CN107778259A - A kind of preparation method of azole compounds - Google Patents
A kind of preparation method of azole compounds Download PDFInfo
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- CN107778259A CN107778259A CN201610796273.0A CN201610796273A CN107778259A CN 107778259 A CN107778259 A CN 107778259A CN 201610796273 A CN201610796273 A CN 201610796273A CN 107778259 A CN107778259 A CN 107778259A
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- LAHOCTIDZQBTOB-UHFFFAOYSA-N NC(CCc1cc(I)ccc1)=O Chemical compound NC(CCc1cc(I)ccc1)=O LAHOCTIDZQBTOB-UHFFFAOYSA-N 0.000 description 1
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of azole compounds N ((5 (3 iodophenyl) 2H 1; 2; the base of 4 triazole 3) methyl) N propyl group the third 1 amine preparation method; using 3 (3 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 processing step of medicine intermediate, more particularly to a kind of azole compounds N- ((5-
(3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine preparation method.
Technical background
Compound N-((5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine, structural formula
For：
This compound N-((5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine and correlation
Derivative there is extensive use in pharmaceutical chemistry and organic synthesis.N- ((5- (3- iodophenyls) -2H-1,2,4- three at present
Azoles -3- bases) 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,
React easily controllable, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses a kind of triazole compounds N- ((5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl) -
The preparation method of N- propyl group 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- (3- 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 prepare compound 2 is selected from hydroboration
Sodium；Reagent used in described acylation reaction prepare compound 3 is selected from ammoniacal liquor；The described institute of imidization prepare compound 4
Reagent is selected from triethyl group oxygen father-in-law's tetrafluoro boric acid；Reagent used in described ring closure reaction prepare compound 5 is selected from 2- (uncles N-
Butoxy carbonyl) ethyl acetate；Reagent used in described de- Boc reaction prepare compounds 6 is selected from hydrogen chloride；Described alkyl
Change the alkali used in reaction prepare compound 7 and be selected from potassium hydroxide.
In a preferred embodiment, the solvent used in described reduction reaction prepare compound 2 is selected from methanol；It is described
Acylation reaction prepare compound 3 used in solvent be selected from water；Solvent choosing used in described imidization prepare compound 4
From tetrahydrofuran；Solvent used in described ring closure reaction prepare compound 5 is selected from isopropanol；It is prepared by described de- Boc reactions
Solvent used in compound 6 is selected from dichloromethane；Solvent used in described alkylated reaction prepare compound 7 is selected from toluene.
In a preferred embodiment, the reaction temperature used in described reduction reaction prepare compound 2 is room temperature；Institute
The temperature used in acylation reaction prepare compound 3 stated is 80 DEG C；Temperature used in described imidization prepare compound 4
It is the reflux temperature of solvent；Temperature used in described ring closure reaction prepare compound 5 is the reflux temperature of solvent；Described is de-
Temperature used in Boc reaction prepare compounds 6 is room temperature；Temperature used in described alkylated reaction prepare compound 7 is molten
The reflux temperature of agent.
The present invention relates to a kind of azole compounds N- ((5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N-
The preparation method of propyl group propyl- 1- amine, 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 3- (3- iodophenyls) ethyl propionate
25g 3- (3- iodophenyls) ethyl acrylate is added in 260ml methanol, adds 19g sodium borohydrides, room temperature is stirred
Mix 3 hours, cool down, concentration, add water and ethyl acetate, extract liquid separation, collect organic phase, dry, concentration, obtain 19g 3-
(3- iodophenyls) ethyl propionate.
(2) synthesis of 3- (3- iodophenyls) propionamide
19g 3- (3- bromophenyls) ethyl propionate is added in 600ml ammoniacal liquor, 200ml 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 16g 3- (3- iodophenyls) propionyl
Amine.
(3) synthesis of 3- (3- iodophenyls) third imino-ester
15g 3- (3- iodophenyls) propionamide is added in 180ml tetrahydrofurans, is slowly added to 11g triethyl group oxygen father-in-law four
Fluoboric acid, stirring 6 hours is heated to reflux, cooled down, filtering, collect filtrate, concentrated, silica gel post separation obtains 12g3- (3- on residue
Iodophenyl) the third imino-ester.
(4) synthesis of tertbutyloxycarbonyl (5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl amine
11g 3- (3- iodophenyls) third imino-ester is added in 290ml isopropanols, is slowly added to 10g 2- (the tertiary fourths of N-
Epoxide carbonyl) ethyl acetate and 16ml 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 13g tertbutyloxycarbonyls of silicagel column on residue (5- (3- iodophenyls) -2H-1,2,
4- triazole -3- bases) methyl amine.
(5) synthesis of (5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methylamine
12g tertbutyloxycarbonyls (5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl amine is added to 150ml dichloros
Methane, addition hydrogen chloride is passed through, stirred 12 hours, add saturated sodium bicarbonate aqueous solution, extract liquid separation, collect organic phase, done
It is dry, it is concentrated to give 7g (5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methylamine.
(6) synthesis of N- ((5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine
7g (5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methylamine is added in 110ml toluene, adds 5g hydrogen
Potassium oxide and 16g 1- N-Propyl Bromides, stirring 7 hours is heated to reflux, adds water and ethyl acetate, extract liquid separation, collect organic phase,
Dry, concentration, residue obtains 7.2g N- ((5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) first with ethyl alcohol recrystallization
Base)-N- propyl group propyl- 1- amine.
Claims (4)
1. a kind of azole compounds N- ((5- (3- iodophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine
Preparation method, using 3- (3- iodophenyls) ethyl acrylate as initiation material, by reducing, being acylated, imidization, cyclization, de- Boc,
Alkylated reaction obtains target product 7, and synthetic route is as follows：
2. method according to claim 1, it is characterised in that the reducing agent choosing used in described reduction reaction prepare compound 2
From sodium borohydride, Lithium Aluminium Hydride, potassium borohydride, iron powder, zinc powder, lithium borohydride, sodium cyanoborohydride, triacetoxy boron hydride
The mixture of one or both of sodium；Reagent used in described acylation reaction prepare compound 3 is selected from ammoniacal liquor；Described Asia
Reagent used in aminating reaction prepare compound 4 is selected from triethyl group oxygen father-in-law's tetrafluoro boric acid；Described ring closure reaction prepare compound 5
Reagent used is selected from 2- (N- tert-butoxycarbonyls) ethyl acetate；Reagent used in described de- Boc reaction prepare compounds 6
One or more of mixtures in hydrogen chloride, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid；Described alkane
Alkali used in glycosylation reaction prepare compound 7 is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, three second
One or more of mixtures in amine, pyridine.
3. method according to claim 1, it is characterised in that the solvent used in described reduction reaction prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
One kind in dinethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid, trimethyl orthoformate or
Several mixtures；Solvent used in described acylation reaction prepare compound 3 be selected from methanol, ethanol, normal propyl alcohol, isopropanol,
Tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- dimethyl
One or more of mixtures in acetamide, acetonitrile, water；Solvent choosing used in described imidization prepare compound 4
From methanol, ethanol, normal propyl alcohol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, neighbour two
One kind or several in toluene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetic acid, water
The mixture of kind；Solvent used in described ring closure reaction prepare compound 5 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, second
Nitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- bis-
One or more of mixtures in NMF, DMAC N,N' dimethyl acetamide, acetic acid, water；It is prepared by described de- Boc reactions
Solvent used in compound 6 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, trichlorine
Methane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile,
One or more of mixtures in POCl3；Solvent used in described alkylated reaction prepare compound 7 be selected from methanol,
Ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, to diformazan
One or more of mixtures in benzene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile.
4. method according to claim 1, it is characterised in that the reaction temperature used in described reduction reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described acylation reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent
Degree；Temperature used in described imidization prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described ring closure reaction
Temperature used in prepare compound 5 is the reflux temperature of 0 DEG C~solvent；Temperature used in described de- Boc reaction prepare compounds 6
Degree is the reflux temperature of 0 DEG C~solvent；Temperature used in described alkylated reaction prepare compound 7 is returning for 0 DEG C~solvent
Flow temperature.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986837A (en) * | 2017-05-31 | 2017-07-28 | 湖南华腾制药有限公司 | A kind of preparation method of azole compounds |
| CN107698528A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of 3-triazole compounds |
| CN107778258A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of the triazole compounds containing iodine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844528A (en) * | 2015-05-04 | 2015-08-19 | 湖南华腾制药有限公司 | Preparation method of triazole derivative |
-
2016
- 2016-08-31 CN CN201610796273.0A patent/CN107778259A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844528A (en) * | 2015-05-04 | 2015-08-19 | 湖南华腾制药有限公司 | Preparation method of triazole derivative |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107698528A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of 3-triazole compounds |
| CN107778258A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of the triazole compounds containing iodine |
| CN106986837A (en) * | 2017-05-31 | 2017-07-28 | 湖南华腾制药有限公司 | A kind of preparation method of azole compounds |
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