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Synthesis method of noradrenaline and bitartrate thereof

A norepinephrine and synthesis method technology, applied in the field of organic synthesis, can solve the problems of harsh reaction temperature and pH conditions, unsuitability for industrial production, cumbersome post-treatment process, etc., achieve low content, reduce recrystallization chiral resolution The effect of increasing the number of times and increasing the total yield

Pending Publication Date: 2021-11-30
CHENGDU SINO STRONG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] This synthetic method uses (-)-diisopinepinocampylchloroborane to prepare norepinephrine, and this synthetic route also has the problems of high cost and complex reaction by using a special CBS reduction system to prepare chiral alcohol groups, and the reaction temperature , harsh pH conditions, cumbersome post-treatment process, not suitable for industrial production

Method used

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  • Synthesis method of noradrenaline and bitartrate thereof
  • Synthesis method of noradrenaline and bitartrate thereof
  • Synthesis method of noradrenaline and bitartrate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1, the preparation of norepinephrine of the present invention

[0066] 1. Preparation of intermediate III (compound A is R-(+)-N-benzyl-1-phenylethylamine)

[0067] Add 50.0g 3,4-dihydroxy-2'-chloroacetophenone, 113.5g R-(+)-N-benzyl-1-phenethylamine, 150ml N,N-dimethyl For formamide, heat up to 40-50°C to react, and monitor the reaction by TLC until the reaction of 3,4-dihydroxy-2'-chloroacetophenone is complete. The reaction solution was poured into 500ml of water, a large amount of solids were precipitated, filtered, stirred and washed with a mixed solution of 100ml ethyl acetate and 200ml petroleum ether, filtered and dried to obtain 90.1g of intermediate III with a molar yield of 92.9%.

[0068] 2. Preparation of intermediate IV (compound A is R-(+)-N-benzyl-1-phenylethylamine)

[0069] Add 80.0g of intermediate III, 400ml of tetrahydrofuran, and 400ml of ethanol to the reaction bottle in turn, stir until the solid is completely dissolved, add 25.4g of...

Embodiment 2

[0072] Embodiment 2, the preparation of norepinephrine of the present invention

[0073] 1. Preparation of intermediate III (compound A is R(+)-α-methylbenzylamine)

[0074] Add 10.0g 3,4-dihydroxy-2'-chloroacetophenone, 13.0g R(+)-α-methylbenzylamine, 40ml N,N-dimethylformamide to the reaction flask in sequence, heat up The reaction was carried out at 50-60°C, and the reaction was monitored by TLC until the conversion of 3,4-dihydroxy-2'-chloroacetophenone ceased. The reaction liquid was dropped into 120ml of water, a large amount of solids were precipitated, filtered, the filter cake was stirred and washed with a mixed solution of 20ml of ethyl acetate and 40ml of petroleum ether, filtered and dried to obtain 9.7g of intermediate III, with a molar yield of 66.7%.

[0075] 2. Preparation of intermediate IV (compound A is R(+)-α-methylbenzylamine)

[0076] Add 8.0g of intermediate III and 40ml of methanol successively in the reaction flask, stir until the solid is completely...

Embodiment 3

[0079] Embodiment 3, the preparation of norepinephrine bitartrate

[0080] Add the wet product of norepinephrine prepared in Example 1 or 2, 30.0g of water, 600ml of ethanol, and 24.8g of L-tartaric acid in sequence in the reaction flask, the solid is first dissolved and then precipitated, stirred evenly, and filtered to obtain a salt-forming solid (wet product).

[0081] The resulting solid was added to a reaction flask, 30.0 g of water and 800 ml of ethanol were added, heated until the solid was completely dissolved, turned off the heating, crystallized naturally, filtered, and dried to obtain 17.7 g of norepinephrine bitartrate (Compound I), the total molar yield 31.8% (based on intermediate V). HPLC purity 99.964%, isomer content 0.144%. HPLC purity chart see figure 2 , isomer content map see image 3 . It shows that making bitartrate further increases the content of norepinephrine in R-configuration. After only one chiral resolution of crystallization, the norepine...

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Abstract

The invention provides a synthesis method of noradrenaline. The synthesis method comprises the following steps: with 3,4-dihydroxy-2'-chloroacetophenone or 3,4-dihydroxy-2'-bromoacetophenone as a raw material, conducting reacting with a chiral compound in a polar aprotic solvent, performing reducing with a reducing agent, and carrying out catalytic hydrogenation reaction. The invention also discloses a method for preparing noradrenaline bitartrate by salifying noradrenaline and L-tartaric acid and splitting the salified noradrenaline and L-tartaric acid. According to the method, a chiral reagent is introduced into the chemical structure of the intermediate, the content of R-configuration products is increased through induction in a carbonyl reduction step, the subsequent resolution times of salifying with L-tartaric acid are reduced, and yield is greatly improved. The norepinephrine bitartrate synthesis method is simple, raw materials are easy to obtain, the prepared norepinephrine bitartrate is high in optical purity, and the method is low in cost and has excellent industrial production application prospects.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a method for synthesizing norepinephrine and norepinephrine bitartrate. Background technique [0002] The structure of norepinephrine is shown below. It is a common neurotransmitter, which is mainly synthesized and secreted by sympathetic postganglionic neurons and adrenergic nerve endings in the brain. It is also a hormone, synthesized and secreted by the adrenal medulla; Norepinephrine in the circulating blood mainly comes from the adrenal medulla, whose main function is to maintain vascular tone, that is, to maintain blood pressure. In the emergency mechanism, for harmful stimuli that can change blood pressure levels, the body regulates the content of norepinephrine to ensure circulatory function. [0003] [0004] Therefore, as a clinical drug, norepinephrine is mainly used for shock caused by various etiologies, including cardiogenic shock, low-emission low-resistance (w...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C213/08C07C215/60C07C221/00C07C225/16C07C59/255C07C51/41C07C51/43
CPCC07C213/00C07C213/08C07C221/00C07C225/16C07C51/412C07C51/43C07B2200/07C07C215/60C07C59/255
Inventor 匡建明刘力超贾淼刘肖林伍伟陈旭红
Owner CHENGDU SINO STRONG PHARMA
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