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Stable isotope tag R-clorprenaline and preparation method thereof

A technology of stable isotope and chlorprenaline, which is applied in the field of stable isotope labeling R-chlorprenaline and its preparation, can solve the problems of no synthetic steps of chlorprenaline, long reaction route, cumbersome preparation, etc., and achieve economical Good performance and use value, high utilization rate of isotope atoms, and simple process route

Inactive Publication Date: 2018-11-30
SHANGHAI RES INST OF CHEM IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Natural chlorprenaline and its hydrochloride are mostly obtained by resolution of the racemate using chiral mobile phase additives or chiral immobilization. This method is cumbersome to prepare, high in cost, and poor in separation effect
Rajesh Kumar Pandey et al. reported that the synthesis of natural chiral chlorprenaline is to use expensive o-chlorostyrene, react with chiral reagents to generate chiral o-diol, and then prepare through three-step reactions. The raw material price of this route is Expensive, difficult to obtain, and the reaction route is long, low yield is not suitable for stable isotope labeling R-chlorprenaline synthesis
Shanghai Institute of Metrology Li Jie et al disclosed in the patent the synthesis of deuterium-labeled phenylethanolamine β-receptor agonist, using a highly irritating and highly toxic bromoacetyl chloride bromide reagent, and then aminated reduction to prepare racemic Deuterium-labeled β-agonist enantiomers (simple isopropylamine-D only 6 label), rather than a stable isotope labeled R-chlorprenaline of a single configuration, and there is no detailed synthetic step of chlorprenaline in the patent

Method used

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  • Stable isotope tag R-clorprenaline and preparation method thereof
  • Stable isotope tag R-clorprenaline and preparation method thereof
  • Stable isotope tag R-clorprenaline and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] A stable isotope labeled R-chlorprenaline- 13 C 11 The preparation method comprises the following steps:

[0044] 1. Stable isotope labeled o-chloroacetophenone- 13 C 8 preparation of

[0045] Under anhydrous and anaerobic conditions, 11.9g chlorobenzene- 13 C 6Add it into a 250ml three-necked flask, add 25ml of tetrahydrofuran, 5g of titanium tetrachloride, stir and disperse, add dropwise acetic anhydride- 13 C 4 11.5g, after the dropwise addition, the temperature was raised to 80°C for 2 hours, washed with water, dried and recrystallized to obtain o-chloroacetophenone- 13 C 8 15.6g, yield 94.3%, purity 99.5%, abundance 99.5atom% 13 c.

[0046] 2. Stable isotope labeling α-bromo-o-chloroacetophenone- 13 C 8 preparation of

[0047] Under anhydrous and anaerobic conditions, add 8.1g o-chloroacetophenone to a 250mL three-necked flask- 13 C 6 , add 15g of DBBA, add 20ml each of methanol and ethyl acetate, control the temperature at 60°C, react for 4 hours,...

Embodiment 2

[0053] A stable isotope labeled R-chlorprenaline-D 16 The preparation method comprises the following steps:

[0054] 1. Stable isotope labeling o-chloroacetophenone-D 7 preparation of

[0055] Under anhydrous and anaerobic conditions, 11.7g of chlorobenzene-D 5 Add it into a 250ml three-necked flask, add 35ml of deuterated chloroform, 3g of zirconium tetrachloride, stir and disperse, add dropwise acetic anhydride-D 6 12.0g, after the dropwise addition, the temperature was raised to 60°C for 2 hours, washed with heavy water, dried and recrystallized to obtain o-chloroacetophenone-D 7 15.4g, yield 95.8%, purity 99.6%, abundance 99.0% atom%D.

[0056] 2. Stable isotope labeling of α-bromo-o-chloroacetophenone-D 7 preparation of

[0057] Under anhydrous and anaerobic conditions, add 8.1g o-chloroacetophenone-D to a 250mL three-necked flask 7 , add 14g of DBI, add 20ml of deuterated chloroform, control the temperature at 40°C, react for 3 hours, wash with water, dry and re...

Embodiment 3

[0063] A stable isotope labeled R-chlorprenaline- 15 N preparation method, the method comprises the following steps:

[0064] 1, the preparation of o-chloroacetophenone

[0065] Under anhydrous and anaerobic conditions, add 11.2g of chlorobenzene into a 250ml three-necked flask, add 35ml of dichloromethane, 2g of antimony trichloride, stir and disperse, add 12.9g of acetic anhydride dropwise, after the dropwise addition, raise the temperature React at 50°C for 1 hour, wash with water, dry and recrystallize to obtain 14.6 g of o-chloroacetophenone with a yield of 94.3% and a purity of 99.5%.

[0066] 2. Preparation of α-bromo-o-chloroacetophenone

[0067] Under anhydrous and anaerobic conditions, add 7.5g of o-chloroacetophenone, 10.1g of dibromohydantoin, and 20ml of methanol into a 250mL three-necked flask, and then add 20ml of methanol, keep the temperature at 40°C, react for 4 hours, wash with water, dry, and recrystallize Finally, 10.4 g of yellow solid was obtained, wi...

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Abstract

The invention relates to a stable isotope tag R-clorprenaline and a preparation method thereof. The preparation method comprises the following steps: utilizing an organic synthesis method, taking a stable isotope tag chlorobenzene as a raw material and carrying out riedel-Crafts reaction to generate a stable isotope tag chloroacetophenone; carrying out bromination to obtain a stable isotope tag alpha-bromochloroacetophenone; then carrying out one-pot reaction on the stable isotope tag alpha-bromochloroacetophenone, a stable isotope tag isopropylamine and a reducing agent to obtain the stable isotope tag R-clorprenaline. Compared with the prior art, the stable isotope tag R-clorprenaline prepared by the preparation method has the advantages that the chemical purity reaches 99 percent or more and the isotope abundance is 99 percent or more; the stable isotope tag R-clorprenaline can be used for researching a metabolic mechanism of a medicine clorprenaline and detecting the residue of a prohibited veterinary drug clorprenaline in the field of food safety.

Description

technical field [0001] The invention relates to the technical field of isotope labeling, in particular to a stable isotope-labeled R-chlorprenaline and a preparation method thereof. Background technique [0002] Chlorprenaline is a commonly used drug for the treatment of respiratory diseases and belongs to the selective beta 2 Receptor stimulant drugs are widely used clinically for bronchiectasis, bronchial asthma, asthmatic bronchitis, etc., with high selectivity and strong action. It contains a chiral carbon atom in its molecule and is a chiral compound. At present, this drug is still mainly administered in the form of racemate. However, studies have shown that for such β 2 Receptor stimulant drugs, different enantiomers may have different efficacy. The study of the pharmacodynamic activity of enantiomers requires the synthesis of stable isotope-labeled R-chlorprenaline in a single configuration. Therefore, the synthesis and separation of stable isotope-labeled enantiom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/30C07C213/04C07C45/63C07C49/80
CPCC07B2200/05C07B2200/07C07C45/63C07C213/04C07C215/30C07C49/80
Inventor 徐仲杰白少飞邓晓军涂亚辉孙雯王浩然罗勇古淑青赵超敏
Owner SHANGHAI RES INST OF CHEM IND
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