CN102690226A - Multi-nitrogen substituted isatin derivative and synthetic method of multi-nitrogen substituted isatin derivative - Google Patents
Multi-nitrogen substituted isatin derivative and synthetic method of multi-nitrogen substituted isatin derivative Download PDFInfo
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- CN102690226A CN102690226A CN2012101455645A CN201210145564A CN102690226A CN 102690226 A CN102690226 A CN 102690226A CN 2012101455645 A CN2012101455645 A CN 2012101455645A CN 201210145564 A CN201210145564 A CN 201210145564A CN 102690226 A CN102690226 A CN 102690226A
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Abstract
The invention discloses multi-nitrogen substituted isatin derivative and a synthetic method of the multi-nitrogen substituted isatin derivative. The multi-nitrogen substituted isatin derivative has a structure general formula of the formula (I); the synthetic method of the multi-nitrogen substituted isatin derivative comprises the steps of taking isatin derivative, dissolving into halogenated substance, refluxing reaction substrate in acetonitrile or N,N'-dimethyl formamide solvent for 2-8 hours under existence of inorganic bases such as potassium carbonate or sodium hydride, spin-drying, filtering, carrying out column chromatography and recrystallizing to obtain target compound. The synthetic method has the advantages of convenience, fast reaction speed, mild condition, simple treatment and high yield. Since the derivative has excellent antibacterial activity and acetylcholinesterase inhibitory activity, the multi-nitrogen substituted isatin derivative can be used as lead compound for resisting alzheimer's disease, and also can be applied to synthesis of pharmaceutical intermediates.
Description
Technical field
The invention belongs to the technical field of medicine and pharmaceutical intermediate, be specifically related to a kind of polynary nitrogen and replace Isatine derivatives and compound method thereof.
Background technology
Isatin (isatin) has another name called istain.It is a kind of important natural product, extensively is present in the endogenous activeconstituents in mammalian tissues and the body fluid.Isatin itself also has remarkable pharmacologically active as the precursor compound of cancer therapy drug Indirubin.Isatin and verivate thereof have multiple biological activity, and antiviral antitumor, fermentation such as neuroprotective have important use.
Senile dementia is one type of important neural subject disease.Although human scientific research is explored the development of advancing by leaps and bounds has been arranged, regrettably, do not understood yet so far for the reason of this hyperpraxia.Though people fundamentally do not treat Psychiatric disorders, have obtained certain progress yet, wherein tyraminase (MAO)-B suppressor factor is the medicine of one type of treatment Psychiatric disorders.Show that through research isatin and verivate thereof have the effect of protection to neural system, isatin has effective restraining effect to MAO-B.Dopamine HCL passes through MAO-B oxidative degradation in brain, and in the process of its degraded, produces a large amount of virose oxygen free radical injury neurones.And isatin suppresses that to MAO-B specificity is arranged, and helps correcting neurotransmitter balance in the brain, keep on the neuronic normal function significant.
At present, synthetic biologically active isatin analog derivative has become the synthetic hot research fields of medicine.By means of the molecular recognition technology; The recognition capability that molecule exists and the specificity of identification and intramolecularly exist between symmetry to be contacted directly; Through polynary replacement strategy; The recognition site that increases drug molecule is conciliate and is made a concerted effort, and this has a wide range of applications aspect medicine and is worth and has a vast potential for future development.Analyze from structure, two carbonyls of isatin molecule are fine hydrogen bond receptors, and in conjunction with the aromatic ring effect of isatin skeletal aromatic ring, this helps molecular recognition and acts synergistically each other, and its biological activity is amplified, but the report of no this respect temporarily at present.The present invention is based on this has synthesized and has had
C 2,
C 3,
C 4Serial polynary N-etc. the symmetry structure replaces Isatine derivatives, optimizes synthesis condition through research, confirms compound method.
Summary of the invention
The problem that the present invention will solve provides one type to be had
C 2,
C 3,
C 4Replace the isatin compound etc. the polynary nitrogen of symmetry structure, and the method for synthesizing this compounds easy, efficient, mild condition.
A kind of polynary nitrogen provided by the invention replaces Isatine derivatives, has the general structure of formula (I):
Wherein the R substituting group is alkyl or aralkyl.Alkyl is meant saturated side chain or non-branched hydrocarbyl fully.Preferred alkyl contains 2-16 carbon atom.The representative instance of alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec.-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 3-methyl hexyl, 2; 2-dimethyl-amyl group, 2,3-dimethyl-amyl group, n-heptyl, n-octyl, n-nonyl or positive decyl etc.Alkyl group also can be substituted, and it is preferably replaced by 1,2 or 3 substituting group, and said substituting group is selected from halogen, nitro, naphthenic base, alkenyl, alkoxyl group or cycloalkyloxy.
R
1Substituting group is hydrogen, halogen or alkyl.Halogen or halo are meant fluorine, chlorine, smell, iodine; Replacement can be two replacements or polysubstituted, also can be different types of halogen atom.Alkyl is meant saturated side chain or non-branched hydrocarbyl fully.Preferred alkyl contains 2-16 carbon atom.The representative instance of alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec.-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 3-methyl hexyl, 2; 2-dimethyl-amyl group, 2,3-dimethyl-amyl group, n-heptyl, n-octyl, n-nonyl or positive decyl etc.Alkyl group also can be substituted, and it is preferably replaced by 1,2 or 3 substituting group, and said substituting group is selected from halogen, nitro, naphthenic base, alkenyl, alkoxyl group or cycloalkyloxy.
The present invention also provides a kind of polynary nitrogen to replace the compound method of Isatine derivatives, gets Isatine derivatives and is dissolved in halides, under the reaction conditions of normal pressure reflux; In the presence of alkaline substance salt of wormwood or sodium hydride, reaction substrate refluxed in the N'-solvent dimethylformamide 2 ~ 8 hours at acetonitrile or N; Revolve driedly, filter column chromatography; Promptly obtain target compound behind the recrystallization, concrete grammar is following:
(1) binary nitrogen replaces the compound method of Isatine derivatives
(2) ternary nitrogen replaces the compound method of Isatine derivatives
(3) quaternary nitrogen replaces the compound method of Isatine derivatives
The mol ratio of halides and Isatine derivatives is 1:2.3 in the said method (1); The mol ratio of halides and Isatine derivatives is 1:3.5 in the method (2); The mol ratio of halides and Isatine derivatives is 1:5 in the method (3).
Said alkaline substance refers to add salt of wormwood, and indivedual lower reactions of productive rate can be used sodium hydride; The mol ratio of Isatine derivatives and alkaline substance is 1:10.
Said temperature of reaction is 65～110 ℃.
The employed solvent of said reaction is an acetonitrile, when tetrasubstituted reacts, uses sodium hydride as alkaline substance, is used N simultaneously, and the N'-N is as solvent.
Said product solid that obtains or oily matter directly obtain pure article through using chloroform and hexanaphthene mixing solutions recrystallization; Indivedual filler is 200～300 order purification on normal-phase silica gel through the column chromatography method separation and purification, and eluent is a chloroform, obtains pure article behind the recrystallization.
Said Isatine derivatives is isatin, 4-bromo-isatin, 5-bromoisatin, 6-bromo-isatin, 7-bromo-isatin, 4-bromo-5-methyl isatin, 4-fluoro indigo red, 5-fluoro indigo red, 6-fluoro indigo red, 7-fluoro indigo red, 4; 6-two fluoro indigo reds, 4; 7-two fluoro indigo reds, 4-chlorisatide, 5-chlorisatide, 6-chlorisatide, 7-chlorisatide, 4; 6-two chlorisatides, 4,7-two chlorisatides, 4-iodine isatin, 5-iodine isatin, 6-iodine isatin, 7-iodine isatin, 4-methyl isatin, 5-methyl isatin, 6-methyl isatin, 7-methyl isatin, 4-ethyl isatin, 5-ethyl isatin, 6-ethyl isatin or 7-ethyl isatin.
Said halides is glycol dibromide or 1,3-dibromopropane or 1,4-dibromobutane or pentamethylene bromide or 1,6-dibromo-hexane or 1,7-dibromo-heptane or 1; 8-two bromooctanes or 1,9-two bromononanes or 1,10-dibromo-decane or 1,4-two (brooethyl) benzene or 1,3-two (brooethyl) benzene or 2,4-two (brooethyl)-1; 3,5 Three methyl Benzenes or 2,4-two (brooethyl)-1,3,5 triethylbenzene or 1,3; 5-three (brooethyl) benzene or 1,3,5-three (brooethyl)-2,4,6-Three methyl Benzene or 1,3; 5-three (brooethyl)-2,4,6-triethylbenzene season penta tetrabromo or 1,2,4,5-four (brooethyl) benzene.
The invention has the beneficial effects as follows:
This method in acetonitrile or DMF solvent condition refluxed, was reacted 2 ~ 8 hours under alkaline condition, revolved driedly, and chloroform drip washing is filtered, and recrystallization directly obtains product, or through column chromatography, promptly obtains target compound behind the recrystallization.Other salt of alkali bag basic metal carbonic acid (comprising sodium, potassium and caesium etc.) also comprise sodium hydride and hydrolith.This simple synthetic method, speed of response is fast, and mild condition is handled simply, and productive rate is high, and purity is high, and is with low cost.Because this compounds has good bacteriostatic activity and inhibiting activity of acetylcholinesterase,, can be used as anti-senile dementia disease lead compound, also can further be applied to the synthetic of pharmaceutical intermediate.
Embodiment
Following type reaction is used for illustrating the present invention, within the technical scheme that simple replacement of in this area, invention being done or improvement etc. all belong to the present invention to be protected.
Synthetic (with the 1a2,4,6-trimethylammonium-1,3-dimethylene benzene diacetoxylphenylisatin is an example) of embodiment 1:1a～1d
Take by weighing isatin 1.290 g (8.76 mmol), 1.046 g (3.00 mmol) 2,4-dibromo methyl isophthalic acid, 3,5 triethylbenzene, K
2CO
31.008 g (7.30 mmol).1.290 g (8.76 mmol) isatin is dissolved with 40 ml acetonitriles, and stirring at normal temperature is an orange until the complete solvent soln color of isatin.To wherein adding the K that has weighed up
2CO
3, this moment, solution colour was deepened, and was dark garnet.Adding is dissolved in 2,4-dibromo methyl isophthalic acid, 60 mL acetonitrile solutions of 3,5 triethylbenzene after stirring half a hour.Slowly be warming up to 60 ℃.Reaction in about 3 hours finishes.The product of recrystallization is orange red solid, and productive rate is 89.0%.ESI-MS?
m/z?503.5?([m+NH
4]
?+，100.0%)。
1H?NMR?(300?MHz，DMSO)?δ?7.54?(d，
J?=?7.4，1.1?Hz,?2H)，7.40?(t，
J?=?7.8，1.4?Hz，2H)，7.05?(d，
J?=?13.6，6.0?Hz,?4H)，6.70?(d，
J?=?8.0?Hz，2H)，4.95?(s，4H)，?2.95?(d，
J?=?7.5?Hz，2H)，2.64?(q，
J=7.5?Hz，4H)，1.07?(t，
J?=?7.4?Hz，6H)，0.96?(t，
J?=?7.3?Hz，4H)。m.p：226℃。
Embodiment 2:2a～2d, synthetic (with the 2a2,4,6-trimethylammonium-1,3,5-trimethylene benzene three isatin are example) of 3a～3d
Take by weighing 1.80 g isatin, 1.40 g1,3,5-trisbromomethyl-2,4, the 6-Three methyl Benzene, 1.70 g salt of wormwood are dissolved in the 100 mL acetonitriles.After stirring 4h under 60 ℃, stopped reaction.Vacuum rotary steam obtains red solid, adds the methylene dichloride dissolving, filters away a large amount of salt of wormwood.Filtrate water washing three times, anhydrous CaCl
2Dry.Dried red solid is revolved in decompression.Column chromatography for separation.Developping agent is a chloroform.Recrystallization, productive rate: 87.0%.
1H?NMR?(300?MHz，DMSO)?δ?7.50?(dd，
J?=?7.3，1.2?Hz,?3H)，7.18?(td，
J?=?7.8，1.3?Hz，3H)，7.01?(dd，
J?=?17.4，10.0?Hz，3H),?6.51?(d，
J?=?7.9，Hz，3H)，5.00?(s，6H)，2.37?(s，9H)，ESI-HRMSm/z?620.2?([M+Na]
+，100%)。m.p：273℃。
Synthetic (with the 4a1,2,4,5-four phenmethyls four isatin are example) of embodiment 3:4a～4d
Take by weighing 1.80 g isatin, 1.00 g 1,2,4,5-tetrabromo methylbenzene, 2.00 g salt of wormwood are dissolved among the 80 mL DMF.Stopped reaction behind the stirring 24h under 120 ℃.Vacuum rotary steam obtains red solid, adds a large amount of methylene dichloride dissolvings, filters and removes salt of wormwood.Filtrate water washing three times, anhydrous CaCl
2After the dry night, dried red powder is revolved in decompression.Column chromatography for separation, developping agent are chloroform.Behind the recrystallization, productive rate: 60.0%.
1H?NMR?(300?MHz,?DMSO)?δ?8.05?(dd，
J?=?7.3，1.2?Hz，4H)，7.65?(td,?
J?=?7.8,?1.3?Hz,?4H),?7.47?(dd，
J?=?17.4，10.0?Hz，4H)，7.23?(d，
J?=?7.9?Hz，4H)，6.75?(s，2H)，4.63?(s，8H)，ESI-HRMSm/z?737.32?([M+Na]
+，100%)。m.p>300℃。
1a ~ 4d is synthetic to sum up like following table:
| Sequence number | Alkali | Solvent | Temperature ℃ | Time h | Productive rate % |
| 1a | K 2CO 3 | Acetonitrile | 60 | 3 | 89 |
| 1b | K 2CO 3 | Acetonitrile | 60 | 3 | 86 |
| 1c | K 2CO 3 | Acetonitrile | 60 | 3 | 80 |
| 1d | K 2CO 3 | Acetonitrile | 60 | 3 | 92 |
| 2a | K 2CO 3 | Acetonitrile | 60 | 4 | 87 |
| 2b | K 2CO 3 | Acetonitrile | 60 | 4 | 90 |
| 2c | K 2CO 3 | Acetonitrile | 60 | 4 | 91 |
| 2d | K 2CO 3 | Acetonitrile | 60 | 4 | 83 |
| 3a | K 2CO 3 | Acetonitrile | 60 | 5 | 93 |
| 3b | K 2CO 3 | Acetonitrile | 60 | 5 | 90 |
| 3c | K 2CO 3 | Acetonitrile | 60 | 5 | 90 |
| 3d | K 2CO 3 | Acetonitrile | 60 | 5 | 93 |
| 4a | NaH | DMF | 120 | 8 | 60 |
| 4b | NaH | DMF | 120 | 8 | 63 |
| 4c | NaH | DMF | 120 | 8 | 52 |
| 4d | NaH | DMF | 12- | 8 | 76 |
Claims (9)
1. a polynary nitrogen replaces Isatine derivatives, and it is characterized in that: have the general structure as shown in the formula (I), wherein the R substituting group is alkyl or aralkyl, R
1Substituting group is hydrogen, halogen or alkyl;
2. the compound method of the said polynary nitrogen replacement Isatine derivatives of claim 1 is characterized in that: get Isatine derivatives and be dissolved in halides, under the reaction conditions of normal pressure reflux; In the presence of alkaline substance salt of wormwood or sodium hydride, reaction substrate refluxed in the N'-solvent dimethylformamide 2 ~ 8 hours at acetonitrile or N; Revolve driedly, filter column chromatography; Promptly obtain target compound behind the recrystallization, concrete grammar is following:
(1) binary nitrogen replaces the compound method of Isatine derivatives
(2) ternary nitrogen replaces the compound method of Isatine derivatives
(3) quaternary nitrogen replaces the compound method of Isatine derivatives
3. compound method as claimed in claim 2 is characterized in that: the mol ratio of halides and Isatine derivatives is 1:2.3 in the said concrete grammar (1); The mol ratio of halides and Isatine derivatives is 1:3.5 in the method (2); The mol ratio of halides and Isatine derivatives is 1:5 in the method (3).
4. compound method as claimed in claim 2 is characterized in that: said alkaline substance refers to add salt of wormwood, and indivedual lower reactions of productive rate can be used sodium hydride; The mol ratio of Isatine derivatives and alkaline substance is 1:10.
5. compound method as claimed in claim 2 is characterized in that: said temperature of reaction is 65～110 ℃.
6. compound method as claimed in claim 2 is characterized in that: the employed solvent of said reaction is an acetonitrile, when tetrasubstituted reacts, uses sodium hydride as alkaline substance, is used N simultaneously, and the N'-N is as solvent.
7. compound method as claimed in claim 2 is characterized in that: said product solid that obtains or oily matter directly obtain pure article through using chloroform and hexanaphthene mixing solutions recrystallization; Indivedual filler is 200～300 order purification on normal-phase silica gel through the column chromatography method separation and purification, and eluent is a chloroform, obtains pure article behind the recrystallization.
8. compound method as claimed in claim 2; It is characterized in that: said Isatine derivatives is isatin, 4-bromo-isatin, 5-bromoisatin, 6-bromo-isatin, 7-bromo-isatin, 4-bromo-5-methyl isatin, 4-fluoro indigo red, 5-fluoro indigo red, 6-fluoro indigo red, 7-fluoro indigo red, 4; 6-two fluoro indigo reds, 4; 7-two fluoro indigo reds, 4-chlorisatide, 5-chlorisatide, 6-chlorisatide, 7-chlorisatide, 4; 6-two chlorisatides, 4,7-two chlorisatides, 4-iodine isatin, 5-iodine isatin, 6-iodine isatin, 7-iodine isatin, 4-methyl isatin, 5-methyl isatin, 6-methyl isatin, 7-methyl isatin, 4-ethyl isatin, 5-ethyl isatin, 6-ethyl isatin or 7-ethyl isatin.
9. compound method as claimed in claim 2 is characterized in that: said halides is glycol dibromide or 1,3-dibromopropane or 1,4-dibromobutane or pentamethylene bromide or 1,6-dibromo-hexane or 1; 7-dibromo-heptane or 1,8-two bromooctanes or 1,9-two bromononanes or 1,10-dibromo-decane or 1,4-two (brooethyl) benzene or 1,3-two (brooethyl) benzene or 2,4-two (brooethyl)-1; 3,5 Three methyl Benzenes or 2,4-two (brooethyl)-1,3,5 triethylbenzene or 1,3; 5-three (brooethyl) benzene or 1,3,5-three (brooethyl)-2,4,6-Three methyl Benzene or 1,3; 5-three (brooethyl)-2,4,6-triethylbenzene season penta tetrabromo or 1,2,4,5-four (brooethyl) benzene.
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Cited By (4)
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|---|---|---|---|---|
| CN110963996A (en) * | 2017-10-25 | 2020-04-07 | 西南大学 | Indanazolol compound containing acetophenone substituent, preparation method and medical application thereof |
| CN111747883A (en) * | 2020-07-23 | 2020-10-09 | 中南大学 | 1-benzyl isatin derivative and synthesis method and application thereof |
| CN113754681A (en) * | 2020-06-05 | 2021-12-07 | 天津理工大学 | Synthetic method of penta-substituted cyclopentane with double-spiro structure |
| CN114591214A (en) * | 2022-03-25 | 2022-06-07 | 北京大学深圳医院 | Isatin derivative and preparation method thereof |
-
2012
- 2012-05-11 CN CN2012101455645A patent/CN102690226A/en active Pending
Non-Patent Citations (7)
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110963996A (en) * | 2017-10-25 | 2020-04-07 | 西南大学 | Indanazolol compound containing acetophenone substituent, preparation method and medical application thereof |
| CN111018840A (en) * | 2017-10-25 | 2020-04-17 | 西南大学 | 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof |
| CN110963996B (en) * | 2017-10-25 | 2022-09-09 | 西南大学 | Indanazolol compound containing acetophenone substituent, preparation method and medical application thereof |
| CN111018840B (en) * | 2017-10-25 | 2022-09-09 | 西南大学 | 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof |
| CN113754681A (en) * | 2020-06-05 | 2021-12-07 | 天津理工大学 | Synthetic method of penta-substituted cyclopentane with double-spiro structure |
| CN113754681B (en) * | 2020-06-05 | 2023-08-04 | 天津理工大学 | Synthesis method of penta-substituted cyclopentane with double-spiro structure |
| CN111747883A (en) * | 2020-07-23 | 2020-10-09 | 中南大学 | 1-benzyl isatin derivative and synthesis method and application thereof |
| CN111747883B (en) * | 2020-07-23 | 2022-07-01 | 中南大学 | 1-benzyl isatin derivative and synthesis method and application thereof |
| CN114591214A (en) * | 2022-03-25 | 2022-06-07 | 北京大学深圳医院 | Isatin derivative and preparation method thereof |
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Application publication date: 20120926 |