Preparation method of ractopamine-D6 hydrochloride

A technology of ractopamine hydrochloride and salt-forming reaction is applied in the field of drug synthesis, which can solve the problems of insufficient labeled compounds, expensive labeled raw materials, low yield and the like, and achieves the effects of low price, low synthesis cost and easy operation.

Pending Publication Date: 2021-07-02
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

[0004] At present, the synthetic method of isotope-labeled ractopamine has been reported in the literature, wherein the patent (CN102786426A) reacts with octopamine-Dm and raspberry ketone-Dn to obtain deuterated ractopamine through dehydration reduction, but this method uses expensive Marked raw materials, and the yield is not high, the cost is high
Another patent (CN104387282A) uses ketones as raw materials to obtain deuterated ractopamine through reduction, protection, coupling, and deprotection. However, this scheme only marks 1 D, and the marked product is only one mass number different from the naturally abundant ractopamine. , and when the stable isotope labeling reagent is used as an internal standard reagent in isotope dilution mass spectrometry, it is generally required to have a difference of at least 3 mass numbers, so the labeled compound prepared by this method has obvious shortcomings in practical application.

Method used

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  • Preparation method of ractopamine-D6 hydrochloride
  • Preparation method of ractopamine-D6 hydrochloride
  • Preparation method of ractopamine-D6 hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0030] (1) Dissolve compound I (5.0g, 1.0eq) in dry 1,4-dioxane (50mL) at room temperature, under nitrogen protection, add 40% NaOD (17.3g, 6.0eq) heavy aqueous solution under stirring , then add D 2 O (100 mL), the temperature was raised to 50°C and the reaction was stirred overnight. The reaction solution was adjusted to pH=6 with deuterium hydrochloric acid aqueous solution, then extracted with dry methyl tert-butyl ether, the organic phases were combined, dried, and concentrated to obtain 5 g of compound IIa with a yield of 95%, which was directly used for Next step, the structural formula of compound IIa is:

[0031] (2) At room temperature, dissolve compound IIa (4g, 1.0eq) in CH 3OD (50mL), then add intermediate III (4.14g, 1.0eq), acetic acid (0.26g, 0.2eq), and cool to 0°C under nitrogen protection, at this temperature, add sodium cyanoborodeuteride in batches ( 2.2g, 1.5eq), returned to room temperature and stirred overnight. The reaction was monitored by TLC (...

Embodiment 2

[0035] (1) Dissolve compound I (5.0g, 1.0eq) in 50mL of dry tetrahydrofuran at room temperature, under nitrogen protection, add 40% NaOD (12.1g, 6.0eq) heavy aqueous solution under stirring, then add D 2 O (100 mL), heated to 50°C and stirred overnight. Adjust the pH of the reaction solution to about 6 with deuterium hydrochloric acid solution, then extract it with dry methyl tert-butyl ether, combine the organic phases, dry, and concentrate to obtain 5 g of compound IIb. The yield is 95%, and it is directly used for Next step, the structural formula of compound IIb is:

[0036] (2) at room temperature, compound IIb (4g, 1.0eq) was dissolved in 50mL of CH 3 In OD, add compound III (2.9g, 1.0eq), acetic acid (0.19, 0.2eq), and cool to 0°C under nitrogen protection. At this temperature, add sodium cyanoborodeuteride (1.5g, 1.5eq ), returned to room temperature and stirred overnight, and TLC (DCM:MeOH=10:1) monitored the reaction. After the reaction, the reaction solution wa...

Embodiment 3

[0039] The difference with embodiment 1 is that the specific operation of step (1) is:

[0040] Compound Ia (5.0 g, 1.0 eq) was dissolved in dry CH at room temperature 3 OD (50 mL), under nitrogen protection, sodium methoxide (4.6 g, 3.0 eq) was added with stirring, and the temperature was raised to 50° C. and the reaction was stirred overnight. The reaction solution was adjusted to pH=6 with deuterium hydrochloric acid aqueous solution, and then extracted with dry methyl tert-butyl ether, the organic phases were combined, dried, and concentrated to obtain 4.8g of compound IIa with a yield of 94%, which was directly used without purification in the next step.

[0041] Step (2) and step (3) are the same as in Example 1.

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Abstract

The invention provides a preparation method of ractopamine-D6 hydrochloride. a compound I is used as an initial raw material, and isotope-labeled ractopamine-D6 hydrochloride is synthesized through H-D exchange, reductive amination, deprotection and salt forming reaction. According to the preparation method, the target product is obtained through 2-3 steps of conventional chemical reactions, the purity of the prepared target product reaches 98% or above, the total yield reaches about 44%, the isotope abundance is controllable and reaches 96% or above, the process design is reasonable, the raw material price is low, the experimental process is controllable, operation is easy and convenient, and the process reproducibility is high.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of ractopamine hydrochloride-D6. Background technique [0002] Ractopamine is a synthetic β-adrenoreceptor agonist (commonly known as β-stimulant) compound, which is a less toxic and fast-metabolizing clenbuterol substitute developed by an American pharmaceutical company and belongs to the second generation Clenbuterol. Because of its ability to regulate protein synthesis, it is also called protein repartitioner (Repartitioner) abroad, and it is mainly used clinically to treat bronchial asthma, congestive heart failure and muscular dystrophy. However, excessive intake of ractopamine will cause different degrees of poisoning reactions in the human body. The symptoms are similar to the symptoms of animal poisoning. Those who can cause high blood pressure, heart disease and even death. The World Anti-Doping Agency (WADA) has clearly listed ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C215/60
CPCC07C45/61C07C213/08C07C213/00C07C49/753C07C217/54C07C215/60
Inventor 张磊刘晓佳韩世磊
Owner 阿尔塔(天津)标准物质研究院有限公司
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