CN107778264A - A kind of preparation method of the substitution oxadiazole compound containing fluorobenzene - Google Patents
A kind of preparation method of the substitution oxadiazole compound containing fluorobenzene Download PDFInfo
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- CN107778264A CN107778264A CN201610755263.2A CN201610755263A CN107778264A CN 107778264 A CN107778264 A CN 107778264A CN 201610755263 A CN201610755263 A CN 201610755263A CN 107778264 A CN107778264 A CN 107778264A
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- prepare compound
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- XULWGWRQQOUMPB-UHFFFAOYSA-N COc(cc1-c2n[o]c(CCl)n2)ccc1F Chemical compound COc(cc1-c2n[o]c(CCl)n2)ccc1F XULWGWRQQOUMPB-UHFFFAOYSA-N 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
Abstract
The invention discloses one kind containing fluorobenzene substitution oxadiazole compound N ((3 (methoxyphenyls of 2 fluorine 5) 1,2, the base of 4 oxadiazoles 5) methyl) ethamine preparation method, using 4 fluoroanisoles as initiation material, target product 7 is obtained by aldehyde radical, oximate, elimination, addition, cyclization, substitution reaction, product of the present invention synthesizes diversified compound library as template small molecule.
Description
Technical field
It is more particularly to a kind of containing fluorobenzene substitution oxadiazoles the present invention relates to a kind of novel processing step of medicine intermediate
The preparation method of compound N- ((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,4- oxadiazoles -5- bases) methyl) ethamine.
Technical background
Compound N-((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,4- oxadiazoles -5- bases) methyl) ethamine, structural formula are：
This compound N-((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,4- oxadiazoles -5- bases) methyl) ethamine and correlation
Derivative has extensive use in pharmaceutical chemistry and organic synthesis.N- ((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,4- at present
Oxadiazoles -5- bases) methyl) ethamine synthesis it is more difficult.Therefore it is easy to get, it is necessary to develop a raw material, easy to operate, reaction is easy
In control, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses one kind containing fluorobenzene substitution oxadiazole compound N- ((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,
4- oxadiazoles -5- bases) methyl) ethamine preparation method, using 4- fluoroanisoles as initiation material, by aldehyde radical, oximate, disappear
Remove, addition, cyclization, substitution reaction obtain target product 7, synthesis step is as follows：
(1) using 4- fluoroanisoles as initiation material, 2 are obtained by aldehyde glycosylation reaction,
(2) oximation reaction is carried out 2, obtains 3,
(3) 3 progress elimination reactions are obtained 4,
(4) 4 progress addition reactions are obtained 5,
(5) 5 progress ring closure reactions are obtained 6,
(6) 6 progress substitution reactions are obtained 7；
In a preferred embodiment, the reagent used in described aldehyde glycosylation reaction prepare compound 2 is selected from N, N- bis-
NMF；Reagent used in described oximation reaction prepare compound 3 is selected from hydroxylamine hydrochloride；It is prepared by described elimination reaction
Reagent used in compound 4 is selected from POCl3；Reagent used in described addition reaction prepare compound 5 is selected from hydrochloric acid hydroxyl
Amine；Reagent used in described pass cyclization prepare compound 6 is selected from chloracetyl chloride；Described substitution reaction prepare compound
Alkali used in 7 is selected from potassium carbonate.
In a preferred embodiment, the solvent used in described aldehyde glycosylation reaction prepare compound 2 is selected from tetrahydrochysene furan
Mutter；Solvent used in described oximation reaction prepare compound 3 is selected from ethanol；Used in described elimination reaction prepare compound 4
Solvent be selected from tetrahydrofuran；Solvent used in described addition reaction prepare compound 5 is selected from the mixture of first alcohol and water；Institute
The solvent used in pass cyclization prepare compound 6 stated is selected from dichloromethane；Used in described substitution reaction prepare compound 7
Solvent be selected from N,N-dimethylformamide.
In a preferred embodiment, the reaction temperature used in described aldehyde glycosylation reaction prepare compound 2 is -78 DEG C
~room temperature；Temperature used in described oximation reaction prepare compound 3 is the reflux temperature of solvent；It is prepared by described elimination reaction
Temperature used in compound 4 is the reflux temperature of solvent；Temperature used in described addition reaction prepare compound 5 is room temperature；
Temperature used in described pass cyclization prepare compound 6 is room temperature；Temperature used in described substitution reaction prepare compound 7
Degree is 100 DEG C.
The present invention relates to one kind containing fluorobenzene substitution oxadiazole compound N- ((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,4-
Oxadiazoles -5- bases) methyl) ethamine 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 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 the fluoro- 5- methoxybenzaldehydes of 2-
20g 4- fluoroanisoles are added in 230ml tetrahydrofurans, are cooled to -78 DEG C, are adding 130ml 2.5M just
Butyl lithium, stirring reaction 2 hours, adds DMF, warms naturally to be stirred overnight at room temperature, and adds 1N salt
Acid, ethyl acetate is added, extract liquid separation, collect organic phase, dried, concentration, obtain the fluoro- 5- methoxybenzaldehydes of 17g 2-.
(2) synthesis of the fluoro- 5- methoxybenzaldehydes oximes of 2-
The fluoro- 5- methoxybenzaldehydes of 17g 2- are added in 210ml ethanol, 14g hydroxylamine hydrochlorides is added, is heated to reflux 4
Hour, water and ethyl acetate extraction liquid separation are added, organic phase is collected, dries, be concentrated to give the fluoro- 5- methoxybenzaldehydes of 15g 2-
Oxime.
(3) synthesis of the fluoro- 5- HOMOVERATRONITRILEs of 2-
The fluoro- 5- methoxybenzaldehydes oximes of 15g 2- are added in 150ml tetrahydrofurans, add 40g TFAAs, then
20ml triethylamines are added, concentration, water and ethyl acetate extraction liquid separation is added, collection organic phase, dries, concentration, silicon on residue
Glue post separation obtains the fluoro- 5- HOMOVERATRONITRILEs of 11g 2-.
(4) synthesis of the fluoro- N'- hydroxy-5-methyls epoxide benzenecarboximidamides of 2-
The fluoro- 5- HOMOVERATRONITRILEs of 11g 2- are added to the in the mixed solvent of 200ml methanol and 100ml water, add 9g
Hydroxylamine hydrochloride and 12g anhydrous sodium acetates, are heated to reflux stirring reaction 12 hours, add water and ethyl acetate, extract liquid separation, collect
Organic phase, dry, concentration, the fluoro- N'- hydroxy-5-methyls epoxide benzenecarboximidamides of the isolated 9g 2- of silicagel column on residue.
(5) synthesis of 3- (the fluoro- 5- methoxyphenyls of 2-) -5- (chloromethyl) -1,2,4- oxadiazoles
The fluoro- N'- hydroxy-5-methyls epoxide benzenecarboximidamides of 8g 2- are added in 180ml dichloromethane, 7g triethylamines is added, adds
Entering 10g chloracetyl chlorides, be stirred at room temperature 4 hours, filter, concentration, residue is added in 150ml toluene, heated overnight at reflux,
Water and ethyl acetate are added, extracts liquid separation, collects organic phase, dries, is concentrated to give 6g 3- (the fluoro- 5- methoxyphenyls of 2-) -5-
(chloromethyl) -1,2,4- oxadiazoles.
(6) synthesis of N- ((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,4- oxadiazoles -5- bases) methyl) ethamine
5g 3- (the fluoro- 5- methoxyphenyls of 2-) -5- (chloromethyl) -1,2,4- oxadiazoles is added to 120ml N, N- bis-
In NMF, 4g potassium carbonate and 3.6g ethylamine hydrochlorides are added, is heated to 100 DEG C, is stirred 3 hours, adds water and second
Acetoacetic ester, liquid separation is extracted, collect organic phase, dried, concentration, the isolated 3g N- of residue silicagel column ((3- (the fluoro- 5- of 2-
Methoxyphenyl) -1,2,4- oxadiazoles -5- bases) methyl) ethamine.
Claims (5)
1. one kind substitution oxadiazole compound N- containing fluorobenzene ((3- (the fluoro- 5- methoxyphenyls of 2-) -1,2,4- oxadiazoles -5- bases)
Methyl) ethamine preparation method, using 4- fluoroanisoles as initiation material, by aldehyde radical, oximate, elimination, addition, cyclization, take
Generation reaction obtains 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) using 4- fluoroanisoles as initiation material, 2 are obtained by aldehyde glycosylation reaction,
(2) oximation reaction is carried out 2, obtains 3,
(3) 3 progress elimination reactions are obtained 4,
(4) 4 progress addition reactions are obtained 5,
(5) 5 progress ring closure reactions are obtained 6,
(6) 6 progress substitution reactions are obtained 7；
3. method according to claim 1, it is characterised in that the reagent choosing used in described aldehyde glycosylation reaction prepare compound 2
From N,N-dimethylformamide；Reagent used in described oximation reaction prepare compound 3 is selected from hydroxylamine hydrochloride；Described elimination
React one or more of mixing of the reagent used in prepare compound 4 in POCl3, the concentrated sulfuric acid, TFAA
Thing；Reagent used in described addition reaction prepare compound 5 is selected from hydroxylamine hydrochloride；Described pass cyclization prepare compound
Reagent used in 6 is selected from chloracetyl chloride；Alkali used in described substitution reaction prepare compound 7 is selected from sodium carbonate, potassium carbonate, hydrogen
One or more of mixtures in sodium oxide molybdena, potassium hydroxide, triethylamine, pyridine.
4. method according to claim 1, it is characterised in that the solvent choosing used in described aldehyde glycosylation reaction prepare compound 2
From methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene,
One kind in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid, trimethyl orthoformate
Or several mixture；Solvent used in described oximation reaction prepare compound 3 is selected from methanol, ethanol, normal propyl alcohol, isopropyl
Alcohol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- bis-
One or more of mixtures in methylacetamide, acetonitrile, ammoniacal liquor；It is molten used in described elimination reaction prepare compound 4
Agent be selected from methanol, ethanol, normal propyl alcohol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene,
One kind in ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetic acid, water
Or several mixture；Solvent used in described addition reaction prepare compound 5 is selected from methanol, ethanol, normal propyl alcohol, isopropyl
Alcohol, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene,
One or more of mixtures in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetic acid, water；Described cyclization
React the solvent used in prepare compound 6 and be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane
Alkane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- dimethylacetamides
One or more of mixtures in amine, acetonitrile, ammoniacal liquor；Solvent used in described substitution reaction prepare compound 7 is selected from first
Alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, to two
One or more of mixtures in toluene, 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 aldehyde glycosylation reaction prepare compound 2
Degree is the reflux temperature of -78 DEG C~solvent；Temperature used in described oximation reaction prepare compound 3 is returning for 0 DEG C~solvent
Flow temperature；Temperature used in described elimination reaction prepare compound 4 is the reflux temperature of room temperature~solvent；Described addition is anti-
Answer the reflux temperature that the temperature used in prepare compound 5 is room temperature~solvent；Used in described pass cyclization prepare compound 6
Temperature be 0 DEG C~room temperature；Temperature used in described substitution reaction prepare compound 7 is the reflux temperature of room temperature~solvent.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817515A (en) * | 2015-04-22 | 2015-08-05 | 湖南华腾制药有限公司 | Preparation method of benzene substituent oxadiazole compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817515A (en) * | 2015-04-22 | 2015-08-05 | 湖南华腾制药有限公司 | Preparation method of benzene substituent oxadiazole compound |
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Application publication date: 20180309 |