6, 7-dihydrocyclopenta [b] pyridine-5-ketone as well as synthesis method and application thereof

Abstract

The invention discloses 6, 7-dihydrocyclopenta [b] pyridine-5-ketone and a synthesis method and application thereof.The method comprises the steps that a compound 1, namely 1, 3-cyclopentanedione, is added into an organic solvent I, ammonium acetate is added, the temperature is increased to 70-160 DEG C under inert gas protection, stirring reaction is conducted for 4-10 hours, after raw materials are consumed up, reaction liquid is subjected to first-time aftertreatment, and after the reaction liquid is subjected to second-time aftertreatment, a compound 2, namely 1, 3-cyclopentanedione is obtained; the compound 2 is 3-aminocyclopentyl-2-ketene; and adding the compound 2 obtained in the previous step, namely 3-aminocyclopentyl-2-ketene, into an organic solvent II, then adding p-methyl phenyl sulfonic acid hydrate, malonaldehyde and sulfate, heating to 60-150 DEG C under the protection of inert gas, stirring for 8-20 hours, and after the raw materials are completely consumed, carrying out secondary post-treatment on the reaction liquid to obtain a target compound 3, namely 6, 7-dimethoxy-2-(3-aminocyclopentyl-2-ketene). The invention relates to 2, 7-dihydrocyclopenta [b] pyridine-5-ketone.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, specifically to a 6,7-dihydrocyclopentano[b]pyridine-5-one, its synthesis method, and its uses. Background Technology

[0002] Compound 6,7-dihydrocyclopentano[b]pyridin-5-one is an important molecular building block. For example, it has been used in the synthesis of AhR inhibitors in Chinese patent publication CN114835687A; and in the synthesis of salt and crystal forms of Vanin enzyme inhibitors in Chinese patent publication CN116768909A. The salt of this inhibitor has high stability and good water solubility, which is beneficial for enhancing oral absorption and improving bioavailability. The crystal form of this inhibitor has high stability, good solubility, and low hygroscopicity, showing good drug development prospects. It has also been used in international patent application publication WO2023 / 040830 for AhR inhibitors with AhR inhibitory activity. Synthesis of inhibitors; used in the synthesis of PDE4 activators in international patent application publication number WO2019193342; used in the synthesis of SHP2 inhibitors in international patent application publication number WO2021 / 249057; used in the synthesis of MASP-2 inhibitors in international patent application publication number CN116514772A. These inhibitors can be used in the preparation of drugs for treating IgA nephropathy, TA-TMA, aHUS, lupus nephritis, and other diseases.

[0003] In existing technologies, 6,7-dihydrocyclopentenylpyridine is generally used as a starting material to synthesize the compound 6,7-dihydrocyclopentano[b]pyridin-5-one. However, this approach has several technical drawbacks. First, it suffers from poor selectivity, with byproducts generated during synthesis and low yields of the target product. Second, post-processing is complex, requiring column chromatography purification, which significantly increases separation costs during scale-up production. Therefore, based on the current technological status, it is necessary to develop a synthetic method for 6,7-dihydrocyclopentano[b]pyridin-5-one that offers mild reaction conditions, high selectivity, and high yield. Summary of the Invention

[0004] To solve the above-mentioned technical problems, this application provides a method for synthesizing 6,7-dihydrocyclopentano[b]pyridin-5-one, the method comprising:

[0005] b101, Compound 1, namely 1,3-cyclopentanedione, was added to organic solvent I, then ammonium acetate was added, and under inert gas protection, the temperature was raised to 70~160℃ and the reaction was stirred for 4~10 hours. After the raw materials were consumed, the reaction solution was subjected to the first post-treatment to obtain compound 2, namely 3-aminocyclopent-2-enone.

[0006] b102, compound 2, namely 3-aminocyclopentan-2-enone, obtained through the above steps, is added to organic solvent II, followed by p-methylphenylsulfonic acid hydrate, malondialdehyde, and sulfate. Under inert gas protection, the mixture is heated to 60-150°C and stirred for 8-20 hours. After the raw materials are consumed, the reaction solution undergoes a second post-treatment to obtain target compound 3, namely 6,7-dihydrocyclopentano[b]pyridin-5-one.

[0007] According to an embodiment of this application, in step b101, the organic solvent I is selected from one or more of ethanol, methanol, isopropanol, and propylene glycol.

[0008] According to an embodiment of this application, in step b101, at least one of the following conditions is satisfied:

[0009] The mass-to-volume ratio of compound 1, namely 1,3-cyclopentanedione, to organic solvent I is 1:1~5 (g / mL).

[0010] The molar ratio of compound 1, namely 1,3-cyclopentanedione, to ammonium acetate is 1:1~3.

[0011] According to an embodiment of this application, in step b101, the first post-processing includes:

[0012] After the raw materials are consumed, organic solvent III is added to the reaction solution, and the mixture is allowed to cool naturally to room temperature and stirred for 8 to 20 hours. The mixture is then filtered under inert gas protection.

[0013] Subsequently, the filter cake was washed with organic solvent IV. After washing, the inert gas protection was terminated, the solid was collected, and dried to obtain compound 2, namely 3-aminocyclopentan-2-enone.

[0014] According to an embodiment of this application, in the first post-processing process of step b101, at least one of the following conditions is satisfied:

[0015] The organic solvent III is selected from at least one of ethyl acetate, butyl acetate, and ethyl propionate;

[0016] The organic solvent IV is selected from at least one of petroleum ether, diethyl ether, and methyl tert-butyl ether.

[0017] According to one embodiment of this application, in step b102, the organic solvent II is selected from one or more of methanol, ethanol, isopropanol, n-butanol, and propylene glycol.

[0018] According to an embodiment of this application, in step b102, at least one of the following conditions is satisfied:

[0019] The mass-to-volume ratio of compound 2, namely 3-aminocyclopentan-2-enone, to organic solvent II is 1:5~40 (g / mL).

[0020] The molar ratio of compound 2, namely 3-aminocyclopent-2-enone, to malondialdehyde is 1:1~4;

[0021] The molar ratio of compound 2, namely 3-aminocyclopentan-2-enone, to p-methylphenylsulfonic acid hydrate is 1:0.1~0.8;

[0022] The molar ratio of compound 2, namely 3-aminocyclopentan-2-enone, to sulfate is 1:0.2~0.8.

[0023] According to an embodiment of this application, in step b102, the second post-processing includes:

[0024] After the raw materials are consumed, the reaction solution is filtered while hot, and the filtrate is concentrated into an emulsion.

[0025] Then add organic solvent V, add water, and stir for 20-40 minutes;

[0026] The pH of the mixture was adjusted to 7 with an alkaline aqueous solution, filtered, the filter cake was washed with organic solvent V, the filtrate was collected, separated, the aqueous phase was extracted with organic solvent V, the organic phases were combined, and the organic phases were dried and then evaporated to dryness.

[0027] Organic solvent VI was then added to the concentrate, stirred at room temperature for 8–20 hours, filtered, the filter cake was washed with organic solvent VI, the solid was collected, and dried to obtain target compound 3, namely 6,7-dihydrocyclopentano[b]pyridin-5-one.

[0028] According to an embodiment of this application, in the second post-processing process of step b102, at least one of the following conditions is met: the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, or potassium hydroxide solution.

[0029] The organic solvent V includes at least one of chloroform, trichloroethane, dichloromethane, dichloroethane, and dichloropropane;

[0030] The organic solvent VI is selected from at least one of petroleum ether, diethyl ether, and methyl tert-butyl ether.

[0031] According to another aspect of this application, this application provides a dihydrocyclopentano[b]pyridin-5-one, which is synthesized by any of the above-described synthetic methods.

[0032] According to another aspect of this application, this application provides the use of dihydrocyclopentano[b]pyridin-5-one synthesized by any of the above-described synthetic methods for the synthesis of inhibitors.

[0033] Beneficial effects

[0034] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0035] The method for preparing 6,7-dihydrocyclopentano[b]pyridin-5-one proposed in this application uses 1,3-cyclopentanedione as a starting material, and obtains the intermediate 3-aminocyclopentan-2-enone with high regioselectivity and yield under the action of ammonium acetate. This intermediate is then converted to the target compound 6,7-dihydrocyclopentano[b]pyridin-5-one via an acid-catalyzed condensation cyclization reaction. This synthetic method ultimately yields 6,7-dihydrocyclopentano[b]pyridin-5-one with a short procedure, simple operation, low cost, relatively mild reaction conditions, and ideal yield, providing a potential route for the large-scale production of 6,7-dihydrocyclopentano[b]pyridin-5-one. Attached Figure Description

[0036] Figure 1 A route diagram is shown for the synthesis of 6,7-dihydrocyclopentano[b]pyridin-5-one according to this application.

[0037] Figure 2 The 1H NMR spectrum of 3-aminocyclopentan-2-enone of this application is shown.

[0038] Figure 3 The 1H NMR spectrum of 6,7-dihydrocyclopentano[b]pyridin-5-one of this application is shown. Detailed Implementation

[0039] The following description is intended to disclose the present invention and enable those skilled in the art to implement it. The preferred embodiments described below are merely examples, and other obvious variations will occur to those skilled in the art. The basic principles of the invention defined in the following description can be applied to other embodiments, modifications, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the invention.

[0040] refer to Figure 1 A method for synthesizing 6,7-dihydrocyclopentano[b]pyridin-5-one according to a preferred embodiment of this application will be described in detail below. The compound 6,7-dihydrocyclopentano[b]pyridin-5-one is an important molecular building block that can be used in the synthesis of inhibitors.

[0041] The method for synthesizing the 6,7-dihydrocyclopentano[b]pyridin-5-one includes:

[0042] b101, Compound 1, namely 1,3-cyclopentanedione, was added to organic solvent I, followed by ammonium acetate. Under inert gas protection, the mixture was heated to 70-160°C and stirred for 4-10 hours. After the raw materials were consumed, the reaction solution underwent a first post-treatment to obtain Compound 2, namely 3-aminocyclopentane-2-enone.

[0043] It is worth mentioning that in step b101, the organic solvent I is selected from one or more of ethanol, methanol, isopropanol, and propylene glycol.

[0044] It is also worth mentioning that in step b101, the mass-to-volume ratio of 1,3-cyclopentanedione to organic solvent I is 1:1~5 (g / mL).

[0045] In addition, in step b101, the molar ratio of 1,3-cyclopentanedione to ammonium acetate is 1:1~3.

[0046] Preferably, the first post-processing step b101 includes:

[0047] After the raw materials are consumed, organic solvent III is added to the reaction solution, and the mixture is allowed to cool naturally to room temperature and stirred for 8 to 20 hours. The mixture is then filtered under inert gas protection.

[0048] Subsequently, the filter cake was washed with organic solvent IV. After washing, the inert gas protection was terminated, the solid was collected, and dried to obtain 3-aminocyclopentan-2-enone.

[0049] Preferably, in the first post-treatment process of step b101, the organic solvent III is selected from at least one of ethyl acetate, butyl acetate, and ethyl propionate.

[0050] Preferably, in the first post-processing step b101, the organic solvent IV is selected from at least one of petroleum ether, diethyl ether, and methyl tert-butyl ether.

[0051] Furthermore, the method for synthesizing the 6,7-dihydrocyclopentano[b]pyridin-5-one includes:

[0052] b102, the 3-aminocyclopentan-2-enone obtained through the above steps is added to organic solvent II, followed by p-methylphenylsulfonic acid hydrate, malondialdehyde and sulfate, and under inert gas protection, the temperature is raised to 60~150℃ and stirred for 8~20 hours. After the raw materials are consumed, the reaction solution is post-treated a second time to obtain the target compound 3:6,7-dihydrocyclopentano[b]pyridin-5-one.

[0053] Preferably, in step b102, the sulfate is selected from at least one of magnesium sulfate and sodium sulfate.

[0054] Preferably, in step b102, the organic solvent II is selected from one or more of methanol, ethanol, isopropanol, n-butanol, and propylene glycol.

[0055] Preferably, in step b102, the mass-to-volume ratio (g / mL) of 3-aminocyclopentan-2-enone to organic solvent II is 1:5~40.

[0056] Preferably, in step b102, the molar ratio of 3-aminocyclopentan-2-enone to malondialdehyde is 1:1~4;

[0057] Preferably, in step b102, the molar ratio of 3-aminocyclopentan-2-enone to p-methylphenylsulfonic acid hydrate is 1:0.1~0.8;

[0058] Preferably, in step b102, the molar ratio of 3-aminocyclopentan-2-enone to sulfate is 1:0.2~0.8.

[0059] Preferably, in step b102, the second post-processing procedure includes:

[0060] After the raw materials are consumed, the reaction solution is filtered while hot, and the filtrate is concentrated into an emulsion.

[0061] Then add organic solvent V, add water, and stir for 20-40 minutes;

[0062] The pH of the mixture was adjusted to 7 with an alkaline aqueous solution, filtered, the filter cake was washed with organic solvent V, the filtrate was collected, separated, the aqueous phase was extracted with organic solvent V, the organic phases were combined, and the organic phases were dried and then evaporated to dryness.

[0063] Organic solvent VI was then added to the concentrate, stirred at room temperature for 8–20 hours, filtered, the filter cake was washed with organic solvent VI, the solid was collected, and dried to obtain target compound 3, namely 6,7-dihydrocyclopentano[b]pyridin-5-one.

[0064] Preferably, in the second post-processing step b102, the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, or potassium hydroxide solution.

[0065] Preferably, in the second post-processing step b102, the organic solvent V includes at least one of chloroform, trichloroethane, dichloromethane, and dichloropropane.

[0066] Also preferably, in the second post-processing step b102, the organic solvent VI is selected from at least one of petroleum ether, diethyl ether, and methyl tert-butyl ether.

[0067] Example 1

[0068] In this embodiment, the compound 6,7-dihydrocyclopentano[b]pyridin-5-one was synthesized using the following steps:

[0069] Step (1): Compound 1, 1,3-cyclopentanedione (6.00 kg, 61.16 mol, 1.00 eq) was added to ethanol (9.0 L), followed by ammonium acetate (5.66 kg, 73.39 mol, 1.20 eq). Under nitrogen protection, the mixture was heated to 90 °C and stirred for 5 hours. After the raw materials were consumed, ethyl acetate (18.0 L) was added to the reaction mixture, and the mixture was allowed to cool naturally to room temperature and stirred for 12 hours. The mixture was filtered under nitrogen protection, and the filter cake was washed with petroleum ether (5.0 L). After washing, the nitrogen protection was stopped, the solid was collected, and dried to obtain compound 2, 3-aminocyclopentane-2-enone (5.89 kg, 98% purity, 97% yield).

[0070] The proton NMR spectrum of the obtained compound 2 is as follows: Figure 2 As shown, the characterization data is as follows:

[0071] 1 H NMR (400 MHz, dmso) δ 7.20 (d, J = 80.2 Hz, 2H), 4.76 (s, 1H), 2.46 – 2.36 (m, 2H), 2.16 – 2.06 (m, 2H).

[0072] Step (2): Compound 2 (5.00 kg, 51.48 mol, 1.00 eq) was added to ethanol (50.0 L), followed by p-methylphenylsulfonic acid hydrate (3.92 kg, 20.59 mol, 0.40 eq), malondialdehyde (4.45 kg, 61.78 mol, 1.20 eq), and magnesium sulfate (2.48 kg, 20.59 mol, 0.40 eq). Under nitrogen protection, the mixture was heated to 85 °C and stirred for 10 hours. After the raw materials were consumed, the reaction solution was filtered while hot, and the filtrate was concentrated to an emulsion. Dichloromethane (8.0 L) and water (5.0 L) were added, and the mixture was stirred for 30 minutes. The pH of the mixture was adjusted to 7 with an alkaline aqueous solution, filtered, and the filter cake was washed with dichloromethane (3.0 L). The filtrate was collected. The aqueous phase was extracted with dichloromethane (5.0 L), and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate and then evaporated to dryness. Petroleum ether (20.0 L) was added to the concentrate, and the mixture was stirred at room temperature for 12 hours. The mixture was filtered, and the filter cake was washed with petroleum ether (5.0 L). The solid was collected and dried to obtain the target compound 3, namely 6,7-dihydrocyclopentano[b]pyridin-5-one (weight 6.70 kg, purity 99%, yield 97%).

[0073] The 1H NMR spectrum of the obtained compound 4 (6,7-dihydrocyclopentano[b]pyridin-5-one) is as follows: Figure 3 As shown, the characterization data is as follows:

[0074] 1 H NMR (400 MHz, cdcl3) δ 8.80 (dd, J = 4.8, 1.6 Hz, 1H), 8.02 (dd, J= 7.7, 1.6 Hz, 1H), 7.33 (dd, J = 7.7, 4.8 Hz, 1H), 3.33 – 3.22 (m, 2H), 2.85– 2.70 (m, 2H).

[0075] Example 2

[0076] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that malondialdehyde (4.45 kg, 61.78 mol, 1.20 eq) in step (2) was replaced with malondialdehyde (3.71 kg, 51.48 mol, 1.00 eq), and the yield of compound 3 was 93%.

[0077] Example 3

[0078] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that malondialdehyde (4.45 kg, 61.78 mol, 1.20 eq) in step (2) was replaced with malondialdehyde (7.42 kg, 102.97 mol, 2.00 eq), and the yield of compound 3 was 97%.

[0079] Example 4

[0080] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that malondialdehyde (4.45 kg, 61.78 mol, 1.20 eq) in step (2) was replaced with malondialdehyde (14.84 kg, 205.94 mol, 4.00 eq), and the yield of compound 3 was 92%.

[0081] Example 5

[0082] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that p-methylphenylsulfonic acid hydrate (3.92 kg, 20.59 mol, 0.40 eq) in step (2) was replaced with p-methylphenylsulfonic acid hydrate (979.30 g, 5.15 mol, 0.10 eq). The yield of compound 3 was 89%.

[0083] Example 6

[0084] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that p-methylphenylsulfonic acid hydrate (3.92 kg, 20.59 mol, 0.40 eq) in step (2) was replaced with p-methylphenylsulfonic acid hydrate (5.88 kg, 30.89 mol, 0.60 eq), and the yield of compound 3 was 97%.

[0085] Example 7

[0086] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that p-methylphenylsulfonic acid hydrate (3.92 kg, 20.59 mol, 0.40 eq) in step (2) was replaced with p-methylphenylsulfonic acid hydrate (7.83 kg, 41.19 mol, 0.80 eq), and the yield of compound 3 was 97%.

[0087] Example 8

[0088] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that magnesium sulfate (2.48 kg, 20.59 mol, 0.40 eq) in step (2) was replaced with magnesium sulfate (1.24 kg, 10.30 mol, 0.20 eq), and the yield of compound 3 was 92%.

[0089] Example 9

[0090] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that magnesium sulfate (2.48 kg, 20.59 mol, 0.40 eq) in step (2) was replaced with magnesium sulfate (3.72 kg, 30.89 mol, 0.60 eq), and the yield of compound 3 was 97%.

[0091] Example 10

[0092] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that magnesium sulfate (2.48 kg, 20.59 mol, 0.40 eq) in step (2) was replaced with magnesium sulfate (4.96 kg, 41.19 mol, 0.80 eq), and the yield of compound 3 was 96%.

[0093] Example 11

[0094] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that magnesium sulfate (2.48 kg, 20.59 mol, 0.40 eq) in step (2) was replaced with sodium sulfate (4.39 kg, 30.89 mol, 0.60 eq), and the yield of compound 3 was 96%.

[0095] Example 12

[0096] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that 85°C in step (2) was replaced with 60°C, and the yield of compound 3 was 89%.

[0097] Example 13

[0098] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that 85°C in step (2) was replaced with 110°C, and the yield of compound 3 was 97%.

[0099] Example 14

[0100] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that the 10 hours in step (2) were replaced with 8 hours, and the yield of compound 3 was 91%.

[0101] Example 15

[0102] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that the 10 hours in step (2) were replaced with 20 hours, and the yield of compound 3 was 97%.

[0103] Example 16

[0104] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that ethanol in step (2) was replaced with isopropanol, and the yield of compound 3 was 95%.

[0105] Example 17

[0106] Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that ethanol in step (2) was replaced with n-butanol, and the yield of compound 3 was 90%.

[0107] p-Methylphenylsulfonic acid hydrate (dosage) Malondialdehyde (dosage) Types and dosages of sulfates Solvent II Step (2) Reaction temperature (°C) Step (2) Reaction time (h) 6,7-Dihydrocyclopentano[b]pyridin-5-one (yield %) Example 1 3.92 kg, 20.59 mol, 0.40 eq 4.45 kg, 61.78 mol, 1.20 eq Magnesium sulfate (2.48 kg, 20.59 mol, 0.40 eq) ethanol 85 10 97 Example 2 Same as Example 1 3.71 kg, 51.48 mol, 1.00 eq Same as Example 1 ethanol 85 10 93 Example 3 Same as Example 1 7.42 kg, 102.97 mol, 2.00 eq Same as Example 1 ethanol 85 10 97 Example 4 Same as Example 1 14.84 kg, 205.94 mol, 4.00 eq Same as Example 1 ethanol 85 10 92 Example 5 979.30g, 5.15mol, 0.10eq Same as Example 1 Same as Example 1 ethanol 85 10 89 Example 6 5.88 kg, 30.89 mol, 0.60 eq Same as Example 1 Same as Example 1 ethanol 85 10 97 Example 7 7.83 kg, 41.19 mol, 0.80 eq Same as Example 1 Same as Example 1 ethanol 85 10 97 Example 8 Same as Example 1 Same as Example 1 Magnesium sulfate (1.24 kg, 10.30 mol, 0.20 eq) ethanol 85 10 92 Example 9 Same as Example 1 Same as Example 1 Magnesium sulfate (3.72 kg, 30.89 mol, 0.60 eq) ethanol 85 10 97 Example 10 Same as Example 1 Same as Example 1 Magnesium sulfate (4.96 kg, 41.19 mol, 0.80 eq) ethanol 85 10 96 Example 11 Same as Example 1 Same as Example 1 Sodium sulfate (4.39 kg, 30.89 mol, 0.60 eq) ethanol 85 10 96 Example 12 Same as Example 1 Same as Example 1 Same as Example 1 ethanol 60 10 89 Example 13 Same as Example 1 Same as Example 1 Same as Example 1 ethanol 110 10 97 Example 14 Same as Example 1 Same as Example 1 Same as Example 1 ethanol 85 8 91 Example 15 Same as Example 1 Same as Example 1 Same as Example 1 ethanol 85 20 97 Example 16 Same as Example 1 Same as Example 1 Same as Example 1 Isopropanol 85 10 95 Example 17 Same as Example 1 Same as Example 1 Same as Example 1 n-Butanol 85 10 90 Combining the table above and Examples 1-4, it can be seen that in step (2), when the molar ratio of compound 2 to malondialdehyde is 1.0:(1.0~4.0), the yield of compound 3 is relatively high. Among them, the product yields when the molar ratio of compound 2 to malondialdehyde is 1.0:1.2 and 1.0:2.0 are basically the same, and the reaction effect is better.

[0108] As can be seen from Examples 1 and 5-7, in step (2), when the molar ratio of compound 2 to p-methylphenylsulfonic acid hydrate is 1.0:(0.1~0.8), the yield of compound 3 is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 2 to p-methylphenylsulfonic acid hydrate is 1.0:0.4 and 1.0:0.6, and the reaction effect is better.

[0109] Based on the table above and Examples 1 and 8-10, it can be seen that in step (2), when the molar ratio of compound 2 to magnesium sulfate is 1.0:(0.2~0.8), the yield of compound 3 is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 2 to magnesium sulfate is 1.0:0.4 and 1.0:0.6, and the reaction effect is better.

[0110] Combining the table above with Examples 1 and 11, it can be seen that in step (2), magnesium sulfate and sodium sulfate were used for the reaction, and the reaction proceeded smoothly. The yield of compound 3 was high, both exceeding 90%. Among them, the reaction yield was even higher when magnesium sulfate was used for the reaction.

[0111] Based on the table above and Examples 1 and 12-13, it can be seen that in step (2), the reaction effect is optimal when the reaction temperature is 85°C.

[0112] Combining the table above with Examples 1 and 14-15, it can be seen that in step (2), the reaction effect is optimal when the reaction time is 10 hours.

[0113] Combining the table above with Examples 1 and 16-17, it can be seen that in step (2), ethanol, isopropanol and n-butanol were used as solvents for the reaction, and the reaction proceeded smoothly. The yield of compound 3 was high in all cases. Among them, the reaction yield was the highest when ethanol was used as the solvent.

[0114] The above description represents a preferred embodiment of the present invention, but the present invention should not be limited to the content disclosed in this embodiment. Therefore, any equivalent or modified versions made without departing from the spirit of the present invention fall within the scope of protection of the present invention.

[0115] Those skilled in the art should understand that the embodiments of the present invention described above and shown in the accompanying drawings are merely examples and do not limit the invention. The advantages of the present invention have been fully and effectively realized. The functional and structural principles of the present invention have been demonstrated and explained in the embodiments; any variations or modifications can be made to the implementation of the present invention without departing from these principles.

Claims

1. A method for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-ones, characterized in that, The method comprises: b101, 1, 3-cyclopentanone is added to an organic solvent I, ammonium acetate is further added, and the temperature is raised to 70-160 DEG C under inert gas protection, and the reaction is stirred for 4-10 hours. After the raw material is consumed, the reaction liquid is subjected to first post-treatment to obtain 3-aminocyclopent-2-enone; b102, 3-aminocyclopent-2-enone obtained by the above step is added to an organic solvent II, p-methyl phenyl sulfonic acid hydrate, malondialdehyde and sulfate are further added, and the temperature is raised to 60-150 DEG C under inert gas protection, and the reaction is stirred for 8-20 hours. After the raw material is consumed, the reaction liquid is subjected to second post-treatment to obtain 6, 7-dihydrocyclopentano [b] pyridine-5-ketone.

2. The process for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-ones according to claim 1, characterized in that, In step b101, the organic solvent I is selected from one or more of ethanol, methanol, isopropanol and propylene glycol.

3. The process for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-ones according to claim 1, characterized in that, In step b101, at least one of the following conditions is met: 1, 3-cyclopentanone and the organic solvent I have a mass volume ratio g / mL of 1:1-5; The molar ratio of 1, 3-cyclopentanone to ammonium acetate is 1:1-3.

4. The synthesis method of 6, 7-dihydrocyclopentano [b] pyridine-5-ketone according to claim 1, characterized in that, In step b101, the first post-treatment process comprises: After the raw material is consumed, an organic solvent III is added to the reaction liquid, and the temperature is naturally lowered to room temperature and stirred for 8-20 hours under inert gas protection, and then filtered; Subsequently, the filter cake is eluted with an organic solvent IV, the inert gas protection is ended after the elution is completed, and the solid is collected and dried to obtain compound 2, i.e. 3-aminocyclopent-2-enone.

5. The process for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-ones according to claim 4, characterized in that, In the first post-treatment process of step b101, at least one of the following conditions is met: The organic solvent III is selected from at least one of ethyl acetate, butyl acetate and ethyl propionate; The organic solvent IV is selected from at least one of petroleum ether, diethyl ether and methyl tert-butyl ether.

6. The process for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-ones according to claim 1, characterized in that, In step b102, at least one of the following conditions is met: The organic solvent II is selected from one or more of methanol, ethanol, isopropanol, n-butanol and propylene glycol; or The sulfate is selected from at least one of magnesium sulfate and sodium sulfate.

7. The process for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-one according to claim 1, characterized in that, In step b102, at least one of the following conditions is met: The mass volume ratio g / mL of 3-aminocyclopent-2-enone to the organic solvent II is 1:5-40; The molar ratio of 3-aminocyclopent-2-enone to malondialdehyde is 1:1-4; The molar ratio of 3-aminocyclopent-2-enone to p-methyl phenyl sulfonic acid hydrate is 1:0.1-0.8; The molar ratio of 3-aminocyclopent-2-enone to sulfate is 1:0.2-0.

8.

8. The process for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-ones according to claim 1, characterized in that, In step b102, the second post-treatment process comprises: After the raw material is consumed, the reaction liquid is filtered while hot, and the filtrate is concentrated to a milky state; Subsequently, an organic solvent V is added, water is added, and the mixture is stirred for 20-40 minutes; Then, an alkaline aqueous solution is used to adjust the pH of the mixture to 7, and the mixture is filtered, the filter cake is eluted with the organic solvent V, the filtrate is collected, the mixture is separated, the aqueous phase is extracted with the organic solvent V, the organic phases are combined, the organic phase is dried, and the mixture is rotary evaporated; Subsequently, the concentrate is added with an organic solvent VI, stirred at room temperature for 8-20 hours, filtered, the filter cake is rinsed with the organic solvent VI, the solid is collected and dried to obtain the target compound 3, i.e. 6,7-dihydrocyclopenta[b]pyridin-5-one.

9. The process for the synthesis of 6,7-dihydrocyclopenta[b]pyridin-5-ones according to claim 8, characterized in that, In the second post-treatment process of step b102, at least one of the following conditions is met: The basic aqueous solution is selected from one or more of sodium bicarbonate solution or sodium carbonate solution or potassium carbonate solution or sodium hydroxide solution or potassium hydroxide solution; The organic solvent V includes at least one of chloroform, trichloroethane, dichloromethane, dichloroethane, dichloropropane; The organic solvent VI is selected from at least one of petroleum ether, diethyl ether, methyl tert-butyl ether.

10. Use of dihydrocyclopentano[b]pyridin-5-one synthesized by the synthetic method of any one of the above 1-9, characterized in that, It is used for the synthesis of inhibitors.

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