WO2022078306A1 - Large steric hinderance palladium-nitrogen-heterocyclic carbene complex, preparation method for same, applications of same, and synthesis method for sonidegib based on same - Google Patents

Abstract

The present invention relates to the technical field of organic synthesis and chemical catalysis. Disclosed are a large steric hinderance palladium-nitrogen-heterocyclic carbene complex, a preparation method for same, applications of same in efficiently catalyzing a C-N coupling reaction in room temperature conditions, and a synthesis method for sonidegib based on same. The structure of the large steric hinderance palladium-nitrogen-heterocyclic carbene complex of the present invention has diphenylimidazole as the main ligand skeleton and a functionalized allyl as an ancillary ligand, with the introduction of the functionalized allyl to serve as an ancillary ligand beside the metal center of a catalyst, provides significantly increased catalytic activity and stability, is applicable in efficiently catalyzing the C-N coupling reaction, specifically, efficiently catalyzing the C-N coupling reaction at room temperature conditions, and attains a yield of up to 99%. Also provided in the present invention is a method for synthesizing in three steps at room temperature with an aryl/aliphatic amine and an aryl chloride as reactants and catalyzed by a palladium catalytic system. The synthesis method of the present invention has few steps and attains a total yield of up to 74.5%.

Description

A kind of large sterically hindered nitrogen heterocyclic carbene palladium complex and its preparation method and application and the synthetic method of sononi Gibb based on the same technical field

The invention belongs to the technical field of organic synthesis and chemical catalysis, and in particular relates to a large sterically hindered nitrogen heterocyclic carbene palladium complex and a preparation method thereof and its application in efficient catalysis of C-N coupling reaction at room temperature, and a sony Gibb based on the same synthetic method.

Background technique

Phosphine ligands and nitrogen heterocyclic carbene (NHC) ligands are both strong electron-donating ligands, and their palladium complexes can efficiently catalyze oxidative addition rate-determining reactions, but they have great differences in steric structures. . In 1991, Arduengo successfully isolated the nitrogen heterocyclic free carbene for the first time; in 1997, Tolman et al. conducted in-depth research on the steric structure of phosphine ligands, and believed that the steric structure of phosphine ligands was conical in shape, with large steric substitution on P. The group is far away from the metal active center, cannot wrap the metal center well, and lacks stability. The nitrogen heterocyclic carbene ligand is just the opposite, the substituent on the N-aromatic ring is in a pendant state, and the distance from the metal center is closer, which makes the catalyst more stable, and it is not easy to generate palladium black, so it can be used in air or even in water. efficient catalysis in the system. In the following two decades, the research on N-heterocyclic carbene metal complexes has developed rapidly and has become a research hotspot in the field of metal-organic catalysis, especially the C-C, C-O, C-N coupling catalyzed by N-heterocyclic carbene palladium complexes The response and so on have been fruitful.

The transition metal-catalyzed C-N bond formation reaction has a profound impact on the synthesis of nitrogen-containing molecules, especially the palladium-catalyzed amination of aryl halides, which has become a very valuable tool in industrial production and academic research, and is widely used in Synthesis and modification of functional compounds such as medicines, pesticides and functional materials. As shown in the following formula, the anti-chronic myeloid leukemia drugs Imatinib (imatinib) and Nilotinib (nilotinib), the anti-acute myeloid leukemia drug Enasidenib (ensidipine), the anti-basal cell carcinoma drug Sonidegib (Sony Digi), the anti-Parkinsonian drug Piribedil (piribedil), and the anti-inflammatory drug Mornifiumate (moniflumate).

To date, the main route for the synthesis of diarylamines is through the palladium-catalyzed C-N coupling reaction of aryl halides with arylamines. At present, there are two main challenges in this type of reaction, one is the challenge of the type of substrate applicable, and the other is the challenge of the reaction conditions. How to make this type of reaction milder, greener, and applicable to a wider range of substrates is the core issue for the development of efficient ligands and catalysts.

Since aromatic heterocyclic chlorides are relatively inert compounds, it is difficult for transition metals to insert C-Cl bonds for substrate activation at room temperature. Therefore, most of the C-N coupling of aromatic heterocyclic chlorides is performed at high temperature. Completed under [(a)Chem.Commun.2011,47,12358.(b)Chem.Sci.2013,4,916.(c)Angew.Chem.2017,129,10705.(d)J.Am.Chem. Soc.2018,140,4721.(e)J.Org.Chem.2018,83,9144.], although there are also literature reports of reaction at room temperature [(a)J.Am.Chem.Soc.2006,128, 4101. (b) Angew. Chem. 2014, 126, 6600.], but its catalytic efficiency is low. Therefore, finding new catalytic systems and catalysts for efficient C-N coupling reactions at room temperature is still a hot and difficult point.

Sonidegib, English name Sonidegib, is a SMO receptor antagonist developed by Novartis and approved by FDA and EMA on July 24, 2015 and August 14, 2015, respectively. Inhibits the Hedgehog pathway, thereby preventing or reducing the development of cancer. Sonnygib is used to treat patients with locally advanced basal cell carcinoma who are inoperable and inoperable with radiation therapy, or who have recurred after surgery or radiation therapy. The drug is currently one of only two marketed drugs for the treatment of basal cell carcinoma. Sonny Gibb's chemical name is N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridyl]-2-methyl-4'-(trifluoro Methoxy)-[1,1'-biphenyl]-3-carboxamide, the CAS number is 956697-53-3, the structural formula is as follows:

At present, the synthetic routes of Sony Gibb mainly include the following:

Literature (ACS Med.Chem.Lett.2010,1,130-134) and patent literature WO2011009852 reported that 2-chloro-5-nitropyridine was used as the starting material, through substitution, palladium carbon hydrogenation reduction, condensation acylation, Suzuki Coupling and other four-step reactions were used to obtain Sonny Gibb with a total yield of 42.8%.

Patent document WO2017163258 reports a method similar to the above-mentioned route 1, the difference is that it first performs Suzuki coupling to obtain biphenyl intermediates, and then performs condensation acylation to obtain the target product Sony Gibb, and the total yield is 63.1%.

Patent document CN105330658A reported a new route, through the intermolecular condensation reaction of industrial raw material L-lactate to obtain cis-2R, 2'S-bis (propionate) ether, the intermediate is then subjected to reduction reaction, sulfonylation Reaction and cyclization with N-(6-aminopyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide , the Sony Gibb was obtained with a total yield of 15.1%.

Patent document CN109293649A reported another new route, utilizing 2-amino-5-nitropyridine and R-epoxy propylene (or S-epoxy propylene) through epoxy ring-opening substitution reaction, and then through condensation reaction to prepare Sony Gibb Intermediates. The intermediate is reduced by catalytic hydrogenation to obtain (2S,6R)-2,6-dimethyl-4-(5-aminopyridin-2-yl)morpholine, 2-methyl-4'-( Trifluoromethoxy)-[1,1'-biphenyl]-3-carboxylic acid and acid chloride reagent were subjected to acid chloride reaction, and then reacted with the above (2S,6R)-2,6-dimethyl-4-(5 -Aminopyridin-2-yl)morpholine was prepared by amidation reaction of Sonnigib with a total yield of 58.5%.

The above four synthetic routes not only have many synthetic routes, but also require hydrogenation reduction of palladium-carbon, and 5-amino-2-nitropyridine is expensive, which imposes certain restrictions on industrial production. Therefore, the design and development of a new, concise and economical synthesis route has important practical significance for the industrial production of Sony Gibb.

SUMMARY OF THE INVENTION

In order to overcome the shortcomings and deficiencies of the above-mentioned prior art that the carbene palladium complex has low reactivity and cannot efficiently catalyze the reaction under room temperature conditions, the primary purpose of the present invention is to provide a large sterically hindered nitrogen heterocyclic carbene palladium complex.

The large sterically hindered nitrogen heterocyclic carbene palladium complex structure of the present invention takes diphenylimidazole as the main ligand skeleton and the functionalized allyl group as the auxiliary ligand, has significantly improved catalytic activity and stability, and is applied to catalysis The C-N coupling reaction of aromatic heterocyclic chlorides realizes the efficient catalytic C-N coupling of aromatic heterocyclic chlorides at room temperature, and the yield can be as high as 99%.

Another object of the present invention is to provide a preparation method of the above-mentioned large sterically hindered nitrogen heterocyclic carbene palladium complex.

The large sterically hindered nitrogen heterocyclic carbene palladium complex of the present invention takes the large sterically hindered imidazolium salt substituted by phenyl as the skeleton, and is carried out with the functionalized palladium dimer [Pd-(allyl-R ³ )(uX)] ₂ It is obtained by coordination, more specifically, substituted or unsubstituted diphenylethylenediamine is used as the starting material, and the target product can be obtained through three to four chemical reactions. The synthesis method is simple, economical, and suitable for industrial production.

Another object of the present invention is to provide the application of the above-mentioned large sterically hindered nitrogen heterocyclic carbene palladium complex in the efficient catalysis of C-N coupling reaction, especially the C-N coupling reaction can be efficiently catalyzed at room temperature.

Another object of the present invention is to provide a method for synthesizing a sonny Gibb. The synthesis method of the invention is a three-step synthesis to obtain the target product, which not only has few synthesis steps and high yield, avoids the palladium-carbon hydrogenation process, but also can carry out the reaction at room temperature, thereby being safer and lower in cost, and suitable for industrialization mass production. In particular, when the large sterically hindered nitrogen heterocyclic carbene palladium complex of the present invention is used, a remarkably improved yield of the reaction at room temperature can be obtained.

The object of the present invention is realized through the following scheme:

A large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the complex is a compound having the chemical structural formula shown in formula (A) or its enantiomer (B) or racemate (C) ):

Wherein: R ¹ , R ^1' , R ² , R ^2' which are the same or different are hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted C4-20 heterocyclic group, respectively. Unsubstituted C1-20 hydrocarbyloxy, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-20 cycloalkyl, halogen, -Bn, -CF ₃ , -NO ₂ , substituted at least one of amino groups;

R ³ is hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-20 Any of the cycloalkyl and substituted amino groups;

X may be one of -Cl, -Br, -I, CH ₃ COO-, CF ₃ COO-, -BF ₄ , -PF ₆ , -SbF ₆ , -OTf.

The same or different substitutions mentioned above mean that one or more hydrogen atoms in the group can be replaced by C6-20 aryl, C4-20 heterocyclic, C1-20 hydrocarbyloxy, C1-20 alkyl, Substitution of C3-20 cycloalkyl, -CF ₃ , -NO ₂ , halogen group and the like.

The structure of the large sterically hindered nitrogen heterocyclic carbene palladium complex of the present invention takes diphenylimidazole as the main ligand skeleton and the functionalized allyl group as the auxiliary ligand. By introducing the functionalized allyl group next to the metal center of the catalyst as the auxiliary ligand The ligand, because the allylic position is not very tightly bound to the metal center, makes it easy to be activated to zero-valent palladium at room temperature, insert the C-Cl bond of the aromatic heterocyclic chloride, carry out oxidative addition, and assist the ligand The facile nature also greatly facilitates the reductive elimination step in the catalytic cycle, thereby enhancing the overall catalytic activity. Secondly, two phenyl groups are introduced on the imidazole ring, and during oxidative addition, the phenyl group can generate π-π stacking with the aryl substrate, which enhances the electron donating effect of the system, thereby promoting the rate-determining step (oxidation) of the catalytic cycle. addition); the large sterically hindered diphenyl skeleton can well wrap the metal active center and enhance the stability of the catalyst; the existence of R ¹ , R ^1' , R ² , R ^2' , R ³ groups is beneficial to Fine tuning of electrical and steric hindrance of ligands and catalysts. Therefore, compared with the organic phosphine ligands, the carbene ligands and catalysts obtained by the present invention are very stable in air and water, and have low toxicity; they are suitable for industrial production.

The present invention also provides a preparation method of the above-mentioned large sterically hindered nitrogen heterocyclic carbene palladium complex. The large sterically hindered nitrogen heterocyclic carbene palladium complex of the present invention takes the large sterically hindered imidazolium salt substituted by phenyl as the skeleton, and is carried out with the functionalized palladium dimer [Pd-(allyl-R ³ )(uX)] ₂ It can be obtained by coordination; more specifically, substituted or unsubstituted diphenylethylenediamine is used as the starting material, and the target product can be obtained through three to four chemical reactions. The synthesis method is simple, economical, and suitable for industrial production.

Described large sterically hindered imidazole salt is a large sterically hindered imidazole X-generation salt, and its structural formula is one of the following:

Wherein: R ¹ , R ^1' , R ² , R ^2' which are the same or different are hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted C4-20 heterocyclic group, respectively. Unsubstituted C1-20 hydrocarbyloxy, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-20 cycloalkyl, halogen, -Bn, -CF ₃ , -NO ₂ , substituted at least one of amino groups;

X may be one of Cl, Br, I, CH ₃ COO, CF ₃ COO, BF ₄ , PF ₆ , SbF ₆ , and OTf.

The palladium dimer [Pd-(allyl-R ³ )(uX)] ₂ has the following structural formula,

Wherein, R ³ is hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3 Any one of -20 cycloalkyl, substituted amino;

X may be one of Cl, Br, I, CH ₃ COO, CF ₃ COO, BF ₄ , PF ₆ , SbF ₆ , and OTf.

The molar ratio of the phenyl-substituted bulky sterically hindered imidazolium salt to the functionalized palladium dimer is preferably 1:3-3:1, more preferably 2:1-2.4:1.

The above coordination reaction is carried out under nitrogen protection and in the presence of inorganic bases.

The molar ratio of the amount of the inorganic base to the phenyl-substituted bulky sterically hindered imidazolium salt is preferably 1:1-4:1.

The temperature of the above coordination reaction may be 20-120°C, preferably 25-60°C; the reaction time may be 0.5-48h, preferably 2-24h.

The above-mentioned coordination reaction is preferably carried out in an organic solvent environment, and the organic solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, m-xylene, ethylbenzene, mesitylene, ethylene glycol dimethylbenzene At least one of ether, diethyl ether, methyl tert-butyl ether, anisole, and the like.

The large sterically hindered imidazole salt of the present invention is a large sterically hindered imidazole X-generation salt, which uses substituted or unsubstituted diphenylethylenediamine (compound 1) as the starting material, and substituted or unsubstituted 2,6- Diisopropyl bromobenzene is subjected to C-N coupling reaction to obtain amino-protected substituted or unsubstituted diphenylethylenediamine derivatives (compound 2), which is then reacted with inorganic X-generation salts to obtain large sterically hindered imidazole X-generation salts ( Compound 3) is then complexed with a palladium dimer to finally obtain an NHC-Pd complex (compound 4) (see the following reaction equation for specific structural examples of each compound). The reaction temperature of the C-N coupling reaction is preferably 25-130° C., and the reaction time is preferably 1-96 h. The reaction is preferably carried out in the environment of an inorganic base, a palladium catalyst and an organic solvent.

The reaction temperature for the reaction of the compound 2 with the inorganic X-substituted salt is preferably 25-120° C., and the reaction time is preferably 1-48 h. The molar ratio of the inorganic X-generation salt to compound 2 is preferably 1:1-4:1, and the reaction can be carried out in an organic solvent.

More specifically, the large sterically hindered nitrogen heterocyclic carbene palladium complex of the present invention uses substituted or unsubstituted diphenylethylenediamine as a starting material to obtain the target product, and the substituted or unsubstituted diphenylethylenediamine It can be in different configurations, and the reaction equation for one of the configurations is shown below:

route one

route two

Referring to the above reaction scheme, by changing the configuration of substituted or unsubstituted diphenylethylenediamine (compound 1), the enantiomer and racemate of the above compound 4 (ie formula (B) and formula (C) can be prepared compounds shown).

The large sterically hindered nitrogen heterocyclic carbene palladium complex has significantly improved catalytic activity and stability, and can be applied to efficiently catalyze the C-N coupling reaction, especially the C-N coupling reaction can be efficiently catalyzed at room temperature. Apply it (the compound of the chemical structural formula shown in formula (A) or its enantiomer (B) or racemate (C)) to the C-N coupling reaction of catalyzed inert large aromatic heterocyclic chlorides to achieve the Efficient catalysis at room temperature, and the target product can be obtained in a yield of up to 99%.

The present invention also provides a method for synthesizing a sony Gibb. The three-step synthesis method of the invention not only has few synthesis steps and high yield, but also avoids the palladium-carbon hydrogenation process, and can carry out the reaction at room temperature, thereby being safer and lower in cost, and being suitable for large-scale industrial production.

The synthetic method uses aryl/aliphatic amine and aryl chloride as reactants, and a palladium catalyzed system to carry out a C-N coupling reaction under the condition of an alkaline solution.

More specifically, 3-bromo-2-methylbenzoic acid is subjected to Suzuki coupling reaction with 4-(trifluoromethoxy) phenylboronic acid to obtain biphenyl intermediate 2-methyl-3-(trifluoromethoxy) phenyl)-benzoic acid (I), then condensation reaction with 5-amino-2-chloropyridine to obtain amide intermediate (II), and finally, under the catalysis of palladium catalytic system, with 2,6-dimethyl C-N coupling reaction of morpholine to obtain the final product sononigibb (III). After the reaction, the mixture can be separated by column chromatography.

The reaction equation is as follows:

The molar ratio of the 3-bromo-2-methylbenzoic acid to 4-(trifluoromethoxy)benzeneboronic acid is preferably 1:1.2-1:2.0. The temperature of the Suzuki coupling reaction is preferably 50-150°C. The reaction is preferably carried out under the conditions of an alkali and a palladium catalyst, and the palladium catalyst can be palladium acetate, palladium chloride, Pd ₂ (dba) ₃ , tetrakistriphenylphosphine palladium, etc.; the alkali can be sodium carbonate , potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, etc. The reaction is preferably carried out in a solvent, such as toluene, ethylbenzene, xylene, mesitylene, dioxane, methyl tert-butyl ether, anisole, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran , 2-methyltetrahydrofuran, C1-C5 alcohol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, water or a combination of two or more mixed solvents thereof.

The temperature of the condensation reaction is preferably 0-80°C; the reaction is preferably carried out in an organic solvent, such as dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, Toluene, xylene, ethylbenzene, mesitylene, dioxane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, ethylene glycol dimethyl ether, C1-C4 alcohol, dimethyl sulfoxide, etc.

The temperature of the CN coupling reaction is preferably 25-130° C., and the reaction time is 1-96 h. The reaction is preferably carried out in the presence of a base, such as sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, and the like. The reaction is preferably carried out in a solvent, such as dioxane, ethylene glycol dimethyl ether, diethyl ether, methyl tert-butyl ether, anisole, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, m-xylene , ethylbenzene, mesitylene, C1-C5 alcohol, dimethylformamide, dimethylacetamide, DMSO, acetonitrile, water or a combination of two or more mixed solvents. The palladium catalyst system can be a conventional palladium complex catalyst, such as monophosphine ligands (such as biphenyls, binaphthyls, biaryls, indoles, carbazoles, ferrocenes, bridging Side chain biphenyl-based monophosphine ligands, etc.)/palladium (eg PdCl ₂ , Pd(OAc) ₂ , Pd(dba) ₂ , Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ , etc.) catalytic system, etc., preferably the large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd) - the compound of the chemical structural formula represented by the formula (A) or its enantiomer (B) or Racemate (C). More preferably, when the palladium complex is the large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd) of the present invention, the temperature of the CN coupling reaction may be 25-40°C.

The Sony Gibb synthesis method provided by the invention has few synthesis steps and high yield, avoids the palladium-carbon hydrogenation process, is safer, has lower cost, and is suitable for large-scale industrial production; the large sterically hindered nitrogen heterocyclic carbene of the invention is Palladium complex (NHC-Pd)——the compound of the chemical structural formula shown in formula (A) or its enantiomer (B) or racemate (C) is applied in the above synthesis method, which can realize catalysis at room temperature Efficient C-N coupling of aromatic heterocyclic chlorides to aromatic heterocyclic amines in yields as high as 99%.

Detailed ways

The present invention will be described in further detail below with reference to the examples, but the embodiments of the present invention are not limited thereto. The materials involved in the following examples can be obtained from commercial channels unless otherwise specified. The methods are conventional methods unless otherwise specified.

One embodiment, a large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the structural formula is as follows:

Another embodiment, a large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the structural formula is as follows:

Yet another embodiment, a large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd complex), the structural formula is as follows:

It should be noted that the large sterically hindered nitrogen heterocyclic carbene palladium complex structure of the present invention takes diphenylimidazole as the main ligand skeleton and the functionalized allyl group as the auxiliary ligand. As an auxiliary ligand, the allyl position is not very tightly bound to the metal center, so it is easily activated to zero-valent palladium at room temperature, inserting the C-Cl bond of the aromatic heterocyclic chloride, and performing oxidative addition. The easy-to-leave nature of auxiliary ligands also greatly facilitates the reductive elimination step in the catalytic cycle, thereby enhancing the overall catalytic activity. Secondly, two phenyl groups are introduced on the imidazole ring, and during oxidative addition, the phenyl group can generate π-π stacking with the aryl substrate, which enhances the electron donating effect of the system, thereby promoting the rate-determining step (oxidation) of the catalytic cycle. addition); the large sterically hindered diphenyl skeleton can well wrap the metal active center and enhance the stability of the catalyst. Therefore, compared with the organic phosphine ligands, the carbene ligands and catalysts obtained in the present invention are very stable in air and water, and have low toxicity; they are suitable for industrial production; and they can catalyze relatively inert aromatic heterocyclic chlorides and aromatic heterocyclic compounds at room temperature. Efficient C-N coupling of cyclic amines with yields as high as 99%.

Further, the large sterically hindered nitrogen heterocyclic carbene palladium complex of the present invention achieves excellent catalytic effect mainly through diphenylimidazole as the main ligand skeleton and functionalized allyl as the auxiliary ligand. The substituents R ¹ , R ^1' , R ² , R ^2' , R ³ introduced into its structure can be used to finely adjust the three-dimensional structure and electrical properties of the ligand and catalyst, but generally do not affect the large sterically hindered nitrogen of the present invention Heterocyclic carbene palladium complexes can efficiently catalyze CN coupling at room temperature, and can achieve catalytic effects in yields as high as 99%.

For example, in one of the embodiments, the R ¹ and R ^1' are H, and the phenyl group in the structure can generate π-π stacking with the aryl substrate, which enhances the electron donating effect of the system, thereby promoting the The rate-determining step (oxidative addition) of the catalytic cycle. In one embodiment, the R ¹ and R ^1' are electron-donating groups, such as one of -OMe, cycloalkyl, -Ph, etc. In this case, the donating groups of R ¹ and R ^1' The electron group enhances the electron-donating effect of the introduced phenyl group and increases the electrical property of the system; for another example, in one embodiment, the R ¹ and R ^1' are electron-withdrawing groups, such as -Cl, One of -NO ₂ , -CF ₃ , etc. At this time, the electron-withdrawing groups of R ¹ and R ^1' weaken the electron-donating effect of the introduced phenyl group, so that the electrical properties of the system become smaller, and the catalysis of the obtained complexes Although there is a certain change in the activity, it does not affect the catalytic effect of high-efficiency catalysis of CN coupling at room temperature and can obtain a yield of up to 99%; therefore, for those of ordinary skill in the art, without departing from the concept of the present invention. Under the premise of the present invention, several improvements are made to R ¹ and R ^1' , which all belong to the protection scope of the present invention.

Also, in one embodiment, R ² and R ^2' are H; in another embodiment, R ² and R ^2' are electron donating groups, such as -N(CH ₃ ) ₂ , cycloalkane In another example, in one embodiment, the R ² and R ^2' are electron withdrawing groups, such as one of -Cl, -NO ₂ , -CF ₃ , etc.; In an example, the R ² is H, and R ^{2 '} is an electron withdrawing or electron donating group, such as one of naphthyl, methoxy, -N(CH ₃ ) ₂ , -CF ₃ , etc.; According to the examples, the substitution of R ² and R ^2' can adjust the electrical properties of the catalyst. Although the catalytic activity of the obtained complex has a certain change, it does not affect its efficient catalytic CN coupling at room temperature, and can obtain up to 99 Therefore, for those of ordinary skill in the art, under the premise of not departing from the concept of the present invention, several improvements are made to R ² and R ^2' , which all belong to the protection scope of the present invention.

Also, in one embodiment, R ³ is H; in another embodiment, R ³ is -Ph; in another embodiment, R ³ is -CH(CH ₃ ) ₂ ; according to The examples show that the substitution of R ³ can adjust the electrical properties of the catalyst. Although the catalytic activity of the obtained complex has a certain change, it does not affect its ability to catalyze CN coupling efficiently at room temperature, and can obtain up to 99% of the yield. Catalytic effect; therefore, for those of ordinary skill in the art, without departing from the concept of the present invention, several improvements are made to R ³ , which all belong to the protection scope of the present invention.

In one embodiment, X is one of -Cl, _-Br , -I, _CH3COO- , CF3COO-, _-BF4 , _-PF6 , _-SbF6 , -OTf.

The following is the specific example section.

Example 1: Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-1

(1) Synthesis of diamine compound 2a:

5mmol of (1S,2S)-(-)-1,2-diphenylethylenediamine, 18mmol of tBuONa, 15mmol of 2,6-diisopropylbromobenzene, 1.5mmol of IPrMe·HCl, 0.5mmol of Pd(dba) ₂ was mixed, 20 mL of anhydrous toluene was added, and the reaction was carried out at 110 °C for 24 h under nitrogen atmosphere. The reaction was completed, diluted with water, extracted with ethyl acetate three times, and dried over anhydrous Na ₂ SO ₄ . The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether/dichloromethane=10:1). Product yield: 1.70 g, yield: 65%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.06-6.99 (m, 16H), 4.58 (s, 2H), 4.24 (s, 2H), 3.29 (dt, J=13.1, 6.4 Hz, 4H), 1.23 ( d, J=6.6Hz, 12H), 0.91 (d, J=6.5Hz, 12H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 143.1, 141.3, 140.2, 128.4, 127.8, 127.0, 123.7, 123.4, 69.1, 27.7 , 24.2, 23.6.

(2) Synthesis of azacyclic carbene X-generation salts 3a-3c:

1. Synthesis of azacyclic carbene tetrafluoroborate 3a

2 mmol of diamine compound 2a, 2.1 mmol of ammonium tetrafluoroborate, 2 drops of formic acid, 5 mL of methyl orthoformate, and 5 mL of tetrahydrofuran were reacted at 120° C. for 24 h under nitrogen atmosphere. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a white solid was obtained after silica gel column chromatography (eluent: petroleum ether/dichloromethane=2:1, then pure ethyl acetate). Product yield: 1.1 g, yield: 90%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.94 (s, 1H), 7.47-7.31 (m, 10H), 7.26-7.25 (m, 4H), 7.04 (d, J=7.6Hz, 2H), 5.89 ( s,2H),3.22(dt,J＝13.5,6.7Hz,2H),2.64(dt,J＝13.4,6.7Hz,2H),1.72(d,J＝6.8Hz,6H),1.46(d,J =6.7Hz, 6H), 1.12(d, J=6.8Hz, 6H), 0.43(d, J=6.7Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 158.8, 147.3, 145.6, 131.6, 130.9, 129.9, 129.7, 128.9, 127.7, 125.0, 124.8, 74.2, 29.9, 29.7, 25.2, 24.8, 24.7, 22.0.

2. Synthesis of azacyclic carbene hydrochloride 3b

2 mmol of diamine compound 2a, 2.1 mmol of ammonium chloride, 2 drops of formic acid, 5 mL of methyl orthoformate, and 5 mL of tetrahydrofuran were added to a pressure-resistant sealed tube, and the reaction was carried out at 120 °C for 24 h under nitrogen atmosphere. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a white solid was obtained after silica gel column chromatography (eluent: petroleum ether/dichloromethane=2:1, then pure ethyl acetate). Product yield: 867 mg, yield: 75%.

3. Synthesis of azacyclic carbene hexafluorophosphate 3c

2 mmol of diamine compound 2a, 2.1 mmol of ammonium hexafluorophosphate, 2 drops of formic acid, 5 mL of methyl orthoformate, and 5 mL of tetrahydrofuran were reacted at 80° C. for 24 h under nitrogen atmosphere. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a white solid was obtained after silica gel column chromatography (eluent: petroleum ether/dichloromethane=2:1, then pure ethyl acetate). Product yield: 963 mg, yield: 70%.

(3) Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-1:

Mix 2.1 mmol of azacyclic carbene tetrafluoroborate 3a, 1.0 mmol of cinnamyl palladium chloride dimer, and 2.1 mmol of potassium tert-butoxide into a pressure-sealed tube, add 10 mL of anhydrous tetrahydrofuran, and react at room temperature under nitrogen atmosphere 16 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a yellow solid was obtained after silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1). Product yield: 1.2 g, yield: 75%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.26 (m, 14H), 7.22-7.13 (m, 5H), 7.05 (d, J=7.3 Hz, 2H), 5.70 (s, 2H), 5.13 ( s, 1H), 4.46 (d, J=13.1Hz, 1H), 3.79–3.56 (m, 2H), 3.38–3.14 (m, 2H), 1.65 (d, J=6.2Hz, 6H), 1.60 (d , J=6.5Hz, 6H), 1.36 (d, J=6.2Hz, 6H), 1.29 (s, 2H), 0.30 (d, J=6.4Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ209 .6,148.7,146.3,137.6,137.2,135.3,129.0,128.9,128.8,128.3,128.2,127.3,126.8,124.6,124.5,109.1,75.5,29.1,28.3,26.7,26.6,24.7,24. HR-MS (ESI): m/z 765.3357 (Calcd. [M-Cl] ⁺ ), 765.3389 (Found [M-Cl] ⁺ ).

Example 2: Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-2

(1) Synthesis of diamine compound 2b:

5 mmol of (1S,2S)-(-)-1,2-diphenylethylenediamine, 18 mmol of tBuONa, 15 mmol of 2,4,6-triisopropylbromobenzene, 1.5 mmol of IPrMe·HCl, 0.5 mmol of Pd(dba) ₂ was mixed, 20 mL of anhydrous toluene was added, and the reaction was carried out at 110° C. for 24 h under nitrogen atmosphere. The reaction was completed, diluted with water, extracted with ethyl acetate three times, and dried over anhydrous Na ₂ SO ₄ . The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether/dichloromethane=10:1). Product yield: 2.15 g, yield: 70%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.10-6.94(m, 10H), 6.86(s, 4H), 4.57(d, J=4.3Hz, 2H), 4.18(s, 2H), 3.45-3.13( m, 4H), 2.95–2.63 (m, 2H), 1.33–1.12 (m, 24H), 0.87 (d, J=6.8Hz, 12H). ¹³ C NMR (101MHz, CDCl ₃ )δ143.7,143.0,140.5, 139.0, 128.5, 127.7, 126.8, 121.2, 69.2, 33.8, 27.8, 24.4, 24.1, 24.0, 23.6.

(2) Synthesis of azacyclic carbene tetrafluoroborate 3d:

2 mmol of diamine compound 2b, 2.1 mmol of ammonium tetrafluoroborate, 2 drops of formic acid, and 5 mL of methyl orthoformate were added to a pressure-resistant sealed tube, and the reaction was carried out at 120° C. for 24 h under nitrogen atmosphere. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a white solid was obtained after silica gel column chromatography (eluent: petroleum ether/dichloromethane=2:1, then pure ethyl acetate). Product yield: 1.4 g, yield: 90%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.53 (s, 1H), 7.44-7.35 (m, 6H), 7.32-7.23 (m, 4H), 7.16 (d, J=1.9Hz, 2H), 6.86 ( d, J=1.9Hz, 2H), 5.90 (s, 2H), 3.27–3.14 (m, 2H), 2.96–2.81 (m, 2H), 2.66–2.59 (m, 2H), 1.71 (d, J= 6.8Hz,6H),1.44(d,J=6.8Hz,6H),1.23(dd,J=6.9,2.0Hz,12H),1.10(d,J=6.9Hz,6H),0.44(d,J= 6.7Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ158.1, 152.3, 146.9, 145.3, 130.9, 129.9, 129.7, 129.0, 125.3, 123.0, 122.8, 74.3, 34.1, 29.9, 29.6, 25.5, 25.0, 24 , 23.7, 23.6, 22.0.

(3) Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-2:

Mix 2.1 mmol of azacyclic carbene tetrafluoroborate 3d, 1.0 mmol of cinnamyl palladium chloride dimer, and 2.1 mmol of potassium tert-butoxide into a pressure-sealed tube, add 10 mL of anhydrous tetrahydrofuran, and react at room temperature under nitrogen atmosphere 16 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a yellow solid was obtained after silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1). Product yield: 1.3 g, yield: 70%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.27-7.22(m, 12H), 7.20-7.15(m, 3H), 7.09(s, 2H), 6.86(s, 2H), 5.66(s, 2H), 5.09(s, 1H), 4.44(d, J=13.1Hz, 1H), 3.76-3.57(m, 2H), 3.36-3.14(m, 2H), 2.96-2.78(m, 2H), 1.61(d, J＝6.2Hz, 6H), 1.57(d, J＝6.5Hz, 6H), 1.32(d, J＝6.3Hz, 6H), 1.29(s, 2H), 1.26(d, J＝6.7Hz, 12H) ,0.24(d,J=6.5Hz,6H). ¹³ C NMR(101MHz, CDCl ₃ )δ210.2,148.8,148.3,145.9,137.8,137.4,133.2,128.8,128.6,128.3,128.2,127.2,126.7,122.4, 122.2, 109.0, 75.3, 33.9, 29.0, 28.3, 26.6, 26.5, 24.7, 24.3, 24.0, 23.9. HR-MS (ESI): m/z 849.4333 (Calcd. [M-Cl] ⁺ ), 849.4332 (Found [M-Cl] ⁺ ).

Example 3: Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-3

(1) Synthesis of diamine compound 2c:

5 mmol of (1S,2S)-1,2-bis(4-(dimethylamino)phenyl)ethane-1,2-diamine, 18 mmol of tBuONa, 15 mmol of 2,6-diisopropyl bromide Benzene, 1.5 mmol of IPrMe·HCl, and 0.5 mmol of Pd(dba) ₂ were mixed, 20 mL of anhydrous toluene was added, and the reaction was carried out at 110° C. for 24 h under nitrogen atmosphere. The reaction was completed, diluted with water, extracted with ethyl acetate three times, and dried over anhydrous Na ₂ SO ₄ . The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether/dichloromethane=10:1). Product yield: 1.85 g, yield: 61%.

(2) Synthesis of azacyclic carbene tetrafluoroborate 3e:

2 mmol of diamine compound 2c, 2.1 mmol of ammonium tetrafluoroborate, 2 drops of formic acid, and 5 mL of methyl orthoformate were added to a pressure-sealed tube, and the reaction was carried out at 120° C. for 24 h under nitrogen atmosphere. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a white solid was obtained after silica gel column chromatography (eluent: petroleum ether/dichloromethane=2:1, then pure ethyl acetate). Product yield: 1.1 g, yield: 90%.

(3) Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-3:

Mix 2.1 mmol of azacyclic carbene tetrafluoroborate 3e, 1.0 mmol of cinnamyl palladium chloride dimer, and 2.1 mmol of potassium tert-butoxide into a pressure-sealed tube, add 10 mL of anhydrous tetrahydrofuran, and react at room temperature under nitrogen atmosphere 16 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a yellow solid was obtained after silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1). Product yield: 1.0 g, yield: 56%.

Example 4: Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-4

(1) Synthesis of diamine compound 2d:

5mmol of (1S,2S)-1-(4-nitrophenyl)-2-phenylethane-1,2-diamine, 18mmol of tBuONa, 15mmol of 2,6-diisopropylbromobenzene, 1.5 mmol of IPrMe·HCl and 0.5 mmol of Pd(dba) ₂ were mixed, 20 mL of anhydrous toluene was added, and the reaction was carried out at 110° C. for 24 h under nitrogen atmosphere. The reaction was completed, diluted with water, extracted with ethyl acetate three times, and dried over anhydrous Na ₂ SO ₄ . The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether/dichloromethane=10:1). Product yield: 1.81 g, yield: 63%.

(2) Synthesis of azacyclic carbene hexafluorophosphate 3f:

2 mmol of diamine compound 2d, 2.1 mmol of ammonium hexafluorophosphate, 2 drops of formic acid, and 5 mL of methyl orthoformate were added to a pressure-resistant sealed tube, and the reaction was carried out at 120° C. for 24 h under nitrogen atmosphere. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a white solid was obtained after silica gel column chromatography (eluent: petroleum ether/dichloromethane=2:1, then pure ethyl acetate). Product yield: 1.29 g, yield: 88%.

(3) Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-4:

Mix 2.1 mmol of azacyclic carbene hexafluorophosphate 3f, 1.0 mmol of allyl palladium chloride dimer, and 2.1 mmol of potassium tert-butoxide into a pressure-sealed tube, add 10 mL of anhydrous tetrahydrofuran, and react at room temperature under nitrogen atmosphere 16 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a yellow solid was obtained after silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1). Product yield: 1.05 g, yield: 67%.

Example 5: Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-5

(1) Synthesis of monoamine compound 2e-1:

5mmol (1S,2S)-(-)-1,2-diphenylethylenediamine, 9mmol of tBuONa, 6mmol of 2,6-diisopropyl-4-methoxybromobenzene, 1.5mmol of IPrMe ·HCl and 0.5 mmol of Pd(dba) ₂ were mixed, 20 mL of anhydrous toluene was added, and the reaction was carried out at 110° C. for 24 h under nitrogen atmosphere. The reaction was completed, diluted with water, extracted with ethyl acetate three times, and dried over anhydrous Na ₂ SO ₄ . The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether/dichloromethane=10:1). Product yield: 1.4 g, yield: 70%.

(2) Synthesis of diamine compound 2e:

Mix 5 mmol of compound 2e-1, 9 mmol of tBuONa, 6 mmol of 2,6-diisopropyl-bromobenzene, 1.5 mmol of IPrMe HCl, 0.5 mmol of Pd(dba) ₂ , add 20 mL of anhydrous toluene, under nitrogen atmosphere The reaction was carried out at 110°C for 24h. The reaction was completed, diluted with water, extracted with ethyl acetate three times, and dried over anhydrous Na ₂ SO ₄ . The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether/dichloromethane=10:1). Product yield: 1.82 g, yield: 65%.

(3) Synthesis of azacyclic carbene trifluoroacetate 3g:

2 mmol of diamine compound 2e, 2.1 mmol of ammonium trifluoroacetate, 2 drops of formic acid, and 5 mL of methyl orthoformate were added to a pressure-resistant sealed tube, and the reaction was carried out at 120° C. for 24 h under nitrogen atmosphere. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a white solid was obtained after silica gel column chromatography (eluent: petroleum ether/dichloromethane=2:1, then pure ethyl acetate). Product yield: 1.05 g, yield: 79%.

(4) Synthesis of nitrogen heterocyclic carbene palladium complex Pd-NHC-5:

3 g of 2.1 mmol azacyclic carbene trifluoroacetate, 1.0 mmol of cinnamyl palladium chloride dimer, and 2.1 mmol of potassium tert-butoxide were mixed in a pressure-sealed tube, 10 mL of anhydrous tetrahydrofuran was added, and the reaction was carried out at room temperature under nitrogen atmosphere. 16h. After the reaction was completed, the solvent was spin-dried under reduced pressure, and a yellow solid was obtained after silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1). Product yield: 1.05 g, yield: 60%.

Example 6: Follow the procedure of Example 1, except replace (1S,2S)-(-)-1,2-diphenylethylenediamine with (1R,2R)-(-)-1,2-diamine Phenylethylenediamine, other raw materials and steps are the same, and finally the azacyclic carbene palladium complex Pd-NHC-1' is prepared. The NMR data of Pd-NHC-1' are as follows: ¹ H NMR (400MHz, CDCl ₃ )δ7.35-7.27(m,14H),7.22-7.11(m,5H),7.05(d,J=7.5Hz,2H) , 5.69(s, 2H), 5.12(s, 1H), 4.46(d, J=13.1Hz, 1H), 3.82–3.56(m, 2H), 3.38–3.14(m, 2H), 1.65(d, J =6.2Hz,6H),1.62(d,J=6.5Hz,6H),1.35(d,J=6.2Hz,6H),1.30(s,2H),0.30(d,J=6.4Hz,6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 209.7, 148.7, 146.3, 137.5, 137.2, 135.3, 129.0, 128.9, 128.8, 128.3, 128.2, 127.3, 126.9, 124.6, 124.5, 109.0, 75.5, 296.1, 28 , 24.7, 24.4. HR-MS (ESI): m/z 765.3357 (Calcd. [M-Cl] ⁺ ), 765.3379 (Found [M-Cl] ⁺ ).

Using racemic 1,2-diphenylethylenediamine as the starting material, the racemic azacyclic carbene palladium complex rac-Pd-NHC-1 can be obtained. The nuclear magnetic data of rac-Pd-NHC-1 are as follows: ¹ H NMR (400MHz, CDCl ₃ )δ7.35-7.25(m,14H),7.22-7.08(m,5H),7.05(d,J=7.3Hz,2H ), 5.70(s, 2H), 5.11(s, 1H), 4.45(d, J=13.2Hz, 1H), 3.78–3.53(m, 2H), 3.38–3.11(m, 2H), 1.67(d, J=6.3Hz,6H),1.60(d,J=6.5Hz,6H),1.36(d,J=6.2Hz,6H),1.29(s,2H),0.31(d,J=6.3Hz,6H) . ¹³ C NMR (101MHz, CDCl ₃ )δ209.6,148.8,146.1,137.6,137.2,135.2,129.0,128.9,128.8,128.3,128.2,127.2,126.7,124.6,124.5,109.1,7,5.4,29.1 26.6, 24.7, 24.4. HR-MS (ESI): m/z 765.3357 (Calcd. [M-Cl] ⁺ ), 765.3384 (Found [M-Cl] ⁺ ).

According to the basic principle of chemistry, the configuration of the substituted or unsubstituted diphenylethylenediamine of the starting material is changed, and other raw materials and synthesis methods remain unchanged, and the enantiomeric carbene palladium complex or racemate can be obtained. Under the condition that the reaction product is achiral, the catalytic reaction results obtained by adopting the opposite configuration and enantiomeric optically pure nitrogen-heterocyclic carbene palladium complex and racemic nitrogen-heterocyclic carbene palladium complex are equivalent; and the product is a chiral compound When , different configurations of chiral catalysts will produce corresponding asymmetric catalytic results. Therefore, in this paper, Pd-NHC-1' and rac-Pd-NHC-1 are selected as the representative of the catalytic effect of the enantiomer and racemate of the carbene palladium catalyst to illustrate the comparison of Pd-NHC-1.

Example 7: Synthesis of Sonny Gibb

The synthetic routes that have been reported so far not only have many synthetic routes, but also all require palladium-carbon hydrogenation reduction, and the starting materials are expensive, which brings certain restrictions to industrial production. Therefore, the design and development of a new, concise and economical synthesis route has important practical significance for the industrial production of Sony Gibbs. As shown below, the route of the present invention has few synthetic steps and high yield, avoids the palladium-carbon hydrogenation process, and can react at room temperature, thereby being safer, having lower cost, and being suitable for large-scale industrial production.

(1) Synthesis of compound I:

Under nitrogen, 3-bromo-2-methylbenzoic acid (1.0 mmol), 4-(trifluoromethoxy)benzeneboronic acid (2.0 mmol), sodium carbonate (4.0 mmol), Pd( _PPh3 ) ₄ (0.05 mmol), 4 mL of DME, and 1 mL of water were mixed and reacted at 130 °C for 12 h. After the reaction was completed, it was diluted with water, extracted three times with ethyl acetate, spin-dried under reduced pressure, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography to obtain a white solid with a yield of 90% (266.3 mg).

(2) Synthesis of Compound II

Compound I (1.0 mmol), 5-amino-2-chloropyridine (1.0 mmol), HAUT (2.0 mmol, 410 mg), triethylamine (4.0 mmol), and 4 mL of DMF were mixed and reacted at room temperature for 12 h. The reaction was completed, diluted with water, extracted with ethyl acetate three times, spin-dried under reduced pressure, and dried over anhydrous sodium sulfate. After silica gel column chromatography, a white solid was obtained, and II in a yield of 92% (373.3 mg) was obtained.

(3) Synthesis of compound III

Compound II (1.0 mmol, 1.0 equiv), (2S,6R)-2,6-dimethylmorpholine (1.2 equiv), NHC-palladium catalytic system (5 mol%), sodium tert-butoxide (1.2 equiv), 4 mL of ethylene glycol dimethyl ether, closed the bottle, and stirred at 25-100 °C for 16 h under nitrogen. Add water to dilute, extract 3 times with ethyl acetate, spin dry under reduced pressure, dry with anhydrous sodium sulfate, and obtain white solid after silica gel column chromatography to obtain product III. Product Spectroscopic Data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (d, J=2.6 Hz, 1H), 8.03 (dd, J=9.1, 2.7 Hz, 1H), 7.54 (s, 1H), 7.46 (dd, J=5.7, 3.3Hz, 1H), 7.33–7.23 (m, 6H), 6.66 (d, J=9.1Hz, 1H), 3.99 (dd, J=12.7, 1.7Hz, 2H), 3.76– 3.68(m, 2H), 2.50(dd, J=12.5, 10.7Hz, 2H), 2.32(s, 3H), 1.26(d, J=6.3Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ168 .5, 156.8, 148.4, 142.2, 140.1, 139.8, 137.6, 133.4, 131.5, 131.2, 130.5, 126.0, 125.8, 125.6, 121.7, 120.6, 119.2, 106.8, 71.5, 51.1, 18.9, 17.5.

Wherein, when using the Pd-NHC-1 catalyzed reaction of the present invention, the dosage is 5 mol%, and the reaction is carried out for 16 hours under the condition of nitrogen at room temperature, and the yield is as high as 90%.

(4) Catalytic synthesis from compound II to III is carried out with different phosphine ligand/palladium catalytic systems, the amount of phosphine ligands (L1-L8) is controlled to be 5 mol%, the amount of palladium is 5 mol%, and stirring is performed under nitrogen conditions at 100° C. For 72h, the structural formula and yield of the phosphine ligands used are shown below.

The reaction equation is as follows:

The structure and catalytic efficiency of the phosphine ligands of each catalytic system are shown as follows:

The total yield of the patent document WO2011009852 is 42.8%, the total yield of the patent document WO2017163258 is 63.1%, the total yield of the patent document CN105330658A is 15.1%, the total yield of the patent document CN109293649A is 58.5%, the synthesis method of the present invention adopts Pd The total yield when catalyzed by -NHC-1 was 74.5%.

In the synthesis method of the present invention, the large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd) of the present invention is used to realize the efficient C-N coupling of aromatic heterocyclic chloride and aromatic heterocyclic amine for the first time at room temperature, and The synthesis steps are few, the yield is high, the palladium-carbon hydrogenation process is avoided, and the reaction can be carried out at room temperature, thereby being safer and lower in cost, and suitable for industrialized large-scale production.

Example 8: Comparison of catalytic efficiency using the catalysts of Examples 1 to 6 of the present invention and existing catalysts in the art

Based on the C-N coupling reaction in step (3) in the synthesis method of Example 7, the catalyst dosage was 5 mol%, and the mixture was stirred for 16 h under nitrogen at room temperature. The catalytic efficiency of each catalyst is shown in Table 1 below. The structural formula of each existing catalyst is as follows:

Table 1 Efficiency of different catalysts for C-N coupling reaction

It can be seen from the table that under the same room temperature reaction conditions, the large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd) of the present invention achieves the effect of efficiently catalyzing C-N coupling, and the catalytic yield can be as high as 93%.

Embodiment 9: The nitrogen heterocyclic carbene palladium complex of the present invention is applied to the C-N coupling reaction. Compared with the yield obtained by the catalysis of the classical carbene palladium complex, the raw materials used in the reactions (1) to (6) of this embodiment and The solvent is: 1 mmol of aryl (hetero) ring chloride, 1.2 mmol of amine, 1.2 mmol of sodium tert-butoxide, 4 mL of ethylene glycol dimethyl ether.

According to the preparation method of Example 1-Example 5, the azacyclic carbene palladium complexes Pd-NHC-6 to Pd-NHC-31 substituted with different substituents of the present invention are prepared, and the structural formulas are as follows:

Reaction (1): The reaction equation is shown below, and the catalytic efficiency of each catalyst is shown in Table 2 below.

Table 2 Efficiency of different catalysts for C-N coupling reaction

It can be seen from the table that under the same room temperature reaction conditions, the large sterically hindered nitrogen heterocyclic carbene palladium complex (NHC-Pd) of the present invention achieves the effect of catalyzing C-N coupling efficiently; The lowest catalytic rate is only 10%, and the highest is only 75%. The catalytic rate of the complex of the present invention is all close to 90%, and the highest can be as high as 99%.

Reaction (2): The reaction equation is shown below, and the catalytic efficiency of each catalyst is shown in Table 3 below by taking Pd-NHC-1 as an example.

Table 3 Efficiency of different catalysts for C-N coupling reaction

Reaction (3): The reaction equation is shown below, and the catalytic efficiency of each catalyst is shown in Table 4 below by taking Pd-NHC-2 as an example.

Table 4 Efficiency of different catalysts for C-N coupling reaction

Reaction (4): The reaction equation is shown below, and the catalytic efficiency of each catalyst is shown in Table 5 below by taking Pd-NHC-3 as an example.

Table 5 Efficiency of different catalysts catalyzing C-N coupling reaction

Reaction (5): The reaction equation is shown below, and the catalytic efficiency of each catalyst is shown in Table 6 below by taking Pd-NHC-4 as an example.

Table 6 Efficiency of different catalysts for C-N coupling reaction

Reaction (6): The reaction equation is shown below, and the catalytic efficiency of each catalyst is shown in Table 7 below by taking Pd-NHC-5 as an example.

Table 7 Efficiency of different catalysts for C-N coupling reaction

Example 10: The azacyclic carbene palladium complex of the present invention is applied to C-N coupling reaction to synthesize compounds with potential pharmacological activity

(1) Synthesis of imidazopyridine derivatives

Under _N2 environment, compound 1m (1.0 mmol, 1.0 equiv), compound 2m (1.2 equiv), Pd-NHC-3 (5 mol%), sodium tert-butoxide (1.2 equiv), 4 mL of ethylene glycol dimethyl ether, The bottle was closed and stirred at room temperature under nitrogen for 16 hours. Add water to dilute, extract 3 times with ethyl acetate, spin dry under reduced pressure, and dry over anhydrous sodium sulfate. After silica gel column chromatography, a white solid was obtained in a yield of 89% (438.7 mg). Product spectral data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.16 (s, 1H), 8.04–7.92 (m, 2H), 7.81–7.67 (m, 3H), 7.47–7.36 (m, 3H), 7.29(t,J＝7.4Hz,1H),6.85-6.78(m,2H),6.68-6.61(m,1H),6.54(d,J＝9.4Hz,1H),6.39(d,J＝7.4Hz ,1H),4.23–3.98(m,2H),3.68(s,4H),2.84(s,4H),2.68–2.48(m,2H),1.96–1.73(m,4H) ^.13C NMR(101MHz) , CDCl ₃ )δ164.8,161.3,143.6,141.2,140.8,140.7,140.3,134.0,129.0,128.5,127.5,125.9,118.6,117.9,114.1,112.7,112.6,108.4,106.4,53.9. 49.1, 27.1, 23.2.

(2) Synthesis of flavonoid derivatives

Under _N2 environment, compound 1l (1.0 mmol, 1.0 equiv), compound 2l (1.2 equiv), Pd-NHC-2 (5 mol%), sodium tert-butoxide (1.2 equiv), 4 mL of ethylene glycol dimethyl ether were combined , closed the bottle, and stirred at room temperature under nitrogen for 16 hours. Diluted with water, extracted three times with ethyl acetate, spin-dried under reduced pressure, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography to obtain a white solid in a yield of 82% (361.6 mg). Product Spectroscopic Data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, J=5.2 Hz, 1 H), 8.22 (dd, J=8.0, 1.5 Hz, 1 H), 7.71 (ddd, J=8.7, 7.2, 1.7Hz, 1H), 7.60–7.54 (m, 1H), 7.47–7.39 (m, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 7.02 (dd, J=5.2, 1.3Hz ,1H),6.90(s,1H),6.83(s,1H),6.80–6.73(m,1H),5.95(s,2H),3.69–3.60(m,4H),3.48(s,2H), 2.61–2.53(m, 4H). ¹³ C NMR (101MHz, CDCl ₃ )δ178.2,161.9,159.9,156.1,149.0,147.6,146.6,140.5,134.0,131.7,125.7,125.4,124.0,122.1,118.1,1 109.1, 108.9, 107.8, 103.1, 100.8, 62.7, 52.6, 45.1.

(3) Synthesis of Buspar

Under _N2 environment, compound 1n (1.0 mmol, 1.0 equiv), compound 2n (1.2 equiv), Pd-NHC-1 (5 mol%), sodium tert-butoxide (1.2 equiv), 4 mL of ethylene glycol dimethyl ether were combined , closed the bottle, and stirred at room temperature under nitrogen for 16 hours. Add water to dilute, extract 3 times with ethyl acetate, spin dry under reduced pressure, dry over anhydrous sodium sulfate, and obtain a white solid after silica gel column chromatography in a yield of 90% (346.8 mg). Other conditions remain unchanged, using Pd-NHC-1' and rac-Pd-NHC-1 instead of Pd-NHC-1 for catalysis, the reaction yields obtained were 91% and 90%, respectively. Product Spectroscopic Data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=4.7 Hz, 2H), 6.46 (t, J=4.7 Hz, 1 H), 3.84-3.80 (m, 4H), 3.77 (t, J=6.9Hz, 2H), 2.57 (s, 4H), 2.53–2.46 (m, 4H), 2.39 (d, J=6.5Hz, 2H), 1.74–1.64 (m, 4H), 1.58– 1.42 (m, 8H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 172.1, 161.5, 157.6, 109.7, 58.2, 52.9, 44.9, 43.4, 39.4, 39.2, 37.5, 25.9, 24.1, 24.0.

(4) Synthesis of Piribedil

Under _N2 environment, compound 1o (1.0 mmol, 1.0 equiv), compound 2o (1.2 equiv), Pd-NHC-1 (2 mol%), sodium tert-butoxide (1.2 equiv), 4 mL of ethylene glycol dimethyl ether were combined , closed the bottle, and stirred at room temperature under nitrogen for 16 hours. Add water to dilute, extract 3 times with ethyl acetate, spin dry under reduced pressure, and dry over anhydrous sodium sulfate. After silica gel column chromatography, a white solid was obtained in a yield of 98% (292.1 mg). Other conditions remain unchanged, using Pd-NHC-1' and rac-Pd-NHC-1 instead of Pd-NHC-1 for catalysis, the reaction yields obtained are also 98%. Product Spectroscopic Data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=4.7 Hz, 2H), 6.88 (s, 1H), 6.75 (s, 2H), 6.46 (t, J=4.7 Hz) , 1H), 5.94(s, 2H), 3.87–3.73(m, 4H), 3.45(s, 2H), 2.54–2.40(m, 4H). ¹³ C NMR (101MHz, CDCl ₃ )δ161.6,157.6,147.6 , 146.6, 131.7, 122.2, 109.6, 109.4, 107.8, 100.8, 62.8, 52.8, 43.6.

(5) Synthesis of Brexpiprazole

Under _N2 environment, compound 1p (1.0 mmol, 1.0 equiv), compound 2p (1.2 equiv), Pd-NHC-1 (5 mol%), sodium tert-butoxide (1.2 equiv), 4 mL of ethylene glycol dimethyl ether were combined , closed the bottle, and stirred at room temperature under nitrogen for 16 hours. Add water to dilute, extract 3 times with ethyl acetate, spin dry under reduced pressure, and dry over anhydrous sodium sulfate. After silica gel column chromatography, a white solid was obtained in a yield of 95% (411.3 mg). Other conditions remained unchanged, and Pd-NHC-1' and rac-Pd-NHC-1 were used instead of Pd-NHC-1 for catalysis, and the reaction yields were 96% and 95%, respectively. Product Spectroscopic Data: ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.55 (s, 1H), 7.72 (d, J=9.4 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.46-7.36 (m,3H),7.26(dd,J=8.3,7.4Hz,1H),6.88(dd,J=8.8,4.9Hz,2H),6.81(dd,J=8.7,2.3Hz,1H),6.55( d, J=9.4Hz, 1H), 4.11 (t, J=6.2Hz, 2H), 3.21 (s, 4H), 2.74 (s, 4H), 2.60–2.49 (m, 2H), 1.94–1.84 (m , 2H), 1.82–1.72(m, 2H). ¹³ C NMR (101MHz, CDCl ₃ )δ165.0,161.3,148.4,141.0,140.8,140.4,134.0,128.9,124.9,124.8,121.8,117.8,116.9,114.1, 112.6, 112.1, 99.0, 68.1, 58.2, 53.5, 52.0, 27.1, 23.3.

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (10)

1. A large sterically hindered nitrogen heterocyclic carbene palladium complex, characterized in that the complex is a compound with a chemical structural formula shown in formula (A):

   

   in

   R ¹ , R ^1' , R ² , R ^2' which are the same or different are hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted, respectively C1-20 alkoxy, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-20 cycloalkyl, halogen, -Bn, -CF ₃ , -NO ₂ , substituted amino at least one of;

   R ³ is hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-20 Any of the cycloalkyl and substituted amino groups;

   X is one of -Cl, -Br, -I, CH ₃ COO-, CF ₃ COO-, -BF ₄ , -PF ₆ , -SbF ₆ , and -OTf.
2. A large sterically hindered nitrogen heterocyclic carbene palladium complex, characterized in that the complex is an enantiomer or a racemate of the compound of the formula (A) chemical structural formula described in claim 1, and the enantiomer has the formula (B) The chemical structural formula shown, the racemate has the chemical structural formula shown in formula (C):

   

   in

   R ¹ , R ^1' , R ² , R ^2' which are the same or different are hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted, respectively C1-20 alkoxy, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-20 cycloalkyl, halogen, -Bn, -CF ₃ , -NO ₂ , substituted amino at least one of;

   R ³ is hydrogen, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C4-20 heterocyclyl, substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-20 Any of the cycloalkyl and substituted amino groups;

   X is one of -Cl, -Br, -I, CH ₃ COO-, CF ₃ COO-, -BF ₄ , -PF ₆ , -SbF ₆ , and -OTf.
3. The large sterically hindered nitrogen heterocyclic carbene palladium complex according to claim 1 or 2, wherein the substitution refers to that one or more hydrogen atoms in the group are replaced by C6-20 aryl, C4-20 heterocycle group, C1-20 hydrocarbyloxy group, C1-20 alkyl group, C3-20 cycloalkyl group, -CF ₃ , -NO ₂ , halogen group substitution.
4. A kind of preparation method of the described large sterically hindered nitrogen heterocyclic carbene palladium complex of claim 1 or 2 or 3, it is characterized in that taking the large sterically hindered imidazolium salt substituted by phenyl as skeleton, and functionalized palladium dimer [Pd-(allyl-R ³ )(uX)] ₂ is obtained by coordination.
5. The preparation method of large sterically hindered nitrogen heterocyclic carbene palladium complex according to claim 4, it is characterized in that described large sterically hindered imidazole salt is large sterically hindered imidazole X generation salt, and its structural formula is as follows:

   

   Wherein, X is one of Cl, Br, I, CH ₃ COO, CF ₃ COO, BF ₄ , PF ₆ , SbF ₆ , and OTf.
6. The preparation method of large sterically hindered nitrogen heterocyclic carbene palladium complex according to claim 4, it is characterized in that: described large sterically hindered imidazole salt is large sterically hindered imidazole X-generation salt, with substituted or unsubstituted diphenyl Ethylenediamine is used as the starting material, and is obtained by C-N coupling reaction with substituted or unsubstituted 2,6-diisopropyl bromobenzene, and then reacting with inorganic X-substituted salt.
7. The method for preparing a large sterically hindered nitrogen heterocyclic carbene palladium complex according to claim 6, wherein the reaction temperature of the C-N coupling reaction is 25-130°C, and the reaction time is 1-96h; The reaction temperature of the inorganic X-substituted salt reaction is 25-120°C, and the reaction time is 1-48h.
8. The application of the large sterically hindered nitrogen heterocyclic carbene palladium complex according to claim 1 or 2 or 3 in catalyzing C-N coupling reaction.
9. A method for synthesizing Sony Gibb, which is characterized in that a C-N coupling reaction is carried out under alkaline solution conditions with aryl/aliphatic amine and aryl chloride as reactants and a palladium catalytic system;

   The palladium catalytic system comprises at least one of the monophosphine ligand/palladium catalytic system and the large sterically hindered nitrogen heterocyclic carbene palladium complex described in claim 1 or 2 or 3; the monophosphine ligand/palladium The monophosphine ligands in the catalytic system include at least biphenyls, binaphthyls, biaryls, indoles, carbazoles, ferrocenes, and biphenyl monophosphine ligands containing bridged side chains. One; palladium in the monophosphine ligand/palladium catalytic system includes PdCl ₂ , Pd(OAc) ₂ , Pd(dba) ₂ , Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ at least one; the temperature of the coupling reaction is 25-130 ° C, and the reaction time is 1-96 h; the alkali of the alkaline solution is sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, hydrogen At least one of sodium oxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate; the solvent of the alkaline solution includes dioxane, ethylene glycol dimethyl ether, diethyl ether, methyl tert-butyl ether, Anisole, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, m-xylene, ethylbenzene, mesitylene, C1-C5 alcohols, dimethylformamide, dimethylacetamide, DMSO, acetonitrile, water or both A combination of one or more mixed solvents.
10. synthetic method according to claim 9, is characterized in that, specifically, 3-bromo-2-methylbenzoic acid and 4-(trifluoromethoxy) benzeneboronic acid carry out Suzuki coupling reaction, make biphenyl intermediate 2-methyl-3-(trifluoromethoxyphenyl)-benzoic acid, then condensation reaction with 5-amino-2-chloropyridine to obtain an amide intermediate, which is prepared in a monophosphine ligand/palladium catalytic system, Carry out C-N coupling reaction with 2,6-dimethylmorpholine under at least one catalysis of the large sterically hindered nitrogen heterocyclic carbene palladium complex according to claim 1 or 2 or 3 to obtain the final product Sony Gibb .