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Preparation method of tropisetron

A technology of tropisetron and tropinol, which is applied in the field of preparation of antiemetic drug tropisetron, can solve the problems of reduced purity, high reaction temperature, and increased impurities, so as to reduce costs, operational risks, and mild reaction conditions , the effect of high safety factor

Active Publication Date: 2013-01-23
QILU PHARMA HAINAN +1
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Problems solved by technology

CN102532128 discloses a method for preparing tropisetron by directly esterifying indole-3-carboxylic acid and tropinol in an inert solvent by using an aromatic organic sulfonic acid compound as a catalyst, and the reaction temperature is 50-150°C; The reaction time is 2~35h; although this process adopts the reaction mechanism of one-step esterification, the reaction process is a heterogeneous reaction, which is not conducive to the full progress of the reaction, and the process of removing water needs to be continuously performed during the reaction process. The process is complicated and the used Molecular sieves and other water-removing substances are not easy to handle, and the reaction temperature is high, which may cause the decomposition of the target product, thereby increasing the impurities and reducing the purity, and the post-reaction treatment requires acid-base adjustment, the process is complicated, and it is not suitable for industrial applications.

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  • Preparation method of tropisetron
  • Preparation method of tropisetron

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[0009] A preparation method for tropisetron, the method comprising: in an inert solvent, using a C2-C4 aliphatic halogenated carboxylic acid as a catalyst, a C2-C4 aliphatic halogenated carboxylic acid anhydride as an activating reagent, and indole -3-Formic acid is activated as a mixed acid anhydride, and then a solution of tropine alcohol dissolved in an inert solvent is added dropwise to carry out a condensation reaction to prepare tropisetron; the indole-3-formic acid: C2~C4 aliphatic halogenated Carboxylic anhydride: C2~C4 aliphatic halogenated carboxylic acid: tropinol, the material molar ratio is 1:0.5~2:0.1~3:0.5~5.

[0010] Preferably, a kind of preparation method of tropisetron comprises the following steps:

[0011] (1) Add inert solvent and catalyst C2~C4 aliphatic halogenated carboxylic acid to indole-3-carboxylic acid, add activating reagent C2~C4 aliphatic halogenated carboxylic acid anhydride under stirring, activate at -10~40°C for 0.5 ~10h; After the activat...

Embodiment 1

[0038] Add 200ml of dichloromethane and 1.4g of trifluoroacetic acid to 20g of indole-3-carboxylic acid, add 50g of trichloroacetic anhydride under stirring, and activate at 20°C for 2h. After the activation was completed, the temperature was lowered to -5°C, and 50 ml of dichloromethane solution containing 17.6 g of tropinol was added dropwise. After the dropwise addition, the reaction solution was clear and reacted for 1 h. After the reaction is complete, wash twice with 100ml of 1mol / L NaOH aqueous solution and 100ml of purified water each time, add 50g of sodium sulfate to dry for 2h, filter with suction, evaporate the filtrate to dryness, add 50ml of ethyl acetate to make a slurry, cool down at 0-5°C and analyze crystallization, suction filtration, and drying to obtain 28.3 g of tropisetron, with a yield of 80.2% and a purity of 99.4%.

Embodiment 2

[0040]Add 125ml of chloroform and 12.7g of trichloroacetic acid to 25g of indole-3-carboxylic acid, add 51g of heptafluorobutyric anhydride under stirring, and activate at 40°C for 0.5h. After the activation was completed, the temperature was lowered to -10°C, and 100 ml of a chloroform solution containing 22 g of tropinol was added dropwise. After the dropwise addition, the reaction solution was clear and reacted for 4 hours. After the reaction is complete, wash twice with 125ml of 1mol / L NaOH aqueous solution and 125ml of purified water each time, add 50g of sodium sulfate to dry for 2h, filter with suction, evaporate the filtrate to dryness, add 50ml of ethyl acetate for beating, 0-5°C Cooling and crystallization, suction filtration, and drying gave 36 g of tropisetron with a yield of 82% and a purity of 99.8%.

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Abstract

The invention provides a preparation method of tropisetron, which comprises the following steps: in an inert solvent, activating indolyl-3-formic acid into mixed anhydride by using C2-C4 aliphatic halogenated carboxylic acids as a catalyst and C2-C4 aliphatic halogenated carboxylic acid anhydride as an activating reagent, and dropwisely adding a tropine alcoholic solution dissolved in the inert solvent to carry out condensation reaction, thereby obtaining the tropisetron. The method provided by the invention is simple to operate, has the advantages of mild reaction conditions, high safety coefficient, fewer side reactions, high yield and high purity, lowers the production cost and operating risk, and is especially suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an antiemetic drug tropisetron. Background technique [0002] Tropisetron, whose chemical name is 1H-indole-3-carboxylic acid-8-methyl-8-azabicyclic bridge [3.2.1]oct-3-yl ester, has a structural formula as shown in formula I, which is a strong It is an effective and selective 5-HT3 receptor antagonist, developed by Novartis, and its hydrochloride was launched in the UK in 1992, and is now on the market in dozens of countries around the world. Nausea and vomiting, also used to prevent and treat postoperative nausea and vomiting in adults. [0003] [0004] The early preparation process of tropisetron is generally to use indole carboxylic acid and acid chloride reagents such as oxalyl chloride, thionyl chloride reaction to generate acid chloride intermediates - indole carbonyl chloride, tropinol and n-butyllithium or strong base such as S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/12
Inventor 刘俊岐吴玉彬
Owner QILU PHARMA HAINAN
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