JPS6025957A - Method for producing 2-nitrobenzaldehyde - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate, easily, in high yield, using an easily available reactant, by reacting beta-dimethylamino-2-nitrostyrene with an oxidizing agent. CONSTITUTION:The objective 2-nitrobenzaldehyde of formula II is produced by reacting beta-dimethylamino-2-nitrostyrene of formula I with an oxidizing agent (e.g. hydrogen peroxide, sodium hypochlorite, etc.). Although 2-nitrobenzal chloride of formula III is produced as a by-product when sodium hypochlorite is used as the oxidizing agent, however, the by-product can be converted easily to the compound of formula II by hydrolysis. The reaction of the compound of formula I with the oxidizing agent is preferably carried out in a solvent under neutral or basic condition. The compound of formula II is an intermediate compound useful for the preparation of 4-nitrophenyl-1,4-dihydropyridine derivative having pharmacological activity.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing 2-nitrobenzaltehyalpha, which has conventionally been difficult to produce, using a completely new process.

This substance is an extremely useful intermediate compound in synthetic chemistry, as it can be used, for example, as an intermediate in the production of pharmacologically active 4-nitrophenyl-1,4-dihydropyridine derivatives.

Most of the conventional altehyde synthesis methods are useless in the production of 2-nitrobenzaldehyde, making it extremely difficult to obtain even though it has been known for a long time. Even now, there is a lack of literature.

K and υJ, a method of oxidizing chromium in acid anhydride using 2-nitrotoluene as a raw material, which is easy to do manually (organ
ic 5ynthesis Co11. Vol, M,
(page 641) has an extremely low yield (total yield 17
%), it has the disadvantage of producing cool-quality by-products that are difficult to separate.

23-24% 74% Total yield 17% Many other synthetic methods use 2-nitrobenzal chloride or 2-nitrobenzyl chloride as a starting material, or it is difficult to obtain these compounds themselves. It is. For example, if 2-nitrotoluene is reacted with expensive N-bromosuccinimide to obtain the radical state, 2-nitrotoluene can be obtained with a yield of 45-60%. (Organic 5ynthe
ses Vol, 468] (1966)). However, this method cannot be used industrially.

The formation of 2-trowenyl birhinic acid ester/L by the reaction of 2-21.luene with oxalic acid diester in the presence of alcohol-1. The erulate salt of this ester is hydrolyzed with water IW l-,2
-Nitrophenylpyruvic acid noalkali gold salt is formed, and 2-2[.rowenylpyruvic acid can be obtained in a yield of about 80% (B
er, 30], 030(], 897)).

Therefore, the production method of 2-nitrohenzaltehyde via 2-nitrobenylvirhinic acid near R was not proposed (Japanese Patent Publication No. 56-6980). , 77-82.5% -(COONa)2 77.8-83.5 by reacting an aqueous alkaline solution of 2-ditroenylbilbyrhinic acid with an aqueous solution of alkali metal chlorate. % 77% 2-nitrohensal chloride yield I77.8-83.
5%, and by hydrolyzing it in the presence of water, 2-nitrobenzaltehyde is obtained in a yield of 77% (table yield 461-53.0%). However, in the reaction of 2-nitrotoluene and oxalic acid diester in the presence of alcohol-1.
ert) reaction, when using ester oxalate and l-lium ethylate, I (ψ high yield 82.5%, reaction rate 62.3% (2-nitro)ruyun standard), For other oxalate esters and alcoholades, the yield is 50%.
It decreases to about 60%. In addition, there are many problems in that it is difficult to maintain the reaction conditions, and the amount of moisture in the reaction system greatly affects the reaction rate.

Recently, the reaction of 2-nitrotoluene with the methyl group and the reaction with N,N-dimethylformamito and sialylacecure as a highly reactive reagent has been reported, for example, 2
-Nitrotoluene and N,N-dimethylformamide β-dimethylamino-
2-2) Rostyrene can be obtained with an 11-fold ratio of 97% [J
,Org,Chem,44(22)3748,
(1979); Ger, Paj, DE 2057840
(1980)).

The present inventors have surprisingly found that β-dimethylamino-2-dil-rostyrene obtained here is oxidized using an oxidizing agent such as hydrogen peroxide or sodium hypochlorite. It was found that 2-nitrobenzaldehyde or 2-nitrobenzaldehyde or 2-nitrobenzal chloride can be obtained in high yield by this method.

The present invention is based on this knowledge, and is a method for producing 2-nitrohenzaltech+-=[U], which is characterized by allowing an oxidizing agent to act on β-dimethylamine-2-nitrostyrene. be.

[111,3 Acid f arsenic, l! For example, if hydrogen peroxide is used, the reaction []]->group] will proceed, or if sodium hypochlorite is used, the reaction will proceed [month->[III]→(II ,
1 (7) process. In this process, a portion of the intermediate 2-nitrobenzal chloride [J11] is also formed, which can be easily converted into 2-nitrobenzaltehyde (J11) by hydrolysis.

β-dimethylamino-2-nitrosdyrene is N,N-
It is prepared by the reaction of dimethylpolamide sialylacecour with 2-nitrotoluene and can be isolated and used in the process of the invention, or can be used in its crude form without purification if desired.

As the oxidizing agent, one that can cleave the ethenyl group and convert it into an aldehyde group is used, such as hydrogen peroxide, alkali metal hypochlorite, alkali metal permancate, alkali metal chromium, etc. Examples include acid salts. The reaction between the ethenamine compound [■] and the oxidizing agent may be carried out in a solvent under neutral or basic conditions. As the solvent, water, an organic solvent, or a mixed solvent thereof can be used. The organic solvent may be a water-miscible solvent such as acetonitrile, or an incompatible solvent such as toluene. These organic solvents are used in combination with water, if necessary. Preferred is a mixed solvent of water and a water-compatible solvent (eg, acetonitrile) that is stable under oxidizing conditions. The reaction proceeds unevenly when heated to a high temperature, and in general, the reaction formula is completed under cooling.

From the obtained reaction mixture, fill the solvent as necessary.
I [M L i: Later, I
21·l”l Hen 7: 7 Ruthehyde can be separated.

The hydrolysis of 2-nitrobenzal chloride can also be carried out in an alkaline medium, but preferably under acidic conditions, for example using 90% sulfuric acid.

The resulting 2-nitrohenzaltehyde can also be purified to a higher purity, for example, by distillation under reduced pressure.

According to the method of the present invention, β-dimethylamino-2-nitrostyrene can be obtained in high yield by fI ↑
Not only can nitrohenzaltehyde be obtained, but also 2-
A new synthetic route starting from nitrotoluene and reaching 2-nitrohenzaltehyde via β~dimedylamy/-2-nitrostyrene has been developed, and all the necessary reactants are easily available, and the yield of each step is low. Since the yield is also good, it is far superior to conventional methods as a method for producing 2-nitrohenzaldehyde.

The method of the present invention is illustrated by the following examples, but the present invention is not limited thereto.

Reference example β-dimethylamino-2-nitrostyrene tM Shimoguchi 1
', 1m & 1m, stainless steel McMahon filled distillation pipe (30X2.4crn), equipped with a stirrer k 5
00 +nl 4 rows, 2-nitrotoluene] 32.3j7 (0,965 mol), N,
Charge N-dimethylpolamide 151□, 1, N2
Heat under air flow and stir. After the reaction temperature reaches 120'C, 100 g (0,839 mol) of N,N-dimethylformamide dimethyl acecool is added dropwise over about 10 hours. The mixture is heated to a reaction temperature of 130° C. to 40° C., and the reaction is carried out while distilling off by-products, and the reaction is carried out for about 30 hours. After the reaction is completed, N,N-dimethylformamide is distilled off from the reaction mixture under reduced pressure, and unreacted 2-nitrotoluene is recovered under reduced pressure and heating. The residue is 145.8! As a result of GC analysis, the purity was 92.2.
The yield based on %5 reacted 2-nitrotoluene was 92.
It was 3%.

Example 1 a, 2-nitrobenzalchloride l'' and 2-:l
・5007rf equipped with Robenzaltehyde dropping funnel, humidity drip, and stirrer
, Into 4 tube flasks, add sulfur and lithium hypochlorite aqueous solution (
], 33.4% 167.0 g (0.3mod) and 3 oml of acetonyl. β-dimethylamino-2-nitrostyrene (92°5%) 20.78 g
(0.1mo6) was dissolved in 50d of acetonitrile,
The reaction humidity is maintained at 5 to 15° C. and the mixture is added dropwise over a period of 3 hours. After the addition is complete, stir at room temperature for 1 hour. After the reaction is complete, sodium bisulfite is added to decompose the remaining hypochlorous acid (IJium) L% 50
” Neutralize by adding BeH2sO4. After the treatment, acetonitrile is recovered under heating. The treated solution is extracted with 200 ml of chloroform, the extract is washed with an aqueous sodium carbonate solution, and dried with anhydrous sulfuric acid.) do.

The solvent is distilled off, and the residue is distilled under reduced pressure to separate the product. Product +: J, 15.75 g, GC analysis No. 4
Yoshika, 2-nitrohenzaldehy 1-18.8%, 2-
Contains 78.2% nitropensal chloride. Yield is 7
It's 8.2%.

)), 2-Nitrochensartecht 300, equipped with dropping funnel, thermometer, stirrer, . 4
．． In the fourth flask, add β-dimethylamino-2-nitrostyrene (92,5%) 20.78!9 (0,] n10
(J), 40 ml of acetonitrile, and 60 J of water. Hydrogen peroxide (30%) 60.111 (0,2
6mo6) is mixed with 80.4% of water and added dropwise from the dropping funnel over 1 hour while keeping the reaction temperature at 5 to 15°C. After the addition is complete, stir at room temperature for 1 hour. After the reaction is completed, sodium hyposulfite is added to decompose the remaining hydrogen peroxide, and acetonitrile is recovered under heating. The processing liquid is toluene 100. Extract with nIV and dry with anhydrous sodium sulfate. The solvent is distilled off, and the residue is distilled under reduced pressure to separate the product. The product contains 8.27gXGC analysis containing 97.5% 2-chotrohenzaldehyl'. The yield was 547%.

Example 2 2-200 mL 4 with Nitrogens Altech temperature drop, stir bar, and reflux condenser
III Flask VC2-2)・Hensal Chloride 20.65! /(2-nitrobenzal chloride 77.
0%) (0,]moN), 90% sulfuric acid 7
Pour 6°3 g (0.7m06). Under N2 flow,
Heat, stir, and maintain the reaction humidity at 65-70°C for 3 hours, stirring until hydrogen chloride generation stops. After the reaction is completed, the reaction solution is poured into ice water and extracted with toluene. The extract is washed with an aqueous solution of carbonic acid and IJum, and dried with anhydrous sulfuric acid and IJum. The solvent is distilled off and the product is purified by distillation under reduced pressure. The main distillate is J2.0 (l
As a result of GC analysis, 2-nitrohenzaldehyde was found to be 99.
The yield was 79.0%.

Procedural summary (spontaneous) 1. Indication of the case t1ri Japanese Patent Application No. 133086 2. Title of the invention 2. Process for producing nitrobenzaldehyde 3. Person making the amendment Relationship with the case Patent applicant address Osaka Prefecture 4 Niitaka, Yodogawa-ku, Osaka City, Agent 5, Date of amendment order Voluntary -゛-□ Feno-
3 corrections to "Mino group".

Written amendment to the above procedure (I) April 73, 1980 1, Indication of the case 1988 Patent Application No.] 33086 3, Person making the amendment Relationship with the case Gi 5 Applicant's address Osaka, about Inusaka 2-6-6-4 Niitaka, Yodo-ku, Ichiyodo-ku Agent 5, Correctional Life, A+h 1fli Date of '19 Showa Year Month
Day (shipment date, Monday, Showa, daily) 6 Number of inventions increased by supplementary IE O specification page 4,
In the formula on the right end of the 10th stage of the opposite 1-core type;

Below 1-

Claims (1)

[Scope of Claims] [1] A method for producing 2-nitrohenzaltehyde, which comprises reacting β-dimethylamino-2-nidrosthenyl with an oxidizing agent. (2) The production according to claim 1, in which hypochlorite is used as an oxidizing agent, and 2-nitrobenzal chloride produced together with 2-nitrobenzaldehyde is hydrolyzed to 2-nitrobenzaldehyde. Law.