CN105859643B - A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine - Google Patents
A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine Download PDFInfo
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- CN105859643B CN105859643B CN201610403628.5A CN201610403628A CN105859643B CN 105859643 B CN105859643 B CN 105859643B CN 201610403628 A CN201610403628 A CN 201610403628A CN 105859643 B CN105859643 B CN 105859643B
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- 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
- C07D241/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The present invention discloses a kind of 2- ethyl -3,5, and the synthetic method of 6- trimethylpyrazine includes the following steps：S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, aqueous hydrogen peroxide solution, heating is added, insulated and stirred removes glacial acetic acid, adjusts pH, and extraction removes methylene chloride and obtains 1- oxo -2,3,5- trimethylpyrazines, wherein aqueous hydrogen peroxide solution is added in three times, and each additional amount is identical；S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and phosphorus oxychloride are mixed, and heating, insulated and stirred obtains solution A；Solution A is added in trash ice and mixes cooling, adjusts pH, extraction removes methylene chloride and obtains 2- chloro- 3,5,6- trimethylpyrazines；S3, preparation 2- ethyl -3,5,6- trimethylpyrazine.
Description
Technical field
The present invention relates to 2- ethyl -3,5,6- trimethylpyrazine preparation technical field more particularly to a kind of 2- ethyl -3,5,
The synthetic method of 6- trimethylpyrazine.
Background technique
Ligustrazine is colorless needle crystals, and its chemical name is Tetramethylpyradine, abbreviation Tetramethylpyrazine divides
Son amount is 138.20, and boiling point is 190 DEG C.With special foreign odor, there is hygroscopicity, easily distils.It is soluble in hot water, petroleum ether, is dissolved in
Chloroform, dilute hydrochloric acid, are slightly soluble in ether, do not dissolve in cold water.It has expansion blood vessel, slight decompression, inhibits platelet adhesion reaction aggregation
With thrombosis, the pharmacological action for inhibiting smooth muscle cell and fibroblast proliferation etc. better, the country is caused at present
The extensive concern of outer medical field.Now obliterative vascular disease clinically mainly used for treating, as cerebral embolism, coronary heart disease, the heart twist
Bitterly, vasculitis, chronic cardiopulmonary disease, chronic renal failure etc., structural formula are：
2- ethyl -3,5,6- trimethylpyrazine are the impurity for synthesizing ligustrazine and being easy to produce in the process, and can be with this
Many pyrazine compounds are synthesized for starting point, the ligustrazine that the miscellaneous Quality Research of ligustrazine and guarantee are prepared for convenience
Quality is needed to 2- ethyl -3,5, and 6- trimethylpyrazine is studied, and monitors its content in ligustrazine, it is therefore desirable to
Prepare 2- ethyl -3,5,6- trimethylpyrazine monomer.Synthesis 2- ethyl -3,5 at present, the method for 6- trimethylpyrazine, operation are multiple
Miscellaneous, side reaction is more, and yield and purity are lower.
Summary of the invention
Basic background technique, the invention proposes a kind of 2- ethyl -3,5,6- trimethylpyrazine
Synthetic method, operation of the present invention is simple, and side reaction is few, and product is easily isolated purifying, high income, purity is high.
A kind of 2- ethyl -3,5 proposed by the present invention, the synthetic method of 6- trimethylpyrazine include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, it is added
Aqueous hydrogen peroxide solution, heating, insulated and stirred are concentrated under reduced pressure and remove glacial acetic acid, adjust pH=6-8, and methylene chloride extraction is added,
Organic layer is taken, removing methylene chloride is concentrated under reduced pressure and obtains 1- oxo -2,3,5- trimethylpyrazine, wherein aqueous hydrogen peroxide solution
It is added in three times, each additional amount is identical；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and three
Chlorethoxyfos mix, and heating, insulated and stirred obtains solution A；Solution A is added in trash ice and mixes cooling, adjusts pH=6-8, is added
Methylene chloride extraction, takes organic layer, and removing methylene chloride is concentrated under reduced pressure and obtains 2- chloro- 3,5,6- trimethylpyrazines；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and dry
Dry tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, bromoethane is added
2-4h is stirred at room temperature in Grignard Reagent, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, and dry, reduced pressure removes
Methylene chloride is gone to obtain 2- ethyl -3,5,6- trimethylpyrazine.
Preferably, in S1, after 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, aqueous hydrogen peroxide solution, heating is added
It to 60-80 DEG C, insulated and stirred 3-5h, is concentrated under reduced pressure and removes glacial acetic acid, adjust pH=6-8 with saturated aqueous sodium carbonate, be added
Methylene chloride extraction, takes organic layer, dry, is concentrated under reduced pressure and removes methylene chloride and obtain 1- oxo -2,3,5- trimethylpyrazine,
In, aqueous hydrogen peroxide solution is added in three times, and each additional amount is identical.
Preferably, in S1, the mass fraction of aqueous hydrogen peroxide solution is 30-35wt%.
Preferably, in S1,2,3,5- trimethylpyrazines, aqueous hydrogen peroxide solution bulking value (g/ml) than be 5-7：
33-47。
Preferably, in S1,2,3,5- trimethylpyrazines, glacial acetic acid bulking value (g/ml) than be 5-7：35-45.
Preferably, in S2, by 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and phosphorus oxychloride are mixed, and are warming up to
60-80 DEG C, insulated and stirred 1.5-2.5h obtains solution A；Solution A is added to mix in trash ice and is cooled to 8-12 DEG C, uses hydroxide
Sodium water solution adjusts pH=6-8, and methylene chloride extraction is added, takes organic layer, and dry, reduced pressure removes methylene chloride and obtains 2-
Chloro- 3,5,6- trimethylpyrazines.
Preferably, in S2,1- oxo -2,3, the bulking value (g/ml) of 5- trimethylpyrazine and phosphorus oxychloride is than being 0.8-
1.2：8-12.
Preferably, in S3, the solvent of bromoethane Grignard Reagent is one of tetrahydrofuran or ether, the examination of bromoethane grignard
The concentration of agent is 0.8-1.2mol/l.
Preferably, it in S3, is concentrated under reduced pressure and removes methylene chloride, column chromatographs to obtain 2- ethyl -3,5,6- trimethylpyrazine.
Preferably, in S3,2- chloro- 3, the bulking value (g/ml) of 5,6- trimethylpyrazines and tetrahydrofuran is than being 1：8-
12。
Preferably, in S3,2- chloro- 3,5,6- trimethylpyrazines and 1, the weight ratio of bis- (diphenylphosphine) the propane nickel chlorides of 3-
For 1-3：0.05-0.15.
Preferably, in S3, bulking value (g/ml) ratio of 2- chloro- 3,5,6- trimethylpyrazines and bromoethane Grignard Reagent are
1：2.1-3.1.
Above-mentioned water is deionized water.
In above-mentioned S2, the effect of trash ice is cooling and removes excessive phosphorus oxychloride, does not provide its dosage, according to specific behaviour
Make to determine its dosage.
In above-mentioned S2, the effect of sodium hydrate aqueous solution is to adjust pH value, does not provide its concentration.
In above-mentioned S3, the effect of water is quenching reaction, does not provide its dosage, determines its dosage according to concrete operations.
The effect of methylene chloride is extraction in above-mentioned S1, S2, S3, does not provide its dosage, determines its use according to concrete operations
Amount, and methylene chloride is both needed to be recycled.
2- ethyl -3,5 provided by the invention, the synthetic method of 6- trimethylpyrazine, synthetic route are as follows：
The present invention selects 2,3,5- trimethylpyrazines and hydroperoxidation to obtain 1- oxo -2,3,5- trimethylpyrazine,
1- oxo -2,3,5- trimethylpyrazine and phosphorus oxychloride reaction obtain 2- chloro- 3,5,6- trimethylpyrazines, then through bromoethane grignard
Reagent docks to obtain 2- ethyl -3,5,6- trimethylpyrazine；React by totally 3 steps by the present invention, and route is short, easy to operate, is suitble to industry
Metaplasia produces；Reaction condition of the present invention is mild, and the reaction time is short, can reduce energy consumption, reduces cost of the invention；The present invention reacts single
One, side reaction is few, high income, and purity is high can further improve 2- ethyl -3,5,6- trimethyl pyrrole using column chromatographic isolation and purification
The purity of piperazine.
Specific embodiment
In the following, technical solution of the present invention is described in detail by specific embodiment.
Embodiment 1
A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, it is added
Aqueous hydrogen peroxide solution, heating, insulated and stirred are concentrated under reduced pressure and remove glacial acetic acid, adjust pH=7, and methylene chloride extraction is added, takes
Organic layer is concentrated under reduced pressure removing methylene chloride and obtains 1- oxo -2,3,5- trimethylpyrazine, wherein aqueous hydrogen peroxide solution point
It is added three times, each additional amount is identical；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and three
Chlorethoxyfos mix, and heating, insulated and stirred obtains solution A；Solution A is added in trash ice and mixes cooling, adjusts pH=7, is added two
Chloromethanes extraction, takes organic layer, and removing methylene chloride is concentrated under reduced pressure and obtains 2- chloro- 3,5,6- trimethylpyrazines；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and dry
Dry tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, bromoethane is added
2-4h is stirred at room temperature in Grignard Reagent, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, and dry, reduced pressure removes
Methylene chloride is gone to obtain 2- ethyl -3,5,6- trimethylpyrazine.
Embodiment 2
A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, it is added
Mass fraction is 30wt% aqueous hydrogen peroxide solution, is warming up to 80 DEG C, insulated and stirred 3h, is concentrated under reduced pressure and removes glacial acetic acid, with full
PH=8 is adjusted with aqueous sodium carbonate, methylene chloride extraction is added, takes organic layer, dry, reduced pressure removes methylene chloride and obtains
To 1- oxo -2,3,5- trimethylpyrazine, wherein aqueous hydrogen peroxide solution is added in three times, and each additional amount is identical, and 2,3,5-
Trimethylpyrazine, aqueous hydrogen peroxide solution bulking value (g/ml) than be 5：The weight of 47,2,3,5- trimethylpyrazines, glacial acetic acid
Volume (g/ml) is measured than being 1：9；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and three
Chlorethoxyfos mix, and are warming up to 60 DEG C, insulated and stirred 2.5h obtains solution A；Solution A is added to mix in trash ice and is cooled to 8 DEG C, is used
Sodium hydrate aqueous solution adjusts pH=8, and methylene chloride extraction is added, takes organic layer, and dry, reduced pressure removes methylene chloride and obtains
To 2- chloro- 3,5,6- trimethylpyrazines, wherein the bulking value (g/ of 1- oxo -2,3,5- trimethylpyrazine and phosphorus oxychloride
Ml) than being 0.2：3；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and dry
Dry tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, concentration, which is added, is
0.8mol/l bromoethane Grignard Reagent, is stirred at room temperature 4h, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, does
It is dry, it is concentrated under reduced pressure and removes methylene chloride, column chromatographs to obtain 2- ethyl -3,5,6- trimethylpyrazine, wherein bromoethane Grignard Reagent
Solvent be tetrahydrofuran or ether, 2- chloro- 3, the bulking value (g/ml) of 5,6- trimethylpyrazines and tetrahydrofuran is than being 1：
8,2- chloro- 3,5,6- trimethylpyrazines and 1, the weight ratio of bis- (diphenylphosphine) the propane nickel chlorides of 3- is 3：0.05,2- chloro- 3,5,
The bulking value (g/ml) of 6- trimethylpyrazine and bromoethane Grignard Reagent is than being 1：3.1.
Embodiment 3
A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, it is added
Mass fraction is 35wt% aqueous hydrogen peroxide solution, is warming up to 60 DEG C, insulated and stirred 5h, is concentrated under reduced pressure and removes glacial acetic acid, with full
PH=6 is adjusted with aqueous sodium carbonate, methylene chloride extraction is added, takes organic layer, dry, reduced pressure removes methylene chloride and obtains
To 1- oxo -2,3,5- trimethylpyrazine, wherein aqueous hydrogen peroxide solution is added in three times, and each additional amount is identical, and 2,3,5-
Trimethylpyrazine, aqueous hydrogen peroxide solution bulking value (g/ml) than be 7：The weight of 33,2,3,5- trimethylpyrazines, glacial acetic acid
Volume (g/ml) is measured than being 1：5；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and three
Chlorethoxyfos mix, and are warming up to 80 DEG C, insulated and stirred 1.5h obtains solution A；Solution A is added to mix in trash ice and is cooled to 12 DEG C,
PH=6 is adjusted with sodium hydrate aqueous solution, methylene chloride extraction is added, takes organic layer, it is dry, it is concentrated under reduced pressure and removes methylene chloride
Obtain 2- chloro- 3,5,6- trimethylpyrazines, wherein the bulking value (g/ of 1- oxo -2,3,5- trimethylpyrazine and phosphorus oxychloride
Ml) than being 0.3：2；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and dry
Dry tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, concentration, which is added, is
1.2mol/l bromoethane Grignard Reagent, is stirred at room temperature 2h, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, does
It is dry, it is concentrated under reduced pressure and removes methylene chloride, column chromatographs to obtain 2- ethyl -3,5,6- trimethylpyrazine, wherein bromoethane Grignard Reagent
Solvent be tetrahydrofuran or ether, 2- chloro- 3, the bulking value (g/ml) of 5,6- trimethylpyrazines and tetrahydrofuran is than being 1：
12,2- chloro- 3,5,6- trimethylpyrazines and 1, the weight ratio of bis- (diphenylphosphine) the propane nickel chlorides of 3- is 1：0.15,2- chloro- 3,
The bulking value (g/ml) of 5,6- trimethylpyrazines and bromoethane Grignard Reagent is than being 1：2.1.
Embodiment 4
A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, it is added
Mass fraction is 32wt% aqueous hydrogen peroxide solution, is warming up to 75 DEG C, insulated and stirred 3.5h, is concentrated under reduced pressure and removes glacial acetic acid, is used
Saturated aqueous sodium carbonate adjusts pH=7.5, and methylene chloride extraction is added, takes organic layer, dry, is concentrated under reduced pressure and removes dichloromethane
Alkane obtains 1- oxo -2,3,5- trimethylpyrazine, wherein and aqueous hydrogen peroxide solution is added in three times, and each additional amount is identical, and 2,
3,5- trimethylpyrazines, aqueous hydrogen peroxide solution bulking value (g/ml) than be 5.5：42,2,3,5- trimethylpyrazines, ice vinegar
The bulking value (g/ml) of acid is than being 5.5：43；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and three
Chlorethoxyfos mix, and are warming up to 65 DEG C, insulated and stirred 2.3h obtains solution A；Solution A is added to mix in trash ice and is cooled to 9 DEG C, is used
Sodium hydrate aqueous solution adjusts pH=7.5, and methylene chloride extraction is added, takes organic layer, dry, is concentrated under reduced pressure and removes methylene chloride
Obtain 2- chloro- 3,5,6- trimethylpyrazines, wherein the bulking value (g/ of 1- oxo -2,3,5- trimethylpyrazine and phosphorus oxychloride
Ml) than being 0.9：11；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and dry
Dry tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, concentration, which is added, is
0.9mol/l bromoethane Grignard Reagent, is stirred at room temperature 3.5h, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, does
It is dry, it is concentrated under reduced pressure and removes methylene chloride, column chromatographs to obtain 2- ethyl -3,5,6- trimethylpyrazine, wherein bromoethane Grignard Reagent
Solvent be tetrahydrofuran or ether, 2- chloro- 3, the bulking value (g/ml) of 5,6- trimethylpyrazines and tetrahydrofuran is than being 1：
9,2- chloro- 3,5,6- trimethylpyrazines and 1, the weight ratio of bis- (diphenylphosphine) the propane nickel chlorides of 3- is 2.5：0.07,2- chloro- 3,
The bulking value (g/ml) of 5,6- trimethylpyrazines and bromoethane Grignard Reagent is than being 1：2.7.
Embodiment 5
A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, it is added
Mass fraction is 34wt% aqueous hydrogen peroxide solution, is warming up to 65 DEG C, insulated and stirred 4.5h, is concentrated under reduced pressure and removes glacial acetic acid, is used
Saturated aqueous sodium carbonate adjusts pH=6.5, and methylene chloride extraction is added, takes organic layer, dry, is concentrated under reduced pressure and removes dichloromethane
Alkane obtains 1- oxo -2,3,5- trimethylpyrazine, wherein and aqueous hydrogen peroxide solution is added in three times, and each additional amount is identical, and 2,
3,5- trimethylpyrazines, aqueous hydrogen peroxide solution bulking value (g/ml) than be 6.5：38,2,3,5- trimethylpyrazines, ice vinegar
The bulking value (g/ml) of acid is than being 6.5：37；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and three
Chlorethoxyfos mix, and are warming up to 75 DEG C, insulated and stirred 1.7h obtains solution A；Solution A is added to mix in trash ice and is cooled to 11 DEG C,
PH=6.5 is adjusted with sodium hydrate aqueous solution, methylene chloride extraction is added, takes organic layer, it is dry, it is concentrated under reduced pressure and removes dichloromethane
Alkane obtains 2- chloro- 3,5,6- trimethylpyrazines, wherein 1- oxo -2,3, the bulking value of 5- trimethylpyrazine and phosphorus oxychloride
(g/ml) than being 1.1：9；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and dry
Dry tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, concentration, which is added, is
1.1mol/l bromoethane Grignard Reagent, is stirred at room temperature 2.5h, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, does
It is dry, it is concentrated under reduced pressure and removes methylene chloride, column chromatographs to obtain 2- ethyl -3,5,6- trimethylpyrazine, wherein bromoethane Grignard Reagent
Solvent be tetrahydrofuran or ether, 2- chloro- 3, the bulking value (g/ml) of 5,6- trimethylpyrazines and tetrahydrofuran is than being 1：
11,2- chloro- 3,5,6- trimethylpyrazines and 1, the weight ratio of bis- (diphenylphosphine) the propane nickel chlorides of 3- is 1.5：0.13,2- is chloro-
The bulking value (g/ml) of 3,5,6- trimethylpyrazines and bromoethane Grignard Reagent is than being 1：2.3.
Embodiment 6
A kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, it is added
Mass fraction is 30wt% aqueous hydrogen peroxide solution, is warming up to 70 DEG C, insulated and stirred 4h, is concentrated under reduced pressure and removes glacial acetic acid, with full
PH=7 is adjusted with aqueous sodium carbonate, methylene chloride extraction is added, takes organic layer, dry, reduced pressure removes methylene chloride and obtains
To 1- oxo -2,3,5- trimethylpyrazine, wherein aqueous hydrogen peroxide solution is added in three times, and each additional amount is identical, and 2,3,5-
Trimethylpyrazine, aqueous hydrogen peroxide solution bulking value (g/ml) than be 3：The weight of 20,2,3,5- trimethylpyrazines, glacial acetic acid
Volume (g/ml) is measured than being 3：20；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and three
Chlorethoxyfos mix, and are warming up to 70 DEG C, insulated and stirred 2h obtains solution A；Solution A is added to mix in trash ice and is cooled to 10 DEG C, is used
Sodium hydrate aqueous solution adjusts pH=7, and methylene chloride extraction is added, takes organic layer, and dry, reduced pressure removes methylene chloride and obtains
To 2- chloro- 3,5,6- trimethylpyrazines, wherein the bulking value (g/ of 1- oxo -2,3,5- trimethylpyrazine and phosphorus oxychloride
Ml) than being 1：10；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and dry
Dry tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, concentration, which is added, is
1mol/l bromoethane Grignard Reagent, is stirred at room temperature 3h, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, dry,
It is concentrated under reduced pressure and removes methylene chloride, column chromatographs to obtain 2- ethyl -3,5,6- trimethylpyrazine, wherein bromoethane Grignard Reagent
Solvent is tetrahydrofuran, 2- chloro- 3, and the bulking value (g/ml) of 5,6- trimethylpyrazines and tetrahydrofuran is than being 1：10,2- is chloro-
3,5,6- trimethylpyrazines and 1, the weight ratio of bis- (diphenylphosphine) the propane nickel chlorides of 3- are 2：0.1,2- chloro- 3,5,6- trimethyls
The bulking value (g/ml) of pyrazine and bromoethane Grignard Reagent is than being 1：2.5.
The yield of each reaction step of embodiment 5 is calculated, it is as a result as follows：
The yield of each step reaction of the present invention is higher as can be seen from the above table, so overall yield is higher, purity is also preferable.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of 2- ethyl -3,5, the synthetic method of 6- trimethylpyrazine, which is characterized in that include the following steps：
S1, preparation 1- oxo -2,3,5- trimethylpyrazine：After 2,3,5- trimethylpyrazines and glacial acetic acid are mixed, peroxide is added
Change aqueous solution of hydrogen, heating, insulated and stirred is concentrated under reduced pressure and removes glacial acetic acid, adjusts pH=6-8, and methylene chloride extraction is added, has taken
Machine layer is concentrated under reduced pressure removing methylene chloride and obtains 1- oxo -2,3,5- trimethylpyrazine, wherein aqueous hydrogen peroxide solution point three
Secondary addition, each additional amount are identical；
S2, preparation 2- chloro- 3,5,6- trimethylpyrazines：By 1- oxo -2,3 obtained in S1,5- trimethylpyrazine and trichlorine oxygen
Phosphorus mixes, and is warming up to 60-80 DEG C, insulated and stirred 1.5-2.5h obtains solution A；Solution A is added to mix in trash ice and is cooled to 8-
12 DEG C, pH=6-8 is adjusted with sodium hydrate aqueous solution, methylene chloride extraction is added, takes organic layer, is concentrated under reduced pressure and removes dichloromethane
Alkane obtains 2- chloro- 3,5,6- trimethylpyrazines, wherein 1- oxo -2,3, the bulking value of 5- trimethylpyrazine and phosphorus oxychloride
(g/ml) than being 0.8-1.2：8-12；
S3, preparation 2- ethyl -3,5,6- trimethylpyrazine：By 2- obtained in S2 chloro- 3,5,6- trimethylpyrazines and drying
Tetrahydrofuran mixes, and in nitrogen atmosphere, after bis- (diphenylphosphine) the propane nickel chlorides mixings of 1,3- are added, bromoethane grignard is added
2-4h is stirred at room temperature in reagent, adds water quenching reaction, and methylene chloride extraction is added, takes organic layer, dry, is concentrated under reduced pressure and removes two
Chloromethanes obtains 2- ethyl -3,5,6- trimethylpyrazine.
2. 2- ethyl -3,5 according to claim 1, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S1, by 2,
After 3,5- trimethylpyrazines and glacial acetic acid mix, aqueous hydrogen peroxide solution is added, is warming up to 60-80 DEG C, insulated and stirred 3-5h subtracts
Pressure concentration removes glacial acetic acid, adjusts pH=6-8 with saturated aqueous sodium carbonate, and methylene chloride extraction is added, takes organic layer, does
It is dry, removing methylene chloride is concentrated under reduced pressure and obtains 1- oxo -2,3,5- trimethylpyrazine, wherein aqueous hydrogen peroxide solution is in three times
It is added, each additional amount is identical.
3. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S1,
The mass fraction of aqueous hydrogen peroxide solution is 30-35wt%.
4. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S1,
2,3,5- trimethylpyrazines, aqueous hydrogen peroxide solution bulking value (g/ml) than be 5-7：33-47.
5. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S1,
2,3,5- trimethylpyrazines, glacial acetic acid bulking value (g/ml) than be 5-7：35-45.
6. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S3,
The solvent of bromoethane Grignard Reagent is one of tetrahydrofuran or ether, and the concentration of bromoethane Grignard Reagent is 0.8-
1.2mol/l。
7. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S3,
It is concentrated under reduced pressure and removes methylene chloride, column chromatographs to obtain 2- ethyl -3,5,6- trimethylpyrazine.
8. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S3,
The bulking value (g/ml) of 2- chloro- 3,5,6- trimethylpyrazines and tetrahydrofuran is than being 1：8-12.
9. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S3,
2- chloro- 3,5,6- trimethylpyrazines and 1, the weight ratio of bis- (diphenylphosphine) the propane nickel chlorides of 3- are 1-3：0.05-0.15.
10. 2- ethyl -3,5 according to claim 1 or claim 2, the synthetic method of 6- trimethylpyrazine, which is characterized in that in S3,
The bulking value (g/ml) of 2- chloro- 3,5,6- trimethylpyrazines and bromoethane Grignard Reagent is than being 1：2.1-3.1.
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