CN117143026A - Synthesis method of heteroaryl trifluoromethyl compound - Google Patents

Synthesis method of heteroaryl trifluoromethyl compound Download PDF

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CN117143026A
CN117143026A CN202311118914.3A CN202311118914A CN117143026A CN 117143026 A CN117143026 A CN 117143026A CN 202311118914 A CN202311118914 A CN 202311118914A CN 117143026 A CN117143026 A CN 117143026A
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trifluoromethyl
compound
heteroaryl
reaction
catalyst
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郦荣浩
王治国
李世江
刘宝平
郭小燕
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Shanghai Bide Medical Technology Co ltd
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Shanghai Bide Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-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
    • C07D237/12—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention discloses a synthesis method of heteroaryl trifluoromethyl compounds. The synthesis method is that heteroaryl iodide, catalyst and trifluoromethyl reagent are mixed and subjected to trifluoromethyl reaction. The invention provides a method for generating heteroaryl trifluoromethyl compounds by reacting heteroaryl iodo with sodium triflate under copper catalysis, wherein copper powder and sodium triflate used in the method are low in price, have low requirements on moisture of a reaction system, are simple and convenient to react, do not generate byproducts, are simple in aftertreatment, have good substrate compatibility, and are suitable for industrial scale-up production.

Description

Synthesis method of heteroaryl trifluoromethyl compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of heteroaryl trifluoromethyl compounds.
Background
The introduction of fluorine atoms results in organic and inorganic compounds having unique physical, chemical properties and physiological activities. Fluorine chemistry has shown a trend toward vigorous development since the early freon in the thirty-second century. Many sophisticated technologies (atomic energy industry, rocket, aerospace, etc.), and some significant industrial projects and pharmaceuticals employ fluorine-containing compounds.
The general methods employed for the synthesis of organofluorine compounds are: synthesizing a fluorine compound by addition of an unsaturated C-C bond, synthesizing a fluorine compound by diazonium salt, nucleophilic fluoro, electrophilic fluoro, introduction of trifluoromethyl (trifluoromethylation reaction), and the like.
Trifluoromethyl has strong electron withdrawing induction effect, lipophilicity and stable C-F bond, and various properties of target molecules can be changed obviously by introducing the trifluoromethyl into organic molecules. For example, the trifluoromethyl is introduced into the drug molecules, so that the acting time of the drug molecules in organisms can be effectively prolonged, and the metabolic stability is enhanced; at the same time, the introduction of trifluoromethyl generally increases the fat solubility of the drug molecules, thereby facilitating the absorption, transmission and diffusion of the drug molecules in the living body. The anticancer medicine sorafenib (Sorafenib tosylate), the antidepressant Fluoxetine (Fluoxetine), the novel broad-spectrum bactericide Trifloxystrobin (Trifloxystrobin), the typical material ZLI-2857 of a liquid crystal display screen and the like all contain trifluoromethyl. Therefore, how to introduce trifluoromethyl into a target molecule becomes an important subject in fluorine chemistry.
Many methods of introducing trifluoromethyl have been developed over the years, such as with SF 4 The carboxyl is converted into trifluoromethyl, and the introduction of the trifluoromethyl is mainly divided into three categories according to the reaction mechanism: free radical trifluoromethylation, nucleophilic trifluoromethylation, and electrophilic trifluoromethylation.
In the case of free radical trifluoromethylation, the trifluoromethyl free radical can be obtained in a variety of ways, and can undergo electrophilic addition reaction with electron-rich benzene rings due to its strong electrophilicity. However, this method has low productivity, poor selectivity, and difficult reaction control, so that the application in organic synthesis is limited.
For electrophilic trifluoromethylation, umemoto reported in 1990 the synthesis and use of compounds I and II, the first electrophilic trifluoromethylating reagent. Subsequently Umemoto reports the synthesis and use of compounds III and IV. The several compounds are stable crystals with good stability. The benzo ring is a good leaving group, and is easy to leave in the substitution process, so that the reaction is facilitated. The reaction is easy to process, especially the compound IV, and the sulfonic acid generated by the reaction is water-soluble and is easy to remove. In addition, compound V, compound VI and compound VII are also common electrophilic trifluoromethylating agents.
This trifluoromethylation is not by CF 3+ Is not S N 2, possibly by a SET mechanism to generate trifluoromethyl radicals, followed by electrophilic addition to carbanions. The method is strong in general type, and trifluoromethyl can be introduced into various nucleophilic compounds by the method. However, these reagents are difficult to prepare and expensive, which limits their use.
Another class of methods for introducing trifluoromethyl into compounds in terms of nucleophilic trifluoromethylation is by CF 3 - The implementation of nucleophilic reactions of (2) mainly comprises two main classes: based on CuCF 3 Nucleophilic substitution of para-halobenzene and TMSCF 3 Nucleophilic substitution of carbonyl compounds.
The earliest discovery method was based on CuCF 3 As CF (CF) 3 - Nucleophilic substitution of a source of para-halobenzene (typically bromobenzene or iodobenzene, the latter being more reactive) synthesizes trifluoromethyl substituted aryl compounds. This method was first reported in 1969 by McLoughlin, and has been developed over the years as one of the most prominent methods for trifluoromethylation.
CuCF 3 Can be made available in the presence of Cu by a variety of methods.
Another method is TMSCF 3 Nucleophilic substitution of carbonyl compounds (Prakash reagent). The method is firstly reported by Ruppert in 1984, and then Prakash has a great deal of work on the application of the method, which is the most convenient method for synthesizing the trifluoromethyl compound from the carbonyl compound, has mild reaction conditions, convenient operation and higher yield, and is widely applied to organic synthesis.
In addition, recently Dolbier et al used CF 3 I/TDAE systems also successfully achieved trifluoromethylation of electrophilic species under mild conditions.
Through many years of research, many methods of trifluoromethylation have been developed. However, the trifluoromethylation of heteroaryl is still relatively difficult to achieve, and is generally achieved by the nucleophilic reaction of heteroaryl halides and trifluoromethyl reagents such as Ruppert reagent, umemoto reagent, chen Shiji, etc. which are all involved in the strict anhydrous requirement on the reaction system and are relatively expensive, and the by-product is troublesome in aftertreatment or can generate harmful gas, etc. and is not suitable for industrial scale-up production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of a heteroaryl trifluoromethyl compound. The invention provides a method for generating heteroaryl trifluoromethyl compound by the reaction of heteroaryl iodo-compound and sodium triflate under copper catalysis for the first time, wherein the reaction uses cheap copper powder and sodium triflate, has low water requirement on a reaction system, generates no byproducts, has simple post-treatment, has good substrate compatibility, and is suitable for industrial scale-up production.
The technical scheme of the invention is as follows:
the synthesis method comprises the steps of mixing heteroaryl iodide, a catalyst and a trifluoromethyl reagent, and carrying out a trifluoromethylation reaction;
the trifluoromethyl reagent is sodium trifluoromethanesulfonate.
Further, the catalyst comprises one or more of copper, gold and silver.
Further, the catalyst is preferably copper.
Further, the synthetic method is as follows:
wherein:
R 1 including one of the heterocyclic aromatic groups;
R 2 comprising hydrogen atoms, halogens, C 1 -C 6 Alkyl, C of (2) 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 3 Is one or more of cyano groups.
Further, the R 1 Comprises one of five-membered, six-membered, seven-membered heterocyclic ring and condensed heterocyclic aromatic groups.
Further, the R 2 Including one or more of hydrogen atom, fluorine, chlorine, bromine, methyl, methoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, methyl ester group, and methyl cyano.
Further, the R 1 Including one of thiazolyl, thienyl, pyridazinyl, pyrazinyl, pyridyl, pyrazolopyridyl.
Further, the synthesis method specifically comprises the following steps:
(1) Dissolving the compound 1 in an organic solvent I, adding a catalyst and a trifluoromethyl reagent, and reacting under the protection of inert gas to obtain a reaction solution;
(2) Adding water into the reaction solution, extracting with an organic solvent II, merging organic phases, washing, drying, and carrying out reduced pressure spin drying to obtain a target compound 2;
the compound 1 is heteroaryl iodide.
Further, the extraction is carried out by using an organic solvent II, the washing is carried out by using saturated saline water, the drying is carried out by using anhydrous sulfate, and the decompression spin-drying is carried out by adopting low-temperature decompression spin-drying.
Further, the anhydrous sulfate includes, but is not limited to, anhydrous sodium sulfate, anhydrous magnesium sulfate.
Further, in the step (1), the organic solvent I is one or more selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene, acetone, 1, 3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide and N-methylpyrrolidone.
Further, in the step (1), the molar ratio of the compound 1, the catalyst and the trifluoromethyl reagent is 1.0: (1.0-4.0): (1.0 to 6.0); the mass volume ratio g/mL of the compound 1 to the organic solvent I is 1:3 to 40.
Further, in the step (1), the inert gas is selected from one or more of nitrogen and argon; the temperature of the reaction is 40-130 ℃, preferably 30-100 ℃, most preferably 70 ℃; the reaction time is 1 to 30 hours, preferably 5 to 30 hours, most preferably 12 hours.
Further, in the step (2), adding water means adding a proper amount of water, and the volume ratio of the reaction solution to the water is preferably 1:1-1:20;
further, in the step (2), the organic solvent II is one or more selected from ethyl acetate, butyl acetate, chloroform, toluene, methylene dichloride and dichloroethane.
The beneficial technical effects of the invention are as follows:
according to the invention, heteroaryl iodo-compound is used as a raw material, copper powder is used as a catalyst, sodium triflate is used as a trifluoromethyl reagent, and a trifluoromethyl reaction is carried out to obtain heteroaryl trifluoromethyl compound.
The copper powder and the sodium triflate used in the method are cheaper, the water requirement on a reaction system is low, the reaction operation is simple and convenient, no byproducts are produced, the post-treatment is simple, and the method has good substrate compatibility and is suitable for industrial scale-up production. The method overcomes the defects of the prior art of trifluoromethyl of heteroaryl, such as expensive catalyst and trifluoromethyl reagent, strict anhydrous requirement on a reaction system, by-product generation, difficult purification, low yield, difficult industrial scale-up production and the like.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a target compound (2 a) according to an embodiment of the present invention.
Fig. 2 is a nuclear magnetic resonance hydrogen spectrum of the target compound (2 b) according to the embodiment of the present invention.
Fig. 3 is a nuclear magnetic resonance hydrogen spectrum of the target compound (2 c) according to the embodiment of the present invention.
Fig. 4 is a nuclear magnetic resonance hydrogen spectrum of the target compound (2 d) according to the embodiment of the present invention.
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the target compound (2 e) according to the embodiment of the present invention.
Detailed Description
The present invention will be described in detail below with reference to the drawings and examples. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention. Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
In the following examples, reagents and materials were used as commercially available unless otherwise specified.
The invention provides a synthesis method of heteroaryl trifluoromethyl compounds, which comprises the following synthesis routes:
wherein,
R 1 is one of heterocyclic aromatic groups;
R 2 is hydrogen atom, halogen, C 1 -C 6 Alkyl, C of (2) 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 3 Is one or more of cyano groups.
In one embodiment of the invention, R 1 Is one of five-membered, six-membered, seven-membered heterocyclic ring and condensed heterocyclic aromatic group.
In one embodiment of the invention, R 1 Is one of thiazolyl, thienyl, pyridazinyl, pyrazinyl, pyridyl and pyrazolopyridyl.
In one embodiment of the invention, R 2 Is one or more of hydrogen atom, fluorine, chlorine, bromine, methyl, methoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, methyl ester group and methyl cyano.
In one embodiment of the invention, R 1 Comprises one of pyridazinyl, pyridyl and pyrazolopyridyl;
in one embodiment of the invention, R 2 Including one or more of chlorine, bromine, methyl, amine groups.
The invention will be further described by examples and the like.
Example 1
The synthesis of the compound 3, 6-dichloro-4-iodopyridazine (1 a) is as follows:
2, 6-tetramethylpiperidine (237.05 g,1.68mol,2.5 eq) was dissolved in THF (1000 mL), and n-butyllithium (107.50 g,1.68mol,2.5 eq) was added dropwise under the protection of inert gas while maintaining the temperature at-40℃and the mixture was stirred for 1 hour after the addition was completed. Then, a THF solution of zinc chloride (256.14 g,1.88mol,2.8 eq) was added dropwise while maintaining the temperature at-10℃and, after completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour to obtain a mixed solution containing TMPZnCl LiCl.
(II) A THF solution of the compound Aa (100.00 g,671.26mmol,1 eq) was added to the TMPZnCl. LiCl solution, and the mixture was stirred at room temperature for 30 minutes. A solution of iodine (255.56 g,1.01mol,1.5 eq) in THF was then added dropwise to the mixture, and the reaction was stirred at room temperature for 12 hours.
After the completion of the reaction, the reaction mixture was quenched with saturated sodium thiosulfate, aqueous ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product obtained was purified by column chromatography to give 128.00g of compound 1a as a pale yellow solid with a purity of 96% and a yield of 70%.
The synthesis of the compound 3, 6-dichloro-4- (trifluoromethyl) pyridazine (2 a) is as follows:
(1) Compound 1a (50.00 g,181.90mmol,1 eq) was dissolved in dry DMF (500 mL), copper powder (23.12 g,363.81mmol,2 eq) and sodium triflate (220.65 g,545.71mmol,3 eq) were added and reacted for 12h at 70℃under nitrogen.
(2) After completion of the reaction, water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure at a low temperature to give 34.73g of a white solid 2a having a purity of 98% and a yield of 88%.
The nuclear magnetic hydrogen spectrum of the obtained 2a is shown in fig. 1, and the obtained characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.80(s,1H).
19 F NMR(377MHz,CDCl 3 )δ-65.86(s).
examples 2 to 6
Examples 2 to 6 are the same as example 1 except that the catalyst, trifluoromethyl reagent, solvent, reaction temperature and the like used in the reaction are adjusted, specifically as shown in Table 1.
Comparative examples 1 to 5
Comparative examples 1 to 5 are the same as example 1 except that the trifluoromethyl reagent, additives, solvents and the like used in the reaction were adjusted, specifically as shown in Table 1.
The influence of each reaction condition on the reaction yield in the synthesis of 2a was examined by examples 1 to 6 and comparative examples 1 to 5, and the results obtained by the reaction are shown in Table 1.
Table 1 conditions and results for the synthesis of examples and comparative examples
In Table 1, the structure of the trifluoromethyl reagent used is as follows:
as is clear from Table 1, in comparative examples 1 to 3, the amount of the catalyst and the trifluoromethyl reagent used was halved, which resulted in deterioration of the conversion, and the reaction yield was decreased, and the molar amount of the trifluoromethyl reagent was slightly larger than that of the catalyst, which was also more advantageous for the progress of the reaction.
Comparative examples 1, 4, 5 and comparative example 1 in solvent CH 3 The reaction hardly proceeds in CN, and DMF, DMSO and toluene all have promotion effects, wherein DMF is the best solvent.
As is clear from comparison of examples 1 and 6, the reaction temperature was lowered, the reaction rate was retarded, the reaction yield was lowered, and the reaction at 70℃was more suitable.
Comparative example 1, comparative examples 2-5, show that the use of copper powder and sodium triflate significantly facilitates the reaction.
Example 7
The synthesis of the compound 3, 5-dichloro-4- (trifluoromethyl) pyridine (2 b) is as follows:
referring to the synthesis of 2a in example 1, compound 1 was maintained starting from 3, 5-dichloro-4-iodopyridine 1b (28.00 g,102.23mmol,1.0 eq): catalyst: the molar ratio of the trifluoromethyl reagent is 1:2:3, the other conditions were the same as in example 1, to obtain 18.99g of a colorless oily compound 2b, which was 97% pure and 86% yield.
The nuclear magnetic hydrogen spectrum of the obtained 2b is shown in fig. 2, and the obtained characterization data are as follows:
1 H NMR(400MHz,DMSO)δ8.89(d,J＝0.6Hz,2H).
19 F NMR(377MHz,DMSO)δ-56.95(s).
comparative example 6
Comparative example 6 the same as example 6 except that the catalyst used in comparative example 6 was cuprous iodide and the trifluoromethyl reagent was methyl fluorosulfonyl difluoroacetate. The yield of the target compound 2b was only 54% and the ratio to the by-product 3, 5-dichloro-4- ((trifluoromethyl) thio) pyridine was 3:1. it can be seen that when the catalyst and trifluoromethyl reagent are changed, the yield of the product is reduced and the by-product is relatively high.
Example 8
The synthesis of the compound 3-bromo-2-methyl-6- (trifluoromethyl) pyridine (2 c) is as follows:
referring to the synthesis of 2a in example 1, starting from 3-bromo-6-iodo-2-methylpyridine 1c (18.50 g,62.10mmol,1.0 eq), compound 1 is maintained: catalyst: the molar ratio of the trifluoromethyl reagent is 1:2:3, the other conditions were the same as in example 1, to obtain 13.56g of colorless liquid compound 2c, with a purity of 96% and a yield of 91%.
The nuclear magnetic hydrogen spectrum of the obtained 2c is shown in fig. 3, and the obtained characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝8.2Hz,1H),7.38(d,J＝8.2Hz,1H),2.73(s,3H).
19 F NMR(377MHz,CDCl 3 )δ-67.91(s).
example 9
The compound 6- (trifluoromethyl) -1H-pyrazolo [4,3-b ] pyridine (2 d) is synthesized as follows:
with reference to the synthesis of 2a in example 1, starting from 6-iodo-1H-pyrazolo [4,3-b ] pyridine 1d (50.00 g,204.06mmol,1.0 eq), organic solvent 1: catalyst: the molar ratio of the trifluoromethyl reagent is 1:2:3, the other conditions were the same as in example 1, to obtain 31.20g of compound 2d, with a purity of 99% and a yield of 82%.
The nuclear magnetic hydrogen spectrum of the obtained 2d is shown in fig. 4, and the obtained characterization data are as follows:
1 H NMR(600MHz,CDCl 3 )δ8.89(d,J＝1.0Hz,1H),8.47(s,1H),8.19(s,1H).
example 10
The synthesis of the compound 2-amino-4-trifluoromethylpyridine (2 e) is as follows:
referring to the synthesis of 2a in example 1, starting from 4-iodo-2-aminopyridine 1e (50.00 g,227.26mmol,1.0 eq), compound 1 was maintained: catalyst: the molar ratio of the trifluoromethyl reagent is 1:2:3, the other conditions were the same as in example 1, to obtain 31.98g of off-white powder 2e, with a purity of 98% and a yield of 87%.
The nuclear magnetic hydrogen spectrum of the obtained 2e is shown in fig. 5, and the obtained characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.22(s,1H),6.96–6.52(m,2H),4.57(s,2H).
the above is only a preferred embodiment of the present invention, and the present invention is not limited to the above examples. It is to be understood that other modifications and variations which may be directly derived or contemplated by those skilled in the art without departing from the spirit and concepts of the present invention are deemed to be included within the scope of the present invention.

Claims (10)

1. The synthesis method is characterized in that heteroaryl iodide, a catalyst and a trifluoromethyl reagent are mixed and subjected to a trifluoromethylation reaction to obtain the heteroaryl trifluoromethyl compound;
the trifluoromethyl reagent is sodium trifluoromethane sulfonate, and the catalyst comprises one or more of copper, gold and silver.
2. The method of synthesis according to claim 1, wherein the catalyst is copper.
3. The synthetic method according to claim 1, characterized in that the synthetic method is routed as follows:
wherein:
R 1 including one of the heterocyclic aromatic groups;
R 2 comprising hydrogen atoms, halogens, C 1 -C 6 Alkyl, C of (2) 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 3 Is one or more of cyano groups.
4. The heteroaryl trifluoromethyl compound of claim 3, wherein R is 1 Comprises one of five-membered, six-membered, seven-membered heterocyclic ring and condensed heterocyclic aromatic groups.
5. A method of synthesis according to claim 3, wherein R 2 Comprising hydrogen atoms, fluorine, chlorine, bromine, methyl, methoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, methyl ester groups,One or more of the methylcyano groups.
6. A method of synthesis according to claim 3, wherein R 1 Including one of thiazolyl, thienyl, pyridazinyl, pyrazinyl, pyridyl, pyrazolopyridyl.
7. The synthesis method according to claim 1, characterized in that it comprises in particular the following steps:
(1) Dissolving the compound 1 in an organic solvent I, adding a catalyst and a trifluoromethyl reagent, and reacting under the protection of inert gas to obtain a reaction solution;
(2) Adding water into the reaction solution, extracting with an organic solvent II, merging organic phases, washing, drying, and carrying out reduced pressure spin drying to obtain a target compound 2;
the compound 1 is heteroaryl iodide.
8. The synthetic method according to claim 7, wherein in the step (1), the organic solvent i is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene, acetone, 1, 3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and N-methylpyrrolidone.
9. The synthetic method according to claim 7, wherein in the step (1), the molar ratio of the compound 1, the catalyst and the trifluoromethyl reagent is 1.0: (1.0-4.0): (1.0 to 6.0); the mass volume ratio g/mL of the compound 1 to the organic solvent I is 1:3 to 40; the inert gas is selected from one or more of nitrogen and argon; the temperature of the reaction is 40-130 ℃, preferably 30-100 ℃, most preferably 70 ℃; the reaction time is 1 to 30 hours, preferably 5 to 30 hours, most preferably 12 hours.
10. The synthetic method according to claim 7, wherein in the step (2), the organic solvent II is one or more selected from the group consisting of ethyl acetate, butyl acetate, chloroform, toluene, methylene chloride and dichloroethane.
CN202311118914.3A 2023-08-31 2023-08-31 Synthesis method of heteroaryl trifluoromethyl compound Pending CN117143026A (en)

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