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Preparation method of chiral higenamine and derivatives of chiral higenamine

A technology of higenamine and chirality, which is applied in the field of preparation of chiral higenamine and its derivatives, and can solve the problem that it is difficult to meet the medical use requirements of higenamine isomers, and it is difficult to obtain higenamine Eliminate problems such as isomers of hiratine, and achieve high selectivity and high product purity

Active Publication Date: 2014-03-12
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned methods for extracting or biosynthesizing isomers often obtain a mixture of various compounds, and complex separation and purification operations are required to obtain high-purity chiral higenamine, so it is difficult to obtain nor Higenamine isomers, it is difficult to meet the medical use needs of higenamine isomers

Method used

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  • Preparation method of chiral higenamine and derivatives of chiral higenamine
  • Preparation method of chiral higenamine and derivatives of chiral higenamine
  • Preparation method of chiral higenamine and derivatives of chiral higenamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment one: the preparation of (R)-higenamine hydrochloride

[0041] Take a 500mL three-neck flask, add 40mL dichloromethane and 20g (0.12mol) 4-methoxyphenylacetic acid (compound III) under nitrogen protection, start stirring, cool to 0°C in an ice-salt bath, add 1.75g ​​(0.024mol) ) N,N-dimethylformamide as catalyst, then slowly add 18.3g (0.144mol) oxalyl chloride dropwise, raise the temperature to 25°C, and stir for 4 hours. When TCL detects that the reaction of compound III is complete, stop stirring, and distill under reduced pressure The solvent was removed to obtain 23.8 g of 4-methoxyphenylacetyl chloride (compound IV) as an oil.

[0042] Dissolve 21.7g (0.12mol) of 2-(3,4-dimethoxy)phenethylamine in 40mL of dichloromethane, add 12.1g (0.12mol) of triethylamine as an acid trap, and cool in an ice-salt bath to 0°C, dissolve 23.8g of the obtained oily 4-methoxyphenylacetyl chloride (compound IV) in 40mL of dry dichloromethane and slowly add it dropwise to th...

Embodiment 2

[0055] Embodiment two: the preparation of (S)-higenamine hydrobromide

[0056]Take a 500mL three-necked flask, add 40mL dichloromethane and 20g (0.12mol) 4-methoxyphenylacetic acid (compound III) under nitrogen protection, start stirring, cool to 0°C in an ice-salt bath, add 4.38g (0.06mol) ) N,N-dimethylformamide as a catalyst, then slowly add 28.6g (0.24mol) of thionyl chloride dropwise, raise the temperature to 45°C, stir and reflux for 3 hours, when TCL detects that the reaction of compound III is complete, stop stirring, The solvent was distilled off under reduced pressure to obtain 22.3 g of oily 4-methoxyphenylacetyl chloride (compound IV).

[0057] Dissolve 21g (0.116mol) of 2-(3,4-dimethoxy)phenethylamine in 35mL of dichloromethane, add 9.2g (0.116mol) of pyridine as an acid trap, cool to 0-5°C, and The prepared 22.3g of oily 4-methoxyphenylacetyl chloride (compound IV) was dissolved in 45mL of dry dichloromethane and slowly added dropwise to the reaction solution. ...

Embodiment 3

[0070] Embodiment three: structural identification

[0071] Adopt elemental analyzer, measure respectively the C, H, H, N composition, the measurement results are shown in Table 1 and Table 2.

[0072] Table 1 (R) - elemental analysis results of higenamine hydrochloride

[0073]

[0074] Table 2 (S) - elemental analysis results of higenamine hydrobromide

[0075]

[0076] Using a high-resolution mass spectrometer (Thermo Finnigan of U.S. Thermo Finnigan, the model is MAT95XP), the (R)-higenamine hydrochloride prepared in Example 1 and the ( S)-higenamine hydrobromide was subjected to mass spectrometry analysis, and its fast atom bombardment ionization (+FAB) mass spectrometry results were as follows figure 1 , figure 2 shown. figure 1 , figure 2 The assignment of the m / z272 ion peak in is as follows:

[0077]

[0078] A superconducting pulsed Fourier transform NMR spectrometer (BRUKEROPTICS, model JY / T007-1996), with deuterated dimethyl sulfoxide (DMSO-D6) as...

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Abstract

The invention discloses a preparation method of chiral higenamine. The chiral higenamine is prepared from 4-methoxyphenylacetic acid by the following steps: chlorination, acylation and asymmetric reduction, cyclization, asymmetric reduction, removal of protecting groups and the like. The preparation method has the advantages of high selectivity, simplicity, efficiency and the like. The ee. value of the product is over 95%, the purity of the product is high, and the total yield can reach 30%. Production and preparation in a large scale can be realized.

Description

technical field [0001] The invention relates to a preparation method of higenamine and its derivatives, in particular to a preparation method of chiral higenamine and its derivatives. Background technique [0002] Higenamine has cardiac β-adrenoceptor stimulatory effect, and its action on α-adrenergic receptor can relax blood vessels and anti-platelet aggregation activity, and can also inhibit the inducible type 1 in macrophages, vascular smooth muscle and other cells. Expression of nitric oxide synthase (iNOS) and production of nitric oxide (NO) have potential therapeutic value in the treatment of disseminated intravascular coagulation (DIC) and multiple organ failure (MOF). Higenamine has been used as a cardiac stress test drug for echocardiography and myocardial perfusion imaging in the diagnosis of coronary heart disease. [0003] Higenamine (1-(4-hydroxy-benzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is a benzotetrahydroisoquinoline alkaloid , which has a chira...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
CPCY02P20/55C07D217/20
Inventor 关东陈新民周爱新莫泽艺李必禄
Owner 珠海润都制药股份有限公司
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