Method for aryl debromination and acylation of brominated benzazepine compound

Abstract

The present invention relates to the field of compound synthesis, and in particular to a method for aryl debromination and acylation of a brominated benzazepine compound. The method comprises the following steps: mixing a solution containing a brominated benzazepine compound with a solution containing a dehydrogenation reagent to implement a first reaction to remove active hydrogen from an azacyclic ring, so as to obtain a first material; mixing the first material with a solution containing a debromination reagent to implement a second reaction to obtain a second material; subjecting the second material and a solution containing an amide compound to a third reaction, so that a nucleophilic substitution occurs in a substitution position of original bromine on the aryl of the brominated benzazepine compound to obtain an acylated substituent; and after the reaction is complete, quenching the resulting material and performing work-up to obtain an acyl-substituted benzazepine compound, wherein the brominated benzazepine compound is selected from one of a brominated indole compound, a brominated benzimidazole compound, a brominated indazole compound, a brominated indoline compound, and a brominated carbazole compound. The method of the present invention employs mild conditions and provides a product yield of 80% or more.

Description

Methods for the aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds Technical Field

[0001] This invention relates to the field of compound synthesis, and more specifically to a method for the aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds. Background Technology

[0002] Benzoazo heterocyclic compounds are important fine chemical raw materials, widely found in nature. Due to their unique chemical structure and biological activity, they are widely used in industries such as pesticides, pharmaceuticals, fragrances, dyes, feed, food, and additives. Therefore, the synthesis and preparation of benzoazo heterocyclic compounds has always attracted widespread attention and research. Among the many synthetic methods, direct functional group conversion is one of the most effective methods. Acyl groups are highly reactive converting groups, allowing for easier conversion to other functional groups. Therefore, acyl-substituted benzoazo heterocyclic compounds are often used as starting materials for the synthesis of pharmaceutical intermediates and active pharmaceutical ingredients. For example, indole-5-carboxaldehyde, obtained by substituting a formyl group at the C5 position of an indole aryl group, is an important raw material that can be used to prepare the migraine drug Naratriptan. It can also be used to prepare 5-piperazinylmethyl-N1-arylsulfonylindole, a compound that can serve as a 5-HT6R ligand and is a potential drug prodrug for treating schizophrenia and Alzheimer's disease [ACS Med. Chem. Lett. 2010, 1, 340–344]. Therefore, the development of industrial synthesis processes for formyl-substituted benzo[a]azine heterocyclic compounds is of great significance.

[0003] Currently, the main method for preparing acyl-substituted benzo[a]azine heterocyclic compounds involves heating the corresponding bromide under reflux with a strong base, sodium amino, to obtain a sodium salt intermediate. This intermediate is then reacted with tert-butyllithium to remove bromine, followed by a nucleophilic reaction with a nucleophile to finally yield aryl-substituted indole derivatives via a two-step, one-pot method [J.Org.Chem.1986,51(26):5106-5110]. This method requires stringent reaction conditions, needing to be carried out in an anhydrous and oxygen-free environment at -78°C, making large-scale production difficult.

[0004] Besides using bromobenzoza heterocyclic compounds as raw materials, N-Boc benzoza heterocyclic compounds substituted with boric acid can be reacted with tetrahydroquinoline as a catalyst and formic acid as an acylation reagent at room temperature for 36 hours to obtain N-Boc substituted aryl indole derivatives. This method is mild, but the reaction time is long and the reaction yield is low. In addition, the reaction raw materials need to be pre-prepared and the product needs to be deprotected to obtain the final indole-5-carboxaldehyde product, which increases the difficulty of the reaction process and post-processing. At the same time, the reaction yield is low [Angew. Chem. 2017, 129, 8313–8317].

[0005] The methods described above either have harsh reaction conditions, are cumbersome with high production costs, or require pretreatment or post-treatment of both raw materials and products, resulting in low yields. Therefore, none of them are suitable for large-scale production. Summary of the Invention

[0006] To address the aforementioned technical deficiencies, this invention provides a method for the aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds. This method is simple to operate, uses readily available raw materials, has a high yield, and is relatively easy to process, making it suitable for large-scale industrial production. It efficiently prepares acylbenzo[a]azine heterocyclic compounds.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0008] A method for the aryl debromination and acylation of brominated benzo[a]azine heterocyclic compounds includes the following steps:

[0009] S1. A solution containing a bromobenzoxazine heterocyclic compound is mixed with a solution containing a hydrogen-removing reagent to carry out the first reaction, removing the active hydrogen on the azine heterocycle to obtain the first material;

[0010] S2. Mix the first material with a solution containing a debromination reagent to carry out a second reaction, and obtain the second material;

[0011] S3. The second material is reacted with a solution containing an amide compound to produce a nucleophilic substitution reaction at the substitution position of the original bromine on the aryl group of the bromobenzo[a]azine heterocyclic compound to obtain an acylated substituent. After the reaction is completed, the reaction is quenched and post-processed to obtain the acylated substituted benzo[a]azine heterocyclic compound.

[0012] The bromobenzoza heterocyclic compound is selected from one of the following: bromoindole compounds, bromobenzimidazole compounds, bromoindazole compounds, bromoindoline compounds, and bromocarbazole compounds.

[0013] The dehydrogen-removing reagent is an aminoalkylsilane compound; the debromination reagent is a C1-C20 ortho- or iso-alkyllithium.

[0014] Furthermore, the bromobenzo[a]azine heterocyclic compound has the following chemical structure:

[0015] Wherein, X is selected from nitrogen atom or carbon atom; when X is nitrogen atom, R1 does not exist; when X is carbon atom, R1 is selected from one of hydrogen atom, C1-C6 normal or isoalkyl group, chlorine atom; R5 is selected from halogen atom, such as fluorine atom;

[0016] R2 and R3 are each selected from one of hydrogen atom, C1-C6 normal or isoalkoxy, and C1-C6 normal or isoalkyl. R2 and R3 may be the same or different.

[0017] R4 is selected from one of hydrogen atom, C1-C6 ortho- or iso-alkoxy group;

[0018] R6 and R7 are each selected from one of hydrogen atoms, C1-C6 normal or isoalkyl groups, and R6 and R7 may be the same or different.

[0019] The aminoalkylsilane compound is selected from sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and lithium bis(trimethylsilyl)amino.

[0020] The alkyl lithium is n-butyllithium;

[0021] The amide compound is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methoxy-N-methylbenzamide, N-methoxy-N-methylacetamide, and N-methyl-N-methoxy-[(2S)-O-(tert-butyldimethylsilyl)-N'-(ethoxyformyl)]propionamide.

[0022] Furthermore, the bromobenzo[a]azine heterocyclic compound is selected from one of 4-bromoindole, 5-bromoindole, 6-bromoindole, 7-bromoindole, 6-fluoro-5-bromoindole, 7-fluoro-6-bromoindole, 3-methyl-7-bromoindole, 3-ethyl-7-bromoindole, 3-chloro-7-bromoindole, 3-chloro-5-bromoindole, 3-bromocarbazole, 8-methoxy-3-bromocarbazole, 1-methyl-3-bromo-carbazole, 1,7-dimethyl-3-bromo-carbazole, 1,6-dimethyl-3-bromo-carbazole, 7-methoxy-3-bromo-carbazole, 3-bromo-6-methoxy-carbazole, 6,7-dimethoxy-3-bromo-carbazole, 4-bromobenzimidazole, 5-bromobenzimidazole, 7-bromo-indazole, 5-bromo-indazole, 5-bromo-indoline, and 5-bromo-2-oxoindoline.

[0023] Furthermore, the first reaction is carried out in the first group of microchannel continuous flow reactors, the second reaction is carried out in the second group of microchannel continuous flow reactors, and the third reaction is carried out in the third group of microchannel continuous flow reactors; the first group of microchannel continuous flow reactors, the second group of microchannel continuous flow reactors, and the third group of microchannel continuous flow reactors are connected to each other by microchannels; each raw material is injected into the reactor of each reaction stage by an injection pump.

[0024] Furthermore, the first group of microchannel continuous flow reactors consists of three glass chips, the second group of microchannel continuous flow reactors consists of five glass chips, and the third group of microchannel continuous flow reactors consists of two glass chips, with each glass chip holding 20 mL of liquid.

[0025] Furthermore, the reaction temperature of the first reaction is in the range of 23℃-65℃, and the residence time is in the range of 100 seconds-200 seconds; the reaction temperature of the second reaction is in the range of -35℃--10℃, and the residence time is in the range of 80 seconds-180 seconds; the reaction temperature of the third reaction is in the range of 12℃-50℃, and the residence time is in the range of 30 seconds-55 seconds.

[0026] Preferably, the reaction temperature of the first reaction is 25℃-60℃, and the residence time is 120 seconds-180 seconds; the reaction temperature of the second reaction is -30℃--20℃, and the residence time is 100 seconds-150 seconds; the reaction temperature of the third reaction is 15℃-45℃, and the residence time is 35 seconds-50 seconds.

[0027] Furthermore, the molar ratio of the bromobenzo[a]azine heterocyclic compound, the dehydrogenating reagent, the debromination reagent, and the amide compound is 1:1:2:2-4.

[0028] Furthermore, the solvents in the solutions containing bromobenzo[a]azine heterocyclic compounds, the solutions containing dehydrogenating reagents, the solutions containing debrominating reagents, and the solutions containing amide compounds are anhydrous tetrahydrofuran or n-hexane, respectively.

[0029] The concentration of the solution containing the bromobenzo[a]azine heterocyclic compound is 0.8-1.5 mol / L, and the flow rate in the reactor is 10-30 mL / min;

[0030] The concentration of the solution containing the dehydrogenating agent is 0.8-2 mol / L, and the flow rate in the reactor is 20-40 mL / min;

[0031] The concentration of the solution containing the debromination reagent is 0.8-2 mol / L, and the flow rate in the reactor is 20-40 mL / min;

[0032] The concentration of the amide-containing solution is 1.5-5 mol / L, and the flow rate in the reactor is 10-30 mL / min.

[0033] Furthermore, the post-processing includes the following operations: cooling the third material collected from the third group of microchannel continuous flow reactors to below 5°C, adding phosphoric acid aqueous solution to quench the reaction, extracting with ester solvents, combining the organic phases, washing, drying, removing solvent, and recrystallizing.

[0034] Beneficial technical effects:

[0035] This invention develops a method for introducing an acyl group onto the benzene ring of a brominated benzo[a]azine heterocyclic compound. The method efficiently synthesizes acyl-containing benzo[a]azine heterocyclic compounds using microchannel continuous flow technology. An organic base (such as sodium bis(trimethylsilyl)amino) (HMDSNa) is used as a dehydrogenating agent to remove the active hydrogen atom from the nitrogen atom of the nitrogen ring in the brominated benzo[a]azine heterocyclic compound. Then, an alkyllithium is used as a debrominating agent to remove bromine from the benzene ring. The subsequent reaction with an amide compound in a microchannel allows for milder reaction conditions, eliminating the need to reach the -78°C required in conventional techniques. Intermediate products in the reaction process do not require separation and can directly proceed to the next step. After the reaction, only simple quenching and extraction are needed to obtain high-purity acyl-containing benzo[a]azine heterocyclic compounds.

[0036] The reaction conditions of this invention are relatively mild, the raw materials are simple, the yield is high, the purity is good, the reaction can be carried out continuously and scaled up, and there is little "three wastes", making it green and environmentally friendly and suitable for large-scale industrial production. Attached Figure Description

[0037] Figure 1 is a schematic diagram of the microchannel continuous flow process for preparing indole-5-formaldehyde. Detailed Implementation

[0038] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0039] Unless otherwise specifically stated, the numerical values ​​set forth in these embodiments do not limit the scope of the invention. Techniques and methods known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques and methods should be considered part of the specification. In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0040] Furthermore, it should be noted that the use of terms such as "first" and "second" to define reaction temperature, microchannel continuous flow reactor, etc., is merely for the purpose of distinguishing each reaction step. Unless otherwise stated, the above terms have no special meaning and therefore should not be construed as limiting the scope of protection of this invention.

[0041] Experimental methods not specified in the following examples are generally performed according to national standards; if there is no corresponding national standard, they are performed according to general standard requirements or general methods.

[0042] The yields described below are mass products, expressed in wt%, with wt% omitted below.

[0043] Residence time refers to the time required for materials to pass through a microchannel continuous flow reactor. The specific calculation method is: residence time = liquid holding volume × (60 s / min) / total volume flow rate;

[0044] The liquid holding volume is the capacity of the microchannel continuous flow reactor, and the liquid holding capacity of a single glass core is a fixed value of 20 mL.

[0045] The total volumetric flow rate is the sum of the flow rates of each syringe pump.

[0046] Example 1

[0047] Preparation of indole-5-carboxaldehyde using conventional methods:

[0048] 19.6 g (0.1 mol) of 5-bromoindole was added to a 500 mL three-necked flask. Under nitrogen protection, 100 mL of anhydrous tetrahydrofuran was added, and the mixture was stirred until the 5-bromoindole was completely dissolved. Then, sodium bis(trimethylsilyl)amino (100 mL, 1 M, tetrahydrofuran solution) was added, and the mixture was stirred for 1 h at room temperature. The reaction mixture was then cooled to -78 °C, and a solution of n-butyllithium (125 mL, 1.6 M, n-hexane solution) was slowly added dropwise. After the addition was complete, the mixture was stirred for another 1 h. Finally, N,N-dimethylformamide (0.2 mol, DMF, 15.5 mL dissolved in 85 mL of tetrahydrofuran solution) was added, and the reaction temperature was raised to room temperature. The mixture was stirred continuously, and the reaction was monitored by TLC until complete. The reaction was stopped, the temperature was lowered to 0°C, and the reaction was quenched by slowly adding 1M H3PO4 aqueous solution. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated NaHCO3 aqueous solution, dried over anhydrous MgSO4, and rotary evaporated to obtain the crude product. The crude product was recrystallized from ethanol to give indole-5-carboxaldehyde, with a yield of 89 wt%.

[0049] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows:

[0050] 1 H NMR (400MHz, CDCl3) δ10.04(s,1H),8.53(s,1H),8.19(s,1H),7.79(dd,J=8 .5,1.5Hz,1H),7.49(d,J=8.5Hz,1H),7.35-7.30(m,1H),6.74-6.69(m,1H);

[0051] 13C NMR (101MHz, CDCl3) δ192.74,139.37,129.78,127.74,126.38,126.10,122.31,111.76,104.50.

[0052] Example 2

[0053] The method for aryl debromination and acylation of brominated benzo[a]azine heterocyclic compounds, specifically the preparation of indole-5-carboxaldehyde via microchannel continuous flow, is shown in Figure 1, and includes the following steps:

[0054] S1, Preparation of 5-bromoindole solution: Add 5-bromoindole (raw material, 19.6 g, 0.1 mol) to a 500 mL three-necked flask, add 80 mL of anhydrous tetrahydrofuran under nitrogen protection, and stir until 5-bromoindole is completely dissolved.

[0055] A sodium bis(trimethylsilyl)amino sodium solution (alkali, HMDSNa, 100 mL, 1 M tetrahydrofuran solution) and a 5-bromoindole solution (100 mL, 1 M tetrahydrofuran solution) were respectively introduced into the first group of microchannel continuous flow reactors ③ using syringe pumps ① and ②, with a flow rate set at 10 mL / min (or the sodium bis(trimethylsilyl)amino sodium solution was added to the 5-bromoindole tetrahydrofuran solution, mixed thoroughly, and then introduced into the first group of microchannel continuous flow reactors ③ using a single syringe pump, with a flow rate set at 20 mL / min). The mixture underwent a first reaction in the first group of microchannel continuous flow reactors ③, with the temperature set at 25 °C and the retention time of the mixture within it at 3 min. The first material was obtained by exiting the first group of microchannel continuous flow reactors ③.

[0056] S2, dilution of n-butyllithium: cool the n-butyllithium solution (nBuLi, 125 mL, 1.6 M n-hexane solution) to -20 °C, add 75 mL of anhydrous tetrahydrofuran solution to obtain a 1 M dilution of n-butyllithium;

[0057] The first material and the diluent solution of n-butyllithium introduced by the injection pump ④ are simultaneously introduced into the second set of microchannel continuous flow reactors ⑤ to form a mixture for the second reaction. The flow rate of the diluent solution of n-butyllithium is set to 20 mL / min, the temperature of the second set of microchannel continuous flow reactors ⑤ is set to -20℃, the retention time of the mixture in the second set of microchannel continuous flow reactors ⑤ is 2.5 min, and the second material is obtained by flowing out of the second set of microchannel continuous flow reactors ⑤.

[0058] S3. Preparation of DMF solution: Dissolve anhydrous DMF (nucleophile, 15.5 mL, 0.2 mol) in 85 mL of anhydrous tetrahydrofuran solution, mix well, and prepare a 2 M DMF tetrahydrofuran solution.

[0059] The second material and the DMF solution introduced by the injection pump ⑥ are simultaneously introduced into the second set of microchannel continuous flow reactors ⑦ to form a mixture for the third reaction. The flow rate of the DMF solution is set to 10 mL / min, the temperature of the third set of microchannel continuous flow reactors ⑦ is set to 25℃, and the retention time of the mixture in the third set of microchannel continuous flow reactors ⑦ is 48 s. The mixture flows out of the third set of microchannel continuous flow reactors ⑦ and is collected to obtain the third material.

[0060] Post-processing: The third material was cooled to 0°C, and the reaction was quenched by slowly adding 1M H3PO4 aqueous solution. The mixture was then extracted with ethyl acetate. The organic phases were combined, washed with saturated NaHCO3 aqueous solution, dried over anhydrous MgSO4, and the solvent was removed by vacuum distillation to obtain the crude product. Recrystallization from ethanol yielded purified indole-5-carboxaldehyde.

[0061] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0062] Example 3

[0063] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the first group of microchannel continuous flow reactors ③ is set to 40°C.

[0064] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0065] Example 4

[0066] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the first group of microchannel continuous flow reactors ③ is set to 60°C.

[0067] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0068] Example 5

[0069] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the second microchannel continuous flow reactor ⑤ is set to -30℃.

[0070] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0071] Example 6

[0072] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the second group of microchannel continuous flow reactors ⑤ is set to -10℃.

[0073] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0074] Example 7

[0075] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the second microchannel continuous flow reactor ⑤ is set to 0°C.

[0076] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0077] Example 8

[0078] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the third microchannel continuous flow reactor ⑦ is set to 15°C.

[0079] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0080] Example 9

[0081] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the third microchannel continuous flow reactor ⑦ is set to 35°C.

[0082] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0083] Example 10

[0084] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that the temperature of the third group of microchannel continuous flow reactors (⑦) is set to 45°C.

[0085] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0086] Example 11

[0087] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that: the mixture in S2 is retained for 2 min in the second group of microchannel continuous flow reactors ⑤; the flow rate of the n-butyllithium dilution solution is set to 30 mL / min; and the mixture in S3 is retained for 40 s in the third group of microchannel continuous flow reactors ⑦.

[0088] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0089] Example 12

[0090] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow reactor. The preparation process is the same as in Example 2, except that: the retention time of the mixture in S2 in the second group of microchannel continuous flow reactors ⑤ is 100 s; the flow rate of the n-butyllithium dilution solution is set to 40 mL / min; and the retention time of the mixture in S3 in the third group of microchannel continuous flow reactors ⑦ is 35 s.

[0091] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0092] Example 13

[0093] This case specifically describes the preparation of indole-5-carboxaldehyde using microchannel continuous flow. The preparation process is the same as in Example 2, except that: the mixture in S1 (if there are two groups of materials, the flow rate is set to 20 mL / min and 10 mL / min respectively; if it is a mixture, the flow rate is set to 30 mL / min) has a retention time of 120 s in the first group of microchannel continuous flow reactors ③; the mixture in S2 has a retention time of 120 s in the second group of microchannel continuous flow reactors ⑤; and the mixture in S3 has a retention time of 40 s in the third group of microchannel continuous flow reactors ⑦.

[0094] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0095] Example 14

[0096] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 2, except that: in S3, the DMF solution was prepared by dissolving 8 mL of anhydrous DMF (0.1 mol) in 92 mL of anhydrous tetrahydrofuran solution, mixing thoroughly to obtain a 1 M DMF tetrahydrofuran solution, and setting the flow rate of the DMF tetrahydrofuran solution to 20 mL / min; in S3, the retention time of the mixture in the third group of microchannel continuous flow reactors ⑦ was 40 s.

[0097] That is, n in Examples 2-13(原料) :n (碱) :n (nBuLi) :n (亲核试剂) = 1:1:2:2, while in this case n (原料) :n (碱) :n (nBuLi) :n (亲核试剂) = 1:1:2:1.

[0098] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0099] Example 15

[0100] This case specifically describes the preparation of indole-5-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 2, except that in S3, the DMF solution was prepared by dissolving 31 mL of anhydrous DMF (0.4 mol) in 70 mL of anhydrous tetrahydrofuran solution and mixing thoroughly to obtain a 1 M DMF tetrahydrofuran solution.

[0101] That is, n in Examples 2-13 (原料) :n (碱) :n (nBuLi) :n (亲核试剂) = 1:1:2:2, while in this case n (原料) :n (碱) :n (nBuLi) :n (亲核试剂) = 1:1:2:4.

[0102] The product yield in this case is shown in Table 1. The peak positions of the product's 1H and 1C NMR spectra are the same as in Example 1.

[0103] The reaction conditions and yields of the product indole-5-carboxaldehyde in Examples 1-15 above are shown in Table 1.

[0104] Table 1. Yields of indole-5-carboxaldehyde under different reaction conditions in Examples 1-15

[0105] As shown in Table 1, when the molar ratio of the brominated benzo[a]a heterocyclic compound (raw material), the dehydrogenating reagent (base), the debromination reagent (nBuLi), and the amide compound (nucleophile) is 1:1:2:2-4, the preferred reaction temperature for the first reaction in the first group of microchannel continuous flow reactors is 25℃-60℃, and the preferred residence time is 120-180 seconds; the preferred reaction temperature for the second reaction in the second group of microchannel continuous flow reactors is -30℃--20℃, and the preferred residence time is 100-150 seconds; the preferred reaction temperature for the third reaction in the third group of microchannel continuous flow reactors is 15℃-45℃, and the preferred residence time is 35-50 seconds. The yield of the acylated benzo[a]a heterocyclic compound (the product indole-5-carboxaldehyde in Examples 2-15) is above 90%, and even as high as 99%.

[0106] Example 16

[0107] This case specifically describes the preparation of carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the raw material is 3-bromocarbazole (amount: 24.4 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is carbazole-3-carbaldehyde with a yield of 97%.

[0108] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ10.10(s,1H),8.61(s,1H),8.56(s,1H),8.13(d,J=8. 0Hz,1H),7.98(dd,J=8.4,1.6Hz,1H),7.52-7.47(m,3H),7.36-7.26(m,1H);

[0109] 13 C NMR (100MHz, CDCl3): δ192.03,143.33,140.00,129.07,127.34,126.97,124.11,123.56,123.22,120.76,120.73,111.17,110.97.

[0110] Example 17

[0111] This case specifically describes the preparation of 8-methoxy-9H-carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 8-methoxy-3-bromocarbazole (CAS No. 1916473-46-5, amount: 27.5 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 8-methoxy-9H-carbazole-3-carbaldehyde with a yield of 87%.

[0112] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (500MHz, CDCl3): δ = 4.03 (s, 3H), 6.97 (d, J = 7.9Hz, 1H), 7.25 (t, J = 7.9Hz, 1H), 7.53 (d, J = 8.5Hz, 1H), 7. 73(d,J=7.9Hz,1H),7.98(dd,J=8.5,1.6Hz,1H),8.59(d,J=0.6Hz,1H),8.62(br.s,1H),10.10(s,1H)ppm.;

[0113] 13 C NMR and DEPT (125MHz, CDCl3): δ = 55.75, 107.07, 111.40, 113.14, 121.35, 123.97, 124.37, 124.70, 127.17, 129.22, 130.42, 142.95, 145.97, 192.06.

[0114] Example 18

[0115] This case specifically describes the preparation of 1-methyl-9H-carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the raw material is 1-methyl-3-bromo-carbazole (amount: 25.8 g, 0.1 mol, which is synthesized using method CN113480470A, starting with the corresponding monosubstituted diphenylamine, first cyclizing and then adding bromine, or using the corresponding monosubstituted carbazole to directly add bromine at the 3-position with NBS). The nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 1-methyl-9H-carbazole-3-carbaldehyde with a yield of 91%.

[0116] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (500MHz, CDCl3): δ=2.62(s,3H,CH3),7.32(m,1H),7.48(br,1H),7.51(br,1H),7.80(br s,1H),8.12(br,1H),8.35(br s,1H),8.45(d,J=1.0Hz,1H),10.07(s,1H);

[0117] 13 C NMR (125MHz, CDCl3): δ=16.8,111.2,120.4,120.78,120.80,122.5,123.0,123.8,126.8,127.0,129.4,139.9,142.9,192.1.

[0118] Example 19

[0119] This case specifically describes the preparation of 1,7-dimethyl-9H-carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the raw material is 1,7-dimethyl-3-bromo-carbazole (amount: 27.3 g, 0.1 mol, which is synthesized using method CN113480470A, starting with diphenylamine with the corresponding disubstituted form, first cyclizing and then adding bromine, or using the corresponding disubstituted carbazole with NBS to directly add bromine at the 3-position [J], Bioorganic & Medicinal Chemistry Letters, 2012, 22(1), P363-366), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 1,7-dimethyl-9H-carbazole-3-carbaldehyde with a yield of 97%.

[0120] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1H NMR (500MHz, CDCl3): δ = 2.56 (s, 3H), 2.61 (s, 3H), 7.14 (br d, J = 8.0Hz, 1H), 7.30 (br s, 1H), 7.77 (br s, 1H), 8.00 (d, J = 7.9Hz, 1H), 8.26 (br s,1H,NH),8.41(br s,1H),10.1(s,1H);

[0121] 13 C NMR (125MHz, CDCl3): δ = 16.7, 22.1, 111.3, 120.2, 120.4, 121.4, 122.1, 122.3, 123.1, 126.7, 129.3, 137.1, 140.3, 142.8, 192.1.

[0122] Example 20

[0123] This case specifically describes the preparation of 1,6-dimethyl-9H-carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the raw material is 1,6-dimethyl-3-bromo-carbazole (amount: 27.3 g, 0.1 mol, which is synthesized using method CN113480470A, starting with diphenylamine with the corresponding disubstituted form, first cyclizing and then adding bromine, or using the corresponding disubstituted carbazole with NBS to directly add bromine at the 3-position [J], Bioorganic & Medicinal Chemistry Letters, 2012, 22(1), P363-366), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 1,6-dimethyl-9H-carbazole-3-carbaldehyde with a yield of 91%.

[0124] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (500MHz, CDCl3): δ = 2.56 (s, 3H), 2.61 (s, 3H), 7.30 (m, 1H), 7.40 (d, J = 7.8Hz, 1H), 7.78 (br s, 1H), 7.91 (br s, 1H), 8.29 (br s, 1H, NH), 8.42 (br s,1H),10.07(s,1H);

[0125] 13C NMR (125MHz, CDCl3): δ = 16.7, 21.5, 110.9, 120.3, 120.7, 122.6, 122.8, 123.9, 126.8, 128.1, 129.2, 130.3, 138.0, 143.1, 192.1.

[0126] Example 21

[0127] This case specifically describes the preparation of 7-methoxy-9H-carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 7-methoxy-3-bromo-carbazole (CAS No. 1353492-63-3, amount: 28.9 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 7-methoxy-9H-carbazole-3-carbaldehyde with a yield of 93%.

[0128] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (500MHz, acetone-d6): δ = 2.62 (s, 3H), 3.88 (s, 3H), 6.90 (m, 1H), 7.08 (d, J = 2.2Hz, 1H), 7.69 (br s, 1H), 8.09 (d, J = 8.5Hz, 1H), 8.42 (br s,1H),10.03(s,1H),10.65(br,1H,NH);

[0129] 13 C NMR (125MHz, acetone-d6): δ = 17.6, 56.5, 96.8, 110.7, 118.7, 122.1, 122.5, 122.9, 124.6, 126.9, 131.1, 143.8, 144.8, 161.3, 192.8.

[0130] Example 22

[0131] This case specifically describes the preparation of 6-methoxy-9H-carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 3-bromo-6-methoxy-9H-carbazole (CAS No. 200289-73-2, amount: 28.9 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 6-methoxy-9H-carbazole-3-carbaldehyde with a yield of 87%.

[0132] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1H NMR (500MHz, CDCl3 / DMSO-d6, 9:1): δ = 2.55 (s, 3H), 3.85 (s, 3H), 7.00 (m, 1H), 7.39 (d, J = 8.5Hz, 1H), 7.49 (d, J = 2.5Hz, 1H), 7.64 (br s, 1H), 8.31 (br s,1H),9.94(s,1H),10.78(br s,1H,NH);

[0133] 13 C NMR (125MHz, CDCl3 / DMSO-d6, 9:1): δ=16.4,55.2,102.2,111.8,115.0,120.4,121.8,122.0,123.2,125.4,127.5,134.8,143.4,153.5,191.3.

[0134] Example 23

[0135] This case specifically describes the preparation of 6,7-dimethoxy-9H-carbazole-3-carbaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 6,7-dimethoxy-3-bromo-carbazole (32.0 g, 0.1 mol), the nucleophile is DMF (31 mL, 0.4 mol), and the product is 6,7-dimethoxy-9H-carbazole-3-carbaldehyde with a yield of 83%.

[0136] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (500MHz, CDCl3): δ = 2.59 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 7.02 (s, 1H), 7.55 (s, 1H), 7.71 (br s, 1H), 8.23 ​​(br s, 1H, NH), 8.34 (br s,1H),10.06(s,1H);

[0137] 13 C NMR (125MHz, CDCl3): δ=16.7,56.2,56.5,94.7,102.7,115.9,120.1,121.4,123.3,125.7,129.2,134.5,142.6,145.4,150.0,192.2.

[0138] Example 24

[0139] This case specifically describes the preparation of indole-4-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the raw material is 4-bromoindole (19.6 g, 0.1 mol), the nucleophile is DMF (31 mL, 0.4 mol), and the product is indole-4-carboxaldehyde with a yield of 91%.

[0140] The product in this case was analyzed by proton nuclear magnetic resonance spectroscopy, and the results are as follows: 1 HNMR (400MHz, CDCl3): δ = 7.3-7.45 (m, 3H), 7.6-7.7 (m, 2H), 8.65 (br s, 1H), 10.4 (s, 1H).

[0141] Example 25

[0142] This case specifically describes the preparation of indole-6-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the raw material is 6-bromoindole (19.6 g, 0.1 mol), the nucleophile is DMF (31 mL, 0.4 mol), and the product is indole-6-carboxaldehyde with a yield of 95%.

[0143] The product in this case was analyzed by proton nuclear magnetic resonance spectroscopy, and the results are as follows: 1 NMR (400MHz, CDCl3): δ = 6.64 (br s, 1H), 7.46 (m, 1H), 7.65 (d, 1H, J = 8.1), 7.74 (d, 1H, J = 8.1), 7.96 (s, 1H), 8.8 (br s, 1), 10.0 (s, 1H).

[0144] Example 26

[0145] This case specifically describes the preparation of indole-7-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the raw material is 7-bromoindole (19.6 g, 0.1 mol), the nucleophile is DMF (31 mL, 0.4 mol), and the product is indole-7-carboxaldehyde with a yield of 93%.

[0146] The product in this case was analyzed by proton nuclear magnetic resonance spectroscopy, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 6.61 (m, 1H), 7.24 (t, J = 7.5, 1H), 7.32 (m, 1H), 7.62 (d, J = 7.2, 1H), 7.92 (d, J = 7.9, 1H).

[0147] Example 27

[0148] This case specifically describes the preparation of 6-fluoro-indole-5-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 6-fluoro-5-bromoindole (CAS No. 434960-42-6, amount: 21.2 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 6-fluoro-indole-5-carboxaldehyde with a yield of 85%.

[0149] The product from this case was subjected to proton NMR, carbon NMR, and fluorine atom detection, and the results are as follows: 1 H NMR (400MHz, DMSO-d6): δ = 11.60 (s, 1H), 10.16 (s, 1H), 8.06 (d, J = 6.8Hz, 1H,), 7.47 (t, J = 3.0Hz, 1H,), 7.28 (d, J = 12.0Hz, 1H,), 6.61 (s, 1H);

[0150] 13 C NMR (100MHz, DMSO-d6): δ = 188.2 (d, J CF =5Hz), 160.2(d,J CF =246Hz), 139.7(d,J) CF =13Hz), 128.8(d,J CF =3Hz), 124.9, 123.2(d,J) CF =4Hz), 117.9(d,J CF =11Hz), 103.7, 98.4 (d, J) CF =25Hz);

[0151] 19 F NMR (DMSO-d6): δ = 130.24.

[0152] Example 28

[0153] This case specifically describes the preparation of 7-fluoro-indole-6-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 7-fluoro-6-bromoindole (CAS No. 936901-94-9, amount: 21.2 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 7-fluoro-indole-6-carboxaldehyde with a yield of 81%.

[0154] The product from this case was subjected to proton NMR, carbon NMR, and fluorine atom detection, and the results are as follows: 1H NMR (400MHz, DMSO-d6): δ = 10.28 (s, 1H), 7.67-7.34 (m, 2H), 7.41-7.37 (m, 1H), 6.59 (s, 1H);

[0155] 13 C NMR (100MHz, DMSO-d6): δ = 187.3 (d, 3JCF = 7Hz), 152.7 (d, J CF =259Hz), 137.0(d,J CF =8Hz), 131.6, 123.2 (d, J) CF =11Hz), 117.9, 117.0 (d, J) CF =3Hz), 116.5(d,J CF =3Hz), 103.7(d,J CF =1Hz);

[0156] 19 F NMR (DMSO-d6): δ = 140.48.

[0157] Example 29

[0158] This case specifically describes the preparation of 3-methyl-indole-7-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 3-methyl-7-bromoindole (CAS No. 86915-22-2, amount: 21.0 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 3-methyl-indole-7-carboxaldehyde with a yield of 92%.

[0159] The product in this case was analyzed by proton nuclear magnetic resonance spectroscopy, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 10.12 (s, 1H), 9.85 (s, 1H), 7.89 (d, J = 7.8Hz, 1H), 7.65 ( d,J=8.1Hz,1H),7.25(d,J=7.6Hz,1H),7.12-7.09(m,1H),2.37(d,J=1.1Hz,3H).

[0160] Example 30

[0161] This case specifically describes the preparation of 3-ethyl-indole-7-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 3-ethyl-7-bromoindole (CAS No. 1360962-55-5, amount: 22.4 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 3-ethyl-indole-7-carboxaldehyde with a yield of 96%.

[0162] The product in this case was analyzed by proton nuclear magnetic resonance spectroscopy, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 10.12 (s, 1H), 9.87 (s, 1H), 7.92 (d, J = 7.8Hz, 1H), 7.65 (d, J = 7.3Hz, 1H), 7.26 (d, J = 7.5Hz, 1H), 7.14-7.10 (m, 1H), 2.83 (q, J = 7.5Hz, 2H), 1.35 (t, J = 7.5Hz, 3H).

[0163] Example 31

[0164] This case specifically describes the preparation of 3-chloro-indole-5-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 3-chloro-5-bromoindole (CAS No. 1388073-38-8, amount: 17.9 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 3-chloro-indole-5-carboxaldehyde with a yield of 86%.

[0165] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 7.31 (s, 2H), 4.45 (bs, 2H);

[0166] 13 C NMR (100MHz, CDCl3): δ=139.4, 130.2, 120.0, 107.9.

[0167] Example 32

[0168] This case specifically describes the preparation of 5-benzoylindole using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 5-bromoindole (19.6 g, 0.1 mol), the nucleophile is N-methoxy-N-methyl-benzamide (66 g, 0.4 mol), and the product is 5-benzoylindole with a yield of 97%.

[0169] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 8.85 (bs, NH, 1H), 8.14 (s, 1H), 7.86-7.77 (m, 3H), 7 .61-7.55(m,1H),7.52-7.42(m,3H),7.31-7.29(m,1H),6.69-6.60(m,1H);

[0170] 13 C NMR (100MHz, CDCl3): δ=197.7,139.0,138.4,131.7,130.0,129.6,128.2,127.2,125.9,125.4,124.2,111.2,104.2.

[0171] Example 33

[0172] This case specifically describes the preparation of 7-benzoylindole using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 7-bromoindole (19.6 g, 0.1 mol), the nucleophile is N-methoxy-N-methyl-benzamide (66 g, 0.4 mol), and the product is 7-benzoylindole with a yield of 91%.

[0173] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 9.79 (s, 1H), 7.90 (d, J = 7.6Hz, 1H), 7.80 (d, J = 7.2Hz, 1H), 7.53-7.39 (m, 5H), 7.25-7.21 (m, 2H), 6.74 (d, J = 3.2Hz, 1H);

[0174] 13 C NMR (100MHz, CDCl3): δ=189.0,142.4,136.1,131.8,131.4,130.2,128.7,127.8,126.3,124.8,122.2,120.2,104.

[0175] Example 34

[0176] This case specifically describes the preparation of 5-acetylindole using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 5-bromoindole (19.6 g, 0.1 mol), the nucleophile is N-methoxy-N-methyl-acetamide (41.2 g, 0.4 mol), and the product is 5-acetylindole with a yield of 87%.

[0177] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 8.78 (s, 1H), 8.43-8.28 (m, 1H), 7.88 (dd, J = 8.6, 1.7Hz, 1 H),7.42(dd,J=8.6,0.9Hz,1H),7.26(s,1H),6.67(m,1H),2.68(d,J=2.2Hz,3H);

[0178] 13 C NMR (101MHz, CDCl3): δ=198.9,138.7,130.0,127.5,126.0,123.3,122.3,111.2,104.3,26.8.

[0179] Example 35

[0180] This case specifically describes the microchannel continuous flow preparation of (2S)-4-[(3-tert-butyldimethylsilyl)-2-(ethoxyformamido)-1-oxopropyl]-1H-indole. The preparation process is the same as in Example 15, except that the starting material is 4-bromoindole (19.6 g, 0.1 mol), the nucleophile is N-methyl-N-methoxy-[(2S)-O-(tert-butyldimethylsilyl)-N'-(ethoxyformyl)]propionamide (33.4 g, 0.2 mol), and the product is (2S)-4-[(3-tert-butyldimethylsilyl)-2-(ethoxyformamido)-1-oxopropyl]-1H-indole, with a yield of 87%.

[0181] The product in this case was analyzed by proton nuclear magnetic resonance spectroscopy, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = -0.21 (s, 3H), -0.19 (s, 3H), 0.75 (s, 9H), 1.23 (t, J = 7.1Hz, 3H), 3.97 (d, J = 2Hz, 2H), 4.18 (q ,J=7.1Hz,2H),5.52(m,1H),6.0(d,J=7.1Hz,1H,),7.2-7(m,3H),7.6(d,J=6.2Hz,1H),7.7(d,J=6.1Hz,1H),8.8(br s,1H).

[0182] Example 36

[0183] This case specifically describes the preparation of 1H-benzimidazole-5-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 5-bromobenzimidazole (CAS No. 4887-88-1, amount: 19.5 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 1H-benzimidazole-5-carboxaldehyde with a yield of 86%.

[0184] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1H NMR (400MHz, CDCl3): δ = 7.55 (d, J = 8.4, 1H), 7.65 (m, 1H), 8.01 (br s, 1H), 8.24 (s, 1H), 9.85 (s, 1H,);

[0185] 13 C NMR (100MHz, CDCl3): δ=116.3, 120.5, 124.5, 133.1, 139.7, 142.8, 145.9, 194.0.

[0186] Example 37

[0187] This case specifically describes the preparation of 1H-benzimidazole-4-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 4-bromobenzimidazole (CAS No. 83741-35-9, amount: 19.5 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 1H-benzimidazole-4-carboxaldehyde with a yield of 80%.

[0188] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1 H NMR (300MHz, DMSO-d6): δ = 10.24 (s, 1H), 8.33 (s, 1H), 8.00 (dd, J = 8.0, 1.0Hz, 1H), 7.83 (dd, J = 7.4, 1.0Hz, 1H), 7.40 (dd, J = 8.0, 7.4Hz, 1H);

[0189] 13 C NMR (75MHz, DMSO) δ191.7,144.2,142.5,127.0,124.6,122.2,121.4.

[0190] Example 38

[0191] This case specifically describes the preparation of 1H-indazole-7-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 7-bromo-1H-indazole (CAS No. 53857-58-2, amount: 19.5 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 1H-indazole-7-carboxaldehyde with a yield of 83%.

[0192] The product in this case was analyzed by proton and carbon NMR spectra, and the results are as follows: 1H NMR (300MHz, CDCl3): δ = 12.02 (s, 1H), 10.15 (s, 1H), 8.19 (s, 1H), 8.05 (dd, J = 8.0, 0.9Hz, 1H), 7.85 (dd, J = 7.1, 0.9Hz, 1H), 7.31 (dd, J = 8.1, 7.1Hz, 1H);

[0193] 13 C NMR (75MHz, CDCl3) δ192.2,136.7,134.9,133.2,128.4,124.4,120.7,120.4.

[0194] Example 39

[0195] This case specifically describes the preparation of 1H-indazole-5-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 5-bromo-1H-indazole (CAS No. 53857-57-1, amount: 19.5 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 1H-indazole-5-carboxaldehyde with a yield of 88%.

[0196] The product in this case was analyzed by proton nuclear magnetic resonance spectroscopy, and the results are as follows: 1 H NMR (400MHz, CDCl3): δ = 10.54 (br s, 1H, NH), 10.07 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.99 (d, J = 9.0Hz, 1H), 7.62 (d, J = 9.0Hz, 1H).

[0197] Example 40

[0198] This case specifically describes the preparation of 2-oxoindoline-5-carboxaldehyde using a microchannel continuous flow method. The preparation process is the same as in Example 15, except that the starting material is 5-bromoindoline (CAS No. 20870-78-4, amount: 21.1 g, 0.1 mol), the nucleophile is DMF (amount: 31 mL, 0.4 mol), and the product is 2-oxoindoline-5-carboxaldehyde with a yield of 92%.

[0199] The product from this case was analyzed by proton NMR spectroscopy, and the results are as follows: 1 H NMR (500MHz, DMSO-d6): δ = 7.83 (d, J = 1.5Hz, 1H), 7.69-7.65 (m, 2H), 6.85 (dd, J = 17.6, 10.9Hz, 1H), 5.97 (dd, J=17.6, 0.9Hz, 1H), 5.38 (dd, J=10.9, 0.8Hz, 1H), 4.37 (s, 2H).

[0200] The raw materials and products of Examples 15-40 above are shown in Table 2.

[0201] Table 2. Raw materials, corresponding products, and yields of Examples 15-40

[0202] As shown in Table 2, the method of the present invention can introduce an acyl group onto the benzene ring of a bromobenzo[a]azine heterocyclic compound, and the yield of the corresponding acylated product is above 80%.

[0203] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for the aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds, characterized in that, Includes the following steps: S1. A solution containing a bromobenzoxazine heterocyclic compound is mixed with a solution containing a hydrogen-removing reagent to carry out the first reaction, removing the active hydrogen on the azine heterocycle to obtain the first material; S2. Mix the first material with a solution containing a debromination reagent to carry out a second reaction, and obtain the second material; S3. The second material is reacted with a solution containing an amide compound to produce a nucleophilic substitution reaction at the substitution position of the original bromine on the aryl group of the bromobenzo[a]azine heterocyclic compound to obtain an acylated substituent. After the reaction is completed, the reaction is quenched and post-processed to obtain the acylated substituted benzo[a]azine heterocyclic compound. The bromobenzoza heterocyclic compound is selected from one of the following: bromoindole compounds, bromobenzimidazole compounds, bromoindazole compounds, bromoindoline compounds, and bromocarbazole compounds. The dehydrogen-removing reagent is an aminoalkylsilane compound; the debromination reagent is a C1-C20 ortho- or iso-alkyllithium.

2. The method for aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds according to claim 1, characterized in that, The bromobenzo[a]azine heterocyclic compound has the following chemical structure: Wherein, X is selected from nitrogen atom or carbon atom; when X is nitrogen atom, R1 does not exist; when X is carbon atom, R1 is selected from one of hydrogen atom, C1-C6 normal or isoalkyl, chlorine atom; R5 is selected from halogen atom; R2 and R3 are each selected from one of hydrogen atom, C1-C6 normal or isoalkoxy, and C1-C6 normal or isoalkyl. R2 and R3 may be the same or different. R4 is selected from one of hydrogen atom, C1-C6 ortho- or iso-alkoxy group; R6 and R7 are each selected from one of hydrogen atoms, C1-C6 normal or isoalkyl groups, and R6 and R7 may be the same or different. The aminoalkylsilane compound is selected from sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and lithium bis(trimethylsilyl)amino. The alkyl lithium is n-butyllithium; The amide compound is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methoxy-N-methylbenzamide, N-methoxy-N-methylacetamide, and N-methyl-N-methoxy-[(2S)-O-(tert-butyldimethylsilyl)-N'-(ethoxyformyl)]propionamide.

3. The method for aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds according to claim 2, characterized in that, The bromobenzoxazine heterocyclic compound is selected from one of the following: 4-bromoindole, 5-bromoindole, 6-bromoindole, 7-bromoindole, 6-fluoro-5-bromoindole, 7-fluoro-6-bromoindole, 3-methyl-7-bromoindole, 3-ethyl-7-bromoindole, 3-chloro-7-bromoindole, 3-chloro-5-bromoindole, 3-bromocarbazole, 8-methoxy-3-bromocarbazole, 1-methyl-3-bromo-carbazole, 1,7-dimethyl-3-bromo-carbazole, 1,6-dimethyl-3-bromo-carbazole, 7-methoxy-3-bromo-carbazole, 3-bromo-6-methoxy-carbazole, 6,7-dimethoxy-3-bromo-carbazole, 4-bromobenzimidazole, 5-bromobenzimidazole, 7-bromoindazole, 5-bromoindazole, 5-bromo-indole, 5-bromo-indoline, and 5-bromo-2-oxoindoline.

4. The method for aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds according to any one of claims 1-3, characterized in that, The first reaction is carried out in the first group of microchannel continuous flow reactors, the second reaction is carried out in the second group of microchannel continuous flow reactors, and the third reaction is carried out in the third group of microchannel continuous flow reactors; the first group of microchannel continuous flow reactors, the second group of microchannel continuous flow reactors, and the third group of microchannel continuous flow reactors are connected to each other by microchannels; each raw material is injected into the reactor of each reaction stage by an injection pump.

5. The method for aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds according to claim 4, characterized in that, The first group of microchannel continuous flow reactors consists of three glass chips, the second group of microchannel continuous flow reactors consists of five glass chips, and the third group of microchannel continuous flow reactors consists of two glass chips, each glass chip holding 20 mL of liquid.

6. The method for aryl debromination and acylation of brominated benzo[a]azine heterocyclic compounds according to claim 5, characterized in that, The reaction temperature of the first reaction is in the range of 23℃-65℃, and the residence time is in the range of 100 seconds-200 seconds; the reaction temperature of the second reaction is in the range of -35℃--10℃, and the residence time is in the range of 80 seconds-180 seconds; the reaction temperature of the third reaction is in the range of 12℃-50℃, and the residence time is in the range of 30 seconds-55 seconds.

7. The method for aryl debromination and acylation of brominated benzo[a]azine heterocyclic compounds according to claim 6, characterized in that, The reaction temperature of the first reaction is 25℃-60℃, and the residence time is 120 seconds-180 seconds; the reaction temperature of the second reaction is -30℃--20℃, and the residence time is 100 seconds-150 seconds; the reaction temperature of the third reaction is 15℃-45℃, and the residence time is 35 seconds-50 seconds.

8. The method for aryl debromination and acylation of brominated benzo[a]azine heterocyclic compounds according to claim 4, characterized in that, The molar ratio of the bromobenzo[a]azine heterocyclic compound, the dehydrogenating reagent, the debromination reagent, and the amide compound is 1:1:2:2-4.

9. The method for aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds according to claim 4, characterized in that, The solvents in the solutions containing bromine-containing benzo[a]azine heterocyclic compounds, the solutions containing dehydrogenating reagents, the solutions containing debrominating reagents, and the solutions containing amide compounds are anhydrous tetrahydrofuran or n-hexane, respectively. The concentration of the solution containing the bromobenzo[a]azine heterocyclic compound is 0.8-1.5 mol / L, and the flow rate in the reactor is 10-30 mL / min; The concentration of the solution containing the dehydrogenating agent is 0.8-2 mol / L, and the flow rate in the reactor is 20-40 mL / min; The concentration of the solution containing the debromination reagent is 0.8-2 mol / L, and the flow rate in the reactor is 20-40 mL / min; The concentration of the amide-containing solution is 1.5-5 mol / L, and the flow rate in the reactor is 10-30 mL / min.

10. The method for aryl debromination and acylation of bromobenzo[a]azine heterocyclic compounds according to claim 4, characterized in that, The post-processing includes the following operations: cooling the third material collected from the third group of microchannel continuous flow reactors to below 5°C, adding phosphoric acid aqueous solution to quench the reaction, extracting with acid ester solvents, combining the organic phases, washing, drying, removing solvents, and recrystallizing.

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