CN106905249A - A kind of preparation method of azepine class compound - Google Patents
A kind of preparation method of azepine class compound Download PDFInfo
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- CN106905249A CN106905249A CN201710105616.9A CN201710105616A CN106905249A CN 106905249 A CN106905249 A CN 106905249A CN 201710105616 A CN201710105616 A CN 201710105616A CN 106905249 A CN106905249 A CN 106905249A
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- XIYWAXSCZQLJEU-UHFFFAOYSA-N CCCN(CCC)Cc1nc(CCc2cc(O)ccc2)n[nH]1 Chemical compound CCCN(CCC)Cc1nc(CCc2cc(O)ccc2)n[nH]1 XIYWAXSCZQLJEU-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
Abstract
The invention discloses a kind of azepine class compound N ((5 (3 hydroxy phenyl) 2H 1; 2; the base of 4 triazole 3) methyl) amine of N propyl group the third 1 preparation method; it is initiation material with 3 (3 hydroxy phenyl) ethyl acrylates; target product 7 is obtained by reduction, acylation, imidization, cyclization, de- Boc, alkylated reaction, 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 azepine class compound N-((5-
(3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine preparation method.
Technical background
Compound N-((5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine, structure
Formula is：
This compound N-((5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine and phase
The derivative of pass has extensive use in pharmaceutical chemistry and organic synthesis.Current N- ((5- (3- hydroxy phenyls) -2H-1,2,4-
Triazole -3- bases) methyl)-N- propyl group propyl- 1- amine synthesis it is more difficult.Accordingly, it would be desirable to develop a raw material be easy to get, operation side
Just, easily controllable, the suitable synthetic method of overall yield is reacted.
The content of the invention
The invention discloses a kind of azepine class compound N-((5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) first
Base)-N- propyl group propyl- 1- amine preparation method, with 3- (3- hydroxy phenyls) ethyl acrylate as initiation material, by reduction, acyl
Change, 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 with 3- (3- hydroxy phenyls) ethyl acrylate,
(2) acylation reaction is carried out 2, obtains 3,
(3) carry out imidization 3 and obtain 4,
(4) carry out ring closure reaction 4 and obtain 5,
(5) de- Boc reactions are carried out 5 and obtain 6,
(6) it is alkylated reaction 6 and obtains 7；
One preferred embodiment in, reducing agent used by described reduction reaction prepare compound 2 is selected from hydroboration
Sodium；Reagent used by 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 by described ring closure reaction prepare compound 5 is selected from 2- (uncles N-
Butoxy carbonyl) ethyl acetate；Reagent used by described de- Boc reaction prepare compounds 6 is selected from hydrogen chloride；Described alkyl
Change the alkali used by reaction prepare compound 7 and be selected from potassium hydroxide.
One preferred embodiment in, solvent used by described reduction reaction prepare compound 2 is selected from methyl alcohol；It is described
Acylation reaction prepare compound 3 used by solvent be selected from water；Solvent choosing used by described imidization prepare compound 4
From tetrahydrofuran；Solvent used by described ring closure reaction prepare compound 5 is selected from isopropanol；It is prepared by described de- Boc reactions
Solvent used by compound 6 is selected from dichloromethane；Solvent used by described alkylated reaction prepare compound 7 is selected from toluene.
One preferred embodiment in, the reaction temperature used by described reduction reaction prepare compound 2 is room temperature；Institute
The temperature used by acylation reaction prepare compound 3 stated is 80 DEG C；Temperature used by described imidization prepare compound 4
It is the reflux temperature of solvent；Temperature used by described ring closure reaction prepare compound 5 is the reflux temperature of solvent；Described is de-
Temperature used by Boc reaction prepare compounds 6 is room temperature；Temperature used by described alkylated reaction prepare compound 7 is molten
The reflux temperature of agent.
The present invention relates to a kind of azepine class compound N-((5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) first
Base)-N- propyl group propyl- 1- amine preparation method, currently without other Patents documents report.
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 made to technical characteristic of the invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 3- (3- hydroxy phenyls) ethyl propionate
25g 3- (3- hydroxy phenyls) ethyl acrylate is added in 260ml methyl alcohol, 19g sodium borohydrides, room temperature is added
Stirring 3 hours, cooling, concentration adds water and ethyl acetate, extraction point liquid to collect organic phase, dry, and concentration obtains 19g 3-
(3- hydroxy phenyls) ethyl propionate.
(2) synthesis of 3- (3- hydroxy phenyls) propionamide
19g 3- (3- hydroxy phenyls) ethyl propionate is added in 600ml ammoniacal liquor, 200ml water is added, 80 are heated to
DEG C, stir 10 hours, ethyl acetate extraction point liquid is added, organic phase is collected, dry, it is concentrated to give 16g 3- (3- hydroxy phenyls)
Propionamide.
(3) synthesis of 3- (3- hydroxy phenyls) third imino-ester
15g 3- (3- hydroxy phenyls) propionamide is added in 180ml tetrahydrofurans, 11g triethyl group oxygen father-in-law are slowly added to
Tetrafluoro boric acid, is heated to reflux stirring 6 hours, and cooling, filtering is collected filtrate, concentrated, and silica gel post separation obtains 12g 3- on residue
(3- hydroxy phenyls) third imino-ester.
(4) synthesis of tertbutyloxycarbonyl (5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methyl amine
11g 3- (3- hydroxy phenyls) third imino-ester is added in 290ml isopropanols, 10g 2- (uncles N- are slowly added to
Butoxy carbonyl) ethyl acetate and 16ml hydrazine hydrates, it is heated to reflux 24 hours, concentrate, add water and ethyl acetate, extraction point
Liquid, collects organic phase, dries, concentration, isolated 13g tertbutyloxycarbonyls of silicagel column on residue (5- (3- hydroxy phenyls)-
2H-1,2,4- triazole -3- bases) methyl amine.
(5) synthesis of (5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methylamine
12g tertbutyloxycarbonyls (5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methyl amine is added to 150ml bis-
Chloromethanes, is passed through addition hydrogen chloride, stirs 12 hours, adds saturated sodium bicarbonate aqueous solution, extraction point liquid to collect organic phase,
Dry, be concentrated to give 7g (5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methylamine.
(6) synthesis of N- ((5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl- 1- amine
7g (5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methylamine is added in 110ml toluene, 5g is added
Potassium hydroxide and 16g 1- N-Propyl Bromides, are heated to reflux stirring 7 hours, add water and ethyl acetate, extraction point liquid to collect organic
Phase, dries, and concentration, residue ethyl alcohol recrystallization obtains 7.2g N- ((5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3-
Base) methyl)-N- propyl group propyl- 1- amine.
Claims (5)
1. a kind of azepine class compound N-((5- (3- hydroxy phenyls) -2H-1,2,4- triazole -3- bases) methyl)-N- propyl group propyl-s 1-
The preparation method of amine, with 3- (3- hydroxy phenyls) ethyl acrylate as initiation material, by reduction, acylation, 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 by described 6 steps reaction is,
(1), as initiation material, 2 are obtained by reduction reaction with 3- (3- hydroxy phenyls) ethyl acrylate,
(2) acylation reaction is carried out 2, obtains 3,
(3) carry out imidization 3 and obtain 4,
(4) carry out ring closure reaction 4 and obtain 5,
(5) de- Boc reactions are carried out 5 and 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 by 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
One or two mixture in sodium；Reagent used by described acylation reaction prepare compound 3 is selected from ammoniacal liquor；Described Asia
Reagent used by 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 by described de- Boc reaction prepare compounds 6
Selected from the mixture of one or more in hydrogen chloride, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid；Described alkane
Alkali used by glycosylation reaction prepare compound 7 is selected from lithium hydroxide, NaOH, potassium hydroxide, sodium carbonate, potassium carbonate, three second
The mixture of one or more in amine, pyridine.
4. method according to claim 1, it is characterised in that the solvent used by described reduction reaction prepare compound 2 is selected from
Methyl alcohol, 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 by described acylation reaction prepare compound 3 be selected from methyl alcohol, ethanol, normal propyl alcohol, isopropanol,
Tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- dimethyl
The mixture of one or more in acetamide, acetonitrile, water；Solvent choosing used by described imidization prepare compound 4
From methyl alcohol, ethanol, normal propyl alcohol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, adjacent two
One kind or several in toluene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetic acid, water
The mixture planted；Solvent used by described ring closure reaction prepare compound 5 is selected from methyl alcohol, ethanol, normal propyl alcohol, isopropanol, second
Nitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- bis-
The mixture of one or more in NMF, DMAC N,N' dimethyl acetamide, acetic acid, water；It is prepared by described de- Boc reactions
Solvent used by compound 6 is selected from methyl alcohol, 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,
The mixture of one or more in POCl3；Solvent used by described alkylated reaction prepare compound 7 be selected from methyl alcohol,
Ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, to diformazan
The mixture of one or more 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 by described reduction reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used by described acylation reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent
Degree；Temperature used by described imidization prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described ring closure reaction
Temperature used by prepare compound 5 is the reflux temperature of 0 DEG C~solvent；Temperature used by described de- Boc reaction prepare compounds 6
Degree is the reflux temperature of 0 DEG C~solvent；Temperature used by described alkylated reaction prepare compound 7 is returning for 0 DEG C~solvent
Stream 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2017
- 2017-02-26 CN CN201710105616.9A patent/CN106905249A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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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Application publication date: 20170630 |