Process for the preparation of an intermediate of ipcozide

Abstract

The application belongs to the field of organic synthesis, and discloses a preparation method of an intermediate of iprocavant, comprising the following steps: S1. mixing 2-methyl-4-methoxy aniline, trioxane, a copper catalyst and a ligand to obtain an intermediate A; and S2. mixing the intermediate A obtained in the step S1 with potassium persulfate to obtain a product. The above reaction is carried out in a micro-channel reactor, realizes continuous flow preparation of segmented temperature control, utilizes the advantages of continuous flow segmented reaction, performs imine generation and oxidative cyclization in different zones, shortens the high-temperature contact time of the oxidant and the substrate, inhibits peroxidation and methoxy hydrolysis, and improves the purity and appearance quality of the product. The micro-channel heat exchange is uniform, there is no local hot spot, the process parameters are continuously controllable, the amplification effect is small, and the industrialized scale production is easy.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing an ipocolpan intermediate, and more particularly to a method for preparing the ipocolpan intermediate 5-methoxy-7-methyl-indole via copper-catalyzed free radical CH cyclization in a continuous flow. Background Technology

[0002] Iptacopan, chemically named 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoate, marketed as Fabhalta, is a first-in-class, orally administered, highly selective, small-molecule, reversible inhibitor of complement factor B (CFB) developed by Novartis. As a successfully marketed small-molecule inhibitor of complement factor B (CFB), iptacopan demonstrates that CFB is an effective target for treating diseases related to the alternative complement pathway.

[0003] 5-Methoxy-7-methyl-indole is the core heterocyclic intermediate in the synthesis of iprocoprine, and its main synthetic routes are as follows:

[0004] (1) The synthetic route of 5-methoxy-7-methyl-indole disclosed in Chinese Patent No. CN113880747A is as follows:

[0005] .

[0006] The first step of this route requires an ultra-low temperature reaction of -78℃, which is very demanding. Furthermore, chloroacetonitrile polymerizes at elevated temperatures in the presence of titanium tetrachloride, making stirring impossible. The second step uses sodium borohydride, which is an easily explosive hazardous material and requires purification by column chromatography, making it unsuitable for industrial production.

[0007] (2) The synthetic route of 5-methoxy-7-methyl-indole disclosed in Chinese Patent No. CN112457235A is as follows:

[0008] .

[0009] The first step of this route involves a large reaction device, typically 40 times the volume of the reactants, and a long reaction time. The second step uses an expensive palladium catalyst for ring closure, which also takes a long time. This results in high industrialization costs and makes it unsuitable for industrial production.

[0010] (3) The synthetic route for 5-methoxy-7-methyl-indole disclosed in patent publication number WO2026093943A1 is as follows:

[0011] .

[0012] The second and third steps of this route require purification by column chromatography, and the third step uses Schlenk tubes for photocatalysis, which requires harsh conditions of anhydrous and oxygen-free environments, making it unsuitable for large-scale industrial production.

[0013] Existing patents for 5-methoxy-7-methyl-indole are all limited to batch reactor reaction systems, which suffer from problems such as numerous impurities in the cyclization process, poor product color, harsh experimental conditions, and long reaction times. Therefore, developing a new continuous process that can precisely control temperature, shorten oxidation contact time, and suppress side reactions has significant industrial and innovative value. Summary of the Invention

[0014] To address the shortcomings of the existing technology, this invention provides a method for preparing an iprocoprine intermediate. By utilizing the advantages of continuous flow segmented reaction, imine generation and oxidative cyclization are carried out separately, shortening the high-temperature contact time between the oxidant and the substrate, inhibiting peroxidation and methoxyl hydrolysis, and improving the purity and appearance quality of the product.

[0015] The specific technical solution is as follows:

[0016] A method for preparing an ipocopan intermediate includes the following steps:

[0017] S1. 2-Methyl-4-methoxyaniline, trioxymethylene, copper catalyst and ligand are mixed and reacted to obtain intermediate A;

[0018] S2. The intermediate A obtained in step S1 is mixed with potassium persulfate and reacted to obtain the product 5-methoxy-7-methyl-indole.

[0019] In the above preparation method: 2-methyl-4-methoxyaniline is used as the raw material, paraformaldehyde as the carbon source, and a copper salt-bipyridine coordination system as the catalyst. First, N-(methylene)-2-methyl-4-methoxyaniline is generated at low temperature; then, potassium persulfate is used as the oxidant to induce an intramolecular free radical cyclization reaction. The above reaction is carried out in a microchannel reactor, achieving segmented temperature-controlled continuous flow preparation. Utilizing the advantages of continuous flow segmented reaction, imine generation and oxidative cyclization are carried out separately, shortening the high-temperature contact time between the oxidant and the substrate, inhibiting peroxidation and methoxyl hydrolysis, and improving product purity and appearance quality.

[0020] Furthermore, in step S1: the copper catalyst is at least one of copper acetate, cuprous iodide, and copper sulfate.

[0021] Furthermore, in step S1: the ligand is at least one of 2,2'-bipyridine, 1,10-phenanthroline, and 4,4'-dimethyl-2,2'-bipyridine.

[0022] Furthermore, in step S1, the reaction temperature is 70~80℃.

[0023] Furthermore, in step S1: the reaction is carried out in a microchannel reactor; the reaction time is 90~120 s.

[0024] Furthermore, in step S2, the reaction temperature is 110~120℃.

[0025] Furthermore, in step S2: the reaction is carried out in a microchannel reactor; the reaction time is 60~90 s.

[0026] Furthermore, the reaction solvent is at least one of toluene, 1,4-dioxane, and N,N-dimethylformamide (DMF).

[0027] Specifically, the microchannel reactor is made of silicon carbide, which is resistant to oxidation and corrosion and has high heat exchange efficiency.

[0028] Specifically, the preparation method of the ipocopan intermediate includes: dispersing 2-methyl-4-methoxyaniline, trioxymethylene, copper catalyst and ligand in a solvent to obtain solution A; dispersing potassium persulfate in a solvent to obtain solution B; passing solution A into a microchannel reactor and reacting at 70~80℃ for 90~120 s to obtain intermediate A solution; passing intermediate A solution and solution B into a microchannel reactor and reacting at 110~120℃ for 60~90 s to obtain product solution.

[0029] The preferred flow rate of feed solution A is 40-60 mL / min. -1 The preferred flow rate of intermediate A is 10~30 mL·min. -1 The preferred flow rate of liquid B is 30~50 mL·min. -1 .

[0030] In solution A, the ratio of 2-methyl-4-methoxyaniline to solvent is 1 g : (3.0~5.0) mL.

[0031] In solution B, the ratio of potassium persulfate to solvent is 1 g : (3.0~5.0) mL.

[0032] Preferably, 2-methyl-4-methoxyaniline, trioxymethylene, copper catalyst and ligand are dispersed in a solvent under an inert atmosphere, wherein the inert atmosphere is preferably nitrogen.

[0033] Potassium persulfate is preferably ground, sieved, and then dispersed in a solvent and stirred to form a suspension.

[0034] Preferably, intermediate A and liquid B are mixed in a T-type mixer before being introduced into a microchannel reactor.

[0035] Furthermore, the molar ratio of 2-methyl-4-methoxyaniline to trioxymethylene is 1:(1.0~1.2).

[0036] Furthermore, the molar ratio of 2-methyl-4-methoxyaniline to the copper catalyst is 1:(0.08~0.12).

[0037] Furthermore, the molar ratio of 2-methyl-4-methoxyaniline to the ligand is 1:(0.1~0.2).

[0038] Furthermore, the molar ratio of 2-methyl-4-methoxyaniline to potassium persulfate is 1:(1.1~1.5).

[0039] Furthermore, after the reaction is complete, the product solution is quenched at low temperature. Specifically, the product solution is cooled to -5~5℃ and quenched dropwise with saturated brine. After quenching, the solution is concentrated under reduced pressure, ethyl acetate is added, the mixture is separated, n-heptane is added to the organic phase, recrystallized, and dried to obtain 5-methoxy-7-methyl-indole. The preferred volume ratio of ethyl acetate to n-heptane is 1:(5~8).

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] This invention employs a segmented reaction, first generating imine at low temperature, then cyclizing it at high temperature for a short time, thus avoiding high-temperature polymerization of formaldehyde and improving raw material utilization.

[0042] The reaction of this invention is carried out in a microchannel reactor, achieving continuous flow instantaneous mixing and short residence time. The substrate and oxidant only come into contact for a short time in the high-temperature channel, inhibiting the peroxidative polymerization of aromatic amines at its source and significantly reducing tar impurities. Compared with batch reactor processes, this is beneficial for improving product color and purity. Furthermore, the microchannel provides uniform heat exchange, eliminates local hot spots, allows for continuous control of process parameters, minimizes scale-up effects, and features short reaction steps, high reaction selectivity, high product purity, and ease of industrial-scale production.

[0043] This invention has a short route, high atom economy, low emissions of waste, and is environmentally friendly. Attached Figure Description

[0044] Figure 1 This is a process flow diagram for preparing 5-methoxy-7-methyl-indole in an embodiment of the present invention;

[0045] Figure 2 The HPLC chromatogram of 5-methoxy-7-methyl-indole prepared in Example 1 of this invention is shown below.

[0046] Figure 3 This is the HPLC chromatogram of the blank control in Example 1 of the present invention. Detailed Implementation

[0047] The embodiments of the present invention will be described in further detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0048] Example 1

[0049] The process flow for preparing iprocoprine intermediates is as follows: Figure 1 As shown, the method steps are as follows:

[0050] S1. Under nitrogen protection, 100 g of 2-methyl-4-methoxyaniline, 72.2 g of paraformaldehyde, 14.5 g of copper acetate and 17.1 g of 2,2'-bipyridine were dispersed in 1,4-dioxane and the volume was adjusted to 400 mL to obtain solution A; 216.8 g of potassium persulfate was weighed, ground through a 200-mesh sieve, dispersed in 1,4-dioxane, stirred rapidly and the volume was adjusted to 800 mL to obtain solution B;

[0051] Feed solution A was introduced into microchannel reactor No. 1 via a high-pressure metering pump, and the reaction was carried out at a controlled temperature of 75°C. The flow rate of feed solution A was 50 mL / min. -1 The residence time was 100 s; the reaction yielded intermediate A liquid.

[0052] S2. Intermediate A and intermediate B are instantaneously mixed in a T-type mixer using a high-pressure metering pump and then introduced into microchannel reactor No. 2. The reaction is carried out at a controlled temperature of 115℃, with the flow rate of intermediate A at 20 mL / min. -1 The flow rate of liquid B is 40 mL / min. -1 The residence time was 75 s, and the reaction yielded a product liquid.

[0053] The product solution was cooled to 0℃ and quenched by slowly adding 1000 mL of saturated saline solution. The solution was concentrated under reduced pressure at 60-65℃ to remove most of the 1,4-dioxane-water azeotrope. After evaporation, 200 mL of ethyl acetate was added, and the mixture was separated. The aqueous phase was discarded, and 1000 mL of n-heptane was added dropwise to the organic phase. The solution was cooled to 10℃, stirred, and crystallized for 2 h. The crystals were then filtered and dried to obtain 105.2 g of 5-methoxy-7-methyl-indole. The two-step yield was 89.5%, and the HPLC purity was 99.65%.

[0054] The preparation route is as follows:

[0055] .

[0056] HPLC analysis confirmed the successful synthesis of 5-methoxy-7-methyl-indole, as shown in the HPLC chromatogram. Figure 2 As shown, its blank control HPLC chromatogram is as follows. Figure 3 As shown in Table 1, the HPLC peak results are as follows.

[0057] Table 1. HPLC peak results of the product from Example 1

[0058]

[0059] Example 2

[0060] The intermediate 5-methoxy-7-methyl-indole for preparing iprocoprine was prepared according to the method described in Example 1. The difference from Example 1 was that in step S1, the reaction was carried out at 70°C for a residence time of 120 s; in step S2, the reaction was carried out at 110°C for a residence time of 90 s. The yield of both steps was 85.2%, and the HPLC purity was 99.64%.

[0061] Example 3

[0062] The intermediate 5-methoxy-7-methyl-indole for preparing iprocoprine was prepared according to Example 1. The difference from Example 1 was that in step S1, the reaction was carried out at 80°C for 90 s; and in step S2, the reaction was carried out at 120°C for 60 s. The yield of both steps was 86.8%, and the HPLC purity was 99.52%.

[0063] Through the above embodiments, it is confirmed that the present invention provides a novel method for preparing the iprocopran intermediate 5-methoxy-7-methyl-indole. Compared with route (1) in the background art, the present invention does not require harsh experimental conditions of ultra-low temperature, avoids the use of high-risk materials, and the purification is simpler; compared with route (2) in the background art, the present invention does not require large-scale equipment, the reaction time is significantly shortened, and it does not require the use of expensive palladium catalysts; compared with route (3) in the background art, the present invention does not require harsh conditions of anhydrous and oxygen-free, and the purification is simpler. Unlike the batch reactor reaction system of the prior art, the reaction of the present invention is carried out in a microchannel reactor, realizing continuous flow instantaneous mixing and short residence time reaction, and the product color and purity are significantly better than those of the batch reactor process; moreover, the process parameters are continuously controllable, the scale-up effect is small, and it is easy to produce on an industrial scale.

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing an iprocopran intermediate, characterized in that, Includes the following steps: S1. 2-Methyl-4-methoxyaniline, trioxymethylene, copper catalyst and ligand are mixed and reacted to obtain intermediate A; S2. Mix intermediate A obtained in step S1 with potassium persulfate and react to obtain the product.

2. The preparation method according to claim 1, characterized in that, In step S1: The copper catalyst is at least one of copper acetate, cuprous iodide, and copper sulfate.

3. The preparation method according to claim 1, characterized in that, In step S1: the ligand is at least one of 2,2'-bipyridine, 1,10-phenanthroline, and 4,4'-dimethyl-2,2'-bipyridine.

4. The preparation method according to claim 1, characterized in that, In step S1, the reaction temperature is 70~80℃.

5. The preparation method according to claim 4, characterized in that, In step S1: the reaction takes place in a microchannel reactor.

6. The preparation method according to claim 5, characterized in that, In step S1, the reaction time is 90~120 s.

7. The preparation method according to claim 1, characterized in that, In step S2, the reaction temperature is 110~120℃.

8. The preparation method according to claim 7, characterized in that, In step S2: the reaction takes place in a microchannel reactor.

9. The preparation method according to claim 8, characterized in that, In step S2, the reaction time is 60-90 s.

10. The preparation method according to claim 1, characterized in that, The reaction solvent is at least one of toluene, 1,4-dioxane, and N,N-dimethylformamide.

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