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A technology of iloperidone and intermediates, which is applied in the field of iloperidone products and can solve problems such as inability to remove
Inactive Publication Date: 2017-06-13
BEIJING PHARMA GRP CO LTD
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Problems solved by technology
[0014] The impurity ILPI-07 cannot be removed by recrystallization during the refining process of iloperidone
Method used
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Embodiment 1
[0043] Example 1: Preparation of (2,4-difluorophenyl)-(4-piperidinyl)methanone oxime hydrochloride
[0044] Add 70g of 4-(2,4-difluorobenzoyl)piperidine hydrochloride into 840mL of ethanol, stir and add 70g of hydroxylamine hydrochloride and 80ml of triethylamine, and heat to reflux for about 1h. Cool to room temperature, filter with suction, wash with a small amount of ethanol, and dry to obtain 55 g of white solid.
Embodiment 2
[0045] Example 2: Preparation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride
[0046] Add 27g of potassium hydroxide to 600mL of methanol, add 55g of (2,4-difluorophenyl)-(4-piperidinyl)methanone oxime hydrochloride, and heat to react for about 2.5h. Cool to room temperature, add an appropriate amount of anhydrous MgSO4, and stir for about 1 h. Suction filtration, and the filtrate was concentrated under reduced pressure. Add 500 mL of acetone, stir at room temperature for about 0.5 h, filter, add hydrochloric acid dropwise to the filtrate with stirring to make the pH = 2-3, filter with suction, and dry to obtain 35 g of a white solid. The water content in methanol is 0.4%.
Embodiment 3
[0047] Embodiment three: the preparation of iloperidone
[0048] Add 400mL DMF to 32g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, add 35g of potassium carbonate, 3.5g of potassium iodide and 3-methoxy-4-( 33.5 g of 3-chloropropoxy) acetophenone, heated for about 7 hours. Cool to room temperature, filter with suction, pour the filtrate into 1000 mL of cold water with stirring, stir for about 2 hours, filter with suction, wash with water, and dry to obtain 53 g of a light yellow crude product. After recrystallization from ethanol, 28 g of iloperidone was obtained, and the content of ILPI-07 was detected to be 0.12%.
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Abstract
The invention relates to a preparation method of an iloperidone intermediate. The preparation method comprises the following steps of (1) adding potassium hydroxide into methyl alcohol, and adding (2,4-difluorophenyl)-(4-piperidyl)ketoxime hydrochloride; (2) heating, and reacting for 2 to 3h at the controlled temperature of 50 to 60 DEG C; (3) cooling to room temperature, adding anhydrous MgSO4, stirring for 0.8 to 1.2h, sucking and filtering, and performing vacuum concentration on filtrate; (4) adding acetone, stirring for 0.4 to 0.6h at the room temperature, filtering, dripping a saturated HCl methyl alcohol solution while stirring the filtrate, so as to adjust a pH (potential of hydrogen) value to 2-3, sucking and filtering, and drying, so as to obtain a white solid, wherein the water content of methyl alcohol is less than 0.5%.
Description
[0001] Technical field: [0002] The present invention relates to a preparation method of iloperidone intermediate, in particular to the preparation of iloperidone intermediate 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride Process quality control to prepare high quality iloperidone products. [0003] Background technique: [0004] Iloperidone is a new type of atypical antipsychotic drug, and its research and development has gone through a long and tortuous course of development. Iloperidone was first synthesized and identified by Hearst Rosso Pharmaceutical Company. Later, due to some reasons, the company gave up further research and development of the drug and transferred its development rights to Titan Pharmaceutical Company. Due to some reasons, Titan Pharmaceuticals transferred the drug to Novartis in January 1997. Novartis has developed this product and conducted phase III clinical trials. In 2004, Vanda Pharmaceuticals acquired the development rights from ...
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