CN104341359A - Preparation method of tetramethyl-pyrazine - Google Patents
Preparation method of tetramethyl-pyrazine Download PDFInfo
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- CN104341359A CN104341359A CN201410630743.7A CN201410630743A CN104341359A CN 104341359 A CN104341359 A CN 104341359A CN 201410630743 A CN201410630743 A CN 201410630743A CN 104341359 A CN104341359 A CN 104341359A
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- tetramethylpyrazine
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- ammonium formiate
- pyrazine
- tetramethyl
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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 Low-Molecular-Weight Compounds And Preparation Thereof (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 a kind of preparation method of medicine intermediate Tetramethylpyrazine.
Background technology
Tetramethylpyrazine, chemical formula is: C
8h
14n
2, colorless needle crystals, molecular weight 136.20 fusing point: 82 ~ 84 DEG C, boiling point: 190 DEG C.Its structural formula is:
This material has aromatic odour, and water absorbability easily distils.Be soluble in hot water, sherwood oil, chloroform, be slightly soluble in ether, be insoluble to cold water.
Tetramethylpyrazine can be used as the intermediate of seasonings, spices, food using agent, medicine and agricultural chemicals.People find that again Tetramethylpyrazine is one of effective constituent of chuanxiong (Ligusticum chuanxiong Hort) in recent years, primary treatment ischemic cardio cerebrovascular diseases clinically.Particularly pharmaceutically, there is step-down, vasodilation thrombolytic effect, be mainly used in clinically treating ischemic cardio cerebrovascular diseases, as cardio cerebrovascular affection, cerebral embolism, coronary heart disease, stenocardia, vasculitis, chronic cardiopulmonary disease, chronic renal failure etc.Discovered in recent years has calcium ion retardation, has the effect of chemotherapy sensitizing reversing multiple medicine resistance of tumor cells.
Patent CN1274722A, with zinc powder reduction, at ammonium chloride, prepares Tetramethylpyrazine (" herbal medicine " 1980,11 (3): 198) in water and acetic acid solution.Yield about 35%, its reaction formula is:
The a large amount of Glacial acetic acid of this route consumption and zinc powder, discharged waste is more, and cost is higher, is unfavorable for suitability for industrialized production.
Patent CN1935794A, with 3-hydroxy-2-butanone and ammonium acetate for raw material, take ethanol as solvent, passes into nitrogen, and 5-8h, uncovered stirring 12h are stirred in heating bath, reoxidizes agent Manganse Dioxide and stirs 2h, underpressure distillation twice Tetramethylpyrazine, yield 72%.This reaction time is longer, and aftertreatment is loaded down with trivial details.
Synthesis, (8), 701-2; 1990. is raw material with acetonitrile, and tetrahydrofuran (THF) is solvent, and in the catalysis of titanium tetrachloride and zinc powder, return stirring 4-6d under protection of inert gas, obtains Tetramethylpyrazine with chloroform extraction, yield 44% after enriched material cooling adds solution of potassium carbonate.The method reaction formula is:
This synthetic method reaction times is longer, and yield is not high, is not suitable for suitability for industrialized production.
Patent U.S.6225471B1, with 3-hydroxy-2-butanone for raw material, is that solvent adds ammonium acetate with water, sodium acetate and hydrogen peroxide, adopt decompression condensation equipment, and reaction terminates to collect distillation condensed product, raffinate filters after adding 10%NaOH tune PH, and hot water recrystallization, total recovery can reach 90%.
The method is easy, and yield is high, but needs special decompression condensation equipment.
The method that the coordination catalysis formed by VIII race's metallic compound and organic ligand synthesizes Tetramethylpyrazine has: patent CN1253134A is with CoCl
2pdCl
2for under catalysts conditions, hydrogenation pressure is 4Mpa, and temperature 120 DEG C reduction transformation efficiency is up to 96.52%, and yield is 94.44%.Zhejiang University king is solvent to space with ethanol, and at 150 DEG C of temperature, under palladium-triphenyl phosphine catalyst 1.2MPa pressure, hydrogenation maximum conversion rate reaches 94.69%, yield 91.81%.Article J.Am.Chem.Soc.55,4167 (1933) report under Raney nickel catalyzator condition, with the hydrogen pressure of 10 ~ 20Mp, with biacetyl monoxime be raw material reduction preparation Tetramethylpyrazine.
Although three kinds of catalytic hydrogenation yields are higher, all adopt high-temperature high-voltage reaction condition, from withstand voltage conversion unit and security consideration, there is certain security risk.
Summary of the invention
The object of the invention is to find one under relatively mild reaction conditions, do not relate to corrosive medium, prepare Tetramethylpyrazine by biacetyl monoxime, ammonium formiate through palladium charcoal catalytic hydrogen transfer, obtain the synthetic method of the Tetramethylpyrazine of higher yields.
Realizing technical scheme of the present invention is:
Take biacetyl monoxime as raw material, add water as solvent, palladium charcoal makees catalyzer, and its mol ratio is palladium charcoal: biacetyl monoxime=0.0005 ~ 0.1:1 adds ammonium formiate at reflux in batches, and its mol ratio is: 5 ~ 11:1, reflux temperature is 90 ~ 95 DEG C, after ammonium formiate adds, continue return stirring 2 ~ 4 hours, Filtration of catalyst, dichloromethane extraction after cooling, concentrating under reduced pressure obtains Tetramethylpyrazine.The condition of concentrating under reduced pressure is pressure is 0.9 ~ 1.0Mp, and temperature is 20 ~ 35 DEG C.
The process of preparation feedback is:
Tool of the present invention has the following advantages:
(1) raw material reaction in preparation process of the present invention is complete, and in discharge, organic substance residues amount is few, is beneficial to environmental protection.
(2) the present invention is high compared with other synthetic route Tetramethylpyrazine productive rates.
(3) the present invention adopts the catalysis of palladium charcoal, does not need high-pressure hydrogenation, and reaction conditions is gentle, meets green chemical industry theory, simple to operate, is more suitable for industrialization.
Embodiment
Specific embodiment of the invention step is described in detail below by some embodiments, should by the restriction of these embodiments as the scope of the invention.
Embodiment 1
By 10.0g biacetyl monoxime, 10.0g palladium carbon is added in 120ml methyl alcohol, then stirs and is warming up to 60 DEG C.Add 67.4g ammonium formiate in batches, after ammonium formiate adds, in 60 ~ 65 DEG C of return stirrings 2 hours.After reaction terminates, cloth is crossed and is filtered palladium carbon (recovery), add removal of solvent under reduced pressure methyl alcohol after hydrochloric acid, add 120mL water, NaOH regulates pH 8 ~ 9, with 60ml extraction into ethyl acetate three times, merge organic phase, add anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains Tetramethylpyrazine 5.3g, and yield is 79.2%.
Embodiment 2
By 10.0g biacetyl monoxime, 5.0g palladium carbon is added in 120ml water, then stirs and is warming up to 90 DEG C.Add 50.5g ammonium formiate in batches, after ammonium formiate adds, in 95 ~ 100 DEG C of return stirrings 2 hours.After reaction terminates, removing palladium carbon, filtrate is with methylene dichloride (CH
2cl
2) extract three times, merge organic phase, add anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains Tetramethylpyrazine 5.6g, and yield is 83.7%.
Embodiment 3
By 10.0g biacetyl monoxime, 1.0g palladium carbon is added in 134ml water, then stirs and is warming up to 80 ~ 90 DEG C.Add 67.4g ammonium formiate (HCOONH4) in batches, after ammonium formiate adds, continue return stirring 4 hours.After reacting completely, with Büchner funnel decompress filter removing palladium carbon, filtrate extracts three times with methylene dichloride (CH2Cl2), merges organic phase, adds anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure obtains Tetramethylpyrazine 5.7g, and yield is 84.6%.
Claims (7)
1. a preparation method for medicine intermediate Tetramethylpyrazine, the method comprises the steps:
Take biacetyl monoxime as raw material, water as solvent, palladium charcoal makees catalyzer, adds ammonium formiate, and add the reaction of rear stirring and refluxing, reaction terminates rear Filtration of catalyst, and solvent extraction after cooling, concentrating under reduced pressure obtains Tetramethylpyrazine.
2. the preparation method of Tetramethylpyrazine according to claim 1, is characterized in that: palladium charcoal and biacetyl monoxime mol ratio are: 0.0005 ~ 0.1:1.
3. the preparation method of Tetramethylpyrazine according to claim 1, is characterized in that: the mol ratio of ammonium formiate and biacetyl monoxime is: 5 ~ 11:1.
4. the preparation method of Tetramethylpyrazine according to claim 1, is characterized in that: ammonium formiate adds at reflux in batches.
5. the preparation method of Tetramethylpyrazine according to claim 1, is characterized in that: it is 2 ~ 4h that ammonium formiate adds the rear continuation return stirring time.
6. the preparation method of Tetramethylpyrazine according to claim 1, is characterized in that: Extraction solvent is methylene dichloride, trichloromethane, ethyl acetate.
7. the preparation method of Tetramethylpyrazine according to claim 1, is characterized in that: the condition of concentrating under reduced pressure is pressure is 0.9 ~ 1.0Mp, and temperature is 20 ~ 35 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110156701A (en) * | 2019-06-25 | 2019-08-23 | 吴赣药业（苏州）有限公司 | A kind of synthetic 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1253134A (en) * | 1998-11-11 | 2000-05-17 | 浙江省应用化学重点研究实验室 | Process for preparing tetramethyl pyrazine |
| CN1274722A (en) * | 2000-04-30 | 2000-11-29 | 广东药学院药物研究所 | Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application |
-
2014
- 2014-11-11 CN CN201410630743.7A patent/CN104341359B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1253134A (en) * | 1998-11-11 | 2000-05-17 | 浙江省应用化学重点研究实验室 | Process for preparing tetramethyl pyrazine |
| CN1274722A (en) * | 2000-04-30 | 2000-11-29 | 广东药学院药物研究所 | Compound capable of inhibiting thrombocyte agglutination and resisting thrombosis and its preparation and application |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110156701A (en) * | 2019-06-25 | 2019-08-23 | 吴赣药业（苏州）有限公司 | A kind of synthetic 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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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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