CN113072507A - Preparation method of fluoropyrazine compound - Google Patents

Preparation method of fluoropyrazine compound Download PDF

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CN113072507A
CN113072507A CN202110289410.2A CN202110289410A CN113072507A CN 113072507 A CN113072507 A CN 113072507A CN 202110289410 A CN202110289410 A CN 202110289410A CN 113072507 A CN113072507 A CN 113072507A
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compound
acid
ligand
preparation
molar ratio
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CN113072507B (en
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张新刚
闵巧桥
付夏平
简勇
兰爱虎
段世英
林峰
葛敏
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Nanjing Zhengji Pharmaceutical Research Co ltd
Shanghai Institute of Organic Chemistry of CAS
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Nanjing Zhengji Pharmaceutical Research Co ltd
Shanghai Institute of Organic Chemistry of CAS
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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
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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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

Preparation method of fluoropyrazine compound
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:
Figure BDA0002981846980000011
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+、NH4 +；
R1Is hydrogen or- (CR)2R3)nCONHR4(ii) a Wherein n is an integer of 0 to 20, R2、R3、R4Each independently selected from hydrogen, C1-C6Alkyl or cyclic group ofAn alkyl group;
the fluorinating agent is selected from any one of:
Figure BDA0002981846980000021
preferably selectflur or NFSI;
the solvent is selected from H2One or more of O, 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-pyrimidinone, methyl tert-butyl ether, N-dimethylacetamide, preferably one or more of nitromethane, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-heptane, chlorobenzene, dichlorobenzene;
the silver salt catalyst is selected from AgNO3、Ag2CO3、Ag2O、AgOTf、AgClO4、AgSbF6、AgPF6、 AgTeF6、AgBF4、AgF、AgF2、AgCl、AgBr、AgClO4、AgIO4、Ag3PO4、PhCO2Ag or CH3CO2Ag, preferably AgNO3；
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
Figure BDA0002981846980000022
Compound B is
Figure BDA0002981846980000023
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:
Figure BDA0002981846980000024
Figure BDA0002981846980000031
in some embodiments, the ligand is selected from:
Figure BDA0002981846980000032
in some embodiments, compound a is prepared by reacting compound B with a co-ligand, including but not limited to monodentate nitrogen ligands, monodentate phosphine ligands, and carbene ligands. In some embodiments, the co-ligand is selected from the group consisting of:
Figure BDA0002981846980000033
Figure BDA0002981846980000041
in some embodiments, the co-ligand is selected from
Figure BDA0002981846980000042
In some embodiments, the co-ligand is
Figure BDA0002981846980000043
In some embodiments, an additive is also added during the reaction, the additive being selected from the group consisting of: NaNO3、NaHCO3、 KHCO3、Na2CO3、K2CO3、Cs2CO3、NaOAc、KOAc、CsOAc、KH2PO3、KF、O2、
Figure BDA0002981846980000044
Figure BDA0002981846980000045
Or CF3SO2Cl, preferably NaNO3Or
Figure BDA0002981846980000051
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 advantages 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
Figure BDA0002981846980000061
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
Figure BDA0002981846980000062
Examples R1 Acid(s) Catalyst and process for preparing same Yield of product
1-1 H TsOH(40％) AgNO3,10mol％ 29％
1-2 Na TsOH(140％) AgNO3,10mol％ 36％
The structure confirmation data of the product are shown in tables 1-2,
Figure BDA0002981846980000063
TABLE 1 Nuclear magnetic assay data
Figure BDA0002981846980000064
Figure BDA0002981846980000071
TABLE 2 elemental analysis test data
Figure BDA0002981846980000072
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
Figure BDA0002981846980000073
See the examples for the preparation, the product yields are as follows:
Figure BDA0002981846980000074
Figure BDA0002981846980000081
example 3
Figure BDA0002981846980000082
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
Figure BDA0002981846980000083
See the examples for the preparation, the product yields are as follows:
Figure BDA0002981846980000091
comparative example 1
Figure BDA0002981846980000092
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 CH3CN r.t 5％
1-2 CH3CN 40℃ 5％
1-3 CH3CN 60℃ 15％
1-4 CH3CN 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
Figure BDA0002981846980000093
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
Figure BDA0002981846980000101
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 CH3CN 80℃ 12％
3-2 CH3CN 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 of the application is more efficient, the product yield can reach more than 65% at most, and the selection of a catalytic system is more flexible.

Claims (10)

1. A preparation method of a fluoropyrazine compound is characterized by comprising the following steps:
Figure FDA0002981846970000011
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/organic cation selected from Na+、K+、Ag+Or NH4 +；
R1Is hydrogen or- (CR)2R3)nCONHR4(ii) a Wherein n is an integer of 0 to 20, R2、R3、R4Each independently selected from hydrogen, C1-C6Alkyl or cycloalkyl of (a);
the fluorinating agent is selected from any one of:
Figure FDA0002981846970000012
the solvent is selected from H2O, nitromethane, tetrahydrofuran, diethyl ether, acetonitrile, propionitrile, butyronitrile, dimethyl ethylene glycol ether, 1, 4-dioxane, N-heptane, chlorobenzene, dichlorobenzene, toluene, N-methylpyrrolidone, N-dimethyl methyl methaneOne or more of amide, 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 AgNO3、Ag2CO3、Ag2O、AgOTf、AgClO4、AgSbF6、AgPF6、AgTeF6、AgBF4、AgF、AgF2、AgCl、AgBr、AgClO4、AgIO4、Ag3PO4、PhCO2Ag or CH3CO2Ag；
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.
2. The method of claim 1, further comprising adding a ligand selected from any one of:
Figure FDA0002981846970000021
3. the preparation method according to claim 2, wherein a co-ligand is further added, and the co-ligand is selected from any one of the following:
Figure FDA0002981846970000022
Figure FDA0002981846970000031
4. the method according to claim 1, wherein an additive is further added to the method, wherein the additive is selected from any one of the following additives：NaNO3、NaHCO3、KHCO3、Na2CO3、K2CO3、Cs2CO3、NaOAc、KOAc、CsOAc、KH2PO3、KF、O2、
Figure FDA0002981846970000032
Figure FDA0002981846970000033
CF3SO2Cl。
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 process according to claim 4, wherein the molar ratio of compound A to additive is chosen from 1: 0.1 to 2.
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