CN104341359B - Preparation method of tetramethyl-pyrazine - Google Patents
Preparation method of tetramethyl-pyrazine Download PDFInfo
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- CN104341359B CN104341359B CN201410630743.7A CN201410630743A CN104341359B CN 104341359 B CN104341359 B CN 104341359B CN 201410630743 A CN201410630743 A CN 201410630743A CN 104341359 B CN104341359 B CN 104341359B
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- ammonium formate
- tetramethylpyazine
- pyrazine
- tetramethyl
- solvent
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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
- C07D241/12—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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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a synthesis method of medical intermediate tetramethyl-pyrazine. The method takes butanedione monoxime as raw material, water as a solvent and palladium carbon as a catalyst, and comprises the steps of feeding ammonium formate in a reflux state, continuously carrying out reflux mixing for 4 hours after the ammonium formate is fed, filtering to remove the catalyst, cooling, extracting dichloromethane, and concentrating under the reduced pressure to obtain the tetramethyl-pyrazine. The method for preparing the tetramethyl-pyrazine is mild in reaction conditions and simple and convenient in aftertreatment, has the conversion rate of more than 95% and the yield of more than 80%, and is lower in cost and beneficial to industrial production.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the system of a kind of medicine intermediate tetramethylpyazine
Preparation Method.
Background technology
Tetramethylpyazine, chemical formula is: C8H14N2, colorless needle crystals, molecular weight 136.20 melts
Point: 82～84 DEG C, boiling point: 190 DEG C.Its structural formula is:
This material has aromatic odor, hygroscopicity, easily distils.It is soluble in hot water, petroleum ether, chloroform, micro-
It is dissolved in ether, insoluble in cold water.
Tetramethylpyazine can serve as flavoring agent, spice, food flavor agent, medicine and the centre of pesticide
Body.People find that again tetramethylpyazine is chuanxiong (Ligusticum chuanxiong in recent years
Hort) one of effective ingredient, clinically primary treatment ischemic cardio cerebrovascular diseases.Particularly
Pharmaceutically, there is blood pressure lowering, expand blood vessel thrombolytic effect, be mainly used in clinically treating ischemic cardiac
Cerebrovascular disease, such as cardio cerebrovascular affection, cerebral embolism, coronary heart disease, angina pectoris, vasculitis, chronic
Pulmonary heart disease, chronic renal failure etc..Discovered in recent years has calcium ion retardation, has chemotherapy to increase
Quick reversing multiple medicine resistance of tumor cells effect.
Patent CN1274722A, with zinc powder reduction, prepares tetramethyl in ammonium chloride, water and acetic acid solution
Base pyrazine (" Chinese herbal medicine " 1980,11 (3): 198).Yield about 35%, its reaction equation is:
This route consumes a large amount of glacial acetic acid and zinc powder, and discharge garbage is more, relatively costly, is unfavorable for industry
Metaplasia is produced.
Patent CN1935794A, with 3-hydroxy-2-butanone and ammonium acetate as raw material, with ethanol as solvent,
It is passed through nitrogen, heating bath stirring 5-8h, uncovered stirring 12h, reoxidizes agent manganese dioxide stirring 2h, subtract
Pressure distillation obtains tetramethylpyazine, yield 72% twice.This reaction time is longer, and post processing is loaded down with trivial details.
Synthesis,(8),701-2；1990. with acetonitrile as raw material, and oxolane is solvent, in four chlorinations
Titanium and the catalysis of zinc powder, return stirring 4-6d under inert gas shielding, concentrate cooling adds potassium carbonate
Tetramethylpyazine, yield 44% is obtained with chloroform extraction after solution.The method reaction equation is:
This synthetic method response time is longer, and yield is the highest, is not suitable for industrialized production.
Patent U.S.6225471B1, with 3-hydroxy-2-butanone as raw material, adds acetic acid with water for solvent
Ammonium, sodium acetate and hydrogen peroxide, use decompression condensation equipment, reaction to terminate to collect distillation condensed product,
Residual liquid adds 10%NaOH and adjusts filtration after PH, and hot water recrystallization, total recovery is up to 90%.
The method is easy, and yield is high, but needs special decompression condensation equipment.
By the side of the coordination catalysis synthesis tetramethylpyazine that VIII race's metallic compound and organic ligand are formed
Method has: patent CN1253134A is with CoCl2PdCl2For under catalysts conditions, hydrogenation pressure is
4Mpa, temperature 120 DEG C reduction conversion ratio is up to 96.52%, and yield is 94.44%.Zhejiang University
Wang Xiangyu, with ethanol as solvent, hydrogenates under palladium-triphenyl phosphine catalyst 1.2MPa pressure at a temperature of 150 DEG C
Maximum conversion rate reaches 94.69%, yield 91.81%.Article J.Am.Chem.Soc.55,4167 (1933)
Report under the conditions of Raney Raney nickel, with the Hydrogen Vapor Pressure of 10～20Mp, with diacetyl list
Oxime is that tetramethylpyazine is prepared in raw material reduction.
Although three kinds of catalytic hydrogenation yields are higher, but all use high-temperature high-voltage reaction condition, from resistance to
, there is certain security risk in pressure consersion unit and security consideration.
Summary of the invention
It is an object of the invention to find one under relatively mild reaction condition, be not related to corrosivity and be situated between
Matter, is prepared tetramethylpyazine by biacetyl monoxime, ammonium formate through palladium charcoal catalytic hydrogen transfer, it is thus achieved that higher
The synthetic method of the tetramethylpyazine of yield.
Realization the technical scheme is that
With biacetyl monoxime as raw material, adding water and make catalyst as solvent, palladium charcoal, its mol ratio is palladium
Charcoal: biacetyl monoxime=0.0005～0.1:1 are dividedly in some parts ammonium formate at reflux, its mol ratio is:
5～11:1, reflux temperature is 90～95 DEG C, after ammonium formate adds, and continuation return stirring 2～4 hours,
Filtration of catalyst, dichloromethane extraction after cooling, concentrating under reduced pressure obtains tetramethylpyazine.Reduce pressure dense
Contracting condition be pressure be 0.9～1.0Mp, temperature is 20～35 DEG C.
The process of preparation reaction is:
Present invention have the advantage that
(1) raw material reaction in preparation process of the present invention is complete, and in discharge, organic substance residues amount is few,
It is beneficial to environmental protection.
(2) present invention relatively other synthetic route tetramethylpyazine productivity are high.
(3) present invention uses palladium charcoal to be catalyzed, and is not required to high-pressure hydrogenation, and reaction condition is gentle, meets green
Color chemical industry theory, simple to operate, it is more suitable for industrialization.
Detailed description of the invention
It is embodied as step below by what some embodiments described the present invention in detail, should be real by these
Execute the example restriction as the scope of the invention.
Embodiment 1
By 10.0g biacetyl monoxime, 10.0g palladium carbon adds to 120ml methanol, then stirs intensification
To 60 DEG C.Add 67.4g ammonium formate in batches, after ammonium formate adds, in 60～65 DEG C of return stirrings
2 hours.After reaction terminates, cloth is filtered to remove palladium carbon (recovery), and after adding hydrochloric acid, decompression removes
Solvent methanol, adds 120mL water, and NaOH regulates pH 8～9, extracts three by 60ml ethyl acetate
Secondary, merge organic facies, add anhydrous sodium sulfate and be dried, filter, concentrating under reduced pressure obtains tetramethylpyazine 5.3g,
Yield is 79.2%.
Embodiment 2
By 10.0g biacetyl monoxime, 5.0g palladium carbon adds to 120ml water, and then stirring is warming up to
90℃.Add 50.5g ammonium formate in batches, after ammonium formate adds, in 95～100 DEG C of return stirrings 2
Hour.After reaction terminates, removing palladium carbon, filtrate is with dichloromethane (CH2Cl2) extract three times, close
And organic facies, adding anhydrous sodium sulfate and be dried, filter, concentrating under reduced pressure obtains tetramethylpyazine 5.6g, receives
Rate is 83.7%.
Embodiment 3
By 10.0g biacetyl monoxime, 1.0g palladium carbon adds to 134ml water, and then stirring is warming up to
80～90 DEG C.Add 67.4g ammonium formate (HCOONH4) in batches, after ammonium formate adds, continue
Return stirring 4 hours.After reaction completely, removing palladium carbon with buchner funnel decompression sucking filtration, filtrate is with two
Chloromethanes (CH2Cl2) extracts three times, merges organic facies, adds anhydrous sodium sulfate and is dried, filters,
Concentrating under reduced pressure obtains tetramethylpyazine 5.7g, and yield is 84.6%.
Claims (2)
1. the preparation method of a medicine intermediate tetramethylpyazine, the method comprises the steps: with biacetyl monoxime as raw material, water as solvent, palladium charcoal makees catalyst, adding ammonium formate, be stirred at reflux reaction after adding, reaction terminates rear Filtration of catalyst, solvent extraction after cooling, concentrating under reduced pressure obtains tetramethylpyazine；Palladium charcoal with the mol ratio of biacetyl monoxime is: 0.0005～0.1:1；Ammonium formate is 5～11:1 with the mol ratio of biacetyl monoxime；Ammonium formate adds the most in batches；After ammonium formate adds, the continuation return stirring time is 2～4h.
The preparation method of tetramethylpyazine the most according to claim 1, it is characterised in that: Extraction solvent is dichloromethane
, chloroform
, acetic acid second
Ester.
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| CN104341359B true CN104341359B (en) | 2017-01-11 |
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| CN110156701B (en) * | 2019-06-25 | 2020-10-16 | 吴赣药业（苏州）有限公司 | Synthesis method of 2,3,5, 6-tetramethylpyrazine |
| CN112666292A (en) * | 2020-12-15 | 2021-04-16 | 四川省食品发酵工业研究设计院 | Pretreatment method for determining tetramethylpyrazine in solid matrix and application thereof |
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| CN1173958C (en) * | 2000-04-30 | 2004-11-03 | 广东药学院药物研究所 | Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application |
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Address after: 435229 Huangshi City, Hubei County of Yangxin Province Wang Fu Chi Town No. 18 Fenlu Applicant after: Wuhan Wuyao Pharmaceutical Co., Ltd. Address before: 430035 Hubei province in Qiaokou District of Wuhan city Gutian Road No. 5 Applicant before: Wuhan Wuyao Pharmaceutical Co., Ltd. |
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