CN107698528A - A kind of preparation method of 3-triazole compounds - Google Patents
A kind of preparation method of 3-triazole compounds Download PDFInfo
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- CN107698528A CN107698528A CN201610645677.XA CN201610645677A CN107698528A CN 107698528 A CN107698528 A CN 107698528A CN 201610645677 A CN201610645677 A CN 201610645677A CN 107698528 A CN107698528 A CN 107698528A
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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 3-triazole compounds N ((5 (3 fluorophenyl) 2H 1; 2; the base of 4 triazole 3) methyl) N propyl group the third 1 amine preparation method; using 3 (3 fluorophenyl) 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 3-triazole compounds N- ((5-
(3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine preparation method.
Technical background
Compound N-((5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine, structural formula
For：
This compound N-((5- (3- fluorophenyls) -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- fluorophenyls) -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 3-triazole compounds N- ((5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) first
Base)-N- propyl group propyl- 1- amine preparation method, using 3- (3- fluorophenyls) ethyl acrylate as initiation material, by reducing, being acylated,
Imidization, 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- fluorophenyls) 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 3-triazole compounds N- ((5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methyl) -
The preparation method of N- 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- fluorophenyls) ethyl propionate
25g 3- (3- fluorophenyls) 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- fluorophenyls) ethyl propionate.
(2) synthesis of 3- (3- fluorophenyls) propionamide
19g 3- (3- fluorophenyls) 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- fluorophenyls) propionyl
Amine.
(3) synthesis of 3- (3- fluorophenyls) third imino-ester
15g 3- (3- fluorophenyls) 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
Fluorophenyl) the third imino-ester.
(4) synthesis of tertbutyloxycarbonyl (5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methyl amine
11g 3- (3- fluorophenyls) 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- fluorophenyls) -2H-1,2,
4- triazole -3- bases) methyl amine.
(5) synthesis of (5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methylamine
12g tertbutyloxycarbonyls (5- (3- fluorophenyls) -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- fluorophenyls) -2H-1,2,4- triazole -3- bases) methylamine.
(6) synthesis of N- ((5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine
7g (5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methylamine is added in 110ml toluene, adds 5g hydrogen
Potassium oxide and 16g 1- fluoro-propanes, 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- fluorophenyls) -2H-1,2,4- triazole -3- bases) first with ethyl alcohol recrystallization
Base)-N- propyl group propyl- 1- amine.
Claims (5)
- A kind of 1. 3-triazole compounds N- ((5- (3- fluorophenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine Preparation method, using 3- (3- fluorophenyls) 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 characterized in that described 6 steps reaction is,(1), as initiation material, 2 are obtained by reduction reaction using 3- (3- fluorophenyls) 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；
- 3. 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.
- 4. 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.
- 5. 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 (2)
| 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 |
| 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 |
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| CN104829547A (en) * | 2015-05-04 | 2015-08-12 | 湖南华腾制药有限公司 | Substituted triazole compound preparation method |
| CN104844528A (en) * | 2015-05-04 | 2015-08-19 | 湖南华腾制药有限公司 | Preparation method of triazole derivative |
| CN106905249A (en) * | 2017-02-26 | 2017-06-30 | 长沙深橙生物科技有限公司 | A kind of preparation method of azepine class compound |
| 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 |
| 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 |
| CN107778259A (en) * | 2016-08-31 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of azole compounds |
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2016
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104829547A (en) * | 2015-05-04 | 2015-08-12 | 湖南华腾制药有限公司 | Substituted triazole compound preparation method |
| CN104844528A (en) * | 2015-05-04 | 2015-08-19 | 湖南华腾制药有限公司 | Preparation method of triazole derivative |
| 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 |
| CN107778259A (en) * | 2016-08-31 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of azole compounds |
| CN106905249A (en) * | 2017-02-26 | 2017-06-30 | 长沙深橙生物科技有限公司 | A kind of preparation method of azepine class compound |
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Cited By (2)
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| 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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Application publication date: 20180216 |