CN107698482A - A kind of preparation method of polysubstituted indole derivatives - Google Patents
A kind of preparation method of polysubstituted indole derivatives Download PDFInfo
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- CN107698482A CN107698482A CN201610645904.9A CN201610645904A CN107698482A CN 107698482 A CN107698482 A CN 107698482A CN 201610645904 A CN201610645904 A CN 201610645904A CN 107698482 A CN107698482 A CN 107698482A
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- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of the polysubstituted indole derivatives tert-butyl group 2 (base of 6 bromine, 5 chlorine 1H indoles 3) ethylcarbamate; using the bromo indole of 5 chlorine 6 as initiation material; target product is obtained by Friedel-Crafts reaction, amidatioon, reduction, tertbutyloxycarbonyl protection reaction, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of polysubstituted indole derivatives uncle
The preparation method of butyl 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) ethylcarbamate.
Technical background
Compound tert-butyl group 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) ethylcarbamate, structural formula are：
This compound tert-butyl group 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) ethylcarbamates and correlation spread out
Biology has extensive use in pharmaceutical chemistry and organic synthesis.Tert-butyl group 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) second at present
The synthesis of carbamate is more difficult.Therefore it is easy to get, it is necessary to develop a raw material, easy to operate, reaction is easy to control
System, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses one kind to prepare tert-butyl group 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) tertiary fourth of ethyl carbamic acid
The method of ester, using the chloro- 6- bromo indoles of 5- as initiation material, protected by Friedel-Crafts reaction, amidatioon, reduction, tertbutyloxycarbonyl anti-
Target product 5 should be obtained, synthesis step is as follows：
(1) using the chloro- 6- bromo indoles of 5- as initiation material, 2 are obtained by Friedel-Crafts reaction；
(2) amidation process is carried out 2, obtains 3；
(3) 3 progress reduction reactions are obtained 4；
(4) 4 progress tertbutyloxycarbonyl protection reactions are obtained 5；
In a preferred embodiment, the lewis acid used in described Friedel-Crafts reaction prepare compound 2 is selected from trichlorine
Change aluminium；Reagent used in described amidation process prepare compound 3 is selected from ammoniacal liquor；Described reduction reaction prepare compound 4
Reducing agent used is selected from lithium aluminium hydride；Reagent used in described tertbutyloxycarbonyl protection reaction prepare compound 5 is selected from two
Dimethyl dicarbonate butyl ester.
In a preferred embodiment, the solvent used in described Friedel-Crafts reaction prepare compound 2 is selected from dichloromethane；
Solvent used in described amidation process prepare compound 3 is selected from water；It is molten used in described reduction reaction prepare compound 4
Agent is selected from tetrahydrofuran；Solvent used in described tertbutyloxycarbonyl protection reaction prepare compound 5 is selected from dichloromethane.
In a preferred embodiment, the reaction temperature used in described Friedel-Crafts reaction prepare compound 2 is solvent
Reflux temperature；Temperature used in described amidation process prepare compound 3 is the room temperature of solvent；It is prepared by described reduction reaction
Temperature used in compound 4 is the reflux temperature of solvent；Temperature used in described tertbutyloxycarbonyl protection reaction prepare compound 5
Degree is room temperature.
The present invention relates to a kind of system of tert-butyl group 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) ethylcarbamate
Preparation Method, reported currently without other Patents documents.
The present invention is further described by the following embodiment, and these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) -2- oxo chloroacetic chlorides
The chloro- 6- bromo indoles of 40g 5- are added in 450ml anhydrous methylene chlorides, 15g alchlors is added, adds
60g oxalyl chlorides, it is heated to reflux 2 hours, is cooled to room temperature, add water, liquid separation, drying, concentration, residue upper prop is isolated
47g 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) -2- oxo chloroacetic chlorides.
(2) synthesis of 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) -2- oxoaGetamides
45g 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) -2- oxo chloroacetic chlorides are added to 100ml water and 500ml ammoniacal liquor
Mixture in, be stirred at room temperature 4 hours, add ethyl acetate extraction, liquid separation, drying, concentration, silica gel post separation obtains on residue
32g2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) -2- oxoaGetamides.
(3) synthesis of 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) ethamine
30g 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) -2- oxoaGetamides are added to 200ml anhydrous tetrahydro furans
In, 16g Lithium Aluminium Hydrides are added, are heated to reflux stirring 8 hours, are cooled to room temperature, add sodium hydrate aqueous solution, add acetic acid second
Ester extracts, and dries, concentration, and silica gel post separation obtains 16g 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) ethamine on residue.
(4) synthesis of 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) ethylcarbamate
15g 2- (the bromo- 1H- indol-3-yls of the chloro- 6- of 5-) ethamine is added in 150ml dichloromethane, adds the carbon of 18g bis-
Sour di tert butyl carbonate, 0.5g 4- dimethylamino pyridines are added, be stirred at room temperature 10 hours, concentrated and remove dichloromethane, on residue
Silica gel post separation obtains 12g 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) ethylcarbamate.
Claims (6)
1. one kind prepares polysubstituted indole derivatives tert-butyl group 2- (the chloro- 1H- indol-3-yls of the bromo- 5- of 6-) ethyl carbamic acid uncle
The preparation method of butyl ester, using the chloro- 6- bromo indoles of 5- as initiation material, by Friedel-Crafts reaction, amidatioon, reduction, tertbutyloxycarbonyl
Protection reaction obtains target product 5, and synthetic route is as follows,
2. method according to claim 1, it is characterized in that described 4 steps reaction is,
(1) using the chloro- 6- bromo indoles of 5- as initiation material, 2 are obtained by Friedel-Crafts reaction；
(2) amidation process is carried out 2, obtains 3；
(3) 3 progress reduction reactions are obtained 4；
(4) 4 progress tertbutyloxycarbonyl protection reactions are obtained 5；
3. method according to claim 1, it is characterised in that the lewis acid used in described Friedel-Crafts reaction prepare compound 2
One or more of mixtures in alchlor, ferric trichloride, zinc chloride, stannic chloride；Described amidation process system
Reagent used in standby compound 3 is selected from the mixture of one or both of ammonia, ammoniacal liquor；Described reduction reaction prepares chemical combination
Reducing agent used in thing 4 is in sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine
One or more of mixtures；Reagent used in described tertbutyloxycarbonyl protection reaction prepare compound 5 is selected from two carbonic acid two
The tert-butyl ester.
4. method according to claim 1, it is characterised in that the solvent used in described Friedel-Crafts reaction prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
One or more of mixtures in dinethylformamide, DMAC N,N' dimethyl acetamide；Described amidation process preparationization
Solvent used in compound 3 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, right
One or more of mixtures in dimethylbenzene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, water；Institute
The solvent used in reduction reaction prepare compound 4 stated is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane
Alkane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, trichlorine oxygen
One or more of mixtures in phosphorus, thionyl chloride；It is molten used in described tertbutyloxycarbonyl protection reaction prepare compound 5
Agent is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, a diformazan
One or more of mixtures in benzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
5. method according to claim 1, it is characterised in that the reaction temperature used in described Friedel-Crafts reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described amidation process prepare compound 3 is the backflow of 0 DEG C~solvent
Temperature；Temperature used in described reduction reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described tertiary butyloxycarbonyl
Temperature used in base protection reaction prepare compound 5 is the reflux temperature of 0 DEG C~solvent.
6. method according to claim 1, it is characterised in that the reaction temperature used in described Friedel-Crafts reaction prepare compound 2
It is the reflux temperature of solvent；Temperature used in described amidation process prepare compound 3 is the room temperature of solvent；Described reduction
Temperature used in reaction prepare compound 4 is the reflux temperature of solvent；Described tertbutyloxycarbonyl protection reaction prepare compound 5
Temperature used is room temperature.
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| CN201610645904.9A CN107698482A (en) | 2016-08-08 | 2016-08-08 | A kind of preparation method of polysubstituted indole derivatives |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292145A (en) * | 2014-10-12 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of 6-bromoindole derivative |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292145A (en) * | 2014-10-12 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of 6-bromoindole derivative |
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