1,2,3,4-Tetrahydro-9-methylcarbazol-4-one: Key Intermediate for Antiemetic Drugs

1,2,3,4-Tetrahydro-9-methylcarbazol-4-one is an important nitrogen-containing heterocyclic intermediate belonging to the class of hydrogenated carbazolones. It is commonly used as a key synthetic precursor for ondansetron and other 5-HT3 receptor antagonist antiemetics. The methyl and carbonyl groups on its carbazole ring can undergo targeted modifications; in particular, the 3-position is prone to reactions such as amine methylation and nucleophilic substitution, facilitating the introduction of side-chain structures such as piperazine. Derivatives synthesized based on 1,2,3,4-tetrahydro-9-met often exhibit excellent 5-HT3 receptor binding affinity; some compounds demonstrate antiemetic activity comparable to that of the clinical drug ondansetron, making them of significant value in the development of new drugs for the treatment of chemotherapy-, radiotherapy-, and postoperative-induced nausea and vomiting.

Production method of 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one

1,2,3,4-Tetrahydro-9-methylcarbazol-4-one (N-methyltetrahydrocarbazolone), also known as 1,2,3,4-tetrahydro-9-methylcarbazol-4 -ketone; 1,2,3,4-tetrahydro-9-methyl-4H-carbazolone; 9-methyl-1,2,3,4-tetrahydrocarbazolone; 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, the chemical structure is as follows: 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one is an important intermediate for the synthesis of highly selective 5-hydroxytryptamine receptor antagonist Ondansetron (Ondansetron). At present, dimethyl sulfate, methyl halide, etc. Azolone is prepared by methylation reaction, and the methylation reagents such as dimethyl sulfate and methyl halide used are highly toxic, and the production process is extremely harmful to human health. Dimethyl carbonate is a "green" chemical, basically non-toxic and miscible with most organic substances. It was registered as a non-toxic substance in Europe in 1992. Its molecular structure contains methyl groups and can be used as dimethyl sulfate Alternatives to esters and methyl halides. Utilizing dimethyl carbonate to synthesize 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one greatly improves the safety and environmental protection of the synthesis process. The object of the present invention is to provide a production process of N-methyltetrahydrocarbazolone which is safe and environmentally friendly, has a simple process route and is easy to purify. In order to achieve the above object, the technical scheme adopted in the present invention is to dissolve tetrahydrocarbazolone in an organic solvent, add a kind of inorganic base and dimethyl carbonate successively, stir at 100～150°C for 6～12 hours, After the reaction, it was naturally cooled, and 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one was obtained by distillation under reduced pressure, washing with water, drying and recrystallization from acetone.[1]

Below in conjunction with the embodiment of the present invention is described in further detail: A production method of 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one dissolving tetrahydrocarbazolone in an organic solvent, adding an inorganic base and dimethyl carbonate successively, stirring at 100-150°C After 6 to 12 hours, after the reaction is over, cool naturally, and obtain N-methyltetrahydrocarbazolone product through vacuum distillation, washing with water, drying, and recrystallization from acetone. The molar ratio of tetrahydrocarbazolone to inorganic base is is 1:1.0～1.5, the molar ratio of described tetrahydrocarbazolone and dimethyl carbonate is 1:2.0～4.5, and the described organic solvent consumption is 10～20 milliliters/gram 1,2,3,9- Tetrahydrocarbazolone. Dissolve 18.5 grams (0.1mol) of tetrahydrocarbazolone in 185 milliliters of N,N-dimethylformamide, and add 5.6 grams (0.1mol) of potassium hydroxide and 18.0 grams (0.2mol) of dicarbonate successively under stirring. Methyl ester was stirred at 100°C for 6 hours. After the reaction was over, it was cooled naturally, and 13.0 g of 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one was obtained by distillation under reduced pressure, washing with water, drying, and recrystallization from acetone, with a purity of 97.0% and a yield of 63.4 %.

Synthesis of Novel 5‑HT₃ Receptor Antagonists

5-HT3 receptor antagonists, such as Ondansetron, are used for anti-emesis after chemotherapy, radiotherapy and operations. Some Ondansetron analogs possessing piperazine ring as side chains were synthesized in our lab. Thus, one of the two carbonyl groups of starting material 1,3-cyclohexandione. Through a methylation reaction, 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one was converted to 1,2,3,4-tetrahydro-9-methyl-4H-carbazol-4-one. Nine novel 1,2,3,4-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives were synthesized through nucleophilic substitution reaction of 3-Dimethylaminomethyl substituted compound of 1,2,3,4-Tetrahydro-9-methylcarbazol-4-one with piperazines. The results of preliminary pharmacological test show that part of the novel compounds have antiemetic activity comparable to that of the control Ondansetron.[2]

References

[1]CN102464604A

[2]Xu, Q., Liu, T., Tian, R. et al. Synthesis and antiemetic activity of 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives. Front. Chem. China 4, 63–68 (2009). https://doi.org/10.1007/s11458-009-0017-8