CN1100765C - Process for preparing tetramethyl pyrazine - Google Patents

Abstract

The invention provides a method for preparing tetramethylpyrazine. In the presence of a coordination catalyst formed by a VIII metal compound and an organic ligand, tetramethylpyrazine is obtained by reacting hydrogen with 2,3-butanedione monoxime. Zinc. The catalyst involved in the invention is easy to prepare, the hydrogen pressure required for the reaction is low, and the yield of tetramethylpyrazine is high.

Description

The preparation method of tetramethylpyrazine

The invention uses 2,3-butanedione monoxime as a reactant to prepare tetramethylpyrazine through catalytic hydrogenation.

Tetramethylpyrazine (English name: tetramethylpryazine, abbreviated as TMP) can be used as an intermediate for spices, food fragrances, photosensitizers, medicines and pesticides. In recent years, it has been found that tetramethylpyrazine is one of the active ingredients of the traditional Chinese medicine Ligusticum wallichii franch, which is clinically used to treat cerebrovascular insufficiency, cerebral thrombosis and other ischemic vascular diseases (such as coronary heart disease, Vasculitis, etc.) have achieved significant curative effect, and almost no toxic side effects.

There are mainly two known methods for preparing tetramethylpyrazine from 2,3-butanedione monoxime (English name 2,3-Butanedione monoxime or Diacetyl monoxime, abbreviated as: DAM). One is the reduction of 2,3-butanedione-oxime with chemical reagents; the other is the method of reduction with hydrogen. One of the examples of chemical reduction is the method of preparing TMP in NH ₄ Cl, H ₂ O and acetic acid solution reported by Zhao Jianhua et al. using Zn powder as a reducing agent ("Chinese Herbal Medicine", 1980, 11(3): 198). Another example is the patent method disclosed by Ciurdaru G. et al. (Rom.RO 67,281, 1980), in the presence of SnCl ₂ and hydrochloric acid, 2,3-butanedione monoxime is cyclized to generate dihydrotetramethylpyridine oxazine, and then oxidative dehydrogenation with hydrogen peroxide in acetic acid solution to obtain tetramethylpyrazine. These two methods all need to consume a large amount of chemical reagents (as zinc powder, hydrogen peroxide, sodium hydroxide etc.), also relate to the acetic acid medium that has stronger corrosiveness, so can not be satisfactory. The second type of example is the method of preparing tetramethylpyrazine by reduction of dimethylglyoxime under the presence of Raney nickel catalyst reported by earlier Winans CF etc. with a hydrogen pressure of 10.0-20.0MPa (J.Am.Chem. Soc.55, 4167 (1933)), because the synthesis pressure is too high, it is difficult to apply in industry.

The purpose of the present invention is to develop a kind of can under lower pressure, directly use hydrogen to react with 2,3-butanedione monoxime, do not involve the corrosive reaction medium, can obtain the tetramethylmethanol of higher yield simultaneously again Catalytic synthesis of pyrazines.

After experimental research, we found that in the presence of some coordination catalysts of Group VIII metals, 2,3-butanedione monoxime can be reductively cyclized under very low hydrogen pressure to obtain tetramethylpyridine in higher yields. Zinc.

The main chemical reactions involved in the present invention are:

The method of the invention comprises the composition and preparation method of the catalyst, and reacts 2,3-butanedione monoxime with hydrogen in an organic solvent under proper temperature and hydrogen pressure.

The catalyst system includes two parts of Group VIII metal compound M and organic ligand L.

Suitable Group VIII metal compounds are selected from one or both of halides and carboxylates of Pd, Co, Fe, Ni, Pt and Ru, etc., and the preferred metal components are those of Pd, Co, Ni and Pt halide. Pd is the most preferred metal component.

的含氮双齿配体。(CH)n和(CH)m表示相同或不相同的碳链，n和m代表碳链中的碳及氢原子个数。最优先选择的配体为三苯基膦和2，2’-联吡啶。Suitable organic ligands are organic compounds containing electron-donating groups of N, P atoms, typically trialkyl or triarylamine NR ₁ R ₂ R ₃ , trialkyl or triaryl phosphine PR ₁ R ₂ R ₃ , R ₁ , R ₂ and R ₃ may be the same or different, and represent an alkyl or aryl group with 1 to 12 carbon atoms, and the formula is

nitrogen-containing bidentate ligands. (CH)n and (CH)m represent the same or different carbon chains, and n and m represent the number of carbon and hydrogen atoms in the carbon chain. The most preferred ligands are triphenylphosphine and 2,2'-bipyridine.

The reactant 2,3-butanedione monoxime (English name is: 2,3-Butanedione monoxime, also known as diacetyl monoxime), its molecular structural formula is:

Tetramethylpyrazine (also known as: 2,3,5,6-tetramethylpyrazine, or ligustrazine) prepared by the reaction of 2,3-butanedione-oxime and hydrogen, its molecular structural formula is:

The ratio M/L of the Group VIII metal compound M to the organic ligand L involved in the present invention is 1:0.5--1:5 (molar ratio). The ratio of reactant 2,3-butanedione monooxime DAM to Group VIII metal compound M is usually 100--1000 (molar ratio).

The method of the present invention needs to carry out the reaction in a suitable liquid medium. A suitable liquid medium is preferably an organic solvent capable of dissolving the catalyst components and reactants. Usually it can be one of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, alcohols, esters, etc. or a mixture of them. The preferred liquid medium is one or a mixture of alcohols, naphthenes and aromatic hydrocarbons.

The reaction temperature involved in the present invention is 30-160° C., and the hydrogen pressure is usually 0.6-5.0 MPa.

The specific preparation method of the present invention is: dissolving the Group VIII metal compound and the organic ligand in an organic solvent to prepare a catalyst in advance, and then adding DAM to the reactor separately; or mixing the Group VIII metal compound, the organic ligand and the reactant DAM together The catalyst is added into the reactor to generate the catalyst in situ; then filled with hydrogen to reach an appropriate pressure, and heated to a certain temperature for reaction until it is observed that the hydrogen pressure no longer decreases. The general reaction time is 1--30 hours. After the reaction, it was cooled to room temperature, and the liquid was taken out for analysis. At the same time, it can be separated by distillation or common purification methods

The TMP preparation method provided by the invention has the advantages of low required hydrogen pressure, low medium corrosion, convenient catalyst preparation, high tetramethylpyrazine yield and the like.

Example

The specific implementation steps of the present invention will be described in detail below through some examples, and these examples should not be regarded as limiting the scope of the present invention.

Example 1

2.91 mg of palladium dichloride (PdCl ₂ ) and 6.30 mg of triphenylphosphine (PPh ₃ ) were dissolved in 1 ml of ethanol, respectively, and stirred at room temperature for 0.5 hours to prepare catalyst solutions.

Add the above catalyst solution and 0.5 g of 2,3-butanedione monoxime (hereinafter abbreviated as DAM) into a stainless steel autoclave with a volume of 20 ml filled with 4 ml of ethanol, stir until evenly mixed; fill with hydrogen to make the pressure reach 2.4MPa, heat up to 150°C, start the reaction, after 5--6 hours, the pressure of the reaction system no longer drops, cool to room temperature, take out the reaction liquid for analysis, the results show: the conversion rate of DAM is 94.61%, the conversion rate of TMP is 94.61%. The yield was 85.53%.

Example 2--7

Repeat the operation steps of Example 1, only changing the type and amount of the metal compound, using cobalt chloride (CoCl ₂ ), chloroplatinic acid H ₂ PtCl ₄ , nickel bromide NiBr ₂ , ruthenium trichloride RuCl ₃ , cobalt acetate CoOAc and iron trichloride FeCl ₃ replaced PdCl ₂ ; the dosage of triphenylphosphine was 12.6 mg. The relevant dosage and reaction results are listed in Table 1.

Example 8

Dissolve 2.12 mg of cobalt chloride (CoCl ₂ ), 2.91 mg of palladium dichloride and 12.6 mg of triphenylphosphine (PPh ₃ ) in a small amount of ethanol, mix them and add 4 ml of ethanol to a 20 ml stainless steel In an autoclave, stir until the mixture is uniform; fill with hydrogen to make the pressure reach 0.5 MPa, heat up to 100°C, stir for 1 hour to prepare a catalyst solution, and then cool to room temperature.

Add 0.5g DAM and 4ml ethanol into the stainless steel autoclave containing the above catalyst solution, fill it with hydrogen until the pressure reaches 4.0MPa, raise the temperature to 120°C, and react for about 6 hours until the pressure of the reaction system no longer drops, cool to room temperature, and take out The reaction liquid was analyzed, and the results showed that the conversion rate of DAM was 96.52%, and the yield rate of TMP was 94.44%.

Example 9--11

Repeat the operation step of embodiment 8, just change the consumption of triphenylphosphine, reaction result and the consumption of triphenylphosphine are listed in table 2.

Example 12--16

Repeat the operation steps of Example 1, just change the palladium compound component and its ratio with the organic ligand, and the reaction results are listed in Table 2.

Example 19

2.12 mg of cobalt dichloride (CoCl ₂ ) and 12.6 mg of triphenylphosphine (PPh ₃ ) were added to 2 ml of ethanol, and stirred at room temperature for 0.5 hour to prepare a catalyst solution.

Add the above catalyst solution, 0.5g DAM and 4ml ethanol into a stainless steel autoclave, fill with hydrogen until the pressure reaches 4.0MPa, raise the temperature to 100°C, and react until the pressure of the reaction system no longer drops, cool to room temperature, take out the reaction liquid for analysis, The results showed that the conversion rate of DAM was 67.06%, and the yield of TMP was 56.65%.

Examples 17, 18, 20

Repeat the operation steps of Example 19, just change the amount of triphenylphosphine in the reaction system, and the reaction results are listed in Table 2.

Example 21

2.13 mg of nickel dichloride (NiCl ₂ ) and 12.6 mg of triphenylphosphine (PPh ₃ ) were dissolved in 1 ml of ethanol respectively, and stirred and mixed at room temperature for 0.5 hour to prepare a catalyst solution.

Add the above catalyst solution, 0.5g DAM and 4ml ethanol into a stainless steel autoclave with a volume of 20ml, stir and mix evenly, fill with hydrogen until the pressure reaches 4.0MPa, and then react at 150°C until the pressure of the reaction system no longer drops , cooled to room temperature, and the reaction liquid was taken out for analysis, and the results are listed in Table 2.

Example 22--24

The operation process of Example 21 was repeated except that the amount of triphenylphosphine in the reaction system was changed, and the reaction results were listed in Table 2.

Example 25--27

The PdCl ₂ --PPh ₃ catalyst was prepared according to the steps of Example 1. The method for synthesizing tetramethylpyrazine was basically the same as that of Example 1, except that the reaction temperature was changed. The results are listed in Table 3.

Example 28

0.58 mg of palladium dichloride (PdCl ₂ ) and 0.5 mg of 2,2'-bipyridine (DPY) were dissolved in 1 ml of ethanol respectively, and stirred and mixed at room temperature for 0.5 hour to prepare a catalyst solution.

Add the above catalyst solution, 0.1g DAM and 4ml ethanol into a stainless steel autoclave with a volume of 20ml, stir and mix evenly, fill with hydrogen until the pressure reaches 0.6MPa, then react at 150°C for 6 hours, then cool to room temperature, The reaction liquid was taken out for analysis, and the results are listed in Table 4.

Examples 29-34

Repeat the operation process of embodiment 28, just change the pressure of hydrogen, and reaction result is listed in table 4.

Table 1, the reaction results of catalysts with different metal components Example number Metal Metal Compound Consumption DAM Conversion Rate TMP Productive Rate

(mg) (%) (%)

1 PdCl ₂ 2.91 94.61 85.53

2 CoCl ₂ 2.13 76.47 72.10

3 H ₂ PtCl ₄ 5.56 76.64 49.20

4 NiBr ₂ 3.58 96.25 56.18

5 RuCl3 _3.40 43.69 41.66

6 CoOAc 2.90 31.04 31.04

7 FeCl ₃ 2.31 25.04 13.24 Comparative Example Blank 0.00 ＜1 ＜1

Table 2, Example of Effect of Triphenylphosphine PPh3/Metal M Ratio on Reaction Results Metal Component PPh ₃ /M Reaction Temperature Hydrogen Pressure DAM Conversion Rate TMP Productive Rate

No. (℃) (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 ₂ 5.0 120 4.0 100.0 88.0 Comparative example PdCl ₂ 0 150 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 _CoCl2 5.0 100 4.0 44.09 35.16

21 NiCl2 _1.5 150 4.0 38.21 16.25

22 NiCl2 _2.0 150 4.0 26.23 12.74

23 NiCl2 _3.0 150 4.0 96.25 56.18

24 _NiCl2 5.0 150 4.0 73.98 25.57

Table 3, the influence of temperature on the PdCl2-PPh3 catalyst reaction results Example number Reaction temperature (℃) DAM conversion (%) TMP yield (%) 25 30 5.96 3.2426 60 14.17 14.1727 120 80.14 51.421 150 94.61 85.53 (other reaction conditions For: hydrogen pressure: 2.4MPa, PdCl ₂ /PPh ₃ =1:1.5, DAM=0.5g)

Table 4. Effect of hydrogen pressure on the reaction results of PdCl ₂ -bipyridine (DPY) catalyst system Example number Hydrogen pressure (MPa) DAM conversion rate (%) TMP yield (%) Comparative example 0 <1.0 <1.028 0.6 40.78 39.4729 1.1 97.46 76.9830 1.3 97.22 89.9031 2.0 58.21 54.7432 3.0 100.0 63.8933 4.0 87.28 52.6934 4.6 95.64 49.28

Claims (7)

1, the present invention is a kind of preparation method of tetramethylpyrazine compound, the main chemical reaction involved is: It is characterized in that: using a coordination catalyst formed by a VIII metal compound and an organic ligand, at a temperature of 30-160°C and a hydrogen pressure of 0.6-5.0Mpa, 2,3-butanedione monoxime is mixed with Hydrogen reacts to form tetramethylpyrazine. 2. The preparation method of tetramethylpyrazine according to claim 1 is characterized in that: the Group VIII metal compound M and the organic ligand L are mixed according to the ratio of M/L=1:0.5～1:5 (molar ratio) Ratio, pre-mixed in an organic solvent to make a coordination catalyst, and then mixed with the reactant DAM. 3, according to the preparation method of the described tetramethylpyrazine of claim 1, it is characterized in that: Group VIII metal compound M and organic ligand L, press M/L=1: 0.5～1: 5 (molar ratio) Ratio, mixed with the reactant DAM and added to the reactor at the same time. 4. The preparation method of tetramethylpyrazine according to claim 1, characterized in that: the Group VIII metal compound used is one of the halides or carboxylates of Pd, Co, Fe, Ni, Pt, Ru one or two. 5. According to claim 1 or 4, it is characterized in that: said group VIII metal compound is palladium chloride or acetate. 6. The preparation method of tetramethylpyrazine according to claim 1, characterized in that: the organic ligand used is one or both of triphenylphosphine PPh ₃ and 2,2'-bipyridine. 7. The preparation method of tetramethylpyrazine according to claim 1, characterized in that: the organic solvent used is ethanol.