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Preparation method of rupatadine fumarate

A technology of rupatadine fumarate and desloratadine, which is applied in the field of preparation of rupatadine fumarate, can solve the problems of low yield, low selectivity, and difficult separation, and achieve high yield , good reaction selectivity and high product purity

Inactive Publication Date: 2016-06-29
杭州仟源保灵药业有限公司
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Problems solved by technology

[0006] The disadvantage of this method is that: using NBS to carry out free radical bromination of 3,5-lutidine, the selectivity of this reaction is relatively low, and it is easy to produce multiple impurities when the condensation is carried out in the next step, which is difficult to separate and affects the quality of the product , low yield, not suitable for industrial production
[0009] The disadvantage of this method is that under the action of DCC and HOBT, desloratadine and 5-methylnicotinic acid are condensed, and DCU that is difficult to remove is produced after the DCC reaction, and the separation is difficult.
[0012] The disadvantage of this method is that lithium aluminum tetrahydrogen is used in the reaction, the reaction temperature is below -70~-75°C, the risk is high, and the reaction conditions are harsh, so it is not suitable for industrial production

Method used

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  • Preparation method of rupatadine fumarate
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  • Preparation method of rupatadine fumarate

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preparation example Construction

[0032] A preparation method of rupatadine fumarate shown in formula (VII), the preparation method comprising the steps of:

[0033] (1) using 5-methylnicotinic acid shown in formula (I) as a raw material, reacting in the presence of methanol and a catalyst to obtain the corresponding compound of formula (II);

[0034]

[0035] (2) the compound of formula (II) is reacted to obtain the corresponding compound of formula (III) in the presence of a reducing agent and a solvent;

[0036]

[0037] (3) the compound of formula (III) is reacted to obtain the corresponding compound of formula (IV) in the presence of a brominating agent and a solvent;

[0038]

[0039] (4) condensation of the compound of formula (IV) and desloratadine (V) under the action of an acid-binding agent and a solvent to obtain rupatadine (VI);

[0040]

[0041] (5) reacting rupatadine (VI) in the presence of fumaric acid and a solvent to obtain the corresponding rupatadine fumarate (VII);

[0042] ...

Embodiment 1

[0047]Add 20g of 5-methylnicotinic acid into 100mL of methanol, add 22mL of thionyl chloride dropwise at 20-30°C, heat up to reflux after the dropwise addition, stir for 2-3 hours, concentrate, add 50mL of water, dissolve and adjust with ammonia water pH to 8-9, extracted with ethyl acetate (250mL×2), combined organic phases, washed with saturated brine 100mL, dried the organic layer, concentrated to give 21.1g of compound (II), yield 95.5%; melting point: 44-45°C ; ESI-MS: m / z 151.95 ([M+H]+).

Embodiment 2

[0049] Add 10 g of compound (II) into 100 mL of methanol, dissolve and add 8.8 g of sodium borohydride, heat up to 55°C for 1 h, cool to room temperature, concentrate, add 10 mL of water, stir for 30 minutes, filter, and extract the filtrate with ethyl acetate ( 50 mL×2) twice, combined the organic layers, washed with 50 mL of saturated sodium chloride, dried the organic layer, and concentrated to obtain 7.5 g of compound (III). Yield 92.1%; MS-ESI (m / z): 124 (M)+.

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Abstract

The invention provides a preparation method of rupatadine fumarate shown as a formula (VII). The preparation method comprises the following steps: (1) 5-methylnicotinic acid is taken as a raw material and subjected to a reaction in presence of methanol and a catalyst, and a corresponding compound shown as a formula (II) is obtained; (2) the compound shown as the formula (II) is subjected to a reaction in presence of a reducing agent and a solvent, and a corresponding compound shown as a formula (III) is obtained; (3) the compound shown as the formula (III) is subjected to a reaction in presence of a brominating agent and a solvent, and a corresponding compound shown as a formula (IV) is obtained; (4) the compound shown as the formula (IV) and desloratadine (V) are subjected to condensation under the actions of an acid binding agent and a solvent, and rupatadine (VI) is obtained; (5) rupatadine (VI) is subjected to a reaction in presence of fumaric acid and a solvent, and corresponding rupatadine fumarate (VII) is obtained.

Description

technical field [0001] The invention relates to a preparation method of rupatadine fumarate. technical background [0002] Rupatadine fumarate (Rupatadinefumaratel), the chemical name is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidine Subunit]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate, developed by Uriach Pharmaceutical Company in Spain, has dual antihistamine and platelet activating factor (PAF) An antiallergic drug with an indication for seasonal and perennial allergic rhinitis. The chemical structural formula of rupatadine fumarate is as follows: [0003] [0004] In "Synthesis of Rupatadine" (Xin Shuibo, Chinese Journal of New Drugs, 2005), a synthetic route of rupatadine fumarate is disclosed, specifically: [0005] [0006] The disadvantage of this method is that: using NBS to carry out free radical bromination of 3,5-lutidine, the selectivity of this reaction is relatively low, and it is easy to produce multiple impurities when the...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 汤建拓徐承智陈丹龙张晖邵婷婷孙友虞英民
Owner 杭州仟源保灵药业有限公司
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