3-bromopyridine derivative as well as continuous synthesis method and application thereof

Abstract

The invention discloses a 3-bromopyridine derivative as well as a continuous synthesis method and application thereof, and the synthesis route of the continuous synthesis method comprises the following steps: a, adding a strong base into 3-bromopyridine, and continuously reacting for a period of time; b, adding an acylation reagent into the reaction liquid in the step a, and continuously reacting for a period of time; c, quenching the reaction liquid in the step b to obtain the 3-bromopyridine derivative; wherein the 3-bromopyridine derivative is 2-formyl-3-bromopyridine or 2-acetyl-3-bromopyridine, and the structural formula of the 3-bromopyridine derivative is shown in the description. The continuous synthesis method disclosed by the invention is low in raw material price, low in cost and easy to obtain; less solvent is used, and environmental pollution is reduced; the process is safe and reliable; the obtained product is high in chemical purity; the reactor is simple in structure and easy to obtain.

Description

Technical Field

[0001] The invention relates to 3-bromopyridine derivatives and a continuous synthesis method and application thereof, belonging to the technical field of pharmaceutical intermediate synthesis. Background Art

[0002] 2-Formyl-3-bromopyridine and 2-acetyl-3-bromopyridine are important organic synthesis intermediates and are widely used in the synthesis of medicines and pesticides, such as TYK2 protein kinase (CN 111194317 A), chemotactic cytokine receptor 1 (EP 2 655 371B1), orexin receptor (US 9,994,570 B2), NFK B pathway activation inhibitor (CN 103086958A), TRPM8 antagonist (CN 103906733 A), etc.

[0003]

[0004] Most of the literature reports use selenium dioxide to oxidize 3-bromopyridine, such as WO2002022600, Organic & Biomolecular Chemistry (2012), 10 (6), 1239-1245, CN102675305B, CN103086958A, etc. The main disadvantages of this method are that an excessive amount of highly toxic reagent selenium dioxide is used, which poses a greater safety risk; the crude reaction product needs to be separated and purified by column chromatography, which is not conducive to large-scale production.

[0005]

[0006] Another widely used method is to use NBS to dibrominate 2-methyl-3-bromopyridine and then hydrolyze it into aldehyde, such as WO2012177893. Its main disadvantage is that it requires free radicals to initiate dibromination, free radicals are chain reactions, the reaction is highly exothermic, the process is difficult to control, the safety risk is relatively large, and it is not conducive to large-scale production.

[0007]

[0008] The third method is to treat 2,3-dibromopyridine with a strong base such as butyl lithium, and then react with DMF and hydrolyze, such as WO2016085783A1, WO2016086357 A1, Angewandte Chemie, International Edition (2014), 53 (30), 7933-7937. Its main disadvantage is that the reaction requires continuous low temperature control, and due to the problems of reaction selectivity and intermediate stability, the crude product of the reaction needs to be purified by column chromatography, which is not conducive to large-scale production.

[0009]

[0010] As for 2-acetyl-3-bromopyridine, there are two publicly reported synthesis methods. The first is to use Dess-Martin oxidant to oxidize the corresponding alcohol, such as patent WO2012087782 A1. This method uses a high-valent iodine oxidant, which has low atom economy, very high cost, and certain safety risks. The product needs to be purified by column chromatography, which is not conducive to large-scale production.

[0011]

[0012] The second method is to use 2-cyano-3-bromopyridine and methyl Grignard reagent to add, and then quench to obtain the corresponding ketone, such as Organic & Biomolecular Chemistry (2015), 13 (36), 9418-9426, WO2019023468 A1, WO2015173393 A1. This method has expensive raw materials, requires an excess of methyl Grignard reagent, and has a complex reaction, requiring column chromatography purification and separation, which is not conducive to large-scale production.

[0013] Therefore, the present application proposes 3-bromopyridine derivatives and their continuous synthesis methods and applications. Summary of the invention

[0014] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a 3-bromopyridine derivative and a continuous synthesis method and application thereof, which can improve the efficiency of synthesizing a 3-bromopyridine derivative: 2-formyl-3-bromopyridine or 2-acetyl-3-bromopyridine, and reduce the synthesis cost.

[0015] To achieve the above object, the present invention is implemented by adopting the following technical solutions:

[0016] In one aspect, the present invention provides a continuous synthesis method of a 3-bromopyridine derivative, and the synthesis route is as follows:

[0017]

[0018] Wherein, in formula (2), R is H or Me.

[0019] Further, the synthetic route comprises the following steps:

[0020] Step a: adding a strong base to 3-bromopyridine and continuing the reaction for a period of time;

[0021] Step b: adding an acylating agent to the reaction solution of step a, and continuing the reaction for a period of time;

[0022] Step c: quenching the reaction solution of step b to obtain a 3-bromopyridine derivative;

[0023] Furthermore, the 3-bromopyridine derivative is 2-formyl-3-bromopyridine or 2-acetyl-3-bromopyridine.

[0024] Further, the 3-bromopyridine is 3-bromopyridine or a mixture of 3-bromopyridine and an organic solvent;

[0025] Further, the strong base is selected from one or more of 2,2,6,6-tetramethylpiperidinium magnesium chloride and lithium chloride complex, bis(2,2,6,6-tetramethylpiperidinium) magnesium chloride and lithium chloride complex, 2,2,6,6-tetramethylpiperidinium lithium, and lithium diisopropylamide, or a mixture of one or more of them and an organic solvent;

[0026] Further, the acylating agent is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, methyl acetate, ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, acetyl chloride, acetic anhydride, formic anhydride, or a mixture of one or more of them and an organic solvent;

[0027] Further, the organic solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, toluene, dichloromethane, and n-heptane;

[0028] Furthermore, the quenching reagent in the quenching process is selected from one or more of water, ammonium chloride and acid.

[0029] Furthermore, the acid is selected from one or more of formic acid, sulfuric acid, hydrochloric acid and citric acid.

[0030] Further, the molar ratio of the 3-bromopyridine to the strong base is 1:(1-3);

[0031] Further, the molar ratio of the 3-bromopyridine to the acylating agent is 1:(1-40);

[0032] Furthermore, the molar ratio of 3-bromopyridine to the quenching reagent in the quenching process is 1:(1-3).

[0033] Furthermore, in step a, the reaction time is 5 to 120 seconds; the reaction temperature is -80 to 50 degrees Celsius;

[0034] Furthermore, in step b, the reaction time is 5 to 120 seconds; the reaction temperature is -80 to 50 degrees Celsius;

[0035] Furthermore, in step c, the duration of the quenching process is 5 to 120 seconds; the temperature is -40 to 70 degrees Celsius.

[0036] Furthermore, the continuous synthesis method of the 3-bromopyridine derivative also includes:

[0037] Step d: separating and purifying the reaction solution of step c.

[0038] Furthermore, the purification method is water washing, acid washing and / or distillation.

[0039] In another aspect, the present invention provides a 3-bromopyridine derivative, which is synthesized using the above-mentioned continuous synthesis method of 3-bromopyridine derivatives.

[0040] On the other hand, the present invention provides 3-bromopyridine derivatives synthesized by the continuous synthesis method of the above-mentioned 3-bromopyridine derivatives or the use of the above-mentioned 3-bromopyridine derivatives in the preparation of TYK2 protein kinase, chemokine receptor, orexin receptor, NFK B pathway activation inhibitor, and TRPM8 antagonist.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] The present invention realizes the continuous synthesis of 2-formyl-3-bromopyridine and 2-acetyl-3-bromopyridine; wherein the purity of 2-acetyl-3-bromopyridine is 99.8A%, the yield is 50.6%, and the purity of 2-formyl-3-bromopyridine is 99.5A%, the yield is 56.6%.

[0043] The raw materials are continuously added during the continuous synthesis process of the present invention, so that the product can be synthesized continuously and uninterruptedly, which greatly reduces the preparation time and improves the efficiency of the process.

[0044] The traditional batch process takes at least several hours, and the production time is extended as the reaction is scaled up. However, the total reaction time of the continuous synthesis of the present invention is less than or equal to 2 minutes, which is suitable for commercial production.

[0045] In order to solve the influence of heat transfer, mass transfer, etc. on the synthesis reaction in the transfer process in the traditional process, and overcome the problem that the process cannot be stably scaled up due to the decomposition of intermediates, the continuous synthesis reaction process of the present invention can achieve scaled-up production by extending the system operation time and appropriately increasing the liquid holding volume, so that the reaction section 1 and the reaction section 2 can maintain the same reaction time and reaction temperature, thereby solving the problem of process transfer from small-scale trial to scaled-up production.

[0046] The post-treatment of the continuous synthesis reaction of the present invention is simple. After the reaction is completed, the target product with a purity of more than 99A% in the liquid phase is obtained through simple washing and distillation, which greatly saves production costs and improves production efficiency.

[0047] The continuous synthesis reaction of the present invention implements continuous flow, so the liquid holding capacity of the reactor is smaller than that of the batch process, the process energy consumption is greatly reduced, and the safety is greatly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1It is a schematic diagram of an embodiment of the present invention for preparing 3-bromopyridine derivatives by using a Y-type mixer;

[0049] Figure 2 It is a schematic diagram of an embodiment of the present invention for preparing 3-bromopyridine derivatives by using a microchannel reactor;

[0050] Figure 3 : is a nuclear magnetic resonance mass spectrum of the product 2-acetyl-3-bromopyridine obtained in Example 29 of the present invention;

[0051] Figure 4 : is the nuclear magnetic resonance mass spectrum of the product 2-formyl-3-bromopyridine obtained in Example 30 of the present invention. DETAILED DESCRIPTION

[0052] The present invention will be further described below in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and cannot be used to limit the protection scope of the present invention.

[0053] This application introduces a continuous synthesis method of 3-bromopyridine derivatives, and the synthesis route is as follows:

[0054]

[0055] Wherein, in formula (2), R is H or Me.

[0056] When used, the continuous synthesis reactor is a pipeline reactor, a continuous stirred reactor (CSTR) or a microchannel reactor.

[0057] In some preferred embodiments, the reactor for continuous synthesis is a pipeline reactor or a microchannel reactor.

[0058] In some preferred embodiments, the continuous synthesis reactor is a microchannel reactor.

[0059] The continuous stirred tank reactor is composed of several reactors, each reactor can react at the same temperature or at different temperatures, and the volumes of each reactor can be the same or different.

[0060] The continuous synthesis method of 3-bromopyridine derivatives of the present application comprises the following steps:

[0061] Step a: adding a strong base to 3-bromopyridine and continuing the reaction for a period of time to form an intermediate state.

[0062] The molar ratio of the 3-bromopyridine to the strong base is 1:(1-3); the reaction time is 5-120 seconds; and the reaction temperature is -80-50 degrees Celsius.

[0063] The molar ratio of the 3-bromopyridine to the strong base is preferably 1:(1-1.5); the reaction time is preferably 10-60 seconds; and the reaction temperature is preferably -10-30 degrees Celsius.

[0064] Wherein, 3-bromopyridine is 3-bromopyridine or a mixture of 3-bromopyridine and an organic solvent.

[0065] When used, the organic solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, toluene, dichloromethane, and n-heptane. When used in practice, the organic solvent is preferably tetrahydrofuran or methyltetrahydrofuran.

[0066] In addition, the strong base is selected from one or more of 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex, bis(2,2,6,6-tetramethylpiperidinium) magnesium chloride lithium chloride complex, 2,2,6,6-tetramethylpiperidinium lithium, diisopropylamine lithium, or a mixture of one or more of them with an organic solvent. In practical application, the strong base is preferably a 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex or a mixture of it with an organic solvent.

[0067] In some preferred embodiments, the reaction process of the raw material 3-bromopyridine feed and the strong base in step a can be that 3-bromopyridine is directly fed without dilution, or that 3-bromopyridine is diluted with 10 to 50 times the volume of an organic solvent before feeding. In addition, the mixing form can be mixing in a T-type or Y-type three-way mixer, or mixing in an SK mixer, or mixing using a microchannel mixer.

[0068] Step b: adding an acylating agent to the reaction solution of step a, and continuing the reaction for a period of time.

[0069] The molar ratio of the 3-bromopyridine to the acylating agent is 1:(1-40); the reaction time is 5-120 seconds; and the reaction temperature is -80-50 degrees Celsius.

[0070] The molar ratio of the 3-bromopyridine to the acylating agent is preferably 1:(1-20); the reaction time is preferably 10-60 seconds; and the reaction temperature is preferably -10-30 degrees Celsius.

[0071] Wherein, the acylating agent is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, methyl acetate, ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, acetyl chloride, acetic anhydride, formic anhydride, or a mixture of one or more of them and an organic solvent. In practical application, the acylating agent is preferably N,N-dimethylacetamide, N,N-dimethylformamide, methyl acetate or ethyl formate.

[0072] In some preferred embodiments, in step b, in the process of mixing and reacting the intermediate state and the acylating agent to form the target product, the acylating agent can be pumped in alone, or it can be diluted with 10 to 50 times the volume of the organic solvent and then pumped in. In addition, the mixing form can be mixing with a T-type or Y-type three-way mixer, or mixing with an SK mixer, or mixing using a microchannel.

[0073] In some preferred embodiments, the total reaction time refers to the average time required from the raw materials entering the reactor to the target products exiting the reactor, which can also be called the residence time in the present continuous flow process.

[0074] In some preferred embodiments, the total reaction time is 5-120 seconds.

[0075] In some preferred embodiments, the total reaction time is 5-60 seconds.

[0076] In some preferred embodiments, the precooling stage, reaction stage 1, i.e., step a, and reaction stage 2, i.e., step b, of the reaction process may be at the same temperature or at different temperatures.

[0077] Step c: quenching the reaction solution of step b to obtain a 3-bromopyridine derivative, wherein the 3-bromopyridine derivative is 2-formyl-3-bromopyridine or 2-acetyl-3-bromopyridine.

[0078] When used, the molar ratio of 3-bromopyridine to the quenching reagent in the quenching process is 1:(1-3); the duration is 5-120 seconds; and the temperature is -40-70 degrees Celsius.

[0079] The duration of the quenching process is preferably 10 to 60 seconds; the temperature is preferably 0 to 40 degrees Celsius.

[0080] In addition, the quenching reagent in the quenching process is selected from one or more of water, ammonium chloride, and acid. Among them, the acid is selected from one or more of formic acid, sulfuric acid, hydrochloric acid, and citric acid.

[0081] The quenching agent in the quenching process is preferably ammonium chloride or hydrochloric acid.

[0082] In some preferred embodiments, the continuous quenching process can be performed by pumping 10-30 wt% ammonium chloride aqueous solution, water or 1.5-8 wt% hydrochloric acid aqueous solution at a certain flow rate to mix with the reaction solution of step b, and the reaction is terminated. The mixing unit is a static mixer or a stirring type dynamic mixer. The static mixer is a T-type mixer, a Y-type three-way mixer, a spiral tube mixer or an SK mixer.

[0083] Step d: separating and purifying the reaction solution of step c.

[0084] Wherein, the purification method is water washing, acid washing and / or distillation.

[0085] In addition, the solvent used in the separation process is selected from one or more of toluene, ethyl acetate, methyl tert-butyl ether, dichloromethane, n-heptane, tetrahydrofuran, and methyltetrahydrofuran. In practical application, the solvent used in the separation process is preferably toluene or methyl tert-butyl ether.

[0086] In some preferred embodiments, during the separation and purification process, 3 to 50 times the volume of solvent is first used for extraction, then 3 to 50 times the volume of water is used for washing, 1 to 20 times the volume of 1 to 15 wt% acid is used for acid washing, and finally impurities are removed by distillation, or the crude product is directly purified by distillation.

[0087] In some preferred embodiments, during the separation and purification process, the water used for washing is pure water or brine, and the acid used for pickling is hydrochloric acid, sulfuric acid, acetic acid, citric acid or phosphoric acid.

[0088] In some preferred embodiments, during the separation and purification process, the water used for water washing is pure water, and the acid used for pickling is hydrochloric acid or sulfuric acid.

[0089] According to the above-mentioned continuous synthesis method of 3-bromopyridine derivatives, those skilled in the art can continuously add raw materials during the continuous synthesis process to continuously and uninterruptedly synthesize products, which greatly reduces the preparation time and improves the efficiency of the process.

[0090] Those skilled in the art can synthesize 3-bromopyridine derivatives according to the above-mentioned continuous synthesis method of 3-bromopyridine derivatives, wherein the 3-bromopyridine derivative is 2-formyl-3-bromopyridine or 2-acetyl-3-bromopyridine.

[0091] Those skilled in the art can synthesize 3-bromopyridine derivatives according to the above-mentioned continuous synthesis method of 3-bromopyridine derivatives or use the above-mentioned 3-bromopyridine derivatives in the preparation of TYK2 protein kinase, chemokine receptor, orexin receptor, NFKB pathway activation inhibitor, TRPM8 antagonist. Wherein, the 3-bromopyridine derivative is 2-formyl-3-bromopyridine or 2-acetyl-3-bromopyridine.

[0092] The present invention realizes the continuous synthesis of 2-formyl-3-bromopyridine and 2-acetyl-3-bromopyridine; wherein the purity of 2-acetyl-3-bromopyridine is 99.8A%, the yield is 50.6%, and the purity of 2-formyl-3-bromopyridine is 99.5A%, the yield is 56.6%.

[0093] The raw materials are continuously added during the continuous synthesis process of the present invention, so that the product can be synthesized continuously and uninterruptedly, which greatly reduces the preparation time and improves the efficiency of the process.

[0094] The traditional batch process takes at least several hours, and the production time is extended as the reaction is scaled up. However, the total reaction time of the continuous synthesis of the present invention is less than or equal to 2 minutes, which is suitable for commercial production.

[0095] In order to solve the influence of heat transfer, mass transfer, etc. on the synthesis reaction in the transfer process in the traditional process, and overcome the problem that the process cannot be stably scaled up due to the decomposition of intermediates, the continuous synthesis reaction process of the present invention can achieve scaled-up production by extending the system operation time and appropriately increasing the liquid holding volume, so that the reaction section 1 and the reaction section 2 can maintain the same reaction time and reaction temperature, thereby solving the problem of process transfer from small-scale trial to scaled-up production.

[0096] The post-treatment of the continuous synthesis reaction of the present invention is simple. After the reaction is completed, the target product with a purity of more than 99A% in the liquid phase is obtained through simple washing and distillation, which greatly saves production costs and improves production efficiency.

[0097] The continuous synthesis reaction of the present invention implements continuous flow, so the liquid holding capacity of the reactor is smaller than that of the batch process, the process energy consumption is greatly reduced, and the safety is greatly improved.

[0098] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to be used to describe the present invention.

[0099] The present invention is defined.

[0100] Embodiment 1:

[0101] The product 2-acetyl-3-bromopyridine (200 mg scale) was synthesized using the Batch method.

[0102] Precooling stage: add 200 mg of 3-bromopyridine and 1.6 mL of anhydrous tetrahydrofuran into the reaction bottle, replace with nitrogen three times, and cool to -10 degrees Celsius;

[0103] Reaction stage 1: add 1.5 equivalents of 1.0 mol / L tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex (TMPMgCl.LiCl) to the reaction flask. During the addition, the temperature of the liquid in the reaction flask is controlled between -10 and 0 degrees Celsius. After the addition is completed, the temperature of the liquid in the reaction flask is controlled below 0 degrees. Stir the reaction for 30 minutes.

[0104] Reaction stage 2: 15 equivalents of acylating agent were added dropwise to the reaction flask. During the addition, the temperature of the liquid in the reaction flask was controlled between 0-10°C. After the addition, the temperature of the liquid in the reaction flask was controlled between 0-10°C. The reaction was stirred for 1 hour to obtain a crude product.

[0105] The crude product was taken for liquid phase detection: the product 2-acetyl-3-bromopyridine was 78.2A%, and the raw material 3-bromopyridine remained 15.3A%.

[0106] Embodiment 2:

[0107] The product 2-acetyl-3-bromopyridine (1 g scale) was synthesized using the Batch method.

[0108] The difference between Example 2 and Example 1 is that:

[0109] Precooling section: 3-bromopyridine: 1 g, anhydrous tetrahydrofuran: 8 mL

[0110] Reaction stage 1: TMPMgCl.LiCl 1 equivalent.

[0111] Reaction stage 2: 12 equivalents of acylating agent

[0112] The crude product was taken for liquid phase detection: the product 2-acetyl-3-bromopyridine was 71.1A%, and the raw material 3-bromopyridine remained 23.2A%.

[0113] Embodiment 3:

[0114] The product 2-acetyl-3-bromopyridine was synthesized using isopropylmagnesium chloride (200 mg scale).

[0115] The difference between Example 3 and Example 1 is that:

[0116] In reaction section 1, the 1.0 mol / L tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex is replaced with a 1.0 mol / L tetrahydrofuran solution of isopropyl magnesium chloride.

[0117] The crude product was taken for liquid phase detection: the product 2-acetyl-3-bromopyridine was 31.2A%, and the raw material 3-bromopyridine remained 53.4A%.

[0118] Embodiment 4:

[0119] The product 2-acetyl-3-bromopyridine was synthesized using isopropylmagnesium chloride lithium chloride complex (200 mg scale).

[0120] The difference between Example 4 and Example 1 is that:

[0121] In reaction section 1, the 1.0 mol / L tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex is replaced with a 1.0 mol / L tetrahydrofuran solution of isopropylmagnesium chloride lithium chloride complex.

[0122] The crude product was taken for liquid phase detection: the product 2-acetyl-3-bromopyridine was 28.5A%, and the raw material 3-bromopyridine remained 60.3A%.

[0123] Embodiments 5 to 12:

[0124] The product 2-acetyl-3-bromopyridine was synthesized using a pipeline reactor.

[0125] Dissolve 3-bromopyridine in 9 mL / g of anhydrous tetrahydrofuran to obtain a 0.66 mol / L 3-bromopyridine tetrahydrofuran solution for standby use;

[0126] Precooling section: Take 0.66 mol / L 3-bromopyridine tetrahydrofuran solution and 1.0 mol / L 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex tetrahydrofuran solution (TMPMgCl.LiCl), and precool them in 1 / 8 inch PFA tubes respectively.

[0127] Reaction stage 1: pre-cooled 3-bromopyridine tetrahydrofuran solution and TMPMgCl.LiCl were mixed in a Y-type mixer and reacted in a 1 / 8 inch PFA pipe, refer to Figure 1 .

[0128] Reaction section 2: The pre-cooled N,N-dimethylacetamide (DMAc) and the reaction liquid after the reaction in reaction section 1 were added to a Y-type mixer for mixing, and reacted in a 1 / 8-inch PFA pipe. The liquid phase was sampled at the outlet for detection. The results are shown in Table 1.

[0129] Table 1. Liquid phase detection results of Examples 5 to 12

[0130]

[0131]

[0132] Embodiments 13 to 22:

[0133] Synthesis of 2-acetyl-3-bromopyridine using a microchannel reactor

[0134] Dissolve 3-bromopyridine in 9 mL / g of anhydrous tetrahydrofuran to obtain a 0.66 mol / L 3-bromopyridine tetrahydrofuran solution for standby use;

[0135] Precooling section: Take 0.66 mol / L 3-bromopyridine tetrahydrofuran solution and 1.0 mol / L 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex tetrahydrofuran solution (TMPMgCl.LiCl), and precool them in 1 / 8 inch PFA tubes respectively.

[0136] Reaction stage 1: pre-cooled 3-bromopyridine tetrahydrofuran solution and TMPMgCl.LiCl are mixed and reacted in a Corning G1 microchannel reactor, refer to Figure 2 .

[0137] Reaction section 2: The pre-cooled N,N-dimethylacetamide (DMAc) and the reaction liquid flowing out of the Corning G1 microchannel reactor in reaction section 1 were added to another Corning G1 microchannel reactor for mixed reaction. The liquid phase was sampled at the outlet for detection. The results are shown in Table 2.

[0138] Table 2. Liquid phase detection results of Examples 13 to 22

[0139]

[0140] Embodiments 23 to 27:

[0141] The product 2-acetyl-3-bromopyridine was synthesized using different acylating agents.

[0142] Dissolve 3-bromopyridine in 9 mL / g of anhydrous tetrahydrofuran to obtain a 0.66 mol / L 3-bromopyridine tetrahydrofuran solution for standby use;

[0143] Precooling section: Take 0.66 mol / L 3-bromopyridine tetrahydrofuran solution and 1.0 mol / L 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex tetrahydrofuran solution (TMPMgCl.LiCl), and precool them in 1 / 8 inch PFA tubes respectively.

[0144] Reaction stage 1: The pre-cooled tetrahydrofuran solution of 3-bromopyridine and TMPMgCl.LiCl are mixed and reacted in a Corning G1 microchannel reactor.

[0145] Reaction section 2: The pre-cooled acylating reagent and the reaction liquid flowing out of the Corning G1 microchannel reactor in reaction section 1 were added to another Corning G1 microchannel reactor for mixed reaction. The liquid phase was sampled at the outlet for detection. The results are shown in Table 3.

[0146] Table 3. Synthesis of 2-acetyl-3-bromopyridine using different acetylation reagents

[0147]

[0148] Note: In Examples 23 to 27: the equivalent of TMPMgCl·LiCl is 1.0 eq., and the equivalent of 3-bromopyridine in tetrahydrofuran solution is 1.0 eq.

[0149] Embodiment 28:

[0150] The raw material 3-bromopyridine is directly reacted without dilution to synthesize 2-acetyl-3-bromopyridine.

[0151] Precooling section: Take 50 g of 3-bromopyridine and pump it directly into the PFA tube at a flow rate of 4.9 mL / min for precooling.

[0152] Reaction stage 1: 50 g of pre-cooled 3-bromopyridine and 1.1 equivalents of pre-cooled 1.0 mol / L tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex (TMPMgCl.LiCl) were pumped into the Corning G1 microchannel reactor at a flow rate of 49.6 mL / min and mixed and reacted at 30 degrees Celsius for 9 seconds.

[0153] Reaction stage 2: 11 equivalents of pre-cooled N,N-dimethylacetamide (DMAc) and the reaction solution from the Corning G1 microchannel reactor in reaction stage 1 were pumped into the second Corning G1 microchannel reactor at a flow rate of 46.1 mL / min and mixed and reacted at 30 degrees Celsius for 5 seconds.

[0154] The reaction liquid flowing out of the second Corning G1 microchannel reactor was directly quenched with 50 mL of 5-25 wt % ammonium chloride aqueous solution. The entire system continued to run for 8 minutes, and the quenched reaction liquid was collected.

[0155] The quenched reaction solution was separated, and the aqueous phase was extracted with 500 mL of methyl tert-butyl ether. The combined organic phases were washed with 100 mL of pure water and 100 mL of 5 wt % hydrochloric acid in sequence.

[0156] The washed organic phase was concentrated under reduced pressure to remove the solvent, and 32 g of the product was obtained by distillation under reduced pressure. Liquid phase detection showed that the liquid phase purity was 99.8A% and the yield was 50.6%.

[0157] Embodiment 29:

[0158] The raw material was diluted with tetrahydrofuran to synthesize 2-acetyl-3-bromopyridine

[0159] Precooling section: 60 g of 3-bromopyridine was dissolved in 540 mL of anhydrous tetrahydrofuran to obtain a tetrahydrofuran solution of 3-bromopyridine with a concentration of 0.66 mol / L, and the tetrahydrofuran solution of 3-bromopyridine was pumped into a 1 / 8 inch PFA tube at a flow rate of 32 mL / min for precooling.

[0160] Reaction section 1: The precooled tetrahydrofuran solution of 3-bromopyridine and 1.1 equivalents of precooled 1.0 mol / L 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex tetrahydrofuran solution (TMPMgCl.LiCl) from the precooling section were pumped into the Corning G1 microchannel reactor at a flow rate of 23.2 mL / min and mixed and reacted at 30 degrees Celsius for 9 seconds.

[0161] Reaction stage 2: 11 equivalents of pre-cooled N,N-dimethylacetamide (DMAc) and the reaction solution from the Corning G1 microchannel reactor in reaction stage 1 were pumped into the second Corning G1 microchannel reactor at a flow rate of 21.5 mL / min and mixed and reacted for 6 seconds at 30 degrees Celsius.

[0162] The reaction liquid flowing out of the second Corning G1 microchannel reactor was directly quenched with 60 mL of 5-25 wt % ammonium chloride aqueous solution. The entire system continued to run for 18 minutes, and the quenched reaction liquid was collected.

[0163] The quenched reaction solution was separated, and the aqueous phase was extracted with 500 mL of methyl tert-butyl ether. The combined organic phases were washed with 100 mL of pure water and 100 mL of 5 wt % hydrochloric acid in sequence.

[0164] The washed organic phase was concentrated under reduced pressure to remove the solvent, and 43 g of the product was obtained by distillation under reduced pressure. Liquid phase detection showed that the liquid phase purity was 99.5A% and the yield was 56.6%.

[0165] The product was 2-acetyl-3-bromopyridine according to NMR analysis. Figure 3 .

[0166] Embodiment 30:

[0167] The raw material was diluted with tetrahydrofuran to synthesize 2-formyl-3-bromopyridine.

[0168] Precooling section: Dissolve 10 g of 3-bromopyridine in 90 mL of anhydrous tetrahydrofuran to obtain a tetrahydrofuran solution of 3-bromopyridine with a concentration of 0.66 mol / L, and pump the tetrahydrofuran solution of 3-bromopyridine into a 1 / 8-inch PFA tube at a flow rate of 32 mL / min for precooling.

[0169] Reaction section 1: The precooled tetrahydrofuran solution of 3-bromopyridine and 1.1 equivalents of precooled 1.0 mol / L tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex (TMPMgCl.LiCl) from the precooling section were pumped into the Corning G1 microchannel reactor at a flow rate of 23.2 mL / min and mixed and reacted at 30 degrees Celsius for 9 seconds.

[0170] Reaction section 2: 11 equivalents of pre-cooled N,N-dimethylformamide and the reaction solution from the Corning G1 microchannel reactor in reaction section 1 were pumped into the second Corning G1 microchannel reactor at a flow rate of 15 mL / min and mixed and reacted at 30 degrees Celsius for 6 seconds.

[0171] The reaction liquid flowing out of the second Corning G1 microchannel reactor was directly quenched with an aqueous solution of ammonium chloride. The entire system continued to run for 3 minutes, and the quenched reaction liquid was collected.

[0172] The quenched reaction solution was separated, and the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with pure water and 5 wt % hydrochloric acid in sequence.

[0173] The washed organic phase was concentrated under reduced pressure to remove the solvent, and 7.5 g of the product was obtained by distillation under reduced pressure. Liquid phase detection showed that the liquid phase purity was 99.1A% and the yield was 53.6%.

[0174] The product was 2-formyl-3-bromopyridine according to NMR analysis. Figure 4 .

[0175] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

[0176] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A continuous synthesis method of 3-bromopyridine derivatives, characterized in that: The synthetic route is as follows: Wherein, in formula (2), R is H or Me.

2. The continuous synthesis method of 3-bromopyridine derivatives according to claim 1, characterized in that: The synthetic route comprises the following steps: Step a: adding a strong base to 3-bromopyridine and continuing the reaction for a period of time; Step b: adding an acylating agent to the reaction solution of step a, and continuing the reaction for a period of time; Step c: quenching the reaction solution of step b to obtain a 3-bromopyridine derivative; Wherein, the 3-bromopyridine derivative is 2-formyl-3-bromopyridine or 2-acetyl-3-bromopyridine.

3. The continuous synthesis method of 3-bromopyridine derivatives according to claim 2, characterized in that: The strong base is selected from one or more of 2,2,6,6-tetramethylpiperidinium magnesium chloride and lithium chloride complex, bis(2,2,6,6-tetramethylpiperidinium) magnesium chloride and lithium chloride complex, 2,2,6,6-tetramethylpiperidinium lithium, diisopropylamide lithium, or a mixture of one or more of them and an organic solvent; and / or, the acylating agent is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, methyl acetate, ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, acetyl chloride, acetic anhydride, formic anhydride, or a mixture of one or more of them and an organic solvent; And / or, the 3-bromopyridine is 3-bromopyridine or a mixture of 3-bromopyridine and an organic solvent; And / or, the quenching reagent in the quenching process is selected from one or more of water, ammonium chloride and acid.

4. The continuous synthesis method of 3-bromopyridine derivatives according to claim 3, characterized in that: The organic solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, toluene, dichloromethane and n-heptane; And / or, the acid is selected from one or more of formic acid, sulfuric acid, hydrochloric acid and citric acid.

5. The continuous synthesis method of 3-bromopyridine derivatives according to claim 2, characterized in that: The molar ratio of 3-bromopyridine to the strong base is 1:(1-3); and / or, the molar ratio of the 3-bromopyridine to the acylating agent is 1:(1-40); And / or, the molar ratio of 3-bromopyridine to the quenching reagent in the quenching process is 1:(1-3).

6. The continuous synthesis method of 3-bromopyridine derivatives according to claim 1, characterized in that: In step a, the reaction time is 5 to 120 seconds; the reaction temperature is -80 to 50 degrees Celsius; And / or, in step b, the reaction time is 5 to 120 seconds; the reaction temperature is -80 to 50 degrees Celsius; And / or, in step c, the duration of the quenching process is 5 to 120 seconds; the temperature is -40 to 70 degrees Celsius.

7. The continuous synthesis method of 3-bromopyridine derivatives according to claim 2, characterized in that: Also includes: Step d: separating and purifying the reaction solution of step c.

8. The continuous synthesis method of 3-bromopyridine derivatives according to claim 7, characterized in that: The purification method is water washing, acid washing and / or distillation.

9. A 3-bromopyridine derivative, characterized in that The 3-bromopyridine derivative is synthesized by the continuous synthesis method according to any one of claims 1 to 7.

10. Use of the 3-bromopyridine derivative synthesized by the continuous synthesis method of the 3-bromopyridine derivative according to any one of claims 1 to 7 or the 3-bromopyridine derivative according to claim 9 in the preparation of TYK2 protein kinase, chemokine receptor, orexin receptor, NFK B pathway activation inhibitor, and TRPM8 antagonist.

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