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New preparation method of dopexamine hydrochloride by ArCHR protection strategy

A technology of dopexamine hydrochloride and arylmethyl group, which is applied in the field of new preparation of dopexamine hydrochloride, can solve the problems of many by-products, low yield, easy oxidation, etc., and achieve the effect of reducing catalyst poisoning and improving catalytic activity

Inactive Publication Date: 2012-02-01
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But demethylation condition is harsh, needs high temperature in hydrobromic acid solution, reacts for a long time and can carry out, and by product is more, and yield is lower (57.6%), and, what obtain is the hydrobromic acid of dopexamine Salt needs to be released by alkali neutralization, and then form the required hydrochloride salt form. When alkali neutralization is released, the 1,2-benzenediol structure in the dopexamine molecule is particularly easy to oxidize, forming a quinone by-product

Method used

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  • New preparation method of dopexamine hydrochloride by ArCHR protection strategy
  • New preparation method of dopexamine hydrochloride by ArCHR protection strategy
  • New preparation method of dopexamine hydrochloride by ArCHR protection strategy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]Example 1: Preparation of 6-(2-(3,4-dibenzyloxyphenyl)acetyl)aminocaproic acid (8)

[0023] Below 10°C, the Et 3 N 24.4mL (175mmol) slowly drop to 6-aminocaproic acid 18.3g (140mmol), H 2 O150mL and MeCN 50mL of the mixed solution, stirring while adding. After stirring and dissolving, a solution of 31.2 g (70 mmol) of N-hydroxysuccinimide 3,4-dibenzyloxyphenylacetate in 100 mL of acetonitrile was slowly added dropwise to the mixture. After dropping, the mixture was naturally raised to room temperature, and the stirring was continued for 3 h, and the reaction was basically completed as detected by TLC. Concentrate under reduced pressure to remove most of the solvent, pour the residue into a mixture of 200 mL ethyl acetate and 200 mL ice water, adjust the pH to 2-3 with dilute hydrochloric acid, separate the organic layer, and wash the aqueous layer with ethyl acetate (50 mL×2) After extraction, the combined organic phases were washed with water (100 mL×2), and dried ov...

Embodiment 2

[0025] Example 2: Preparation of 6-(2-(3,4-dibenzyloxyphenyl)acetyl)aminocaproic acid (8)

[0026] Below 10°C, the Et 3 N 24.4mL (175mmol) was slowly dropped into 6-aminocaproic acid 18.3g (140mmol), cyclohexane 150mL and H 2 O 250mL of the mixed solution, stirring while adding. After being dissolved, a solution of 25.7 g (70 mmol) of 3,4-dibenzyloxyphenylacetyl chloride in 100 mL of cyclohexane was slowly added dropwise to the reaction system. After dropping, the mixture was naturally raised to room temperature, and the stirring was continued for 3 h, and the reaction was basically completed as detected by TLC. Adjust the pH to 2-3 with dilute hydrochloric acid, separate the organic layer, extract the aqueous layer with cyclohexane (50mL×2), combine the organic phases, wash with water (100mL×2), and dry over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to obtain 27.6 g of light yellow solid with a yield of 85.5%.

Embodiment 3

[0027] Example 3: Preparation of 6-(2-(3,4-dibenzyloxyphenyl)acetyl)amino-N-(2-phenylethyl)hexanamide (2)

[0028] At room temperature, add 5.8 g (27.0 mmol) of CDI to 6-(2-(3,4-dibenzyloxyphenyl) acetyl) aminocaproic acid (8) 8.3 g (18.0 mmol) of CH 2 Cl 2 After stirring for 2 hours in 200 mL of the solution, 4.5 mL (27.0 mmol) of 2-phenylethylamine was added, and the stirring was continued for 5 hours. TLC detected that the reaction was basically completed. The reaction solution was poured into 300 mL of ice water, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 (50mL×2) for extraction, combined the organic phases, washed with water (100mL×2), and dried over anhydrous sodium sulfate. After filtration and concentration, 8.8 g of white solid was obtained with a yield of 86.3%.

[0029] MS (m / z): [M+H] + 565.3, [M+Na] + 587.3, [M-H] - 563.1, [M+Cl] - 599.1.

[0030] 1 H NMR (CDCl 3 , 600MHz) δ=1.19~1.21(2H, m), 1.36~1.38(2H, m), 1.54...

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PUM

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Abstract

Belonging to the pharmaceutical field, the invention relates to a new preparation method of dopexamine hydrochloride (1), and dopexamine hydrochloride (I) protected by bis-ArCHR and a preparation method thereof. Utilizing an ArCHR protection strategy, the invention first prepares dopexamine hydrochloride (I) protected by bis-ArCHR, and then by making use of catalytic hydrogenation, removing corresponding ArCHR protective groups selectively, thus obtaining dopexamine hydrochloride.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to a new preparation method of dopexamine hydrochloride using an arylmethyl protection strategy. Background technique [0002] Dopexamine hydrochloride is an adrenaline-mimetic drug, the chemical structure is similar to dopamine, and it has a strong β 2 - Adrenergic receptor excitatory effect, can significantly expand arterial blood vessels, increase blood flow of myocardium, kidney, liver, and skeletal muscle, and reduce cardiac afterload; 1 - The adrenergic receptor and dopamine receptor excitatory effects are weak, which can strengthen the myocardial contractility, increase the heart rate, and have a slight natriuretic and diuretic effect. It is indicated for the treatment of patients with acute heart failure and low cardiac output following cardiac surgery. [0003] Fisons company once used adipic acid as raw material to prepare dopexamine hydrochloride (EP0117033A2), and adipic acid reac...

Claims

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Application Information

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IPC IPC(8): C07C215/52C07C213/00C07B43/04C07C217/60C07C213/02C07C237/22C07C231/02C07C233/18C07C237/06C07C237/08
CPCY02P20/55
Inventor 许佑君马占芝张华李亚玲惠帅杨吉宁孙静丁百莲
Owner SHENYANG PHARMA UNIVERSITY
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