CDK drug intermediate 3-(3-bromophenyl) piperidine-2, 6-diketone as well as synthesis method and application thereof

Abstract

The invention relates to a CDK drug intermediate 3-(3-bromophenyl) piperidine-2, 6-diketone as well as a synthesis method and application thereof, and belongs to the technical field of medicine synthesis. The synthetic method of the CDK drug intermediate 3-(3-bromophenyl) piperidine-2, 6-diketone provided by the invention comprises the following steps: (1) mixing 3-bromobenzyl cyanide and acrylonitrile, slowly dropwise adding benzyltrimethylammonium hydroxide, and refluxing to obtain an intermediate 2-(3-bromophenyl) glutaronitrile; and (2) dissolving the intermediate 2-(3-bromophenyl) glutaronitrile in an acetic acid-concentrated sulfuric acid solution, and carrying out hydrolysis cyclization to obtain the target compound 3-(3-bromophenyl) piperidine-2, 6-diketone. According to the invention, 3-bromophenylacetonitrile is used as an initial raw material, and a target product is prepared only through two simple steps. The method has the advantages of easily available raw materials, short reaction route, simple post-treatment and the like, and is suitable for industrial preparation and production.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical synthesis, and particularly relates to a CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione, its synthesis method and application. Background Art

[0002] CDK (Cyclin-dependent kinase), as a key serine / threonine kinase family, precisely regulates the cell cycle process and transcriptional activities. In the field of anti-tumor, CDK drug molecules, as an important treatment means, effectively block the abnormal proliferation of tumor cells by inhibiting the activities of multiple CDKs. 3-(3-bromophenyl)piperidine-2,6-dione is a key intermediate of CDK drugs and has a wide range of applications in medicine. Therefore, developing a simple synthesis method for 3-(3-bromophenyl)piperidine-2,6-dione has high application value.

[0003]

[0004] The currently reported synthesis methods for 3-(3-bromophenyl)piperidine-2,6-dione are as follows:

[0005] (1) The synthesis methods of the prior art US 2023 / 0135894 Al and WO 2023 / 220640 Al start from methyl 3-bromophenylacetate and are prepared through 5 steps including Michael addition, carboxylic acid hydrolysis, lactonization, substitution ring-opening and cyclization. The total yield of the 5 steps is 23%, and the synthesis route is as follows:

[0006]

[0007] This synthesis route is relatively long and the preparation is complex, which is not suitable for industrial scale production.

[0008] (2) The prior art CN 116947840A uses 3-bromobenzyl cyanide as the starting material, reacts with di-tert-butyl dicarbonate under the conditions of LDA (lithium diisopropylamide) and low temperature to obtain tert-butyl 2-(3-bromophenyl)-2-cyanoacetate, and then obtains the target product through a nucleophilic substitution reaction with methyl 3-bromopropionate and ester hydrolysis ring-closure. The total yield of the 3 steps is 20%, and the synthesis route is as follows:

[0009]

[0010] This reaction route is relatively short, but the first step requires a low temperature of -65°C, and the prices of LDA (lithium diisopropylamide) and methyl 3-bromopropionate are expensive, which is not conducive to industrial preparation. Summary of the Invention

[0011] In view of this, the present application provides a CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione, its synthesis method and application. Starting from 3-bromobenzyl cyanide, the target product can be obtained only through simple two steps. This method has the advantages of easily available raw materials, short reaction route, simple post-treatment, etc., and is suitable for industrial production, which can effectively overcome the defects of the existing technical solutions, such as long reaction route, complex preparation, or harsh reaction conditions and low yield, which are not suitable for industrial scale production.

[0012] In the first aspect of the present application, a synthesis method of a CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione is provided, including the following steps:

[0013] (1) Mix 3-bromobenzyl cyanide with acrylonitrile, slowly dropwise add benzyltrimethylammonium hydroxide, and obtain intermediate 2-(3-bromophenyl)glutaronitrile after reflux reaction;

[0014] (2) Dissolve intermediate 2-(3-bromophenyl)glutaronitrile in acetic acid-sulfuric acid solution, hydrolyze and cyclize to obtain the target compound 3-(3-bromophenyl)piperidine-2,6-dione.

[0015] Specifically, the synthesis route of the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione is as follows:

[0016]

[0017] Among them, A-1 is intermediate 2-(3-bromophenyl)glutaronitrile.

[0018] Preferably, in step (1), the reflux reaction temperature is 80-120 °C, the reflux reaction time is 8-24 h, and the preferred reaction time is 12 h.

[0019] Preferably, step (1) specifically includes the following steps: Mix 3-bromobenzyl cyanide and acrylonitrile and heat to 100 °C, then slowly dropwise add benzyltrimethylammonium hydroxide dissolved in a small amount of methanol solution, reflux at 100 °C overnight (12 hours), cool the reaction system to room temperature after TLC detection shows that the raw materials have completely reacted, rotary evaporate the solvent, quench the reaction with water, and obtain intermediate 2-(3-bromophenyl)glutaronitrile after extraction, washing, concentration and column chromatography separation.

[0020] Preferably, in step (1), the molar ratio of 3-bromobenzyl cyanide, acrylonitrile and benzyltrimethylammonium hydroxide is 1.0:(3-6):(1-2).

[0021] Preferably, step (2) specifically includes the following steps: Dissolve the intermediate 2-(3-bromophenyl)glutaronitrile in acetic acid solution, add concentrated sulfuric acid solution, and carry out hydrolysis cyclization reaction. Quench the reaction solution with ice water, extract and concentrate with toluene, and then separate by column chromatography to obtain the target compound 3-(3-bromophenyl)piperidine-2,6-dione.

[0022] Preferably, in step (2), the reaction temperature is 60-120 °C, the reaction time is 2-8 h, and the preferred reaction time is 6 h.

[0023] Preferably, in step (2), the molar ratio of 3-(3-bromophenyl)piperidine-2,6-dione to acetic acid is 1:17, and the volume ratio of acetic acid to concentrated sulfuric acid is 10:1. Specifically, 1 mmol of the intermediate requires 1 ml of acetic acid + 0.1 ml of concentrated sulfuric acid for dissolution.

[0024] Preferably, in step (2), the extraction solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, ether, and toluene.

[0025] The second aspect of the present application also provides a CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione, which is the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione prepared by the above method.

[0026] The third aspect of the present application also provides the application of the above CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione in the preparation of drugs for preventing or treating CDK-related diseases.

[0027] Compared with the prior art, the present application has the following beneficial effects:

[0028] (1) The synthesis route of the present application uses inexpensive and easily available 3-bromobenzyl cyanide and acrylonitrile as starting materials. During the reaction process, complex reaction routes and harsh decarboxylation processes are avoided.

[0029] (2) The synthesis method of the present application has simple starting materials, short reaction steps, simple and feasible operation, and the total yield of two steps is 65%, which is suitable for industrial preparation. Description of the Drawings

[0030] In order to more clearly illustrate the technical solutions in the present application or the prior art, the following will briefly introduce the drawings required for the description of the present application or the prior art. Obviously, the drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0031] Figure 11H NMR spectrum of the target compound 3-(3-bromophenyl)piperidine-2,6-dione synthesized in Example 1 of this application. Detailed implementation manners

[0032] To make the objectives, technical solutions and advantages of this application clearer, the technical solutions in this application will be clearly and completely described below with reference to the accompanying drawings in this application. Obviously, the described embodiments are some, but not all, of the embodiments of this application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in this application without making creative efforts fall within the scope of protection of this application.

[0033] Unless otherwise specified, the experimental methods used in the embodiments of this application are all conventional methods.

[0034] In the following embodiments, unless otherwise specified, all raw materials can be obtained through commercial purchase or prepared by conventional methods.

[0035] Example 1

[0036] a) Synthesis of intermediate A-1:

[0037] Add 3-bromophenylacetonitrile (10 g, 51 mmol) and acrylonitrile (10 g, 188.46 mmol) to a 100 mL round-bottom flask, heat to 100 °C, then dissolve benzyltrimethylammonium hydroxide (10.2 g, 61.2 mmol) in a small amount of methanol solution and slowly add it dropwise to the reaction system. After the addition is complete, the reaction system is refluxed at 100 °C for 12 hours; then the reaction system is cooled to room temperature. Rotate to dry the solvent, add water (50 mL) to quench the reaction; extract with ethyl acetate (50 mL / time, 3 times), combine the organic phases, wash with saturated brine (40 mL), and dry over anhydrous sodium sulfate; evaporate the solvent under reduced pressure and perform column chromatography to obtain the light yellow liquid A-1 intermediate 2-(3-bromophenyl)glutaronitrile with a yield of 79%.

[0038] 1 H NMR (400 MHz, DMSO-d6) 7.53 - 7.45 (m, 2H), 7.31 - 7.28 (m, 2H), 3.89 (t, J = 7.2 Hz, 1H), 2.56 - 2.49 (m, 1H), 2.48 - 2.38 (m, 1H), 2.36 - 2.17 (m, 2H) ppm.

[0039] b) Synthesis of 3-(3-bromophenyl)piperidine-2,6-dione:

[0040] Dissolve 2-(3-bromophenyl) glutarodinitrile (10 mmol) in 25 mL of acetic acid, add 2.5 mL of concentrated sulfuric acid, stir at 80 °C for 6 h. When the reaction of the raw materials is complete detected by TLC, pour it into ice water, extract with toluene, and dry with anhydrous sodium sulfate; Concentrate under reduced pressure to remove the solvent, and obtain the product as a white solid by column chromatography. The separation yield of the target product reaches 82%, and the total yield of steps a) and b) is 65%. The 1H nuclear magnetic resonance spectrum of the product 3-(3-bromophenyl)piperidine-2,6-dione is as follows Figure 1 shown.

[0041] 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.49 - 7.46 (m, 2H), 7.34 - 7.28 (m, 1H), 7.27 - 7.24 (m, 1H), 3.92 - 3.88 (m, 1H), 2.71 - 2.62 (m, 1H), 2.56 - 2.51 (m, 1H), 2.30 - 2.20 (m, 1H), 2.05 - 1.98 (m, 1H) ppm.

[0042] Comparative Example 1

[0043] The synthesis method of Comparative Example 1 can refer to Example 1, the difference is that: benzyltrimethylammonium hydroxide is not added during the synthesis of intermediate A-1 in step a).

[0044] Comparative Example 2

[0045] The synthesis method of Comparative Example 2 can refer to Example 1, the difference is that: benzyltrimethylammonium hydroxide is replaced by sodium hydroxide during the synthesis of intermediate A-1 in step a).

[0046] Comparative Example 3

[0047] The synthesis method of Comparative Example 3 can refer to Example 1, the difference is that: benzyltrimethylammonium hydroxide is replaced by potassium tert-butoxide during the synthesis of intermediate A-1 in step a).

[0048] The yield results of intermediate A-1 in Example 1 and Comparative Examples 1 - 3 are shown in Table 1.

[0049] Table 1

[0050] Additive Yield of Intermediate A-1 Benzyltrimethylammonium hydroxide 79％ No addition 0％ Sodium hydroxide Trace Potassium tert-butoxide 13％

[0051] It can be seen from the data in Table 1 that compared with Example 1, without using a strong base additive, the reaction cannot proceed normally, and using other bases such as sodium hydroxide and potassium tert-butoxide cannot promote the reaction well. While benzyltrimethylammonium hydroxide in Example 1 plays an important role as a strong base and a phase transfer catalyst in the reaction.

[0052] Example 2

[0053] The synthesis method of Example 2 can refer to Example 1, the difference is that: in step b), the extraction solvent for post-treatment is ethyl acetate.

[0054] Example 3

[0055] The synthesis method of Example 3 can refer to Example 1, the difference is that: in step b), the extraction solvent for post-treatment is dichloromethane.

[0056] Example 4

[0057] The synthesis method of Example 4 can refer to Example 1, the difference is that: in step b), the extraction solvent for post-treatment is chloroform.

[0058] Example 5

[0059] The synthesis method of Example 5 can refer to Example 1, the difference is that: in step b), the extraction solvent for post-treatment is diethyl ether.

[0060] The acetic acid content in the extraction liquids of Examples 1-5 is shown in Table 2.

[0061] Table 2

[0062] Extraction agent Acetic acid content (%) Toluene 0.3 Ethyl acetate 18 Dichloromethane 24 Chloroform 27 Diethyl ether 35

[0063] As can be seen from the data in Table 2, the usage amounts of acetic acid and sulfuric acid as solvents are extremely large. Using solutions such as saturated sodium bicarbonate to neutralize acetic acid and then extracting with organic solvents, the post-treatment process will be extremely cumbersome. Therefore, directly selecting a suitable organic solvent for extraction can reduce the post-treatment steps. Compared with Example 1, when ethyl acetate, dichloromethane, chloroform, diethyl ether, etc. are used as extraction solvents, a large amount of acetic acid will still be contained in the extraction liquid. While in Example 1, toluene and acetic acid are almost immiscible, and using toluene as the extraction solvent can effectively extract the product 2-(3-bromophenyl)glutaronitrile.

[0064] 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 them; although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A synthetic method of a CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione, characterized in that, It includes the following steps: (1) Mix 3-bromophenylacetonitrile with acrylonitrile, slowly dropwise add benzyltrimethylammonium hydroxide, and obtain intermediate 2-(3-bromophenyl)glutaronitrile after reflux reaction; (2) Dissolve intermediate 2-(3-bromophenyl)glutaronitrile in acetic acid-concentrated sulfuric acid solution, hydrolyze and cyclize to obtain the target compound 3-(3-bromophenyl)piperidine-2,6-dione.

2. The method for synthesizing the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 1, characterized in that: In step (1), the reflux reaction temperature is 80-120 °C, and the reflux reaction time is 8-24 h.

3. The method for synthesizing the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 2, characterized in that: Step (1) specifically includes the following steps: Mix 3-bromophenylacetonitrile and acrylonitrile and heat to 100 °C, then slowly dropwise add benzyltrimethylammonium hydroxide dissolved in a small amount of methanol solution, reflux at 100 °C overnight, cool the reaction system to room temperature after detecting the complete reaction of the raw materials by TLC, rotary evaporate the solvent, quench the reaction with water, and separate by column chromatography after extraction, washing and concentration to obtain intermediate 2-(3-bromophenyl)glutaronitrile.

4. The synthetic method of the CDK pharmaceutical intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 1, characterized in that, In step (1), the molar ratio of 3-bromophenylacetonitrile, acrylonitrile and benzyltrimethylammonium hydroxide is 1.0:(3-6):(1-2).

5. The synthesis method of the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 1, characterized in that, Step (2) specifically includes the following steps: Dissolve intermediate 2-(3-bromophenyl)glutaronitrile in acetic acid, add concentrated sulfuric acid for hydrolysis and cyclization reaction, quench the reaction solution with ice water, extract and concentrate with toluene, and separate by column chromatography to obtain the target compound 3-(3-bromophenyl)piperidine-2,6-dione.

6. The synthetic method of the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 5, characterized in that, In step (2), the reaction temperature is 60-120 °C, and the reaction time is 2-8 h.

7. The method for synthesizing the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 5, characterized in that: In step (2), the molar ratio of 3-(3-bromophenyl)piperidine-2,6-dione to acetic acid is 1:17, and the volume ratio of acetic acid to concentrated sulfuric acid is 10:

1.

8. The synthetic method of the CDK pharmaceutical intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 5, characterized in that, In step (2), the extraction solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, ether, toluene.

9. A CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione, characterized in that: CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione prepared by the method according to any one of claims 1-8.

10. Use of the CDK drug intermediate 3-(3-bromophenyl)piperidine-2,6-dione according to claim 9 in the preparation of a drug for preventing or treating diseases related to CDK.

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