Preparation method of pyrrolo-aza compound

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of a pyrrolo-aza # imgabs0 # compound. The method comprises the following step: in the presence of a metal salt catalyst and a dehydrating agent, carrying out intramolecular Friedel-Crafts acylation reaction on a compound as shown in a formula (1) to obtain the pyrrolo-aza # imgabs 1 # compound as shown in a formula (2). According to the method, the specific metal salt catalyst is adopted and matched with the dehydrating agent, so that the substrate is subjected to the intramolecular Friedel-Crafts acylation reaction, and the efficient preparation of the pyrrolo-aza # imgabs2 # compound is realized. The method disclosed by the invention is high in yield, simple to operate, mild in condition and more environment-friendly. Formula (1) # imgabs3 # formula (2) # imgabs4 #

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a method for preparing pyrroloazepine compounds. Background Art

[0002] Aldisin marine alkaloids are a class of pyrrololactam compounds with various biological activities. In 1980, Sharma et al. first isolated debromohymenialdisine from the Great Barrier Reef sponge Phakellia flanellata. In 1982, Cimibo et al. first isolated hymenialdisine from the Mediterranean sponge Axinella verrucosa and the Red Sea sponge Acanthella aurantiaca, and determined its chemical structure by single crystal structure. Subsequently, Kitagawa et al. simultaneously isolated debromohymenialdisine and hymenialdisine from the Okinawa sponge Hymeniacidon akdis, and determined the chemical structure by single crystal structure at the same time. In 1985, Schmitz et al. from the University of Oklahoma first isolated two pyrrololactam compounds, 2–bromoaldisin and Aldisin, from the Guam sponge Hymeniacidon aldis de laubenfels, and determined their structures by nuclear magnetic resonance. In 2007, Hassan et al. isolated eighteen alkaloids including two new alkaloids, 3-bromoaldisin and 2,3-dibromoaldisin, from the sponges Axinella damicornis and Stylissa flabelliformis. Activity tests of the above alkaloids on protein kinases showed that the alkaloids Hymenin, Stevensin, and Hymenialdisin had inhibitory activities on the kinases CKD-1, CKD-5, and GSK-3, and their IC 50 values were all lower than 10 μM. The wide biological activities of such natural products have attracted the interest of drug researchers. In order to better conduct activity research, it is very necessary to develop a simple and large-scale synthetic method for such alkaloids.

[0003] In the preparation of such natural products, the efficient preparation of pyrroloazepine compounds is a key step, which determines whether such natural products can be prepared in large quantities. In 2005, Gianluca Papeo et al. reported the Friedel-Crafts acylation reaction under the action of polyphosphoric acid and phosphorus pentoxide for pyrroloazepine Synthesis of compounds of this class. In the same year, Zeng Xiangchao et al. used phosphorus oxychloride as a solvent and condensing agent to complete the synthesis of pyrroloazepine compounds under reflux conditions. However, both of the above two synthesis methods have the disadvantages of high reaction temperature, generation of a large amount of acidic wastewater, cumbersome post-treatment, and low yield. Therefore, how to develop a simple, mild, environmentally friendly and high-yield synthesis method for pyrroloazepine compounds has become an urgent problem to be solved at present. SUMMARY OF THE INVENTION

[0004] The object of the present invention is to overcome the problems existing in the above-mentioned prior art and provide a method for preparing pyrroloazepine compounds. This method has a high yield, is simple to operate, has mild conditions, and is more environmentally friendly.

[0005] To achieve the above object, the present invention provides a method for preparing pyrroloazepine compounds, which includes: carrying out an intramolecular Friedel-Crafts acylation reaction on the compound shown in formula (1) in the presence of a metal salt catalyst and a dehydrating agent to obtain the pyrroloazepine compounds shown in formula (2); wherein, the metal salt catalyst is selected from silver salts and / or copper salts, and the anion of the metal salt catalyst is selected from - [SbX6] - , [BX4] - , [CX3COO] - and [CX3SO3]

[0006]

[0007] one or more of them, wherein each X independently represents one or more of halogens; 1 and R 2 each independently represents one or more of H and halogens, and R 3 and R 4 each independently represents one or more of H, C1-C12 alkyl groups and C1-C12 alkoxy groups.

[0008] By using a specific metal salt catalyst and cooperating with a dehydrating agent, the present invention enables the substrate to undergo an intramolecular Friedel-Crafts acylation reaction, realizing the efficient preparation of pyrroloazepine compounds. The method of the present invention is simple and convenient to operate, has a short reaction time, mild reaction conditions, the solvent can be recycled, the system has little impact on the environment, and has an extremely high reaction yield. DETAILED DESCRIPTION OF THE INVENTION

[0009] The endpoints and any values in the ranges disclosed herein are not limited to the exact ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0010] The present invention provides a method for preparing a pyrroloazepine compound, the method comprising: subjecting the compound shown in formula (1) to an intramolecular Friedel-Crafts acylation reaction in the presence of a metal salt catalyst and a dehydrating agent to obtain a pyrroloazepine compound shown in formula (2); wherein, the metal salt catalyst is selected from silver salts and / or copper salts, and the anion of the metal salt catalyst is selected from [SbX6] - 、[BX4] - 、[CX3COO] - and [CX3SO3] - one or more of them, wherein each X independently represents one or more selected from the halogens;

[0011]

[0012] wherein, R 1 and R 2 each independently represents one or more selected from H and halogens, R 3 and R 4 each independently represents one or more selected from H, C1-C12 alkyls and C1-C12 alkoxys.

[0013] According to the present invention, in order to obtain a better yield, the groups of the compound shown in formula (1) and the compound shown in formula (2) can be further selected. Preferably, R 1 and R 2 each independently represents one or more selected from H, F, Cl and Br, and R 3 and R 4 each independently represents one or more selected from H, C1-C6 alkyls and C1-C6 alkoxys.

[0014] More preferably, R 1 and R 2 each independently represents one or more selected from H and Br, and R 3 and R 4 each independently represents one or more selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentyloxy and n-hexyloxy.

[0015] According to the present invention, the metal salt catalyst can efficiently catalyze the intramolecular Friedel-Crafts acylation reaction, thereby improving the reaction efficiency and yield. To obtain better reaction results, preferably, the metal salt catalyst is selected from silver salts and / or copper salts, and the anion of the metal salt catalyst is selected from [SbF6] - , [BF4] - , [CF3COO] - and [CF3SO3] - or one or more of them.

[0016] More preferably, the metal salt catalyst is selected from one or more of silver hexafluoroantimonate, silver tetrafluoroborate, silver trifluoroacetate, silver trifluoromethanesulfonate, and copper trifluoromethanesulfonate, preferably one or more of silver hexafluoroantimonate, silver trifluoromethanesulfonate, and copper trifluoromethanesulfonate.

[0017] According to the present invention, in order to make the metal salt catalyst exert a more excellent catalytic effect, the dosage of the metal salt catalyst can be adjusted. Preferably, relative to 1 mmol of the compound shown in formula (1), the dosage of the metal salt catalyst is 0.005 - 0.5 mmol, preferably 0.01 - 0.1 mmol, for example, it can be values such as 0.01 mmol, 0.03 mmol, 0.05 mmol, 0.08 mmol, and 0.1 mmol and the ranges between any of these values.

[0018] According to the present invention, in order to promote the progress of the intramolecular Friedel-Crafts acylation reaction, the selection and dosage of the dehydrating agent can be adjusted. Preferably, the dehydrating agent is selected from one or more of phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and trifluoroacetic anhydride, preferably one or more of phosphorus pentoxide and / or trifluoroacetic anhydride.

[0019] Preferably, relative to 1 mmol of the compound shown in formula (1), the dosage of the dehydrating agent is 0.6 - 1.5 mmol, preferably 0.8 - 1.2 mmol, for example, it can be values such as 0.08 mmol, 1 mmol, 1.1 mmol, and 1.2 mmol and the ranges between any of these values.

[0020] According to the present invention, in order to enable the full contact of each material and provide a good reaction environment, the solvent for the intramolecular Friedel-Crafts acylation reaction and its dosage can be adjusted. Preferably, the solvent for the intramolecular Friedel-Crafts acylation reaction is selected from one or more of methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, and polyphosphoric acid, preferably methanesulfonic acid and / or trifluoromethanesulfonic acid.

[0021] Preferably, relative to 1 mmol of the compound shown in formula (1), the amount of the solvent for the intramolecular Friedel-Crafts acylation reaction is 0.1 - 3 mL, preferably 0.3 - 1 mL, and for example, it can be values such as 0.3 mL, 0.5 mL, 0.8 mL, and 1 mL and the ranges between any of these values.

[0022] According to the present invention, in order to further improve the reaction efficiency and yield, the reaction conditions of the intramolecular Friedel-Crafts acylation reaction can be adjusted. Preferably, the conditions of the intramolecular Friedel-Crafts acylation reaction include: the temperature is 60 - 120 °C, and the time is 0.3 - 3 h.

[0023] More preferably, the conditions of the intramolecular Friedel-Crafts acylation reaction include: the temperature is 70 - 100 °C (for example, it can be values such as 70 °C, 80 °C, 90 °C, and 100 °C and the ranges between any of these values), and the time is 0.5 - 2 h (for example, it can be values such as 0.5 h, 0.75 h, 1 h, 1.5 h, and 2 h and the ranges between any of these values).

[0024] According to the present invention, for the reaction to proceed more smoothly, specifically, the preparation method of the pyrroloazepine compounds can, for example, include: preparing a dispersion system A containing a metal salt catalyst and a dehydrating agent, adding the compound shown in formula (1) to the dispersion system A for the intramolecular Friedel-Crafts acylation reaction to obtain the pyrroloazepine compounds shown in formula (2).

[0025] Among them, the preparation process of the dispersion system A can, for example, include: adding a metal salt catalyst and a dehydrating agent to a solvent, heating (generally heating to the same temperature as the reaction temperature of the intramolecular Friedel-Crafts acylation reaction) and stirring (generally stirring for 0.5 - 2 h), and after the system becomes clear, the dispersion system A is obtained.

[0026] According to the present invention, after the intramolecular Friedel-Crafts acylation reaction is completed, the reaction solution can be post-treated. The post-treatment method can be selected within a relatively wide range. In order to obtain a product with higher purity and better state, preferably, the post-treatment method includes: subjecting the reaction solution to vacuum distillation (the solvent can be recovered for recycling), dissolving the obtained solid product with an alkali solution (such as saturated potassium hydroxide aqueous solution, saturated sodium hydroxide aqueous solution, etc.), extracting (such as extracting with ethyl acetate), washing (such as washing the organic phase with saturated brine), and drying (such as drying with desiccants such as anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.) to obtain the pyrroloazepine compounds.

[0027] By using a specific metal salt catalyst and cooperating with a dehydrating agent, the present invention enables the substrate to undergo an intramolecular Friedel-Crafts acylation reaction, realizing pyrroloazepine Efficient preparation of a class of compounds. The method of the present invention is simple and convenient to operate, has a short reaction time, mild reaction conditions, the solvent can be recycled, the system has little impact on the environment, and the reaction yield is as high as over 90%.

[0028] The present invention will be described in detail below through examples.

[0029] In the following examples, the devices used are all conventional experimental devices in the art, the experimental operations adopted are all conventional operations in the art, and the raw materials, reagents, etc. used can all be obtained through commercial purchase.

[0030] Example 1

[0031] This example is used to illustrate the preparation of 6,7-dihydropyrrolo[2,3-c]azepine -4,8(1H,5H)-dione, i.e., the compound shown in formula (2-1).

[0032]

[0033] 1.37 mmol of silver hexafluoroantimonate and 22 mmol of phosphorus pentoxide were added to 20 mL of methanesulfonic acid, the temperature was raised to 80 °C, and the mixture was stirred for 1 h until the system became clear. Then 27.5 mmol of the compound shown in formula (1-1) was added, and the reaction was carried out for 0.75 h. After the reaction was completed, it was cooled to room temperature. The reaction solution was distilled under reduced pressure to recover methanesulfonic acid (recovery rate about 80%). The obtained solid product was dissolved by slowly adding saturated potassium hydroxide aqueous solution, and then extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation, the pyrroloazepine class of compounds shown in formula (2-1) was obtained as a pale yellow solid with a yield of 95% and a purity of 99%.

[0034] Example 2

[0035] This example is used to illustrate the preparation of 6,7-dihydropyrrolo[2,3-c]azepine -4,8(1H,5H)-dione, i.e., the compound shown in formula (2-1).

[0036]

[0037] 0.8 mmol of silver hexafluoroantimonate and 22 mmol of phosphorus pentoxide were added to 15 mL of methanesulfonic acid. The temperature was raised to 100 °C and stirred for 1 h until the system became clear. Then 27.5 mmol of the compound shown in formula (1-1) was added and reacted for 0.75 h. After the reaction, it was cooled to room temperature. The reaction solution was distilled under reduced pressure to recover methanesulfonic acid (recovery rate about 80%). The obtained solid product was dissolved by slowly adding saturated potassium hydroxide aqueous solution, then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by evaporation to obtain the pyrroloazepine compounds shown in formula (2-1), which were light yellow solids, with a yield of 93% and a purity of 98%.

[0038] Example 3

[0039] This example is used to illustrate the preparation of 6,7-dihydropyrrolo[2,3-c]azepine -4,8(1H,5H)-dione, that is, the compound shown in formula (2-1).

[0040]

[0041] 0.8 mmol of silver trifluoromethanesulfonate and 22 mmol of phosphorus pentoxide were added to 15 mL of methanesulfonic acid. The temperature was raised to 90 °C and stirred for 1 h until the system became clear. Then 27.5 mmol of the compound shown in formula (1-1) was added and reacted for 0.5 h. After the reaction, it was cooled to room temperature. The reaction solution was distilled under reduced pressure to recover methanesulfonic acid (recovery rate about 80%). The obtained solid product was dissolved by slowly adding saturated potassium hydroxide aqueous solution, then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by evaporation to obtain the pyrroloazepine compounds shown in formula (2-1), which were light yellow solids, with a yield of 93% and a purity of 99%.

[0042] Example 4

[0043] This example is used to illustrate the preparation of 3-bromo-6,7-dihydropyrrolo[2,3-c]azepine -4,8(1H,5H)-dione, that is, the compound shown in formula (2-2).

[0044]

[0045] According to the method of Example 1, the difference is that the compound shown in formula (1-1) was replaced with the compound shown in formula (1-2), and finally the pyrroloazepine compounds shown in formula (2-2) were prepared, which were yellow solids, with a yield of 90% and a purity of 98%.

[0046] Example 5

[0047] This example is used to illustrate the preparation of 2-bromo-6,7-dihydropyrrolo[2,3-c]azepin -4,8(1H,5H)-dione, i.e., the compound shown in formula (2-3).

[0048]

[0049] According to the method of Example 1, except that the compound shown in formula (1-1) is replaced with the compound shown in formula (1-3), the pyrroloazepin compounds are finally obtained. They are white solids with a yield of 91% and a purity of 98%.

[0050] Example 6

[0051] This example is used to illustrate the preparation of 2,3-dibromo-6,7-dihydropyrrolo[2,3-c]azepin -4,8(1H,5H)-dione, i.e., the compound shown in formula (2-4).

[0052]

[0053] According to the method of Example 1, except that the compound shown in formula (1-1) is replaced with the compound shown in formula (1-4), the pyrroloazepin compounds are finally obtained. They are white solids with a yield of 94% and a purity of 97%.

[0054] Example 7

[0055] According to the method of Example 1, except that silver hexafluoroantimonate is replaced with an equimolar amount of silver trifluoroacetate, the pyrroloazepin compounds are finally obtained. They are light yellow solids with a yield of 91% and a purity of 95%.

[0056] Example 8

[0057] According to the method of Example 1, except that silver hexafluoroantimonate is replaced with an equimolar amount of copper trifluoroacetate, the pyrroloazepin compounds are finally obtained. They are light yellow solids with a yield of 90% and a purity of 95%.

[0058] Example 9

[0059] According to the method of Example 1, except that the amount of silver hexafluoroantimonate used is 0.15 mmol, the pyrroloazepin compounds are finally obtained. They are light yellow solids with a yield of 89% and a purity of 94%.

[0060] Example 10

[0061] According to the method of Example 1, except that the amount of silver hexafluoroantimonate used is 13 mmol, the pyrroloazepine compound shown in formula (2-1) is finally prepared. It is a pale yellow solid with a yield of 91% and a purity of 94%.

[0062] Comparative Example 1

[0063] This comparative example is used to illustrate the preparation of 6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione, that is, the compound shown in formula (2-1). -4,8(1H,5H)-dione, that is, the compound shown in formula (2-1).

[0064]

[0065] Add 20 mL of phosphorus oxychloride to a dry reactor, heat up to 100 °C, add 10 mmol of the compound shown in formula (1-1), and react for 2 h. After the reaction is completed, cool the reaction solution to 40 - 50 °C, and add it to a 50 mL mixture of crushed ice / water. While stirring, add 10 wt% aqueous sodium hydroxide solution to adjust the pH to neutral. Filter to remove insolubles, extract the aqueous phase with ethyl acetate, dry over anhydrous sodium sulfate, distill off ethyl acetate under reduced pressure, and purify the residue by recrystallization to obtain the pyrroloazepine compound shown in formula (2-1). It is a pale yellow solid with a yield of 57% and a purity of 85%.

[0066] Comparative Example 2

[0067]

[0068] According to the method of Comparative Example 1, except that the compound shown in formula (1-1) is replaced with the compound shown in formula (1-2), the pyrroloazepine compound shown in formula (2-2) is finally prepared. It is a yellow solid with a yield of 53% and a purity of 80%.

[0069] Comparative Example 3

[0070]

[0071] According to the method of Comparative Example 1, except that the compound shown in formula (1-1) is replaced with the compound shown in formula (1-3), the pyrroloazepine compound shown in formula (2-3) is finally prepared. It is a white solid with a yield of 53% and a purity of 82%.

[0072] Comparative Example 4

[0073]

[0074] According to the method of Comparative Example 1, except that the compound shown in formula (1-1) was replaced with the compound shown in formula (1-4), the pyrroloazepine compound shown in formula (2-4) was finally prepared. The compound was a white solid with a yield of 70% and a purity of 87%.

[0075] The characterization results of the pyrroloazepine compounds prepared in Examples 1-10 and Comparative Examples 1-4 are shown in Table 1.

[0076]

[0077]

[0078] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the technical concept scope of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.​

Claims

1. A method for preparing a pyrroloazepine compound, characterized in that The method includes: in the presence of a metal salt catalyst and a dehydrating agent, subjecting the compound shown in formula (1) to an intramolecular Friedel-Crafts acylation reaction to obtain the pyrroloazepine compound shown in formula (2); wherein, the metal salt catalyst is selected from silver salts and / or copper salts, and the anion of the metal salt catalyst is selected from [SbX6] , [BX4] - , [CX3COO] - , and [CX3SO3] - , and one or more of [CX3SO3] - , wherein each X is independently selected from one or more of the halogens; Among them, R 1 and R 2 each independently selected from one or more of H and halogen, R 3 and R 4 each independently selected from one or more of H, C1-C12 alkyl, and C1-C12 alkoxy.

2. The method according to claim 1, wherein, R 1 and R 2 each independently selected from one or more of H, F, Cl, and Br, R 3 and R 4 each independently selected from one or more of H, C1-C6 alkyl, and C1-C6 alkoxy; Preferably, R 1 and R 2 are each independently selected from H and Br, and R 3 and R 4 are each independently selected from one or more of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentyloxy and n-hexyloxy.

3. The method according to claim 1 or 2, wherein The metal salt catalyst is selected from silver salts and / or copper salts, and the anion of the metal salt catalyst is selected from [SbF6] - , [BF4] - , [CF3COO] - and [CF3SO3] - one or more of; Preferably, the metal salt catalyst is selected from one or more of silver hexafluoroantimonate, silver tetrafluoroborate, silver trifluoroacetate, silver trifluoromethanesulfonate, and copper trifluoromethanesulfonate, preferably one or more of silver hexafluoroantimonate, silver trifluoromethanesulfonate, and copper trifluoromethanesulfonate.

4. The method according to any one of claims 1 to 3, wherein, Relative to 1 mmol of the compound represented by formula (1), the amount of the metal salt catalyst used is 0.005 - 0.5 mmol, preferably 0.01 - 0.1 mmol.

5. The method according to any one of claims 1-4, wherein The dehydrating agent is selected from one or more of phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and trifluoroacetic anhydride, preferably one or more of phosphorus pentoxide and / or trifluoroacetic anhydride.

6. The method according to any one of claims 1-5, wherein Relative to 1 mmol of the compound represented by formula (1), the amount of the dehydrating agent used is 0.6 - 1.5 mmol, preferably 0.8 - 1.2 mmol.

7. The method according to any one of claims 1-6, wherein The solvent for the intramolecular Friedel-Crafts acylation reaction is selected from one or more of methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, and polyphosphoric acid, preferably methanesulfonic acid and / or trifluoromethanesulfonic acid.

8. The method according to any one of claims 1-7, wherein Relative to 1 mmol of the compound represented by formula (1), the amount of the solvent for the intramolecular Friedel-Crafts acylation reaction used is 0.1 - 3 mL, preferably 0.3 - 1 mL.

9. The method according to any one of claims 1-8, wherein The conditions for the intramolecular Friedel-Crafts acylation reaction include: a temperature of 60 - 120 °C and a time of 0.3 - 3 h.

10. The method according to claim 9, wherein, The conditions for the intramolecular Friedel-Crafts acylation reaction include: a temperature of 70 - 100 °C and a time of 0.5 - 2 h.

Images