Method for preparing 5 (6)-nitro-1-(4-nitrophenyl)-1, 3, 3-trimethylindane

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 5 (6)-nitro-1-(4-nitrophenyl)-1, 3, 3-trimethyl indan, 1, 3, 3-trimethyl-1-phenyl indan and dichloromethane are prepared into a raw material solution, nitric acid and sulfuric acid are prepared into a mixed acid solution, the raw material solution and the mixed acid solution are pumped into a microchannel reactor for reaction, layering is carried out after the reaction is finished, and 5 (6)-nitro-1-(4-nitrophenyl)-1, 3, 3-trimethyl indan is obtained. Separating out an acid water layer; neutralizing the organic layer with alkali until the pH value is 7-8; and separating the aqueous phase, evaporating the organic phase to remove the solvent to obtain a crude product, recrystallizing the crude product through a mixed solvent, pulping with water, and drying to obtain the product. The method is carried out in the micro-channel reactor, so that the problem that the temperature is difficult to control is solved; the consumption of sulfuric acid is obviously reduced; the recrystallization does not need to use a low-flash-point solvent cyclohexane any more, and the safety is good. The HPLC purity of the obtained product is greater than 99.5%, the molar yield is 82-85%, and the method is very suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene. Background Technology

[0002] 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane is the raw material for the polyimide monomer 5(6)-amino-1-(4-aminophenyl)-1,3,3-trimethylindane. 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene 5(6)-Amino-1-(4-aminophenyl)-1,3,3-trimethylindene

[0003] Journal of Polymer Science. 2021, 59: 3161-3166. Post Polymerization Modification of Aromatic Polyimides Via Diels-Alder Cyclo Addition. This paper introduces a method for synthesizing 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene, which uses 1,3,3-trimethyl-1-phenylindene as raw material and chloroform as solvent. The synthesis is carried out by nitration reaction of nitric acid and sulfuric acid in a mixed acid. The reaction temperature is 25℃ and the reaction time is 3h. The material ratio is: n(1,3,3-trimethyl-1-phenylindene):n(nitric acid):n(sulfuric acid) = 1:2.15:6. However, this method has many problems: the amount of mixed acid used is large, which generates a large amount of waste acid water; the reaction requires low temperature, which is difficult to control; the post-reaction treatment method is complicated; and the crystallization process uses cyclohexane, a low flash point solvent, which poses a safety hazard. 1,3,3-Trimethyl-1-phenylindanium

[0004] Therefore, there is a need in the art for a new method for preparing 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene. Summary of the Invention

[0005] To overcome the problems of the above methods, this invention provides a new method for synthesizing 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindanium.

[0006] This invention provides a method for preparing 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane. 1,3,3-trimethyl-1-phenylindane and dichloromethane are mixed in a certain proportion to form a raw material solution. Nitric acid and sulfuric acid are mixed to form a mixed acid solution. The raw material solution and the mixed acid solution are fed into a microchannel reactor at a certain rate for mixing and reaction. After the reaction, the layers separate, and the acid-water layer is separated. The resulting organic layer is neutralized with alkali to a pH of 7-8. The aqueous phase is separated, and the organic phase is evaporated to remove the solvent dichloromethane to obtain crude 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane. The crude product is recrystallized using a mixed solvent composed of acetone and ethanol to obtain a crystalline product, which is then slurried with water and dried to obtain the 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane product.

[0007] In one specific embodiment, the concentration of the nitric acid is greater than 65%, preferably 67-72%; the concentration of the sulfuric acid is greater than 90%, preferably 97%-98%; the raw material solution and the mixed acid solution are pumped into the microchannel reactor by a plunger pump; the alkali is an aqueous solution of sodium hydroxide with a concentration of 20-40%.

[0008] In one specific embodiment, the weight ratio of 1,3,3-trimethyl-1-phenylindanium to dichloromethane is 1:0.9~1.2.

[0009] In one specific embodiment, the method uses 69% nitric acid and 98% sulfuric acid in a weight ratio of 1:2.

[0010] In one specific embodiment, the microchannel reactor is a 10mL microchannel reactor, and the flow rate of the raw material solution is 20~30g / min, and the flow rate of the mixed acid solution is 30~38g / min.

[0011] In one specific embodiment, at the inlet of the microchannel reactor, the molar ratio of 1,3,3-trimethyl-1-phenylindanium and nitric acid in the two streams of raw material solution and mixed acid solution is controlled to be 1:2~2.15.

[0012] In one specific embodiment, the reaction temperature in the microchannel reactor is 30~40℃.

[0013] In one specific embodiment, the weight ratio of the mixed solvent and crude 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene is 1:0.8~1.1. During recrystallization, the temperature is first raised to 60~65°C and stirred for 0.5~2h to dissolve, then the temperature is lowered to 5~10°C and stirred for crystallization for 0.5~2h.

[0014] In one specific implementation, during pulping, the weight ratio of the crystallized product to water is 1:0.9~1.2, the pulping temperature is 20~25℃, and the time is 0.5~2h.

[0015] In one specific embodiment, the weight ratio of acetone to ethanol in the mixed solvent is 1:0.8~1.2.

[0016] The present invention has at least the following beneficial effects: 1. The nitration reaction described in the present invention is carried out in a microchannel reactor, which solves the problem of difficult temperature control in the nitration reaction. 2. The amount of acid water used in the present invention is greatly reduced, specifically the amount of concentrated sulfuric acid is significantly reduced. 3. The mixed solvent used for recrystallization in the present invention consists of acetone and ethanol, and the present invention no longer requires the use of the low flash point solvent cyclohexane, thus the method described in the present invention has good safety. In summary, the HPLC purity of the 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene product obtained by the present invention is greater than 99.5%, and the molar yield is 82-85%, which is very suitable for industrial production. Detailed Implementation

[0017] As those skilled in the art will know, a microreactor, or microchannel reactor, is a miniature reactor manufactured using precision machining technology, with characteristic dimensions ranging from 10 micrometers to 300 micrometers or 1000 micrometers. The "micro" in microreactor indicates that the channels for the process fluid are at the micrometer level, not that the microreactor device is small in size or the product yield is low. Microreactors can contain millions or even tens of millions of microchannels, thus achieving very high yields.

[0018] Chinese invention patent CN202211357644.7 discloses a method for preparing tetrahydropentamethylindane. The method includes the following steps: 1) introducing 1,1,2,3,3-pentamethylindane, a catalyst, a solvent, and hydrogen into a microchannel reactor. Under the action of the catalyst, 1,1,2,3,3-pentamethylindane undergoes a selective hydrogenation reaction to obtain a first hydrogenation reaction solution; 2) the first hydrogenation reaction solution undergoes a second hydrogenation reaction to obtain a second hydrogenation reaction solution. In step 2), 10-2000 ppm of carbon monoxide gas is added to the hydrogen. Tetrahydropentamethylindane exhibits high selectivity and high yield, while the selectivity of over-hydrogenation products such as hexahydropentamethylindane decreases, achieving efficient conversion of 1,1,2,3,3-pentamethylindane. This patent uses a microchannel reactor for the catalytic hydrogenation reaction of the compound.

[0019] Chinese invention patent CN201810970395.6 discloses a method for the catalytic oxidation of dihydroindanone-2-carboxylate under micro-reaction conditions or conventional reaction conditions, belonging to the field of organic chemical synthesis technology. The method involves mixing dihydroindanone-2-carboxylate, a catalyst, and a solvent to obtain a homogeneous solution; dissolving an oxidant in the solvent and extracting and drying it to obtain a homogeneous solution; reacting the two homogeneous solutions under micro-reaction conditions or conventional reaction conditions to obtain a reaction solution; adjusting the pH of the reaction solution to 6.5–7.5 with 10% hydrochloric acid, stirring for 20–30 min, cooling to below 5°C, filtering, rinsing the filter cake with a solvent at 0–5°C, and drying to obtain dihydroindanone-2-hydroxy-2-carboxylate. This invention utilizes the efficient heat and mass transfer capability of a microchannel reactor, combined with the co-catalytic oxidation of chiral phosphorimide acid and organic base. Compared with conventional preparation methods, it offers advantages such as simple process operation, high catalytic oxidation efficiency, short reaction time, simple equipment, high safety, and the ability to obtain products with high chiral purity. This patent uses a microchannel reactor to perform catalytic oxidation reactions of compounds.

[0020] Chinese invention patent application CN201811554173.2 discloses an improved method for preparing rasagiline. This method utilizes a microchannel reactor, using R-(-)-1-aminoindane (structural formula II) as a raw material, reacting it with a propargyl derivative (structural formula III) in the presence of appropriate solvents, temperatures, and alkalis to obtain R-(+)N-propargyl-1-aminoindane (structural formula I), followed by a salt-forming reaction to obtain rasagiline methanesulfonate. This method reduces the dialkyl substitution byproduct N,N-dipropargyl-1-aminoindane, achieving high yield and high purity in the preparation of rasagiline and its salts. It also shortens the reaction time, allows for high-temperature and high-pressure tolerance of the reaction conditions, simplifies post-processing, facilitates the removal of dialkyl substitution byproducts, and enables the separation, recovery, and reuse of unreacted R-(-)-1-aminoindane. The method is low-cost and suitable for industrial production. This patent uses a microchannel reactor for the condensation reaction of the compound.

[0021] However, a search revealed that no existing technologies have shown that the nitration of compounds related to indane is carried out in a microchannel reactor, and even less have they shown that the nitration of 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane prepared from 1,3,3-trimethyl-1-phenylindane is carried out in a microchannel reactor.

[0022] Unless otherwise specified, all concentrations in this invention are weight concentrations.

[0023] The present invention is further illustrated by the following embodiments, but the scope of protection of the present invention is not limited to the following embodiments.

[0024] Example 1

[0025] 100g of 1,3,3-trimethyl-1-phenylindene and 100g of dichloromethane were stirred until completely dissolved. A mixed acid solution was prepared by dissolving 77.4g of 69% nitric acid and 155g of sulfuric acid. The two solutions were pumped into a 10mL microchannel reactor using a plunger pump, with a feed flow rate of 20g / min and a mixed acid solution flow rate of 23.4g / min, maintaining a mixing temperature of 30-40℃. After the reaction, the layers separated; the acid-water layer was discarded. The organic layer was neutralized to pH 7-8 with a 30% sodium hydroxide aqueous solution. The aqueous phase was discarded, and the solvent was evaporated from the organic phase to obtain 140.2g of crude product. 140g of acetone and ethanol (weight ratio 1:1) were added as a mixed solvent, and the mixture was heated to 60-65℃ and stirred for 1 hour. The mixture was then cooled to 5-10℃ and stirred for 1 hour. Filtration yielded 128.2g of crystalline product. 128.2 g of the crystalline product was added to 130 g of water at 20-25 °C and stirred for 1 h. The mixture was then filtered and dried to obtain 113.3 g of the product. The purity was 99.6% (HPLC), and the molar yield was 82.0%.

[0026] Example 2

[0027] 100g of 1,3,3-trimethyl-1-phenylindene and 100g of dichloromethane were stirred until completely dissolved. A mixed acid solution was prepared by mixing 77.4g of 69% nitric acid and 155g of sulfuric acid. The two solutions were pumped into a 10mL microchannel reactor using a plunger pump, with a feed flow rate of 30g / min and a mixed acid solution flow rate of 35.2g / min, maintaining a mixing temperature of 30-40℃. After the reaction, the layers separated; the acid-water layer was discarded. The organic layer was neutralized to pH 7-8 with a 30% sodium hydroxide aqueous solution. The aqueous phase was discarded, and the solvent was evaporated from the organic phase to obtain 141g of crude product. 140g of acetone and ethanol (weight ratio 1:1) were added as a mixed solvent, and the mixture was heated to 60-65℃ and stirred for 1 hour. The mixture was then cooled to 5-10℃ and stirred for 1 hour. Filtration yielded 135.5g of crystalline product. 135.5 g of the crystalline product was added to 135 g of water at 20-25 °C and stirred for 1 hour. The mixture was then filtered and dried to obtain 114.6 g of the product. The purity was 99.7% (HPLC), and the molar yield was 83.0%.

[0028] Example 3

[0029] 100g of 1,3,3-trimethyl-1-phenylindene and 100g of dichloromethane were stirred until completely dissolved. A mixed acid solution was prepared by dissolving 77.4g of 69% nitric acid and 155g of sulfuric acid. The two solutions were pumped into a 10mL microchannel reactor using a plunger pump, with a feed flow rate of 30g / min and a mixed acid solution flow rate of 37g / min, controlling the mixing temperature at 30-40℃. After the reaction, the layers separated; the acid-water layer was separated. The organic layer was neutralized to pH 7-8 with a 30% sodium hydroxide aqueous solution. The aqueous phase was separated, and the solvent was evaporated from the organic phase to obtain 139.5g of crude product. 140g of acetone and ethanol (weight ratio 1:1) were added as a mixed solvent, and the mixture was heated to 60-65℃ and stirred for 1 hour. The temperature was then lowered to 5-10℃ and stirred for 1 hour. The mixture was filtered to obtain 136.9g of crystalline product. 136.9 g of the crystalline product was added to 135 g of water at 20-25 °C and stirred for 1 hour. The mixture was then filtered and dried to obtain 117.2 g of the product. The purity was 99.6% (HPLC), and the molar yield was 84.9%.

[0030] In the prior art, the molar ratio of 1,3,3-trimethyl-1-phenylindene to nitric acid in the nitration reaction of 1,3,3-trimethyl-1-phenylindene carried out in a conventional reactor is 1:2.15. In this invention, the molar ratio of 1,3,3-trimethyl-1-phenylindene to nitric acid is 1:2~2.15, thus the amount of nitric acid used is essentially the same in both. However, in the prior art, the molar ratio of nitric acid to sulfuric acid in the nitration reaction of 1,3,3-trimethyl-1-phenylindene carried out in a conventional reactor is 2.15:6, i.e., a molar ratio of 1:2.79. In the embodiments of this invention, the weight ratio of 69% nitric acid to 98% sulfuric acid is 1:2, i.e., a molar ratio of 1:1.83, which is equivalent to a 34.4% reduction in the amount of sulfuric acid used in this invention. Therefore, by using a microchannel reactor instead of the conventional reactor in the prior art, the amount of sulfuric acid used in the reaction described in this invention is significantly reduced. The reduction in sulfuric acid usage not only saves on material costs, but also means a reduction in the amount of waste acid that needs to be treated in the post-processing stage during industrial production. Both of these factors contribute to the significant cost and process advantages of the method described in this invention.

[0031] Furthermore, through multiple experiments, this invention selected a mixed solvent composed of acetone and ethanol, as described in this invention, for recrystallizing the crude product. This mixed solvent is not only highly safe, but also has a high compatibility with 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene. When used to recrystallize the crude product, it can directly yield 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene products with qualified quality and high molar yield. The mixed solvent used for recrystallization in this invention also makes the preparation method of the 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene products described in this invention very suitable for industrial application.

[0032] In summary, this invention belongs to the field of organic synthesis, specifically relating to a method for preparing 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane. A raw material solution is prepared by mixing 1,3,3-trimethyl-1-phenylindane and dichloromethane, and a mixed acid solution is prepared by mixing nitric acid and sulfuric acid. The raw material solution and the mixed acid solution are fed into a microchannel reactor for reaction. After the reaction, the layers separate, and the acid-water layer is separated. The organic layer is neutralized with alkali to a pH of 7-8. The aqueous phase is separated, and the solvent in the organic phase is evaporated to obtain the crude product. The crude product is recrystallized using a mixed solvent, then slurried with water, and dried to obtain the final product. This invention is carried out in a microchannel reactor, solving the problem of difficult temperature control; the amount of sulfuric acid used is significantly reduced; and recrystallization no longer requires the use of the low flash point solvent cyclohexane, resulting in good safety. The HPLC purity of the product obtained by this invention is greater than 99.5%, and the molar yield is 82-85%, making it very suitable for industrial production.

[0033] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene, characterized in that, 1,3,3-Trimethyl-1-phenylindane and dichloromethane were mixed in a certain proportion to form a raw material solution. Nitric acid and sulfuric acid were mixed to form a mixed acid solution. The raw material solution and the mixed acid solution were injected into a microchannel reactor at a certain rate to mix and react. After the reaction was completed, the layers were separated, and the acid-water layer was separated. The obtained organic layer was neutralized with alkali to a pH of 7-8. The aqueous phase was separated, and the solvent dichloromethane was evaporated from the organic phase to obtain crude 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane. The crude product was recrystallized by a mixed solvent composed of acetone and ethanol to obtain a crystalline product. The crystalline product was then slurried with water and dried to obtain the 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindane product.

2. The method according to claim 1, characterized in that, The concentration of the nitric acid is greater than 65%, preferably 67-72%; the concentration of the sulfuric acid is greater than 90%, preferably 97%-98%; the raw material solution and the mixed acid solution are pumped into the microchannel reactor by a plunger pump; the alkali is an aqueous solution of sodium hydroxide with a concentration of 20-40%.

3. The method according to claim 1, characterized in that, The weight ratio of 1,3,3-trimethyl-1-phenylindanium to dichloromethane is 1:0.9~1.

2.

4. The method according to claim 1, characterized in that, The method uses 69% nitric acid and 98% sulfuric acid in a weight ratio of 1:

2.

5. The method according to claim 1, characterized in that, The microchannel reactor is a 10mL microchannel reactor, and the flow rate of the raw material solution is 20~30g / min, and the flow rate of the mixed acid solution is 30~38g / min.

6. The method according to claim 1, characterized in that, At the inlet of the microchannel reactor, the molar ratio of 1,3,3-trimethyl-1-phenylindanium and nitric acid in the two streams of raw material solution and mixed acid solution is controlled to be 1:2~2.

15.

7. The method according to claim 1, characterized in that, The reaction temperature in the microchannel reactor is 30~40℃.

8. The method according to claim 1, characterized in that, The weight ratio of the mixed solvent and crude 5(6)-nitro-1-(4-nitrophenyl)-1,3,3-trimethylindene is 1:0.8~1.

1. During recrystallization, the temperature is first raised to 60~65℃ and stirred for 0.5~2h to dissolve, then the temperature is lowered to 5~10℃ and stirred for crystallization for 0.5~2h.

9. The method according to claim 1, characterized in that, When pulping, the ratio of crystallized product to water is 1:0.9~1.2, the pulping temperature is 20~25℃, and the time is 0.5~2h.

10. The method according to claim 1, characterized in that, The weight ratio of acetone to ethanol in the mixed solvent is 1:0.8~1.2.

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