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Preparation method of stable isotope-labeled clorprenaline

A technology of stable isotope and clorprenaline, which is applied in the field of preparation of clorprenaline, can solve the problems of not being suitable for large-scale preparation, difficult separation and purification of intermediates, high synthesis cost, etc., and achieves cheap raw materials and reproducibility And the effect of high stability and easy operation

Pending Publication Date: 2021-07-23
阿尔塔(天津)标准物质研究院有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above synthetic methods all involve difficult separation and purification of intermediates in the synthesis process, many by-products in the amination process, long synthesis steps, low overall yield, high synthesis cost, and inability to adapt to large-scale preparations. Fundamentally solve the current situation that restricts our country's testing field to rely on imported products

Method used

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  • Preparation method of stable isotope-labeled clorprenaline
  • Preparation method of stable isotope-labeled clorprenaline
  • Preparation method of stable isotope-labeled clorprenaline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Synthesis of Intermediate II

[0038]

[0039] The raw material 2-bromo-2'-chlorophenylideophenone (compound I) (10.0 g) was dissolved in 100 mL of acetonitrile, dimethyla aminyl sodium (1.2 eq, 7.0 g) was added, and the reaction mixture was stirred at 70 degrees Celsius. 3h. TLC detection (PE; EA = 5: 1) The reaction was complete, and the reaction was also cooled and filtered, concentrated the mother liquor to give a crude product. The crude product was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether = 0% to 30%) to give 9.0 g of intermediate II, yield 92.8%, yellow solid.

Embodiment 2

[0040] Example 2: Synthesis of Intermediate III

[0041]

[0042] 8 g of intermediate II was suspended with 6N HCl (100 mL) aqueous solution, and heated in an oil bath placed in an oil bath at 120 degrees Celsius, and then said, TLC detection (PE: EA = 3: 1) The reaction was complete. Static cooling overnight, precipitated solid, filtrate, dried to give 7.0 g of intermediate III, yield 96.0%, white solid.

Embodiment 3

[0043] Example 3: Synthesis of Intermediate IV

[0044]

[0045]The 7.2 g of intermediate III was dissolved in methanol (100 mL), and sodium borohydride was added at room temperature (ice bath), and sodium borohydride (3.0 Eq, 5.8 g) was added to obtain suspension. The reaction was reacted at room temperature. Add water to the reaction, add a small amount of potassium carbonate to 10 to 10, then extract about 3 times with dichloromethane, washed with saturated brine, dry, concentrate to obtain approximately 5.5 g intermediate IV, yield 91.7%, yellow solid .

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Abstract

The invention relates to a preparation method of stable isotope-labeled clorprenaline. The preparation method comprises the following steps: with 2-bromo-2'-chloroacetophenone as an initial raw material, successively conducting improved Gabriel synthesis (wherein the initial raw material and an amination reagent sodium, namely diformyl amide are subjected to a nucleophilic substitution reaction), hydrolysis, reduction and reductive amination so as to synthesize the isotope-labeled clorprenaline . According to the preparation method disclosed by the invention, through a four-step conventional chemical reaction, process design is reasonable, raw material price is low, an experimental process is controllable, operation is simple and convenient, various required labeled compounds such as D-labeled, 13C-labeled or D / 13C double-labeled compounds can be conveniently synthesized, the purity of the prepared target product is high and reaches 98% or above, total yield reaches 66% or above, the isotope abundance of the final product can reach 98% or above, the phenomenon of isotope abundance dilution is avoided, higher reproducibility and stability are achieved, and the obtained target compound can provide a standard reagent for accurately and quantitatively detecting trace residues of clorprenaline.

Description

Technical field [0001] The present invention belongs to the technical field of drug preparation, and in particular, the preparation method of stabilizing isotope labeled chloropropain is involved. Background technique [0002] Chloroproparin is a new type of β2 receptor agonist, except for the treatment of bronchitis and wheezing bronchitis, is also used as a feed additive to increase the ratio of lean tissue, and its residue will in the animal accumulation. At present, for the content detection of chloroproparin, traditional liquid, temperamentary methods, and other rapid detection methods. These conventional liquid phases, gas chromatography-mass spectrometry are affected by the matrix effect, especially chloroproparin detection samples, and the matrix composition, these sample matrices are complex, difficult to handle, and not scientific The pre-treatment method is also easy to cause a large deviation of the test results, and therefore, the limitation of the conventional detec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C215/30C07C213/00C07C231/12C07C233/90C07C221/00C07C225/16C07B59/00
CPCC07B59/001C07C231/12C07C221/00C07C213/00C07C213/08C07B2200/05
Inventor 张磊韩世磊
Owner 阿尔塔(天津)标准物质研究院有限公司
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