CN108484548A - A kind of preparation method of 5- nitro-benzofurans -2- formic ether compounds - Google Patents
A kind of preparation method of 5- nitro-benzofurans -2- formic ether compounds Download PDFInfo
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- CN108484548A CN108484548A CN201810506887.XA CN201810506887A CN108484548A CN 108484548 A CN108484548 A CN 108484548A CN 201810506887 A CN201810506887 A CN 201810506887A CN 108484548 A CN108484548 A CN 108484548A
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- Prior art keywords
- preparation methods
- formula
- preparation
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- dibromoethylene
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of 5 nitrobenzofuran, 2 formic ether compounds, specifically comprise the following steps：
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of 5- nitro-benzofurans -2- formic ether compounds
Preparation method.
Background technology
Vilazodone (Vilazodone), the trade name Viibryd of hydrochloride are a kind of choosings with double action
Selecting property serotonin reuptake inhibitor and 5-HTIA acceptor portion agonists are clinically mainly used for treating major depression's disease,
U.S. Food and Drug Administration (FDA) approval Vilazodone Hydrochloride piece is for treating severe depression in adult at the beginning of 2011
Disease.Key intermediate 5- substitutions--2 formate ester intermediate of benzofuran is all be unable to do without in the synthetic method reported at present.This
A kind of one-step method of invention offer prepares the preparation method of -2 formate ester intermediate of 5- nitro-benzofurans.
Invention content
The present invention provides a kind of preparation method of -2 formic ether compounds of 5- nitro-benzofurans of Formula II structure,
It is characterized in that including the following steps：
Compound of formula I in organic solvent, reacts production II compounds with sym-dibromoethylene under alkaline reagent effect；
R is selected from the alkyl optionally replaced, the C1-C6 alkyl preferably optionally replaced by halogen, phenyl, further preferred Me,
Et、Bn。
Compound of formula I and the molar ratio of sym-dibromoethylene are 1:1.0-1.5 preferably 1:1.0-1.2；Reaction temperature preferably-
40 DEG C at room temperature；Reaction time is 8-12 hours preferred；The preferred THF of organic solvent, dioxane etc.；Alkaline reagent is selected from
The mole dosage of one or more of LiHMDS, NaHMDS, BuLi, t-BuLi, alkaline reagent are compound of formula I mole
1.5-2.0 again.
Another embodiment of the present invention provides the above-mentioned method for preparing -2 formic ether compounds of 5- nitro-benzofurans
Application in preparing vilazodone.
Compared with the prior art, the advantages of the present invention are as follows：The present invention using Bromofume alkaline reagent effect under with
Compound of formula I single step reaction prepares 5- nitro-benzofuran -2- formic ether compounds, is provided newly for the synthesis of vilazodone
Method and technology path.
Specific implementation mode
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments are only not supposed to be a limitation to the present invention or implementation principle for being better understood from invention, reality of the invention
The mode of applying is not limited to the following contents.
Embodiment 1
Compound 1 (1.0mmol) and sym-dibromoethylene (1.0mmol) are dissolved in THF, at -40 DEG C, LiHMDS is added
(2.0mmol) keeps -40 DEG C of reactions 12 hours (TLC detection compounds 1 completely disappear), saturated ammonium chloride is added, reaction is quenched,
After removing THF under reduced pressure, ethyl acetate extraction is added, is washed successively with saturated sodium bicarbonate, saturated sodium-chloride, merges organic phase
Afterwards, with anhydrous sodium sulfate drying, filtering, after filtrate concentration, chemical combination is obtained through silica gel column chromatography (ethyl acetate/petroleum ether=1/20)
Object 2 (201mg, yield 85.5%, HPLC purity are 97.3%,1H NMR are consistent with known report).
Embodiment 2
Compound 3 (1.0mmol) and sym-dibromoethylene (1.2mmol) are dissolved in THF, under ice salt bath, BuLi is added
(1.5mmol) keeps ice salt bath reaction 8 hours (TLC detection compounds 3 completely disappear), saturated ammonium chloride is added, reaction is quenched,
After removing THF under reduced pressure, ethyl acetate extraction is added, is washed successively with saturated sodium bicarbonate, saturated sodium-chloride, merges organic phase
Afterwards, with anhydrous sodium sulfate drying, filtering, after filtrate concentration, chemical combination is obtained through silica gel column chromatography (ethyl acetate/petroleum ether=1/20)
Object 4 (184mg, yield 83.2%, HPLC purity are 96.5%,1H NMR are consistent with known report).
Embodiment 3
Compound 5 (1.0mmol) and sym-dibromoethylene (1.5mmol) are dissolved in THF, at -20 DEG C, NaHMDS is added
(1.8mmol) keeps -20 DEG C of reactions 10 hours (TLC detection compounds 5 completely disappear), saturated ammonium chloride is added, reaction is quenched,
After removing THF under reduced pressure, ethyl acetate extraction is added, is washed successively with saturated sodium bicarbonate, saturated sodium-chloride, merges organic phase
Afterwards, with anhydrous sodium sulfate drying, filtering, after filtrate concentration, chemical combination is obtained through silica gel column chromatography (ethyl acetate/petroleum ether=1/25)
(96.8%) 120mg, yield 40.4%, HPLC purity are to object 6.1H-NMR(600MHz,CDCl3)：δ 8.06 (d, J=1.9,
1H), 7.85-7.77 (m, 4H), 7.44-7.35 (m, 4H), 5.39 (s, 2H).
Claims (10)
1. a kind of preparation method of -2 formic ether compounds of 5- nitro-benzofurans of Formula II structure, it is characterised in that including
Following steps：
Compound of formula I in organic solvent, reacts production II compounds with sym-dibromoethylene under alkaline reagent effect；Wherein R
Selected from the alkyl optionally replaced.
2. preparation method described in claim 1, it is characterised in that the alkaline reagent is selected from LiHMDS, NaHMDS, BuLi, t-
One or more of BuLi.
3. claim 1-2 any one of them preparation methods, it is characterised in that compound of formula I and the molar ratio of sym-dibromoethylene are
1:1.0-1.5；The mole dosage of alkaline reagent is 1.5-2.0 times of compound of formula I mole.
4. claim 1-3 any one of them preparation methods, it is characterised in that compound of formula I and the molar ratio of sym-dibromoethylene are
1:1.0-1.2。
5. claim 1-4 any one of them preparation methods, it is characterised in that reaction temperature is preferably at -40 DEG C at room temperature.
6. claim 1-5 any one of them preparation methods, it is characterised in that the reaction time is 8-12 hours preferred.
7. claim 1-6 any one of them preparation methods, it is characterised in that the preferred THF of organic solvent, dioxane etc..
8. claim 1-7 any one of them preparation methods, it is characterised in that R is selected from the C1- optionally replaced by halogen, phenyl
C6 alkyl.
9. claim 1-8 any one of them preparation methods, it is characterised in that R is selected from Me, Et, Bn.
10. application of the claim 1-9 any one of them preparation methods in preparing vilazodone.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810506887.XA CN108484548A (en) | 2018-05-23 | 2018-05-23 | A kind of preparation method of 5- nitro-benzofurans -2- formic ether compounds |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810506887.XA CN108484548A (en) | 2018-05-23 | 2018-05-23 | A kind of preparation method of 5- nitro-benzofurans -2- formic ether compounds |
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| Publication Number | Publication Date |
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| CN108484548A true CN108484548A (en) | 2018-09-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810506887.XA Pending CN108484548A (en) | 2018-05-23 | 2018-05-23 | A kind of preparation method of 5- nitro-benzofurans -2- formic ether compounds |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7473786B1 (en) * | 2003-12-05 | 2009-01-06 | University Of Massachusetts | Methods and systems for preparing fused heterocyclic compounds using copper(I) catalysts |
| CN102108070A (en) * | 2011-01-26 | 2011-06-29 | 上海优贝德生物医药有限公司 | Preparation methods of 5-aminobenzofuran-2-formate and intermediate thereof |
| CN103304527A (en) * | 2012-03-16 | 2013-09-18 | 无锡万全医药技术有限公司 | Novel preparation method of 5-nitrobenzofuran-2-formic acid |
-
2018
- 2018-05-23 CN CN201810506887.XA patent/CN108484548A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7473786B1 (en) * | 2003-12-05 | 2009-01-06 | University Of Massachusetts | Methods and systems for preparing fused heterocyclic compounds using copper(I) catalysts |
| CN102108070A (en) * | 2011-01-26 | 2011-06-29 | 上海优贝德生物医药有限公司 | Preparation methods of 5-aminobenzofuran-2-formate and intermediate thereof |
| CN103304527A (en) * | 2012-03-16 | 2013-09-18 | 无锡万全医药技术有限公司 | Novel preparation method of 5-nitrobenzofuran-2-formic acid |
Non-Patent Citations (2)
| Title |
|---|
| VICENTE DEL AMO ET AL.: "General Preparation of Primary, Secondary, and Tertiary Aryl Amines by the Oxidative Coupling of Polyfunctional Aryl and Heteroaryl Amidocuprates", 《ANGEW. CHEM. INT. ED》 * |
| XIAOHONG CHEN ET AL.: "Practical regioselective halogenation of vinylogous esters: synthesis of differentiated mono-haloresorcinols and polyhalogenated resorcinols", 《TETRAHEDRON》 * |
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Application publication date: 20180904 |