CN113072507B - Preparation method of fluoropyrazine compound - Google Patents
Preparation method of fluoropyrazine compound Download PDFInfo
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- CN113072507B CN113072507B CN202110289410.2A CN202110289410A CN113072507B CN 113072507 B CN113072507 B CN 113072507B CN 202110289410 A CN202110289410 A CN 202110289410A CN 113072507 B CN113072507 B CN 113072507B
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention discloses a preparation method of a fluoropyrazine compound, which is characterized in that a compound A is directly subjected to fluorination reaction in a catalytic system to prepare the fluoropyrazine compound B. The preparation method has strong compatibility, is suitable for various reaction substrates, can select different catalytic systems according to the activity of the reaction substrates, and has flexible preparation method and simple and convenient operation; and the reagent is simple and easy to obtain, the catalytic condition is mild, and the catalytic efficiency is high.
Description
Technical Field
The invention relates to a preparation method of a fluoropyrazine compound, in particular to a flexible and efficient preparation method of the fluoropyrazine compound.
Background
The fluorine-containing pyrazine compounds and the derivatives thereof have wide application in the aspects of biological medicine, pesticide, material science and the like. For example, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (fabiravir, favipiravir, T-705, trade name Avigan) is a very important novel broad-spectrum antiviral drug targeting RNA polymerase, and plays an important role in combating new coronavirus. However, the traditional methods for synthesizing the fluorine-containing compounds are usually prepared by preparing halogen-containing precursors or amine precursors thereof and then performing fluorine-halogen exchange or Balz-Schiemann fluorination, and the methods usually have long reaction steps, poor functional group compatibility, and sensitive or corrosive reaction intermediates; the reagent used for synthesis is expensive, the catalyst dosage is high, and the reaction condition is harsh.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a preparation method of a fluoropyrazine compound.
The technical scheme is as follows: the preparation method of the fluoropyrazine compound comprises the following steps:
in a catalytic system, performing fluorination reaction on a compound A in the presence of a fluorinating agent, a solvent, a silver salt catalyst and an acid to prepare a fluoropyrazine compound B;
wherein M is hydrogen or inorganic/organic cation, preferably Li, Na, K, Rb, Cs, organic amine salt or quaternary ammonium salt, specifically selected from Na + 、K + 、Ag + 、Li + 、Rb + 、Cs + 、NH 4 + ;
R 1 Is hydrogen or- (CR) 2 R 3 ) n CONHR 4 (ii) a Wherein n is an integer of 0 to 20, R 2 、R 3 、R 4 Each independently selected from hydrogen, C 1 -C 6 Alkyl or cycloalkyl of (a);
the fluorinating agent is selected from any one of:
preferably selectflur or NFSI;
the solvent is selected from H 2 One or more of O, nitromethane, tetrahydrofuran, diethyl ether, acetonitrile, propionitrile, butyronitrile, dimethyl ethylene diether, 1, 4-dioxane, N-heptane, chlorobenzene, dichlorobenzene, toluene, N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidinone, methyl tert-butyl ether and N, N-dimethylacetamide, preferably one or more of nitromethane, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-heptane, chlorobenzene and dichlorobenzene;
the silver salt catalyst is selected from AgNO 3 、Ag 2 CO 3 、Ag 2 O、AgOTf、AgClO 4 、AgSbF 6 、AgPF 6 、 AgTeF 6 、AgBF 4 、AgF、AgF 2 、AgCl、AgBr、AgClO 4 、AgIO 4 、Ag 3 PO 4 、PhCO 2 Ag or CH 3 CO 2 Ag, preferably AgNO 3 ;
The acid is selected from one or more of p-toluenesulfonic acid, dodecylbenzenesulfonic acid, 2,3,4,5, 6-pentafluorobenzoic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, 4-methoxybenzoic acid and dibenzyl phosphate, and is preferably p-toluenesulfonic acid.
In some embodiments, compound a is a method for preparing compound B, wherein a ligand is further added during the reaction, and the ligand includes but is not limited to a monodentate or bidentate nitrogen ligand, a monodentate or bidentate phosphine ligand, a carbene ligand, and the like, preferably a bidentate nitrogen ligand. In some embodiments, the ligand is selected from:
in some embodiments, the ligand is selected from:
in some embodiments, compound a is prepared by a method of compound B, and a co-ligand is added during the reaction, and the co-ligand includes but is not limited to monodentate nitrogen ligand, monodentate phosphine ligand, and carbene ligand. In some embodiments, the co-ligand is selected from the group consisting of:
In some embodiments, an additive is also added during the reaction, the additive being selected from the group consisting of: NaNO 3 、NaHCO 3 、 KHCO 3 、Na 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 、NaOAc、KOAc、CsOAc、KH 2 PO 3 、KF、O 2 、 Or CF 3 SO 2 Cl, preferably NaNO 3 Or
In some embodiments, the molar ratio of compound a to fluorinating agent is selected from 1: 1-4, preferably 1: 2 to 4, more preferably 1: 3.
in some embodiments, the molar ratio of compound a to silver salt catalyst is selected from 1: 0.01 to 0.2, preferably 1: 0.02 to 0.1, more preferably 1: 0.04 to 0.1, most preferably 1: 0.04 or 1: 0.05.
in some embodiments, the molar ratio of compound a to acid is selected from 1: 1-2, preferably 1: 1 to 1.5, more preferably 1: 1.3 to 1.4.
In some embodiments, the molar volume ratio of compound a to solvent is selected from 1: 10-1: 20, preferably 1: 10-1: 15, more preferably 1: 12.
in some embodiments, the fluorination reaction is carried out at a temperature of from 40 ℃ to 120 ℃, preferably from 60 ℃ to 100 ℃, and more preferably at 70 ℃, 75 ℃ or 80 ℃.
In some embodiments, the molar ratio of compound a to the ligand is selected from 1: 0.01 to 0.2, preferably 1: 0.02 to 0.1, more preferably 1: 0.04 to 0.1, most preferably 1: 0.04 or 1: 0.05.
in some embodiments, the molar ratio of compound a to the co-ligand is selected from 1: 0.1 to 1, preferably 1: 0.2 to 0.5, more preferably 1: 0.3, 1: 0.35 or 1: 0.4.
in some embodiments, the molar ratio of compound a to the additive is selected from 1: 0.1 to 2, preferably 1: 0.1 to 1, more preferably 1: 0.1 to 0.2.
Has the beneficial effects that: compared with the prior art, the invention has the following remarkable advantages:
(1) the preparation method has strong compatibility, is suitable for various reaction substrates, can select different catalytic systems according to the activity of the reaction substrates, and has flexible preparation method and simple and convenient operation;
(2) the reagent is simple and easy to obtain, the catalytic condition is mild, and the catalytic efficiency is high (up to more than 65%).
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Examples of the embodiments
Adding 3-hydroxypyrazine salt, a metal catalyst, a ligand, a cocatalyst, a fluorination reagent, an acid and an ultra-dry anhydrous solvent into a three-neck reaction tube under the protection of anhydrous oxygen-free argon, stirring and reacting for 10-20 minutes at room temperature, adding an additive, stirring for 5 minutes at room temperature, placing in an oil bath at 70-120 ℃ for stirring, adding the rest fluorination reagent into the reaction while stirring after the stirring speed is adjusted to enable the reaction system to be stirred uniformly, adjusting the stirring speed to be as violent as possible after the fluorination reagent is added, and keeping the external temperature of the reaction oil bath at 70-120 ℃ for reacting for 4-72 hours. Then cooling the mixture to room temperature, filtering to remove insoluble solids, washing filter residues by using a proper amount of solution, carrying out reduced pressure concentration on the obtained filtrate, and carrying out column chromatography or recrystallization on the obtained solid to obtain the target product.
Example 1
Examples | R 1 | Acid(s) | Catalyst and process for producing the same | Yield of the product |
1-1 | H | TsOH(40%) | AgNO 3 ,10mol% | 29% |
1-2 | Na | TsOH(140%) | AgNO 3 ,10mol% | 36% |
The structure confirmation data of the product are shown in tables 1-2,
TABLE 1 Nuclear magnetic assay data
TABLE 2 elemental analysis test data
From the above results, it can be seen that the reaction yield substantially reaches 30% or even more when the reaction is catalyzed by silver salt-fluorinating agent-acid.
Example 2
See the examples for the preparation, the product yields are as follows:
example 3
See the examples for the preparation, the product yields are as follows:
examples | Amount of Selectfluor | Temperature of | Yield of |
3-1 | 200 | 75℃ | 51% |
3-2 | 220 | 75℃ | 55% |
3-3 | 240 | 75℃ | 57% |
3-4 | 260 | 75℃ | 60% |
3-5 | 280 | 75℃ | 61% |
3-6 | 300 | 75℃ | 64% |
3-7 | 340 | 75℃ | 61% |
3-8 | 360 | 75℃ | 57% |
Example 4
See the examples for the preparation, the product yields are as follows:
comparative example 1
The solvent is acetonitrile, the reaction results are observed under different temperature conditions respectively, the preparation method is shown in an example, and the product yield is as follows:
comparative example | Solvent(s) | Temperature of | Yield of product |
1-1 | CH 3 CN | r.t | 5% |
1-2 | CH 3 CN | 40℃ | 5% |
1-3 | CH 3 CN | 60℃ | 15% |
1-4 | CH 3 CN | 80℃ | 20% |
From the above results, it can be seen that the reaction yield was less than 20% when the reaction was catalyzed only with silver salt.
Comparative example 2
The solvents were selected from DMF and 1, 2-dichloroethane, and the reaction was observed at the following temperatures, see the examples for the preparation methods, and the product yields were as follows:
comparative example | Solvent(s) | Temperature of | Yield of product |
2-1 | DMF/1, 2-dichloroethane | 80℃ | Less than 1% |
From the above results, it was found that the reaction was hardly caused by the fluorination reagent alone.
Comparative example 3
Acetonitrile is selected as a solvent, silver carbonate is used as a catalyst, and reaction results are observed under different temperature conditions respectively as follows:
comparative example | Solvent(s) | Temperature of | Yield of product |
3-1 | CH 3 CN | 80℃ | 12% |
3-2 | CH 3 CN | 85℃ | 13% |
From the above results, it can be seen that the reaction yield is less than 20% when the reaction is catalyzed only with a silver salt-fluorinating agent.
In conclusion, compared with the preparation method of a comparative example, the preparation method is more efficient, the yield of the product can reach more than 65%, and the catalyst system is more flexible to select.
Claims (10)
1. A preparation method of a fluoropyrazine compound is characterized by comprising the following steps:
in a catalytic system, performing fluorination reaction on a compound A in the presence of a fluorinating agent, a solvent, a silver salt catalyst and an acid to prepare a fluoropyrazine compound B;
wherein M is hydrogen or an inorganic cation selected from Na + 、K + ;
R 1 Is- (CR) 2 R 3 ) n CONHR 4 (ii) a Wherein n is selected from 0, R 4 Selected from hydrogen, C 1 -C 6 Alkyl or cycloalkyl of (a);
the fluorinating agent is selected from any one of:
the solvent is selected from one or more of nitromethane, tetrahydrofuran, diethyl ether, acetonitrile, propionitrile, butyronitrile, dimethyl ethylene glycol ether, 1, 4-dioxane, N-heptane, chlorobenzene, dichlorobenzene, toluene, N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidone, methyl tert-butyl ether and N, N-dimethylacetamide;
the silver salt catalyst is selected from AgNO 3 、Ag 2 CO 3 、Ag 2 O、AgOTf、AgClO 4 、AgSbF 6 、AgPF 6 、AgTeF 6 、AgBF 4 、AgF、AgF 2 、AgCl、AgBr、AgClO 4 、AgIO 4 、Ag 3 PO 4 、PhCO 2 Ag or CH 3 CO 2 Ag;
The acid is selected from one or more of p-toluenesulfonic acid, dodecylbenzenesulfonic acid, 2,3,4,5, 6-pentafluorobenzoic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, 4-methoxybenzoic acid and dibenzyl phosphate.
4. the method of claim 1, further comprising adding an additive selected from any one of: NaNO 3 、NaHCO 3 、KHCO 3 、Na 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 、NaOAc、KOAc、CsOAc、KH 2 PO 3 、KF。
5. The method of claim 1, wherein the molar ratio of compound a to silver salt catalyst is selected from 1: 0.01 to 0.2.
6. The method of claim 1, wherein the molar ratio of compound a to acid is selected from 1: 1 to 2.
7. The method according to claim 1, wherein the fluorination reaction is carried out at a reaction temperature of 40 ℃ to 120 ℃.
8. The method of claim 2, wherein the molar ratio of compound a to ligand is selected from 1: 0.01 to 0.2.
9. The method of claim 3, wherein the molar ratio of compound A to co-ligand is selected from 1: 0.1 to 1.
10. The method according to claim 4, wherein the molar ratio of compound A to additive is selected from 1: 0.1 to 2.
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