CN112645890B - Synthesis method of 2-pyrazine carboxylic ester compound - Google Patents
Synthesis method of 2-pyrazine carboxylic ester compound Download PDFInfo
- Publication number
- CN112645890B CN112645890B CN202011567556.0A CN202011567556A CN112645890B CN 112645890 B CN112645890 B CN 112645890B CN 202011567556 A CN202011567556 A CN 202011567556A CN 112645890 B CN112645890 B CN 112645890B
- Authority
- CN
- China
- Prior art keywords
- compound
- synthesis method
- reaction
- chloride
- dehydrating agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- C07D241/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention provides a synthetic method of 2-pyrazine carboxylic ester compounds. The synthesis method comprises the following steps: step S1, carrying out addition reaction on the compound 1 and glyoxal dioxime under the action of a Lewis acid catalyst to obtain an intermediate 1; step S2, intermediate 1 viaPerforming a first dehydration reaction to obtain a 2-pyrazine carboxylate compound, wherein the structural general formulas of the compound 1, the intermediate 1 and the 2-pyrazine carboxylate compound are as follows in sequence:
R 1 is C 1 ～C 15 Substituted or unsubstituted alkyl of, R 2 Is C 1 ～C 10 Alkyl group of (1). The preparation cost (or the market price) of the starting material compound 1 adopted by the invention is generally far lower than that of a methyl trifluoropyruvate compound; compared with the traditional preparation method of 3-trifluoromethyl-2-pyrazine methyl formate, the method has the advantages of mild reaction conditions, simple operation and wide raw material source, avoids the use of expensive coupling catalyst and greatly reduces the cost.
Description
Technical Field
The invention relates to the technical field of synthesis of 3-trifluoromethyl-2-pyrazine methyl formate, and particularly relates to a synthesis method of 2-pyrazine carboxylate compounds.
Background
Methyl 3-trifluoromethyl-2-pyrazinecarboxylate (compound 1A) is a compound with fungicidal activity. After the compound 1A is prepared into the pyrazinecarboxamide derivative or the salt thereof, the pyrazinecarboxamide derivative or the salt thereof can be used as a bactericide for agriculture and horticulture, so that the 3-trifluoromethyl-2-pyrazinecarboxylate has wider application in synthesizing pesticides to prepare broad-spectrum insecticides. The most common preparation method is shown as reaction 1-1:
the method takes methyl trifluoropyruvate as an initial raw material, and compounds 1A are obtained through cyclization, dehydrogenation, chlorination and esterification reactions of methyl pyruvate and ethylenediamine. The method has the defects that the required methyl trifluoropyruvate compound is often difficult to obtain directly from the market, the methyl trifluoropyruvate can be generated only through multi-step reaction, the preparation process is complex, the preparation yield is not high, the environmental pollution is large, the method needs to use carbon monoxide for coupling, and the coupled catalyst is expensive, so that the overall cost of the method is increased.
Disclosure of Invention
The invention mainly aims to provide a synthetic method of 2-pyrazine carboxylic acid ester compounds, and aims to solve the problems of complex reaction process and high cost of the synthetic method of 3-trifluoromethyl-2-pyrazine methyl formate in the prior art.
In order to achieve the above object, according to an aspect of the present invention, there is provided a synthesis method of a 2-pyrazine carboxylate compound, the synthesis method comprising: step S1, carrying out addition reaction on the compound 1 and glyoxal dioxime under the action of a Lewis acid catalyst to obtain an intermediate 1; step S2, the intermediate 1 undergoes a first dehydration reaction to obtain a 2-pyrazine carboxylate compound, wherein the structural general formulas of the compound 1, the intermediate 1 and the 2-pyrazine carboxylate compound are as follows in sequence:
Further, the Lewis acid catalyst is selected from one or more of ferric chloride, aluminum chloride, titanium chloride, a combination of zinc chloride and lanthanum chloride and zinc chloride, and the dosage of the Lewis acid catalyst is preferably 0.43-5.5 wt% of the compound 1; preferably, the amount of zinc chloride in the combination of zinc chloride and lanthanum chloride is 0.4-5 wt% of the compound 1, and the amount of lanthanum chloride is 0.03-0.5 wt% of the compound 1; further, the mass ratio of zinc chloride to lanthanum chloride in the combination of zinc chloride and lanthanum chloride is preferably 2-10: 1.
Further, when the Lewis acid catalyst is zinc chloride, the temperature of the addition reaction is 90-100 ℃; when the Lewis acid catalyst is aluminum chloride and/or titanium chloride, the temperature of the addition reaction is 50-60 ℃; when the Lewis acid catalyst is a combination of zinc chloride and lanthanum chloride, the temperature of the addition reaction is preferably 60 to 80 ℃, and more preferably 65 to 70 ℃.
Further, the above R 1 Is C 1 ～C 10 Substituted or unsubstituted alkyl of, preferably R 1 Substituted by electron-withdrawing groups, preferably the electron-withdrawing groups are selected from one or more of trifluoromethyl, nitro and halogen atoms.
Go toStep (ii) above R 2 Is C 1 ～C 6 Alkyl of (3), preferably R 2 Is selected from any one of methyl, ethyl and propyl.
Further, the above synthesis method further comprises a preparation process of the compound 1, the preparation process comprises: carrying out reduction reaction on the compound 2 to obtain an intermediate 2; carrying out a second dehydration reaction on the intermediate 2 under the action of a dehydrating agent to obtain a compound 1, wherein the structural general formulas of the compound 2 and the intermediate 2 are as follows in sequence:
Further, a polymerization inhibitor is used in the addition reaction, and the molar ratio of the polymerization inhibitor to the compound 1 is preferably 0.003-0.005: 1; preferably the inhibitor is hydroquinone and/or p-tert-butylcatechol.
Further, the molar ratio of the glyoxal dioxime to the compound 1 is 1.0-1.1: 1.
Further, the addition reaction is carried out in a first solvent, preferably the first solvent is selected from any one or more of toluene, xylene, and chlorobenzene.
Further, the first dehydration reaction is carried out under the catalysis of a catalyst, the catalyst is preferably selected from one or more of titanium tetrachloride, aluminum trichloride and zinc chloride, the molar ratio of the catalyst to the intermediate is preferably 1.0-1.05: 1, the first dehydration reaction is preferably carried out in a second solvent, the second solvent is preferably selected from one or more of tetrahydrofuran, methyl tert-butyl ether and ethylene glycol dimethyl ether, and the temperature of the dehydration reaction is preferably 0-5 ℃.
By applying the technical scheme of the invention, the preparation cost (or the market price) of the starting material compound 1 adopted by the invention is generally far lower than that of a methyl trifluoropyruvate compound; and controlling the carbon-carbon double bond in the compound 1 and the carbon-nitrogen double bond of glyoxal dioxime to carry out addition reaction by a Lewis acid catalyst so as to reduce the self polymerization reaction probability of the compound 1 as much as possible, thereby obtaining a cyclized intermediate, and dehydrating the intermediate to obtain the 2-pyrazine carboxylate compound. Compared with the traditional preparation method of 3-trifluoromethyl-2-pyrazine methyl formate, the method has the advantages of mild reaction conditions, simple operation and wide raw material source, avoids the use of expensive coupling catalyst and greatly reduces the cost.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As analyzed by the background technology, the synthetic method of 3-trifluoromethyl-2-pyrazine methyl formate in the prior art has the problems of complex reaction process and high cost, and the invention provides a synthetic method of 2-pyrazine carboxylic ester compounds in order to solve the problems.
In an exemplary embodiment of the present application, there is provided a method for synthesizing a 2-pyrazine carboxylate compound, the method comprising: step S1, carrying out addition reaction on the compound 1 and glyoxal dioxime under the action of a Lewis acid catalyst to obtain an intermediate 1; step S2, the intermediate 1 undergoes a first dehydration reaction to obtain a 2-pyrazine carboxylate compound, wherein the structural general formulas of the compound 1, the intermediate 1 and the 2-pyrazine carboxylate compound are as follows in sequence:
The preparation cost (or the market price) of the starting material compound 1 adopted by the invention is generally far lower than that of a methyl trifluoropyruvate compound; and controlling the carbon-carbon double bond in the compound 1 and the carbon-nitrogen double bond of glyoxal dioxime to carry out addition reaction by a Lewis acid catalyst so as to reduce the self polymerization reaction probability of the compound 1 as much as possible, thereby obtaining a cyclized intermediate, and dehydrating the intermediate to obtain the 2-pyrazine carboxylate compound. Compared with the traditional preparation method of 3-trifluoromethyl-2-pyrazine methyl formate, the method has the advantages of mild reaction conditions, simple operation and wide raw material source, avoids the use of expensive coupling catalyst and greatly reduces the cost.
In order to improve the efficiency of the addition reaction, the Lewis acid catalyst is preferably selected from one or more of ferric chloride, aluminum chloride, titanium chloride, a combination of zinc chloride and lanthanum chloride and zinc chloride, and the amount of the Lewis acid catalyst is preferably 0.43-5.5 wt% of the compound 1; preferably, the amount of zinc chloride in the combination of zinc chloride and lanthanum chloride is 0.4-5 wt% of the compound 1, and the amount of lanthanum chloride is 0.03-0.5 wt% of the compound 1; further, the mass ratio of zinc chloride to lanthanum chloride in the combination of zinc chloride and lanthanum chloride is preferably 2-10: 1.
According to different catalytic activities of catalysts, the addition reaction needs to be carried out at different reaction temperatures, but the higher the reaction temperature, the higher the self-polymerization probability of the compound 1, and under the effect of both improving the catalytic activity and controlling the self-polymerization as far as possible, preferably, when the Lewis acid catalyst is zinc chloride, the temperature of the addition reaction is 90-100 ℃; when the Lewis acid catalyst is aluminum chloride and/or titanium chloride, the temperature of the addition reaction is 50-60 ℃; when the Lewis acid catalyst is a combination of zinc chloride and lanthanum chloride, the temperature of the addition reaction is preferably 60 to 80 ℃, and more preferably 65 to 70 ℃.
In order to improve the efficiency of the addition reaction, the above R is preferably used 1 Is C 1 ～C 10 Substituted or unsubstituted alkyl of, preferably R 1 Substituted by electron-withdrawing groups, preferably the electron-withdrawing groups are selected from one or more of trifluoromethyl, nitro and halogen atoms.
To reduce R 2 The influence of steric hindrance on the addition reaction, R is preferably as described above 2 Is C 1 ～C 6 Alkyl of (3), preferably R 2 Is selected from any one of methyl, ethyl and propyl.
In one embodiment of the present application, the above synthesis method further comprises a preparation process of compound 1, the preparation process comprising: carrying out reduction reaction on the compound 2 to obtain an intermediate 2; carrying out a second dehydration reaction on the intermediate 2 under the action of a dehydrating agent to obtain a compound 1, wherein the structural general formulas of the compound 2 and the intermediate 2 are as follows:
In order to further reduce the cost of compound 1 and thus the cost of the reaction as a whole, it is preferred that compound 1 is obtained according to the above-described preparation method, wherein all parameter ranges are preferred in order to improve the efficiency of the above-described reduction reaction and the second dehydration reaction. Of course, the person skilled in the art can also purchase or otherwise synthesize compound 1 directly according to actual needs.
The dehydrating agent can be one commonly used in the prior art, and preferably is a sulfate dehydrating agent and/or a p-toluenesulfonic acid dehydrating agent; preferably, when the dehydrating agent is a sulfate dehydrating agent, the molar ratio of the sulfate dehydrating agent to the intermediate 2 is 0.02-0.05: 1; when the dehydrating agent is a p-toluenesulfonic acid dehydrating agent, the molar ratio of the p-toluenesulfonic acid dehydrating agent to the intermediate 2 is preferably 0.01-0.5: 1, and the sulfate dehydrating agent is further preferably selected from one or more of sulfate, zinc sulfate and copper sulfate; the p-benzenesulfonic acid-based dehydrating agent is preferably p-toluenesulfonic acid and/or benzenesulfonic acid. The second dehydration reaction is preferably performed in a homogeneous system to improve the reaction efficiency, the second dehydration reaction is preferably performed in a solvent, and the solvent added in the second dehydration reaction is more preferably a polar solvent, and the polar solvent is preferably one or more selected from cyclohexane, cyclopentane, toluene, petroleum ether, and n-heptane.
In addition, the glyoxal dioxime can be purchased directly or obtained through preparation, in order to reduce the cost of glyoxal dioxime, strong base is preferably adopted to dissociate hydroxylamine from hydroxylamine salt and react with glyoxal, the strong base is prepared into a strong base aqueous solution of 20-30 wt% of sodium hydroxide and/or potassium hydroxide, and the molar ratio of the strong base to the hydroxylamine salt is 1.0-1.1: 1. preferably, the glyoxal is 40 wt% aqueous glyoxal solution; preferably, the hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfuric acid, and the molar ratio of the hydroxylamine salt to glyoxal is 1.0-1.2: 1; specifically, 40 wt% of glyoxal aqueous solution and hydroxylamine salt are added into a reaction container, strong base aqueous solution is dropwise added under the protection of nitrogen, the temperature is controlled to be 0-10 ℃, after the addition is finished, stirring is carried out, the temperature is raised to 50-60 ℃, and heat preservation is carried out continuously for 4-6 hours. And cooling to 20-25 ℃, carrying out suction filtration, washing with water, and drying to obtain a crude glyoxal dioxime product with the yield of about 90-95%.
In order to reduce the self-polymerization probability of the compound 1 as much as possible and further reduce the yield of the addition reaction, a polymerization inhibitor is preferably used in the addition reaction, and the molar ratio of the polymerization inhibitor to the compound 1 is preferably 0.003-0.005: 1; preferably the inhibitor is hydroquinone and/or p-tert-butylcatechol.
In order to increase the conversion rate of the compound 1, the molar ratio of the glyoxal dioxime to the compound 1 is preferably 1.0 to 1.1: 1.
In some embodiments, in order to dissolve the above raw materials in the first solvent as much as possible, thereby improving the efficiency of the addition reaction, it is preferable that the above addition reaction is performed in the first solvent, and the first solvent is preferably selected from any one or more of toluene, xylene, and chlorobenzene.
In order to improve the efficiency of the dehydration reaction, the dehydration reaction is preferably carried out under the catalysis of a catalyst, the catalyst is preferably selected from one or more of titanium tetrachloride, aluminum trichloride and zinc chloride, the molar ratio of the catalyst to the intermediate is preferably 1.0-1.05: 1, the dehydration reaction is preferably carried out in a second solvent, the second solvent is preferably selected from one or more of tetrahydrofuran, methyl tert-butyl ether and ethylene glycol dimethyl ether, and the temperature of the dehydration reaction is preferably 0-5 ℃.
The following description will explain advantageous effects of the present application with reference to specific examples.
Example 1
The first step is as follows: reduction of
Firstly, adding 150mL of tetrahydrofuran and 20.9g (0.387mol) of potassium borohydride into a 500mL glass three-neck flask, stirring and heating to 40-45 ℃ under the protection of nitrogen, controlling the temperature to 40-45 ℃, dropwise adding a mixed solution of 50g (0.352mol) of methyl trifluoroacetoacetate and 50mL of tetrahydrofuran, finishing adding after about 1 hour, heating to 60-65 ℃ after finishing adding, continuously preserving heat for 4 hours, sampling, cooling to 20-25 ℃ after the medium control is qualified, and waiting for hydrolysis; in another 1000mL reaction bottle, 209g of water and 91g of 31% hydrochloric acid (0.774mol) are added, nitrogen is replaced for 3-5 times, and the temperature is reduced to 0-10 ℃ by stirring. Slowly adding the reaction solution into hydrochloric acid water for hydrolysis; stirring and cooling are continuously carried out while adding, and the adding speed is controlled so that the hydrolysis temperature is kept between 0 and 30 ℃. Borane and hydrogen are produced during the hydrolysis. After the addition, stirring was continued at room temperature for 30 minutes to sufficiently hydrolyze the mixture, then 150mL of dichloromethane was added to extract the mixture, 100mL of dichloromethane was added to extract the aqueous layer for separating liquid, the organic layers were combined, 100mL of water was added to wash the mixture once, and the mixture was allowed to stand and separate liquid. The organic layer was washed with 100g of 3% aqueous sodium bicarbonate and then with two more 100mL portions of water. Washing to obtain a neutral organic layer, controlling the temperature below 40 ℃, and concentrating under reduced pressure to remove the solvent to obtain 60.5g of a crude product of the 3-hydroxy-4, 4, 4-trifluoro methyl butyrate, wherein the yield is 100% (theoretical yield: 60.5g), and the crude product can be directly used for the next reaction.
The second step is that: dewatering
Adding 1.13g of zinc sulfate (0.007mol), the crude product of 4,4, 4-trifluoro-3-hydroxy-2-methyl butyrate and 121mL of cyclohexane into a 500mL glass three-necked bottle, stirring and heating to 80 ℃ under the protection of nitrogen after adding, refluxing and dividing water for reaction for 5 hours until no water is separated out, sampling, cooling to 20-25 ℃ after the sample is qualified, adding 100mL of water each time, washing with water to be neutral, and washing for about 3 times. The neutral organic layer was washed with water, passed through a silica gel column, 15g of silica gel, charged with 80mL of cyclohexane, the filtrates were combined and concentrated under reduced pressure at a temperature of 40 ℃ until the solvent was removed to give 51.5g of crude methyl 4,4, 4-trifluoro-2-butenoate in a yield of 95% (theoretical yield: 54.2 g).
The third step: oximation of
Adding 28.1g (0.404mol) of hydroxylamine hydrochloride into a 500mL glass three-neck flask, then adding 53.3g (0.368mol) of 40% glyoxal aqueous solution, controlling the temperature to be between 0 and 10 ℃ under the protection of nitrogen, dripping 76.2g of 21.3% sodium hydroxide aqueous solution (mixed solution of 16.2g (0.405mol) of sodium hydroxide and 60g of water), stirring and heating to 50 to 60 ℃ after the addition is finished, continuously preserving the temperature for 4 hours, cooling to 20 to 25 ℃ after the TLC is controlled to be qualified, carrying out suction filtration, adding 50mL of water into a filter cake each time until the detection flushing liquid is neutral, carrying out vacuum drying on the filter cake below 50 ℃ to obtain 31g of glyoxal oxime crude product with the yield of 95% (theoretical yield: 32.6 g).
The fourth step: ring closing
31g of glyoxal dioxime (0.352mol), 51.5g (0.335mol) of methyl 4,4, 4-trifluoro-2-butenoate, 0.184g of hydroquinone (0.0017mol), 0.08g of lanthanum chloride (0.000335mol), 0.22g of zinc chloride (0.00168mol) and 155mL of toluene are added into a 500mL pressure-resistant reaction vessel, nitrogen gas is replaced, the temperature is increased to 65 ℃, the reaction is carried out for 10h, sampling is carried out, the temperature is reduced to room temperature after the medium control is qualified, and the reaction liquid is poured out. The reaction mixture was passed through a silica gel column (excess glyoxaloxime was removed) in an amount of 10g, 50mL of toluene was added overnight to wash the column, and then the filtrate was concentrated under reduced pressure at a temperature of 70 ℃ or lower to remove toluene to obtain 64.9g of methyl 1, 4-dihydroxy-3-trifluoromethyl-1, 2,3, 4-tetrahydro-2-pyrazinecarboxylate in a yield of 80% (theoretical yield: 81.1 g).
The fifth step: dehydrated to pyrazine ring
In a 500mL glass reaction flask, under the protection of nitrogen, 200mL tetrahydrofuran is firstly added, 64.9g (0.268mol)1, 4-dihydroxy-3-trifluoromethyl-1, 2,3, 4-tetrahydro-2-pyrazine methyl formate is then added,after the addition is finished, replacing the nitrogen for three times, cooling to-5-0 ℃ under the protection of the nitrogen, controlling the temperature to-5-0 ℃, dropwise adding 41.3g (0.268mol) of titanium trichloride, wherein in the dropwise adding process, the heat release is severe, after the addition is finished, heating to 0-5 ℃ under the protection of the nitrogen, reacting for 5 hours, and after the reaction is qualified, hydrolyzing; adding 300mL of water and 63g of 31% hydrochloric acid (0.536mol) into a 1000mL glass reaction bottle, replacing with nitrogen for 3 times, cooling to 0-5 ℃ under stirring, controlling the temperature to be below 10 ℃, adding the reaction solution, continuing stirring at room temperature for 30 minutes for full hydrolysis, adding 250mL of dichloromethane for extraction, adding 100mL of dichloromethane into a liquid separating water layer for extraction, combining organic layers, adding 80mL of water for washing once, standing, separating, adding 80g of 3% sodium bicarbonate aqueous solution into the organic layer for washing, and washing twice with water to be neutral, wherein each 80mL of water is added. Washing to obtain a neutral organic layer, controlling the temperature below 70 ℃, concentrating under reduced pressure to remove the solvent, obtaining 55g of crude product, rectifying to obtain 44.2g of 3-trifluoromethyl-2-pyrazine methyl formate, wherein the gas phase purity is 99.2%, the yield is 80% (theoretical yield: 55.2g), and MS (M/z)206[ M/z ]] + Nuclear magnetic hydrogen spectrum data of 1 H NMR[CDCl 3 ]/TMSδ(ppm)]8.85(1H，d)，8.82(1H，d)，4.05(3H，s)，19F-NMR[CDCl 3 ]/TMSδ(ppm)]65.7(s)。
Example 2
Example 2 differs from example 1 in that the catalyst for the fourth reaction step is 0.80g of zinc chloride, and the temperature of the addition reaction is 90 ℃ to finally obtain methyl 3-trifluoromethyl-2-pyrazinecarboxylate.
Example 3
Example 3 is different from example 1 in that the catalyst of the fourth reaction step is 0.80g of zinc chloride, and the temperature of the addition reaction is 100 ℃, and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester is finally obtained.
Example 4
Example 4 differs from example 1 in that the catalyst for the fourth reaction step is 1.12g of titanium chloride, the temperature of the addition reaction is 60 ℃ and methyl 3-trifluoromethyl-2-pyrazinecarboxylate is finally obtained.
Example 5
Example 5 differs from example 1 in that the catalyst for the fourth reaction step is 1.12g of aluminum chloride, and the temperature of the addition reaction is 50 ℃ to finally obtain methyl 3-trifluoromethyl-2-pyrazinecarboxylate.
Example 6
Example 6 differs from example 1 in that the catalyst for the fourth reaction step is 0.206g of zinc chloride and 0.0155g of lanthanum chloride, and methyl 3-trifluoromethyl-2-pyrazinecarboxylate is finally obtained.
Example 7
Example 7 differs from example 1 in that the catalyst for the fourth reaction step is 2.575g of zinc chloride, 0.2575g of lanthanum chloride, and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester is finally obtained.
Example 8
Example 8 differs from example 1 in that the catalyst for the fourth reaction step is 0.515g of zinc chloride and 0.2575g of lanthanum chloride, and methyl 3-trifluoromethyl-2-pyrazinecarboxylate is finally obtained.
Example 9
Example 9 differs from example 1 in that the catalyst for the fourth reaction step is 0.1803g of zinc chloride and 0.309g of lanthanum chloride, and methyl 3-trifluoromethyl-2-pyrazinecarboxylate is finally obtained.
Example 10
Example 10 differs from example 1 in that the temperature of the addition reaction was 70 ℃ to finally obtain methyl 3-trifluoromethyl-2-pyrazinecarboxylate.
Example 11
Example 11 differs from example 1 in that the temperature of the addition reaction was 60 ℃ and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester was finally obtained.
Example 12
Example 12 differs from example 1 in that the temperature of the addition reaction was 80 ℃ and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester was finally obtained.
Example 13
Example 13 differs from example 1 in that the temperature of the addition reaction was 50 ℃ and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester was finally obtained.
Example 14
Example 14 differs from example 1 in that the temperature of the addition reaction was 90 ℃ and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester was finally obtained.
Example 15
Example 15 differs from example 1 in that, instead of methyl trifluoroacetoacetate, ethyl nitroacetoacetate is used to obtain 3-nitro-2-pyrazinecarboxylic acid ethyl ester, MS (M/z)199[ M] + Nuclear magnetic hydrogen spectrum data of 1 H NMR[CDCl 3 ]/TMSδ(ppm)]8.9(1H,d),8.82(1H,d),4.29(2H,s),1.3(3H,s)。
Example 16
Example 16 differs from example 1 in that 0.0011mol of benzenediol was used to finally obtain methyl 3-trifluoromethyl-2-pyrazinecarboxylate.
Example 17
Example 17 differs from example 1 in that 0.0018mol of benzenediol was used to finally obtain methyl 3-trifluoromethyl-2-pyrazinecarboxylate.
Example 18
Example 18 differs from example 1 in that 0.0004mol of benzenediol finally gives methyl 3-trifluoromethyl-2-pyrazinecarboxylate.
Example 19
Example 19 differs from example 1 in that p-tert-butylcatechol was used instead of benzenediol, and methyl 3-trifluoromethyl-2-pyrazinecarboxylate was finally obtained.
Example 20
Example 20 differs from example 1 in that glyoxaldioxime is 0.335mol, and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester is finally obtained.
Example 21
Example 21 differs from example 1 in that glyoxaldioxime is 0.3685mol, and methyl 3-trifluoromethyl-2-pyrazinecarboxylate is finally obtained.
Example 22
Example 22 differs from example 1 in that glyoxaldioxime is 0.268mol, and methyl 3-trifluoromethyl-2-pyrazinecarboxylate is finally obtained.
Example 23
Example 23 differs from example 1 in that the solvent for the first reaction step is chlorobenzene, and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester is finally obtained.
Example 24
Example 24 differs from example 1 in that the solvent for the first reaction step is 250mL of toluene, and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester is finally obtained.
Example 25
Example 25 differs from example 1 in that the catalyst for the first dehydration reaction is aluminum trichloride, and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester is finally obtained.
Example 26
Example 26 differs from example 1 in that 0.268mol of titanium tetrachloride are used in the fifth step, and 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester is finally obtained.
Example 27
Example 27 differs from example 1 in that the dehydration reaction in the fifth step is carried out in ethylene glycol dimethyl ether to finally obtain methyl 3-trifluoromethyl-2-pyrazinecarboxylate.
Example 28
Example 28 differs from example 1 in that in the first reaction step, potassium borohydride is 0.4576mol, cyclopentyl methyl ether is used instead of tetrahydrofuran, the temperature of the reduction reaction is 65 ℃, the reaction time is 5h, and in the second reaction step, 0.018mol of copper sulfate is used as a dehydrating agent, and toluene is used as a solvent, thereby finally obtaining 3-trifluoromethyl-2-pyrazinecarboxylic acid methyl ester.
Example 29
Example 29 differs from example 1 in that in the first step, 0.4224mol of sodium borohydride, methanol instead of tetrahydrofuran, the temperature of the reduction reaction is 60 ℃, the reaction is carried out for 6h, and in the second step, 0.0123mol of p-toluenesulfonic acid is used as dehydrating agent, cyclopentane is used as solvent, and finally methyl 3-trifluoromethyl-2-pyrazinecarboxylate is obtained.
The yields of the relevant products prepared in the above examples 1 to 29 are shown in Table 1, in which A% represents the yield of the first step reaction, B% represents the yield of the second step reaction, C% represents the yield of the fourth step reaction, and D% represents the yield of the fifth step reaction.
TABLE 1
Compared with the traditional preparation method, the method reduces the raw material cost by 20 percent, the input cost of main and auxiliary equipment by 15 percent and the cost of the preparation process (three wastes treatment, equipment loss and energy consumption cost in labor and environmental protection) by 10 percent, thereby greatly reducing the production cost.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the preparation cost (or the market price) of the starting material compound 1 adopted by the invention is generally far lower than that of a methyl trifluoropyruvate compound; and controlling the carbon-carbon double bond in the compound 1 and the carbon-nitrogen double bond of glyoxal dioxime to carry out addition reaction by a Lewis acid catalyst so as to reduce the self polymerization reaction probability of the compound 1 as much as possible, thereby obtaining a cyclized intermediate, and dehydrating the intermediate to obtain the 2-pyrazine carboxylate compound. Compared with the traditional preparation method of 3-trifluoromethyl-2-pyrazine methyl formate, the method has the advantages of mild reaction conditions, simple operation and wide raw material source, avoids the use of expensive coupling catalyst and greatly reduces the cost.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (34)
1. A synthetic method of 2-pyrazine carboxylate compounds is characterized by comprising the following steps:
step S1, carrying out addition reaction on the compound 1 and glyoxal dioxime under the action of a Lewis acid catalyst to obtain an intermediate 1; the Lewis acid catalyst is selected from any one or more of ferric chloride, aluminum chloride, titanium chloride, zinc chloride and lanthanum chloride;
step S2, the intermediate 1 is subjected to a first dehydration reaction to obtain the 2-pyrazine carboxylate compound,
wherein the structural general formulas of the compound 1, the intermediate 1 and the 2-pyrazine carboxylate compound are as follows in sequence:
2. The synthesis method according to claim 1, wherein the amount of the Lewis acid catalyst is 0.43-5.5 wt% of the compound 1.
3. The method of claim 1, wherein the amount of zinc chloride in the combination of zinc chloride and lanthanum chloride is 0.4-5 wt% of compound 1, and the amount of lanthanum chloride is 0.03-0.5 wt% of compound 1.
4. The synthesis method according to claim 1, wherein the mass ratio of the zinc chloride to the lanthanum chloride in the combination of the zinc chloride and the lanthanum chloride is 2-10: 1.
5. The synthesis method according to claim 1, wherein when the Lewis acid catalyst is zinc chloride, the temperature of the addition reaction is 90-100 ℃.
6. The synthesis method according to claim 1, wherein when the Lewis acid catalyst is aluminum chloride and/or titanium chloride, the temperature of the addition reaction is 50-60 ℃.
7. The synthesis method according to claim 1, wherein when the Lewis acid catalyst is a combination of zinc chloride and lanthanum chloride, the temperature of the addition reaction is 60-80 ℃.
8. The synthesis method according to claim 7, wherein the temperature of the addition reaction is 65-70 ℃.
9. The synthetic method according to any one of claims 1 to 8 wherein R is 2 Is C 1 ～C 6 Alkyl group of (1).
10. The method of synthesis of claim 9, wherein R is 2 Is selected from any one of methyl, ethyl and propyl.
11. The synthetic method according to any one of claims 1 to 8 further comprising a preparation process of the compound 1, the preparation process comprising:
carrying out reduction reaction on the compound 2 to obtain an intermediate 2;
carrying out a second dehydration reaction on the intermediate 2 under the action of a dehydrating agent to obtain the compound 1,
the structural general formulas of the compound 2 and the intermediate 2 are as follows in sequence:
12. the synthesis method according to claim 11, wherein the reducing agent used in the reduction reaction is sodium borohydride and/or potassium borohydride.
13. The synthesis method according to claim 12, wherein the molar ratio of the reducing agent to the compound 2 is 1.1-1.3: 1.
14. the synthesis method according to claim 13, wherein the solvent used in the reduction reaction is selected from one or more of methanol, ethanol, propanol and acetone or one or more of tetrahydrofuran, cyclopentyl methyl ether and ethylene glycol dimethyl ether.
15. The synthesis method according to claim 11, wherein the temperature of the reduction reaction is 60-65 ℃.
16. The synthesis method according to claim 15, wherein the time of the reduction reaction is 4-6 h.
17. The synthesis method according to claim 11, wherein the dehydrating agent is a sulfate-based dehydrating agent and/or a p-benzenesulfonic acid-based dehydrating agent.
18. The synthesis method according to claim 17, wherein when the dehydrating agent is a sulfate dehydrating agent, the molar ratio of the sulfate dehydrating agent to the intermediate 2 is 0.02-0.05: 1.
19. The synthesis method according to claim 17, wherein when the dehydrating agent is a p-benzenesulfonic acid dehydrating agent, the molar ratio of the p-benzenesulfonic acid dehydrating agent to the intermediate 2 is 0.01-0.5: 1.
20. The synthesis method of claim 17, wherein the sulfate dehydrating agent is selected from one or more of sulfate, zinc sulfate and copper sulfate.
21. The synthesis method according to claim 19, wherein the p-benzenesulfonic acid dehydrating agent is p-toluenesulfonic acid and/or benzenesulfonic acid.
22. The synthesis method according to claim 11, wherein the solvent added in the second dehydration reaction is selected from any one or more of cyclohexane, cyclopentane, toluene, petroleum ether and n-heptane.
23. A synthesis process according to any one of claims 1 to 8, characterised in that a polymerisation inhibitor is also used in the addition reaction.
24. The synthesis method according to claim 23, wherein the molar ratio of the polymerization inhibitor to the compound 1 is 0.003-0.005: 1.
25. The synthesis process of claim 23, wherein the polymerization inhibitor is hydroquinone and/or p-tert-butylcatechol.
26. The synthesis method according to any one of claims 1 to 8, wherein the molar ratio of glyoxaldioxime to compound 1 is 1.0-1.1: 1.
27. The synthesis method according to any one of claims 1 to 8, characterized in that the addition reaction is carried out in a first solvent.
28. The synthesis method according to claim 27, wherein the first solvent is selected from any one or more of toluene, xylene and chlorobenzene.
29. The synthesis method according to any one of claims 1 to 8, characterized in that the first dehydration reaction is carried out under catalysis of a catalyst.
30. A synthesis process according to claim 29, wherein the catalyst is selected from any one or more of titanium tetrachloride, aluminium trichloride and zinc chloride.
31. The synthesis method of claim 30, wherein the molar ratio of the catalyst to the intermediate is 1.0-1.05: 1.
32. The method of synthesis of claim 29, wherein the first dehydration reaction is carried out in a second solvent.
33. The synthesis method as claimed in claim 32, wherein the second solvent is one or more selected from tetrahydrofuran, methyl tert-butyl ether and ethylene glycol dimethyl ether.
34. The method of claim 33, wherein the dehydration reaction is at a temperature of 0-5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011567556.0A CN112645890B (en) | 2020-12-25 | 2020-12-25 | Synthesis method of 2-pyrazine carboxylic ester compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011567556.0A CN112645890B (en) | 2020-12-25 | 2020-12-25 | Synthesis method of 2-pyrazine carboxylic ester compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112645890A CN112645890A (en) | 2021-04-13 |
| CN112645890B true CN112645890B (en) | 2022-08-12 |
Family
ID=75363232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011567556.0A Active CN112645890B (en) | 2020-12-25 | 2020-12-25 | Synthesis method of 2-pyrazine carboxylic ester compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112645890B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3205972B2 (en) * | 1993-01-19 | 2001-09-04 | 日本曹達株式会社 | Pyrazine-2-carboxylic acid ester and method for producing the same |
| JP6118817B2 (en) * | 2012-04-27 | 2017-04-19 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Process for producing 5- (difluoromethyl) pyrazine-2-carboxylic acid and its production intermediate |
| CN109369545B (en) * | 2018-12-14 | 2020-04-10 | 东营曜康医药科技有限公司 | Synthesis process of 2-methyl-5-pyrazine formate |
-
2020
- 2020-12-25 CN CN202011567556.0A patent/CN112645890B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN112645890A (en) | 2021-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103922931B (en) | A kind of method of a step catalytically synthesizing glycol ether acetate | |
| US4495373A (en) | Method for partial nuclear hydrogenation of aromatic hydrocarbon compounds and a hydrogenation catalyst therefor | |
| US2105664A (en) | Catalytic hydrogenation of hydroaromatic carboxylic acids and their esters | |
| CN115286559B (en) | Preparation method of key intermediate of anti-new crown drug Pa Luo Weide | |
| CN111269115A (en) | Preparation method of cinnamate in eutectic solvent | |
| CN112645890B (en) | Synthesis method of 2-pyrazine carboxylic ester compound | |
| CN111995522B (en) | Synthetic method of pirimicarb intermediate 2-methyl acetoacetate | |
| CN101863954B (en) | Preparation method of N-tert-butyl-4-aza-5 alpha-androstane-3-ketone-17 beta-formamide | |
| CN111018705A (en) | Preparation method of tetrahydrocurcumin and intermediate thereof | |
| CN109305912B (en) | Method for preparing 2,2, 4-trimethyl-1, 3-pentanediol monoisobutyrate by condensing isobutyraldehyde | |
| CN110878025B (en) | Method for reducing aromatic nitro compound into aromatic amine compound | |
| CN111072450B (en) | Synthesis method of allyl alcohol derivative | |
| CN112250611B (en) | Synthesis method of-2- (2, 5-difluorophenyl) pyrrolidine hydrochloride | |
| CN103012094B (en) | Synthesis method of ionone-type spice intermediate products | |
| CN112062739B (en) | Preparation method for reducing lactone into hemiacetal | |
| CN116082163B (en) | Preparation method of 3',4' -difluoro-2 ' -aminobiphenyl | |
| CN114425451B (en) | Catalyst for synthesizing 3-hydroxy propionate and preparation and use methods thereof | |
| CN116041284B (en) | Application of metal nitrogen turnover porphyrin-cobalt carbonyl multifunctional catalyst in preparation of beta-lactone by catalyzing epoxide | |
| CN110128303B (en) | Method for synthesizing musk extract (2R,5R) -Musclide-A1 | |
| CN111592451B (en) | Preparation method of 4- (4-phenylbutoxy) benzoic acid | |
| CN105152931A (en) | One-step catalytic synthesis method for 2-methoxyethanol benzoate | |
| CN115745866A (en) | Method for preparing phthalimide ionic liquid and method for synthesizing alpha-alkyl unsaturated cyclic carbonate by using phthalimide ionic liquid through catalysis | |
| CN115181047A (en) | Preparation method of chiral 3- (dimethylamino) pyrrolidine | |
| CN116655454A (en) | Synthesis method of cis-1, 4-cyclohexanediol | |
| CN115536494A (en) | Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |