CN107400096A - A kind of synthetic method of triazole compounds - Google Patents
A kind of synthetic method of triazole compounds Download PDFInfo
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- CN107400096A CN107400096A CN201610341563.6A CN201610341563A CN107400096A CN 107400096 A CN107400096 A CN 107400096A CN 201610341563 A CN201610341563 A CN 201610341563A CN 107400096 A CN107400096 A CN 107400096A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The invention discloses a kind of triazole compounds N ((5 (4 iodophenyl) 2H 1; 2; the base of 4 triazole 3) methyl) N propyl group the third 1 amine synthetic method; using 3 (4 iodophenyl) ethyl acrylates as initiation material; by reducing, being acylated, imidization, cyclization, de- Boc, alkylated reaction obtain target product 7, product of the present invention synthesizes diversified compound library as template small molecule.
Description
Technical field
The present invention relates to a kind of novel method for synthesizing of medicine intermediate, more particularly to a kind of triazole compounds N- ((5- (4- iodine
Phenyl) -2H-1,2,4- triazole -3- bases) methyl) and-N- propyl group propyl- 1- amine synthetic method.
Technical background
Compound N-((5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine, structural formula are：
This compound N-((5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine and correlation spread out
Biology has extensive use in pharmaceutical chemistry and organic synthesis.N- ((5- (4- iodophenyls) -2H-1,2,4- triazoles -3- at present
Base) methyl)-N- propyl group propyl- 1- amine synthesis it is more difficult.Therefore it is easy to get, it is necessary to develop a raw material, it is easy to operate, instead
Should be easily controllable, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses a kind of triazole compounds N- ((5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- third
The synthetic method of base propyl- 1- amine, using 3- (3- iodophenyls) ethyl acrylate as initiation material, by reducing, being acylated, imines
Change, cyclization, de- Boc, alkylated reaction obtain target product 7, and synthesis step is as follows：
(1), as initiation material, 2 are obtained by reduction reaction using 3- (4- iodophenyls) ethyl acrylate,
(2) acylation reaction is carried out 2, obtains 3,
(3) 3 progress imidizations are obtained 4,
(4) 4 progress ring closure reactions are obtained 5,
(5) de- Boc is carried out 5 to react to obtain 6,
(6) it is alkylated reaction 6 and obtains 7；
In a preferred embodiment, the reducing agent used in described reduction reaction synthesis compound 2 is selected from sodium borohydride；Institute
The reagent used in acylation reaction synthesis compound 3 stated is selected from ammoniacal liquor；Examination used in described imidization synthesis compound 4
Agent is selected from triethyl group oxygen father-in-law's tetrafluoro boric acid；Reagent used in described ring closure reaction synthesis compound 5 is selected from 2- (the tertiary fourth oxygen of N-
Base carbonyl) ethyl acetate；Reagent used in described de- Boc reaction synthesis compounds 6 is selected from hydrogen chloride；Described alkyl
Change the alkali used in reaction synthesis compound 7 and be selected from potassium hydroxide.
In a preferred embodiment, the solvent used in described reduction reaction synthesis compound 2 is selected from methanol；Described acyl
Change the solvent used in reaction synthesis compound 3 and be selected from water；Solvent used in described imidization synthesis compound 4 is selected from four
Hydrogen furans；Solvent used in described ring closure reaction synthesis compound 5 is selected from isopropanol；Described de- Boc reaction synthesisization
Solvent used in compound 6 is selected from dichloromethane；Solvent used in described alkylated reaction synthesis compound 7 is selected from toluene.
In a preferred embodiment, the reaction temperature used in described reduction reaction synthesis compound 2 is room temperature；Described
Temperature used in acylation reaction synthesis compound 3 is 80 DEG C；Temperature used in described imidization synthesis compound 4 is
The reflux temperature of solvent；Temperature used in described ring closure reaction synthesis compound 5 is the reflux temperature of solvent；Described is de-
Temperature used in Boc reaction synthesis compounds 6 is room temperature；Temperature used in described alkylated reaction synthesis compound 7 is molten
The reflux temperature of agent.
The present invention relates to a kind of triazole compounds N- ((5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group
The synthetic method of propyl- 1- amine, reported currently without other Patents documents.
The present invention is further described by the following embodiment, and these descriptions are not to make further limit to present invention
It is fixed.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or be correspondingly improved, still belong to
Within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 3- (4- iodophenyls) ethyl propionate
21g 3- (4- iodophenyls) ethyl acrylate is added in 220ml methanol, 17g sodium borohydrides is added, is stirred at room temperature
3 hours, cool down, concentration, add water and ethyl acetate, extract liquid separation, collect organic phase, dry, concentration, obtain 16g 3-
(3- iodophenyls) ethyl propionate.
(2) synthesis of 3- (4- iodophenyls) propionamide
15g 3- (3- iodophenyls) ethyl propionate is added in 500ml ammoniacal liquor, 160ml water is added, is heated to 80 DEG C,
Stirring 10 hours, ethyl acetate extraction liquid separation is added, organic phase is collected, dries, be concentrated to give 12g 3- (3- iodophenyls)
Propionamide.
(3) synthesis of 3- (4- iodophenyls) third imino-ester
12g 3- (4- iodophenyls) propionamide is added in 180ml tetrahydrofurans, is slowly added to 9g triethyl group oxygen father-in-law's tetrafluoros
Boric acid, stirring 6 hours is heated to reflux, cooled down, filtering, collect filtrate, concentrated, silica gel post separation obtains 9g 3- on residue
(4- iodophenyls) third imino-ester.
(4) synthesis of tertbutyloxycarbonyl (5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl amine
9g 3- (3- iodophenyls) third imino-ester is added in 250ml isopropanols, is slowly added to 8g 2- (N- tert-butoxies
Carbonyl) ethyl acetate and 15ml hydrazine hydrates, it is heated to reflux 24 hours, concentrates, add water and ethyl acetate, extracts liquid separation,
Organic phase is collected, is dried, concentration, isolated 11g tertbutyloxycarbonyls of silicagel column on residue (5- (4- iodophenyls) -2H-1,2,4-
Triazole -3- bases) methyl amine.
(5) synthesis of (5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methylamine
11g tertbutyloxycarbonyls (5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl amine is added to 130ml dichloromethanes
Alkane, addition hydrogen chloride is passed through, stirred 12 hours, add saturated sodium bicarbonate aqueous solution, extract liquid separation, collect organic phase,
Dry, be concentrated to give 5g (5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methylamine.
(6) synthesis of N- ((5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine
5g (5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methylamine is added in 100ml toluene, adds 4.5g hydrogen
Potassium oxide and 14g 1- iodopropanes, stirring 7 hours is heated to reflux, adds water and ethyl acetate, extract liquid separation, collect organic phase,
Dry, concentration, residue obtains 3.6g N- ((5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl) with ethyl alcohol recrystallization
- N- propyl group propyl- 1- amine.
Claims (4)
- A kind of 1. conjunction of triazole compounds N- ((5- (4- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine Into method, using 3- (4- iodophenyls) ethyl acrylate as initiation material, by reducing, being acylated, imidization, cyclization, De- Boc, alkylated reaction obtain target product 7, and synthetic route is as follows：
- 2. method according to claim 1, it is characterised in that the reducing agent used in described reduction reaction synthesis compound 2 is selected from Sodium borohydride, Lithium Aluminium Hydride, potassium borohydride, iron powder, zinc powder, lithium borohydride, sodium cyanoborohydride, triacetoxyl group The mixture of one or both of sodium borohydride；Reagent used in described acylation reaction synthesis compound 3 is selected from ammoniacal liquor； Reagent used in described imidization synthesis compound 4 is selected from triethyl group oxygen father-in-law's tetrafluoro boric acid；Described ring closure reaction Reagent used in synthesis compound 5 is selected from 2- (N- tert-butoxycarbonyls) ethyl acetate；Described de- Boc reaction synthesis The one kind of reagent in hydrogen chloride, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid used in compound 6 Or several mixture；Alkali used in described alkylated reaction synthesis compound 7 be selected from lithium hydroxide, sodium hydroxide, One or more of mixtures in potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, pyridine.
- 3. method according to claim 1, it is characterised in that the solvent used in described reduction reaction synthesis compound 2 is selected from first Alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, two Toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid, orthoformic acid three One or more of mixtures in methyl esters；Solvent used in described acylation reaction synthesis compound 3 is selected from methanol, second Alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, One or more of mixtures in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, water；Described Asia Aminating reaction synthesis compound 4 used in solvent be selected from methanol, ethanol, normal propyl alcohol, isopropanol, acetonitrile, tetrahydrofuran, Dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- dimethyl One or more of mixtures in formamide, DMAC N,N' dimethyl acetamide, acetic acid, water；Described ring closure reaction synthesis Solvent used in compound 5 be selected from methanol, ethanol, normal propyl alcohol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, Dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- One or more of mixtures in dimethyl acetamide, acetic acid, water；Described de- Boc reaction synthesis compounds 6 institute Solvent is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, three chloromethanes Alkane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, One or more of mixtures in acetonitrile, POCl3；Solvent used in described alkylated reaction synthesis compound 7 Selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, One in ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile Kind or several mixtures.
- 4. method according to claim 1, it is characterised in that the reaction temperature used in described reduction reaction synthesis compound 2 is The reflux temperature of 0 DEG C~solvent；Temperature used in described acylation reaction synthesis compound 3 is the backflow temperature of 0 DEG C~solvent Degree；Temperature used in described imidization synthesis compound 4 is the reflux temperature of 0 DEG C~solvent；Described cyclization is anti- The reflux temperature that the temperature used in compound 5 is 0 DEG C~solvent should be synthesized；Described de- Boc reaction synthesis compounds 6 Temperature used is the reflux temperature of 0 DEG C~solvent；Temperature used in described alkylated reaction synthesis compound 7 is 0 DEG C The reflux temperature of~solvent.
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| CN104844528A (en) * | 2015-05-04 | 2015-08-19 | 湖南华腾制药有限公司 | Preparation method of triazole derivative |
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