CN117362242B - Preparation method of vinyl pyrazine - Google Patents

Preparation method of vinyl pyrazine Download PDF

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Publication number
CN117362242B
CN117362242B CN202311307896.3A CN202311307896A CN117362242B CN 117362242 B CN117362242 B CN 117362242B CN 202311307896 A CN202311307896 A CN 202311307896A CN 117362242 B CN117362242 B CN 117362242B
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pyrazine
vinyl pyrazine
vinyl
reaction
chloropyrazine
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CN117362242A (en
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高明
李新
刘元武
李国辉
陈文更
张明强
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Jinan Enlighten Biotechnology Co ltd
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Abstract

The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of vinyl pyrazine. Under the inert atmosphere and at the temperature of 0-5 ℃, copper salt or palladium salt is used as a catalyst, and 2-chloropyrazine and vinyl magnesium chloride react in an organic solvent to obtain the catalyst; the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether or toluene. The invention can avoid using expensive reagent, and has the advantages of short preparation route, high yield and the like.

Description

Preparation method of vinyl pyrazine
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of vinyl pyrazine.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Vinyl pyrazine (2-vinyl pyrazine), CAS No. 4177-16-6, is an important flavor and pharmaceutical intermediate, particularly synthetic pyrazinethiol (FEMA No. 3230, coE No. 2285), a common food additive with sulfide-like, meat-like, roast-like, beef, chicken, pork, spice-like odors commonly used to formulate beef, pork, chicken, coffee, roast-like flavors. The inventors have studied and appreciated that there are three methods for synthesizing vinyl pyrazine: the first is prepared by partial hydrogenation using ethynyl pyrazine; secondly, methyl pyrazine is used as a raw material, firstly, the methyl pyrazine reacts with formaldehyde and dimethylamine hydrochloride to prepare a Mannich reaction intermediate, then reacts with methyl iodide to prepare quaternary ammonium salt, and trimethylamine is removed under alkaline conditions to obtain a product vinyl pyrazine; the third is prepared by coupling chloropyrazine with vinyl potassium trifluoroborate under the action of catalyst Pd (dppf) 2Cl2. The above synthetic method has the following problems: the ethynyl pyrazine raw material is expensive and is not suitable for large-scale production; the vinyl potassium trifluoroborate and Pd (dppf) 2Cl2 catalysts are also expensive and are of only research value. At present, a relatively reasonable method is to use a methyl pyrazine synthetic route, but the method also has the problems of expensive reagent, long steps and low yield. In view of the above, there is a need to develop a new synthesis method of vinyl pyrazine.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a preparation method of vinyl pyrazine, which can avoid using expensive reagents and has the advantages of short preparation route, high yield and the like.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
The preparation process of vinyl pyrazine includes the reaction of 2-chloropyrazine and vinyl magnesium chloride in organic solvent in inert atmosphere at 0-5 deg.c and with copper salt or palladium salt as catalyst; the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether or toluene.
The invention takes 2-chloropyrazine and vinyl magnesium chloride as raw materials to carry out substitution reaction to obtain the vinyl pyrazine, the preparation route is short, and the reaction raw materials are simple and easy to obtain. However, it was found in experiments that the substitution reaction of 2-chloropyrazine with vinyl magnesium chloride as a raw material was extremely low in activity, so that the yield of the reaction route was extremely low, and it was difficult to realize industrial mass production.
In order to improve the yield, the catalyst is firstly added in the research, the applicable catalyst is mainly a metal catalyst and comprises a nickel salt catalyst, a manganese salt catalyst, a palladium salt catalyst and the like, and generally, the cost of the nickel salt catalyst is lower, and the nickel salt catalyst is preferentially selected, but the research shows that under the reaction system taking 2-chloropyrazine and vinyl magnesium chloride as raw materials, the yield is lower no matter the nickel salt catalyst or the manganese salt catalyst; when the palladium salt catalyst is adopted, the reaction activity can be improved, and the yield is obviously improved. Meanwhile, according to the invention, through experimental accidents, the copper salt catalyst can be used for remarkably improving the reactivity of 2-chloropyrazine and vinyl magnesium chloride, and meanwhile, the catalyst efficiency can reach or even exceed that of a palladium salt catalyst, so that the noble metal catalyst can be avoided.
Secondly, the invention discovers that the selection of the organic solvent can also influence the reactivity of the 2-chloropyrazine and the vinyl magnesium chloride, and compared with organic solvents such as benzene, cyclohexane, pyridine and the like, the selection of tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether or toluene and the like as the organic solvent is more beneficial to improving the reactivity of the 2-chloropyrazine and the vinyl magnesium chloride, thereby further improving the yield of the vinyl pyrazine.
And the reaction temperature is optimized, so that the reaction rate of the 2-chloropyrazine and vinyl magnesium chloride is further improved. Therefore, the invention greatly improves the yield of the vinyl pyrazine prepared by the reaction of the 2-chloropyrazine and the vinyl magnesium chloride through the selection of copper salt catalyst, the selection of solvent and the optimization of reaction temperature.
Preferably, copper salts are used as catalysts, said copper salts being cuprous chloride, cuprous bromide, cupric acetylacetonate or cuprous cyanide.
Preferably, the organic solvent is tetrahydrofuran. Compared with other organic solvents, tetrahydrofuran has lower cost and is more beneficial to improving the reaction yield.
The beneficial effects of the invention are as follows:
According to the invention, chloropyrazine is used as a raw material, and is reacted with a chloroethylene Grignard reagent in one step under the condition of a copper salt catalyst to synthesize the vinyl pyrazine, so that a noble metal catalyst and expensive vinyl potassium trifluoroborate can be avoided, and the production cost is greatly reduced; meanwhile, compared with a methyl pyrazine route, the method shortens the reaction steps, greatly reduces three wastes, reduces the investment cost, has the yield of more than 70 percent and can carry out industrial mass production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a 1 H NMR spectrum of a 2-vinylpyrzine end product prepared in example 1 of the present invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In view of the defects of expensive reagent, long preparation route, low yield and the like in the existing preparation method of the vinyl pyrazine, the invention provides a preparation method of the vinyl pyrazine.
In an exemplary embodiment of the invention, a preparation method of vinyl pyrazine is provided, and under the conditions of inert atmosphere and 0-5 ℃, copper salt or palladium salt is used as a catalyst, and 2-chloropyrazine and vinyl magnesium chloride react in an organic solvent to obtain the vinyl pyrazine; the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether or toluene.
The invention greatly improves the yield of the vinyl pyrazine through the selection of the catalyst, the selection of the solvent and the optimization of the reaction temperature, can avoid using expensive reagents and has shorter reaction route.
In some embodiments, copper salts are used as catalysts, which are cuprous chloride, cuprous bromide, cupric acetylacetonate, or cuprous cyanide. When the copper salt is cuprous bromide, cupric acetylacetonate or cuprous cyanide, especially cuprous cyanide, the yield of the vinyl pyrazine is higher, and the yield can reach more than 80 percent, even approach to 90 percent.
To further reduce costs, in some embodiments, the organic solvent is tetrahydrofuran. In addition, the research shows that when other 2-methyltetrahydrofuran, cyclopentyl methyl ether or toluene are adopted, the tetrahydrofuran is more beneficial to further improving the yield.
In some embodiments, the molar ratio of 2-chloropyrazine to vinyl magnesium chloride is 1:1.01 to 1.1. Preferably 1:1.01 to 1.03, the loss of vinyl magnesium chloride can be further reduced.
In some embodiments, adding 2-chloropyrazine into organic solvent, dispersing uniformly, adding copper salt, cooling to-5 ℃ under inert atmosphere, dropwise adding vinyl magnesium chloride solution, and continuing to react at 0-5 ℃ until the reaction is finished. This operation is more advantageous for the reaction.
In some embodiments, the reaction time is from 4 to 6 hours. Preferably 4 to 5 hours, more preferably 4 to 4.5 hours.
In some embodiments, saturated aqueous ammonium chloride solution is added for extraction after the reaction is finished, and the extracted organic phase is washed by brine, dried and concentrated to obtain a crude product.
In one or more embodiments, the aqueous phase after extraction is re-extracted with an organic solvent, the organic phases are combined, then washed with brine, dried, and concentrated to give the crude product. Product losses during purification can be avoided.
The crude product is rectified to obtain a finished product, and in one or more embodiments, the crude product is rectified after adding a stabilizing agent. The stabilizer is mainly used for inhibiting polymerization and avoiding polymerization of vinyl in the rectification process.
Specifically, the stabilizer is TBC (para-tertiary butyl catechol). The polymerization inhibition with TBC is better.
Specifically, the addition amount of the stabilizer is 0.5-1.5% of the mass of the crude product.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
Example 1
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of THF into a 250ml three-mouth bottle, adding 0.1g of cuprous chloride, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L chloroethylene Grignard reagent (vinyl magnesium chloride, the same applies below), controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding speed, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by THF, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 7.2g and 98%. The yield 70％.(MS＝106.5)1H NMR(DMSO-d6):δ＝5.44(d,1H),7.85(d,1H),6.62(t,1H),8.76(d,1H),8.89(d,1H),9.35(s,1H). is shown in FIG. 1.
Example 2
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of THF into a 250ml three-mouth bottle, adding 0.1g of cuprous bromide, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding speed, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by THF, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 8.5g and 98%. Yield 81% > (ms=106.5).
Example 3
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of THF into a 250ml three-mouth bottle, adding 0.1g of copper acetylacetonate, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding speed, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by THF, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 8.8g and 98%. Yield 85% > (ms=106.5).
Example 4
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of THF into a 250ml three-mouth bottle, adding 0.1g of cuprous cyanide, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding speed, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by THF, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 9g and 98%. Yield 89% > (ms=106.5).
Example 5
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of THF into a 250ml three-mouth bottle, adding 0.1g of anhydrous nickel chloride, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding time after the dropwise adding, and continuously preserving the temperature for reacting for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by THF, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 5.4g and 98%. Yield 54% > (ms=106.5).
Example 6
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of THF into a 250ml three-mouth bottle, adding 0.1g of anhydrous manganese chloride, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding speed, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by THF, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 6.6g and 98%. Yield 65% > (ms=106.5).
Example 7
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of THF into a 250ml three-mouth bottle, adding 0.1g of palladium chloride, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding speed, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by THF, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 8.2g and 98%. Yield 81% > (ms=106.5).
Example 8
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of toluene into a 250ml three-mouth bottle, adding 0.1g of cuprous cyanide, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding speed, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, the aqueous phase is extracted once again by toluene, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 7.8g and 98%. Yield 77% > (ms=106.5).
Example 9
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of cyclopentyl methyl ether into a 250ml three-mouth bottle, adding 0.1g of cuprous cyanide, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L of vinyl chloride Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding time after the dropwise adding, and continuing to perform heat preservation reaction for 4 hours; after the reaction is finished, the system is dropwise added into 200ml of saturated ammonium chloride aqueous solution, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, the aqueous phase is extracted once again by cyclopentyl methyl ether, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained by rectification, wherein the purity is about 8g and 98%. Yield 79% > (ms=106.5).
Example 10
Synthesis of 2-vinyl pyrazine
Dispersing 11.2g of 2-chloropyrazine and 120ml of 2-methyltetrahydrofuran into a 250ml three-mouth bottle, adding 0.1g of cuprous cyanide, stirring and cooling to about 0 ℃ (+/-5 ℃) under the protection of nitrogen, slowly dropwise adding 40ml of 2.5mol/L chloroethylene Grignard reagent, controlling the dropwise adding speed in the dropwise adding process, keeping the internal temperature at 0-5 ℃, keeping the dropwise adding time after the dropwise adding, and continuously preserving the temperature for reacting for 4 hours; after the reaction is finished, the system is added into 200ml of saturated ammonium chloride aqueous solution in a dropwise manner, the temperature is raised to room temperature, the mixture is kept still, an organic phase is separated, an aqueous phase is extracted once again by using 2-methyltetrahydrofuran, the organic phase is combined, the mixture is washed by brine, dried and concentrated under reduced pressure to obtain a crude product, 1% of stabilizer TBC is added into the crude product, and the 2-vinyl pyrazine finished product is obtained through rectification, wherein the purity is about 7.3 g. Yield 72% > (ms=106.5).
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (13)

1. A preparation method of vinyl pyrazine is characterized in that under the condition of inert atmosphere and 0-5 ℃, copper salt or palladium salt is used as a catalyst, and 2-chloropyrazine and vinyl magnesium chloride react in an organic solvent to obtain the vinyl pyrazine; the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether or toluene;
the copper salt is cuprous chloride, cuprous bromide, cupric acetylacetonate or cuprous cyanide;
The mol ratio of the 2-chloropyrazine to the vinyl magnesium chloride is 1:1.01-1.1.
2. The method for preparing vinyl pyrazine as defined in claim 1, wherein copper salt is copper bromide, copper acetylacetonate or copper cyanide as catalyst.
3. The method for preparing vinyl pyrazine as defined in claim 1, wherein the copper salt is cuprous cyanide.
4. The method for producing a vinylpyrzine according to claim 1, wherein the organic solvent is tetrahydrofuran.
5. The method for preparing vinyl pyrazine as defined in claim 1, wherein the molar ratio of 2-chloropyrazine to vinyl magnesium chloride is 1:1.01-1.03.
6. The method for preparing vinyl pyrazine as defined in claim 1, wherein 2-chloropyrazine is added into organic solvent to be dispersed uniformly, copper salt is added, the temperature is reduced to 0-5 ℃ under the inert atmosphere condition, vinyl magnesium chloride solution is added dropwise, and the reaction is continued at 0-5 ℃ until the reaction is finished after the dropwise addition.
7. The method for preparing vinyl pyrazine according to claim 1, wherein the reaction time is 4 to 6 hours.
8. The method for preparing vinyl pyrazine according to claim 1, wherein the reaction time is 4 to 5 hours.
9. The method for preparing vinyl pyrazine according to claim 1, wherein the reaction time is 4 to 4.5 hours.
10. The method for preparing vinyl pyrazine as defined in claim 1, wherein saturated aqueous ammonium chloride solution is added for extraction after the reaction is finished, and the extracted organic phase is washed with brine, dried and concentrated to obtain crude product.
11. The method for preparing vinyl pyrazine as defined in claim 10, wherein the extracted aqueous phase is extracted again with an organic solvent, the organic phases are combined, washed with brine, dried and concentrated to obtain crude product.
12. The method for preparing vinyl pyrazine as defined in claim 10, wherein the crude product is rectified after adding a stabilizer.
13. The method for preparing vinyl pyrazine of claim 12 wherein the stabilizer is TBC;
or the addition amount of the stabilizer is 0.5-1.5% of the mass of the crude product.
CN202311307896.3A 2023-10-10 Preparation method of vinyl pyrazine Active CN117362242B (en)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Convenient Synthesis of Stable Deuterium-Labeled Alkylpyrazines for Use in Stable Isotope Dilution Assays;Fang, Mingchih等;Journal of Agricultural and Food Chemistry;20130325;第61卷(第15期);3580-3588 *
Discovery of Novel 1,3-Diphenylpyrazine Derivatives as Potent S-Phase Kinase- Associated Protein 2 (Skp2) Inhibitors for the Treatment of Cancer.Journal of Medicinal Chemistry.2023,第66卷(第11期), 7221-7242. *
Two Approaches to the Chemical Development and Large-Scale Preparation of a Pyrimidyl Tetrazole Intermediate;Peter Mullens等;Organic Process Research & Development;20160608;第20卷;1075−1087 *
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