Synthesis method and application of chiral triarylmethane compound

Abstract

The invention discloses a synthesis method and application of a chiral triarylmethane compound, and relates to the technical field of organic synthesis, diaryl iodonium salt is used as a raw material, under the action of a chiral copper catalyst and alkali, a ring-opening reaction of the diaryl iodonium salt is selectively carried out, and the chiral triarylmethane compound is obtained. Then carrying out nucleophilic reaction on the chiral triarylmethane compound and a carboxylic acid compound to obtain a chiral triarylmethane compound; the synthesis method provided by the invention is mild in reaction condition, relatively high in yield and enantioselectivity and high in process safety; meanwhile, the synthetic method is suitable for structural modification of carboxylic acid drugs, and side effects of the carboxylic acid drugs can be reduced.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a synthesis method and application of chiral triarylmethane compounds. Background Art

[0002] As a special type of compound structure, triarylmethane skeletons are widely present in many natural products and biologically active molecules in nature, and also occupy an important position in the field of synthetic materials. However, the synthesis of chiral triarylmethane compounds is a very challenging task. The synthesis process of such compounds becomes extremely complicated due to the large steric hindrance between molecules and the difficulty in identification caused by the similarity of the chemical environment between aromatic groups. Therefore, it is particularly important to develop an efficient synthesis method to construct chiral triarylmethane compounds.

[0003] The most direct and universal method for synthesizing triarylmethane compounds is aromatic electrophilic substitution (Friedel-Crafts reaction), which mainly refers to the Friedel-Crafts alkylation reaction of electron-rich aromatic hydrocarbons catalyzed by Lewis acids or protic acids. For example, in 2015, Schneider's group (Chemical Communications. 2015, 51(8): 1461-1464) reported the Friedel-Crafts alkylation reaction of indole or naphthol with in situ generated methylene quinone catalyzed by chiral phosphoric acid to synthesize a series of chiral triarylmethane compounds.

[0004]

[0005] From the perspective of atom economy and step economy, transition metal-catalyzed C(sp 3 It is very desirable to synthesize triarylmethane compounds by direct functionalization of the )-H bond. For example, in 2008, Yu Jinquan's research group (Angew. Chem. Int. Ed. 2008, 120 (26): 4960-4964) reported the transition metal-catalyzed enantioselective synthesis of triarylmethanes. Although this method is very important, its reactivity and selectivity, especially the control of site selectivity and enantioselectivity, remain a major challenge.

[0006]

[0007] As an alternative strategy, enantioselective cross-coupling reaction can well solve the problems of reactivity and selectivity. However, the related catalytic methods involving transition metal catalysis are still limited. Among them, the stereospecific palladium or nickel-catalyzed cross-coupling reaction of enantiomerically enriched diarylmethanol derivatives or boron reagents reported by Jarvo (Angew. Chem. Int. Ed. 2012, 51 (31): 7790-7793), Watson (Accounts of chemical research. 2015, 48 (8): 2344-2353) and Liao (Angew. Chem. Int. Ed. 2015, 54 (41): 12134-12138) teams is an attractive method for synthesizing triarylmethane compounds, but its limitation is that it requires pre-functionalized enantiomerically enriched starting materials.

[0008]

[0009] At the same time, drugs with carboxyl groups have some problems when used, such as a certain acidity, which can easily irritate the gastrointestinal tract when administered orally; and a large polarity, which affects the absorption of drugs. At present, the main modification methods for carboxylic acid drugs are esterification and amidation, but they often require harsh reaction conditions. Therefore, developing new methods to improve their biochemical properties has great research prospects.

[0010] In summary, developing novel synthetic methods to modify carboxylic acid drugs can not only overcome the synthetic difficulty in organic chemistry - the preparation and synthesis of chiral triaryl compounds, but also reduce the side effects of carboxylic acid drugs. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a method for synthesizing chiral triarylmethane compounds, with mild reaction conditions, high yield and enantioselectivity, and high process safety; at the same time, the synthesis method is suitable for structural modification of carboxylic acid drugs and can reduce the side effects of carboxylic acid drugs.

[0012] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0013] One of the purposes of the present invention is to provide a method for synthesizing a chiral triarylmethane compound, which comprises taking a diaryl iodonium salt as a raw material, selectively performing a ring-opening reaction of the diaryl iodonium salt under the action of a chiral copper catalyst and a base, and then reacting the diaryl iodonium salt with a carboxylic acid compound to undergo a nucleophilic reaction to obtain the chiral triarylmethane compound.

[0014] The reaction equation is as follows:

[0015]

[0016] Wherein, Ar is aromatic hydrocarbon or heterocyclic aromatic hydrocarbon; R is alkane or aromatic hydrocarbon.

[0017] The second purpose of the present invention is to provide the application of the synthesis method of the chiral triarylmethane compound in the structural modification of carboxylic acid drugs.

[0018] The beneficial effects of the present invention are:

[0019] (1) The raw materials used in the synthesis method of the chiral triarylmethane compound provided by the present invention are easily available, the reaction conditions are mild, the product is easy to purify, the yield and enantioselectivity are high, the process is safe and reliable, and the applicability is wide.

[0020] (2) The synthesis method of the chiral triarylmethane compounds provided by the present invention can be used for structural modification of carboxylic acid drugs, thereby reducing the side effects of carboxylic acid drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the H NMR spectrum of (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid 2-((S)-(2-iodophenyl)(phenyl)methyl)phenyl ester synthesized in Example 1 of the present invention;

[0022] Figure 2 This is the H NMR spectrum of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate synthesized in Example 3 of the present invention;

[0023] Figure 3 This is the H NMR spectrum of 2-((S)-(2-iodophenyl)(phenyl)methyl)phenyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10α-octahydrophenanthrene-1-carboxylate synthesized in Example 5 of the present invention;

[0024] Figure 4 This is the H NMR spectrum of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 1-methyl-1H-indole-2-carboxylate synthesized in Example 7 of the present invention;

[0025] Figure 5 This is the H NMR spectrum of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 2-(p-tolyl)acetate synthesized in Example 8 of the present invention. DETAILED DESCRIPTION

[0026] In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further described below in conjunction with specific embodiments and diagrams.

[0027] The invention provides a method for synthesizing a chiral triarylmethane compound, which comprises taking a diaryl iodonium salt as a raw material, selectively performing a ring-opening reaction of the diaryl iodonium salt under the action of a chiral copper catalyst and a base, and then performing a nucleophilic reaction with a carboxylic acid compound to obtain the chiral triarylmethane compound.

[0028] The reaction equation is as follows:

[0029]

[0030] Wherein, Ar is aromatic hydrocarbon or heterocyclic aromatic hydrocarbon; R is alkane or aromatic hydrocarbon.

[0031] Furthermore, the chiral copper catalyst is a copper catalyst-chiral ligand complex.

[0032] Preferably, the copper catalyst includes but is not limited to at least one of cuprous iodide, cuprous acetate, cuprous chloride and cuprous bromide.

[0033] Preferably, the chiral ligand includes but is not limited to at least one of (S,S)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline), (4S,4'S)-2,2'-(pentane-3,3-diyl)bis(4-phenyl-4,5-dihydrooxazole), and (4S,4'S)-2,2'-(1,3-diphenylpropane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole).

[0034] Furthermore, the molar ratio of the diaryliodonium salt, the copper catalyst and the chiral ligand is 1:(0.05-0.1):(0.05-0.1).

[0035] In the present invention, copper ions are complexed with chiral ligands to generate chiral copper catalysts, and the chiral copper catalysts undergo a ring-opening reaction with diaryl iodonium salts through oxidative addition to generate active intermediates, and the active intermediates further undergo a nucleophilic reaction with carboxylic acid compounds to generate chiral triarylmethane compounds, that is, the chiral copper catalyst affects the stereoselectivity of the reaction.

[0036] Furthermore, the base includes but is not limited to at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and sodium acetate. The base provides a function of removing protons and increasing the nucleophilicity of the carboxylic acid compound in this reaction.

[0037] Furthermore, the molar ratio of the diaryliodonium salt, the base and the carboxylic acid compound is 1:(1-2):(0.8-1.2).

[0038] Furthermore, the reaction solvents for the ring-opening reaction and the nucleophilic reaction include but are not limited to at least one of dichloromethane, dichloroethane, toluene and tetrahydrofuran.

[0039] Furthermore, the reaction temperature of the ring-opening reaction and the nucleophilic reaction is 30 to 40° C., and the reaction time is 12 to 20 hours.

[0040] The present invention also provides application of the synthesis method of the chiral triarylmethane compound in the structural modification of carboxylic acid drugs.

[0041] Example 1

[0042] Synthesis of 2-((S)-(2-iodophenyl)(phenyl)methyl)phenyl (S)-2-(6-methoxynaphthalen-2-yl)propanoate

[0043]

[0044] Under argon atmosphere, cuprous iodide (1.9 mg, 0.01 mmol), (S,S)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (3.3 mg, 0.01 mmol) and dichloromethane (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium carbonate (15.9 mg, 0.15 mmol) and (S)-2-(6-methoxynaphthalen-2-yl)propionic acid (23 mg, 0.1 mmol) were added, and the reaction was stirred at 35°C for 16 h. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (59.2 mg, 99% yield, 95% de).

[0045] Example 2

[0046] Synthesis of 2-((S)-(2-iodophenyl)(phenyl)methyl)phenyl(2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide

[0047]

[0048] Under argon environment, cuprous acetate (1.2 mg, 0.01 mmol), (4S,4'S)-2,2'-(pentane-3,3-diyl)bis(4-phenyl-4,5-dihydrooxazole) (3.6 mg, 0.01 mmol) and dichloromethane (1 mL) were added to a dry reactor. After stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium bicarbonate (16.8 mg, 0.2 mmol) and (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (18.7 mg, 0.08 mmol) were added and the reaction was stirred at 35 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (39.1 mg, 65% yield, 93% de).

[0049] Example 3

[0050] Synthesis of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

[0051]

[0052] Under argon atmosphere, cuprous iodide (1.9 mg, 0.01 mmol), (S,S)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) (3.3 mg, 0.01 mmol) and dichloromethane (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium carbonate (15.9 mg, 0.15 mmol) and 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (35.8 mg, 0.1 mmol) were added, and the reaction was stirred at 35°C for 16 h. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (71.9 mg, 99% yield, 96% ee).

[0053] Example 4

[0054] Synthesis of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate

[0055]

[0056] Under argon atmosphere, cuprous acetate (1.2 mg, 0.01 mmol), (4S, 4'S)-2,2'-(1,3-diphenylpropane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (4.9 mg, 0.01 mmol) and dichloroethane (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium carbonate (10.6 mg, 0.1 mmol) and 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid (30.0 mg, 0.12 mmol) were added, and the reaction was stirred at 40°C for 16 h. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (58.1 mg, 94% yield, 98% ee).

[0057] Example 5

[0058] Synthesis of 2-((S)-(2-iodophenyl)(phenyl)methyl)phenyl(1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10α-octahydrophenanthrene-1-carboxylate

[0059]

[0060] Under argon environment, cuprous iodide (1.9 mg, 0.01 mmol), (S,S)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline) (3.3 mg, 0.01 mmol) and dichloromethane (1 mL) were added to a dry reactor. After stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), potassium carbonate (20.7 mg, 0.15 mmol) and (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylic acid (30 mg, 0.1 mmol) were added and the reaction was stirred at 35 °C for 20 h. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (66.2 mg, 99% yield, 97% de).

[0061] Example 6

[0062] Synthesis of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 4-methylbenzoate

[0063]

[0064] Under argon atmosphere, cuprous chloride (1.0 mg, 0.01 mmol), (4S, 4'S)-2,2'-(pentane-3,3-diyl)bis(4-phenyl-4,5-dihydrooxazole) (3.6 mg, 0.01 mmol) and dichloromethane (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium carbonate (21.2 mg, 0.2 mmol) and 4-methylbenzoic acid (13.6 mg, 0.1 mmol) were added, and the reaction was stirred at 35 ° C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (49.9 mg, 99% yield, 97% ee).

[0065] Example 7

[0066] Synthesis of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 1-methyl-1H-indole-2-carboxylate

[0067]

[0068] Under argon atmosphere, cuprous iodide (1.9 mg, 0.01 mmol), (S,S)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline) (3.3 mg, 0.01 mmol) and toluene (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium carbonate (15.9 mg, 0.15 mmol) and 1-methyl-1H-indole-2-carboxylic acid (17.5 mg, 0.1 mmol) were added, and the reaction was stirred at 30°C for 16 h. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (50.5 mg, 93% yield, 92% ee).

[0069] Example 8

[0070] Synthesis of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 2-(p-tolyl)acetate

[0071]

[0072] Under argon atmosphere, cuprous bromide (1.4 mg, 0.01 mmol), (4S, 4'S)-2,2'-(1,3-diphenylpropane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (4.9 mg, 0.01 mmol) and dichloromethane (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium acetate (12.3 mg, 0.15 mmol) and 2-(p-tolyl)acetic acid (15.0 mg, 0.1 mmol) were added, and the reaction was stirred at 35 ° C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (44.1 mg, 85% yield, 95% ee).

[0073] Example 9

[0074] Synthesis of (S)-2-((2-iodophenyl)(phenyl)methyl)phenyl 5-chlorovalerate

[0075]

[0076] Under argon atmosphere, cuprous iodide (1.9 mg, 0.01 mmol), (S,S)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline) (3.3 mg, 0.01 mmol) and tetrahydrofuran (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium carbonate (21.2 mg, 0.2 mmol) and 5-chlorovaleric acid (16.4 mg, 0.12 mmol) were added, and the reaction was stirred at 35°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (40.4 mg, 80% yield, 90% ee).

[0077] Example 10

[0078] Synthesis of 1-(tert-butyl)2-(2-((S)-(2-iodophenyl)(phenyl)methyl)phenyl)(S)-pyrrolidine-1,2-dicarboxylate

[0079]

[0080] Under argon atmosphere, cuprous iodide (1.9 mg, 0.01 mmol), (S,S)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline) (3.3 mg, 0.01 mmol) and dichloromethane (1 mL) were added to a dry reactor, and after stirring for 30 min, 10-phenyl-10H-dibenzo[b,e]iodonium-5-trifluoromethanesulfonate (50.2 mg, 0.1 mmol), sodium carbonate (10.6 mg, 0.1 mmol) and (tert-butoxycarbonyl)-L-proline (21.5 mg, 0.1 mmol) were added, and the reaction was stirred at 40°C for 16 h. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the product (47.8 mg, 82% yield, 94% ee).

[0081] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing a chiral triarylmethane compound, characterized in that: Using diaryl iodonium salt as a raw material, under the action of a chiral copper catalyst and a base, a ring-opening reaction of the diaryl iodonium salt is selectively carried out, and then a nucleophilic reaction occurs with a carboxylic acid compound to obtain a chiral triarylmethane compound; The reaction equation is as follows: Wherein, Ar is aromatic hydrocarbon or heterocyclic aromatic hydrocarbon; R is alkane or aromatic hydrocarbon.

2. The method for synthesizing chiral triarylmethane compounds according to claim 1, characterized in that: The chiral copper catalyst is a copper catalyst-chiral ligand complex.

3. The method for synthesizing chiral triarylmethane compounds according to claim 2, characterized in that: The copper catalyst is selected from at least one of cuprous iodide, cuprous acetate, cuprous chloride and cuprous bromide.

4. The method for synthesizing chiral triarylmethane compounds according to claim 2, characterized in that: The chiral ligand is selected from at least one of (S,S)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline), (4S,4'S)-2,2'-(pentane-3,3-diyl)bis(4-phenyl-4,5-dihydrooxazole), and (4S,4'S)-2,2'-(1,3-diphenylpropane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole).

5. The method for synthesizing chiral triarylmethane compounds according to claim 2, characterized in that: The molar ratio of the diaryliodonium salt, the copper catalyst and the chiral ligand is 1:(0.05-0.1):(0.05-0.1).

6. The method for synthesizing chiral triarylmethane compounds according to claim 1, characterized in that: The base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and sodium acetate.

7. The method for synthesizing chiral triarylmethane compounds according to claim 1, characterized in that: The molar ratio of the diaryliodonium salt, the base and the carboxylic acid compound is 1:(1-2):(0.8-1.2).

8. The method for synthesizing chiral triarylmethane compounds according to claim 1, characterized in that: The reaction solvent for the ring-opening reaction and the nucleophilic reaction is selected from at least one of dichloromethane, dichloroethane, toluene and tetrahydrofuran.

9. The method for synthesizing chiral triarylmethane compounds according to claim 1, characterized in that: The reaction temperature of the ring-opening reaction and the nucleophilic reaction is 30-40° C., and the reaction time is 12-20 hours.

10. Use of the synthesis method of chiral triarylmethane compounds according to any one of claims 1 to 9 in the structural modification of carboxylic acid drugs.

Images