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Preparation method of deuterium-labeled higenamine stable isotope compound

A technology of higenamine and its compound, which is applied in the field of isotope internal standard preparation, can solve problems such as unsatisfactory requirements and unsuitability, and achieve the effects of cheap raw materials, cost saving, and high purity

Pending Publication Date: 2021-02-26
天津阿尔塔科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mándity, István M. etc. (Tetrahedron Letters, 2009), reported a kind of synthetic method of 3,4-dimethoxyphenethylamine-D4, and it is raw material with 3,4-dimethoxyphenylacetonitrile, with Raney nickel is used as a catalyst, deuterium gas is used as a deuterium source, and the target product is synthesized with the help of fluid chemistry technology. The yield reaches 70%, but the deuterium exchange rate on the carbon adjacent to the amino group is only 17%, which is far from meeting the requirements.
At the same time, this method requires the use of special equipment and deuterium gas with safety risks, and is not suitable for general laboratory preparation

Method used

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  • Preparation method of deuterium-labeled higenamine stable isotope compound
  • Preparation method of deuterium-labeled higenamine stable isotope compound
  • Preparation method of deuterium-labeled higenamine stable isotope compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the synthesis of 3,4-dimethoxyphenylacetonitrile-D2 (IIa):

[0042]

[0043] The raw material 3,4-dimethoxyphenylacetonitrile (Ia) (10.0g) was dissolved in 100mL of dry THF, cooled to about -78°C, and n-BuLi (2.5M, 55mL, 2.3 eq), after adding, react at this temperature for about 1 hour. The reaction mixture was quenched with about 15 mL of deuterated hydrochloric acid and slowly warmed to room temperature. Add saturated brine and ethyl acetate, extract 2-3 times, combine organic phases, dry, filter, and concentrate under reduced pressure to obtain compound (IIa) (9.0g), yield 90%, MS detection, isotope abundance 98.8% .

Embodiment 2

[0044] Embodiment 2: the synthesis of 3,4-dimethoxyphenylacetonitrile-D2 (IIa):

[0045] The starting material 3,4-dimethoxyphenylacetonitrile (Ia) (10.0 g) was dissolved in 60 mL of dry THF and 100 mL of D 2 O, add pre-dried K 2 CO 3 (31.0g, 4eq), the reaction mixture was stirred at room temperature for 48h. Dry tert-butyl methyl ether was added, separated, and the organic phase was dried, filtered, and concentrated under reduced pressure to obtain compound (IIa) (9.5 g), with a yield of 95%. The isotopic abundance was 99.8% as detected by MS.

Embodiment 3

[0046] Embodiment 3: the synthesis of 3,4-dibenzyloxyphenylacetonitrile-D2 (IIb):

[0047]

[0048] The starting material 3,4-dibenzyloxyphenylacetonitrile (Ib) (5.0 g) was dissolved in 40 mL of dry THF and 50 mL of D 2 O, add pre-dried K 2 CO 3 (8.4g, 4eq), the reaction mixture was stirred at room temperature for 48h. Dry tert-butyl methyl ether was added, separated, and the organic phase was dried, filtered, and concentrated under reduced pressure to obtain compound (IIb) (4.8g), with a yield of 96%. The isotope abundance was 99.8% as detected by MS.

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Abstract

The invention relates to a preparation method of a deuterium-labeled higenamine stable isotope compound. Thepreparation method comprises the following steps: by using a compound (I) as an initial rawmaterial, carrying out D-H exchange, deuteration reduction and deprotection to synthesize an isotope-labeled key intermediate (IV), carrying out Pictet-Spengler cyclization reaction to synthesize an intermediate (VI), and finally, carrying out deprotection reaction to obtain higenamine-D4 (VII). According to the preparation method, the target product is obtained through conventional chemical reaction and five-step reaction, the process design is reasonable, the price of raw materials is low, the cost is saved, the experimental process is controllable, the operation is simple and convenient, the purity of the prepared target product is high and reaches 98% or above, the total yield reaches about 28.0%, isotope abundance of the intermediate in the reaction step is monitored, and can reach more than 96%, the isotope abundance dilution phenomenon is avoided and the reproducibility and the stability are higher.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of an isotope internal standard of higenamine. Background technique [0002] Higenamine was originally isolated and extracted from Japanese aconite by Kosuge et al. Studies have shown that higenamine has a strong effect on the cardiovascular system, can increase heart rate, reduce diastolic blood pressure, and significantly increase coronary artery disease. Improve blood flow, improve sinus node conduction function, etc. The unique pharmacological effects and remarkable therapeutic effects in cardiovascular aspects have great therapeutic value. Clinically, it will be used as cardiotonic agent, diuretic, analgesic and antihypertensive agent, etc. Taking it or taking it by mistake will have a great impact on the performance of athletes. [0003] The World Anti-Doping Agency (WADA) has clearly listed HG as a β2 agonist prohibited substan...

Claims

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Application Information

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IPC IPC(8): C07D217/20
CPCC07D217/20C07B2200/05
Inventor 张磊韩世磊
Owner 天津阿尔塔科技有限公司
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