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Benzocycloheptanopyridine compound, its preparation method and its use

A technology of benzocycloheptane and compounds, which is applied in the field of its preparation and benzocycloheppanopyridine compounds, can solve the problems of lack of reference substances, affecting the detection and monitoring of impurity compounds, and difficulty in separation

Active Publication Date: 2022-02-11
北京鑫开元医药科技有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, the content of the impurity compound in the synthesis process of loratadine is very low, it is difficult to separate, and there is no synthetic method for the impurity compound in the prior art, it is difficult to obtain a large amount of high-purity said impurity compound, lack of The corresponding reference substance has greatly affected the detection and monitoring of the impurity compound in the process of synthesizing loratadine

Method used

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  • Benzocycloheptanopyridine compound, its preparation method and its use
  • Benzocycloheptanopyridine compound, its preparation method and its use
  • Benzocycloheptanopyridine compound, its preparation method and its use

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preparation example Construction

[0046]In the first aspect, the embodiment of the present invention provides a method for preparing the benzocycloheptanopyridine compound as described in the first aspect, comprising the following steps:

[0047]

[0048] (1) Synthesis of format reagents:

[0049] Magnesium and N-methyl-4-chloropiperidine are heated and reacted in the first reaction solvent under the action of an initiator to obtain Grignard reagent;

[0050] (2) Synthesis of Compound I:

[0051] 8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptano[1,2-b]pyridin-11-one (Formula II) and the Grignard reagent in the second reaction solvent The reaction is carried out to obtain compound I, and the reaction temperature is 0°C~70°C;

[0052] (3) Synthesis of Compound IV:

[0053] Compound I is reacted in the third reaction solvent under the action of a reducing agent to obtain compound IV.

[0054] In the preparation method of the benzocycloheptanapyridine compound provided in the embodiment of the present inventi...

Embodiment 1

[0091] (1) Synthesis of format reagents:

[0092] Add magnesium chips (5.72g, 0.24mol) to 220mL tetrahydrofuran, start stirring, add 1,2-dibromoethane (6mL, 0.07mol), heat up to 65°C, add N-methyl-4-chloro Piperidine (32.01g, 0.24mol), after the reaction is initiated, react at 65°C until the magnesium chips disappear completely to obtain the Grignard reagent, cool down to room temperature, add N,N,N,N- to the Grignard reagent Tetramethylethylenediamine (27.90 g, 0.24 mol) was stirred evenly to obtain the first mixed solution.

[0093] (2) Synthesis of Compound I:

[0094] 8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (30.06 g, 0.12 mol) was added to 250 mL tetrahydrofuran, Stir and dissolve to obtain the second mixed solution, add the second mixed solution dropwise to the first mixed solution, control the reaction temperature to 10°C, and continue the reaction after the dropwise addition, the reaction time is 30min, the reaction After the end, add satur...

Embodiment 2

[0109] (1) Synthesis of Grignard Reagent: It is exactly the same as step (1) in Example 1.

[0110] (2) Synthesis of compound I: exactly the same as step (1) in Example 1.

[0111] (3) Synthesis of Compound IV:

[0112] Add 9.79g of 8-chloro-3-(1-methylpiperidin-4-yl)-5,6-dihydro-11H-benzo[5,6]cyclohepta[1, 2-b] Pyridin-11-one (formula Ⅰ, 0.03mol), 100mL methanol and 20mL dichloromethane, stir until the solution is clear, cool down to 15°C, control the reaction temperature to 15°C, add sodium borohydride (1.09g, 0.03mol) was added into the reaction solution in three batches, and the reaction time was 2 hours. After the reaction finishes, add 70mL water to the reaction solution, quench the reaction, extract with 70mL dichloromethane, the organic phase is in the lower floor, separate the layers, the organic phase obtained is dried with anhydrous sodium sulfate, remove sodium sulfate by filtration, and the filtrate is reduced Evaporate under pressure to obtain the crude produc...

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Abstract

The invention belongs to the field of medicine, and in particular relates to a benzocycloheppanopyridine compound, a preparation method and an application thereof. The benzocycloheppanopyridine compound has a structure of formula IV: IV. The preparation method comprises: magnesium and N-methyl-4-chloropiperidine are heated and reacted in the first reaction solvent under the action of an initiator to obtain a Grignard reagent; 8-chloro-5,6-dihydro-11H-benzo [5,6]Cycloheptano[1,2-b]pyridin-11-one is reacted with Grignard reagent in the second reaction solvent to obtain compound I; compound I is reacted in the third reaction solvent under the action of reducing agent The reaction is carried out to obtain compound IV. The benzocycloheptanapyridine compound prepared by the preparation method has high purity, can realize the detection and monitoring of compound IV in the process of synthesizing loratadine, and is important for improving the quality of loratadine bulk drug or its preparations significance.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a benzocycloheptanopyridine compound, a preparation method and an application thereof. Background technique [0002] The chemical name of Loratadine is 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-enyl )-1-piperidinecarboxylate ethyl ester, developed by Schering-Plough Company of the United States, was first listed in Belgium in 1988. The treatment of conjunctivitis, hay fever and other allergic skin diseases is the second generation H 1 Receptor blocking drugs, with long-acting, no central inhibitory or anticholinergic features. [0003] At present, the mainstream synthetic route of loratadine is: [0004] . [0005] In the above synthesis process, in addition to the intermediate A, impurity compound IV (with the following formula IV structure) will be produced during the reaction between compound II and Grignard reagent, the generation of the imp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04G01N30/02
CPCC07D401/04G01N30/02
Inventor 孙学涛黄晓俊王旭王永广苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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