WO2022078306A1 - Complexe palladium-azote-carbène hétérocyclique à fort empêchement stérique, procédé de préparation de ce dernier, applications de ce dernier, et procédé de synthèse du sonidégib se fondant sur ce complexe - Google Patents

Complexe palladium-azote-carbène hétérocyclique à fort empêchement stérique, procédé de préparation de ce dernier, applications de ce dernier, et procédé de synthèse du sonidégib se fondant sur ce complexe Download PDF

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WO2022078306A1
WO2022078306A1 PCT/CN2021/123160 CN2021123160W WO2022078306A1 WO 2022078306 A1 WO2022078306 A1 WO 2022078306A1 CN 2021123160 W CN2021123160 W CN 2021123160W WO 2022078306 A1 WO2022078306 A1 WO 2022078306A1
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substituted
unsubstituted
reaction
palladium
sterically hindered
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邱立勤
欧阳嘉盛
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中山大学
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    • 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
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    • B01J2531/824—Palladium

Definitions

  • 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.
  • 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. .
  • 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.
  • 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.
  • 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.
  • 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.
  • the synthetic routes of Sony Gibb mainly include the following:
  • 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 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.
  • 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.
  • 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) ):
  • 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.
  • 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.
  • 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.
  • 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.
  • the phenyl group can generate ⁇ - ⁇ 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.
  • 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:
  • 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.
  • 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,
  • 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
  • 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.
  • 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:
  • 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.
  • 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 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.
  • 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, dimethyl
  • 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.
  • 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 sul
  • 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.
  • 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,
  • 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
  • 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%.
  • 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.
  • 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.
  • the phenyl group can generate ⁇ - ⁇ 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.
  • 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%.
  • 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%.
  • the R 1 and R 1' are H, and the phenyl group in the structure can generate ⁇ - ⁇ 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.
  • the R 1 and R 1' are electron-donating groups, such as one of -OMe, cycloalkyl, -Ph, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • X is one of -Cl, -Br , -I, CH3COO- , CF3COO-, -BF4 , -PF6 , -SbF6 , -OTf.
  • Example 6 follows 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.
  • racemic 1,2-diphenylethylenediamine as the starting material, the racemic azacyclic carbene palladium complex rac-Pd-NHC-1 can be obtained.
  • 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.
  • 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
  • different configurations of chiral catalysts will produce corresponding asymmetric catalytic results.
  • 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.
  • 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.
  • 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%.
  • 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%.
  • 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
  • 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.
  • Reaction (1) The reaction equation is shown below, and the catalytic efficiency of each catalyst is shown in Table 2 below.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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

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Abstract

La présente invention concerne le domaine technique de la synthèse organique et de la catalyse chimique. L'invention décrit un complexe palladium-azote-carbène hétérocyclique à fort empêchement stérique, un procédé de préparation de ce dernier, des applications de ce dernier pour la catalyse efficace d'une réaction de couplage C-N dans les conditions de température ambiante et un procédé de synthèse du sonidégib se fondant sur ce complexe. La structure du complexe palladium-azote-carbène hétérocyclique à fort empêchement stérique de la présente invention possède un diphénylimidazole en tant que squelette ligand principal et un allyle fonctionnalisé en tant que ligand ancillaire, avec introduction de l'allyle fonctionnalisé pour servir de ligand ancillaire à côté du centre métallique d'un catalyseur, assure une activité et une stabilité catalytiques significativement accrues, peut être utilisées pour catalyser efficacement la réaction de couplage C-N, en catalysant d'une manière spécifique et efficace la réaction de couplage C-N dans les conditions de température ambiante et permet d'obtenir un rendement allant jusqu'à 99 %. La présente invention porte également sur un procédé de synthèse en trois étapes à la température ambiante avec une amine aryl/aliphatique et un chlorure d'aryle en tant que réactifs et catalysé par un système catalytique au palladium. Le procédé de synthèse de la présente invention utilise un petit nombre d'étapes et permet d'obtenir un rendement total allant jusqu'à 74,5 %.
PCT/CN2021/123160 2020-10-14 2021-10-12 Complexe palladium-azote-carbène hétérocyclique à fort empêchement stérique, procédé de préparation de ce dernier, applications de ce dernier, et procédé de synthèse du sonidégib se fondant sur ce complexe WO2022078306A1 (fr)

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