CN111747883B - 1-benzyl isatin derivative and synthesis method and application thereof - Google Patents
1-benzyl isatin derivative and synthesis method and application thereof Download PDFInfo
- Publication number
- CN111747883B CN111747883B CN202010714705.5A CN202010714705A CN111747883B CN 111747883 B CN111747883 B CN 111747883B CN 202010714705 A CN202010714705 A CN 202010714705A CN 111747883 B CN111747883 B CN 111747883B
- Authority
- CN
- China
- Prior art keywords
- solid
- methyl
- added
- solution
- reaction
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a 1-benzyl isatin derivative and a synthesis method and application thereof, belongs to the technical field of medicaments, and relates to a general formula (I), R1，R2，R3Are different substituents. The invention discloses the structures and the synthesis methods of the compounds, the inhibitory activity of acetylcholinesterase and the inhibitory activity of histone deacetylase 6, and the compounds can be further developed into a medicament for treating Alzheimer's disease.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to 1-benzyl isatin derivatives, a synthetic method and medical application thereof.
Technical Field
Alzheimer Disease (AD) is a degenerative disease of the central nervous system, has an insidious onset, is one of the most common types of senile dementia, has an increasing incidence with the increase of age, and has become one of the most serious medical problems faced by current geriatric medicine. The treatment effect of AD aiming at a single target point is not ideal, and the development of the medicine for treating the AD needs to consider a multi-target point treatment method.
Chinese patent CN 1309641A in 2002 discloses a class of N- (indole carbonyl) piperazine derivatives, and the compounds and medicaments thereof are used as potent 5-HT2A antagonists and are suitable for treating psychosis, schizophrenia, depression, Parkinson's disease, Alzheimer's disease and the like. Patent CN 104529866A, CN 105367472A discloses indole derivatives, indoline derivatives and medical application thereof in 2015, the invented compounds and compositions thereof have better affinity to 5-HT6 and can be used as medicaments for treating central nervous system diseases, gastrointestinal tract diseases or obesity related to 5-HT6, in particular Alzheimer's disease, patent CN104774193A in 2015 discloses indolone compounds and preparation methods and medical application thereof, and the invented compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof have regulating effect on the activity of protein kinase, can inhibit the activity of various protein tyrosine kinases and have inhibiting effect on the proliferation of various tumors. However, none of the above patents disclose inhibitory activity against acetylcholinesterase or histone deacetylase 6.
The invention discloses a 1-benzyl isatin derivative and a synthesis method and application thereof. Has good inhibitory activity on acetylcholinesterase and histone deacetylase 6, and can be further developed into drugs for treating Alzheimer's disease.
Disclosure of Invention
The invention aims to provide a series of 1-benzyl isatin derivatives with good acetylcholinesterase and histone deacetylase 6 inhibitory activities, in particular to hydroximic acid with a two-segment aromatic structure.
The two-segment aromatic hydroximic acid has a structure shown in a general formula (I).
R1The substituents can be respectively independent H, F, Cl, Br and NO2、CH3、CH2CH3、CH(CH3)2、C3H7、C6H5、CH2OH、CH2NH2、CHO、CN、CF3、OCF3、C6H4CN；
R2、R3Are each H or CONHOH, and R2And R3Not simultaneously a group.
Each class of groups in formula (I) may be replaced by bioisosteres or isolines.
Another object of the present invention is to provide a method for preparing the above 1-phenylisatin derivative having two-stage structure.
The invention relates to a preparation method of a 1-phenylisatin derivative, which is characterized by comprising the following steps: 4-substituted anilines areRaw material is reacted with chloral hydrate to obtain 5-substituted isatin, which is then reacted with halohydrocarbon (R)4、R5Are each and not simultaneously H or COOCH3) Then the ester group reacts with hydroxylamine hydrochloride to generate hydroximic acid, and the corresponding compound is obtained by adopting the following synthetic reaction steps:
the results of the preliminary pharmacodynamic study show that the compound has good acetylcholinesterase and histone deacetylase 6 inhibitory activity, and can be further developed into a medicine for treating Alzheimer disease.
Detailed description of the invention
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 3- ((5-nitroindole-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
(1) Preparation of methyl m-methylbenzoate
In a dry 100ml three-necked flask, 8g of m-toluic acid and 50ml of dried methanol were added, and 0.4ml of concentrated sulfuric acid was added dropwise to the reaction system under stirring, followed by reaction at 65 ℃ for 7 hours under reflux. The reaction was monitored by TLC (developing solvent: ethyl acetate: petroleum ether: 1:3) during the reaction until the reaction proceeded more than 90%, and the reaction was terminated. At least 80% of the methanol was removed from the system using a rotary evaporator, 40ml of water was added to the remaining liquid, and after extraction with ethyl acetate (3X 20ml), the organic phase was extracted with 10ml of 10% NaHCO3Washing the solution 2-3 times (TLC monitoring the m-toluic acid spot completely disappeared), washing the organic phase once with 10ml water, and washing the organic phase with anhydrous MgSO4Dried overnight. 7.6g of the product is obtained by suction filtration and rotary evaporation, and the product is colorless to light yellow liquid with the yield of 86.6 percent.
(2) Preparation of methyl m-bromomethylbenzoate
Using 30ml CCl47.6g of methyl m-methylbenzoate are dissolved in dryIn a 100ml three-necked flask, 0.23g of AIBN (azobisisobutyronitrile) and 9.36g of NBS (bromosuccinimide) were added to the reaction system in 3 portions (the time between the two additions was about 2 hours), the temperature was raised to 70 ℃, and the system was turned from yellow to orange and finally turned to white during the reaction. TLC tracking (developing agent: ethyl acetate: petroleum ether: 1:5) until the reaction is almost complete, filtering to remove succinimide and unreacted bromosuccinimide, and rotary evaporating the obtained filtrate to obtain yellow oily product 10.2g with yield of 92%.
(3) Preparation of 5-nitroisatin
3.3g chloral hydrate was dissolved in 60ml deionized water, and then 40g Na was added in order2SO42.8g of 4-nitroaniline and 20ml of concentrated HCl and 3.6g of hydroxylamine hydrochloride, the mixture was heated to 70 ℃ and reacted under reflux for 1 hour. The mixture was then cooled to 60 ℃ and the product collected by filtration while hot, washed with an appropriate amount of deionized water and dried under reduced pressure to give 3.1g of product in 74.1% yield.
A100 ml round bottom flask was charged with 35ml of concentrated H2SO4And heated to 70 ℃ and the solid product was added in 3 portions with stirring. The mixture was heated to 80 ℃ for 1 hour, poured into ice water, filtered to collect the solid, and dried to give 2.1g of an orange-yellow solid, 72.2% yield, m.p. 249-251 ℃.
(4) Preparation of methyl 3- ((5-nitroindole-2, 3-dione-1-yl) methyl) benzoate
In a dry 50ml flask, 0.34g of 5-nitroisatin is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ in ice water bath, 0.08g of NaH is added, 0.75g of methyl p-bromomethylbenzoate is added after 5min, the reaction is stopped after about 48h, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated overnight in a refrigerator, orange solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, 10ml of petroleum ether is added, the solid is re-precipitated, filtered and dried, 0.46g of orange-red solid is obtained, the yield is 67.6%, and the melting point is 120-.
(5) Preparation of 3- ((5-nitroindole-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
0.34g of methyl 3- ((5-nitroindole-2, 3-dione-1-yl) methyl) benzoate is dissolved in a mixed solution of 10ml of methanol and 5ml of dichloromethane, 2.74g of hydroxylamine hydrochloride is added, 2.32g of KOH which is prepared into 20 percent methanol solution is slowly dripped into the reaction solution, the reaction is carried out for 6h at room temperature under the protection of nitrogen, 10ml of deionized water is added into the reaction system after the reaction is finished, the pH of the solution is adjusted to 5 by 10 percent HCl, the solid is collected by filtration, the mixed solution of ethyl acetate and petroleum ether is recrystallized, the solid is collected by filtration and dried in vacuum at 40 ℃ for 48h, and 0.202g of yellow gray solid is obtained, the yield is 59.4 percent, and the melting point is 138-.
Example 2
Preparation of 4- ((5-nitroindole-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
(1) Preparation of methyl p-methylbenzoate
In a dry 100ml three-necked flask, 8g of p-toluic acid and 50ml of dried methanol were added dropwise slowly with stirring 0.4ml of concentrated sulfuric acid, and the reaction was carried out at 65 ℃ under reflux for 7 hours. The reaction was monitored by TLC (developing solvent: ethyl acetate: petroleum ether: 1:3) during the reaction until the reaction proceeded more than 90%, and the reaction was terminated. At least 80% of the methanol in the system was removed by rotary evaporator, 40ml of water was added to the remaining liquid, extraction was carried out with ethyl acetate (3X 20ml), and the organic phase was extracted with 10ml of 10% NaHCO3Washing the solution 2-3 times (TLC monitoring the m-toluic acid spot completely disappeared), washing the organic phase once with 10ml water, and washing the organic phase with anhydrous MgSO4Dried overnight. The product 6.5g is obtained by suction filtration and rotary evaporation, and the product is colorless to light yellow liquid with the yield of 70.6 percent.
(2) Preparation of methyl p-bromomethylbenzoate
Using 35ml of CCl46.5g of methyl p-methylbenzoate are dissolved in a dry 100ml three-necked flask, 0.23g of AIBN (azobisisobutyronitrile) and 9.36g of NBS (bromosuccinimide) are added to the reaction system in 3 portions (the time between the two additions is about 2 hours), the temperature is raised to 70 ℃, and the color of the system is changed from yellow to orange during the reaction and finally changed to white. TLC tracking (developing agent: ethyl acetate: petroleum ether: 1:5) to react almost completely, filtering to remove succinimide and unreacted bromosuccinimide, and rotary evaporating the filtrate8.2g of a yellow oily product was obtained, yield 67.2%.
(3) Preparation of methyl 4- ((5-nitroindole-2, 3-dione-1-yl) methyl) benzoate
Dissolving 0.34g of 5-nitroisatin in 10ml of dry DMF solution, cooling to about 0 ℃ in an ice-water bath, adding 0.08g of NaH, adding 0.75g of methyl p-bromomethylbenzoate after 5min, reacting for about 48h to terminate the reaction, adding 50ml of deionized water into the reaction system, refrigerating overnight in a refrigerator, filtering to obtain an orange solid, adding 4ml of ethyl acetate to dissolve the solid, then adding 8ml of petroleum ether to precipitate the solid again, filtering, and drying to obtain 0.35g of the orange solid, wherein the yield is 52%, and the melting point is 140 and 142 ℃.
(4) Preparation of 4- ((5-nitroindole-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
Dissolving 0.34g of methyl 4- ((5-nitroindole-2, 3-diketone-1-yl) methyl) benzoate in a mixed solution of 10ml of methanol and 8ml of dichloromethane, adding 2.74g of hydroxylamine hydrochloride, preparing 2.32g of KOH into a 20% methanol solution, dropwise adding the 20% methanol solution into a reaction solution, reacting at room temperature for 10 hours under the protection of nitrogen, adding 15ml of deionized water into the reaction system after the reaction is finished, dissolving all solids, adjusting the pH of the solution to 5 by using 10% diluted hydrochloric acid, separating out solids, filtering and collecting the solids, dissolving the solids by using 5ml of ethyl acetate, adding 10ml of petroleum ether, re-separating out the solids, filtering and collecting the solids, and performing vacuum drying at 40 ℃ for 24 hours to obtain 0.116g of yellow gray solids, wherein the yield is 34.1%, and the melting point is 223 ℃ and 225 ℃.
Example 3
Preparation of 3- ((indole-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
(1) Preparation of methyl 3- ((indole-2, 3-dione-1-yl) methyl) benzoate
In a dry 50ml flask, 0.30g of isatin is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ in an ice water bath, 0.08g of NaH is added, 0.75g of methyl p-bromomethylbenzoate is added after 5min, the reaction is stopped after about 48h, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated in a refrigerator overnight, orange yellow solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, 10ml of petroleum ether is then added, the solid is re-precipitated, and the solid is filtered and dried to obtain 0.324g of orange red solid, the yield is 55%, and the melting point is 198-199 ℃.
(2) Preparation of 3- ((indole-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
Dissolving 0.30g of methyl 3- ((indole-2, 3-diketone-1-yl) methyl) benzoate in a mixed solution of 12ml of methanol and 10ml of dichloromethane, adding 1.5g of hydroxylamine hydrochloride, preparing 2.32g of KOH into a 20% methanol solution, dropwise adding the methanol solution into a reaction solution, reacting for 10 hours at room temperature under the protection of nitrogen, adding 10ml of deionized water into a reaction system after the reaction is finished, allowing the solution to stratify, adjusting the pH of the solution to 5 by using 10% dilute hydrochloric acid, and using anhydrous MgSO (MgSO) for a lower-layer organic phase4Drying overnight, spin-drying the organic phase and dissolving with 5ml of ethyl acetate, re-precipitating the solid with 10ml of petroleum ether, drying at 40 ℃ under vacuum for 36h to give 0.182g of a yellow powdery solid, 66.4% yield, 208 ℃ melting point and 210 ℃.
Example 4
Preparation of 4- ((indol-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
(1) Preparation of methyl 4- ((indole-2, 3-dione-1-yl) benzoate
In a dry 50ml flask, 0.30g of isatin is dissolved in 10ml of dry DMF solution, the mixture is cooled to about 0 ℃ in ice water bath, 0.08g of NaH is added, 0.75g of methyl p-bromomethylbenzoate is added after 5min, the reaction is stopped after about 48h, 50ml of deionized water is added into the reaction system, the mixture is refrigerated in a refrigerator overnight, orange yellow solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, then 10ml of petroleum ether is added, the solid is re-precipitated, filtered and dried, and 0.306g of orange yellow solid is obtained, the yield is 52 percent, and the melting point is 150-151 ℃.
(2) Preparation of 4- ((indole-2, 3-dione-1-yl) methyl) -N-hydroxybenzamide
0.21g of methyl 4- ((indole-2, 3-dione-1-yl) benzoate was added to 10ml of CH3OH and 8mlCH2Cl2Dissolving the solid completely, adding 1.05g of hydroxylamine hydrochloride, dissolving 0.84g of KOH by using methanol to prepare a solution with the mass fraction of 20%, slowly dropwise adding the solution into a reaction system, reacting at room temperature for 7 hours under the protection of nitrogen, and reacting after the reaction is finished20ml of water is added into the reaction system dropwise, the solid is gradually dissolved, the solution is layered, the pH value of the solution is adjusted to 5 by 10% HCl, turbidity appears, and the solution becomes oily liquid and sinks at the bottom. The lower layer liquid is anhydrous MgSO4Drying overnight, spin-drying the organic phase to give a yellow solid, dissolving the solid in 6ml of ethyl acetate, adding 12ml of petroleum ether, precipitating the solid again, filtering to collect the solid, and drying the solid at 40 ℃ in vacuo for 48h to give 0.125g of a yellow powdery solid, 59.5% yield, 169 ℃ melting point and 171 ℃.
Example 5
Preparation of N-hydroxy-3- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzamide
(1) Preparation of 5-methylisatoic red
3.3g chloral hydrate was dissolved in 50ml deionized water, and 33g Na was added in order2SO41.8g of 4-methylaniline and 13ml of concentrated H2SO4And 3.6g of hydroxylamine hydrochloride, the mixture was heated to 130 ℃ and reacted under reflux for 30 minutes. The mixture was then cooled to 80 ℃ and the product collected by filtration while hot, washed with an appropriate amount of deionized water and dried under reduced pressure to give 2.6g of product in 73.0% yield.
30ml of concentrated H are added to a 100ml round-bottom flask2SO4And heated to 50 ℃ and the solid product was added in 3 portions with stirring. The mixture was heated to 70 ℃ for 1 hour, poured into ice water and the solid collected by filtration to give 2.6g of an orange-yellow solid in 80% yield and melting point 177-178 ℃.
(2) Preparation of methyl 3- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzoate
In a dry 50ml flask, 0.322g (2mmol) of 5-methylisatoic acid is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ in ice water bath, 0.08g of NaH is added, 0.75g of methyl m-bromomethylbenzoate is added after 5min, the reaction is stopped after about 48h, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated in a refrigerator overnight, a red brown solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, then 10ml of petroleum ether is added, the solid is re-precipitated, the filtration and the drying are carried out, 0.320g of red brown solid is obtained, the yield is 51.0 percent, and the melting point is 170 and 173 ℃.
(3) Preparation of N-hydroxy-3- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzamide
0.216g of methyl 3- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzoate is taken and 10ml of CH are added3OH and 8ml CH2Cl2Dissolving the solid completely, adding 1.05g of hydroxylamine hydrochloride, changing the solution from red brown to cyan yellow, dissolving 0.84g of KOH by using methanol to prepare a solution with the mass fraction of 20%, slowly dropwise adding the solution into a reaction system, reacting at room temperature for 7 hours under the protection of nitrogen, dropwise adding 15ml of water into the reaction system after the reaction is finished, gradually dissolving the solid completely, layering the solution, adjusting the pH to 5 by using 10% HCl, separating a lower layer liquid, and using anhydrous MgSO (MgSO) for the lower layer liquid4Drying overnight, spin-drying the organic phase, dissolving in 5ml of ethyl acetate, adding 10ml of petroleum ether, re-precipitating the solid, collecting by filtration, and drying the solid at 40 ℃ for 48h under vacuum to obtain 0.176g of yellow powdery solid, with a yield of 81.5% and a melting point of 192 ℃ and 195 ℃.
Example 6
Preparation of N-hydroxy-4- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzamide
(1) Preparation of methyl 4- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzoate
In a dry 50ml flask, 0.322g of 5-methylisatoic acid is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ by ice water bath, 0.08g of NaH is added, 0.75g of methyl p-bromomethylbenzoate is added after 5min, the reaction is stopped after about 48h, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated overnight in a refrigerator, a reddish-brown solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, then 10ml of petroleum ether is added, the solid is re-precipitated, filtered and dried, 0.257g of the reddish-brown solid is obtained, the yield is 41.6%, and the melting point is 196-.
(2) Preparation of N-hydroxy-4- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzamide
0.250g of methyl 4- ((5-methylindole-2, 3-diketo-1-yl) methyl) benzoate is taken in with 12ml of CH3OH and 10ml CH2Cl2Dissolving, adding 1.20g hydrochloric acidAmine, wherein the solution is changed from reddish brown to cyan yellow, 1.20g of KOH is dissolved by methanol to prepare a solution with the mass fraction of 20%, the solution is slowly dripped into a reaction system, the reaction system reacts for 9 hours at room temperature under the protection of nitrogen, 20ml of water is dripped into the reaction system after the reaction is finished, the solid is gradually dissolved, the solution is layered, the lower layer liquid is separated, the pH value of the upper layer liquid is adjusted to 5, and the solution is layered. Anhydrous MgSO for lower liquid4The organic phase was dried overnight, the solid was dissolved in 5ml of ethyl acetate, 10ml of petroleum ether was added and the solid was re-precipitated, collected by filtration and dried under vacuum at 40 ℃ for 36h to give 0.187g of a yellow solid, 74.8% yield, mp 276-.
Example 7
Preparation of N-hydroxy-3- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzamide
(1) Preparation of 5-bromoisatin
3.3g chloral hydrate was dissolved in 50ml of 40g Na in deionized water2SO44.4g of 4-bromoaniline, 15ml of concentrated H2SO4And 4.0g of hydroxylamine hydrochloride, the mixture was heated to 130 ℃ and refluxed for 1 hour. The mixture was then cooled naturally to 80 ℃ and filtered while hot, the product was collected, washed with an appropriate amount of deionized water and dried under reduced pressure to give 4.1g of product in 85.1% yield which was then used directly in the next step without further purification.
A100 ml three-necked flask was charged with 40ml of concentrated H2SO4The reaction system was heated to 50 ℃ and 4.1g of the above solid product was added to the reaction system in 3 portions with stirring. The mixture was heated to 70 ℃ for 1.5 hours, poured into ice water, filtered to collect the solid, and dried to give 3.0g of an orange-brown solid, 78% yield, m.p. 249-251 ℃.
(2) Preparation of methyl 3- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzoate
In a dry 50ml flask, 0.452g (2mmol) of 5-bromoisatin is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ in an ice water bath, 0.08g of NaH is added, 0.75g of methyl m-bromomethylbenzoate is added after 5min, the reaction is stopped after about 36h at room temperature, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated overnight in a refrigerator, red brown solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, then 10ml of petroleum ether is added, the solid is re-precipitated, filtered and dried to obtain 0.465g of red brown solid, the yield is 62.3%, and the melting point is 162 and 163 ℃.
(3) Preparation of N-hydroxy-3- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzamide
0.373g of methyl 3- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzoate was added with 15ml of CH3OH and 12ml CH2Cl2Until the solid is completely dissolved, then 1.71g of hydroxylamine hydrochloride is added, 0.96g of KOH is dissolved by methanol to prepare a solution with the mass fraction of 20%, the solution is slowly dripped into a reaction system, the reaction system reacts for 9 hours at room temperature under the protection of nitrogen, 20ml of water is dripped into the reaction system after the reaction is finished, the solid is gradually dissolved, the solution is layered, the pH of the upper layer of liquid is adjusted to 5 by 10% of HCl, the lower layer of liquid is separated, and the lower layer of liquid is anhydrous MgSO4The organic phase is dried overnight, the organic phase is dried by spinning, the obtained solid is completely dissolved by 5ml of ethyl acetate, then 10ml of petroleum ether is added, the solid is separated again and filtered, and the yellow solid is dried for 48 hours in vacuum at 40 ℃ to obtain 0.348g of yellow solid, the yield is 93.3 percent, and the melting point is 227 ℃ to 228 ℃.
Example 8
Preparation of N-hydroxy-4- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzamide
(1) Preparation of methyl 4- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzoate
In a dry 50ml flask, 0.452g (2mmol) of 5-bromoisatin is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ in an ice water bath, 0.08g of NaH is added, 0.75g of methyl p-bromomethylbenzoate is added after 5min, the reaction is stopped after about 36h at room temperature, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated overnight in a refrigerator, red brown solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, then 10ml of petroleum ether is added, the solid is re-precipitated, filtered and dried to obtain 0.357g of red brown solid, the yield is 47.9%, and the melting point is 186-187 ℃.
(2) Preparation of N-hydroxy-4- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzamide
Take 0.357g4- ((5-bromoindole-2, 3-dione-1-yl) methyl) benzoic acid methyl ester, with 15ml of CH3OH and 12ml CH2Cl2Dissolving the solid completely, adding 1.62g of hydroxylamine hydrochloride, dissolving 1.14g of KOH by using methanol to prepare a solution with the mass fraction of 20%, slowly dropwise adding the solution into a reaction system, reacting at room temperature for 8 hours under the protection of nitrogen, dropwise adding 25ml of water into the reaction system after the reaction is finished, gradually dissolving the solid, layering the solution, adjusting the pH value of the solution to 5 by using 10% HCl, separating a lower layer liquid, and using anhydrous MgSO (MgSO) as the lower layer liquid4The organic phase was dried overnight, the solid was dissolved in 4ml of ethyl acetate, 8ml of petroleum ether was added and the solid was re-precipitated, the solid was collected by filtration and dried under vacuum at 40 ℃ for 30h to give 0.208g of a yellow solid, 58.2% yield, m.p. 263 and 264 ℃.
Example 9
Preparation of N-hydroxy-3- ((5-chloroindole-2, 3-dione-1-yl) methyl) benzamide
(1) Synthesis of 5-chloroisatin
3.3g chloral hydrate was dissolved in 65ml deionized water, 60g Na was added2SO42.5g of 4-chloroaniline, 17ml of concentrated H2SO4And 3.6g of hydroxylamine hydrochloride, the mixture was heated to 130 ℃ and refluxed for 45 minutes. The mixture was then cooled naturally to 80 ℃ and filtered hot, the solid product was collected, washed with an appropriate amount of deionized water and dried under reduced pressure to give 0.29g of product in 75.1% yield.
A100 ml three-necked flask was charged with 20ml of concentrated H2SO4And heated to 50 ℃ and the solid product was added in 3 portions with stirring. The mixture was heated to 70 ℃ for 1 hour, poured directly into ice water after the reaction was complete, and the solid was collected by filtration to give 2.2g of an orange-yellow solid, a yield of 82.3%, a melting point of 254-.
(2) Preparation of methyl 3- ((5-chloroindole-2, 3-dione-1-yl) methyl) benzoate
In a dry 50ml flask, 0.364g (2mmol) of 5-chloroisatin is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ in ice water bath, 0.08g of NaH is added, 0.75g of methyl m-bromomethylbenzoate is added after 5min, the reaction is stopped after about 48h at room temperature, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated overnight in a refrigerator, red brown solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, then 10ml of petroleum ether is added, the solid is re-precipitated, filtered and dried to obtain 0.319g of orange red solid, the yield is 48.4%, and the melting point is 181 plus 182 ℃.
(3) N-hydroxy-3- ((5-chloroindole-2, 3-dione-1-yl) methyl) benzamide
Taking 0.330g of solid methyl 3- ((5-chloroindole-2, 3-diketone-1-yl) methyl) benzoate and adding 15ml of CH3OH and 12ml CH2Cl2Completely dissolving the solid, adding 1.71g of hydroxylamine hydrochloride, dissolving 1.20g of KOH by using methanol to prepare a solution with the mass fraction of 20%, slowly dropwise adding the solution into a reaction system, reacting at room temperature for 8 hours under the protection of nitrogen, dropwise adding 25ml of water into the reaction system after the reaction is finished, gradually dissolving the solid, layering the solution, adjusting the pH of the solution to 5 by using 10% HCl, separating a lower layer liquid, and using anhydrous MgSO (MgSO) for the lower layer liquid4Drying overnight, spin-drying the organic phase, dissolving the solid with 5ml ethyl acetate, adding 10ml petroleum ether, re-precipitating the solid, filtering and collecting the solid, vacuum-drying at 40 ℃ for 48h to obtain 0.216g of yellow solid, the yield is 65.6%, and the melting point is 233-.
Example 10
Preparation of N-hydroxy-4- ((5-chloroindole-2, 3-dione-1-yl) methyl) benzamide
(1) Preparation of methyl 4- ((5-chloroindole-2, 3-dione-1-yl) methyl) benzoate
In a dry 50ml flask, 0.364g (2mmol) of 5-chloroisatin is dissolved in 10ml of dry DMF solution, the solution is cooled to about 0 ℃ in ice water bath, 0.08g of NaH is added, 0.75g of methyl p-bromomethylbenzoate is added after 5min, the reaction is stopped at about 36h at room temperature, 50ml of deionized water is added into the reaction system, the reaction system is refrigerated overnight in a refrigerator, red brown solid is obtained by filtration, 5ml of ethyl acetate is added to dissolve the solid, then 10ml of petroleum ether is added, the solid is re-precipitated, filtered and dried to obtain 0.384g of orange red solid, the yield is 58.4 percent, and the melting point is 206-207 ℃.
(2) Preparation of N-hydroxy-4- ((5-chloroindole-2, 3-dione-1-yl) methyl) benzamide
0.330g of methyl 4- ((5-chloroindole-2, 3-dione-1-yl) methyl) benzoate solid is taken up in 15ml of CH3OH and 12mlCH2Cl2Dissolving solid, adding 1.71g of hydroxylamine hydrochloride, dissolving 1.00g of KOH by using methanol to prepare a solution with the mass fraction of 20%, slowly dropwise adding the solution into a reaction system, reacting at room temperature for 8 hours under the protection of nitrogen, dropwise adding 20ml of water into the reaction system after the reaction is finished, gradually dissolving the solid, allowing the solution to be layered, adjusting the pH to 5 by using 10% HCl, separating lower-layer liquid, and using anhydrous MgSO (MgSO) for the lower-layer solution4Drying overnight, spin-drying the organic phase, dissolving the solid with 6ml of ethyl acetate, then adding 12ml of petroleum ether, re-precipitating the solid, collecting the solid by filtration, and vacuum-drying at 40 ℃ for 40h to obtain 0.212g of yellow solid, the yield of 64.2%, and the melting point of 285 ℃ and 286 ℃.
Results of Compound Activity test
The principle of the assay for acetylcholinesterase inhibitory activity is as follows: AChE can rapidly decompose substrate thioacetyl choline into thiocholine and acetic acid, and the thiocholine is quantitatively combined with a color developing agent 5,5' -dithiobis (2-nitrobenzoic acid) (DTNB) to generate a yellow substance which has strong absorption at 405 nm. Because the index of the concentration of the yellow substance has a linear relation with the corresponding absorbance value, the corresponding activity of AChE is obtained according to the generation amount of the thiocholine in a certain period of time.
The principle of testing the inhibitory activity of histone deacetylase 6 is as follows: the kit adopts a double-antibody one-step sandwich enzyme-linked immunosorbent assay (ELISA). To the coated microwells previously coated with a human histone deacetylase 6(HDAC6) capture antibody, a specimen, a standard, and a detection antibody labeled with horseradish peroxidase were sequentially added, incubated at 37 ℃ and washed thoroughly. Color development is carried out with the substrate tetramethylbenzidine, which is converted to blue color under the catalysis of peroxidase and to the final yellow color under the action of acid. The shade of color was positively correlated with human histone deacetylase 6(HDAC6) in the sample. The absorbance (OD value) was measured at a wavelength of 450nm with a microplate reader, and the sample concentration was calculated.
The results of the acetylcholinesterase and histone deacetylase 6 inhibitory activities of the compounds of the present invention are shown in the following table.
Claims (5)
1. A1-benzyl isatin derivative is characterized by having a structure of a general formula (I);
R1the substituents can be respectively independent H, F, Cl, Br and NO2、CH3、CH2CH3、CH(CH3)2、C3H7、C6H5、CH2OH、CH2NH2、CHO、CN、CF3、OCF3、C6H4CN；
R2And R3Is selected from H or CONHOH, and R2、R3Not the same group at the same time.
2. A1-benzyl isatin derivative according to claim 1, characterized by the fact that it is a compound I of the structure1～I10Any one of the compounds of (1):
3. use of a compound according to claim 1 or 2 for the preparation of an acetylcholinesterase inhibitor and a histone deacetylase 6 inhibitor.
4. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for alzheimer's disease.
5. A process for producing a 1-benzyl isatin derivative according to claim 1 or 2, which comprises: 4-substituted aniline is used as a raw material, 5-substituted isatin is obtained by reacting with chloral hydrate, then the 5-substituted isatin is reacted with halogenated hydrocarbon, and then ester group is reacted with hydroxylamine hydrochloride to generate hydroximic acid, so that a corresponding compound is obtained, wherein the synthesis reaction steps are as follows:
R4and R5Selected from H or COOCH3And R is4、R5Not being H or COOCH at the same time3。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010714705.5A CN111747883B (en) | 2020-07-23 | 2020-07-23 | 1-benzyl isatin derivative and synthesis method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010714705.5A CN111747883B (en) | 2020-07-23 | 2020-07-23 | 1-benzyl isatin derivative and synthesis method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111747883A CN111747883A (en) | 2020-10-09 |
| CN111747883B true CN111747883B (en) | 2022-07-01 |
Family
ID=72710568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010714705.5A Active CN111747883B (en) | 2020-07-23 | 2020-07-23 | 1-benzyl isatin derivative and synthesis method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111747883B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690226A (en) * | 2012-05-11 | 2012-09-26 | 广东工业大学 | Multi-nitrogen substituted isatin derivative and synthetic method of multi-nitrogen substituted isatin derivative |
| WO2015084731A1 (en) * | 2013-12-02 | 2015-06-11 | The Board Of Trustees Of The Leland Stanford Junior University | Aldehyde dehydrogenase inhibitors and methods of use thereof |
| PT108570A (en) * | 2015-06-23 | 2016-12-23 | Univ De Évora | 3-HYDROXYLOXINDOLE AND 3-ALCOXIOXINDOLE DERIVATIVES AS ACETILCOLINESTERASE AND BETTIRILCOLINESTERASE INHIBITORS |
| CN106946759A (en) * | 2017-03-22 | 2017-07-14 | 中南大学 | 2 indolone derivatives and its p-Coumaric acid and synthetic method and purposes |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101624344B1 (en) * | 2014-11-13 | 2016-05-25 | 충북대학교 산학협력단 | Novel 3-Substituted-2-Oxoindoline-Based N-hydroxypropenamides Having Activity of Inhibiting Histone Deacetylase and Antitumor Composition Comprising the Same |
-
2020
- 2020-07-23 CN CN202010714705.5A patent/CN111747883B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690226A (en) * | 2012-05-11 | 2012-09-26 | 广东工业大学 | Multi-nitrogen substituted isatin derivative and synthetic method of multi-nitrogen substituted isatin derivative |
| WO2015084731A1 (en) * | 2013-12-02 | 2015-06-11 | The Board Of Trustees Of The Leland Stanford Junior University | Aldehyde dehydrogenase inhibitors and methods of use thereof |
| PT108570A (en) * | 2015-06-23 | 2016-12-23 | Univ De Évora | 3-HYDROXYLOXINDOLE AND 3-ALCOXIOXINDOLE DERIVATIVES AS ACETILCOLINESTERASE AND BETTIRILCOLINESTERASE INHIBITORS |
| CN106946759A (en) * | 2017-03-22 | 2017-07-14 | 中南大学 | 2 indolone derivatives and its p-Coumaric acid and synthetic method and purposes |
Non-Patent Citations (2)
| Title |
|---|
| Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases;M. S. Vishnu等;《ChemMedChem》;20190708;第14卷(第14期);第1359-1376页 * |
| Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity;Tran-Thi-Lan Huong等;《Bioorganic Chemistry》;20170208;第71卷;第162页方案2，第163页表1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111747883A (en) | 2020-10-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2119703B1 (en) | Novel indole derivative having inhibitory activity on i b kinase | |
| TWI419882B (en) | Benzimidazole modulators of vr1 | |
| US8975256B2 (en) | 1,2,3,4-tetrahydroquinoxaline compounds having glucocorticoid receptor binding activity | |
| US8569493B2 (en) | Method for treating a homeostasis-related disease or glaucoma by administering a 1,2,3,4-tetrahyroquinoxaline compound | |
| WO2019128918A1 (en) | Aromatic vinyl or aromatic ethyl derivative, preparation method therefor, intermediate, pharmaceutical composition, and application | |
| JP2002509536A (en) | 2- (4-bromo or 4-iodophenylamino) benzoic acid derivatives and their use as MEK inhibitors | |
| EP1740171A1 (en) | Indol-1-yl-acetic acid derivatives | |
| WO2018184585A1 (en) | Compound for inhibiting ido, manufacturing method and use thereof | |
| IE920643A1 (en) | "Hydrazone derivatives, their preparation and use" | |
| RU2583900C2 (en) | 2-arylbenzofurane-7-formamide compounds, method for obtaining and application thereof | |
| US3890347A (en) | Isoindoline derivatives | |
| PL119501B1 (en) | Process for manufacturing novel,condensed pyrimidine derivatives pirimidina | |
| Abouzid et al. | Design, synthesis, and evaluation of anti-inflammatory and ulcerogenicity of novel pyridazinone derivatives | |
| JP2023157909A (en) | Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide | |
| CN108570012B (en) | 1, 3-benzoxazine-2, 4(3H) -diketone derivative and synthetic method and application thereof | |
| TW200804327A (en) | Preventives/remedies for urinary disturbance | |
| CN111747883B (en) | 1-benzyl isatin derivative and synthesis method and application thereof | |
| CN109280032B (en) | Pyridazinone mother nucleus structure histone deacetylase inhibitor and preparation method and application thereof | |
| CN108623537A (en) | The aromatic amine acetylcholinesterase inhibitor of amine-containing base side chain synthesizes and purposes | |
| CN108658887B (en) | Benzo [ d ] [1,3] oxazine-2, 4(1H) -diketone derivative and synthetic method and application thereof | |
| JPH03141244A (en) | Aralkylamine derivative | |
| TW202035406A (en) | Heterocyclic compound as CDK-HDAC dual pathway inhibitor | |
| CN101253146A (en) | Novel derivatives of amino acids for treatment of obesity and related disorders | |
| Lan et al. | Synthesis and evaluation of 6-methylcoumarin derivatives as potent and selective monoamine oxidase B inhibitors | |
| JP2725378B2 (en) | Carbamate derivatives |
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 |