CN112538074A

CN112538074A - Preparation method of debrominated impurities of brimonidine

Info

Publication number: CN112538074A
Application number: CN202011553519.4A
Authority: CN
Inventors: 李方林; 何冬梅; 董祥有
Original assignee: Aixier Shenzhen Medicament Research And Development Co ltd
Current assignee: Aixier Shenzhen Medicament Research And Development Co ltd
Priority date: 2020-12-24
Filing date: 2020-12-24
Publication date: 2021-03-23

Abstract

The invention discloses a preparation method of a bromine brimonidine debromination impurity, which takes 2- (methylthio) -2-imidazoline hydroiodide as a raw material, is protected by tert-butyloxycarbonyl and then reacts with 6-aminoquinoxaline to obtain the compound. The preparation method of the debrominated impurity of brimonidine provided by the invention has the advantages of easily available raw materials, environmental protection and easy operation. The prepared debrominated brimonidine compound provides important basis for evaluating the quality and safety of brimonidine and has important significance for improving the synthesis process.

Description

Preparation method of debrominated impurities of brimonidine

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a debrominated impurity of brimonidine.

Background

Brimonidine, chemical name 5-bromo-6- (imidazoline-2-yl) aminoquinoxaline, molecular formula C₁₁H₁₀BrN₅Molecular weight is 292.1346; brimonidine is a novel highly selective alpha 2 adrenoreceptor agonist, and is clinically used for the treatment of open-angle glaucoma.

As the medicine is used as a special commodity, along with the progress of times and the improvement of the technological level, people pay more and more attention to the safety problem of the medicine. The medicine impurities are important sources of medicine safety problems, and the safety of medicines can be effectively improved by comprehensively researching the medicine impurities and controlling the content of the impurities in the medicines, so that the research on the medicine impurities is more and more focused by medical workers.

The current methods for preparing the debrominated impurities of brimonidine mainly comprise the following two methods:

the method is a method reported in the documents Bioorganic & Medicinal Chemistry Letters (1995), 5 (15), P1745-1750, and the specific reaction scheme is as follows:

according to the method, brimonidine tolbromide impurity is obtained by reacting 6-aminoquinoxaline with 4, 5-dihydro-1H-imidazole-2-sulfonic acid. The raw material 4, 5-dihydro-1H-imidazole-2-sulfonic acid used in the method is expensive and is not suitable for industrial production.

The second method is the method reported in the patent US6323204, and the specific reaction route is as follows:

the method comprises the steps of using 4-nitro-o-phenylenediamine as a raw material, carrying out hydrogenation reduction to obtain 1,2, 4-triaminobenzene, reacting with glyoxal sodium bisulfite to obtain 6-aminoquinoxaline, and carrying out isothiocyanation, aminoethylation and cyclization for 5 steps in total to obtain the compound shown in the formula III. The third step and the fourth step of the route respectively need to use highly toxic thiophosgene and benzene, and the route is longer and is not beneficial to industrial production.

Debrominated impurities can be generated in the process of preparing brimonidine, and the impurities have a structure similar to that of the brimonidine and can cause serious adverse reactions. Extensive research and content control of the impurities are required. However, the existing methods have more problems, such as long route, expensive raw materials or use of highly toxic chemicals; therefore, the invention develops a synthetic method which is easy to operate and has a short process route. Provides a qualified test sample for impurity research of brimonidine.

Disclosure of Invention

The purpose of the invention is as follows: the invention provides a preparation method of a debrominated impurity of brimonidine, which has the advantages of reasonable process design, high yield and convenient and controllable operation process.

The technical scheme is as follows: the invention adopts the following scheme:

a preparation method of a debrominated impurity of brimonidine comprises the following steps:

the preparation method of the debrominated impurity of the brimonidine is characterized by comprising the following steps:

(1) dissolving 2- (methylthio) -2-imidazoline hydroiodide in an organic solvent, and reacting with a protecting group reagent under an alkaline condition to obtain a compound II;

(2) reacting the compound II prepared in the step (1) with 6-aminoquinoxaline to obtain a compound III.

In the step (1), the organic solvent is tetrahydrofuran, dichloromethane or acetonitrile.

In the step (1), the alkali is triethylamine or N, N-diisopropylethylamine, and the molar ratio of the alkali to the 2- (methylthio) -2-imidazoline hydroiodide is 1: 1-5, preferably 1: 3-5.

The reaction time in the step (1) is 3-24h, preferably 8-12 h.

In the step (1), the protecting group reagent is di-tert-butyl dicarbonate or triphenylchloromethane, and preferably di-tert-butyl dicarbonate.

The reaction temperature in the step (2) is 50-100 ℃, preferably 50-80 DEG C

The reaction solvent in the step (2) is formic acid, acetic acid, propionic acid or butyric acid, and acetic acid is preferred.

The molar ratio of the compound II to the 6-aminoquinoxaline in the step (2) is 1: 0.8-2. Preferably 1: 1.

The reaction time in the step (2) is 10-36 h.

Compared with the prior art, the synthesis method of the debrominated impurity of brimonidine provided by the invention has the following advantages:

the raw material 2- (methylthio) -2-imidazoline hydroiodide of the method for synthesizing the debrominated brimonidine impurity is cheap and easy to obtain, the reaction condition is safe and mild, no virulent thiophosgene and benzene are needed, the optimal preparation steps and reaction conditions are screened out through a large number of experiments, and the whole process route is reasonable in design and easy to operate.

Drawings

Fig. 1 is a structural diagram of procapride oxide according to the invention.

Fig. 2 is a flow chart of the preparation method of procapride oxide.

Detailed Description

The present application will be described in detail with reference to specific examples. Example 1 a method for preparing a brimonidine impurity, comprising the steps of:

preparation of compound ii: 30g of compound I was suspended in 300mL of methylene chloride, and 102mL of triethylamine was added to the reaction mixture at room temperature. After stirring the reaction for 1 hour, 80.46 g of di-tert-butyl dicarbonate was slowly added to the above reaction mixture, and stirring was continued at room temperature overnight. When the TLC plate detection showed that the starting material had reacted completely, the reaction solution was concentrated under reduced pressure to give crude II, which was then purified by silica gel column chromatography to give 50g of compound II as a colorless oil in 97% yield.

Preparation of compound iii: dissolving 25 g of compound II and 16.77g of 6-aminoquinoxaline in 200 mL of acetic acid, and directly placing the mixed solution in a solvent of 70^oC was heated in an oil bath for 26 h. After the raw materials completely disappear, the reaction solution is concentrated to be dry under the reduced pressure condition to obtain a crude product. The crude product was then purified by silica gel column chromatography to give 18.56 g of compound III as a yellow-green solid in 75.3% yield. 1H NMR (400 MHz, CDCl 3). delta.8.78 (1H),8.72 (1H), 8.00 (1H), 7.98 (1H), 7.58 (2H),3.59 (4H).

Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims

1. A preparation method of a debrominated impurity of brimonidine is characterized by comprising the following steps:

(2) reacting the compound II with 6-aminoquinoxaline to obtain a compound III; the synthetic route is as follows:

。

2. the method of claim 1, wherein the organic solvent in step (1) is tetrahydrofuran, dichloromethane or acetonitrile.

3. The method of claim 1, wherein the base in step (1) is triethylamine or N, N-diisopropylethylamine.

4. The method of claim 1, wherein the protecting group reagent in step (1) is di-tert-butyl dicarbonate or triphenylchloromethane.

5. The method for preparing the debrominated brimonidine as claimed in claim 1, wherein the reaction temperature in the step (2) is 50-100 ℃.

6. The method for preparing a debrominated impurity of brimonidine as claimed in claim 1, wherein the reaction solvent in the step (2) is formic acid, acetic acid, propionic acid or butyric acid.

7. The method for preparing the debrominated brimonidine impurity according to claim 1, wherein the molar ratio of the compound II to the 6-aminoquinoxaline in the step (2) is 1: 0.8-2.