Preparation method of lorcaserin intermediate

A technology for lorcaserin and intermediates, which is applied in the field of preparation of lorcaserin intermediates, can solve the problems of high price, high toxicity of HBr, complicated operation and the like, and achieves easy storage and use, avoidance of industrial waste water, and reaction operation. simple effect

Active Publication Date: 2017-05-10
天津泰普制药有限公司
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  • Abstract
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  • Application Information

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Problems solved by technology

[0008] The disadvantages of this preparation method: (1) The high price of potassium borohydride will increase the production cost. Raney nickel is a highly toxic and flammable catalyst, and its storage and recovery conditions are harsh, so it is not suitable for industrial production
(2) Post-reaction treatment requires column chromatography to obtain p-chlorophenethylamine, which is cumbersome and unsuitable for industrial production
[0011] The shortcomings of this preparation method: (1) The high price of potassium borohydride will increase the production cost, and copper chloride is not easy to recycle, resulting in a large amount of waste water or waste liquid containing copper
(2) Post-reaction treatment requires column chromatography to obtain p-chlorophenethylamine, which is cumbersome and unsuitable for industrial production
[0016] The disadvantages of this preparation method: (1) the condensing agent 2,5,6-trifluorophenylboronic acid used in the amidation reaction of p-chlorophenylacetic acid and 1-amino-2-propanol is expensive, and the production cost is high, so it is not suitable Industrial production
(2) The reduction process of lorcaserin intermediate I uses borane, which is not friendly to the environment and is not suitable for industrial production
The disadvantages of this preparation method: (1) the high price of the starting material p-chlorophenylethanol raw material will increase the production cost
(2) Thionyl chloride used will produce a large amount of waste gas and waste liquid, which is not environmentally friendly
The disadvantages of this preparation method: (1) the high price of starting raw material p-chlorophenylethanol will increase the production cost
(2) The HBr used in the bromination reaction is too toxic and not suitable for industrial production
The disadvantages of this preparation method: (1) starting raw material p-chlorophenethylamine raw material is not easy, and raw material price is high, can improve production cost
(2) Epichlorohydrin has a boiling point of about 34°C, is volatile, increases the risk of raw material storage and use, and is not suitable for industrial production

Method used

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  • Preparation method of lorcaserin intermediate
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  • Preparation method of lorcaserin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Embodiment 1: the synthesis of p-chlorophenethylamine

[0041]

[0042] Add 50.0g of p-chlorophenylacetonitrile, 22.0g of sodium borohydride and 500ml of tetrahydrofuran into a 1000ml four-neck flask, stir under nitrogen protection, and cool down in an ice-salt bath. When the system temperature is 0~5°C, add 88.4g of boron trifluoride ether Add it into a 1000mL four-necked bottle through a constant pressure dropping funnel. During the dropping process, control the temperature of the reaction system at 0-10°C. A large amount of gas will be generated during the dropping process. After the dropping is completed, a large amount of white solid will be generated in the reaction system. Heat up to 25~35°C and stir for 1 hour, then raise the temperature to 45~55°C and stir for 4~6 hours, follow the reaction by HPLC until the content of p-chlorophenylacetonitrile in the raw material is less than 1.0%, stop heating, cool down to 0~5°C, pass constant pressure Add 20ml of water ...

Embodiment 2

[0043] Embodiment 2: the synthesis of p-chlorophenethylamine

[0044]

[0045]Add 50.0g of p-chlorophenylacetonitrile, 20.0g of sodium borohydride and 500ml of 2-methyltetrahydrofuran into a 1000ml four-necked flask, stir under nitrogen protection, and cool down in an ice-salt bath. When the system temperature is 0~5°C, add 75.0g of Boron fluoride ether was added into a 1000ml four-necked bottle through a constant pressure dropping funnel. During the dropping process, the temperature of the reaction system was controlled at 0-10°C. A large amount of gas was generated during the dropping process. After the dropping, the reaction system had a large amount of gas. A white solid is formed, heat up to 25~35°C and stir for 1 hour, then heat up to 45~55°C and stir for 4~6 hours, follow the reaction by HPLC until the content of p-chlorophenylacetonitrile in the raw material is less than 1.0%, stop heating, and cool down to 0~5°C , add 20ml of water dropwise through the constant pre...

Embodiment 3

[0046] Embodiment 3: Synthesis of lorcaserin intermediate I

[0047]

[0048] Add 30.0g of 1-chloro-2-propanol, 88.0g of potassium carbonate and 500ml of acetonitrile into a 1000ml four-neck flask, stir under nitrogen protection, control the temperature of the system at 20~25°C, and constant Add the pressure drop funnel into a 1000ml four-necked bottle, control the dropping speed, and control it at 30.0~40.0min. After the dropwise addition is completed, raise the temperature to 55~60°C and stir for 8~10 hours. HPLC will track the reaction until the content of p-chlorophenethylamine in the raw material is reached. Less than 1.0%, remove acetonitrile by distillation under reduced pressure, add 300ml water and 500ml ethyl acetate to extract, separate layers, remove ethyl acetate by distillation under reduced pressure to obtain a light yellow solid, and the solid is recrystallized with ethyl acetate and n-heptane (ethyl acetate The volume ratio of n-heptane and n-heptane is 1:8...

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Abstract

The invention discloses a preparation method of a lorcaserin intermediate (I). According to the preparation method, p-chlorobenzyl cyanide is taken as the primary raw material, and the lorcaserin intermediate (I) is obtained after reduction reactions and condensation reactions. The primary raw materials (p-chlorobenzyl cyanide and 1-chloro-2-propanol) are cheap and easily available; raw materials, which can easily get polluted and are explosive, such as sulfoxide chloride, hydrobromic acid, borane, and the like are not used; the preparation method will not produce a large amount of wastewater and is beneficial for the environment protection; moreover, the requirements on the protection of workers are lowered, and safe production is guaranteed. The route design is novel, the raw materials are easily available, the operation is simple and feasible, and the preparation method is environment-friendly and can be applied to massive industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a 5-hydroxytryptamine 2C (5HT2c) receptor agonist and a preparation method of a lorcaserin intermediate used for weight loss indications for controlling appetite. Background technique [0002] Lorcaserin is a weight loss drug approved by the FDA on June 27, 2012. A selective 5HT2c receptor agonist (5HT2c receptorAgonist) developed by Arena Pharmaceuti, activates the 5HT2c receptor in the hypothalamus to satisfy appetite, thereby controlling appetite and achieving weight loss. Its trade name is Belviq. Obesity can cause various diseases, such as cerebral embolism, coronary heart disease, hypertension, fatty liver, cardiopulmonary failure, endocrine and metabolic diseases, etc. Therefore, the further research and development of its intermediate has very important economic value and practical significance. [0003] The synthesis research of p-chlorophenethylamine is repor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/48C07C211/29C07C213/04C07C213/00C07C215/08C07D223/16C07C59/255C07C51/41
CPCC07C209/48C07C213/00C07C213/04C07D223/16C07B2200/07C07C211/29C07C215/08
Inventor 郭心富朱建强刘兆国
Owner 天津泰普制药有限公司
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