CN105061254A - Synthetic method of bromine-containing azide - Google Patents
Synthetic method of bromine-containing azide Download PDFInfo
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- CN105061254A CN105061254A CN201510427509.9A CN201510427509A CN105061254A CN 105061254 A CN105061254 A CN 105061254A CN 201510427509 A CN201510427509 A CN 201510427509A CN 105061254 A CN105061254 A CN 105061254A
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- reaction
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- xylol
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- bromo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 title 1
- 150000001540 azides Chemical class 0.000 title 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 title 1
- 229910052794 bromium Inorganic materials 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 12
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims 8
- 239000000203 mixture Substances 0.000 claims 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical compound CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 238000010992 reflux Methods 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 1
- 229910000564 Raney nickel Inorganic materials 0.000 claims 1
- 229910000085 borane Inorganic materials 0.000 claims 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 1
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- YZPNOJIYNVXSMZ-UHFFFAOYSA-N 3-(2-bromo-4-ethoxyphenyl)prop-2-enoic acid Chemical compound BrC1=C(C=CC(=C1)OCC)C=CC(=O)O YZPNOJIYNVXSMZ-UHFFFAOYSA-N 0.000 abstract 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- DKORSYDQYFVQNS-UHFFFAOYSA-N propyl methanesulfonate Chemical compound CCCOS(C)(=O)=O DKORSYDQYFVQNS-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a synthetic method of 2-bromophenyl azide1-(3-azidopropyl)-2-bromo-4-ethoxybenzene. 3-(2-bromo-4-ethoxyphenyl)acrylic acid is used as a starting material, a target product 5 is obtained through reduction, hydrogenation, Ms (methylsulfonyl) loading and azidation reactions, and the product is used as a template micro-molecule for synthesis of various compound libraries.
Description
Technical field
The present invention relates to a kind of novel method for synthesizing of medicine intermediate, particularly the synthetic method of the bromo-4-phenetole of a kind of 2-bromophenyl triazo-compound 1-(3-Azidopropyl)-2-.
Technical background
The bromo-4-phenetole of compound 1-(3-Azidopropyl)-2-, structural formula is:
This compound 2-bromophenyl triazo-compound 1-(3-Azidopropyl)-2-bromo-4-phenetole and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 2-bromophenyl triazo-compound 1-(3-Azidopropyl)-2-bromo-4-phenetole is comparatively difficult.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses the synthetic method of the bromo-4-phenetole of a kind of 2-bromophenyl triazo-compound 1-(3-Azidopropyl)-2-, with 3-(the bromo-4-ethoxyl phenenyl of 2-) vinylformic acid for starting raw material, obtain target product 5 through reduction, hydrogenation, upper Ms, azido reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) 3-(the bromo-4-ethoxyl phenenyl of 2-) vinylformic acid is starting raw material, obtains 2 through reduction reaction,
(2) carry out hydrogenation reaction 2, obtain 3,
(3) carry out upper Ms 3 and be obtained by reacting 4,
(4) carry out azido reaction 4 and obtain 5,
One preferred embodiment in, described reduction reaction is prepared compound 2 reagent used and is selected from Lithium Aluminium Hydride; Described hydrogenation reaction is prepared compound 3 reagent used and is selected from palladium carbon; Described upper Ms reacts the reagent preparing compound 4 used and is selected from triethylamine; The reagent that described azido reaction prepares compound 5 used is selected from sodiumazide.
One preferred embodiment in, the solvent that described reduction reaction prepares compound 2 used is selected from tetrahydrofuran (THF); Described hydrogenation reaction prepares compound 3 solvent selected from methanol used; Described upper Ms reacts the solvent preparing compound 4 used and is selected from methylene bromide; The solvent that described azido reaction prepares compound 5 used is selected from DMF.
One preferred embodiment in, described reduction reaction prepare compound 2 temperature of reaction used be 0 DEG C to room temperature; It is room temperature that described hydrogenation reaction prepares compound 3 temperature used; Described upper Ms reaction prepare compound 4 temperature used be 0 DEG C to room temperature; It is room temperature that described azido reaction prepares compound 5 temperature used.
The present invention relates to the synthetic method of the bromo-4-phenetole of a kind of 2-bromophenyl triazo-compound 1-(3-Azidopropyl)-2-, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of the bromo-4-phenetole of compound 1-(3-Azidopropyl)-2-.
The present invention is further described by the following embodiment, and these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 3-(the bromo-4-ethoxyl phenenyl of 2-) third-2-alkene-1-alcohol
16g3-(the bromo-4-ethoxyl phenenyl of 2-) vinylformic acid is joined in 200ml tetrahydrofuran (THF), be cooled to 0 DEG C, slowly add 6g Lithium Aluminium Hydride in batches, stirred overnight at room temperature, adds water and ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, obtain 7g3-(the bromo-4-ethoxyl phenenyl of 2-) third-2-alkene-1-alcohol.
(2) synthesis of 3-(the bromo-4-ethoxyl phenenyl of 2-) the third-1-alcohol
7g3-(the bromo-4-ethoxyl phenenyl of 2-) third-2-alkene-1-alcohol is joined in 40ml methyl alcohol, adds 0.5g10% palladium carbon, pass into hydrogen, stirred overnight at room temperature, filters, and collects filtrate, concentrated, obtain 5g3-(the bromo-4-ethoxyl phenenyl of 2-) the third-1-alcohol.
(3) synthesis of 3-(the bromo-4-ethoxyl phenenyl of 2-) propyl Methanesulfonate
5g3-(the bromo-4-ethoxyl phenenyl of 2-) the third-1-alcohol is joined in 50ml methylene bromide, add 3g triethylamine, be cooled to 0 DEG C, add 2.9gMsCl, stirring at room temperature 2 hours, add water again, extraction separatory, collects organic phase, dry, concentrated, on residuum, silicagel column is separated to obtain 3.4g3-(the bromo-4-ethoxyl phenenyl of 2-) propyl Methanesulfonate.
(4) synthesis of the bromo-4-phenetole of 1-(3-Azidopropyl)-2-
3g3-(the bromo-4-ethoxyl phenenyl of 2-) propyl Methanesulfonate is joined 30mlN, in dinethylformamide, add 4g sodiumazide, stirring at room temperature 6 hours, adds water and ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, on residuum, silicagel column is separated to obtain the bromo-4-phenetole of 2.5g1-(3-Azidopropyl)-2-.
Claims (5)
1. the synthetic method of the bromo-4-phenetole of a kind of 2-bromophenyl triazo-compound 1-(3-Azidopropyl)-2-, with 3-(the bromo-4-ethoxyl phenenyl of 2-) vinylformic acid for starting raw material, obtain target product 5 through reduction, hydrogenation, upper Ms, azido reaction, synthetic route is as follows:
2. method according to claim 1, it is characterized by 4 described step reactions is,
(1) 3-(the bromo-4-ethoxyl phenenyl of 2-) vinylformic acid is starting raw material, obtains 2 through reduction reaction,
(2) carry out hydrogenation reaction 2, obtain 3,
(3) carry out upper Ms 3 and be obtained by reacting 4,
(4) carry out azido reaction 4 and obtain 5,
3. according to the method for claim 1-2, it is characterized in that, described reduction reaction is prepared compound 2 reagent used and is selected from one or both mixture in borine, Lithium Aluminium Hydride; Described hydrogenation reaction is prepared compound 3 reagent used and is selected from the mixture of one or more in palladium carbon, palladium hydroxide, Raney's nickel; Described upper Ms reaction is prepared compound 4 reagent used and is selected from the mixture of one or more in triethylamine, pyridine, salt of wormwood, sodium hydroxide; The reagent that described azido reaction prepares compound 5 used is selected from sodiumazide.
4. according to the method for claim 1-2, it is characterized in that, described reduction reaction is prepared compound 2 solvent used and is selected from tetrahydrofuran (THF), methylene bromide, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile; Described hydrogenation reaction prepares compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene bromide, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile; Compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, methylene bromide, methenyl bromide, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described upper Ms reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described azido reaction prepares compound 5 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene bromide, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile.
5. according to the method for claim 1-2, it is characterized in that, it is 0 DEG C of reflux temperature to solvent that described reduction reaction prepares compound 2 temperature of reaction used; It is room temperature that described hydrogenation reaction prepares compound 3 temperature used; It is 0 DEG C of reflux temperature to solvent that compound 4 temperature used is prepared in described upper Ms reaction; It is room temperature that described azido reaction prepares compound 5 temperature used.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510427509.9A CN105061254A (en) | 2015-07-20 | 2015-07-20 | Synthetic method of bromine-containing azide |
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| CN201510427509.9A CN105061254A (en) | 2015-07-20 | 2015-07-20 | Synthetic method of bromine-containing azide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883140A (en) * | 2017-02-26 | 2017-06-23 | 长沙深橙生物科技有限公司 | A kind of preparation method containing azido micromolecular compound |
| CN108117514A (en) * | 2016-11-29 | 2018-06-05 | 湖南华腾制药有限公司 | A kind of preparation method of pyridine azido compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4707488A (en) * | 1985-02-11 | 1987-11-17 | Smithkline Beckman Corporation | Dopamine-β-hydroxylase inhibitors and use thereof |
| CN1438996A (en) * | 2000-05-31 | 2003-08-27 | 沃尼尔·朗伯公司 | Bicyclic cyclohexylamines and their use NMDA receptor antogonists |
-
2015
- 2015-07-20 CN CN201510427509.9A patent/CN105061254A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4707488A (en) * | 1985-02-11 | 1987-11-17 | Smithkline Beckman Corporation | Dopamine-β-hydroxylase inhibitors and use thereof |
| CN1438996A (en) * | 2000-05-31 | 2003-08-27 | 沃尼尔·朗伯公司 | Bicyclic cyclohexylamines and their use NMDA receptor antogonists |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108117514A (en) * | 2016-11-29 | 2018-06-05 | 湖南华腾制药有限公司 | A kind of preparation method of pyridine azido compound |
| CN106883140A (en) * | 2017-02-26 | 2017-06-23 | 长沙深橙生物科技有限公司 | A kind of preparation method containing azido micromolecular compound |
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Application publication date: 20151118 |