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Resolution method for chiral Fenoldopam

A chirality, compound technology, applied in organic chemistry methods, chemical instruments and methods, separation of optically active compounds, etc., can solve the problems of hypokalemia intraocular pressure, side effects, increase, etc., to reduce side effects, improve drug efficacy, and reduce drugs. effect of dosage

Active Publication Date: 2015-09-02
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no relevant report on the separation method of chiral fenoldopam both at home and abroad.
[0006] Fenoldopam mesylate has been clinically proven to be a good drug after more than ten years in foreign countries. Many domestic and foreign companies have successively applied for clinical and marketing registration. However, there are some side effects, the most common adverse reactions are hypotension related to vasodilation, flushing, dizziness, headache, and increased heart rate. Nausea, vomiting, hypokalemia, and increased intraocular pressure may also occur

Method used

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  • Resolution method for chiral Fenoldopam
  • Resolution method for chiral Fenoldopam
  • Resolution method for chiral Fenoldopam

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0035] Experimental Example 1: Synthesis and resolution method of chiral fenoldopam of the present invention

[0036]A. Hydroxyl protection of fenodopam free base is dissolved in absolute ethanol, and Me is added dropwise under stirring at room temperature 2 SO 4 , drop in 2 hours, then continue to stir and react for 0.8-1.2h, add the base shown in claim 5 to adjust the pH to 7.5-8.5; the resulting mixture is extracted with CH2Cl2, the extract is washed with water, then washed with brine, and finally washed with Anhydrous MgSO 4 Drying; the dried extract was filtered, and the filtrate was concentrated in vacuo to obtain a light yellow oil; the crude oil was dried in vacuo overnight to obtain compound III;

[0037] B. The protection compound III of amine group was dissolved in dichloromethane, added triethylamine, added TrCl under stirring at room temperature, and continued the reaction for 4-5hr; filtered, washed the mother liquor three times, and anhydrous MgSO 4 Drying, r...

experiment example 2

[0040] Experimental example 2: Structural characterization and identification of the product

[0041] The structure and atomic number of the obtained product are as follows:

[0042]

[0043] First carry out structural identification with nuclear magnetic resonance spectroscopy, the method is as follows: Weigh an appropriate amount (10-20 mg) of the product sample, put it into a nuclear magnetic tube, and add the deuterated solvent DMSO-d 6 Dissolved, measured with a Bruker400 nuclear magnetic resonance spectrometer at room temperature, the obtained spectrogram is shown below, and the data list and the corresponding hydrogen atoms and structural analysis of each chemical shift value are shown in the following table:

[0044] Chemical shift (ppm)

proton number

Coupled state

Coupling constant (Hz)

attribution

2.33

3

s

CH 2

2.89

1

t

J＝11.7

H2

3.19

1

t

J＝12.5

3.37-3.52

...

Embodiment 1

[0051] A. Hydroxyl protection

[0052] 125g (410mmol) of fenodopam free base (compound II) was dissolved in 1L of absolute ethanol, and Me2SO4116ml (155g, 1.23mol) was added dropwise under stirring at room temperature. 3 h 2 O was adjusted to pH 8; the resulting mixture was treated with CH 2 Cl 2 extraction, the extract was washed with water, then with brine, and finally with anhydrous MgSO 4 dry. The dried extract was filtered, and the filtrate was concentrated to dryness in vacuo to obtain 139 g of light yellow oil; the crude oil was dried in vacuo overnight to obtain 135 g (95% yield) of compound III;

[0053] B. Protection of amine groups

[0054] Dissolve 135g (about 388mmol) of compound III in 600ml of dichloromethane, add 70ml (500mmol) of triethylamine, add 112g (402mmol) of TrCl under stirring at room temperature, and continue the reaction for 4-5hr; filter, wash the solid with dichloromethane, combine the filtrates, Washed three times with water, anhydrous MgSO...

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Abstract

The invention discloses resolution of a D1 dopamine receptor agonist drug and in particular discloses a resolution method of fenoldopam. The resolution method of the D1 dopamine receptor agonist drug comprises the steps of protecting a phenolic hydroxyl group and an amino group in the structure of fenoldopam, then carrying out chemical resolution with a chiral acidic resolution agent to obtain a pure optical isomer, and finally removing a protecting group and salifying to obtain optically pure methanesulfonic acid fenoldopam.

Description

[0001] This application is a divisional application with the application number 201110434784.5 filed on December 22, 2011, and entitled "A Method for Resolution of Chiral Finodopam". technical field [0002] The invention relates to a method for splitting the D1 dopamine receptor agonist drug fenodopam. Background technique [0003] Fenoldopam Mesylate, the chemical name is 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-[1H]-3-benzazepine -7,8-diol methanesulfonate, a fast-acting vasodilator, is a dopamine DA1 receptor agonist. [0004] Fenodopam mesylate primarily stimulates DA1 receptors to induce arteriolar dilation, including robust dilation of renal, mesenteric, coronary, and skeletal muscle vessels. It can not only reduce arterial pressure, but also act on renal small cells to expand renal blood vessels to increase renal blood flow. It has direct natriuretic and diuretic properties, especially for hypertensive patients. Clinical studies have shown that fenodopam mes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16C07B57/00
CPCY02P20/55C07D223/16C07B2200/07
Inventor 王朝阳马静君郭培良李勇邓璐霞沈芃王利春
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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