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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: 2019-06-18
TLC NANJING PHARMA RANDD CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Synthetic method of 3-hydroxy desloratadine metabolite

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Experimental program
Comparison scheme
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; with 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, Concentration and purification by column chromatography afforded 4 g of intermediate III as a white solid with a yield of 67.36%;

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

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, yield 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%;

[0039] (3)...

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Abstract

The invention discloses a synthetic method of 3-hydroxy desloratadine metabolite, belongs to the field of drug metabolism and provides a synthetic method, which is reasonable in technical design, highin operability and high in yield, which is suitable for efficiently converting isotope-labeled materials into labeled target products and which is suitable for industrial production of isotope-labeled 3-hydroxy desloratadine metabolite. The 3-hydroxy desloratadine metabolite is synthesized by subjecting deuterium-2-labeled formaldehyde as a start material to six-step reaction; optimal preparationsteps and reaction conditions are attained by screening of massive experiments; the whole technical design is reasonable, operability is high, labeled materials can be converted into labeled target products efficiently, and the labeled 3-hydroxy desloratadine metabolite prepared via the synthetic method reaches 98.5% and above in chemical purity and reaches >98.5% in label isotope abundance.

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 Applications(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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