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Method for synthesizing dl-norepinephrine 4-sulfate

A technology of norepinephrine and a synthetic method, applied in the field of drug synthesis, can solve the problems of low yield, troublesome purification, inability to synthesize a large amount, etc., and achieve the effects of high yield, simple processing and mild reaction conditions

Inactive Publication Date: 2018-07-20
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The norepinephrine sulfonate metabolite (DL-Norepinephrine 4-Sulfate) obtained in the present invention provides a standard product for the research on the metabolic mechanism of epinephrine and norepinephrine drugs, and can be used to explore the metabolism of the drug in vivo The process has great application research value in clinical pharmacokinetic research, but the yield of the traditional method in the prior art is very low, only 2%, all of which are mentioned as by-products, and the purification is more troublesome and cannot be produced in large quantities. Synthesis

Method used

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  • Method for synthesizing dl-norepinephrine 4-sulfate

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Embodiment 1

[0018] like figure 1 Shown is the reaction flow diagram of the present invention:

[0019] (1) Suspend 12 g of sodium hydride (60%) in 80 mL of DMSO, stir in an ice bath for 0.5 hours, add 20 g of compound I purchased, stir at room temperature for 5 hours, then add 17 g of benzyl chloride to the reaction solution, After the dropwise addition was completed, react at room temperature for 24 hours; add 200 mL of water to the reaction solution, extract with dichloromethane, concentrate the dichloromethane phase, and purify by column chromatography to obtain 18 g of intermediate II as a white solid.

[0020] (2) Dissolve 16 g of intermediate II in 240 mL of tetrahydrofuran, add 34 g of tetrabutylammonium tribromide at room temperature, and react at room temperature for 24 hours to obtain a red suspension; spin the solvent to dryness, add 200 mL of water, and wash with acetic acid Ethyl extraction was carried out, the ethyl acetate phase was concentrated, and purified by column chr...

Embodiment 2

[0027] like figure 1 Shown is the reaction flow diagram of the present invention:

[0028] (1) Suspend 12 g of sodium hydride (60%) in 80 mL of DMSO, stir in an ice bath for 0.5 hours, add 20 g of compound I purchased, stir at room temperature for 5 hours, then add 16 g of benzyl chloride to the reaction solution, After the dropwise addition was completed, react at room temperature for 24 hours; add 200 mL of water to the reaction solution, extract with dichloromethane, concentrate the dichloromethane phase, and purify by column chromatography to obtain 18 g of intermediate II as a white solid.

[0029] (2) Dissolve 16 g of intermediate II in 240 mL of carbon tetrachloride, add 34 g of N-bromosuccinimide at room temperature, and react at room temperature for 30 hours to obtain a red suspension; spin the solvent dry and add 200 mL of water, extracted with ethyl acetate, concentrated the ethyl acetate phase, and purified by column chromatography to obtain 14 g of intermediate I...

Embodiment 3

[0036] like figure 1 Shown is the reaction flow diagram of the present invention:

[0037] (1) Suspend 12 g of sodium hydroxide (60%) in 80 mL of DMSO, stir in an ice bath for 0.5 hours, add 20 g of compound I, and stir at room temperature for 5 hours, then add 16 g of benzyl bromide to the reaction solution , after the dropwise addition was completed, react at room temperature for 24 hours; add 200 mL of water to the reaction solution, extract with dichloromethane, concentrate the dichloromethane phase, and purify by column chromatography to obtain 18 g of intermediate II, a white solid;

[0038] (2) Dissolve 16 g of intermediate II in 240 mL of acetonitrile, add 34 g of N-bromosuccinimide at room temperature, and react at room temperature for 30 hours to obtain a red suspension; spin the solvent dry, add 200 mL of water, It was extracted with ethyl acetate, the ethyl acetate phase was concentrated, and purified by column chromatography to obtain 14 g of intermediate III as ...

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Abstract

The invention discloses a method for synthesizing dl-norepinephrine 4-sulfate, belonging to the field of drug synthesis. In the method, the dl-norepinephrine 4-sulfate is obtained through six-step reactive synthesis by taking 3,4-dihydroxyacetophenone as a starting material. According to the method, optimal preparation steps and reaction conditions are selected through a large number of experiments, the whole process design is reasonable, and the operability is strong. The chemical purity of the prepared product can reach 98.5% or above, and the overall yield is relatively high. The prepared dl-norepinephrine 4-sulfate provides a standard for the study of the metabolic mechanism of adrenaline and norepinephrine medicines, and can be used to explore the metabolic process of the medicines invivo. Dl-norepinephrine 4-sulfate has great application research value in clinical pharmacokinetic research.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing norepinephrine sulfonic acid metabolites. Background technique [0002] Epinephrine is a hormone and neurotransmitter released by the adrenal glands; a hormone secreted by the body. Adrenaline will increase the contractility of the heart, dilate the blood vessels of the heart, liver, and muscles, and constrict the blood vessels of the skin and mucous membranes. It is a must-have for saving dying people or animals. Its chemical name is (R)-4- (2-(methylamino)-1-hydroxyethyl]-1,2-benzenediol is mainly used clinically for cardiac arrest, bronchial asthma, anaphylactic shock, and can also treat urticaria, hay fever and nasal mucosa or Bleeding gums. [0003] Norepinephrine, scientific name 1-(3,4-dihydroxyphenyl)-2-aminoethanol, is a substance formed by removing the N-methyl group of epinephrine, and also belongs to catecholamine in chemical structure, former...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C305/24C07C303/24C07C247/10C07C45/64C07C45/63C07C49/84
CPCC07C45/63C07C45/64C07C247/10C07C303/24C07C49/84C07C305/24
Inventor 张帅胡永铸刘春徐一鸣
Owner TLC NANJING PHARMA RANDD CO LTD
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