Background and overview[1][2]
M-nitrobenzaldehyde can be used as an intermediate in organic synthesis of dyes, surfactants, medicines, etc. It has wide industrial applications and large demand. At present, there are two main methods for synthesizing m-nitrobenzaldehyde in industry: sodium nitrate method and nitric acid method. Both methods are direct nitration of benzaldehyde, but the nitration reagents are different. The former is sodium nitrate and the latter is nitric acid. Low-temperature nitrification is carried out in the presence of concentrated sulfuric acid, and the crude product is recrystallized with ethanol to remove ortho by-products. The yield is about 65%.
Apply[2-5]
M-nitrobenzaldehyde is used as an intermediate in the organic synthesis of dyes, surfactants, and pharmaceuticals. In the pharmaceutical industry, it is used in the production of calcium iopperate, iopanoic acid, calcium cholephanidine, nitrobenzidine, etc. Examples of its application are as follows:
1. Preparation of cardiovascular drug nilvadipine, including the following steps:
(1) The three components of isopropyl 3-aminocrotonate, methyl 4,4-dimethoxyacetoacetate and m-nitrobenzaldehyde are cyclized in a solvent-free or organic solvent I to obtain an intermediate compound Ⅰ；
(2) Dissolve compound I in organic solvent II, add 2-6 equivalents of acid, stir and hydrolyze for 1-12 hours to generate intermediate compound II;
(3) Dissolve intermediate compound II with 1.1-1.3 equivalents of hydroxylamine hydrochloride and 1.4-1.6 equivalents of alkali in organic solvent III, react for 2.5-4 hours, add water, stir, and filter to obtain intermediate compound III;
(4) Compound III is dehydrated in an alkaline environment to obtain nilvadipine IV.
2. Preparation of m-aminophenylacetylene.
The preparation method is to react dimethyl acetone phosphonate and p-toluenesulfonyl azide under strong alkaline conditions to obtain (1-diazo-2-oxopropyl) dimethyl phosphonate ; Then (1-diazo-2-oxopropyl) dimethyl phosphonate and m-nitrobenzaldehyde are reacted under alkaline catalyst conditions to obtain m-nitrobenzene acetylene; finally, m-nitrobenzene acetylene is passed through Reduction gives m-aminophenylacetylene.
Using m-nitrobenzaldehyde, a raw material that is readily available on the market, avoids the use of expensive raw materials m-iodonitrobenzene, m-bromonitrobenzene or m-nitrobenzeneacetylene and reduces production costs. It is simple to operate, does not require high-pressure equipment, does not require vacuum distillation, has simple equipment requirements, saves costs, has little environmental pollution, and is suitable for industrial production.
3. Prepare nitrendipine, including the following steps:
S1 ammoniation reaction: β-aminocrotonate methyl ester produced by the reaction of liquid ammonia and methyl acetoacetate;
S2 condensation reaction: Condensation reaction between m-nitrobenzaldehyde and ethyl acetoacetate under the action of catalyst piperidine and glacial acetic acid to obtain pure 2-(3-nitrobenzylidene)-ethyl acetoacetate ;
S3 Ring Closure Reaction: Michael reaction of β-aminocrotonic acid methyl ester and 2-(3-nitrobenzylidene)-ethyl acetoacetate under the action of catalyst diisopropylethylamine/glacial acetic acid , followed by intramolecular cyclization to obtain nitrendipine;
S4 is refined and prepared using m-nitrobenzaldehyde (SM1), ethyl acetoacetate (SM2) and methyl acetoacetate (SM3) as starting materials. It is heated to close the ring and undergo a three-step reaction to obtain the qualified product Ni Qundiping does not contain special reaction conditions.
Preparation [1-2]
Method 1: Use benzaldehyde as raw material, react with isopropylamine to generate the intermediate benzaldehyde imine, then nitrate it with mixed acid, and then hydrolyze it to obtain the target product m-nitrobenzaldehyde:
The specific steps are as follows:
1) Preparation of benzaldehyde imine intermediate: In a 250 mL four-neck ground round flask equipped with a stirrer, thermometer, and reflux condenser, add 46.6 g (0.44 mol) benzaldehyde and start stirring. , raise the temperature to 30°C, slowly add 26.0 g (0.44 mol) of isopropylamine into the benzaldehyde using a dropping funnel. Complete the addition in about 1.0 h, and keep stirring for about 2.0 h. The reaction is complete. Use a liquid funnel to separate the lower water layer and the organic layer, which is the benzaldehyde imine intermediate, for later use.
2) Nitrification: In a 250mL four-necked round-bottomed flask equipped with a stirrer, thermometer, and 2 dropping funnels, add 308.0 g (3.08 mol) concentrated sulfuric acid, start stirring, and use an ice bath to lower the temperature to 10℃. Slowly add 64.7 g (0.44 mol) of benzaldehyde imide and 38.8 g (0.53 mol) of fuming nitric acid into the concentrated sulfuric acid. Complete the addition in about 1.5 hours and keep it warm at 10 to 15°C.After 2.0 h, the nitrification reaction is basically complete.
3) Hydrolysis: Add 1 000 g of crushed ice into a 2000 mL single-neck ground flask equipped with a stirrer, then pour the complete nitration reaction solution into the crushed ice, stir for 2.5 h, and a light yellow solid will precipitate. After filtration, it was washed with ice water several times, then washed with petroleum ether, and dried in a vacuum to obtain 58.7 g of m-nitrobenzaldehyde, with a total yield of 88.4%, a melting point of 56-58°C, and a mass fraction of 99.1% as detected by gas chromatography.
Method 2: Use m-nitrobenzene as raw material and AIBN (azobisisobutyronitrile) as catalyst to synthesize m-nitrobenzaldehyde. When n (m-nitrotoluene):n (chlorobromic acid):n (hydrogen peroxide)=1:3:3, the bromination temperature is 65~75℃, the bromination time is 8~9 h, and the oxidation and hydrolysis time is 8 h. Under optimized conditions, the product yield was 30.4%, and the purity was 99.2%.
Step 1: Preparation of m-nitrobenzyl bromide (bromination reaction)
Add 13.2 mL (0.1 mol) of m-nitrotoluene and hydrobromic acid (0.3 mol, 40%, m/ m), 60 mL of carbon tetrachloride, raise the temperature to 40℃, add an appropriate amount of catalyst azobisisobutyronitrile (AIBN), when the temperature rises to 55℃, use Slowly add hydrogen peroxide (0.3 mol) dropwise from the dropping funnel, and complete the dropwise addition in 2 to 3 hours. During this period, keep the maximum temperaturet≤65°C (add hydrogen peroxide when the temperature starts to drop). Use a separatory funnel to separate the water layer, and use a rotary evaporator to remove carbon tetrachloride to obtain the brominated product.
Step 2: Hydrolysis and Oxidation
Put the bromide into a four-necked flask, start magnetic stirring and heat the oil bath to 100℃, add the pre-configured 30% sodium carbonate solution, and dropwise add dimethyl sulfoxide (DMSO) ) 15 mL, after the dropwise addition, the reaction was incubated for 8 h. Stop the reaction, cool to precipitate crystals, and obtain dry crude product by suction filtration. Dissolve the crude product with diethyl ether, wash with weak acid until pH=7, and then wash with water once to obtain a light yellow liquid. Dry over anhydrous magnesium sulfate for 2 h, evaporate the solvent under reduced pressure, and dry under vacuum at room temperature to obtain a yellow solid. The yellow m-nitro group Benzaldehyde can be obtained as pure white product through steam distillation.
Main reference materials
[1] Research on new synthesis process of m-nitrobenzaldehyde
[2] Research on the synthesis process of m-nitrobenzaldehyde
[3] CN201310243479.7 Preparation method of cardiovascular drug nilvadipine
[4] CN201710140835.0 A synthesis method of m-aminophenylacetylene
[5] CN201811330615.5 A synthesis process for preparing nitrendipine based on a three-step method
