CN104876918A - Preparation method of pyrazinyl substituted oxadiazole compound - Google Patents
Preparation method of pyrazinyl substituted oxadiazole compound Download PDFInfo
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- CN104876918A CN104876918A CN201510196929.0A CN201510196929A CN104876918A CN 104876918 A CN104876918 A CN 104876918A CN 201510196929 A CN201510196929 A CN 201510196929A CN 104876918 A CN104876918 A CN 104876918A
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- compound
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- pyrazine
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- -1 oxadiazole compound Chemical class 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 125000003373 pyrazinyl group Chemical group 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000001681 protective effect Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 238000007259 addition reaction Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- NGGGZUAEOKRHMA-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CC(C)(C)OC(=O)CC(O)=O NGGGZUAEOKRHMA-UHFFFAOYSA-N 0.000 claims description 3
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 9
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 6
- 238000000034 method Methods 0.000 claims 4
- 239000000203 mixture Substances 0.000 claims 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 3
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical compound CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 1
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- 229960001701 chloroform Drugs 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- ZPBNABIKZKTQQH-UHFFFAOYSA-N 5-bromopyrazine-2-carbonitrile Chemical compound BrC1=CN=C(C#N)C=N1 ZPBNABIKZKTQQH-UHFFFAOYSA-N 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- NYBCQTSQRQNYCN-UHFFFAOYSA-N n-[(2-bromo-5-methoxyphenyl)methylidene]hydroxylamine Chemical compound COC1=CC=C(Br)C(C=NO)=C1 NYBCQTSQRQNYCN-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 0 *c(nc1)cnc1-c1n[o]c(N)n1 Chemical compound *c(nc1)cnc1-c1n[o]c(N)n1 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of a pyrazinyl substituted oxadiazole compound 3-(5-bromopyrazinyl-2-yl)-1,2,4-oxadiazolyl5-amine. By using 2-cyano-5-bromopyrazine as an initial raw material, addition, cyclization and Boc deprotection reaction are performed to obtain the target product 4. The product is used as a template micromolecule for synthesizing various compound libraries.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly a kind of pyrazine replaces the preparation method of oxadiazole compound 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine.
Technical background
Compound 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine, structural formula is:
This compound 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine 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 a kind of pyrazine and replace oxadiazole compound 3-(5-bromo-pyrazine-2-base)-1; 2; the preparation method of 4-oxadiazoles-5-amine; with 2-cyano group-5-bromo-pyrazine for starting raw material; obtain target product 4 through addition, Guan Huan, de-Boc protective reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 2-cyano group-5-bromo-pyrazine for starting raw material, obtain 2 through addition reaction,
(2) carry out ring closure reaction 2, obtain 3,
(3) carry out de-Boc protective reaction 3 and obtain 4,
One preferred embodiment in, the reagent that described addition reaction prepares compound 2 used is selected from oxammonium hydrochloride; Described ring closure reaction is prepared compound 3 reagent used and is selected from 2-(tertbutyloxycarbonyl) acetic acid; The reagent that described de-Boc protective reaction prepares compound 4 used is selected from hydrogenchloride.
One preferred embodiment in, compound 2 solvent selected from ethanol used is prepared in described addition reaction; The solvent that described ring closure reaction prepares compound 3 used is selected from tetrahydrofuran (THF); The solvent that described de-Boc protective reaction prepares compound 4 used is selected from methylene dichloride.
One preferred embodiment in, the reflux temperature that compound 2 temperature of reaction used is solvent is prepared in described additionization reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; It is room temperature that compound 4 temperature used is prepared in described de-Boc protective reaction.
The present invention relates to the preparation method that a kind of benzene replaces oxadiazole compound 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine.
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 2-bromo-5-methoxybenzaldehyde oxime
18g 2-cyano group-5-bromo-pyrazine is joined in 400ml ethanol, and add 15g oxammonium hydrochloride, reflux stirring reaction 2 hours, adds water and ethyl acetate, and extraction separatory, collects organic phase, dry, concentrated, obtains 19g 2-bromo-5-methoxybenzaldehyde oxime.
(2) synthesis of 3-(5-bromopyridine-2-base)-1,2,4-oxadiazoles-5-carbamate
Bromo-for 19g 2-5-methoxybenzaldehyde oxime is joined in 260ml tetrahydrofuran (THF), adds 12g 2-(tertbutyloxycarbonyl) acetic acid, reflux 4 hours, concentrated, residuum adds in 200ml acetic acid, reflux 8 hours, concentrated, add water and extraction into ethyl acetate separatory, collect organic phase, dry, concentrate and obtain 20g 3-(5-bromopyridine-2-base)-1,2,4-oxadiazoles-5-carbamate.
(3) synthesis of 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine
Bromo-for 20g 2-5-methoxybenzaldehyde oxime is joined in 150ml methylene dichloride, pass into hydrogenchloride, stirring at room temperature 24 hours, adds sodium bicarbonate aqueous solution, extraction separatory, collect organic phase, drying, concentrated, on residuum, silicagel column is separated to obtain 13g 3-(5-bromo-pyrazine-2-base)-1,2,4-oxadiazoles-5-amine.
Claims (5)
1. a pyrazine replaces oxadiazole compound 3-(5-bromo-pyrazine-2-base)-1; the preparation method of 2,4-oxadiazoles-5-amine, with 2-cyano group-5-bromo-pyrazine for starting raw material; obtain target product 4 through addition, Guan Huan, de-Boc protective reaction, synthetic route is as follows:
2. method according to claim 1, it is characterized by 3 described step reactions is,
(1) with 2-cyano group-5-bromo-pyrazine for starting raw material, obtain 2 through addition reaction,
(2) carry out ring closure reaction 2, obtain 3,
(3) carry out de-Boc protective reaction 3 and obtain 4,
3. according to the method for claim 1-2, it is characterized in that, the reagent that described addition reaction prepares compound 2 used is selected from oxammonium hydrochloride; Described ring closure reaction is prepared compound 3 reagent used and is selected from 2-(tertbutyloxycarbonyl) acetic acid; Described de-Boc protective reaction is prepared compound 4 reagent used and is selected from the mixture of one or more in hydrochloric acid, sulfuric acid, hydrogenchloride, trifluoroacetic acid.
4. according to the method for claim 1-2, it is characterized in that, compound 2 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described addition reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, triethylamine, pyridine, acetonitrile, acetic acid, trimethyl orthoformate; Described ring closure reaction prepares compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, ammoniacal liquor; Compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described de-Boc protective reaction; the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetic acid, water.
5. according to the method for claim 1-2, it is characterized in that, the reflux temperature that compound 2 temperature of reaction used is solvent is prepared in described additionization reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; It is room temperature that compound 4 temperature used is prepared in described de-Boc protective reaction.
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| CN201510196929.0A CN104876918A (en) | 2015-04-23 | 2015-04-23 | Preparation method of pyrazinyl substituted oxadiazole compound |
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| CN201510196929.0A CN104876918A (en) | 2015-04-23 | 2015-04-23 | Preparation method of pyrazinyl substituted oxadiazole compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299333A (en) * | 2017-01-12 | 2018-07-20 | 湖南华腾制药有限公司 | One kind 3,5- bis- replaces the preparation method of oxadiazole compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101663278A (en) * | 2007-02-02 | 2010-03-03 | Irm责任有限公司 | Compounds and compositions as modulators of GPR119 activity |
| CN104292180A (en) * | 2014-10-12 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of oxadiazole derivative |
-
2015
- 2015-04-23 CN CN201510196929.0A patent/CN104876918A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101663278A (en) * | 2007-02-02 | 2010-03-03 | Irm责任有限公司 | Compounds and compositions as modulators of GPR119 activity |
| CN104292180A (en) * | 2014-10-12 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of oxadiazole derivative |
Non-Patent Citations (1)
| Title |
|---|
| YASAR DÜRÜST，ET AL.: ""Synthesis and anti-protozoal activity of novel dihydropyrrolo[3,4-d][1,2,3]triazoles"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299333A (en) * | 2017-01-12 | 2018-07-20 | 湖南华腾制药有限公司 | One kind 3,5- bis- replaces the preparation method of oxadiazole compound |
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