CN115353510A - Preparation method and application of isoindole compound - Google Patents

Preparation method and application of isoindole compound Download PDF

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CN115353510A
CN115353510A CN202211007526.3A CN202211007526A CN115353510A CN 115353510 A CN115353510 A CN 115353510A CN 202211007526 A CN202211007526 A CN 202211007526A CN 115353510 A CN115353510 A CN 115353510A
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isoindole
methyl
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李先纬
陈慈
黄智玮
马培林
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Guangdong University of Technology
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Abstract

The patent application discloses a preparation method and application of an isoindole compound. The method utilizes the oxidation Heck reaction of the combination of easily-converted imidate and a plurality of 1,2-disubstituted alkene to realize the simple construction of the isoindole compound compatible with the strong coordination heterocycle, and further develops the connection and the conversion between the drug and the natural product, thereby simply constructing the isoindole compound and realizing the oxidation Heck reaction with site selectivity and strong coordination groups. The conversion overcomes the problems of strong coordination heterocyclic ring guiding priority and catalyst poisoning, the method has atom and step economy, the substrate application range is wide, the method can be suitable for selective modification of unconventional sites containing strong coordination drug molecules, and a new idea is provided for development of related new drugs.

Description

Preparation method and application of isoindole compound
Technical Field
The patent application relates to the technical field of organic compound synthesis, and more particularly relates to a preparation method and application of an isoindole compound.
Background
How to accurately, efficiently and greenly synthesize target structure molecules, and simply construct molecular complexity to enrich molecular libraries in the application field of the target structure molecules are always problems faced by the field of synthetic chemistry. Richard F.heck, ei-ichi Negishi and Akira Suzuki are issued in 2010 by Nobel chemical prize to show the contribution of the Richard F.heck and the like in palladium-catalyzed cross-coupling reaction, wherein the Heck reaction of palladium-catalyzed olefin developed by Richard F.heck and the like can quickly realize the quick construction of related bioactive molecules. Under the initiation, the Heck reaction based on the catalysis of transition metals such as palladium, cobalt and the like makes great progress and is applied to the fields of biological medicines and materials.
Heck reaction, i.e. coupling reaction of aryl halide catalyzed by zero-valent palladium with terminal olefin, constructed disubstituted olefins, which was discovered by Heck in the last 60 th century, and first instance oxidation Heck reaction was discovered by Fujiwara in 1976. On the basis, the carbon-carbon bond coupling through carbon-hydrogen bond activation is a powerful strategy for simply constructing molecular complexity, the rapid development of metal catalytic carbon-hydrogen activation provides important theoretical support for the oxidation Heck reaction, the conversion not only avoids the pre-preparation of aryl halide, but also reduces the generation of stoichiometric waste acid in the reaction process, and the oxidation Heck reaction promoted by the guide strategy has been developed into a powerful method for rapidly coupling and constructing olefin and heterocyclic rings after decades of development.
Although the oxidative Heck reaction facilitated by the targeting strategy has good atom and step economy, and site selectivity, when the substrate contains a strongly coordinating heterocycle, the metal catalyst will preferentially coordinate with the strongly coordinating heterocycle, resulting in coordination saturation, and even poisoning of the metal catalyst, resulting in difficulty in achieving high efficiency and high selectivity of the reaction for the substrate containing the strongly coordinating heterocycle.
However, the heterocycle is an important skeleton ubiquitous in human production and life and widely exists in biology, medicine, pesticides and materials, so that the development of the site-selective carbon-hydrogen bond activation reaction capable of overcoming the strong coordination heterocycle plays an important role in the simple, efficient and high-selectivity construction of important functional molecules and promotes the development of the field of metal organic chemistry.
Therefore, how to overcome the limitation of site selectivity and guide priority problem when strong coordination heterocycle participates in C-H activation, and the efficient synthesis of organic compounds containing heterocycle, especially nitrogen heterocyclic organic compounds becomes a problem which needs to be solved urgently by organic synthesis workers.
Content of the patent application
To overcome at least one of the problems of the prior art described above, the present application provides a process for the preparation of compatible strongly coordinating dehydroisoindole compounds: based on the strong coordination imido ester and 1,2 disubstituted alkene, the oxidation Heck reaction is realized, and the limitation of a strong coordination heterocyclic ring is overcome, so that the isoindole compound is quickly constructed.
In order to solve the technical problem, the technical scheme adopted by the patent application is as follows:
a method for preparing an isoindole compound: reacting strongly coordinating imidate (formula II) with 1,2-disubstituted alkene compound (formula III) in an inert solvent and under the action of a trivalent rhodium catalyst to obtain isoindole compound (formula I), wherein the reaction formula is as follows:
Figure BDA0003809672000000021
wherein Het is a substituent group containing strong coordination heteroatom such as pyrazole, triarylamine, pyridine, oxypyridine and the like; r 1 Is saturated alkane; r 2 Ester group and amide group.
Preferably, the inert solvent is any one or more of 1,2-dichloroethane, toluene, N' -dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile and gamma-valerolactone.
Preferably, the trivalent rhodium catalyst is: pentamethylcyclopentadienylrhodium chloride dimer, other trivalent rhodium catalysts, or combinations thereof.
Preferably, the halide ion capturing agent is any one of silver hexafluoroantimonate and silver bis (trifluoromethanesulfonyl) imide or a combination thereof.
Preferably, the oxidizing agent is any one or more of copper acetate, sodium percarbonate, oxygen, sodium percarbonate and copper acetate.
Preferably, the additive is sodium acetate.
Preferably, the amount of the trivalent rhodium catalyst is 3mol% of the amount of the strongly coordinating imidate (formula II).
Preferably, the reaction is carried out at 100 ℃; the reaction is carried out for 10 to 24 hours.
The process for the preparation of isoindole compounds in some preferred embodiments of the present patent application comprises the following specific steps:
s1: sequentially adding 2.4mg of pentamethylcyclopentadienylrhodium dichloride dimer, 5.0mg of silver trifluoromethanesulfonylimide, 24mg of sodium percarbonate, 16.0mg of sodium acetate, 1.0mL of gamma-valerolactone serving as a solvent, 15.5mg of ethyl 4- (1H-pyrazol-1-yl) benzimidate and 30mg of methyl crotonate into a reactor;
s2: reacting the reaction solution at 100 ℃ for 10 hours;
s3: and after the reaction is finished, separating the mixture by using a column chromatography separation technology to obtain the target compound.
The present application also provides a medicament comprising celecoxib having the isoindole compound prepared by the above method for alleviating the symptoms and signs of rheumatoid arthritis in humans.
The strong coordination imidoester and 1,2 disubstituted alkene compound based on the application realizes the oxidized Heck reaction and overcomes the limitation of a strong coordination heterocycle, thereby quickly constructing the isoindole compound. The converted functional group has good compatibility and wide substrate applicability, not only can quickly construct the multi-aromatic heterocyclic skeleton, but also avoids the use of halogenated reagents and metal reagents, and provides a new idea for simply and efficiently constructing functional drug molecules and material molecules.
Compared with the prior art, the beneficial effect of this patent application is:
the preparation method of the multiple dehydrogenation isoindole compound provided by the patent application has the characteristics of compatibility with strong coordination azacyclo, multiple dehydrogenation, high efficiency, atom economy and step economy.
Drawings
FIG. 1 is a NMR spectrum of Compound 1a prepared in example 1 of the present application;
FIG. 2 is a NMR carbon spectrum of Compound 1a prepared in example 1 of the present patent application;
FIG. 3 is a NMR chart of Compound 1b prepared in example 2 of the present patent application;
FIG. 4 is a NMR carbon spectrum of Compound 1b prepared in example 2 of the present patent application;
FIG. 5 is a NMR spectrum of Compound 1c prepared in example 2 of the present application;
FIG. 6 shows the NMR spectrum of Compound 1c prepared in example 3 of the present application;
FIG. 7 is a NMR spectrum of Compound 1d prepared in example 3 of the present application;
FIG. 8 is a NMR spectrum of Compound 1d prepared in example 4 of the present application;
FIG. 9 is a NMR spectrum of Compound 1e prepared in example 4 of the present application;
FIG. 10 is a NMR carbon spectrum of Compound 1e prepared in example 4 of the present patent application;
FIG. 11 is a NMR chart of Compound 1f prepared in example 5 of the present patent application;
FIG. 12 is a NMR carbon spectrum of Compound 1f prepared in example 4 of the present application;
FIG. 13 is a NMR spectrum of 1g of compound prepared in example 5 of the present patent application;
FIG. 14 shows the NMR spectrum of 1g of compound prepared in example 4 of the present patent application;
FIG. 15 is a NMR spectrum of compound 1h prepared in example 5 of the present application for hydrogen;
FIG. 16 is the NMR carbon spectrum of compound 1h prepared in example 4 of the present patent application.
Detailed Description
Embodiments of the present patent application will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present patent application and should not be construed as limiting the scope of the present patent application. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
It should be noted that:
all embodiments and preferred methods mentioned herein can be combined with each other to form new solutions, if not specifically stated in the present patent application.
In this application, unless otherwise indicated, individual reactions or process steps may be performed sequentially or in sequence. Preferably, the reaction processes herein are carried out sequentially.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art. Moreover, any methods or materials similar or equivalent to those described herein can also be used in the present application.
The present application provides a process for the preparation of isoindole compounds: reacting strongly coordinated imidate (formula II) with 1,2 disubstituted alkene compound (formula III) in an inert solvent and under the action of a trivalent rhodium catalyst to obtain isoindole compound (formula I), wherein the reaction formula is as follows:
Figure BDA0003809672000000041
wherein Het is a substituent group containing strong coordination heteroatom such as pyrazole, triarylamine, pyridine, oxypyridine and the like; r 1 Is saturated alkane; r 2 Ester group and amide group.
In some examples, the inert solvent is any one or more of 1,2-dichloroethane, toluene, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, gamma valerolactone.
In some examples, the trivalent rhodium catalyst is: any one of pentamethylcyclopentadienylrhodium chloride dimer, other trivalent rhodium catalysts, or combinations thereof.
In some embodiments, the halide ion scavenger is any one of silver hexafluoroantimonate, silver bis (trifluoromethanesulfonylimide), or a combination thereof.
In some embodiments, the oxidizing agent is any one or more of copper acetate, sodium percarbonate, oxygen, sodium percarbonate, and copper acetate.
In some embodiments, the additive is sodium acetate.
In some embodiments, the trivalent rhodium catalyst is used in an amount of 3mol% of the amount of the strongly coordinating imidate (formula II).
In some embodiments, the reaction is carried out at 100 ℃; the reaction is carried out for 10 to 24 hours.
The application discloses site-selective carbon-hydrogen bond activation for overcoming strong coordination heterocycle limitation, so that an isoindole compound is simply constructed, and an oxidative coupling reaction (also called Heck reaction) with site selectivity and compatibility with a strong coordination group is realized. Specifically, under the condition of an inert solvent and under the common promotion of a trivalent rhodium catalyst and an oxidant, the imidoester containing the strong coordination heterocycle is used as a guide group to perform oxidation Heck coupling reaction with 1,2-disubstituted olefin compounds, the conversion overcomes the problems of guiding priority and catalyst poisoning of the strong coordination heterocycle, the method has atom and step economy, the substrate application range is wide, the method can be suitable for unconventional site selective modification of the drug molecule containing the strong coordination heterocycle, and a new idea is provided for development of related new drugs.
The preparation method of the isoindole compound disclosed by the patent application is a guide strategy, overcomes the trivalent rhodium catalytic oxidation Heck reaction limited by the strong coordination heterocycle, namely, realizes simple construction of the isoindole compound compatible with the strong coordination heterocycle by utilizing the oxidation Heck reaction of easily-converted imidate and a plurality of 1,2-disubstituted olefin compounds, and further develops connection and conversion between a medicament and a natural product.
Next, the preparation method of the isoindole compound of the present patent application is described in detail with specific examples.
Example 1 preparation and characterization of methyl 2- (3-ethoxy-1-propyl-6- (1H-pyrazol-1-yl) -1H-isoindol-1-yl) acetate (1 a)
To a 15mL Schlenk reaction tube, ethyl 4- (1H-pyrazol-1-yl) benzimidate 2a (43.0 mg,0.20 mmol), (E) -methyl 2-hexanoate 3a (38.4 mg,0.30 mmol), and a trivalent rhodium catalyst [ Cp. RhCl ] were sequentially added under an atmospheric air atmosphere 2 ] 2 (2.4 mg, 0.003mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01mmol), sodium percarbonate (24mg, 0.2mmol), sodium acetate (16.4 mg, 0.20mmol), gamma-valerolactone (GVL, 1.0 mL) were reacted at 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of petroleum ether to ethyl acetate of selected developing solvent is 5: the product, methyl 2- (3-ethoxy-1-methyl-6- (1H-pyrazole) -1H-isoindol-1-yl) acetate (1 a), was obtained in 85% yield. The chemical reaction equation for this example is as follows:
Figure BDA0003809672000000061
the nuclear magnetic hydrogen spectrum and the carbon spectrum of the chemical combination prepared in example 1 are shown in fig. 1 and fig. 2. As can be seen from fig. 1: 1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝2.4Hz,1H),7.83(d,J＝1.6Hz, 1H),7.75(d,J＝1.6Hz,1H),7.67(dd,J＝2.0,8.4Hz,1H),7.54(d,J＝8.2Hz,1H), 6.50-6.49(m,1H),4.49-4.43(m,2H),3.49(s,3H),2.99(d,J＝14.4,1H),2.88(d,J＝ 14.6Hz,1h) 2.13-1.94 (m, 4H), 1.45 (t, J =7.1Hz, 3H), 0.81-0.75 (m, 3H). From FIG. 2 can be seen 13 C NMR(100MHz, CDCl 3 ) Delta 170.5,167.5,156.7,141.5,141.0,131.2,127.2,121.5,118.4,112.7, 108.0, 64.2,51.3,43.1,40.4,16.5,14.4,14.1 molecular carbon spectrum peak energy corresponds to target product one to one, and the quantity is reasonable. Based on the results of the nuclear magnetic hydrogen spectroscopy and the carbon spectroscopy, the product obtained in example 1 was methyl 2- (3-ethoxy-1-propyl-6- (1H-pyrazol-1-yl) -1H-isoindol-1-yl) acetate (1 a).
In this example, in the case of a trivalent rhodium catalyst [ Cp RhCl ] 2 ] 2 Under the action, 4- (1H-pyrazole-1-yl) ethyl benzimidate 2a containing a strong coordination heterocyclic pyrazole ring and 1,2-disubstituted alkene compound (E) -2-methyl hexanoate 3a overcome site selective carbon-hydrogen bond activation limited by the strong coordination heterocyclic pyrazole ring in an inert solvent gamma-valerolactone solvent, so that the isoindole compound 2- (3-ethoxy-1-propyl-6- (1H-pyrazole-1-yl) -1H-isoindole-1-yl) methyl acetate (1 a) is constructed simply and efficiently (the yield reaches 85%).
The isoindole compound preparation method in the embodiment only uses the simple and easily obtained strong coordination imidate 2a and the 1,2 disubstituted alkene compound 3a as reaction substrates, has the advantages of few steps, simple and convenient operation, wide application range of the substrates and easy subsequent further conversion. In addition, the chemical conversion in the embodiment provides a rapid construction isoindole compound, and the chemical conversion of the application uses pyrazole phenylimine ester as a raw material and has good site selectivity.
Example 2 preparation and characterization of methyl 2-methyl- (3-ethoxy-1-methyl-5- (1H-pyrazole) -1H-isoindole) acetate (1 b)
To a 15mL Schlenk reaction tube were added ethyl 3- (1H-pyrazol-1-yl) benzimidate 2b (21.5mg, 0.10 mmol), methyl crotonate 3b (30.0 mg,0.30 mmol), and a trivalent rhodium catalyst [ Cp. RhoCl ] in that order under an atmospheric air atmosphere 2 ] 2 (2.4mg, 0.003mmol), silver trifluoromethanesulfonylimide (3.9 mg, 0.01mmol), copper acetate (4.0mg, 0.2mmol), sodium percarbonate (24mg, 0.2mmol), sodium acetate (16.4mg,0.20 mmol), gamma-valerolactone (GVL, 1.0 mL), at a temperature of 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of petroleum ether to ethyl acetate of the selected developing solvent is 5: the product methyl 2-methyl- (3-ethoxy-1-methyl-5- (1H-pyrazole) -1H-isoindole) acetate (1 b) was obtained in 79% yield. The chemical reaction equation for this example is as follows:
Figure BDA0003809672000000071
the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the compound prepared in example 2 are shown in fig. 3 and 4. As can be seen from fig. 3: 1 H NMR(400MHz,CDCl 3 ) δ 7.98 (d, J =2.5hz, 1h), 7.86 (d, J =1.7 Hz, 1h), 7.74 (d, J =1.5hz, 1h), 7.68 (dd, J =8.2,1.8hz, 1h), 7.55 (d, J =8.2Hz, 1H), 6.48 (t, J =2.1hz, 1h), 4.52-4.35 (m, 2H), 2.96 (d, J =14.7hz, 1h), 2.84 (d, J =14.8hz, 1h), 1.58 (s, 3H), 1.44 (t, J =7.1hz, 3h), as can be seen from fig. 4: 13 C NMR(100 MHz,CDCl 3 ) δ 170.5,167.2,158.0,141.5,141.1,130.3,127.1,121.7,118.5, 112.6,108.0,69.9,64.1,51.3,43.4,25.5,14.3. The results of the nuclear magnetic hydrogen spectroscopy and the carbon spectroscopy showed that the product obtained in example 2 was methyl 2-methyl- (3-ethoxy-1-methyl-5- (1H-pyrazole) -1H-isoindole) acetate (1 b).
In this example, in the case of a trivalent rhodium catalyst [ Cp RhCl ] 2 ] 2 Under the action, 3- (1H-pyrazole-1-yl) benzimidate ethyl 2b containing a strong coordination heterocyclic pyrazole ring and 1,2-disubstituted alkene compound methyl crotonate 3b overcome selective carbon-hydrogen bond activation of a site limited by the strong coordination heterocyclic pyrazole ring in an inert solvent gamma-valerolactone solvent, so that the isoindole compound methyl 2-methyl- (3-ethoxy-1-methyl-5- (1H-pyrazole) -1H-isoindole) acetate (1 b) is constructed simply, conveniently and efficiently (the yield reaches 79%).
The preparation method of the isoindole compound in the embodiment only uses simple and easily obtained strong coordination imido ester 2b and 1,2 disubstituted alkene compound 3b as reaction substrates, has the advantages of few steps, simple and convenient operation, wide application range of the substrates and easy subsequent further transformation. In addition, the chemical conversion in the embodiment provides a rapid construction isoindole compound, and the chemical conversion of the application uses pyrazole phenylimine ester as a raw material and has good site selectivity.
Example 3 methyl 2-methyl (3-ethoxy-1-methyl-6- (pyridine-2-acyloxy) -1H-isoindole) acetate
(1c) Preparation and characterization of
To a 15mL Schlenk reaction tube, ethyl 4- (pyridine-2-acyloxy) benzimidate 2c (48.4 mg, 0.20mmol), methyl crotonate 3b (30.0mg, 0.30 mmol), and a trivalent rhodium catalyst [ Cp. Multidot. RhCl ] were sequentially added under an atmospheric pressure air atmosphere 2 ] 2 (2.4 mg, 0.003mmol), silver trifluoromethanesulphonimide (3.9 mg, 0.01mmol), copper acetate (60.0mg, 0.30mmol), sodium acetate (16.4 mg, 0.20mmol), 1,2 dichloroethane (DCE, 1.0 mL) were reacted at 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 5: the product, methyl 2-methyl (3-ethoxy-1-methyl-6- (pyridine-2-acyloxy) -1H-isoindole) acetate (1 c), was obtained in 70% yield. The chemical reaction equation for this example is as follows:
Figure BDA0003809672000000081
the nuclear magnetic hydrogen spectrum and the carbon spectrum of the compound prepared in example 3 are shown in fig. 5 and 6. From FIG. 6, it can be seen that H NMR (400MHz, CDCl) 3 ) δ 8.20 (dd, J =1.2hz,4.4hz, 1h), 7.73-7.70 (m, 1H), 7.49 (d, J =8.0hz, 1h), 7.23 (d, J =2.0hz, 1h), 7.12 (dd, J =2.0hz,8.4hz, 1h), 6.92 (d, J =8.0hz, 1h), 4.50-4.39 (m, 2H), 3.53 (s, 3H), 2.88 (d, J =14.4hz, 1h), 2.73 (d, J =14.8hz, 1h), 1.58 (s, 3H), 1.43 (t, J =6.8hz, 3h), as can be seen from fig. 7: 13 C NMR(100MHz,CDCl 3 ) Delta 170.7,167.3,163.4,158.2,155.8,147.8,139.6,134.1, 128.5,121.9,120.5,118.9,116.5,114.7,111.9,69.7,64.0,51.3,43.6,25.2,14.4 combining the above nuclear magnetic hydrogen spectrum and carbon spectrum results, the product obtained in example 3 is 2-methyl (3-ethoxy-1-methyl-6- (pyridine-2-Acyloxy) -1H-isoindole) acetic acid methyl ester (1 c).
In this example, in a trivalent rhodium catalyst [ Cp RhCl 2 ] 2 Under the action, 4- (pyridine-2-acyloxy) ethyl benzimidate 2c containing a strong coordination heterocyclic pyridine ring and 1,2-disubstituted alkene compound methyl crotonic acid 3b overcome site selective carbon-hydrogen bond activation limited by the strong coordination heterocyclic ring in an inert solvent dichloroethane solvent, so that the isoindole compound methyl 2-methyl (3-ethoxy-1-methyl-6- (pyridine-2-acyloxy) -1H-isoindole) acetate (1 c) is constructed simply, conveniently and efficiently (the yield reaches 70%).
In the preparation method of the isoindole compound in the embodiment, only the simple and easily obtained strong coordination imidate 2c and the 1,2 disubstituted alkene compound 3b are used as reaction substrates, the steps are few, the operation is simple and convenient, the application range of the substrates is very wide, and the subsequent further conversion is easy. In addition, the chemical transformation in the embodiment takes oxypyridine as a raw material, the oxypyridine is one of important frameworks of various drug molecules, the reaction overcomes the carbon-hydrogen bond activation of the oxypyridine at a target site in strong coordination, and a new synthesis idea is provided for drug construction.
Example 4 preparation and characterization of methyl 2- (3-ethoxy-1-methyl-6- (2-pyridine) -1-isoindole) acetate (1 d)
To a 15mL Schlenk reaction tube, ethyl 4- (2-pyridine) benzimidate 2d (45.2mg, 0.20mmol), methyl crotonate 2b (30.0mg, 0.30mmol), and a trivalent rhodium catalyst [ Cp. RhCl ] were sequentially added under an atmospheric pressure air atmosphere 2 ] 2 (2.4mg, 0.003mmol)), silver trifluoromethanesulfonimide (3.9 mg,0.01 mmol), copper acetate (60.0mg, 0.30mmol), sodium acetate (16.4mg, 0.20mmol), 1,2 dichloroethane (DCE, 1.0 mL) at 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 5: the product, methyl 2- (3-ethoxy-1-methyl-6- (2-pyridine) -1-isoindole) acetate (1 d), was obtained in 71% yield. The corresponding chemical reaction equation of this example is as follows:
Figure BDA0003809672000000091
the nuclear magnetic hydrogen spectrum and the carbon spectrum of the compound prepared in example 4 are shown in fig. 8 and 9. As can be seen from fig. 7: 1 H NMR(400MHz,CDCl 3 ) δ 7.76-7.74 (m, 1H), 7.73 (d, J =4.4hz, 2H), 7.70 (d, J =8.0hz, 2H), 7.59 (s, 2H), 4.50-4.45 (m, 2H), 3.55 (s, 3H), 2.99 (d, J =14.4hz, 1h), 2.80 (d, J =14.4hz, 1h), 1.61 (s, 3H), 1.46 (t, J =7.2hz, 3H), as can be seen from fig. 8: 13 C NMR(100MHz,CDCl 3 ) Delta 170.7,167.4,157.3,145.4,140.5,132.6,128.2,128.0, 127.2,121.7,121.4,120.6,111.3,64.2,51.4,43.5,25.4,14.4 from the above results of nuclear magnetic hydrogen spectroscopy and carbon spectroscopy, the product obtained in example 4 was methyl 2- (3-ethoxy-1-methyl-6- (2-pyridine) -1-isoindole) acetate (1 d).
In this example, in a trivalent rhodium catalyst [ Cp RhCl 2 ] 2 Under the action, 4- (2-pyridine) benzimidate ethyl ester 2d containing a strong coordination heterocyclic pyridine ring and 1,2-disubstituted alkene compound crotonic acid methyl ester 3b overcome site selective carbon-hydrogen bond activation limited by the strong coordination heterocyclic ring in an inert solvent dichloroethane solvent, so that the isoindole compound 2- (3-ethoxy-1-methyl-6- (2-pyridine) -1-isoindole) methyl acetate (1 d) is constructed simply, conveniently and efficiently (the yield reaches 71%).
The isoindole compound preparation method in the embodiment only uses the simple and easily obtained strong coordination imidate 2d and the 1,2 disubstituted alkene compound 3b as reaction substrates, has the advantages of few steps, simple and convenient operation, wide application range of the substrates and easy subsequent further conversion. In addition, pyridine is used as a well-known strong coordination group in the chemical conversion in the embodiment, imine ester of phenylpyridine is used as a raw material in the chemical conversion in the embodiment, and multiple dehydrogenation of the pyridine at a target site through strong coordination is overcome, so that a new synthesis idea is provided for drug construction.
Example 5 preparation and characterization of (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl 2- (3-ethoxy-1-methyl-6- (1-pyrazo) -1-isoindole) acetic acid methyl ester (1 e)
To a 15mL Schlenk reaction tube under an atmosphere of atmospheric airTo this mixture were added ethyl 4- (1H-pyrazol-1-yl) benzimidate 2a (43.0 mg,0.0 mmol), menthol crotonate 3e (69.2 mg,0.30 mmol), and a trivalent rhodium catalyst [ Cp. RhCl ] 2 ] 2 (2.4 mg, 0.003mmol), silver trifluoromethanesulphonimide (3.9 mg, 0.01mmol), copper acetate (60.0mg, 0.30mmol), sodium acetate (16.4 mg, 0.20mmol), 1,2 dichloroethane (DCE, 1.0 mL) were reacted at 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 5:1, the product methyl (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl 2- (3-ethoxy-1-methyl-6- (1-pyrazole) -1-isoindole) acetate (1 e) was obtained in a yield of 76%. The chemical reaction equation for this example is as follows:
Figure BDA0003809672000000111
the nuclear magnetic hydrogen spectrum and the carbon spectrum of the compound prepared in example 5 are shown in fig. 10 and 11. As can be seen from fig. 10: 1 H NMR(400MHz,CDCl 3 ) δ 7.95 (d, J =2.4hz, 1h), 7.89-7.75 (m, 2H), 7.72 (d, J =1.6hz, 1h), 7.53 (t, J =8.0hz, 1h), 6.47 (t, J =2.4hz, 1h), 4.46-4.42 (m, 2H), 2.99-2.90 (m, 2H), 2.20 (s, 1H), 1.96-1.92 (m, 2H), 1.83-1.79 (m, 2H), 1.69-1.61 (m, 3H), 1.55 (d, J = 1.3 hz, 6H), 1.46-1.42 (m, 3H), 1.27-1.22 (m, 3H), 0.80-0.75 (m, 6H), 0.62-0.59 (m, 3H), as can be seen from fig. 11: 13 C NMR(100MHz,CDCl 3 ) Delta 169.6,167.2,154.3,141.2,140.0,133.8,126.9,122.4,120.5,111.5,111.45,107.8, 77.4,77.0,76.7,46.7,44.1,40.6,34.1,32.7,31.2,30.8,26.4,23.1,21.9,20.7,16.0 from the results of nuclear magnetic hydrogen and carbon spectrograms, the product of example 5 was 5- (5 '-bromo- [2,2' -bithiophene)]-5-yl) -4- (2,4-dichlorophenyl) -2-methyloxazole (1 e).
In the embodiment, 4- (1H-pyrazol-1-yl) benzimidate ethyl ester 2a containing a strong-coordination heterocyclic pyrazole ring and 1,2-disubstituted alkene compound, namely, menthol crotonate 3e overcome site-selective carbon-hydrogen bond activation limited by the strong-coordination heterocyclic pyrazole ring in an inert solvent dichloroethane solvent, so that the methyl isoindole compound (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl 2- (3-ethoxy-1-methyl-6- (1-pyrazole) -1-isoindole) acetate (1 e) is constructed simply, conveniently and efficiently (the yield is up to 76%).
The preparation method of the isoindole compound in the embodiment has high efficiency and good chemical selectivity, and meanwhile, the method only uses simple and easily obtained strong coordination imidate and popular chemical 1,2 disubstituted olefin compound as reaction substrates, has few steps, is simple and convenient to operate, has a wide application range on the substrates, and is easy for subsequent further conversion. The application has good atom economy and the by-product is water.
The chemical conversion in the embodiment is connected with natural product menthol, which can be used as perfuming agent in cosmetic, and can be used for cooling and relieving itching on skin or mucosa
EXAMPLE 6 preparation and characterization of methyl (3S, 8R,9S,10S,13R,14S, 17R) -10,13-dimethyl-17- (R) -6 (2-methylheptane) hexadecahydro-1H-cyclopenta [ a ] phenanthren-3-yl 2- (3-ethoxy-1-methyl-6- (1H-pyrazol-1-yl) -1H-isoindol-1-yl) acetate (1 f)
To a 15mL Schlenk reaction tube, 4- (1H-pyrazol-1-yl) benzimidate ethyl 2a (43.0 mg,0.0 mmol), cholesteryl crotonate 3f (136.8 mg,0.30 mmol), and a trivalent rhodium catalyst [ Cp ] RhCl were sequentially added under an atmospheric pressure air atmosphere 2 ] 2 (2.4 mg, 0.003mmol)), silver trifluoromethanesulfonimide (3.9 mg, 0.01mmol), copper acetate (60.0 mg, 0.30mmol), sodium acetate (16.4 mg,0.20 mmol), 1,2 dichloroethane (DCE, 1.0 mL) were reacted at 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing solvent or eluent to the petroleum ether to the ethyl acetate is 5:1, the product (3S, 8R,9S,10S,13R,14S, 17R) -10,13-dimethyl-17- (R) -6- (2-methylheptane) hexadecahydro-1H-cyclopentane [ a]Phenanthren-3-yl 2- (3-ethoxy-1-methyl-6- (1H-pyrazole) -1H-isoindol-1-yl) acetic acid methyl ester (1 f). The corresponding chemical reaction equation for this example is as follows:
Figure BDA0003809672000000121
the nuclear magnetic hydrogen spectrum and the carbon spectrum of the compound prepared in example 6 are shown in fig. 11 and 12. As can be seen from fig. 12: 1 H NMR(400MHz,CDCl 3 ) δ 7.99 (d, J =2.4Hz, 1h), 7.86 (d, J =1.2Hz, 1H), 7.75 (d, J =1.6Hz, 1h), 7.69-7.67 (m, 1H), 7.55 (d, J =8.0hz, 1h), 6.49 (t, J =2.0hz, 1h), 5.28-5.24 (m, 1H), 4.50-4.39 (m, 2H), 2.97 (d, J =18.4Hz, 1h), 2.89-2.85 (m, 1H), 2.24-2.07 (m, 2H), 2.06 (d, J =10.7Hz, 1H), 1.97-1.91 (m, 1H), 1.84-1.71 (m, 1H), 1.62 (d, J =6.8hz, 1H), 1.58 (s, 2H), 1.47-1.42 (m, 3H), 1.32 (d, J =5.6Hz, 2H), 1.25 (d, J =7.2Hz, 2H), 1.14-0.98 (m, 4H), 0.93-0.89 (m, 3H), 0.87-0.84 (m, 2H), 0.65 (s, 2H), as can be seen from fig. 13: 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.2,158.13,141.5,141.08,139.6,130.5,127.1,122.5,121.6,118.4,112.8, 108.07,73.8,70.1,64.2,56.6,56.1,50.0,44.2,42.3,39.7,39.5,37.8,37.7,36.9,36.5, 36.2,35.8,33.9,31.8,28.2,28.0,27.5,25.9,25.6,24.9,24.3,23.8,22.8,22.6,21.0, 19.21,18.7,14.5,14.2,11.8 from the above results of nuclear magnetic hydrogen spectroscopy and carbon spectrograms, the product obtained in example 6 was (3S, 8R,9S,10S,13R,14S, 17R) -10,13-dimethyl-17- (R) -6 (2-methylheptane) hexadecahydro-1H-cyclopentane [ a]Phenanthren-3-yl 2- (3-ethoxy-1-methyl-6- (1H-pyrazol-1-yl) -1H-isoindol-1-yl) acetic acid methyl ester (1 f).
In this example, 4- (1H-pyrazol-1-yl) benzimidate ethyl ester 2a and 1,2-disubstituted alkene compound cholesteryl crotonate 3f containing strongly coordinating heterocyclic pyrazole rings are subjected to site-selective carbon-hydrogen bond activation in an inert solvent dichloroethane solvent to overcome the restriction of the strongly coordinating heterocyclic pyrazole rings, so that the isoindole compound (3S, 8R,9S,10S,13R,14S, 17R) -10,13-dimethyl-17- (R) -6- (2-methylheptane) hexadecahydro-1H-cyclopenta [ a ] phenanthren-3-yl 2- (3-ethoxy-1-methyl-6- (1H-pyrazole) -1H-isoindole-1-acyl) methyl acetate (1 f) can be constructed simply and efficiently (yield is up to 72%).
The chemical transformation in this example can link natural product cholesterol, which is mainly synthesized by the human body itself, providing a platform for subsequent transformation and modification of natural product molecules.
Example 7 preparation and characterization of (N, N-dipropylsulfamoyl) benzyl 2- (3-ethoxy-1-methyl-6- (1H-pyrazole) -1H-isoindol-1-yl) acetate (1 g)
To a 15mL Schlenk reaction tube, 4- (1H-pyrazol-1-yl) benzimidate ethyl 2a (43.0 mg,0.0 mmol), probenecid crotonate 3g (105.9 mg,0.30 mmol), and a trivalent rhodium catalyst [ Cp. RhCl ] were sequentially added under an atmospheric pressure air atmosphere 2 ] 2 (2.4 mg, 0.003mmol)), silver trifluoromethanesulfonimide (3.9mg, 0.01mmol), copper acetate (60.0mg, 0.30mmol), sodium acetate (16.4 mg,0.20 mmol), 1,2 dichloroethane (DCE, 1.0 mL) at 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 5:1, the product (3S, 8R,9S,10S,13R,14S, 17R) -10,13-dimethyl-17- (R) -6- (2-methylheptane) hexadecahydro-1H-cyclopentane [ a]Methyl phenanthren-3-yl 2- (3-ethoxy-1-methyl-6- (1H-pyrazol-1-yl) -1H-isoindol-1-yl) acetate (1 g). The corresponding chemical reaction equation of this example is as follows:
Figure BDA0003809672000000131
the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the compound prepared in example 7 are shown in fig. 13 and 14. As can be seen from fig. 14: 1 H NMR(400MHz,CDCl 3 ) δ 7.97 (d, J =6.4hz, 1h), 7.86 (d, J = 0.8hz, 1h), 7.73 (d, J =1.6hz, 1h), 7.64 (d, J =8.0hz, 2h), 7.61-7.59 (m, 1H), 7.47 (d, J =8.0hz, 1h), 7.23 (d, J =4.4hz, 2h), 6.49 (t, J =2.0hz, 1h), 4.95 (d, J =8.4hz, 2h), 4.42-4.37 (m, 2H), 3.04-3.00 (m, 6H), 1.56 (s, 3H), 1.55-1.51 (m, 4H), 1.41 (t, J =4.4hz, 3h), 0.84 (t, J = 7.4, 6H), 15 hz: 13 C NMR(100 MHz,CDCl 3 ) Delta 169.4,167.2,157.7,141.5,141.0,140.1,139.6,130.1,128.1,127.1, 127.0,121.7,118.2,112.5,108.1,69.9,64.8,64.1,50.0,43.5,25.9,22.0,14.3,11.1 from the above results of nuclear magnetic hydrogen and carbon spectrograms, the product obtained in example 7 was (N, N-dipropylsulfamoyl) benzylThe radical 2- (3-ethoxy-1-methyl-6- (1H-pyrazole) -1H-isoindol-1-yl) acetate (1 g).
In this example, in the case of a trivalent rhodium catalyst [ Cp RhCl ] 2 ] 2 Under the action, 4- (1H-pyrazol-1-yl) ethyl benzimidate 2a containing a strong coordination heterocyclic pyrazole ring and 3g of probenecid crotonate in an inert solvent dichloroethane solvent overcome site-selective carbon-hydrogen bond activation limited by the strong coordination heterocyclic pyridine ring, so that the isoindole compound (3S, 8R,9S,10S,13R,14S, 17R) -10,13-dimethyl-17- (R) -6- (2-methylheptane) hexadecahydro-1H-cyclopentane [ a ] is simply, conveniently and efficiently constructed (the yield reaches 63 percent)]Methyl phenanthren-3-yl 2- (3-ethoxy-1-methyl-6- (1H-pyrazol-1-yl) -1H-isoindol-1-yl) acetate (1 g).
The preparation method of the isoindole compound in the embodiment only uses simple and easily obtained strong coordination imidate 2a and 1,2 disubstituted alkene compound 3g as reaction substrates, has few steps, simple and convenient operation, wide application range of the substrates and easy subsequent further conversion. The chemical transformation in this example links the drug to a reduction of probenecid, which is a common drug used to treat gout.
Example 8 preparation and characterization of methyl-2- (3-ethoxy-1-methyl-6- (3-methyl-5- (p-tolyl) -1H-pyrazole) -1H-isoindol-1-yl) acetate (1H)
To a 15mL Schlenk reaction tube, 4- (3-methyl-5- (p-tolyl) -1H-pyrazole) ethyl benzimidate 2i (63.8mg, 0.20mmol), methyl crotonate 3b (30.0mg, 0.30mmol), and a trivalent rhodium catalyst [ Cp. Multidot. RhCl ] were sequentially added under an atmospheric pressure air atmosphere 2 ] 2 (2.4 mg, 0.003mmol), silver trifluoromethanesulfonylimide (3.9mg, 0.01mmol), copper acetate (60.0mg, 0.30mmol), sodium acetate (16.4 mg,0.20 mmol), 1,2-dichloroethane (DCE, 1.0 mL) at 100 ℃ for 10 hours. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 5: the product methyl-2- (3-ethoxy-1-methyl-6- (3-methyl-5- (p-tolyl) -1H-pyrazole) -1H-isoindol-1-yl) acetate was obtained in 67% yield (1H). This embodiment pairThe corresponding chemical reaction equation is as follows:
Figure BDA0003809672000000151
the nuclear magnetic hydrogen spectrum and the carbon spectrum of the compound prepared in example 8 are shown in fig. 15 and 16. As can be seen from fig. 15: 1 H NMR(400MHz,CDCl 3 ) δ 7.41 (d, J =8.0hz, 1h), 7.32 (s, 1H), 7.28 (dd, J =1.2hz,8.0hz, 1h), 7.10 (s, 1H), 7.07 (s, 3H), 6.29 (s, 1H), 4.47-4.38 (m, 2H), 3.49 (s, 3H), 7.75 (dd, J =10.8hz,20.0hz, 2h), 2.39 (s, 3H), 2.32 (s, 3H), 1.44 (s, 3H), 1.43-1.38 (m, 3H), as can be seen from fig. 16: 13 C NMR(100MHz,CDCl 3 ) Delta 170.3, 167.2,157.1,149.8,144.1,141.1,138.1,129.1,128.6,124.6,121.0,118.3,107.9, 69.8,64.1,51.2,43.3,25.3,21.2,14.3,13.6 from the above results of nuclear magnetic hydrogen spectrum and carbon spectrum, the product obtained in example 8 was methyl-2- (3-ethoxy-1-methyl-6- (3-methyl-5- (p-tolyl) -1H-pyrazole) -1H-isoindole-1-yl) acetate (1H).
In this example, in a trivalent rhodium catalyst [ Cp RhCl 2 ] 2 Under the action, 4- (3-methyl-5- (p-tolyl) -1H-pyrazole) benzimidate ethyl 2i containing a strong coordination heterocyclic pyrazole ring and crotonic acid methyl ester 3b overcome site selective carbon-hydrogen bond activation limited by the strong coordination heterocyclic ring pyridine ring in an inert solvent dichloroethane solvent, so that the isoindole compound methyl-2- (3-ethoxy-1-methyl-6- (3-methyl-5- (p-tolyl) -1H-pyrazole) -1H-isoindole-1-acyl) methyl acetate (1H) is constructed simply, conveniently and efficiently (the yield reaches 67%).
The isoindole compound preparation method in the embodiment only uses the simple and easily obtained strong coordination imidate 2i and the 1,2 disubstituted alkene compound 3b as reaction substrates, has the advantages of few steps, simple and convenient operation, wide application range of the substrates and easy subsequent further conversion.
The chemical transformation of the application enables celecoxib to be used for relieving symptoms and physical signs of osteoarthritis and relieving symptoms of human rheumatoid arthritis, and the medicine contains a strong coordination azacyclic ring, so that the application of the medicine compatible with strong coordination reaction is met.
The method realizes derivatization of analogues of a strong coordination medicament Celecoxib, realizes unconventional site-selective carbon-hydrogen bond activation reaction, and is also the first example of oxidation Heck reaction for overcoming limitation of a strong coordination heterocyclic ring at present.
According to the preparation method, nitrogen heterocyclic ring-containing phenylimino ester and ester group activated 1,2 disubstituted olefin are subjected to Heck reaction under the catalysis of trivalent rhodium, so that the compatible strong-coordination dehydroisoindole compound is obtained, and the method has high atom economy and step economy and wide substrate application range.
In summary, the patent application relates to a trivalent rhodium catalytic oxidation Heck reaction for overcoming the limitation of a strong coordination heterocycle under a guiding strategy, namely, an easily-converted imidoester is utilized to react with the oxidation Heck compounded by a plurality of 1,2 disubstituted olefins, so that the simple construction of the isoindole compound compatible with the strong coordination heterocycle is realized, and the connection and the conversion between a medicament and a natural product are further developed.
The patent application discloses an isoindole compound which overcomes site-selective carbon-hydrogen bond activation limited by a strong coordination heterocycle, so that the isoindole compound is simply constructed, and site-selective oxidation and oxidation Heck reaction compatible with a strong coordination group are realized; specifically, under the condition of an inert solvent and under the co-promotion of a trivalent rhodium catalyst and an oxidant, the imidoester containing the strong coordination heterocycle is used as a guide group and is reacted with 1,2-disubstituted olefin, so that the problems of the guide priority of the strong coordination heterocycle and the catalyst poisoning are overcome, and the oxidation Heck coupling reaction is realized. The method has atom and step economy, and the substrate has wide application range.
In the description herein, references to the description of the terms "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," or "some examples" or the like mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present patent application. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
While several embodiments of the present patent application have been shown and described, it will be appreciated by those of ordinary skill in the art that: numerous changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the present patent application, the scope of which is defined by the claims and their equivalents.

Claims (10)

1. A process for the preparation of isoindole compounds characterized by: reacting strongly coordinating imidate (formula II) with 1,2-disubstituted alkene compound (formula III) in an inert solvent and under the action of a trivalent rhodium catalyst to obtain isoindole compound (formula I), wherein the reaction formula is as follows:
Figure FDA0003809671990000011
wherein Het is a substituent group containing strong coordination heteroatom such as pyrazole, triarylamine, pyridine, oxypyridine and the like; r is 1 Is saturated alkane; r is 2 Ester group and amide group.
2. The process for producing an isoindole compound according to claim 1, wherein: the inert solvent is any one or more of 1,2-dichloroethane, toluene, N' -dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile and gamma-valerolactone.
3. The process for producing an isoindole compound according to claim 1, wherein: the trivalent rhodium catalyst is: pentamethylcyclopentadienylrhodium chloride dimer, other trivalent rhodium catalysts, or combinations thereof.
4. The process for producing an isoindole compound according to claim 1, wherein: the halide ion capturing agent is any one or the combination of silver hexafluoroantimonate and bis (trifluoromethyl) sulfonyl imide silver.
5. The process for producing an isoindole compound according to claim 1, wherein: the oxidant is any one or more of copper acetate, sodium percarbonate, oxygen, sodium percarbonate and copper acetate.
6. The process for producing an isoindole compound according to claim 1, wherein: the additive is sodium acetate.
7. The process for producing an isoindole compound according to claim 1, wherein: the amount of the trivalent rhodium catalyst is 3mol% of the amount of the strongly coordinating imidate (formula II).
8. The process for producing an isoindole compound according to claim 1, wherein: the reaction is carried out at 100 ℃; the reaction is carried out for 10 to 24 hours.
9. The process for producing an isoindole compound according to claim 1, wherein: the method comprises the following specific steps:
s1: sequentially adding 2.4mg of pentamethylcyclopentadienylrhodium dichloride dimer, 5.0mg of silver trifluoromethanesulfonylimide, 24mg of sodium percarbonate, 16.0mg of sodium acetate, 1.0mL of gamma-valerolactone serving as a solvent, 15.5mg of ethyl 4- (1H-pyrazol-1-yl) benzimidate and 30mg of methyl crotonate into a reactor;
s2: reacting the reaction solution at 100 ℃ for 10 hours;
s3: and after the reaction is finished, separating the mixture by using a column chromatography separation technology to obtain the target compound.
10. A medicament comprising celecoxib for use in alleviating the symptoms and signs of rheumatoid arthritis in humans, wherein: the celecoxib having an isoindole compound prepared by the process of claim 1.
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