A kind of synthetic method of 3-hydroxy desloratadine metabolite

A technology of loratadine and synthetic method, which is applied in the field of synthesis of 3-hydroxydesloratadine metabolites, can solve the problem of unsuitable 3-hydroxydesloratadine metabolites, low product yield, and expensive raw materials and other issues, to achieve the effect of great application research value, reasonable process design, and strong operability

Active Publication Date: 2021-11-02
TLC NANJING PHARMA RANDD CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The current synthesis method of desloratadine metabolites (non-labeled synthesis method) is to use intermediate II, thionyl chloride or other chlorination reagents to chlorinate the hydroxyl group, then make Grignard reagents, and then combine with the intermediate Body IV reaction, this method not only wastes a large amount of deuterated raw materials, but also the Grignard reaction is difficult to initiate, even if the Grignard reaction is triggered, the final product yield is also very low, because the deuterated raw materials are very expensive, this The method cannot efficiently convert deuterium-labeled starting materials into labeled target products, so it is not suitable for the synthesis of deuterated 3-hydroxydesloratadine metabolites
But there is no report about the synthetic method of isotope-labeled 3-hydroxydesloratadine metabolites

Method used

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  • A kind of synthetic method of 3-hydroxy desloratadine metabolite
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  • A kind of synthetic method of 3-hydroxy desloratadine metabolite

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Experimental program
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Effect test

Embodiment 1

[0022] Such as figure 1 Shown, a kind of synthetic method of 3-hydroxy desloratadine metabolite comprises the following steps:

[0023] (1) Take 20 g of benzylamine hydrochloride I, put it into a 150 mL round bottom flask, add 6 g of 20 % deuterium 2 labeled formaldehyde heavy aqueous solution, 16 mL of allyltrimethylsilane, at 40 °C React for 48 hours; use 1M sodium hydroxide solution to adjust the pH of the reaction solution to 11, extract with dichloromethane, concentrate the dichloromethane phase, and purify by column chromatography to obtain 12g of intermediate II as a yellow oil, with a yield of 66.3% ;

[0024] (2) Dissolve 6 g of intermediate II in 60 mL of dry toluene, add 14 g of Dess-Martin oxidant, react at 60°C for 8 hours, add 200 mL of water, extract with dichloromethane, and separate the dichloromethane phase Come out, concentrate, and purify by column chromatography, obtain 5g intermediate III, be white solid, yield is 84.2%;

[0025] (3) Suspend 15 g of al...

Embodiment 2

[0029] Such as figure 1 Shown, a kind of synthetic method of 3-hydroxy desloratadine metabolite comprises the following steps:

[0030] (1) Take 20 g of benzylamine trifluoroacetate I, put it into a 150 mL round bottom flask, add 6 g of 20% deuterium 2 labeled heavy formaldehyde solution, 14 mL of allyltrimethylsilane, 60 Reaction at ℃ for 48 hours; use 1M sodium hydroxide solution, adjust the pH of the reaction solution to 11, extract with dichloromethane, concentrate the dichloromethane phase, and purify by column chromatography to obtain 10 g of intermediate II as a yellow oil. rate 56.7%;

[0031] (2) Dissolve 6 g of intermediate II in 60 mL of dry toluene, add 12 g of PCC oxidant, react at 40 ° C for 24 hours, add 200 mL of water, extract with dichloromethane, and separate the dichloromethane phase, Concentrate and purify by column chromatography to obtain 4g of intermediate III as a white solid with a yield of 67.36%;

[0032] (3) Suspend 16 g of ferric chloride into ...

Embodiment 3

[0036] Such as figure 1 Shown, a kind of synthetic method of 3-hydroxy desloratadine metabolite comprises the following steps:

[0037] (1) Take 20 g of benzylamine hydrochloride Ⅰ, put it into a 150 mL round bottom flask, add 6 g of 20 % deuterium 2-labeled formaldehyde heavy aqueous solution, 16 mL of allyltrimethylsilane, at 60 °C React for 12 hours; use 1M sodium hydroxide solution to adjust the pH of the reaction solution to 11, extract with dichloromethane, concentrate the dichloromethane phase, and purify by column chromatography to obtain 11.3 g of intermediate II as a yellow oil, with a yield of 62.4 %;

[0038] (2) Dissolve 6 g of intermediate II in 60 mL of dry toluene, add 20 g of manganese dioxide oxidant, react at 60 °C for 8 hours, filter, add 200 mL of water, extract with dichloromethane, dichloromethane The phases were separated, concentrated, and purified by column chromatography to obtain 4.6 g of intermediate III as a white solid with a yield of 77.5%;

...

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Abstract

The invention discloses a method for synthesizing 3-hydroxydesloratadine metabolites, which belongs to the field of drug metabolism, and provides a method with reasonable process design, strong operability, high yield, and efficient conversion of isotope-labeled raw materials In order to mark the target product, a synthetic method for the industrial production of isotope-labeled 3-hydroxydesloratadine metabolites can be realized. The present invention uses deuterium 2-labeled formaldehyde as the starting material, and synthesizes it through six-step reactions. The optimal preparation steps and reaction conditions are screened out through a large number of experiments. The whole process design is reasonable, the operability is strong, and the labeled The raw material is converted into a labeled target product, and the labeled 3-hydroxydesloratadine metabolite prepared by the present invention has a chemical purity of over 98.5% and a labeled isotope abundance >98.5%.

Description

technical field [0001] The invention belongs to the field of drug metabolism, in particular to a method for synthesizing 3-hydroxydesloratadine metabolites. Background technique [0002] Desloratadine, whose chemical name is 8-chloro-6,11-dihydro-11(4-piperidinylidene)-5H-benzo-[5,6]heptane[1,2-b] Pyridine; Desloratadine, also known as AERIUS (Schering-Plough) / DENOSIN (Lax), is a non-sedating long-acting tricyclic antihistamine, which is an active metabolite of loratadine, which can be selectively Antagonize peripheral H1 receptors to relieve symptoms related to allergic rhinitis or chronic idiopathic urticaria. [0003] The current synthesis method of desloratadine metabolites (non-labeled synthesis method) is to use intermediate II, thionyl chloride or other chlorination reagents to chlorinate the hydroxyl group, then make Grignard reagents, and then combine with the intermediate Body IV reaction, this method not only wastes a large amount of deuterated raw materials, bu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
Inventor 张帅胡永铸刘春徐一鸣
Owner TLC NANJING PHARMA RANDD CO LTD
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