Preparation method of high-purity 2-bromo-5-formyl pyridine

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of high-purity 2-bromo-5-formylpyridine, which comprises the following steps: S1, taking 2, 5-dibromopyridine and butyl lithium as raw materials, and reacting to obtain an intermediate I; s2, reacting the intermediate I obtained in the step S1 with DMF (Dimethyl Formamide) to obtain an intermediate II; and S3, reacting the intermediate II obtained in the step S2 with acetic acid to obtain 2-bromo-5-formyl pyridine. According to the preparation method disclosed by the invention, the 2-bromo-5-formylpyridine is synthesized through the micro-channel reactor, the operation is simple and convenient, the intermediate state can be directly reacted without separation, the yield is high, and the purity is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing high-purity 2-bromo-5-aldehyde pyridine. Background Technology

[0002] Abemaciclib, chemically known as N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridyl]-5-fluoro-4-[4-fluoro-1-(1-isopropyl)-2-methyl-1H-benzimidazol-6-yl]-2-pyrimidinylamine, was approved by the US FDA in September 2017 under the brand name Verzenio. It is used to treat advanced or metastatic breast cancer and has shown better tolerability compared to previously approved CDK inhibitors such as ribociclib (Kisqali) and palbociclib (Ibrance), with milder neutrophil-lowering side effects, making it particularly advantageous for patients with weakened immune systems.

[0003] 2-Bromo-5-aldehyde pyridine, as a key intermediate of abexicillin, has attracted much attention. Its synthesis methods mainly include the following:

[0004] (1) Chinese Patent CN107698497A discloses a method for preparing 2-bromo-5-aldehyde pyridine, and the synthetic route is as follows:

[0005]

[0006] The first step of this route requires distillation and purification, which is quite complicated; the second step requires heating and sealing for reaction, which poses certain safety risks and is not suitable for industrial production.

[0007] (2) The literature “Synthesis of 2-bromo-5-pyridinecarboxaldehyde, Chemical Reagents, 2006, 28(7), 433-434” discloses a method for preparing 2-bromo-5-aldehyde pyridine. The synthetic route is as follows:

[0008]

[0009] The reaction was incomplete in this route. The second step used column chromatography for purification, but the yield was only 40%, which is too low. The industrialization cost is too high, making it unsuitable for industrial production. Summary of the Invention

[0010] To address the shortcomings of the prior art, this invention provides a method for preparing high-purity 2-bromo-5-aldehyde pyridine. The method involves using 2,5-dibromopyridine and butyllithium as raw materials to prepare a lithium salt solution via a lithium halide exchange reaction. This solution is then reacted with DMF to obtain a solution similar to a hemiacetal, and finally hydrolyzed with acetic acid to yield 2-bromo-5-aldehyde pyridine.

[0011] The specific plan is as follows:

[0012] A method for preparing high-purity 2-bromo-5-aldehyde pyridine includes the following steps:

[0013] S1 uses 2,5-dibromopyridine and butyllithium as raw materials to obtain intermediate I through reaction;

[0014] S2 Intermediate I obtained in step S1 reacts with DMF to obtain intermediate II;

[0015] S3 Intermediate II obtained in step S2 is reacted with acetic acid to obtain 2-bromo-5-aldehyde pyridine.

[0016] The synthesis route (example) is as follows:

[0017] .

[0018] Furthermore, in step S1, the reaction temperature is -80 to -70°C; the molar ratio of 2,5-dibromopyridine to butyllithium is 1:(1.5 to 3.0).

[0019] Preferably, in step S1, the reaction is carried out in a microchannel reactor. Specifically, a 2,5-dibromopyridine solution is prepared using 2,5-dibromopyridine and an organic solvent; a butyllithium solution is prepared using butyllithium and an organic solvent; the 2,5-dibromopyridine solution and the butyllithium solution are then introduced into the microchannel reactor to react and obtain intermediate I solution. The organic solvent is preferably toluene, diethyl ether, or tetrahydrofuran; the concentration of the 2,5-dibromopyridine solution is preferably 20wt%~30wt%, and the flow rate is preferably 10~30mL·min. -1 The preferred concentration of the butyllithium solution is 15wt%~25wt%, and the preferred flow rate is 10~20mL·min. -1 .

[0020] Furthermore, in step S1, the reaction time is preferably 1 to 5 minutes.

[0021] Furthermore, in step S2, the reaction temperature is -10 to 0°C; the molar ratio of 2,5-dibromopyridine to DMF is 1:(1.1~2.0).

[0022] Preferably, in step S2, the reaction is carried out in a microchannel reactor. Specifically, a DMF solution is prepared using DMF and an organic solvent; the intermediate I solution obtained in step S1 is then introduced into the microchannel reactor along with the DMF solution to react and obtain an intermediate II solution. The organic solvent is preferably toluene, diethyl ether, or tetrahydrofuran; the concentration of intermediate I solution is preferably 20wt%~30wt%, and the flow rate is preferably 25~35 mL·min. -1 The preferred concentration of the DMF solution is 60wt%~70wt%, and the preferred flow rate is 2~5mL·min.-1 .

[0023] Furthermore, in step S2, the reaction time is preferably 1 to 3 minutes.

[0024] Furthermore, in step S3, the reaction temperature is -10~0℃; the molar ratio of 2,5-dibromopyridine to acetic acid is 1:(1.0~3.0).

[0025] Preferably, in step S3, the reaction is carried out in a microchannel reactor. Specifically, an aqueous acetic acid solution is prepared; the intermediate II solution obtained in step S2 is passed into the microchannel reactor and reacted with the aqueous acetic acid solution to obtain 2-bromo-5-aldehyde pyridine. The concentration of the intermediate II solution is preferably 20wt%~30wt%, and the flow rate is preferably 35~45mL·min. -1 The preferred concentration of the acetic acid aqueous solution is 5wt%~10wt%, and the preferred flow rate is 25~35mL·min. -1 .

[0026] Furthermore, in step S3, the reaction time is preferably 0.5 to 2 minutes.

[0027] The beneficial effects are as follows:

[0028] The preparation method of this invention synthesizes 2-bromo-5-aldehyde pyridine via a microchannel reactor. The operation is simple, the intermediate state does not need to be separated and can be reacted directly, with high yield and high purity. In addition, the use of microchannel technology enables precise feeding and temperature control, short reaction time, and a closed reaction space to prevent the solution from contacting air and generating impurities. It realizes automated and continuous production, shortens the cycle, saves costs, and is suitable for industrial production. Attached Figure Description

[0029] Figure 1 The image shows the HPLC chromatogram of 2-bromo-5-aldehyde pyridine prepared in Example 1. Detailed Implementation

[0030] The embodiments of the present invention will be described in further detail below. The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0031] The microchannel reactor used in the following examples is the HAMM RMHS201006 microchannel reactor.

[0032] Example 1

[0033] A method for preparing high-purity 2-bromo-5-aldehyde pyridine includes the following steps:

[0034] S1. 100 g of 2,5-dibromopyridine was diluted to 400 mL with tetrahydrofuran to obtain a 2,5-dibromopyridine solution. The 2,5-dibromopyridine solution and 300 mL of 2.5 M butyllithium tetrahydrofuran solution were then introduced into microchannel reactor No. 1 using a constant flow pump; the flow rate of the 2,5-dibromopyridine solution was 20 mL / min. -1 The flow rate of the butyllithium solution was 15 mL / min. -1 The residence time was 1.5 min, the temperature was -75℃, and 690 mL of intermediate I reaction solution (concentration of 21.3 wt%) was obtained.

[0035] S2 Weigh 61.7 g of DMF (99.9% purity) and dilute to 100 mL with tetrahydrofuran to obtain a DMF solution; 690 mL of intermediate I reaction solution (21.3 wt% concentration) obtained in step S1 and the DMF solution are fed into microchannel reactor No. 2 using a constant flow pump, with the flow rate of intermediate I reaction solution being 28 mL / min. -1 The flow rate of the DMF solution was 4 mL / min. -1 The residence time was 3 min, the temperature was -5℃, and 785 mL of intermediate II reaction solution (concentration of 26.4 wt%) was obtained.

[0036] S3 Weigh 50g of acetic acid (99.5% purity) and dilute to 600mL with purified water to prepare an acetic acid solution; use a constant flow pump to pass 785mL of intermediate II reaction solution (26.4wt%) obtained in step S2 and the acetic acid solution into microchannel reactor No. 3, wherein the flow rate of intermediate II reaction solution is 40mL·min. -1 The flow rate of the acetic acid solution was 30 mL / min. -1 The residence time was 0.5 min, the temperature was -5℃, and a 2-bromo-5-aldehyde pyridine solution was obtained from the pipeline outlet. Subsequently, the 2-bromo-5-aldehyde pyridine solution was separated, the aqueous phase was discarded, the organic phase was concentrated to dryness, 300 mL of methyl tert-butyl ether was added, the temperature was raised to 55℃ and refluxed, stirred for 1 h, cooled to 0℃, stirred and crystallized for 2 h, filtered, and dried to obtain 72.6 g of high-purity 2-bromo-5-aldehyde pyridine, with a yield of 92.5% and an HPLC purity of 99.901%.

[0037] like Figure 1 Table 1 shows the HPLC chromatogram of 2-bromo-5-aldehyde pyridine prepared in Example 1, and the corresponding peak results.

[0038] Table 1 Peak Results

[0039]

[0040] Example 2

[0041] A method for preparing high-purity 2-bromo-5-aldehyde pyridine includes the following steps:

[0042] S1. 100 g of 2,5-dibromopyridine was diluted to 400 mL with tetrahydrofuran to obtain a 2,5-dibromopyridine solution. The 2,5-dibromopyridine solution and 300 mL of 2.5 M butyllithium tetrahydrofuran solution were then introduced into microchannel reactor No. 1 using a constant flow pump; the flow rate of the 2,5-dibromopyridine solution was 20 mL / min. -1 The flow rate of the butyllithium solution was 15 mL / min. -1 The residence time was 1.5 min, the temperature was -75℃, and 690 mL of intermediate I reaction solution (concentration of 21.3 wt%) was obtained.

[0043] S2 Weigh 59.3 g of DMF (99.9% purity) and dilute to 100 mL with tetrahydrofuran to obtain a DMF solution; 690 mL of intermediate I reaction solution (21.3 wt%) obtained in step S1 and the DMF solution are fed into microchannel reactor No. 2 using a constant flow pump, with the flow rate of intermediate I reaction solution being 28 mL / min. -1 The flow rate of the DMF solution was 4 mL / min. -1 The residence time was 3 min, the temperature was -5℃, and 785 mL of intermediate II reaction solution (concentration of 26.3 wt%) was obtained.

[0044] S3 Weigh 40g of acetic acid (purity 99.5%) and dilute to 600mL with purified water to prepare an acetic acid solution; use a constant flow pump to pass 785mL of intermediate II reaction solution (concentration 26.3wt%) obtained in step S2 and the acetic acid solution into microchannel reactor No. 3, wherein the flow rate of intermediate II reaction solution is 40mL·min. -1 The flow rate of the acetic acid solution was 30 mL / min. -1 The residence time was 0.5 min, the temperature was -5℃, and a 2-bromo-5-aldehyde pyridine solution was obtained from the pipeline outlet. Subsequently, the 2-bromo-5-aldehyde pyridine solution was separated, the aqueous phase was discarded, the organic phase was concentrated to dryness, 300 mL of methyl tert-butyl ether was added, the temperature was raised to 58℃ and refluxed, stirred for 1 h, cooled to 0℃, stirred and crystallized for 2 h, filtered, and dried to obtain 70.6 g of high-purity 2-bromo-5-aldehyde pyridine, with a yield of 89.9% and an HPLC purity of 99.342%.

[0045] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing high-purity 2-bromo-5-aldehyde pyridine, characterized in that, Includes the following steps: S1 uses 2,5-dibromopyridine and butyllithium as raw materials to obtain intermediate I through reaction; S2 Intermediate I obtained in step S1 reacts with DMF to obtain intermediate II; S3 Intermediate II obtained in step S2 is reacted with acetic acid to obtain 2-bromo-5-aldehyde pyridine.

2. The preparation method according to claim 1, characterized in that, In step S1, the reaction temperature is -80 to -70°C; the molar ratio of 2,5-dibromopyridine to butyllithium is 1:(1.5 to 3.0).

3. The preparation method according to claim 1, characterized in that, In step S1, the reaction takes place in a microchannel reactor; the reaction time is 1~5 min.

4. The preparation method according to claim 1, characterized in that, In step S2, the reaction temperature is -10 to 0℃; the molar ratio of 2,5-dibromopyridine to DMF is 1:(1.1~2.0).

5. The preparation method according to claim 1, characterized in that, In step S2, the reaction takes place in a microchannel reactor; the reaction time is 1-3 min.

6. The preparation method according to claim 1, characterized in that, In step S3, the reaction temperature is -10 to 0°C; the molar ratio of 2,5-dibromopyridine to acetic acid is 1:(1.0 to 3.0).

7. The preparation method according to claim 1, characterized in that, In step S3, the reaction is carried out in a microchannel reactor; the reaction time is 0.5~2 min.

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