Application of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride_Kain Industrial Additive

Background and Overview^[1][2]

6-Fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride is an intermediate for the preparation of paliperidone. Paliperidone is the main active metabolite of the anti-tension agent risperidone (Risperdone); risperidone metabolized in the liver is mainly hydroxylated into 9-hydroxyrisperidone or paliperidone through the cytochrome (CYP) P4502D6 pathway. Risperidone. Paliperidone has pharmacological properties and potency comparable to the parent drug risperidone, but has a longer elimination half-life. Paliperidone differs from risperidone and most other antitension agents due to its relatively low degree of enzymatic metabolism.

Apply^[4]

6-Fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride is an intermediate for the preparation of paliperidone. The preparation process is: heating 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4- ketone (CMHTP, 100g), 6-fluoro-3-(piperidin-4-yl)1,2-benzisoxazole hydrochloride (FBIP, 106g) (i.e., 6-fluoro-3-piperidin-4-yl) A mixture of 1,2-benzisoxazole hydrochloride), diisopropylamine (DIPA) (98g) and methanol (500ml) was brought to 60 to 70°C and stirred for 24 hours. After the reaction was completed, the reaction mixture was cooled to 25 to 35°C and stirred for 30 minutes, then further cooled to 0 to 5°C and stirred for a further 60 minutes. The solid material was filtered and crystallized in a mixture of acetonitrile (2400 ml) and water (600 ml) to provide 140 g of crude paliperidone.

In addition, 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole is a related substance of risperidone and plays an important role in the quality control of risperidone. Risperidone is a new generation of atypical antipsychotic drugs. It is a selective cholamine blocker with unique properties. It has high affinity to 5-HT2 receptors and dopamine D2 receptors. It can also Binds to α1-adrenergic receptors, and with smaller affinity to H1-histamine receptors and α2-adrenergic receptors, but not to cholinergic receptors. It can be completely absorbed after oral administration. The plasma concentration reaches the peak within 1 to 2 hours. The half-life is 3 hours. The main metabolite is 9-hydroxyrisperidone. The limits on relevant substances in the raw material quality standards of risperidone in the pharmacopoeias of various countries vary. The EP lists 12 types (6 specific impurities A, B, C, D, E, K and 6 general impurities F, H, I, J, L, M), in which the impurity M is 6-fluoro-3-(piperidin-4-yl)-1,2-benzisoxazole, so the method established is simple, sensitive, and has good linearity, accuracy, and precision. , the analysis method of related substances with low detection limit and quantification limit plays an important role in the quality control of risperidone.

Reference materials

[1] CN201310388545.X Improved method for preparing paliperidone and its intermediates

[2] Yan Xiaodan, Cai Zhenhua, Gao Ming, et al. Research progress on chromatographic analysis of risperidone content and related substances [D]. , 2012.