CN1100765C - Process for preparing tetramethyl pyrazine - Google Patents
Process for preparing tetramethyl pyrazine Download PDFInfo
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- CN1100765C CN1100765C CN98124478A CN98124478A CN1100765C CN 1100765 C CN1100765 C CN 1100765C CN 98124478 A CN98124478 A CN 98124478A CN 98124478 A CN98124478 A CN 98124478A CN 1100765 C CN1100765 C CN 1100765C
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- tetramethylpyrazine
- preparation
- metallic compound
- viii family
- hydrogen
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Abstract
The present invention provides a method for preparing tetramethyl pyrazine. Hydrogen reacts with 2, 3-butyldione-oxime to obtain tetramethyl pyrazine under the existence of a coordination catalyst formed by the compounds of metal in a VIII group and organic matching bodies. The catalyst of the present invention can be conveniently prepared, the pressure of required hydrogen is low, and the yield of the tetramethyl pyrazine is high.
Description
The present invention is with 2, and 3-dimethyl diketone monoxime is a reactant, prepares the method for Tetramethylpyrazine by shortening.
Tetramethylpyrazine (English name is: tetramethylpryazine is abbreviated as TMP) can be used as the intermediate of spices, food using agent, photosensitizers, medicine and agricultural chemicals.People find again in recent years, Tetramethylpyrazine is one of effective constituent of Chinese medicine Ligusticum wallichii (ligusticum wallichii franch), be used for the treatment of cerebrovascular blood supply insufficiency, cerebral thrombosis and other ischemic angiopathy (as coronary heart disease, vasculitis etc.) clinically and obtained tangible curative effect, and almost non-toxic side effect.
Knownly pass through 2, (English name 2,3-Butanedione monoxime or Diacetyl monoxime are abbreviated as: the method that DAM) prepares Tetramethylpyrazine mainly contains two classes to 3-dimethyl diketone monoxime.One class is to use the chemical reagent reductase 12,3-dimethyl diketone monoxime; Another kind of is the method for using hydrogen reducing.One of example of chemical reduction be reports such as Zhao Jianhua be reductive agent with the Zn powder, at NH
4Cl, H
2The method (" herbal medicine ", 1980,11 (3): 198) that prepare TMP in O and the acetic acid solution.An other example is disclosed patented methods (Rom.RO 67,281,1980) such as Ciurdaru G., at SnCl
2Exist down with hydrochloric acid, make 2, the cyclisation of 3-dimethyl diketone monoxime generates the dihydro Tetramethylpyrazine, then makes Tetramethylpyrazine with the hydrogen peroxide oxidation dehydrogenation again in acetic acid solution.These two kinds of methods all need to consume a large amount of chemical reagent (as zinc powder, hydrogen peroxide, sodium hydroxide etc.), also relate to the acetic acid medium than severe corrosive, so can not be satisfactory.The second class example be report such as more early stage Winans C.F. in the presence of the Raney nickel catalyzator, hydrogen pressure with 10.0-20.0MPa, make the dimethylglyoxime reduction prepare the method (J.Am.Chem.Soc.55 of Tetramethylpyrazine, 4167 (1933)), because synthesis pressure is too high, is difficult to apply industrial.
The objective of the invention is to develop and a kind ofly can directly use hydrogen and 2 under lower pressure, the reaction of 3-dimethyl diketone monoxime does not relate to corrosive reaction medium, can obtain the process for catalytic synthesis of the Tetramethylpyrazine of higher yields simultaneously again.
Through experimental study, we find can make 2 in the presence of the coordination catalyst of some VIII family metal, and 3-dimethyl diketone monoxime reductive cyclization under very low hydrogen pressure obtains the Tetramethylpyrazine of higher yields.
The main chemical reactions that the present invention relates to is:
Method of the present invention comprises the composition of catalyzer and preparation method, under suitable temperature and hydrogen pressure, 2,3-dimethyl diketone monoxime in organic solvent with hydrogen reaction.
Catalyst system comprises the metallic compound M of VIII family and organic ligand L two portions.
The VIII family metallic compound that is fit to is selected from Pd, Co, and Fe, Ni, the halogenide of Pt and Ru etc. and in the carboxylate salt one or both thereof, preferred metal component is Pd, Co, the halogenide of Ni and Pt.Pd is the metal component that override is selected.
The organic ligand that is fit to is to contain N, and the organic compound of the electronation group of P atom is generally trialkyl or triarylamine NR
1R
2R
3, trialkyl or triaryl phosphine PR
1R
2R
3, R
1, R
2And R
3Can be identical or different, alkyl or aryl and formula that expression has 1～twelve carbon atom are
Nitrogenous bitooth ligand.(CH) n represents carbochain identical or inequality with (CH) m, and n and m represent carbon and the hydrogen atom number in the carbochain.The part that override is selected is triphenylphosphine and 2,2 '-dipyridyl.
Reactant 2,3-dimethyl diketone monoxime (English name is: 2,3-Butanedione monoxime claims Diacetylmonoxime again), its molecular structural formula is:
By 2, the Tetramethylpyrazine (being called again: 2, or Ligustrazine) of 3-dimethyl diketone monoxime and hydrogen reaction preparation, its molecular structural formula is:
Metallic compound M of VIII family that relates among the present invention and the ratio M/L=1 of organic ligand L: 0.5--1: 5 (mol ratios).Reactant 2, the ratio of 3-dimethyl diketone monoxime DAM and the metallic compound M of VIII family is generally 100--1000 (mol ratio).
Method of the present invention needs to react in suitable liquid medium.Suitable liquid medium preferably can the catalyst-solvent component and the organic solvent of reactant.Usually can be one of them of aliphatic hydrocarbon, aromatic hydrocarbon, ether, alcohol, ester class etc. or their mixture.Preferred liquid medium is a kind of in alcohols, naphthenic hydrocarbon and the aromatic hydrocarbon or their mixture.
Temperature of reaction involved in the present invention is at 30-160 ℃, and hydrogen pressure is usually at 0.6-5.0MPa.
Concrete preparation method of the present invention is: VIII family metallic compound, organic ligand are dissolved in are mixed with catalyzer in the organic solvent in advance, add reactor respectively with DAM again; Perhaps VIII family metallic compound, organic ligand and reactant DAM are added together the reactor original position and generate catalyzer; Charge into hydrogen then and reach suitable pressure, be heated under the certain temperature and react, till the observation hydrogen pressure no longer reduces.The general reaction times was at 1--30 hour.Reaction is cooled to room temperature after finishing, and takes out liquid and analyzes.Can isolate with fractionation by distillation or common method of purification simultaneously
TMP preparation method provided by the invention has that required hydrogen pressure is lower, corrosive medium is little, Preparation of Catalyst is convenient and the productive rate advantages of higher of Tetramethylpyrazine.
Embodiment
Describe concrete implementation step of the present invention in detail below by some embodiment, these embodiment should be used as the restriction of the scope of the invention.
Embodiment 1
Palladium chloride (PdCl with 2.91mg
2), the triphenylphosphine (PPh of 6.30mg
3) be dissolved in respectively in the 1ml ethanol, at room temperature stir then and made catalyst solution in 0.5 hour.
With 2 of above-mentioned catalyst solution, 0.5g, it is in the stainless steel autoclave of 20ml that 3-dimethyl diketone monoxime (the following DAM that all is abbreviated as) adding fills 4ml alcoholic acid volume, is stirred to mix; Charge into hydrogen and make pressure reach 2.4MPa, be warming up to 150 ℃, begin reaction, after 5--6 hour, the pressure of reaction system no longer descends, and is cooled to room temperature, take out reaction liquid and analyze, the result shows: the transformation efficiency of DAM is 94.61%, and the productive rate of TMP is 85.53%.
Embodiment 2--7
Repeat the operation steps of embodiment 1, only change the kind and the consumption of metallic compound, use cobalt chloride (CoCl respectively
2), Platinic chloride H
2PtCl
4, nickelous bromide NiBr
2, ruthenium trichloride RuCl
3, cobaltous acetate CoOAc, iron trichloride FeCl
3Replace PdCl
2The equal 12.6mg of triphenylphosphine consumption.Relevant consumption and reaction result are listed table 1 in.
Embodiment 8
Cobalt chloride (CoCl with 2.12mg
2), the palladium chloride of 2.91mg and triphenylphosphine (PPh
3) after 12.6mg is dissolved in small amount of ethanol respectively, mixes and add that to fill 4ml alcoholic acid volume be in the stainless steel autoclave of 20ml, be stirred to mix; Charge into hydrogen and make pressure reach 0.5MPa, be warming up to 100 ℃, stir and made catalyst solution in 1 hour, be cooled to room temperature then.
0.5gDAM and 4ml ethanol are joined in the stainless steel autoclave that fills above-mentioned catalyst solution, fill hydrogen to pressure and reach 4.0MPa, be warming up to 120 ℃, reacting the about 6 hours pressure to reaction system no longer descends, be cooled to room temperature, take out reaction liquid and analyze, the result shows: the transformation efficiency of DAM is 96.52%, and the productive rate of TMP is 94.44%.
Embodiment 9--11
Repeat the operation steps of embodiment 8, just change the consumption of triphenylphosphine, the consumption of reaction result and triphenylphosphine is listed table 2 in.
Embodiment 12--16
Repeat the operation steps of embodiment 1, just change the palladium compound component and with the ratio of organic ligand, reaction result is listed table 2 in.
Embodiment 19
Cobalt dichloride (CoCl with 2.12mg
2), the triphenylphosphine (PPh of 12.6mg
3) add in the 2ml ethanol, at room temperature stirred 0.5 hour, make catalyst solution.
Above-mentioned catalyst solution, 0.5gDAM and 4ml ethanol are joined in the stainless steel autoclave, fill hydrogen to pressure and reach 4.0MPa, be warming up to 100 ℃, react to the pressure of reaction system and no longer descend, be cooled to room temperature, take out reaction liquid and analyze, the result shows: the transformation efficiency of DAM is 67.06%, and the productive rate of TMP is 56.65%.
Embodiment 17,18, and 20
Repeat the operation steps of embodiment 19, just change the consumption of triphenylphosphine in the reaction system, reaction result is listed table 2 in.
Embodiment 21
Nickel Chloride (NiCl with 2.13mg
2), the triphenylphosphine (PPh of 12.6mg
3) divide to be clipped to add in the 1ml ethanol and dissolve, at room temperature mixed 0.5 hour, make catalyst solution.
With above-mentioned catalyst solution, 0.5gDAM with join that to fill 4ml ethanol volume be in the stainless steel autoclave of 20ml, mix, fill hydrogen to pressure and reach 4.0MPa, then under 150 ℃, react to the pressure of reaction system and no longer descend, be cooled to room temperature, take out reaction liquid and analyze, the result lists table 2 in.
Embodiment 22--24
Repeat the operating process of embodiment 21, just change the consumption of triphenylphosphine in the reaction system, reaction result is listed table 2 in.
Embodiment 25--27
Step according to embodiment 1 prepares PdCl
2--PPh
3Catalyzer, the method for synthetic Tetramethylpyrazine is identical with embodiment 1 basically, just changes the temperature of reaction, and the result lists table 3 in.
Embodiment 28
Palladium chloride (PdCl with 0.58mg
2), 2 of 0.5mg, 2 '-dipyridyl (DPY) add respectively in the 1ml ethanol and dissolve, and at room temperature mix 0.5 hour, make catalyst solution.
With above-mentioned catalyst solution, 0.1gDAM with join that to fill 4ml ethanol volume be in the stainless steel autoclave of 20ml, mix, fill hydrogen to pressure and reach 0.6MPa, under 150 ℃, react after 6 hours then, be cooled to room temperature, take out reaction liquid and analyze, the result lists table 4 in.
Embodiment 29-34
Repeat the operating process of embodiment 28, just change the pressure of hydrogen, reaction result is listed table 4 in.
The reaction result embodiment metallized metal compound amount DAM transformation efficiency TMP productive rate of the catalyzer of table 1, different metal component
(mg) (％) (％)
1 PdCl
2 2.91 94.61 85.53
2 CoCl
2 2.13 76.47 72.10
3 H
2PtCl
4 5.56 76.64 49.20
4 NiBr
2 3.58 96.25 56.18
5 RuCl
3 3.40 43.69 41.66
6 CoOAc 2.90 31.04 31.04
7 FeCl
32.31 25.04 13.24 comparative example blank 0.00＜1＜1
Table 2, triphenylphosphine PPh3/ metal M ratio influence embodiment metal component PPh to reaction result
3/ M temperature of reaction hydrogen pressure DAM transformation efficiency TMP productive rate
Number (℃) (MPa) (%) (%)
8 CoCl
2，PdCl
2 1.5 120 4.0 96.52 94.44
9 CoCl
2，PdCl
2 2.0 120 4.0 90.29 73.54
10 CoCl
2，PdCl
2 3.0 120 4.0 100.0 79.29
11 CoCl
2, PdCl
25.0 120 4.0 100.0 88.0 comparative example PdCl
20 150 2.4 1.93 0.08
12 PdCl
2 0.5 150 2.4 78.65 43.63
13 PdCl
2 1.5 150 2.4 94.61 85.53
14 PdOAc 2.0 150 2.4 75.94 52.98
15 PdOAc 3.0 150 2.4 79.08 73.98
16 PdCl
2 5.0 150 2.4 69.03 59.61
17 CoCl
2 1.5 100 4.0 14.42 10.56
18 CoCl
2 2.0 100 4.0 49.83 40.16
19 CoCl
2 3.0 100 4.0 67.06 56.65
20 CoCl
2 5.0 100 4.0 44.09 35.16
21 NiCl
2 1.5 150 4.0 38.21 16.25
22 NiCl
2 2.0 150 4.0 26.23 12.74
23 NiCl
2 3.0 150 4.0 96.25 56.18
24 NiCl
2 5.0 150 4.0 73.98 25.57
Table 3, temperature to PdCl2-PPh3 catalyst reaction result influence the embodiment temperature of reaction (℃) (other reaction conditionss are DAM transformation efficiency (%) TMP productive rate (%) 25 30 5.96 3.24 26 60 14.17 14.17 27 120 80.14 51.42 1 150 94.61 85.53: hydrogen pressure: 2.4MPa, PdCl
2/ PPh
3=1: 1.5, DAM=0.5g)
Table 4, hydrogen pressure are to PdCl
2The reaction result of-bipyridyl (DPY) catalyst system affect embodiment Hydrogen Vapor Pressure (MPa) DAM conversion ratio (%) TMP productive rate (%) comparative example 0＜1.0＜1.0 28 0.6 40.78 39.47 29 1.1 97.46 76.98 30 1.3 97.22 89.90 31 2.0 58.21 54.74 32 3.0 100.0 63.89 33 4.0 87.28 52.69 34 4.6 95.64 49.28
Claims (7)
1, the present invention is a kind of preparation method of Tetramethylpyrazine compound, and the main chemical reactions that relates to is:
It is characterized in that: the coordination catalyst that adopts VIII family's metallic compound and organic ligand to form, under the hydrogen pressure of 30～160 ℃ temperature and 0.6～5.0Mpa, 2,3-dimethyl diketone monoxime in organic solvent with hydrogen reaction, generate Tetramethylpyrazine.
2, the preparation method of Tetramethylpyrazine according to claim 1, it is characterized in that: with the metallic compound M of VIII family and organic ligand L in M/L=1: the ratio of 0.5～1: 5 (mol ratios), in organic solvent, be pre-mixed and make coordination catalyst, mix with reactant DAM again.
3, according to the preparation method of the described Tetramethylpyrazine of claim 1, it is characterized in that: metallic compound M of VIII family and organic ligand L, in M/L=1: the ratio of 0.5～1: 5 (mol ratios) and adds reactor after reactant DAM mixes simultaneously.
4, the preparation method of Tetramethylpyrazine according to claim 1 is characterized in that: the VIII family metallic compound of employing is Pd, Co, Fe, Ni, Pt, the halogenide of Ru or in the carboxylate salt one or both.
5, according to claim 1 or 4, it is characterized in that: described VIII family metallic compound is the muriate or the acetate of palladium.
6, the preparation method of Tetramethylpyrazine according to claim 1 is characterized in that: the organic ligand of employing is triphenylphosphine PPh
3With 2, one or both in 2 '-dipyridyl.
7, the preparation method of Tetramethylpyrazine according to claim 1 is characterized in that: the organic solvent of employing is an ethanol.
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|---|---|---|---|
| CN98124478A CN1100765C (en) | 1998-11-11 | 1998-11-11 | Process for preparing tetramethyl pyrazine |
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|---|---|---|---|
| CN98124478A CN1100765C (en) | 1998-11-11 | 1998-11-11 | Process for preparing tetramethyl pyrazine |
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| CN1100765C true CN1100765C (en) | 2003-02-05 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1296409C (en) * | 2003-10-15 | 2007-01-24 | 北京理工大学 | Ligustrazine polyethleneglycol ester and preparation method thereof |
| CN100556895C (en) * | 2006-10-18 | 2009-11-04 | 张锋 | The preparation method of Ligustrazine |
| CN103664803A (en) * | 2012-09-17 | 2014-03-26 | 王天桃 | Novel synthesis method of 2, 3, 5, 6-tetramethylpyrazine |
| CN104341359B (en) * | 2014-11-11 | 2017-01-11 | 武汉武药制药有限公司 | Preparation method of tetramethyl-pyrazine |
| 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 |
-
1998
- 1998-11-11 CN CN98124478A patent/CN1100765C/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| 同位素,第5卷第4期 1992-11-01 * |
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