CN107513041A - A kind of preparation method of pyrazines derivatives - Google Patents
A kind of preparation method of pyrazines derivatives Download PDFInfo
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- CN107513041A CN107513041A CN201710726687.0A CN201710726687A CN107513041A CN 107513041 A CN107513041 A CN 107513041A CN 201710726687 A CN201710726687 A CN 201710726687A CN 107513041 A CN107513041 A CN 107513041A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
- C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
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Abstract
The invention discloses a kind of preparation method of the formamide of 3 amino 6 (aminomethyl phenyl of 3 chlorine 5) pyrazine of pyrazines derivatives 2, using the carboxylic acid of 3 Aminopyrazine 2 as initiation material, target product is obtained through over-churning, amidatioon, upper bromine, coupling reaction, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of pyrazines derivatives 3- amino-
The preparation method of 6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides.
Technical background
Compound 3- amino -6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides, structural formula are：
This compound 3- amino -6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides and the derivative of correlation are in medicine
There is extensive use in and organic synthesis.The synthesis of 3- amino -6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides at present
It is more difficult.Therefore it is easy to get, it is necessary to develop a raw material, it is easy to operate, react easily controllable, the overall yield suitably side of synthesis
Method.
The content of the invention
The invention discloses one kind to prepare pyrazines derivatives 3- amino -6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides
Preparation method, using 3- Aminopyrazine -2- carboxylic acids as initiation material, mesh is obtained through over-churning, amidatioon, upper bromine, coupling reaction
Product 5 is marked, synthesis step is as follows：
(1) using 3- Aminopyrazine -2- carboxylic acids as initiation material, 2 are obtained by esterification；
(2) amidation process is carried out 2, obtains 3；
(3) carry out upper bromine reaction 3 and obtain 4；
(4) 4 progress coupling reactions are obtained 5；
In a preferred embodiment, the reagent used in described esterification prepare compound 2 is selected from thionyl chloride
With the mixture of methanol；Reagent used in described amidation process prepare compound 3 is selected from ammoniacal liquor；Described upper bromine reaction system
Reducing agent used in standby compound 4 is selected from bromine；Reagent used in described coupling reaction prepare compound 5 is selected from four (triphens
Base phosphine) palladium.
In a preferred embodiment, the solvent used in described esterification prepare compound 2 is selected from methanol；It is described
Amidation process prepare compound 3 used in solvent be selected from ammoniacal liquor；Solvent used in described upper bromine reaction prepare compound 4
Selected from acetic acid；Solvent used in described coupling reaction prepare compound 5 is selected from tetrahydrofuran.
In a preferred embodiment, the reaction temperature used in described esterification prepare compound 2 is room temperature；Institute
The temperature used in amidation process prepare compound 3 stated is room temperature；Temperature used in described upper bromine reaction prepare compound 4
It is the reflux temperature of solvent；Temperature used in described coupling reaction prepare compound 5 is the reflux temperature of solvent.
The present invention relates to a kind of preparation of pyrazines derivatives 3- amino -6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides
Method, reported currently without other Patents documents.
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 3- Aminopyrazines -2- methyl formates
15g 3- Aminopyrazine -2- carboxylic acids are added in 200ml methanol, 10ml thionyl chlorides are added dropwise, were stirred at room temperature
At night, concentration, 200ml toluene is added, concentration, obtains 18g 3- Aminopyrazine -2- methyl formates.
(2) synthesis of 3- Aminopyrazines -2- formamides
17g 3- Aminopyrazine -2- methyl formates are added in 300ml ammoniacal liquor, are stirred at room temperature 22 hours, add acetic acid
Ethyl ester extracts liquid separation, collects organic phase, dries, and concentration, obtains 12g 3- Aminopyrazine -2- formamides.
(3) synthesis of 3- amino -6- bromo-pyrazines -2- formamides
12g 3- Aminopyrazine -2- formamides are added in 150ml acetic acid, 19g bromines is slowly added to, is heated to reflux stirring
Mix 3 hours, concentrate, add water and ethyl acetate carries out extraction liquid separation, concentrate, silica gel post separation obtains 10g 3- ammonia on residue
Base -6- bromo-pyrazine -2- formamides.
(4) synthesis of 3- amino -6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides
10g 3- amino -6- bromo-pyrazine -2- formamides are added in 120ml tetrahydrofurans, add (the triphens of 0.1g tetra-
Base phosphine) palladium and 12.6g sodium carbonate, then add the chloro- 5- methylphenylboronic acids of 14g 3- and be heated to reflux stirring 5 hours, concentrate, add
Water and ethyl acetate, extraction, liquid separation, organic phase is collected, concentrated, the isolated 7g 3- amino -6- (3- of silicagel column on residue
Chloro- 5- aminomethyl phenyls) pyrazine -2- formamides.
Claims (6)
1. one kind prepares the preparation method of pyrazines derivatives 3- amino -6- (the chloro- 5- aminomethyl phenyls of 3-) pyrazine -2- formamides, with
3- Aminopyrazine -2- carboxylic acids are initiation material, obtain target product 5 through over-churning, amidatioon, upper bromine, coupling reaction, synthesize road
Line is as follows,
2. method according to claim 1, it is characterized in that described 4 steps reaction is,
(1) using 3- Aminopyrazine -2- carboxylic acids as initiation material, 2 are obtained by esterification；
(2) amidation process is carried out 2, obtains 3；
(3) carry out upper bromine reaction 3 and obtain 4；
(4) 4 progress coupling reactions are obtained 5；
3. method according to claim 1, it is characterised in that the reagent used in described esterification prepare compound 2 is selected from
Thionyl chloride, sulfuric acid, hydrogen chloride, N, one in N- carbonyl dimidazoles, dicyclohexylcarbodiimide, p-methyl benzenesulfonic acid, methanol
Kind or several mixtures；One kind in ammoniacal liquor, ammonia of reagent used in described amidation process prepare compound 3 or
Two kinds of mixture；Reducing agent used in described upper bromine reaction prepare compound 4 is selected from bromine, hydrogen bromide, N- bromos fourth two
One or more of mixtures in acid imide；Reagent used in described coupling reaction prepare compound 5 is selected from palladium, chlorine
Change palladium, [1,1'- double (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, one kind in tetrakis triphenylphosphine palladium or
Several mixtures.
4. method according to claim 1, it is characterised in that the solvent used in described esterification prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
One or more of mixtures in dinethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile；Described
Solvent used in amidation process prepare compound 3 be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane,
Toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, water, ammonia
One or more of mixtures in water, hydrochloric acid, the concentrated sulfuric acid, oleum；Used in described upper bromine reaction prepare compound 4
Solvent is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, neighbour two
One kind in toluene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, acetic acid or
Several mixtures；Solvent used in described coupling reaction prepare compound 5 be selected from methanol, ethanol, normal propyl alcohol, isopropanol,
Tetrahydrofuran, dioxane, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide,
One or more of mixtures in DMAC N,N' dimethyl acetamide.
5. method according to claim 1, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is the reflux temperature of -80 DEG C~solvent；Temperature used in described amidation process prepare compound 3 is returning for 0 DEG C~solvent
Flow temperature；Temperature used in described upper bromine reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described coupling is anti-
Answer the reflux temperature that the temperature used in prepare compound 5 is 0 DEG C~solvent.
6. method according to claim 1, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is room temperature；Temperature used in described amidation process prepare compound 3 is room temperature；Described upper bromine reaction prepare compound 4
Temperature used is the reflux temperature of solvent；Temperature used in described coupling reaction prepare compound 5 is the backflow temperature of solvent
Degree.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104387331A (en) * | 2014-10-27 | 2015-03-04 | 湖南华腾制药有限公司 | Preparation method of pyrazine derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104387331A (en) * | 2014-10-27 | 2015-03-04 | 湖南华腾制药有限公司 | Preparation method of pyrazine derivative |
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Application publication date: 20171226 |