CN110156701B - Synthesis method of 2,3,5, 6-tetramethylpyrazine - Google Patents
Synthesis method of 2,3,5, 6-tetramethylpyrazine Download PDFInfo
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- CN110156701B CN110156701B CN201910556094.3A CN201910556094A CN110156701B CN 110156701 B CN110156701 B CN 110156701B CN 201910556094 A CN201910556094 A CN 201910556094A CN 110156701 B CN110156701 B CN 110156701B
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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 invention relates to a synthetic method of 2,3,5, 6-tetramethylpyrazine, which comprises the following steps: s1, preparing butanedione monoxime: the method comprises the following steps of (1) adding ammonia water and hydrogen peroxide into butanedione serving as a raw material, toluene serving as a solvent and a titanium silicalite molecular sieve serving as a catalyst to react; s2, preparing 2,3,5, 6-tetramethylpyrazine: and (3) uniformly mixing the crude butanedione monoxime obtained in the step (S1) with water, adding palladium carbon as a catalyst, and reacting in a hydrogen atmosphere. The synthesis method of the 2,3,5, 6-tetramethylpyrazine uses ammonia water, hydrogen peroxide and butanedione to obtain butanedione monoxime under the catalysis of the titanium silicalite molecular sieve, and then uses palladium-carbon as a catalyst in a hydrogen atmosphere to synthesize the 2,3,5, 6-tetramethylpyrazine, and the synthesis method has the advantages of low prices of the ammonia water and the hydrogen peroxide, repeated use of the titanium silicalite molecular sieve, low cost and suitability for industrial production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a synthetic method of 2,3,5, 6-tetramethylpyrazine.
Background
2,3,5, 6-tetramethylpyrazine is the chemical name of ligustrazine, is an alkaloid monomer separated and purified from Ligusticum wallichii of the genus Ligusticum of the family Umbelliferae, and is one of the effective components of Ligusticum wallichii.
2,3,5, 6-tetramethylpyrazine, of the formula: c8H14N2Colorless needle crystals, molecular weight 136.20, melting point: 82-84 ℃, boiling point: 190 ℃. The structural formula is as follows:
2,3,5, 6-tetramethylpyrazine is used as a flavor, mainly meat and cocoa, nut, peanut, coffee, chocolate and other flavors; it can also be used as flavoring agent, correctant in cigarette, and supplement. The important aroma component in the vinegar is ligustrazine which endows the vinegar with special nut aroma and baking aroma and also endows the vinegar with health care value; it is also an important aroma compound in Chinese liquor.
The 2,3,5, 6-tetramethylpyrazine can also be used for producing ligustrazine phosphate, ligustrazine injection, and pyrazine ferulate, and can be used for treating ischemic cardiovascular and cerebrovascular diseases.
The preparation method of the 2,3,5, 6-tetramethylpyrazine comprises a biological synthesis method and a chemical synthesis method. Among them, the biosynthesis method such as the biological fermentation method has a low yield.
In the chemical synthesis method, the reaction process of the preparation is as follows:
in the route, hydroxylamine hydrochloride and butanedione react to produce butanedione monoxime, and then 2,3,5, 6-tetramethylpyrazine is obtained through reduction and cyclization, and the purity of the 2,3,5, 6-tetramethylpyrazine reaches 99 wt%. However, the cost of the hydroxylamine hydrochloride used as the raw material in the route is high, which is not favorable for industrial production.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a synthetic method of 2,3,5, 6-tetramethylpyrazine with low production cost.
In order to achieve the purpose, the invention adopts the technical scheme that: a synthetic method of 2,3,5, 6-tetramethylpyrazine comprises the following steps:
s1, preparing butanedione monoxime: the method comprises the following steps of (1) adding ammonia water and hydrogen peroxide into butanedione serving as a raw material, toluene serving as a solvent and a titanium silicalite molecular sieve serving as a catalyst to react;
s2, preparing 2,3,5, 6-tetramethylpyrazine: and (3) uniformly mixing the crude butanedione monoxime obtained in the step (S1) with water, adding palladium carbon as a catalyst, and reacting in a hydrogen atmosphere.
Specifically, the titanium silicalite molecular sieve is a TS-I type titanium silicalite molecular sieve and can be repeatedly used for many times.
Preferably, the titanium silicalite molecular sieve is a TS-I type titanium silicalite molecular sieve and can be repeatedly used for 2-200 times.
Further preferably, the titanium silicalite molecular sieve is a TS-I type titanium silicalite molecular sieve and can be reused for 90-100 times.
Specifically, in S1, the mass ratio of the butanedione to the titanium silicalite molecular sieve is 17.2: 0.9-1.1.
Preferably, in S1, the mass ratio of the butanedione to the titanium silicalite molecular sieve is 17.2: 1-1.1.
Further preferably, in S1, the mass ratio of the butanedione to the titanium silicalite molecular sieve is 17.2: 1-1.05.
Specifically, in S1, the ammonia water is 20-30% by mass, and the hydrogen peroxide is 20-30% by mass.
Preferably, in S1, the ammonia water is 25-30% by mass, and the hydrogen peroxide is 25-30% by mass.
Specifically, in S1, the molar ratio of butanedione to ammonia water is 1: 1.1-1.3.
Preferably, in S1, the molar ratio of butanedione to ammonia water is 1: 1.15-1.25.
Further preferably, in S1, the molar ratio of butanedione to ammonia water is 1: 1.18-1.23.
Specifically, in S1, the molar ratio of the butanedione to the hydrogen peroxide is 1:1.1-1.3, and the molar ratio of the hydrogen peroxide to the ammonia water is not less than 1.
Preferably, in S1, the molar ratio of butanedione to hydrogen peroxide is 1:1.15-1.25, and the molar ratio of hydrogen peroxide to ammonia water is greater than or equal to 1.
Further preferably, the molar ratio of the butanedione to the hydrogen peroxide is 1:1.19-1.22, and the molar ratio of the hydrogen peroxide to the ammonia water is more than 1.
Specifically, in S1, the reaction temperature is 45-50 ℃ and the reaction time is 0.8-2 h.
Preferably, in S1, the reaction temperature is 46-49 ℃ and the reaction time is 1-1.8 h.
Specifically, in S2, the reaction temperature is 130-150 ℃, the reaction time is 3.5-5.5h, and the pressure of the hydrogen is 1.0-1.5 MPa.
Preferably, in S2, the reaction temperature is 140-150 ℃, the reaction time is 4-5h, and the pressure of the hydrogen is 1.2-1.4 MPa.
Specifically, in S2, the mass ratio of the palladium carbon to the crude butanedione monoxime is 1: 18-22.
Preferably, in S2, the mass ratio of the palladium carbon to the crude butanedione monoxime is 1: 19-21.
Specifically, the synthesis method of 2,3,5, 6-tetramethylpyrazine comprises the following steps:
s1, preparing butanedione monoxime: adding ammonia water into a high-pressure reaction kettle by taking butanedione as a raw material, toluene as a solvent and a titanium silicalite molecular sieve as a catalyst, and then adding hydrogen peroxide in batches to perform stirring reaction;
s2, preparing 2,3,5, 6-tetramethylpyrazine: and (3) uniformly mixing the crude butanedione monoxime obtained in the step (S1) with water, putting the mixture into a high-pressure reaction kettle, adding palladium-carbon serving as a catalyst, replacing the catalyst with nitrogen, replacing the catalyst with hydrogen, and stirring the mixture to react in a hydrogen atmosphere.
Preferably, the synthesis method of the 2,3,5, 6-tetramethylpyrazine comprises the following steps:
s1, preparing butanedione monoxime: adding ammonia water into a high-pressure reaction kettle by using butanedione as a raw material, toluene as a solvent and a titanium silicalite molecular sieve as a catalyst, adding hydrogen peroxide in batches, controlling the temperature, and carrying out stirring reaction; after the reaction is finished, filtering to remove the titanium silicalite molecular sieve, removing the water phase, and evaporating to remove the toluene to obtain a crude product of the butanedione monoxime;
s2, preparing 2,3,5, 6-tetramethylpyrazine: uniformly mixing the crude butanedione monoxime obtained in the step S1 with water, putting the mixture into a high-pressure reaction kettle, adding palladium-carbon serving as a catalyst, sealing the reaction kettle, replacing the reaction kettle with nitrogen for three times, replacing the reaction kettle with hydrogen for three times, adjusting the hydrogen atmosphere, heating, and carrying out stirring reaction; after the reaction is finished, filtering to remove palladium carbon, distilling to remove water, collecting fractions under reduced pressure, and cooling to obtain needle crystals.
The preparation process comprises the following steps:
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the synthesis method of the 2,3,5, 6-tetramethylpyrazine uses ammonia water, hydrogen peroxide and butanedione to obtain butanedione monoxime under the catalysis of the titanium silicalite molecular sieve, and then uses palladium-carbon as a catalyst in a hydrogen atmosphere to synthesize the 2,3,5, 6-tetramethylpyrazine, and the synthesis method has the advantages of low prices of the ammonia water and the hydrogen peroxide, repeated use of the titanium silicalite molecular sieve, low cost and suitability for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not mentioned are conventional conditions in the industry.
Example 1
The embodiment provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which comprises the following steps:
s1, preparing butanedione monoxime: taking 0.86t of butanedione as a raw material, 2000L of toluene as a solvent, 50kg of TS-I type titanium silicalite molecular sieve as a catalyst, and adding 0.82t of ammonia water with the mass concentration of 25% to 10%4Adding 1.65t of hydrogen peroxide with the mass concentration of 25% into the high-pressure reaction kettle of L in batches within 1 hour, and stirring and reacting for 1 hour at 48 ℃; and after the reaction is finished, filtering to remove the TS-I type titanium silicalite molecular sieve, extracting to obtain an organic layer, and carrying out reduced pressure concentration to remove toluene to obtain 1.01t of the crude product of the butanedione monoxime.
S2, preparing 2,3,5, 6-tetramethylpyrazine: uniformly mixing the crude product of the butanedione monoxime obtained in the step S1 with 2000L of water, putting the mixture into a high-pressure reaction kettle, adding 50kg of 10% palladium carbon as a catalyst, sealing the reaction kettle, performing nitrogen replacement three times, performing hydrogen replacement three times, adjusting the hydrogen pressure to be 1.3MPa, heating to 140 ℃, and performing stirring reaction for 4.5 hours; after the reaction is finished, the reaction kettle is opened, palladium carbon is removed by filtration, water is removed by distillation under the reduced pressure of 20mmHg, fractions at the temperature of 90-95 ℃ are collected and cooled to obtain 4.1t of 2,3,5, 6-tetramethylpyrazine needle crystals, and the yield is 60.3%.
Example 2
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: and in S1, adding 55kg of TS-I type titanium silicalite molecular sieve as a catalyst. Cooling to obtain needle crystal 4.20t of 2,3,5, 6-tetramethyl pyrazine in 61.7% yield.
Example 3
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: adding 0.748t of 25 mass percent ammonia water into S1 to 104And adding 1.496t of hydrogen peroxide with the mass concentration of 25 percent into the high-pressure reaction kettle of the L in batches within 1 hour. Cooling to obtain needle crystal 3.97t of 2,3,5, 6-tetramethylpyrazine with yield 58.3%.
Example 4
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: adding 0.884t of 25% ammonia water to 10 mass percent in S14And adding 1.675t of hydrogen peroxide with the mass concentration of 25 percent into the high-pressure reaction kettle of the L in batches within 1 hour. Cooling to obtain needle crystal 4.27t of 2,3,5, 6-tetramethyl pyrazine in 62.7% yield.
Example 5
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: in S1, the reaction was stirred at 45 ℃ for 1 hour. Cooling to obtain needle crystal 4.09t of 2,3,5, 6-tetramethylpyrazine with yield 60.1%.
Example 6
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: in S1, the reaction was stirred at 50 ℃ for 2 h. Cooling to obtain 4.13t of needle-shaped crystals of 2,3,5, 6-tetramethylpyrazine with the yield of 60.6 percent.
Example 7
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: the TS-I type titanium silicalite molecular sieve is reused for the 100 th time. Cooling to obtain needle crystal of 2,3,5, 6-tetramethyl pyrazine in 3.98t yield of 58.4%.
Example 8
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: in S2, 56.1kg of 10% palladium on carbon was added as a catalyst. Cooling to obtain needle crystal 4.11t of 2,3,5, 6-tetramethyl pyrazine in 60.4% yield.
Example 9
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: in S2, the temperature was raised to 150 ℃ and the reaction was stirred for 3.5 hours. Cooling to obtain needle crystal 4.09t of 2,3,5, 6-tetramethylpyrazine with yield 60.1%.
Comparative example 1
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, in which 0.695t of hydroxylamine hydrochloride and 0.86t of butanedione are reacted first to generate butanedione monoxime, and then reduced to obtain 2,3,5, 6-tetramethylpyrazine, and the yield of the reaction is about 60%, but the cost is high.
The market price of hydroxylamine hydrochloride is 3.8 ten thousand yuan/ton, and in comparative example 1, the feeding molar ratio of hydroxylamine hydrochloride to butanedione is 1:1, and the hydroxylamine hydrochloride and the butanedione participate in the reaction. 0.695t of hydroxylamine hydrochloride is fed into 0.86t of butanedione. The cost of the hydroxylamine hydrochloride is 2.641 ten thousand yuan.
In examples 1 to 9, the price of ammonia water was 0.2 ten thousand yuan/ton, the price of hydrogen peroxide was 0.02 ten thousand yuan/ton, and the price of the TS-I type titanium silicalite molecular sieve was 1 ten thousand yuan/ton, but the reaction amount was small and the molecular sieve was reused 100 times with high efficiency. If, according to example 1, 0.86t of butanedione needs to be dosed: 50kg of TS-I type titanium silicalite molecular sieve (0.05 ten thousand yuan, average to 100 times, 0.005 ten thousand yuan each time), 0.82t of ammonia water (0.164 ten thousand yuan), 1.65t of hydrogen peroxide (0.033 ten thousand yuan), and the cost of raw materials except butanedione is 0.202 ten thousand yuan.
Comparative example 2
This example provides a method for synthesizing 2,3,5, 6-tetramethylpyrazine, which has the steps substantially the same as those in example 1, except that: in S1, 1.65t of hydrogen peroxide with the mass concentration of 25 percent is added at one time. Cooling to obtain needle crystal 3.43t of 2,3,5, 6-tetramethyl pyrazine in 50.4% yield.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (8)
1. A synthetic method of 2,3,5, 6-tetramethylpyrazine is characterized by comprising the following steps:
s1 preparation of butanedione monoxime: the method comprises the following steps of (1) adding ammonia water and hydrogen peroxide into butanedione serving as a raw material, toluene serving as a solvent and a titanium silicalite molecular sieve serving as a catalyst to react; the reaction temperature is 45-50 ℃ and the reaction time is 0.8-2 h;
s2 preparation of 2,3,5, 6-tetramethylpyrazine: uniformly mixing the crude product of the butanedione monoxime obtained in the step S1 with water, adding palladium carbon as a catalyst, and reacting in a hydrogen atmosphere; the reaction temperature is 130-150 ℃, the reaction time is 3.5-5.5h, and the pressure of the hydrogen is 1.0-1.5 MPa.
2. The method for synthesizing 2,3,5, 6-tetramethylpyrazine according to claim 1, wherein the method comprises the following steps: the titanium silicalite molecular sieve is a TS-I type titanium silicalite molecular sieve and can be repeatedly used for many times.
3. The method for synthesizing 2,3,5, 6-tetramethylpyrazine according to claim 1 or 2, characterized in that: in S1, the mass ratio of the butanedione to the titanium silicalite molecular sieve is 17.2: 0.9-1.1.
4. The method for synthesizing 2,3,5, 6-tetramethylpyrazine according to claim 1, wherein the method comprises the following steps: in S1, the ammonia water is 20-30% by mass, and the hydrogen peroxide is 20-30% by mass.
5. The method for synthesizing 2,3,5, 6-tetramethylpyrazine according to claim 1 or 4, characterized in that: in S1, the molar ratio of butanedione to ammonia water is 1: 1.1-1.3.
6. The method for synthesizing 2,3,5, 6-tetramethylpyrazine according to claim 1 or 4, characterized in that: in S1, the molar ratio of the butanedione to the hydrogen peroxide is 1:1.1-1.3, and the molar ratio of the hydrogen peroxide to the ammonia water is more than or equal to 1.
7. The method for synthesizing 2,3,5, 6-tetramethylpyrazine according to claim 1, wherein the method comprises the following steps: in S2, the mass ratio of the palladium carbon to the crude butanedione monoxime is 1: 18-22.
8. The method for synthesizing 2,3,5, 6-tetramethylpyrazine according to claim 1, wherein the method comprises the following steps: it comprises the following steps:
s1 preparation of butanedione monoxime: adding ammonia water into a high-pressure reaction kettle by taking butanedione as a raw material, toluene as a solvent and a titanium silicalite molecular sieve as a catalyst, and then adding hydrogen peroxide in batches to perform stirring reaction;
s2 preparation of 2,3,5, 6-tetramethylpyrazine: and (3) uniformly mixing the crude butanedione monoxime obtained in the step (S1) with water, putting the mixture into a high-pressure reaction kettle, adding palladium-carbon serving as a catalyst, performing replacement by using nitrogen, performing replacement by using hydrogen, and performing stirring reaction in a hydrogen atmosphere.
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