334648820000032
b. the preparation of the pharmaceutical salt of the isatin alcohol compound containing the acetophenone substituent shown as the general formula III: dissolving a compound shown in a general formula I in an organic solvent, adding a carbonyl compound, and performing condensation reaction under the action of alkali to obtain a medicinal salt of the acetophenone substituent-containing isatin alcohol compound shown in a general formula III;
c. the preparation of the pharmaceutical salt of the isatin alcohol compound containing the acetophenone substituent shown as the general formula IV: the compound shown in the general formula III is dehydrated under the catalysis of acid to prepare the medicinal salt of the isatin alcohol compound shown in the general formula IV, which contains acetophenone substituent.
Preferably, in step a, the temperature of the ring-opening reaction is 60 ℃; the reaction time is 12 h; the alkali is potassium carbonate; the mass ratio of isatin to potassium carbonate is 1.25: 1;
in the step b, the alkali used in the aldol condensation reaction is diethylamine; the reaction is carried out at 18-25 ℃; after the reaction is finished, the crude product can be obtained by direct reduced pressure distillation;
in the step c, the acid used in the dehydration reaction is a mixed acid of glacial acetic acid and hydrochloric acid; the volume ratio of the hydrochloric acid to the glacial acetic acid is 1: 3; the reaction is carried out under reflux; after the reaction is finished, sodium bicarbonate is needed for neutralization.
3. The preparation containing the isatin alcohol compound containing the acetophenone substituent and the pharmaceutically acceptable salt thereof.
Preferably, the preparation is tablets, capsules, powder, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols or transdermal patches.
4. The isatin alcohol compound containing acetophenone substituent and the medicinal salt thereof are applied to the preparation of antibacterial and/or antifungal medicaments.
Preferably, the bacteria is any one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa and acinetobacter baumannii; the fungus is any one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus and Candida parapsilosis.
The invention has the beneficial effects that: the invention utilizes the drug design split principle to introduce the azolol fragment on indole for the first time, designs and synthesizes a series of isatinol compounds containing acetophenone substituent groups with novel structures, and the compounds are detected by in vitro antimicrobial activity to find that the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923 and staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli 25922 and Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC90023 and Candida parapsilosis ATCC20019), and can be used for preparing antibacterial and/or antifungal drugs, thereby providing more efficient and more efficient antibacterial and/or antifungal drugs for clinical antimicrobial treatment, Safe candidate drugs are helpful for solving clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly emerged harmful microorganisms and the like.
Detailed Description
The preferred embodiments of the present invention will be described in detail below.
In the present invention, the isatin derivative VI is referred to as "Mehra N V, Hopper M, Patel N, Hall D, Wrischnik L A, Land K M, Kumar V.design and synthesis of β -amino alcohol based β -lactic-acid bacteria and preliminary analysis of in vitro activity acquisition of the microbial pathway.
Figure BDA0002334648820000041
VII to VIII are prepared: reference to the literature"Chouhan M, Senwar K R, Sharma R, Grover V, Nair V A. registration approach for the synthesis of 3-hydroxy-3-aminomethydondolin-2-one derivative. Green chem.,2011,13, 2553-2560. Senwar K R, Sharma P, Reddy T.S., Jeengar M K, Nayak V.L, Naidu V G M, Kamal A, Shankara N.Spirooxindole-derivative methyl-fused-1, 2, 3-triazoles" -Design, synthesis, cytoxicity assay and kinetic assay. J.413. 11. Eur.424; r in the general formulae VII to VIII 6 Hydrogen, alkyl, alkenyl, phenyl, substituted phenyl. Wherein R in VIII-1 6 Is hydrogen, R in VIII-2 6 Is vinyl, R in VIII-3 6 Is phenyl, R in VIII-4 6 Is p-fluorophenyl, R in VIII-5 6 Is p-chlorophenyl, R in VIII-6 6 Is 2, 4-dichlorophenyl.
In the following examples, the room temperature is 18 to 25 ℃.
Example 1 preparation of Compound I-1
Figure BDA0002334648820000051
A50 mL round-bottomed flask was charged with 2-methyl-5-nitroimidazole (1.90g,15mmol) and potassium carbonate (1.65g,12mmol), stirred at 60 ℃ for 1 hour using 20mL acetonitrile as a solvent, added with isatin derivative VI (2.03g,10mmol), and the reaction was continued at 60 ℃ and followed by thin layer chromatography until the reaction was complete. Distilling under reduced pressure to remove acetonitrile, extracting with water and chloroform, concentrating, recrystallizing, drying, etc. to obtain compound I-1(2.47g) with yield of 74.8%; a yellow solid; melting point: 235 ℃ and 237 ℃. 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.30(s,1H,Im-H-4),7.68(t,J＝7.8Hz,1H,isatin-H-6),7.57(d,J＝6.5Hz,1H,isatin-H-4),7.27(d,J＝8.0Hz,1H,isatin-H-7),7.14(t,J＝7.5Hz,1H,isatin-H-5),5.56(d,J＝4.8Hz,1H,-OH),4.20-4.16(m,1H,CH 1a -Im),4.10-4.06(m,1H,OHCH),4.03(dd,J＝13.6,9.1Hz,1H,CH 1b -Im),3.75(dd,J＝5.8,1.6Hz,2H,NCH 2 ),2.38(s,3H,CH 3 -Im)。
Example 2 preparation of Compound I-2
Figure BDA0002334648820000052
A50 mL round-bottom flask was charged with 4-nitroimidazole (1.69g,15mmol) and potassium carbonate (1.65g,12mmol), stirred at 60 ℃ for 1 hour with 20mL acetonitrile as solvent, added with isatin derivative VI (2.03g,10mmol), and the reaction was stirred at 60 ℃ and followed by thin layer chromatography until the reaction was complete. Distilling under reduced pressure to remove acetonitrile, extracting with water and chloroform, concentrating, recrystallizing, and drying to obtain compound I-2(2.50g) with yield of 64.8%; a yellow solid; melting point: 221-223 ℃. 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.35(s,1H,Im-H-5),7.81(s,1H,Im-H-2),7.67(t,J＝7.8Hz,1H,isatin-H-6),7.57(d,J＝8.3Hz,1H,isatin-H-4),7.23(d,J＝8.0Hz,1H,isatin-H-7),7.14(t,J＝7.5Hz,1H,isatin-H-5),5.62(s,1H,-OH),4.31-4.26(m,1H,CH 1a -Im),4.09(t,J＝8.5Hz,2H,CH 1b -Im,OHCH),3.71(d,J＝4.8Hz,2H,NCH 2 )。
Example 3 preparation of Compound II-1
Figure BDA0002334648820000061
A50 mL round bottom flask was charged with hydroxylamine hydrochloride (0.04g,0.60mmol) dissolved in 5mL ethanol with catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.20g,0.60mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux and thin layer chromatography followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying, etc. to obtain compound II-1(0.17g) with yield of 81.3%; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 ,ppm):δ13.39(s,1H,-NOH),8.33(s,1H,Im-H-4),8.00(d,J＝8.3Hz,1H,isatin-H-4),7.44(t,J＝7.2Hz,1H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.09(t,J＝7.3Hz,1H,isatin-H-5),5.53(d,J＝5.5Hz,1H,-OH),4.17(dd,J＝14.0,2.6Hz,1H,CH 1a -Im),4.10-4.05(m,1H,OHCH),),3.99(dd,J＝9.0Hz,13.8Hz,1H,CH 1b -Im),3.79(dd,J＝13.1,6.3Hz,2H,NCH 2 ),2.38(s,3H,CH 3 -Im)。
example 4 preparation of Compound II-2
Figure BDA0002334648820000062
A50 mL round bottom flask was charged with hydrazine hydrate (0.04mL,0.90mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.30g,0.90mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-2(0.21g) with yield of 67.7%; a red solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 ,ppm):δ8.90(s,2H,NNH 2 ),8.33(s,1H,Im-H-4),7.97(d,J＝7.5Hz,1H,isatin-H-4),7.30(t,J＝7.7Hz,1H,isatin-H-6),7.17(d,J＝8.0Hz,1H,isatin-H-7),7.04(t,J＝7.5Hz,1H,isatin-H-5),5.48(d,J＝5.7Hz,1H,-OH),4.15(dd,J＝14.1,2.6Hz,1H,CH 1a -Im),4.09-4.05(m,1H,OHCH),3.96(dd,J＝14.1,8.9Hz,1H,CH 1b -Im),3.79(d,J＝6.0Hz,2H,NCH 2 ),2.35(s,3H,CH 3 -Im)。
example 5 preparation of Compound II-3
Figure BDA0002334648820000071
A50 mL round bottom flask was charged with phenylhydrazine (0.12mL,1.21mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.30g,0.90mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-3(0.28g), with yield of 73.6%; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ12.69(s,1H,＝NNHAr),8.32(s,1H,Im-H-4),7.61(d,J＝7.4Hz,1H,isatin-H-4),7.46(d,J＝7.8Hz,2H,Ar-H),7.39(t,J＝7.9Hz,2H,Ar-H),7.34(t,J＝7.7Hz,1H,isatin-H-6),7.26(d,J＝7.9Hz,1H,isatin-H-7),7.13(t,J＝7.5Hz,1H,isatin-H-5),7.06(t,J＝7.3Hz,1H,Ar-H),5.56(d,J＝4.8Hz,1H,-OH),4.21(dd,J＝14.1,2.8Hz,1H,CH 1a -Im),4.16-4.10(m,1H,OHCH),4.03(dd,J＝14.1,8.9Hz,1H,CH 1b -Im),3.90-3.83(m,2H,NCH 2 ),2.38(s,3H,CH 3 -Im)。
example 6 preparation of Compound II-4
Figure BDA0002334648820000072
A50 mL round bottom flask was charged with 2, 4-dinitrophenylhydrazine (0.18mL,0.90mmol) dissolved in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.30g,0.90mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-4(0.32g), with yield of 69.5%; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ14.44(s,1H,N-NH),8.89(d,J＝2.5Hz,1H,Ar-H),8.51(dd,J＝9.5,2.5Hz,1H,Ar-H),8.31(d,J＝10.6Hz,2H,Im-H-4,Ar-H),7.70(d,J＝7.5Hz,1H,isatin-H-4),7.47(t,J＝7.8Hz,1H,isatin-H-6),7.30(d,J＝7.9Hz,1H,isatin-H-7),7.17(t,J＝7.5Hz,1H,isatin-H-5),5.57(s,1H,-OH),4.22(dd,J＝13.9,2.3Hz,1H,CH 1a -Im),4.15-4.11(m,1H,OHCH),4.06(dd,J＝13.9,9.2Hz,1H,CH 1b -Im),3.91-3.83(m,2H,NCH 2 ),2.39(s,3H,CH 3 -Im)。
example 7 preparation of Compound II-5
Figure BDA0002334648820000081
A50 mL round bottom flask was charged with thiosemicarbazide (0.082g,0.90mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.30g,0.90mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, thin layer chromatography followed byThe reaction was continued until the end of the reaction. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-5(0.25g) with yield of 69.4%; a red solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 ,ppm):δ12.41(s,1H,＝NNHCSNH 2 ),9.07(s,1H,＝NNHCSNH 1a ),8.73(s,1H,＝NNHCSNH 1b ),8.30(s,1H,Im-H-4),7.72(d,J＝7.3Hz,1H,isatin-H-4),7.44(t,J＝7.4Hz,1H,isatin-H-6),7.27(d,J＝7.8Hz,1H,isatin-H-7),7.16(t,J＝7.4Hz,1H,isatin-H-5),5.56(d,J＝4.6Hz,1H,-OH),4.19(d,J＝13.7Hz,1H,CH 1a -Im),4.14-4.07(m,1H,OHCH),4.03(dd,J＝13.5,9.6Hz,1H,CH 1b -Im),3.88-3.79(m,2H,NCH 2 ),2.37(s,3H,CH 3 -Im)。
example 8 preparation of Compound II-6
Figure BDA0002334648820000082
A50 mL round-bottomed flask was charged with Compound II-5(0.20g, 0.49mmol) and 40% chloroacetaldehyde in water (0.05g,0.73mmol), 20mL ethanol as a solvent, a catalytic amount of triethylamine was added at room temperature, the reaction was stirred under reflux for 2 to 3 hours, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying, etc. to obtain compound II-6(0.17g), with yield of 64.5%; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ13.18(s,1H,＝NNHCSNH 2 ),8.32(s,1H,Im-H-4),7.58(d,J＝7.2Hz,1H,isatin-H-4),7.46-7.40(m,2H,isatin-H-6,thiazole-H-4),7.29(d,J＝7.8Hz,1H,isatin-H-7),7.22(s,1H,thiazole-H-5),7.16(t,J＝7.2Hz,1H,isatin-H-5),5.57(d,J＝4.9Hz,1H,-OH),4.20(d,J＝14.0Hz,1H,CH 1a -Im),4.15-4.10(m,1H,OHCH),4.05(d,J＝13.8Hz,1H,CH 1b -Im),3.87-3.80(m,2H,NCH 2 ),2.38(s,3H,CH 3 -Im)。
example 9 preparation of Compound II-7
Figure BDA0002334648820000091
A50 mL round bottom flask was charged with hydroxylamine hydrochloride (0.054g,0.79mmol) dissolved in 5mL ethanol with catalytic amount of hydrochloric acid followed by slow dropwise addition of a solution of I-2(0.25g,0.79mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux and thin layer chromatography followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-7(0.21g) with yield of 80.7%; a brown solid; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ13.36(s,1H,-NOH),8.38(s,1H,Im-H-5),8.00(d,J＝7.4Hz,1H,isatin-H-4),7.83(s,1H,Im-H-2),7.44(t,J＝8.2Hz,1H,isatin-H-6),7.17(d,J＝7.9Hz,1H,isatin-H-7),7.09(t,J＝7.5Hz,1H,isatin-H-5),5.56(s,1H,-OH),4.28(dd,J＝13.2,2.0Hz,1H,CH 1a -Im),4.13-4.06(m,1H,OHCH),4.04(dd,J＝13.3,8.7Hz,1H,CH 1a -Im),3.75(d,J＝5.7Hz,2H,NCH 2 )。
example 10 preparation of Compound II-8
Figure BDA0002334648820000092
A50 mL round bottom flask was charged with hydrazine hydrate (0.039mL,0.79mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slowly adding I-2(0.25g,0.79mmol) in 5mL ethanol dropwise at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-8(0.17g) with yield of 65.3%; a brown solid; melting point:>250℃； 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.91(s,2H,NNH 2 ),8.39(s,1H,Im-H-5),7.97(d,J＝7.5Hz,1H,isatin-H-4),7.83(s,1H,Im-H-2),7.30(t,J＝7.7Hz,1H,isatin-H-6),7.14(d,J＝7.9Hz,1H,isatin-H-7),7.05(t,J＝7.5Hz,1H,isatin-H-5),5.51(d,J＝5.6Hz,1H,-OH),4.24(dd,J＝13.6,2.3Hz,1H,CH 1a -Im),4.10-4.05(m,1H,OHCH),4.01(dd,J＝13.6,8.6Hz,1H,CH 1b -Im),3.79-3.72(m,2H,NCH 2 )。
example 11 preparation of Compound II-9
Figure BDA0002334648820000093
A50 mL round bottom flask was charged with phenylhydrazine (0.07mL,0.63mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-2(0.20g,0.63mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying, and processing to obtain compound II-9(0.20g) with yield of 80.0%; a yellow solid; melting point:>250℃； 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ12.68(s,1H,＝NNHAr),8.39(s,1H,Im-H-5),7.85(s,1H,Im-H-2),7.61(d,J＝7.4Hz,1H,isatin-H-4),7.46(d,J＝7.7Hz,2H,Ar-H),7.39(t,J＝7.9Hz,2H,Ar-H),7.34(t,J＝8.2Hz,1H,isatin-H-6),7.22(d,J＝7.9Hz,1H,isatin-H-7),7.13(t,J＝7.6Hz,1H,isatin-H-5),7.06(t,J＝7.3Hz,1H,Ar-H),5.62(d,J＝5.4Hz,1H,-OH),4.31(dd,J＝13.6,2.6Hz,1H,CH 1a -Im),4.18-4.13(m,1H,OHCH),4.08(dd,J＝13.7,8.5Hz,1H,CH 1b -Im),3.83(d,J＝5.9Hz,2H,NCH 2 )。
example 12 preparation of Compound II-10
Figure BDA0002334648820000101
A50 mL round bottom flask was charged with 2, 4-dinitrophenylhydrazine (0.12g,0.63mmol) in 5mL ethanol and catalytic amount of hydrochloric acid, followed by dropwise addition of a 5mL ethanol solution of I-2(0.20g,0.63mmol) slowly at room temperature, stirring the reaction under reflux and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-10(0.23g) with yield of 73.4%; an orange solid; melting point:>250℃； 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ14.40(s,1H,N-NH),8.87(d,J＝2.6Hz,1H,Ar-H),8.50(dd,J＝9.5,2.5Hz,1H,Ar-H),8.37(d,J＝1.2Hz,1H,Im-H-5),8.29(d,J＝9.5Hz,1H,Ar-H),7.83(d,J＝1.2Hz,1H,Im-H-2),7.67(d,J＝7.3Hz,1H,isatin-H-4),7.45(t,J＝7.7Hz,1H,isatin-H-6),7.24(d,J＝7.9Hz,1H,isatin-H-7),7.16(t,J＝7.5Hz,1H,isatin-H-5),5.63(s,1H,-OH),4.32(d,J＝11.3Hz,1H,CH 1a -Im),4.16-4.13(m,1H,OHCH),4.12-4.08(m,1H,CH 1b -Im),3.82(d,J＝5.8Hz,2H,NCH 2 )。
example 13 preparation of Compound II-11
Figure BDA0002334648820000102
A50 mL round bottom flask was charged with thiosemicarbazide (0.057g,0.63mmol) in 5mL ethanol, with catalytic amounts of hydrochloric acid, followed by slow dropwise addition of a solution of I-2(0.20g,0.63mmol) in 5mL ethanol at room temperature, the reaction stirred under reflux and followed by thin layer chromatography until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying, etc. to obtain compound II-11(0.17g) with yield of 69.1%; a yellow solid; melting point:>250℃； 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ12.40(s,1H,＝NNHCSNH 2 ),9.08(s,1H,＝NNHCSNH 1a ),8.74(s,1H,＝NNHCSNH 1b ),8.37(s,1H,Im-H-5),7.82(s,1H,Im-H-2),7.72(d,J＝7.4Hz,1H,isatin-H-4),7.44(t,J＝7.7Hz,1H,isatin-H-6),7.23(d,J＝8.0Hz,1H,isatin-H-7),7.16(t,J＝7.5Hz,1H,isatin-H-5),5.61(d,J＝5.2Hz,1H,-OH),4.29(dd,J＝11.4,1.8Hz,1H,CH 1a -Im),4.14-4.11(m,1H,OHCH),4.07(dd,J＝13.2,8.4Hz,1H,CH 1b -Im),3.79(d,J＝5.7Hz,2H,NCH 2 )。
example 14 preparation of Compound III-1
Figure BDA0002334648820000111
Adding compound I-1(0.50g,1.51mmol) and 4-chloroacetophenone (0.19mL,1,51mmol) in a 50mL round-bottom flask, adding diethylamine (0.15mL,1.51mmol) at room temperature, reacting at room temperature, performing thin layer chromatography until the reaction is finished, concentrating, extracting, and performing column chromatographyPerforming chromatographic separation, recrystallization, drying and other post-treatments to obtain a compound III-1(0.55g), wherein the yield is 75.3%; a white solid; melting point: 231 ℃ and 233 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.30(s,1H,Im-H-4),7.92(d,J＝8.6Hz,2H,Ar-H),7.56(d,J＝8.5Hz,2H,Ar-H),7.37(d,J＝7.4Hz,1H,isatin-H-4),7.28(t,J＝8.1Hz,1H,isatin-H-6),7.17(d,J＝7.9Hz,1H,isatin-H-7),6.97(t,J＝7.6Hz,1H,isatin-H-5),6.18(s,1H,-OH),5.60(d,J＝4.8Hz,1H,-OH),4.24-4.19(m,1H,CH 1a -Im),4.15-4.08(m,3H,CH 1b -Im,OHCH,C(OH)CH 1a CO),3.86-3.76(m,2H,NCH 2 ),3.69(d,J＝17.7Hz,1H,C(OH)CH 1b CO),2.37(s,3H,CH 3 )。
example 15 preparation of Compound III-2
Figure BDA0002334648820000112
Adding compound I-1(0.50g,1.51mmol) and 4-methylacetophenone (0.20mL,1,51mmol) into a 50mL round-bottom flask, taking 10mL methanol as a solvent, adding diethylamine (0.15mL,1.51mmol) at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound III-2(0.48g), wherein the yield is 68.5%; a white solid; melting point: 179-181 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.34(s,1H,Im-H-4),7.83(d,J＝8.1Hz,2H,Ar-H),7.38(d,J＝7.1Hz,1H,isatin-H-4),7.31(d,J＝8.0Hz,2H,Ar-H),7.28(t,J＝8.1Hz,1H,isatin-H-6),7.18(d,J＝7.9Hz,1H,isatin-H-7),6.96(t,J＝7.5Hz,1H,isatin-H-5),6.17(s,1H,-OH),5.64(d,J＝3.5Hz,1H,-OH),4.22(d,J＝17.8Hz,CH 1a -Im),4.14-4.08(m,2H,CH 1b -Im,OHCH),3.84-3.77(m,2H,NCH 2 ),3.68(d,J＝17.8Hz,1H,C(OH)CH 1a CO),3.17(d,J＝5.2Hz,1H,C(OH)CH 1b CO),2.38(s,3H,CH 3 ),2.36(s,3H,Ar-CH 3 )。
example 16 preparation of Compound III-3
Figure BDA0002334648820000121
Adding compound I-1(0.50g,1.51mmol) and acetophenone (0.17mL,1,51mmol) into a 50mL round-bottom flask, adding diethylamine (0.15mL,1.51mmol) into the flask at room temperature, reacting at room temperature, tracking the reaction by thin layer chromatography until the reaction is finished, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound III-3(0.51g) with the yield of 74.8%; a white solid; melting point: 207 ℃ and 209 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):8.33(s,1H,Im H-4),7.93(d,J＝7.5Hz,2H,Ar-H),7.65(t,J＝7.3Hz,1H,Ar-H),7.51(t,J＝7.6Hz,2H,ArH),7.39(d,J＝7.1Hz,1H,isatin-H-4),7.28(t,J＝7.7Hz,1H,isatin-H-6),7.19(d,J＝7.8Hz,1H,isatin-H-7),6.97(t,J＝7.5Hz,1H,isatin-H-5),6.19(s,1H,-OH),5.64(d,J＝3.9Hz,1H,-OH),4.25(d,J＝17.9Hz,1H,CH 1a -Im),4.15-4.10(m,3H,CH 1b -Im,OHCH,NCH 1a ),3.83-3.79(m,1H,NCH 1b ),3.72(d,J＝17.8Hz,1H,C(OH)CH 1a CO),3.48-3.41(m,1H,C(OH)CH 1b CO),2.38(d,J＝5.8Hz,3H,CH 3 )。
example 17 preparation of Compound III-4
Figure BDA0002334648820000122
Adding a compound I-2(0.50g,1.58mmol) and 4-chloroacetophenone (0.20mL,1,58mmol) into a 50mL round-bottom flask, taking 10mL methanol as a solvent, adding diethylamine (0.16mL,1.58mmol) at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain a compound III-4(0.52g), wherein the yield is 70.2%; a white solid; melting point: 235-237 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.35(s,1H,Im-H-5),7.93(d,J＝8.6Hz,2H,Ar-H),7.81(s,1H,Im-H-2),7.57(d,J＝8.6Hz,2H,Ar-H),7.38(d,J＝6.9Hz,1H,isatin-H-4),7.28(t,J＝7.2Hz,1H,isatin-H-6),7.14(d,J＝7.9Hz,1H,isatin-H-7),6.97(t,J＝7.4Hz,1H,isatin-H-5),6.19(s,1H,-OH),5.65(d,J＝4.6Hz,1H,-OH),4.24-4.19(m,2H,CH 2 -Im),4.13-4.07(m,2H,NCH 2 ),3.76-3.73(m,1H,OHCH),3.68(d,J＝17.7Hz,1H,C(OH)CH 1a CO),3.17(d,J＝5.2Hz,1H,C(OH)CH 1b CO)。
example 18 preparation of Compound III-5
Figure BDA0002334648820000131
Adding compound I-2(0.50g,1.58mmol) and 4-methylacetophenone (0.21mL,1,58mmol) into a 50mL round-bottom flask, adding diethylamine (0.16mL,1.58mmol) into the flask at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound III-5(0.46g), wherein the yield is 64.7%; a white solid; melting point: 229 ℃ and 231 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.35(s,1H,Im-H-5),7.81(d,J＝8.3Hz,3H,Im H-2,Ar-H),7.38(d,J＝7.2Hz,1H,isatin-H-4),7.31(d,J＝8.0Hz,2H,Ar-H),7.28(t,J＝7.8Hz,1H,isatin-H-6),7.14(d,J＝7.9Hz,1H,isatin-H-7),6.96(t,J＝7.4Hz,1H,isatin-H-5),6.15(s,1H,-OH),5.65(d,J＝4.2Hz,1H,-OH),4.24-4.17(m,2H,CH 2 -Im),4.13-4.07(m,2H,NCH 2 ),3.79-3.73(m,1H,OHCH),3.66(d,J＝17.7Hz,1H,C(OH)CH 1a CO),3.17(d,J＝5.2Hz,1H,C(OH)CH 1b CO),2.36(s,3H,ArCH 3 )。
example 19 preparation of Compound III-6
Figure BDA0002334648820000132
Adding the compound I-2(0.50g,1.58mmol) and acetophenone (0.18mL,1,58mmol) into a 50mL round-bottom flask, adding the diethylamine (0.16mL,1.58mmol) into the flask at room temperature by using 10mL of methanol as a solvent, reacting at room temperature, tracking the reaction by using a thin layer chromatography until the reaction is finished, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain the compound III-6(0.53g), wherein the yield is 77.9%; a white solid; melting point: 225 ℃ and 227 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.36(s,1H,Im-H-5),7.92(d,J＝7.5Hz,2H,Ar-H),7.81(s,1H,Im-H-2),7.64(t,J＝7.4Hz,1H,Ar-H),7.51(t,J＝7.7Hz,2H,Ar-H),7.39(d,J＝7.2Hz,1H,isatin-H-4),7.28(t,J＝7.6Hz,1H,isatin-H-6),7.15(d,J＝7.9Hz,1H,isatin-H-7),6.97(t,J＝7.4Hz,1H,isatin-H-5),6.18(s,1H,-OH),5.66(d,J＝4.3Hz,1H,-OH),4.27-4.20(m,2H,CH 2 -Im),4.12(d,J＝8.5Hz,2H,NCH 2 ),3.79-3.75(m,1H,OHCH),3.70(d,J＝17.8Hz,1H,C(OH)CH 1a CO),3.18(d,J＝5.3Hz,1H,C(OH)CH 1b CO)。
example 20 preparation of Compound IV-1
Figure BDA0002334648820000141
Adding compound III-1(0.24g, 0.50mmol) into a 50mL round-bottom flask, adding 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound IV-1(0.22g), wherein the yield is 92.1%; an orange solid; melting point: 211-213 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.35(s,1H,Im-H-4),8.10(d,J＝8.2Hz,2H,Ar-H),8.03(d,J＝7.6Hz,1H,isatin-H-4),7.78(s,1H,CHalkene),7.68(d,J＝7.4Hz,2H,Ar-H),7.45(t,J＝7.6Hz,1H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.04(t,J＝7.6Hz,1H,isatin-H-5),5.57(s,1H,-OH),4.20(d,J＝15.9Hz,1H,CH 1a -Im),4.16-4.07(br m,1H,OHCH),4.03(dd,J＝13.9,9.0Hz,1H,CH 1b -Im),3.85-3.80(m,2H,NCH 2 ),2.39(s,3H,CH 3 )。
example 21 preparation of Compound IV-2
Figure BDA0002334648820000142
Adding compound III-2(0.23g, 0.50mmol) and 10mL ethanol as solvent into a 50mL round-bottom flask, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, reacting at 120 deg.C, and tracking by thin layer chromatography until reverse reactionAfter the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain a compound IV-2(0.20g) with the yield of 91.5 percent; an orange solid; melting point: 216 ℃ and 218 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.35(s,1H,Im-H-4),7.99-7.95(m,3H,Ar-H,isatin-H-4),7.78(s,1H,CHalkene),7.42(d,J＝7.6Hz,3H,Ar-H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.02(t,J＝7.6Hz,1H,isatin-H-5),5.57(s,1H,-OH),4.20(d,J＝13.8Hz,1H,CH 1a -Im),4.15-4.08(m,1H,OHCH),4.03(dd,J＝13.9,9.0Hz,1H,CH 1b -Im),3.86-3.79(m,2H,NCH 2 ),2.42(s,3H,Ar-CH 3 ),2.39(s,3H,CH 3 )。
example 22 preparation of Compound IV-3
Figure BDA0002334648820000151
Adding a compound III-3(0.23g, 0.50mmol) into a 50mL round-bottom flask, using 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by using a thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain a compound IV-3(0.20g), wherein the yield is 93.5%; an orange solid; melting point: 173-175 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.35(s,1H,Im-H-4),8.08(d,J＝7.4Hz,2H,Ar-H),7.99(d,J＝7.6Hz,1H,Ar-H),7.81(s,1H,CHalkene),7.74(t,J＝7.4Hz,1H,isatin-H-4),7.62(t,J＝7.7Hz,2H,Ar-H),7.44(t,J＝7.7Hz,1H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.03(t,J＝7.6Hz,1H,isatin-H-5),5.57(d,J＝5.5Hz,1H,-OH),4.20(d,J＝13.9Hz,1H,CH 1a -Im),4.16-4.10(m,1H,OHCH),4.03(dd,J＝14.0,9.0Hz,1H,CH 1b -Im),3.85-3.80(d,J＝28.6Hz,2H,NCH 2 ),2.41(d,J＝18.1Hz,3H,CH 3 )。
example 23 preparation of Compound IV-4
Figure BDA0002334648820000152
Adding compound III-4(0.24g, 0.50mmol) into a 50mL round-bottom flask, using 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound IV-4(0.21g), wherein the yield is 91.5%; an orange solid; melting point: 131 ℃ and 133 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.40(s,1H,Im-H-5),8.10(d,J＝8.5Hz,2H,Ar-H),8.02(d,J＝7.6Hz,1H,isatin-H-4),7.85(s,1H,CHalkene),7.78(s,1H,Im-H-2),7.68(d,J＝8.5Hz,2H,Ar-H),7.44(t,J＝7.7Hz,1H,isatin-H-6),7.19(d,J＝7.9Hz,1H,isatin-H-7),7.03(t,J＝7.6Hz,1H,isatin-H-5),4.94(s,1H,-OH),4.31(d,J＝14.7Hz,1H,CH 1a -Im),4.14-4.06(m,2H,NCH 2 ),3.79(d,J＝5.6Hz,2H,CH 1b -Im,OHCH)。
example 24 preparation of Compound IV-5
Figure BDA0002334648820000161
Adding the compound III-5(0.23g, 0.50mmol) into a 50mL round-bottom flask, using 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain a compound IV-5(0.20g), wherein the yield is 93.1%; an orange solid; melting point: 117 ℃ and 119 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.40(d,J＝1.0Hz,1H,Im-H-5),7.99(d,J＝8.1Hz,2H,Ar-H),7.95(d,J＝7.6Hz,1H,isatin-H-4),7.85(d,J＝1.0Hz,1H,CHalkene),7.79(s,1H,Im-H-2),7.42(dd,J＝7.1,4.9Hz,3H,Ar-H,isatin-H-6),7.19(d,J＝7.9Hz,1H,isatin-H-7),7.02(t,J＝7.6Hz,1H,isatin-H-5),4.76(brs,1H,-OH),4.30(d,J＝14.9Hz,1H,CH 1a -Im),4.13-4.06(m,2H,NCH 2 ),3.79(d,J＝5.7Hz,2H,CH 1b -Im,OHCH),2.42(s,3H,Ar-CH 3 )。
example 25 preparation of Compound IV-6
Figure BDA0002334648820000162
Adding compound III-6(0.22g, 0.50mmol) into a 50mL round-bottom flask, adding 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, reacting at 120 ℃, tracking by thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and performing concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound IV-6(0.19g), wherein the yield is 94.7%; an orange solid; melting point: 99-101 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.40(s,1H,Im-H-5),8.09(d,J＝7.2Hz,2H,Ar-H),7.98(d,J＝7.6Hz,1H,isatin-H-4),7.85(s,1H,CHalkene),7.81(s,1H,Im-H-2),7.74(t,J＝7.4Hz,1H,Ar-H),7.62(t,J＝7.8Hz,2H,Ar-H),7.43(t,J＝8.1Hz,1H,isatin-H-6),7.19(d,J＝7.9Hz,1H,isatin-H-7),7.02(t,J＝7.5Hz,1H,isatin-H-5),4.88(br s,1H,-OH),4.31(dd,J＝13.2,2.1Hz,1H,CH 1a -Im),4.15-4.05(m,2H,CH 1b -Im,OHCH),3.80(d,J＝5.7Hz,2H,NCH 2 )。
example 26 preparation of Compound V-1
Figure BDA0002334648820000171
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-1(0.94g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-1(1.12g) with yield of 71.3%; a white solid; melting point: 201-203 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ7.83(s,1H,Im-H-4),7.37(t,J＝7.7Hz,1H,isatin-H-6),7.10-7.04(m,2H,isatin-H-4,5),6.96(d,J＝6.9Hz,1H,isatin-H-7),6.68(s,1H,-OH),4.33(q,J＝14.5Hz,2H,NCH 2 ),3.66(dd,J＝33.3,14.1,7.1Hz,2H,CH 2 -Im),2.07(s,3H,CH 3 -Im),1.08(t,J＝7.2Hz,3H,NCH 2 CH 3 )。
example 27 preparation of Compound V-2
Figure BDA0002334648820000172
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-2(1.0g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-2(1.24g), with 75.6% yield; a white solid; melting point: 169 ℃ and 171 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ7.89(s,1H,Im-H-4),7.35(t,J＝7.7Hz,1H,isatin-H-6),7.06(t,J＝7.5Hz,1H,isatin-H-4),6.96(dd,J＝13.5,7.6Hz,2H,isatin-H-5,7),6.76(s,1H,-OH),5.81-5.75(m,1H,CH＝CH 2 ),5.13-5.09(m,2H,CH＝CH 2 ),4.40-4.33(m,2H,CH 2 -Im),4.32-4.22(m,2H,NCH 2 ),2.07(s,3H,CH 3 -Im)。
example 28 preparation of Compound V-3
Figure BDA0002334648820000181
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-3(1.25g,5.0mmol), reacting under reflux, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-3(1.51g) with 79.8% yield; a white solid; melting point: 115 ℃ and 117 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ7.85(s,1H,Im-H-4),7.29(t,J＝7.8Hz,3H,isatin-H-6,Ar-H),7.25(d,J＝7.1Hz,1H,isatin-H-4),7.21(d,J＝7.6Hz,2H,Ar-H),7.05(t,J＝7.4Hz,1H,isatin-H-5),7.02(d,J＝6.5Hz,1H,Ar-H),6.89(d,J＝7.8Hz,1H,isatin-H-7),6.86(d,J＝4.0Hz,1H,-OH),4.87(s,2H,CH 2 -Im),4.47-4.39(m,2H,NCH 2 ),2.09(s,3H,CH 3 -Im)。
example 29 preparation of Compound V-4
Figure BDA0002334648820000182
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-4(1.34g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-4(1.54g) with 77.7% yield; a white solid; melting point: 228 ℃ and 230 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ7.83(s,1H,Im-H-4),7.32-7.27(m,3H,isatin-H-6,Ar-H),7.12(t,J＝8.9Hz,2H,Ar-H),7.06(t,J＝7.3Hz,1H,isatin-H-5),7.01(d,J＝7.3Hz,1H,isatin-H-4),6.93(d,J＝7.8Hz,1H,isatin-H-7),6.83(s,1H,-OH),4.85(d,J＝6.2Hz,2H,CH 2 -Im),4.41(d,J＝6.7Hz,2H,NCH 2 ),2.09(s,3H,CH 3 -Im)。
example 30 preparation of Compound V-5
Figure BDA0002334648820000191
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-5(1.42g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-5(1.79g), with 86.8% yield; a white solid; melting point: 231 ℃ and 233 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ7.83(s,1H,Im-H-4),7.35(d,J＝8.5Hz,2H,Ar-H),7.31(t,J＝7.7Hz,1H,isatin-H-6),7.25(d,J＝8.4Hz,2H,Ar-H),7.06(t,J＝7.4Hz,1H,isatin-H-5),7.02(d,J＝7.3Hz,1H,isatin-H-4),6.91(d,J＝7.9Hz,1H,isatin-H-7),6.83(s,1H,-OH),4.86(s,2H,NCH 2 ),4.45-4.39(m,2H,CH 2 -Im),2.09(s,3H,CH 3 -Im)。
example 31 preparation of Compound V-6
Figure BDA0002334648820000192
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-6(1.59g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-6(1.85g) with 82.9% yield; a white solid; melting point: 118 ℃ and 120 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ7.90(s,1H,Im-H-4),7.70(s,1H,Ar-H),7.32(dd,J＝17.2,8.2Hz,2H,isatin-H-6,Ar-H),7.09(t,J＝7.3Hz,1H,isatin-H-5),7.02(d,J＝7.0Hz,1H,isatin-H-4),6.96(d,J＝8.3Hz,1H,Ar-H),6.89(s,1H,-OH),6.86(d,J＝7.8Hz,1H,isatin-H-7),4.91(s,2H,NCH 2 ),4.47-4.40(m,2H,CH 2 -Im),2.08(s,3H,CH 3 -Im)。
example 32 preparation of Compound V-7
Figure BDA0002334648820000201
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-1(0.94g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-7(1.18g), and making into final productThe rate is 78.6%; a white solid; melting point: 188-190 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ7.98(s,1H,Im-H-5),7.52(s,1H,Im-H-2),7.36(t,J＝7.7Hz,1H,isatin-H-6),7.05(dd,J＝8.5,5.8Hz,2H,isatin-H-4,5),6.97(d,J＝7.2Hz,1H,isatin-H-7),6.74(s,1H,-OH),4.44(q,J＝13.9Hz,2H,NCH 2 ),3.68(dd,J＝14.1,7.1Hz,1H,CH 1a -Im),3.61(dd,J＝14.1,7.1Hz,1H,CH 1b -Im),1.06(t,J＝7.1Hz,3H,NCH 2 CH 3 )。
example 33 preparation of Compound V-8
Figure BDA0002334648820000202
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-2(1.0g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-8(1.24g) with yield of 78.9%; a white solid; melting point: 180 ℃ and 182 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.02(s,1H,Im-H-5),7.55(s,1H,Im-H-2),7.34(t,J＝7.8Hz,1H,isatin-H-6),7.05(d,J＝7.5Hz,1H,isatin-H-4),6.96(d,J＝8.4Hz,2H,isatin-H-5,7),6.80(s,1H,-OH),5.78-5.73(m,1H,CH＝CH 2 ),5.11(dd,J＝12.5,10.5Hz,2H,CH＝CH 2 ),4.51-4.44(m,2H,CH 2 -Im),4.31-4.21(m,2H,NCH 2 )。
example 34 preparation of Compound V-9
Figure BDA0002334648820000211
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-3(1.25g,5.0mmol), reacting under reflux, tracking by thin layer chromatography until the reaction is finished, and concentratingPerforming post-treatment such as condensation, extraction, column chromatography separation, recrystallization, drying and the like to obtain a compound V-9(1.60g), wherein the yield is 87.9%; a white solid; melting point: 103-105 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.02(s,1H,Im-H-5),7.58(s,1H,Im-H-2),7.29-7.25(m,4H,isatin-H-6,Ar-H),7.21(d,J＝7.4Hz,2H,Ar-H),7.05(t,J＝7.4Hz,1H,isatin-H-5),7.01(d,J＝7.3Hz,1H,isatin-H-4),6.90(s,1H,-OH),6.88(d,J＝7.9Hz,1H,isatin-H-7),4.89-4.82(m,2H,NCH 2 ),4.57-4.49(m,2H,CH 2 -Im)。
example 35 preparation of Compound V-10
Figure BDA0002334648820000212
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-4(1.34g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-10(1.39g) with yield of 72.7%; a white solid; melting point: 220 ℃ and 222 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.00(d,J＝1.3Hz,1H,Im-H-5),7.57(d,J＝1.3Hz,1H,Im-H-2),7.31-7.28(m,3H,isatin-H-6,Ar-H),7.11(t,J＝8.9Hz,2H,Ar-H),7.05(d,J＝7.4Hz,1H,isatin-H-4),7.00(d,J＝7.3Hz,1H,Ar-H,isatin-H-5),6.92(d,J＝7.8Hz,1H,Ar-H,isatin-H-7),6.87(s,1H,-OH),4.84(s,2H,CH 2 -Im),4.55-4.48(m,2H,NCH 2 )。
example 36 preparation of Compound V-11
Figure BDA0002334648820000221
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. After cooling to room temperature, compound VIII-5(1.42g,5.0mmol) was added, the reaction was carried out under reflux, and thin layer chromatography was followedAfter the reaction is finished, carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain a compound V-11(1.69g), wherein the yield is 84.9%; a white solid; melting point: 216 ℃ and 218 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.01(s,1H,Im-H-5),7.57(s,1H,Im-H-2),7.35(d,J＝8.5Hz,2H,Ar-H),7.29(t,J＝7.1Hz,1H,isatin-H-6),7.26(d,J＝8.5Hz,2H,Ar-H),7.06(t,J＝7.5Hz,1H,isatin-H-5),7.01(d,J＝7.2Hz,1H,isatin-H-4),6.90(d,J＝7.9Hz,1H,isatin-H-7),6.88(s,1H,-OH),4.85(s,2H,NCH 2 ),4.56-4.49(m,2H,CH 2 -Im)。
example 37 preparation of Compound V-12
Figure BDA0002334648820000222
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-6(1.59g,5.0mmol), reacting under reflux, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-12(1.57g), with yield of 72.6%; a white solid; melting point: 110-112 ℃; 1 H NMR(600MHz,DMSO-d 6 ,ppm):δ8.05(s,1H,Im-H-5),7.69(d,J＝2.0Hz,1H,Ar-H),7.59(s,1H,Im-H-2),7.33-7.28(m,2H,isatin-H-6,Ar-H),7.10(t,J＝7.5Hz,1H,isatin-H-5),7.03(d,J＝7.2Hz,1H,isatin-H-4),6.96(d,J＝8.4Hz,1H,Ar-H),6.94(s,1H,-OH),6.85(d,J＝7.8Hz,1H,isatin-H-7),4.89(t,J＝11.5Hz,2H,NCH 2 ),4.53(q,J＝14.0Hz,2H,CH 2 -Im)。
note: im is imidazole, and Ar is a benzene ring.
Example 38 in vitro antimicrobial Activity of isatinol Compounds
The Minimal Inhibitory Concentrations (MICs) of the isazoyl alcohol compounds prepared in examples 1-37 against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC20019) were examined by a 96-well microdilution method meeting the Clinical Laboratory Standards Institute (CLSI) set by the national Committee of the United states of America, and the test compounds were dissolved in a small amount of dimethyl sulfoxide, diluted with water to a 1.28mg/mL solution, and then diluted to 128. mu.g/mL with the culture medium, after incubation at 35 ℃ for 24-72 hours, the plates were shaken well on a shaker and MIC was measured at 490nm, the results are shown in tables 1 and 2.
TABLE 1 in vitro antibacterial Activity data (MIC, μ g/mL) of isatinozolol Compounds I-1-V-12
Figure BDA0002334648820000231
Figure BDA0002334648820000241
As can be seen from Table 1, the compounds I-1-V-12 prepared in examples 1-37 of the present invention showed certain inhibitory effect on the tested bacteria, and more importantly, the antibacterial activity of some compounds was comparable to or even stronger than that of norfloxacin as the reference drug.
TABLE 2 in vitro antifungal Activity data (MIC, μ g/mL) for Inidazool Compounds I-1-V-12
Figure BDA0002334648820000242
Figure BDA0002334648820000251
As can be seen from Table 2, the compounds I-1 to V-12 prepared in examples 1 to 37 of the present invention exhibited certain inhibitory effects on the fungi tested, and more importantly, some of the compounds exhibited antibacterial activities comparable to, or even stronger than, that of the reference drug fluconazole.
Example 39 pharmaceutical use of isatin alcohol Compounds
According to the antimicrobial activity detection result, the isatin alcohol compound has good antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single-component preparations, for example, the medicines are prepared from isatin alcohol compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound preparation is prepared by the isatin alcohol compound with one structure, the existing antibacterial and antifungal active ingredients (such as norfloxacin, ciprofloxacin, sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or is prepared by a plurality of isatin alcohol compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-1 tablets
Prescription: the tablet is prepared from compound I-110 g, lactose 187g, corn starch 50g, magnesium stearate 3.0g, and ethanol solution with volume percentage concentration of 70% in a proper amount, and is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-1 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound II-2 Capsule
Prescription: compound II-225 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound II-2 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each tablet weighs 50mg, and the content of active ingredient is 25 mg.
3. Preparation of Compound III-1 granules
Prescription: compound III-126 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound III-1, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of compound IV-2 injection
Prescription: the total amount of compound IV-210 g, propylene glycol 500mL, and water for injection 500mL was made up to 1000 mL.
The preparation method comprises the following steps: weighing the compound IV-2, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the compound IV-2.
5. Preparation of compound V-1 powder injection
The preparation method comprises the following steps: and subpackaging the compound V-1 sterile powder under the aseptic condition to obtain the compound V-1.
6. Preparation of Compound V-4 eye drops
Prescription: 43.78 g of compound V, 0.9g of sodium chloride, 3g of phenethyl alcohol, a proper amount of boric acid buffer solution and distilled water are added to 1000 mL.
The preparation method comprises the following steps: weighing the compound V-4 and sodium chloride, adding into 500mL of distilled water, adjusting the pH value to 6.5 by using a boric acid buffer solution after complete dissolution, adding distilled water to 1000mL, uniformly stirring, filtering by using a microporous filter membrane, filling, sealing, and sterilizing for 1 hour by using circulating steam at 100 ℃ to obtain the compound V-4.
7. Preparation of compound V-6 liniment
Prescription: compound V-64 g, potassium soap 7.5g, camphor 5g, distilled water added to 100 mL.
The preparation method comprises the following steps: dissolving camphor with 95% ethanol solution by volume percentage concentration for later use; heating potassium soap to liquefy, weighing compound V-6, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying, and adding distilled water to full volume.
8. Preparation of compound V-8 suppository
Prescription: compound V-84 g, gelatin 14g, glycerol 70g, distilled water to 100mL, metric 100.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound V-8, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound V-9 ointment
Prescription: 90.5-2 g of compound V, 6-8 g of hexadecanol, 8-10 g of white vaseline, 8-19 g of liquid paraffin, 2-5 g of monoglyceride, 2-5 g of polyoxyethylene (40) stearate, 5-10 g of glycerol, 0.1g of ethylparaben and distilled water which is added to 100 g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely melt, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound V-9, stirring, and cooling.
10. Preparation of compound V-11 and fluconazole compound powder injection
Prescription: the compound V-1150 g, fluconazole 50g and sodium benzoate 1g are prepared into 100 bottles.
The preparation method comprises the following steps: taking the compound V-11, the fluconazole and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the compound.
11. Preparation of Compound II-4 Aerosol
Prescription: 42.5 g of compound II, 203 g, 4g of talcum powder (100 meshes) and trichlorofluoromethane added in a proper amount.
The preparation method comprises the following steps: respectively placing the compound II-4, the Span20 and the talcum powder in a vacuum drying oven for drying for a plurality of hours, placing in a dryer for cooling to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the trichloromonofluoromethane.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (9)

1. The isatin alcohol compound containing acetophenone substituent or the medicinal salt thereof is characterized in that: the structure is shown in general formulas III and IV:
Figure FDA0003645431380000011
in the formula, R 1 Hydrogen and methyl; r 2 Hydrogen and nitro; r 3 Hydrogen and nitro; r 5 Hydrogen, chlorine and methyl.
2. The isatinol compound or a pharmaceutically acceptable salt thereof containing an acetophenone substituent as claimed in claim 1, which is any one of the following compounds:
Figure FDA0003645431380000012
Figure FDA0003645431380000021
3. the method for producing an isatin alcohol compound containing an acetophenone substituent as claimed in claim 1 or 2, characterized in that:
a. preparation of isatin alcohol compounds represented by general formula I: dissolving an azole compound in an organic solvent, and carrying out a ring-opening reaction with the isatin epoxide shown in the general formula VI under the action of alkali to obtain an isatin azole alcohol compound shown in the general formula I;
Figure FDA0003645431380000022
b. the preparation of the isatin alcohol compound containing acetophenone substituent shown in the general formula III: dissolving a compound shown in a general formula I in an organic solvent, adding a carbonyl compound, and carrying out a condensation reaction under the action of alkali to obtain an isatin alcohol compound shown in a general formula III and containing acetophenone substituent groups;
c. the preparation of the isatin alcohol compound containing acetophenone substituent shown in the general formula IV: the compound shown in the general formula III is dehydrated under the catalysis of acid, and the isatin alcohol compound containing acetophenone substituent shown in the general formula IV is prepared.
4. The method for preparing an isatin alcohol compound containing acetophenone substituents as claimed in claim 3, characterized in that:
in the step a, the temperature of the ring-opening reaction is 60 ℃; the reaction time is 12 h; the alkali is potassium carbonate; the mass ratio of the isatin to the potassium carbonate is 1.25: 1;
in the step b, the alkali used in the aldol condensation reaction is diethylamine; the reaction is carried out at 18-25 ℃; after the reaction is finished, the crude product can be obtained by direct reduced pressure distillation;
in the step c, the acid used in the dehydration reaction is a mixed acid of glacial acetic acid and hydrochloric acid; the volume ratio of the hydrochloric acid to the glacial acetic acid is 1: 3; the reaction is carried out under reflux; after the reaction is finished, sodium bicarbonate is needed for neutralization.
5. A preparation containing the isatin alcohol compound containing acetophenone substituents or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2.
6. The formulation of claim 5, wherein: the preparation is tablet, capsule, powder, granule, dripping pill, injection, solution, suspension, emulsion, suppository, ointment, gel, pellicle, aerosol or transdermal patch.
7. The formulation of claim 6, wherein: the preparation is powder for injection.
8. Use of the acetophenone substituent-containing isatinol compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of antibacterial and/or antifungal agents.
9. The use according to claim 8, wherein the bacteria is any one or more of Staphylococcus aureus, enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii; the fungi are any one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus and Candida parapsilosis.
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