CN113880778B - Method for preparing 6-amino-5-nitroquinoxaline - Google Patents
Method for preparing 6-amino-5-nitroquinoxaline Download PDFInfo
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Abstract
The invention provides a method for preparing 6-amino-5-nitroquinoxaline,the reaction is as follows:wherein R is 1 Selected from 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or 2, 4-dinitrobenzenesulfonyl; the method for preparing the 6-amino-5-nitroquinoxaline by using the novel intermediate compound is simple and convenient, has milder reaction conditions, high yield and lower cost, and the obtained product has high purity, is beneficial to industrial production and provides guarantee for the subsequent preparation of high-quality medicines.
Description
Technical Field
The invention relates to the field of organic chemistry, and relates to a method for preparing 6-amino-5-nitroquinoxaline.
Background
6-amino-5-nitroquinoxalines are important intermediates for the synthesis of pharmaceuticals, pesticides and other valuable chemicals. Luiz Everson et al and Galiana-Rosell et al report their role as intermediates in the preparation of leishmania and trypanosoma killing drugs, respectively. The potential of chimeric compounds with quinoxaline cores substituted with aliphatic hydrophobic chains in the treatment of neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, is demonstrated in WO2010007179A 1. Aminoquinoxaline derivatives are also reported in WO2012131080A1 for the treatment of neurodegenerative diseases.
The existing method for preparing the 6-amino-5-nitroquinoxaline mainly uses 6-quinoxaline amine as a starting material, has harsh direct nitration reaction conditions and very low yield; robert J. Et al, journal of Agricultural and Food Chemistry (2005), 53 (8), 3248-3258, report the reaction of 3-nitrobenzene-1, 2, 4-triamine using glyoxal to form 6-amino-5-nitroquinoxaline, as follows:
however, the 3-nitrobenzene-1, 2, 4-triamine raw material is difficult to obtain, the cost is high, and the industrial production is not facilitated.
Accordingly, in order to overcome the drawbacks of the prior art, in order to improve the production efficiency of 6-amino-5-nitroquinoxaline, the present invention proposes a novel intermediate for preparing 6-amino-5-nitroquinoxaline, and a method for preparing 6-amino-5-nitroquinoxaline through the intermediate.
Disclosure of Invention
The invention aims to develop a novel method which is more suitable for industrial production of 6-amino-5-nitroquinoxaline and a corresponding intermediate thereof. The method starts from cheap initial raw materials, reduces the generation of impurities by reasonably protecting and optimizing and controlling the nitration reaction, thereby improving the yield and being suitable for commercial scale-up production.
According to one aspect of the present invention, there is provided a novel 6-amino-5-nitroquinoxaline intermediate having the specific structural formula:
wherein R is 1 Selected from 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or 2, 4-dinitrobenzenesulfonyl, R 2 Is nitro; or R is 1 Is 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl or 2, 4-dinitrobenzenesulfonyl, R 2 Is hydrogen.
The invention also provides a synthetic method for preparing the 6-amino-5-nitroquinoxaline, which comprises the following steps:
wherein R is 1 Selected from 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or 2, 4-dinitrobenzenesulfonyl;
comprises the following steps:
step 1, performing nitration reaction, wherein a compound shown in a formula III reacts with a nitration reagent to obtain a compound shown in a formula II;
step 2, deprotection reaction, wherein the compound of formula II is reacted with deamination protecting group reagent to obtain 6-amino-5-nitroquinoxaline.
In the step 1, the nitrifying reagent is selected from concentrated nitric acid, fuming nitric acid-acetic acid, fuming nitric acid, concentrated sulfuric acid-potassium nitrate or concentrated sulfuric acid-nitric acid;
in step 1, the nitrifying reagent is selected from fuming nitric acid-acetic acid, wherein the molar ratio of the compound III to fuming nitric acid is 1:1 to 3.0, preferably 1:1.2 to 2.0, the mass volume ratio (g/mL) of the compound III to the acetic acid is 1:5 to 12, preferably 1:6 to 10, most preferably 1: 8-10;
the invention further provides that in step 1, the nitrating agent is selected from fuming nitric acid-acetic acid, and the reaction conditions are preferably organic solvents or solvent-free systems;
further, the nitration temperature is 0 to 75 ℃, preferably 30 to 75 ℃, most preferably 35 to 75 ℃;
further, the nitration time is 6 to 36 hours, preferably 18 to 24 hours;
in step 1, the nitrifying reagent is selected from concentrated sulfuric acid-potassium nitrate, wherein the mass-volume ratio (g/mL) of the compound III to the concentrated sulfuric acid is 1:1 to 5, preferably 1:2 to 4; the molar ratio of the compound III to the potassium nitrate is 1:1-2, preferably 1:1.2-1.5; the reaction solvent is selected from chloroform, dichloromethane, etc., preferably dichloromethane.
In step 1, the nitrifying reagent is selected from concentrated sulfuric acid-nitric acid, wherein the molar ratio of the compound III to the nitric acid is 1:1 to 1.6, the volume ratio of the concentrated sulfuric acid to the nitric acid is 2 to 6:1, a step of; the concentration of the concentrated sulfuric acid is 95-98%; the concentration of the nitric acid is 65-68%, and the reaction condition is an organic solvent or a solvent-free system.
The inventors have found that the above preferred nitration reaction temperature, reaction time, material feed ratio, nitration reagent selection, etc., unexpectedly give compound II in high purity and high yield.
Further, after the completion of the nitration reaction, water is added to the reaction mixture, preferably 6 to 30 times by volume of water, preferably 20 to 30 times by volume of the above reaction mixture; filtering to obtain solid; the solid obtained is further optionally recrystallized, wherein the recrystallization solvent is selected from one or any combination of nitriles, alcohols, fatty alkanes, ethers, aromatic alkanes, preferably one or any combination of acetonitrile, ethanol, methanol, methyl tert-butyl ether, tetrahydrofuran, dichloromethane or toluene.
In the step 2, the deamination protecting group reagent is selected from concentrated sulfuric acid or sulfuric acid aqueous solution or alkali and mercaptan system, preferably concentrated sulfuric acid, and the sulfuric acid aqueous solution is preferably 50-90% of sulfuric acid aqueous solution by mass fraction;
when the deamination protecting group reagent is selected from concentrated sulfuric acid, the mass-to-volume ratio (g/mL) of the compound of formula II to the concentrated sulfuric acid is 1:1 to 10, preferably 1:2 to 5; the reaction temperature is controlled to be 20-70 ℃, preferably 20-50 ℃, more preferably 25-40 ℃ and the reaction time is 1-24 hours, preferably 10-16 hours; the reaction condition is an organic solvent or a solvent-free system;
when the deamination protecting agent is selected from the group consisting of a base and thiol system, the deprotection reaction is performed in a solvent selected from acetonitrile, THF, DMF or N, N-dimethylacetamide DMAc, preferably acetonitrile; the mercaptan may be t-butylmercaptan, dodecylmercaptan or thiophenol, and the base is selected from sodium alkoxide, potassium alkoxide, alkali metal carbonate or alkaline earth metal carbonate; sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate or cesium carbonate is preferred, and potassium carbonate, sodium carbonate or cesium carbonate is more preferred; the reaction temperature is controlled to be between room temperature and reflux temperature, preferably between 25 and 85 ℃;
when the deamination protecting group reagent is selected from aqueous sulfuric acid, it is preferably 50-90% by mass of aqueous sulfuric acid; the mass-to-volume ratio (g/mL) of the compound formula II to the sulfuric acid aqueous solution is 1:5 to 15, preferably 1:5 to 10; the reaction temperature is controlled to be 70-100 ℃, preferably 90-100 ℃, and the reaction condition is an organic solvent or a solvent-free system.
The present invention also provides compounds of formula III prepared by the following process:
the method comprises the steps of reacting 6-quinoxaline amine containing compound IV with a sulfonylation reagent in an organic solvent in the presence of a base to obtain a compound represented by a formula III;
wherein R is 1 Selected from 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or 2, 4-dinitrobenzenesulfonyl.
The invention further provides a molar ratio of the sulfonylation reagent to the compound IV 6-quinoxaline amine of 1.05-1.3:1; the sulfonylating agent is selected from 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2, 4-dinitrobenzenesulfonyl chloride.
The invention further provides that the base is pyridine; the molar ratio of the amount of the base to the compound IV 6-quinoxaline amine is 1.0 to 8.0:1, preferably 1.2 to 5.0:1, more preferably 1.2 to 3.0:1; the organic solvent is selected from dichloromethane.
The 6-amino-5-nitroquinoxaline is an important intermediate for synthesizing medicaments, pesticides and other valuable chemicals, and the novel intermediate compounds and the preparation method of the 6-amino-5-nitroquinoxaline are preferably used for preparing medicaments for treating neurodegenerative diseases quinoxaline derivatives.
The inventor finds that the one-step method for preparing the 6-amino-5-nitroquinoxaline by taking the compound IV 6-quinoxaline amine as a starting material has more severe direct nitration reaction conditions, and the direct nitration yield is only less than 5%; the acetyl protecting group on the amino group of the compound IV is reacted overnight in acetic anhydride at the temperature of about 80 ℃ or the acylating agent is reacted in methylene chloride solution under the action of triethylamine serving as an acid binding agent at the temperature of room temperature to 40 ℃, and the inventor finds that no reaction product or only a very small amount of product is detected.
The inventors also found that the Cbz protecting group on the amino group of compound IV was reacted overnight in methylene chloride solution at 25-40℃under the action of triethylamine as an acid-binding agent using CbzCl, and that no reaction product or only a very small amount of product was detected.
However, according to the technical scheme, the compound II with high purity and high yield can be unexpectedly obtained by the preferable nitration reaction temperature, reaction time, material feeding ratio, nitration reagent selection and the like; and further, the compound I with high purity and high yield is obtained by optimizing the deprotection reaction.
Compared with the prior art, the invention provides a 6-amino-5-nitroquinoxaline synthesis method with higher yield and lower cost, and a novel intermediate of the synthesis method, which is beneficial to subsequent industrial production;
the invention uses the intermediate compound to be novel, has mild reaction condition and good yield, and the obtained product has high purity, thereby providing guarantee for the subsequent preparation of high-quality medicines.
Detailed Description
The present invention will be further described below, but it should be understood by those skilled in the art that the scope of the present invention is not limited to the following specific examples. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of the present invention.
Example 1
Step 1: 2000ml of dichloromethane DCM was added into a reaction flask, 200g of 6-quinoxaline amine was added, after stirring for 5min, 142g of pyridine was added, 320g of 4-nitrobenzenesulfonyl chloride was added in portions below 30℃to the reaction system, and the temperature was controlled to 20-30℃for reaction. After the reaction was completed, water was added, stirred at room temperature for 30min and suction-filtered, the filter cake was washed with water for 2 times, the DCM was concentrated under reduced pressure, suction-filtered, and the filter cake was dried by air blast to give 419g of brown solid with a yield of 92.1%.
1 H-NMR(400MHz,DMSO-d6):δ11.41(br,1H),8.88(dd,J＝2.0Hz,J＝8.4Hz,2H),8.42-8.39(m,2H),8.16-8.14(m,2H),8.06(d,J＝9.2Hz,1H),7.77(d,J＝2.4Hz,1H),7.70(dd,J＝2.4Hz,J＝9.2Hz,1H).
Step 2: 1000ml of acetic acid is added into a reaction bottle, 100g of 4-nitro-N- (quinoxaline-6-yl) benzenesulfonamide is added into the reaction bottle under stirring, fuming nitric acid 24.1g is dropwise added into the reaction system at the temperature of 70-75 ℃, the system is cooled to room temperature after 3 hours of reaction, water is added, suction filtration is carried out after water is carried out, and air blast drying is carried out, thus 86g of 4-nitro-N- (5-nitroquinoxaline-6-yl) benzenesulfonamide is obtained, and the brown solid is obtained, wherein the yield is 75.7%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.97(dd,J＝2.0Hz,J＝5.2Hz,2H),8.39-8.37(m,2H),8.20(d,J＝9.2Hz,1H),8.03-8.00(m,2H),7.87(d,J＝9.6Hz,1H).
Step 3: 100ml of concentrated sulfuric acid is added into a reaction bottle, the temperature is reduced to below 20 ℃, 42g of 4-nitro-N- (5-nitroquinoxalin-6-yl) benzenesulfonamide is added in batches, and the reaction system is naturally warmed to room temperature overnight. Adding the reaction solution into 400g of ice cubes, regulating the pH to about 8 by using NaOH, stirring for 30min, carrying out suction filtration, carrying out forced air drying overnight, adding 110ml of water chamber into the crude product, pulping for 2h, filtering, leaching the filter cake by using 40ml of water, and carrying out reduced pressure drying to obtain 18.5g of the product, wherein the yield is 86.9%, and the purity is 98.0%.
Example two
Step 1: 44g of 6-quinoxaline amine, 440ml of dichloromethane DCM and 48g of pyridine are added into a reaction bottle, the reaction system is cooled to 0-10 ℃, 80g of 2-nitrobenzenesulfonyl chloride is added in batches for reaction overnight until the reaction is completed, water is added and stirred for 2h for suction filtration, a filter cake is leached by water, and 66g of 2-nitro-N- (quinoline-6-yl) benzenesulfonamide is obtained by drying, and the yield is 65.9% of dark brown solid.
1 H-NMR(400MHz,DMSO-d6):δ11.54(br,1H),8.87(dd,J＝2.0Hz,J＝13.6Hz,2H),8.07(d,J＝10.0Hz,1H),8.02-7.99(m,2H),7.88-7.82(m,2H),7.70-7.67(m,2H).
Step 2: 30g of 2-nitro-N- (quinolin-6-yl) benzenesulfonamide, 300ml of acetic acid and 8.6g of fuming nitric acid were added to a reaction flask, stirred at room temperature for 10 minutes, raised to 50℃overnight, and after completion of the reaction, water was added to the system and filtered to give 21.7g of 2-nitro-N- (5-nitroquinoxalin-6-yl) benzenesulfonamide as a yellow solid in a yield of 63.7% and a purity of 90.43%.
1 H-NMR(400MHz,DMSO-d 6 ):δ8.96(dd,J＝2.0Hz,J＝5.2Hz,2H),8.19(d,J＝8.8Hz,1H),7.95-7.91(m,2H),7.85-7.77(m,3H).
Step 3: 150ml of concentrated sulfuric acid are added into a reaction bottle, the temperature is reduced to 0-10 ℃, 30g of 2-nitro-N- (5-nitroquinoxalin-6-yl) benzenesulfonamide is added in batches, and the mixture is naturally cooled to room temperature overnight. The reaction solution was poured into 600g of ice water, pH was adjusted to 13-14 with NaOH, and the resultant was extracted with methyl-THF and concentrated to give 12.2g of a product with a yield of 80.3% and a purity of 95.2%.
Comparative examples
Table 1 comparative example Ts protecting group removal reaction summary table:
the amount (molar amount) of the above reactants may be 1 to 5 times, preferably 1.5 to 3 times the molar amount of the compound A; as shown in the data of the above table 1, the inventors found that the removal of the Ts protecting group is very difficult, so that the compound I6-amino-5-nitroquinoxaline is prepared by taking compound IV 6-quinoxaline amine as a raw material, performing the nitration and then removing the protecting group after the protection of the Ts amino group, and the route is not feasible.
Claims (8)
1. A process for preparing 6-amino-5-nitroquinoxaline, which reacts as follows:
wherein R is 1 Selected from 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or 2, 4-dinitrobenzenesulfonyl;
comprises the following steps:
step 1, performing nitration reaction, wherein a compound shown in a formula III reacts with a nitration reagent to obtain a compound shown in a formula II;
step 2, deprotection reaction, namely, under the action of deamination protecting group reagent, obtaining 6-amino-5-nitroquinoxaline;
in the step 1, the nitration reaction comprises the following steps:
the method comprises the following steps: in the nitration reaction, the nitration reagent is selected from fuming nitric acid-acetic acid, wherein the molar ratio of the compound III to fuming nitric acid is 1:1 to 3.0, the mass volume ratio of the compound III to the acetic acid is 1: 5-12 g/mL;
the second method is as follows: in the nitration reaction, the nitration reagent is selected from concentrated sulfuric acid-potassium nitrate, wherein the mass volume ratio of the compound III to the concentrated sulfuric acid is 1: 1-5 g/mL; the molar ratio of the compound III to the potassium nitrate is 1:1-2; the nitration solvent is selected from chloroform and dichloromethane;
and a third method: in the nitration reaction, the nitration reagent is selected from concentrated sulfuric acid-nitric acid, wherein the molar ratio of the compound III to the nitric acid is 1:1 to 1.6, the volume ratio of the concentrated sulfuric acid to the nitric acid is 2 to 6:1, a step of; the concentration of the concentrated sulfuric acid is 95-98%; the concentration of the nitric acid is 65-68%;
the deamination protecting group reagent in the step 2 is selected from concentrated sulfuric acid.
2. The method according to claim 1, characterized in that: in the first method, the molar ratio of the compound III to fuming nitric acid is 1:1.2 to 2.0, the mass volume ratio of the compound III to the acetic acid is 1: 6-10 g/mL;
in the second method, the mass volume ratio of the compound III to the concentrated sulfuric acid is 1: 2-4 g/mL, wherein the molar ratio of the compound III to the potassium nitrate is 1:1.2-1.5, and the nitration reaction solvent is selected from dichloromethane.
3. The method according to claim 2, characterized in that: the mass volume ratio of the compound III to the acetic acid is 1: 8-10 g/mL.
4. The method according to claim 1, characterized in that: the temperature of the mononitration reaction is 0-75 ℃; the nitration time is 6-36 hours.
5. The method according to claim 4, wherein: the temperature of the mononitration reaction is 30-75 ℃, and the nitration reaction time is 18-24 hours.
6. The method according to any one of claims 1 to 5, wherein: in the step 2, when the deamination protecting group reagent is selected from concentrated sulfuric acid, the mass-volume ratio of the compound formula II to the concentrated sulfuric acid is 1: 1-10 g/mL; the reaction temperature is controlled to be 20-70 ℃;
the reaction time is 1-24 hours.
7. The method according to claim 6, wherein: the mass volume ratio of the compound formula II to the concentrated sulfuric acid is 1: 2-5 g/mL, the reaction temperature is controlled to be 20-50 ℃ and the reaction time is 10-16 hours.
8. An intermediate of 6-amino-5-nitroquinoxaline, which has the following structural formula:
wherein R is 1 Selected from any one of 2-nitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl and 2, 4-dinitrobenzenesulfonyl, R 2 Is nitro; or R is 1 Is any one of 2-nitrobenzenesulfonyl, 2, 4-dinitrobenzenesulfonyl and R 2 Is hydrogen.
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| One-scale basicities of diaminobenzenes and diaminonaphthalenes: from aniline to proton sponge;Marina P. Vlasenko et al.;《J. Phys. Org. Chem.》;第30卷;第1-7页 * |
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