Synthesis method of compound 7-bromo-3, 4-dihydroquinoline-2 (1H)-ketone and 7-bromo-3, 4-dihydroquinoline-2 (1H)-ketone

Abstract

The invention provides a synthesis method of 7-bromo-3, 4-dihydroquinoline-2 (1H)-ketone and the 7-bromo-3, 4-dihydroquinoline-2 (1H)-ketone, and the method specifically comprises the following steps: taking a compound 2-amino-4-bromobenzaldehyde as a raw material, and reacting with isopropyl malonate under a formic acid-triethylamine system to obtain a target compound 7-bromo-3, 4-dihydroquinoline-2 (1H)-ketone. According to the synthetic method, the compound 2-amino-4-bromobenzaldehyde is converted into the compound 7-bromo-3, 4-dihydroquinoline-2 (1H)-ketone through one-step reaction, the reaction condition is mild, aftertreatment and purification are simple, and manufacturability amplification can be achieved; finally, the compound 7-bromo-3, 4-dihydroquinoline-2 (1H)-ketone is prepared through short steps, simple and convenient operation, low cost and relatively mild reaction conditions.

Description

Technical Field

[0001] The embodiments of the present application belong to the technical field of chemical synthesis, and in particular, relate to a method for synthesizing the compound 7-bromo-3,4-dihydroquinoline-2(1H)-one. Background Art

[0002] The compound 7-bromo-3,4-dihydroquinolin-2(1H)-one is an important molecular building block. As a key intermediate, for example, in patent WO2021 / 151062, it is used for the synthesis of novel heterocyclic compounds that can inhibit aldehyde dehydrogenase or be used to treat various cancers, cancer metastasis, type 2 diabetes, pulmonary arterial hypertension (PAH) or neointimal hyperplasia (NIH); in patent WO2023 / 122140, it is used for the synthesis of PARP1 inhibitors that can be used to inhibit PARP1 or treat diseases related to PARP1; in patent WO2018 / 23434 5, it is used for the synthesis of IRAK4 regulators; in patent CN114436955A, it is used for the synthesis of tetrahydroquinoline and benzomorpholine derivatives, which have RORγt agonist or partial agonist activity and can be used to prepare drugs for preventing or treating diseases related to RORγt or Th17 cell differentiation (including viral infection, tumor or cancer and immunodeficiency disorder, etc.); in patent WO2017 / 024406, it is used for the synthesis of N-substituted bicyclic lactams, which can be used to treat or prevent proliferative diseases, autoimmune diseases, inflammatory diseases, skin diseases and tumors, etc. Therefore, it is of great significance to study the synthesis method of compound 7-bromo-3,4-dihydroquinoline-2(1H)-one.

[0003] In the prior art, the conventional synthetic route of the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one is to use 6-bromoindanone as the starting material and to prepare it through different pathways, which has the disadvantages of cumbersome reaction steps, complicated operation, high safety risks, and unsuitability for process scale-up. Summary of the invention

[0004] In order to solve or alleviate the problems in the prior art. Therefore, the present application proposes a method for synthesizing the compound 7-bromo-3,4-dihydroquinoline-2(1H)-one, which has the advantages of low cost, short steps and easy operation, relatively mild reaction conditions, low safety hazards and ideal yield. The synthesis method uses 2-amino-4-bromobenzaldehyde as a raw material, reacts with cycloisopropyl malonate in a formic acid-triethylamine system to obtain the target compound 7-bromo-3,4-dihydroquinoline-2(1H)-one, and the synthesis route is as follows:

[0005]

[0006] As a preferred embodiment of the present application, the synthesis method comprises the following steps:

[0007] Step 1: adding formic acid dropwise to triethylamine at a first temperature, stirring at a second temperature for 10-30 minutes after the addition is complete, then adding organic solvent I, and then adding the compound 2-amino-4-bromobenzaldehyde and cycloisopropyl malonate in sequence, heating the mixture to a third temperature, and stirring for 3-5 days until the reaction is complete;

[0008] Step 2: Post-treat the reaction solution to obtain the target compound 7-bromo-3,4-dihydroquinolin-2(1H)-one.

[0009] As a preferred embodiment of the present application, the first temperature is -5°C-5°C; the second temperature is 15°C-40°C; and the third temperature is 80°C-200°C.

[0010] As a preferred embodiment of the present application, the organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and N-methylpyrrolidone.

[0011] As a preferred embodiment of the present application, the mass volume ratio of the compound 1 to the organic solvent I is 1:5-40; or, the molar ratio of the compound 1 to cycloisopropyl malonate is 1:1-3.

[0012] As a preferred embodiment of the present application, in step 2, the post-treatment of the reaction solution includes: cooling the reaction solution and adding it to water, a solid precipitates, filtering, rinsing the filter cake with water, collecting the filter cake, drying to obtain a solid, and purifying the solid to obtain the target compound 7-bromo-3,4-dihydroquinolin-2(1H)-one.

[0013] As a preferred embodiment of the present application, the method for purifying the solid is one or more of slurrying, column chromatography, recrystallization or distillation.

[0014] Compared with the prior art, the present application provides a method for synthesizing 7-bromo-3,4-dihydroquinolin-2(1H)-one, using compound 2-amino-4-bromobenzaldehyde as a raw material, reacting with cycloisopropyl malonate in a formic acid-triethylamine system to obtain the target compound 7-bromo-3,4-dihydroquinolin-2(1H)-one. The synthesis method realizes the one-step conversion of compound 2-amino-4-bromobenzaldehyde into compound 7-bromo-3,4-dihydroquinolin-2(1H)-one, and the reaction conditions are mild, post-treatment and purification are simple, and process amplification can be achieved; finally, compound 7-bromo-3,4-dihydroquinolin-2(1H)-one is obtained with short steps, simple operation, low cost, and relatively mild reaction conditions.

[0015] In a second aspect, the present application further provides a compound 7-bromo-3,4-dihydroquinolin-2(1H)-one, characterized in that it is prepared by the method described in the first aspect.

[0016] Compared with the prior art, the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one provided in the present application is an important molecular building block and is considered to be an important organic synthesis intermediate. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The drawings described herein are used to provide a further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute an improper limitation on the present application. Some specific embodiments of the present application will be described in detail in an illustrative and non-restrictive manner with reference to the drawings. The same reference numerals in the drawings indicate the same or similar components or parts. It should be understood by those skilled in the art that these drawings are not necessarily drawn to scale. In the drawings:

[0018] Figure 1 This is the nuclear magnetic hydrogen spectrum of 7-bromo-3,4-dihydroquinolin-2(1H)-one prepared in the present application. DETAILED DESCRIPTION

[0019] In order to enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only embodiments of a part of the present application, not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work should fall within the scope of protection of the present application.

[0020] 7-bromo-3,4-dihydroquinolin-2(1H)-one was synthesized by the following example. Compound 1 (2-amino-4-bromobenzaldehyde) was used as a raw material and reacted with cycloisopropyl malonate in a formic acid-triethylamine system to obtain the target compound 2 (7-bromo-3,4-dihydroquinolin-2(1H)-one). The synthesis route is as follows:

[0021]

[0022] The technical solution of the present invention is further explained below by way of embodiments.

[0023] In this example, the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one was synthesized by the following steps:

[0024] (1) Formic acid (55.22 g, 1.20 mol, 1.20 eq) was slowly added dropwise to triethylamine (242.82 g, 2.40 mol, 2.40 eq) at 0°C. After the addition was complete, the mixture was stirred at room temperature for 15 minutes. N,N-dimethylformamide (2.0 L) was then added, followed by the compound 2-amino-4-bromobenzaldehyde (200.00 g, 999.83 mmol, 1.00 eq) and cycloisopropyl malonate (144.10 g, 999.83 mmol, 1.00 eq). The mixture was heated to 100°C and stirred for 3 days.

[0025] (2) After the reaction is complete, the reaction solution is cooled and added to water (6.0 L), and solids are precipitated. Filter, rinse the filter cake with water (400 mL), collect the filter cake, and dry to obtain a light yellow solid. The solid is stirred and slurried with a mixed organic solvent (300 mL of petroleum ether and 60 mL of ethyl acetate) at room temperature for 1 hour. Filter, collect the filter cake, and dry to obtain the target compound 2, i.e., 7-bromo-3,4-dihydroquinolin-2(1H)-one (weight 219.10 g, purity 97%, yield 94%).

[0026] The H NMR spectrum of the obtained compound 2 (7-bromo-3,4-dihydroquinolin-2(1H)-one) is as follows: Figure 1 The characterization data are as follows:

[0027] 1 H NMR (400 MHz, CDCl 3 )δ8.22(s,1H),7.11(dd,J=8.0,1.8Hz,1H),7.03(d,J=8.0Hz,1H),6.94(d,J=1.8Hz,1H),2.94(dd,J=14.9,7.8Hz,2H),2.64(dd,J=8.4,6.7Hz,2H).

[0028] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for synthesizing a compound 7-bromo-3,4-dihydroquinolin-2(1H)-one, characterized in that: The synthesis method uses 2-amino-4-bromobenzaldehyde as a raw material, and reacts with cycloisopropyl malonate in a formic acid-triethylamine system to obtain the target compound 7-bromo-3,4-dihydroquinolin-2(1H)-one. The synthesis route is as follows:

2. The method for synthesizing the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one according to claim 1, characterized in that: The synthesis method comprises the following steps: Step 1: adding formic acid dropwise to triethylamine at a first temperature, stirring at a second temperature for 10-30 minutes after the addition is complete, then adding organic solvent I, and then adding the compound 2-amino-4-bromobenzaldehyde and cycloisopropyl malonate in sequence, heating the mixture to a third temperature, and stirring for 3-5 days until the reaction is complete; Step 2: Post-treat the reaction solution to obtain the target compound 7-bromo-3,4-dihydroquinolin-2(1H)-one.

3. The method for synthesizing the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one according to claim 1, characterized in that: The first temperature is -5°C-5°C; the second temperature is 15°C-40°C; and the third temperature is 80°C-200°C.

4. The method for synthesizing the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one according to claim 2, characterized in that: The organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and N-methylpyrrolidone.

5. The method for synthesizing the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one according to claim 2, characterized in that: The mass volume ratio of the compound 1 to the organic solvent I is 1:5-40; or, the molar ratio of the compound 1 to cycloisopropyl malonate is 1:1-3.

6. The method for synthesizing the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one according to claim 2, characterized in that: In step 2, the post-treatment of the reaction solution includes: cooling the reaction solution and adding it to water, a solid precipitates, filtering, rinsing the filter cake with water, collecting the filter cake, drying to obtain a solid, and purifying the solid to obtain the target compound 7-bromo-3,4-dihydroquinolin-2(1H)-one.

7. The method for synthesizing the compound 7-bromo-3,4-dihydroquinolin-2(1H)-one according to claim 6, characterized in that: The solid is purified by one or more of slurrying, column chromatography, recrystallization or distillation.

8. A compound 7-bromo-3,4-dihydroquinolin-2(1H)-one, characterized in that Prepared by the method according to any one of claims 1 to 7.

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