Preparation method of 9-methyl-beta-carboline

Abstract

The invention discloses a preparation method of 9-methyl-beta-carboline, which comprises the following steps: by taking 3-bromopyridine as a raw material, carrying out serial reaction of SN Ar and Fischer rearrangement cyclization on the 3-bromopyridine and 1-methyl-1-phenylhydrazine in a reaction solvent under the catalytic action of acid to obtain the final product 9-methyl-beta-carboline in one step. The preparation method of 9-methyl-beta-carboline provided by the invention has the advantages that the synthesis cost is effectively reduced, the use of dangerous and toxic reagents is avoided, the generation of three industrial wastes is effectively reduced, the process is simple, the operation is convenient, the raw materials are cheap and easy to obtain, the yield is high, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing 9-methyl-β-carboline. Background Art

[0002] 9-Methyl-β-carboline is a heterocyclic amine of the β-carboline family with virtually no known natural sources. Its chemical structure is shown below:

[0003]

[0004] 9-Methyl-β-carboline enhances cognition through multiple mechanisms. It upregulates tyrosine hydroxylase, leading to elevated dopamine levels. It also inhibits monoamine oxidase activity, preventing the breakdown of dopamine and other monoamine neurotransmitters. Furthermore, 9-methyl-β-carboline stimulates astrocytes to express neurotrophic factors, promoting neuronal growth and survival. In healthy individuals, it can also improve cognition by optimizing neurotransmitter levels and supporting neuronal growth, which can enhance memory, attention, and learning. The compound's ability to increase BDNF and NGF levels also contributes to long-term cognitive health, making it a popular choice for those seeking to improve mental performance and prevent cognitive decline. Currently, it is primarily used as a cognitive enhancer and neuroprotectant. It is sought after for its ability to improve memory, learning, and overall mental performance. Furthermore, 9-methyl-β-carboline is widely used in the pharmaceutical, pesticide, and dye industries as a raw material and intermediate, for example, in the synthesis of numerous compounds with antimicrobial and anti-inflammatory properties.

[0005] According to relevant literature, the existing preparation method of 9-methyl-β-carboline uses tryptophan as the starting material, and undergoes Pectet-Spengler reaction cyclization, thionyl chloride esterification, selenium dioxide high-temperature oxidative decarboxylation aromatization, and sodium hydrogen iodide system methylation. This method uses highly toxic reagents such as selenium dioxide and iodine methyl, as well as the explosive and highly dangerous reagent sodium hydrogen. The production risk factor is too high, the route is long, the cost is high, and the yield cannot be guaranteed.

[0006] Therefore, it is necessary to propose a new preparation method of 9-methyl-β-carboline to solve some problems existing in the above process. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing 9-methyl-β-carboline in view of the deficiencies in the above-mentioned prior art.

[0008] To solve the above technical problems, the present invention adopts a technical solution: a method for preparing 9-methyl-β-carboline, wherein 3-bromopyridine is used as a raw material, and 1-methyl-1-phenylhydrazine is reacted in a reaction solvent under acid catalysis to undergo a tandem reaction of SN Ar and Fischer rearrangement cyclization to obtain the final product 9-methyl-β-carboline in one step. The reaction scheme is as follows:

[0009]

[0010] The reaction mechanism is as follows:

[0011]

[0012] Preferably, the acid is at least one of trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, and most preferably trifluoroacetic acid.

[0013] Preferably, the molar ratio of the acid to 3-bromopyridine is 6:1 to 3:1, for example, 5:1, 4:1, 3:1 or any value therebetween, and most preferably 5:1.

[0014] Preferably, the molar ratio of 1-methyl-1-phenylhydrazine to 3-bromopyridine is 1.3:1 to 1.0:1, for example, 1.0:1, 1.1:1, 1.2:1 or any value therebetween, and most preferably 1.2:1.

[0015] Preferably, the method comprises the following steps:

[0016] S1. Add 3-bromopyridine and 1-methyl-1-phenylhydrazine to a reaction solvent, add acid dropwise, raise the temperature to react after addition, cool after reaction is complete, distill the reaction product under reduced pressure, add dichloromethane and water to the reaction product, adjust the pH to 7-8, separate the organic phase, extract the aqueous phase with dichloromethane until extraction is complete, combine the dichloromethane phases and wash with water and saturated sodium chloride aqueous solution in sequence, dry and concentrate to obtain a crude product of 9-methyl-β-carboline;

[0017] S2. The crude 9-methyl-β-carboline product is added to toluene, heated for recrystallization, cooled and filtered, and the filter cake is rinsed with toluene and vacuum dried to obtain the final product 9-methyl-β-carboline.

[0018] Preferably, the reaction temperature in step S1 is 60-85°C, for example, 60°C, 75°C, 80°C or any value therebetween, and most preferably 85°C.

[0019] Preferably, the reaction time in step S1 is 6-12 h, for example, 6, 8, 10, 12 h or any value between any two of them, and most preferably 8 h.

[0020] Preferably, the reaction solvent may be at least one of chloroform, 1,2-dichloroethane, and toluene, and most preferably 1,2-dichloroethane.

[0021] Preferably, the volume of the reaction solvent is 6 to 12 times the weight of 3-bromopyridine, measured in units of volume (L) and mass (kg), for example, 6, 7, 8, 9, 10, 11, 12 times or any value in between.

[0022] Preferably, the method comprises the following steps:

[0023] S1. Add 3-bromopyridine and 1-methyl-1-phenylhydrazine to a reaction solvent, control the temperature to 5-20° C., add acid dropwise, raise the temperature to 60-85° C. after the addition, and keep the temperature to react for 6-12 hours. After the reaction is complete, cool the temperature to 20-30° C., directly distill the reaction product under reduced pressure, add dichloromethane and water to the reaction product, adjust the pH to 7-8 with sodium hydroxide, separate the organic phase, extract the aqueous phase with dichloromethane until the extraction is complete, combine the dichloromethane phases, wash once with water and once with a saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product of 9-methyl-β-carboline;

[0024] S2. The crude 9-methyl-β-carboline was added to toluene, heated to 50-70°C for recrystallization, then cooled to 20-30°C for filtration. The filter cake was rinsed with toluene and dried in vacuo at 40-60°C to obtain the final product, 9-methyl-β-carboline.

[0025] The beneficial effects of the present invention are:

[0026] The preparation method of 9-methyl-β-carboline provided by the present invention effectively reduces the synthesis cost, avoids the use of dangerous and toxic reagents, effectively reduces the generation of industrial waste, and has a simple process, convenient operation, cheap and readily available raw materials, high yield, and is conducive to large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the NMR spectrum of the pure 9-methyl-β-carboline prepared in Example 1;

[0028] Figure 2 This is the HPLC spectrum of the pure 9-methyl-β-carboline prepared in Example 1. DETAILED DESCRIPTION

[0029] The present invention is further described in detail below with reference to the embodiments so that those skilled in the art can implement the invention with reference to the description.

[0030] It should be understood that terms such as “having”, “including” and “comprising” used herein do not preclude the existence or addition of one or more other elements or combinations thereof.

[0031] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Materials and reagents used in the following examples are commercially available unless otherwise specified. In the following examples, where specific conditions are not specified, the experiments were conducted under conventional conditions or those recommended by the manufacturer. Reagents and instruments used, where the manufacturer is not specified, are commercially available conventional products.

[0032] Example 1

[0033] A method for preparing 9-methyl-β-carboline, the reaction scheme is as follows:

[0034]

[0035] The specific steps include:

[0036] S1. Add 32 L of 1,2-dichloroethane to a 50 L glass reactor, then add 3-bromopyridine (3.16 kg, 20 mol) and 1-methyl-1-phenylhydrazine (2.93 kg, 24 mol). Start the cooling cycle to reduce the internal temperature to about 10 °C, slowly add trifluoroacetic acid (11.40 kg, 100 mol) dropwise, and control the temperature not to exceed 20 °C during the addition. After the addition is complete, slowly raise the temperature to 85 °C and keep the reaction for 8 h. After the TLC reaction was complete, the temperature was lowered to about 25° C. The reaction solution was directly distilled under reduced pressure to about 5 L, 15 L of dichloromethane and 15 L of water were added, and the pH was adjusted to 7-8 with 10 wt % sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted once with 10 L of dichloromethane until the extraction was complete. The dichloromethane phases were combined, washed once with 15 L of water and once with 10 L of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a brown crude 9-methyl-β-carboline product with a wet weight of 3.1 kg.

[0037] The crude 9-methyl-β-carboline was further dissolved and recrystallized by heating with 10 L of toluene at 60° C., then cooled to 25° C. and filtered. The filter cake was rinsed twice with 2 L of toluene and dried under vacuum at 50° C. to obtain 2.96 kg of pure 9-methyl-β-carboline with a yield of 81.29%.

[0038] The NMR spectrum of pure 9-methyl-β-carboline is as follows Figure 1 As shown, the NMR data are as follows:

[0039] 1H NMR (400MHz, CDCl3) δ8.88 (1H, S), 8.46-8.47 (1H, d, J = 2Hz),

[0040] 8.13-8.14(1H,d,J=6Hz),7.94-7.95(1H,d,J=5Hz),7.59-7.62(1H,m),

[0041] 7.45-7.46(1H,d,J=8.5Hz),7.25-7.30(1H,m),3.93(3H,S).

[0042] The HPLC spectrum of pure 9-methyl-β-carboline is as follows Figure 2 shown.

[0043] Example 2

[0044] A method for preparing 9-methyl-β-carboline, the reaction scheme is as follows:

[0045]

[0046] The specific steps include:

[0047] S1, in 50L glass reactor, add 25L trichloromethane, then add 3-bromopyridine (3.16kg, 20mol), 1-methyl-1-phenylhydrazine (2.69kg, 22mol), open cooling cycle and cool the interior temperature to about 10 ℃, slowly drip trifluoroacetic acid (6.84kg, 60mol), temperature control does not exceed 20 ℃ during the addition, slowly heat to 60 ℃ after adding and keep incubation for 12h. After TLC reaction is complete, cool to about 25 ℃, the reaction solution is directly distilled under reduced pressure to about 5L, add 15L dichloromethane and 15L water, regulate pH to 7-8 with 10wt% sodium hydroxide, separate organic phase, aqueous phase is extracted once with 10L dichloromethane again until extraction is complete. The dichloromethane phases were combined, washed once with 15 L of water and once with 10 L of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a brown crude 9-methyl-β-carboline product with a wet weight of 2.98 kg.

[0048] The crude 9-methyl-β-carboline was further dissolved and recrystallized by heating 10 L of toluene at 60° C., then cooled to 25° C. and filtered. The filter cake was rinsed twice with 2 L of toluene and dried under vacuum at 50° C. to obtain 2.87 kg of pure 9-methyl-β-carboline with a yield of 78.86%.

[0049] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the description and implementation methods. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing 9-methyl-β-carboline, characterized in that: This method uses 3-bromopyridine as a raw material, and carries out a tandem reaction of SN Ar and Fischer rearrangement cyclization with 1-methyl-1-phenylhydrazine in a reaction solvent under acid catalysis to obtain the final product 9-methyl-β-carboline. The reaction scheme is as follows:

2. The method for preparing 9-methyl-β-carboline according to claim 1, characterized in that: The acid is at least one of trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid.

3. The method for preparing 9-methyl-β-carboline according to claim 2, characterized in that: The molar ratio of the acid to 3-bromopyridine is 6:1 to 3:

1.

4. The method for preparing 9-methyl-β-carboline according to claim 1, wherein The molar ratio of 1-methyl-1-phenylhydrazine to 3-bromopyridine is 1.3:1 to 1.0:

1.

5. The method for preparing 9-methyl-β-carboline according to claim 1, characterized in that: The method comprises the following steps: S1. Add 3-bromopyridine and 1-methyl-1-phenylhydrazine to a reaction solvent, add acid dropwise, raise the temperature to react after addition, cool after reaction is complete, distill the reaction product under reduced pressure, add dichloromethane and water to the reaction product, adjust the pH to 7-8, separate the organic phase, extract the aqueous phase with dichloromethane until extraction is complete, combine the dichloromethane phases and wash with water and saturated sodium chloride aqueous solution in sequence, dry and concentrate to obtain a crude product of 9-methyl-β-carboline; S2. The crude 9-methyl-β-carboline product is added to toluene, heated for recrystallization, cooled and filtered, and the filter cake is rinsed with toluene and vacuum dried to obtain the final product 9-methyl-β-carboline.

6. The method for preparing 9-methyl-β-carboline according to claim 5, characterized in that: The reaction temperature in step S1 is 60-85°C.

7. The method for preparing 9-methyl-β-carboline according to claim 5, characterized in that: The reaction time in step S1 is 6-12 h.

8. The method for preparing 9-methyl-β-carboline according to claim 1, characterized in that: The reaction solvent may be at least one of chloroform, 1,2-dichloroethane, and toluene.

9. The method for preparing 9-methyl-β-carboline according to claim 8, characterized in that: The volume of the reaction solvent is 6 to 12 times the weight of 3-bromopyridine, measured in units of volume (L) and mass (kg).

10. The method for preparing 9-methyl-β-carboline according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: S1. Add 3-bromopyridine and 1-methyl-1-phenylhydrazine to a reaction solvent, control the temperature to 5-20° C., add acid dropwise, raise the temperature to 60-85° C. after the addition, and keep the temperature to react for 6-12 hours. After the reaction is complete, cool the temperature to 20-30° C., directly distill the reaction product under reduced pressure, add dichloromethane and water to the reaction product, adjust the pH to 7-8 with sodium hydroxide, separate the organic phase, extract the aqueous phase with dichloromethane until the extraction is complete, combine the dichloromethane phases, wash once with water and once with a saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product of 9-methyl-β-carboline; S2. The crude 9-methyl-β-carboline was added to toluene, heated to 50-70°C for recrystallization, then cooled to 20-30°C for filtration. The filter cake was rinsed with toluene and dried in vacuo at 40-60°C to obtain the final product, 9-methyl-β-carboline.

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