A kind of synthesis method of 1-(2-pyrazinyl)ethanol

Abstract

The invention discloses a method for synthesizing 1-(2-pyrazinyl)ethanol, and belongs to the technical field of organic synthesis. The method for synthesizing provided by the invention comprises the following steps: under an inert atmosphere, pyrazine and dipropionyl peroxide react under the action of a divalent iron catalyst to generate an ethylpyrazine intermediate; under an inert atmosphere, the ethylpyrazine intermediate and p-nitrobenzonitrile undergo an oxidation reaction under the action of ultraviolet light to generate 1-(2-pyrazinyl)ethanol. The invention can obtain 1-(2-pyrazinyl)ethanol by a two-step method, which is simple to operate, has a short reaction route, mild conditions, low reaction raw material cost, and a two-step total yield of 1-(2-pyrazinyl)ethanol of more than 65%.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 1-(2-pyrazinyl)ethanol. Background Art

[0002] The information disclosed in the background of the invention is only intended to enhance the understanding of the overall background of the invention and should not be necessarily regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] 1-(2-pyrazinyl)ethanol is a direct raw material of an important edible flavoring acetylpyrazine and a synthetic intermediate of pyrazine drugs. The currently reported synthesis method of 1-(2-pyrazinyl)ethanol mainly uses pyrazine as a starting material, first undergoes acetylation to obtain acetylpyrazine, and then undergoes catalytic hydrogenation under the action of a reducing agent such as lithium aluminum hydride, sodium borohydride, or a catalyst such as metal ruthenium to obtain it. The problems existing in this method mainly include the following aspects: first, the conversion rate of the acetylation process is low, and there is a lot of residual raw materials; second, the reducing agents lithium aluminum hydride and sodium borohydride have the risk of being flammable and explosive, which increases the safety hazard during transportation and use; third, metal catalysts such as ruthenium are expensive, which increases the production cost. Therefore, it is urgent to develop a synthesis method of 1-(2-pyrazinyl)ethanol that is simple to operate, safe, and has a high yield to make up for the problems and shortcomings of the existing methods. Summary of the invention

[0004] In view of this, the present invention provides a method for synthesizing 1-(2-pyrazinyl)ethanol, which solves the problems of low raw material safety or high cost and low conversion rate in the synthesis of 1-(2-pyrazinyl)ethanol in the prior art.

[0005] The present invention provides a method for synthesizing 1-(2-pyrazinyl)ethanol, comprising the following steps:

[0006] Step 1, under an inert atmosphere, pyrazine and dipropionyl peroxide react under the action of a divalent iron catalyst to generate an ethylpyrazine intermediate; the molar ratio of the pyrazine, dipropionyl peroxide and the divalent iron catalyst is 1:(1-1.5):(0.08-0.12);

[0007] Step 2: Under an inert atmosphere, the ethylpyrazine intermediate and p-nitrobenzonitrile undergo an oxidation reaction under the action of ultraviolet light to generate 1-(2-pyrazinyl)ethanol.

[0008] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0009] The invention uses pyrazine and dipropionyl peroxide as starting materials, reacts under the action of a divalent iron catalyst to generate an ethylpyrazine intermediate, and then reacts the ethylpyrazine intermediate with p-nitrobenzonitrile under ultraviolet light to obtain 1-(2-pyrazinyl)ethanol. The synthesis method provided by the invention has the advantages of simple operation, short reaction route, mild conditions, low cost of reaction raw materials, and a two-step total yield of 1-(2-pyrazinyl)ethanol of more than 65%. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The drawings constituting part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute an improper limitation of the present invention. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0011] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the product 1-(2-pyrazinyl)ethanol of Example 1 of the present invention. DETAILED DESCRIPTION

[0012] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0013] The present invention provides a method for synthesizing 1-(2-pyrazinyl)ethanol, comprising the following steps:

[0014] Step 1, pyrazine and dipropionyl peroxide react under the action of a divalent iron catalyst to generate an ethylpyrazine intermediate; the molar ratio of the pyrazine, dipropionyl peroxide and the divalent iron catalyst is 1:(1-1.5):(0.08-0.12);

[0015] Step 2: The ethylpyrazine intermediate reacts with p-nitrobenzonitrile under the action of ultraviolet light to undergo an oxidation reaction to generate 1-(2-pyrazinyl)ethanol.

[0016] The invention uses pyrazine as a starting material to synthesize an ethylpyrazine intermediate. Compared with directly using ethylpyrazine as a reaction raw material, pyrazine has a wide source and is low in price, and can greatly reduce the synthesis cost of 1-(2-pyrazinyl)ethanol.

[0017] In step 1 of the present invention, dipropionyl peroxide is broken down into carboxyl radicals CH under the action of divalent iron. 3 CH 2 COO·, further decomposes and decarboxylates to give ethyl radicals (CH 3 CH 2·), ethyl radical is added to pyrazine, and ethyl pyrazine is obtained after oxidation and deprotonation. The present invention does not impose any special restrictions on the source of dipropionyl peroxide, which can be purchased from commercial sources or prepared by itself. The present invention does not impose any special restrictions on its synthesis method, and the present invention is preferably obtained by reacting hydrogen peroxide with propionic acid.

[0018] In step 2 of the present invention, after p-nitrobenzonitrile is excited by light, a triplet double free intermediate is obtained, and then the hydrogen atom at the benzylic position of ethylpyrazine is captured through a hydrogen atom transfer process to obtain an alkyl radical and a dihydroxyaniline oxygen radical. The alkyl radical and the dihydroxyaniline oxygen radical are combined, and the nitrogen-oxygen bond is broken and protonated to obtain a hydroxyl product, i.e., 1-(2-pyrazinyl)ethanol.

[0019] In the present invention, the molar ratio of the pyrazine, dipropionyl peroxide and divalent iron catalyst is preferably 1:(1.2-1.4):(0.09-0.11).

[0020] In the present invention, the divalent iron catalyst is selected from one or both of ferrous bromide and ferrous chloride.

[0021] In step 1 of the present invention, the reaction temperature is 20-30° C., the reaction in step 1 of the present invention can be carried out without heating, and the reaction conditions are mild; the reaction time is 8-15 h.

[0022] In step 1 of the present invention, the solvent of the reaction is selected from acetonitrile, and the amount ratio of pyrazine to the solvent is 1g: (4-10)mL. When acetonitrile is used as a solvent, it has good solubility for the divalent iron catalyst.

[0023] After the reaction in step 1 is completed, the present invention further includes a step of purifying the reaction product, which is not particularly limited in the present invention, and those skilled in the art can purify the product according to commonly used purification methods in the art. The present invention preferably comprises: subjecting the reaction liquid after the reaction in step 1 to reduced pressure distillation, and then adding NaHCO 3 The aqueous solution is added to remove the acetic acid produced in the reaction, and then extracted with dichloromethane, and the organic phase is distilled under reduced pressure to obtain the product.

[0024] In the present invention, the molar ratio of the ethylpyrazine intermediate to p-nitrobenzonitrile is 1:(1.0-1.5), more preferably 1:(1.05-1.3).

[0025] In step 2 of the present invention, the temperature of the oxidation reaction is 20-30° C. The reaction can be carried out at room temperature without heating the reaction, and the reaction conditions are mild; the oxidation reaction time is 10-24 h, more preferably 10-15 h.

[0026] In step 2 of the present invention, the solvent for the oxidation reaction is selected from one or both of dichloromethane and chloroform; the dosage ratio of the ethylpyrazine intermediate to the solvent is 1 g: (4-10) mL.

[0027] In the present invention, the wavelength of the ultraviolet light is preferably 390-400 nm.

[0028] After step 2, the present invention further comprises a step of purifying the target product. The present invention preferably comprises performing reduced pressure distillation on the reaction solution to remove the solvent, and then performing column chromatography separation to obtain purified 1-(2-pyrazinyl)ethanol.

[0029] The inert atmosphere in step 1 and step 2 of the present invention is selected from one or more of nitrogen or rare gases, and nitrogen is further preferred; the reaction needs to be carried out under water- and oxygen-free conditions to avoid adverse effects on the reaction and affect the reaction yield.

[0030] In order to increase the reaction rate, the reactions in step 1 and step 2 of the present invention are preferably carried out under stirring conditions, and the present invention does not impose any particular limitation on the stirring speed.

[0031] The technical solution of the present invention is further described below in conjunction with specific embodiments. The reaction scheme in the following embodiments is as follows:

[0032] .

[0033] Unless otherwise specified, the reagents in the following examples can be obtained from commercial sources. The room temperature in the following examples refers to 25±3°C.

[0034] The dipropionyl peroxide in the following example was prepared by the following steps: 4-dimethylaminopyridine (1.5 mmol), 30wt% hydrogen peroxide solution (19 mmol) and propionic acid (15 mmol) were added to 20 mL of dichloromethane, the mixture was cooled to -15°C, stirred for 15 minutes, and then dicyclohexylcarbodiimide (16.5 mmol) was added and stirred at 0°C for 6 hours. After the reaction was completed, 20 mL of petroleum ether was added to the reaction mixture, and filtered through diatomaceous earth and washed with an additional 50 mL of solvent (petroleum ether / DCM = 10 / 1, v / v). Concentrated using a rotary evaporator at 10-15°C to obtain 1.2 g of dipropionyl peroxide. The preparation was repeated several times for subsequent use.

[0035] Example 1

[0036] This embodiment provides a method for synthesizing 1-(2-pyrazinyl)ethanol, and the specific method is as follows:

[0037] (1) Under nitrogen atmosphere, pyrazine (1 g, 12.5 mmol), dipropionyl peroxide (2.4 g, 16.3 mmol), FeBr 2 (0.27 g, 1.25 mmol) and 6 mL of acetonitrile. The reaction was stirred at room temperature for 10 h. After the reaction was completed, the solvent was distilled off under reduced pressure and 20 mL of 1M NaHCO 3 The mixture was diluted with aqueous solution and extracted with dichloromethane (2×20 mL). The organic phases were combined and the solvent was removed by distillation under reduced pressure to obtain 1.2 g of ethylpyrazine intermediate.

[0038] (2) Under nitrogen atmosphere, 1.2 g of ethylpyrazine (11.1 mmol) obtained in step (1) was added to a 10 mL Shrek tube, and p-nitrobenzonitrile (1.8 g, 12.5 mmol) and 6 mL of dichloromethane were added. The mixture was stirred at room temperature for 12 h under ultraviolet light irradiation at 390-395 nm. The organic solvent was removed by rotary evaporation under reduced pressure, and the product 1-(2-pyrazinyl)ethanol 1.1 g (8.9 mmol) was separated by column chromatography. The total yield of the two steps was 71%. The H NMR spectrum of the product is shown in Figure 2. Figure 1 As shown, 1 H NMR (500 MHz, CDCl 3 ): δ 8.67 (s, 1H), 8.53-8.42 (m, 2H), 4.97 (q, J = 6.7 Hz, 1H), 3.74 (s, 1H), 1.55 (d, J = 6.6 Hz, 3H).

[0039] Example 2

[0040] The difference between this embodiment and embodiment 1 is that the solvent in step (2) is chloroform.

[0041] Step (2) of this embodiment is as follows:

[0042] Under nitrogen atmosphere, 1.2 g of ethylpyrazine (11.1 mmol) obtained in step (1) was added to a 10 mL Shrek tube, and p-nitrobenzonitrile (1.8 g, 12.5 mmol) and 6 mL of chloroform were added. The mixture was stirred at room temperature for 12 h under ultraviolet light irradiation at 390-395 nm. The organic solvent was removed by rotary evaporation under reduced pressure, and the product 1-(2-pyrazinyl)ethanol 1.15 g (9.3 mmol) was separated by column chromatography. The total yield of the two steps was 74%.

[0043] Example 3

[0044] The difference between this embodiment and embodiment 1 is that in step (1), FeCl 2 Replacement of FeBr 2 The specific steps are as follows:

[0045] (1) Under nitrogen atmosphere, pyrazine (1 g, 12.5 mmol), dipropionyl peroxide (2.4 g, 16.3 mmol), FeCl 2 (0.16 g, 1.25 mmol) and 6 mL of acetonitrile. The reaction was stirred at room temperature for 10 h. After the reaction was completed, the solvent was distilled off under reduced pressure and 20 mL of 1M NaHCO 3 The mixture was diluted with aqueous solution and extracted with dichloromethane (2×20 mL). The organic phases were combined and the solvent was removed by distillation under reduced pressure to obtain 1.1 g of ethylpyrazine intermediate.

[0046] (2) Under nitrogen atmosphere, 1.1 g of ethylpyrazine (10.1 mmol) obtained in step (1) was added to a 10 mL Shrek tube, and p-nitrobenzonitrile (1.7 g, 11.4 mmol) and 6 mL of chloroform were added. The mixture was stirred at room temperature for 12 h under ultraviolet light irradiation at 390-395 nm. The organic solvent was removed by rotary evaporation under reduced pressure, and the product 1-(2-pyrazinyl)ethanol (1.05 g, 8.5 mol) was separated by column chromatography. The total yield of the two steps was 68%.

[0047] Example 4

[0048] The present embodiment differs from the embodiment 1 in that in step (1), the ultraviolet light of 390-395 nm is replaced by the ultraviolet light of 395-400 nm.

[0049] Step (2) of this embodiment is as follows:

[0050] Under nitrogen atmosphere, 1.2 g of ethylpyrazine (11.1 mmol) obtained in step (1) was added to a 10 mL Shrek tube, and p-nitrobenzonitrile (1.8 g, 12.5 mmol) and 6 mL of dichloromethane were added. The mixture was stirred at room temperature for 12 h under ultraviolet light irradiation at 395-400 nm. The organic solvent was removed by rotary evaporation under reduced pressure, and the product 1-(2-pyrazinyl)ethanol 1.06 g (8.5 mmol) was separated by column chromatography. The total yield of the two steps was 68%.

[0051] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 1-(2-pyrazinyl)ethanol, characterized in that: The steps include: Step 1, under an inert atmosphere, pyrazine and dipropionyl peroxide react under the action of a divalent iron catalyst to generate an ethylpyrazine intermediate; the molar ratio of the pyrazine, dipropionyl peroxide and the divalent iron catalyst is 1:(1-1.5):(0.08-0.12); Step 2: Under an inert atmosphere, the ethylpyrazine intermediate and p-nitrobenzonitrile undergo an oxidation reaction under the action of ultraviolet light to generate 1-(2-pyrazinyl)ethanol.

2. The synthesis method according to claim 1, characterized in that The divalent iron catalyst is selected from one or both of ferrous bromide and ferrous chloride.

3. The synthesis method according to claim 1, characterized in that In step 1, the reaction temperature is 20-30° C., and the reaction time is 8-15 h.

4. The synthesis method according to claim 1, characterized in that In step 1, the solvent of the reaction is acetonitrile.

5. The synthesis method according to claim 4, characterized in that In step 1, the usage ratio of pyrazine to solvent is 1 g: (4-10) mL.

6. The synthesis method according to claim 1, characterized in that The molar ratio of the ethylpyrazine intermediate to p-nitrobenzonitrile is 1:(1.0-1.5).

7. The synthesis method according to claim 1, characterized in that In step 2, the temperature of the oxidation reaction is 20-30° C., and the time of the oxidation reaction is 10-24 h.

8. The synthesis method according to claim 1, characterized in that In step 2, the solvent of the oxidation reaction is selected from one or both of dichloromethane and chloroform; the dosage ratio of the ethylpyrazine intermediate to the solvent is 1 g: (4-10) mL.

9. The synthesis method according to claim 1, characterized in that The wavelength of the ultraviolet light is 390-400nm.

10. The synthesis method according to claim 1, characterized in that The inert atmosphere in step 1 and step 2 is selected from one or more of nitrogen or rare gases.

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