Purification method of p-isopropylbenzoic acid

Abstract

The invention provides a purification method of p-isopropylbenzoic acid, and belongs to the technical field of organic compound purification. The method comprises the following steps: carrying out esterification reaction on p-isopropylbenzoic acid with low purity and methanol in the presence of a catalyst to obtain high-purity methyl p-isopropylbenzoate; and carrying out hydrolysis reaction by using high-purity methyl p-isopropylbenzoate to obtain the high-purity p-isopropylbenzoic acid. By adopting the purification method disclosed by the invention, the purity of the obtained p-isopropylbenzoic acid can reach 99.5% or above, and the problem that the purity of the p-isopropylbenzoic acid cannot reach 99.5% or above no matter how purification is carried out in a traditional physical purification method is solved.

Description

Technical Field

[0001] This invention belongs to the field of organic compound purification technology, specifically relating to a method for purifying p-isopropylbenzoic acid. Background Technology

[0002] p-Isopropylbenzoic acid is an important fine chemical with wide applications in polymer materials, oil improvement, liquid crystal displays, pharmaceuticals, and pesticides. In recent years, in particular, p-isopropylbenzoic acid has demonstrated its significant value as a pharmaceutical intermediate. For example, it is used as a preservative in the wood industry and as a corrosion inhibitor in automotive antifreeze. It can also be used as a raw material for synthesizing polymeric thermistors, as well as for synthesizing the antidiabetic drug nateglinide and the NHE-1 inhibitor cariporide (HOE-642).

[0003] There are two main routes for synthesizing p-isopropylbenzoic acid in the prior art: one is using cumene as a raw material and the other is using p-isopropyltoluene as a raw material. The main routes for synthesizing p-isopropylbenzoic acid using cumene as a raw material are as follows: (1) Cumene is first subjected to chloromethylation reaction with phosphorus trichloride to obtain p-isopropylbenzyl chloride; p-isopropylbenzyl chloride is reacted with hexamethylene and then hydrolyzed under acidic conditions to obtain p-isopropylbenzaldehyde; p-isopropylbenzaldehyde is then oxidized by hydrogen peroxide to obtain p-isopropylbenzoic acid (DOI: 10.3969 / j.issn.1005-8257.2012.04.032). (2) Cumene reacts with acetyl chloride in the presence of aluminum trichloride via a Friedel-Crafts reaction to yield p-isopropylacetophenone; p-isopropylacetophenone is hydrolyzed under alkaline conditions and then acidified to yield p-isopropylbenzoic acid (DOI: 10.3969 / j.issn.1005-0108.2002.02.009). (3) Cumene reacts with anhydrous chloroacetaldehyde in the presence of aluminum trichloride, then is oxidized with hydrogen peroxide under alkaline conditions, and finally acidified to produce p-isopropylbenzoic acid (DOI: 10.1002 / CHIN.198810134). (4) Cumene undergoes Friedel-Crafts acylation with acetic anhydride under aluminum trichloride catalysis to give p-isopropylacetophenone; p-isopropylacetophenone reacts with bromine under alkaline conditions to form bromoform, and then crystallizes under acidic conditions to give p-isopropylbenzoic acid (DOI: 10.3969 / j.issn.0258-3283.2005.02.017).

[0004] All four synthetic routes described above suffer from poor selectivity, resulting in the formation of p-isopropylbenzoic acid and o-isopropylbenzoic acid isomers during the reaction. These isomers are difficult to separate after the reaction, ultimately leading to insufficient product purity. Furthermore, p-isopropylbenzoic acid, when used as a raw material for nateglinide and calcipopropylbenzyl, requires high purity. However, traditional physical purification methods (e.g., recrystallization, extraction, distillation) cannot achieve the required purity for use as a raw material for pharmaceutical active ingredients (APIs). Summary of the Invention

[0005] In industrial production, the applicant uses route (4) described above, which uses cumene as a raw material to synthesize p-isopropylbenzoic acid. The resulting product has a purity of approximately 90%, which is insufficient to meet the downstream demand for high-purity p-isopropylbenzoic acid. Therefore, to improve the purity of p-isopropylbenzoic acid, the applicant has developed a purification method. This method differs from traditional physical purification methods. It involves a chemical reaction to first convert p-isopropylbenzoic acid into high-purity methyl p-isopropylbenzoate, and then hydrolyzing the high-purity methyl p-isopropylbenzoate to obtain high-purity p-isopropylbenzoic acid.

[0006] Specifically, the present invention adopts the following technical solution to achieve the above objectives: A method for purifying p-isopropylbenzoic acid includes the following steps: S1. P-Isopropylbenzoic acid (≤93%) is reacted with methanol in the presence of a catalyst to obtain methyl p-isopropylbenzoate. The main reaction equations are as follows: ; S2. The methyl p-isopropylbenzoate obtained in step S1 is hydrolyzed to obtain p-isopropylbenzoic acid with a purity ≥ 99.5%; the main reaction equations are as follows: .

[0007] In a preferred embodiment of the present invention, in step S1, the mass ratio of p-isopropylbenzoic acid to methanol is 1:(1~3).

[0008] In a preferred embodiment of the present invention, in step S1, the catalyst is a strong acid; more preferably, concentrated sulfuric acid.

[0009] In a further preferred embodiment of the present invention, the amount of concentrated sulfuric acid used in step S1 is 0.7% to 0.9% of the mass of p-isopropylbenzoic acid with a content ≤93%, and the concentrated sulfuric acid is added to the reaction system by dropping for 30 to 60 minutes.

[0010] In a preferred embodiment of the present invention, in step S1, the esterification reaction conditions are as follows: the mixture of p-isopropylbenzoic acid, methanol and catalyst is heated to reflux and maintained under reflux for 3 to 8 hours.

[0011] In a preferred embodiment of the present invention, step S1 includes the following steps: after the esterification reaction is completed, the reaction system is cooled to 30~50°C, brine is added, the mixture is homogeneous, the organic phase is separated, the organic phase is distilled under normal pressure, and the fraction at 244°C~246°C is collected.

[0012] In a further preferred embodiment, the brine is an aqueous solution of at least one of sodium chloride, ammonium chloride, and potassium chloride, and the solute content in the aqueous solution is 10wt% to 20wt%.

[0013] In a preferred embodiment of the present invention, in step S2, the hydrolysis reaction is carried out under conditions of pH=9~14.

[0014] In a further preferred embodiment, in step S2, the hydrolysis reaction uses an alkaline aqueous solution to adjust the pH, and the mass ratio of methyl isopropylbenzoate to water in the alkaline aqueous solution is 1:(4~10).

[0015] In a preferred embodiment of the present invention, in step S2, the hydrolysis reaction conditions are: 65℃~75℃, maintained for 3~8 hours.

[0016] In a preferred embodiment of the present invention, step S2 includes the following steps: after the hydrolysis reaction is completed, the reaction system is heated to 90~95℃, the pH is adjusted to 3.2~3.8, the temperature is lowered to 50~70℃, centrifuged, the solid is rinsed with water, centrifuged again, and dried to obtain purified p-isopropylbenzoic acid.

[0017] In a further preferred embodiment, in step S2, the pH is adjusted to 3.2 to 3.8 using 7.5 wt% to 15 wt% sulfuric acid.

[0018] Compared with the prior art, the technical solution of the present invention has the following beneficial effects: This invention employs a chemical reaction method to first prepare high-purity methyl p-isopropylbenzoate from p-isopropylbenzoic acid with insufficient purity. Then, the high-purity methyl p-isopropylbenzoate is hydrolyzed to obtain high-purity p-isopropylbenzoic acid, solving the problem that traditional physical purification methods cannot achieve a purity of over 99.5% for p-isopropylbenzoic acid. This allows the purified p-isopropylbenzoic acid to serve as an important raw material for the active ingredients of drugs such as nateglinide and calicipheride; it can also serve as a raw material for other downstream products that require high-purity p-isopropylbenzoic acid. Detailed Implementation

[0019] The following description, in conjunction with embodiments, clearly and completely describes the technical solutions of this application, so that those skilled in the art can fully understand this application. Obviously, the described embodiments are merely some preferred embodiments of this application, and not all embodiments. Any equivalent modifications or substitutions made by those skilled in the art to the following embodiments without creative effort are within the protection scope of this application.

[0020] In this application, the p-isopropylbenzoic acid raw material before purification has a p-isopropylbenzoic acid content of ≤93%. The quality of the purified p-isopropylbenzoic acid product, as determined by high performance liquid chromatography (HPLC), must meet the following requirements: the impurity content with a relative retention time of (1.8±0.1) min is ≤0.2%, the impurity content with a relative retention time of (3.8±0.2) min is ≤0.1%, the p-isopropylbenzoic acid content with a relative retention time of (4.4±0.2) min is ≥99.5%, and the impurity content with a relative retention time of (6.2±0.2) min is ≤0.2%.

[0021] The HPLC conditions for detecting p-isopropylbenzoic acid in this application are as follows: Mobile phase: Acetonitrile: 0.2wt% phosphoric acid aqueous solution = 55:45 (V / V); Chromatographic column: C18 column, 4.6mm*300mm; Flow rate: 1 mL / min; Injection volume: 10 μL; Detection wavelength: 210nm; Column temperature: 20~30℃.

[0022] Example 1 A method for purifying p-isopropylbenzoic acid includes the following steps: S1, Esterification reaction 80 kg of p-isopropylbenzoic acid (HPLC results: 1.6 min 0.8%, 1.8 min 4%, 3.8 min 0.2%, 4.4 min 91%, 6.2 min 4%) and 168 kg of methanol were added to a 1000 L glass-lined reactor equipped with a condenser. 56 kg of concentrated sulfuric acid was added dropwise (dropping time was 30 min). The mixture was heated to reflux and subjected to esterification reaction for 4 hours. Then, it was cooled to 50 °C, and 400 L of water and 70.6 kg of sodium chloride were added. The mixture was stirred for half an hour and transferred to a layered reactor. The lower water layer containing methanol was separated and the methanol was recovered for reuse. The waste sulfuric acid was neutralized with 30% liquid alkali to pH=7.5. The upper oil layer was separated and subjected to atmospheric distillation. The fore fraction, methyl p-isopropylbenzoate, and the back fraction were collected to obtain 73 kg of methyl p-isopropylbenzoate (purity 99.8%) at 244~246 °C.

[0023] S2, hydrolysis reaction 73 kg of methyl p-isopropylbenzoate obtained in step S1 and 300 L of 10 wt% sodium hydroxide aqueous solution were added to a 1000 L glass-lined reactor. The pH was adjusted to 14 (tested with pH paper), and the mixture was heated to (70±2) °C for hydrolysis for 3 hours. The temperature was further increased to 90 °C, and the mixture was acidified with 7.5 wt% dilute sulfuric acid until the pH reached 3.8. The mixture was cooled to 60 °C, centrifuged to dry, rinsed with water and centrifuged again, and dried under reduced pressure at 80 °C to obtain 65 kg of p-isopropylbenzoic acid (HPLC results: 1.8 min 0.12%, 3.8 min 0.07%, 4.4 min 99.71%, 6.2 min 0.1%).

[0024] Example 2 A method for purifying p-isopropylbenzoic acid includes the following steps: S1, Esterification reaction 80 kg of p-isopropylbenzoic acid (HPLC results: 1.6 min 1%, 1.8 min 3.2%, 3.8 min 0.6%, 4.4 min 91.2%, 6.2 min 4%) and 175 kg of methanol were added to a 1000 L glass-lined reactor equipped with a condenser. 60 kg of concentrated sulfuric acid was added dropwise (dropping time was 40 min). The mixture was heated to reflux and subjected to esterification reaction for 5 hours. Then, it was cooled to 40 °C, and 300 L of water and 33.5 kg of ammonium chloride were added. The mixture was stirred for half an hour and then transferred to a layered reactor. The lower water layer containing methanol was separated and the methanol was recovered for reuse. The waste sulfuric acid was neutralized with 30 wt% liquid alkali to pH=6. The upper oil layer was separated and subjected to atmospheric distillation. The fore fraction, methyl p-isopropylbenzoate, and the back fraction were collected to obtain 70 kg of methyl p-isopropylbenzoate (purity 99.6%) at 244~246 °C.

[0025] S2, hydrolysis reaction 70 kg of methyl p-isopropylbenzoate obtained in step S1 and 300 L of 10% sodium hydroxide aqueous solution were added to a 1000 L glass-lined reactor to adjust the pH to 13. The reactor was then heated to (67±2) °C for 6 hours for hydrolysis. The temperature was further increased to 90 °C, and the mixture was acidified with 10 wt% dilute sulfuric acid until the pH reached 3.6. The mixture was then cooled to 60 °C, centrifuged to dry, rinsed with water and centrifuged again, and dried under reduced pressure at 80 °C to obtain 61 kg of p-isopropylbenzoic acid (HPLC results: 1.8 min 0.07%, 3.8 min 0.05%, 4.4 min 99.78%, 6.2 min 0.1%).

[0026] Example 3 A method for purifying p-isopropylbenzoic acid includes the following steps: S1, Esterification reaction 80 kg of p-isopropylbenzoic acid (HPLC results: 1.6 min 0.9%, 1.8 min 3.9%, 3.8 min 0.2%, 4.4 min 92%, 6.2 min 3%) and 200 kg of methanol were added to a 1000 L glass-lined reactor equipped with a condenser. 70 kg of concentrated sulfuric acid was added dropwise (dropping time was 60 min). The mixture was heated to reflux and subjected to esterification reaction for 5 hours. Then, it was cooled to 45 °C, and 400 L of water and 100 kg of potassium chloride were added. The mixture was stirred for half an hour and then transferred to a layered reactor. The lower water layer containing methanol was separated and the methanol was recovered for reuse. The waste sulfuric acid was neutralized with 30% liquid alkali to pH=9. The upper oil layer was separated and subjected to atmospheric distillation. The fore fraction, methyl p-isopropylbenzoate, and the back fraction were collected to obtain 72 kg of methyl p-isopropylbenzoate (purity 99.7%) at 244~246 °C.

[0027] S2, hydrolysis reaction 72 kg of methyl p-isopropylbenzoate obtained in step S1 and 300 L of 10% sodium hydroxide aqueous solution were added to a 1000 L glass-lined reactor. The pH was adjusted to 12, and the mixture was heated to (73±2) °C for hydrolysis for 6 hours. The temperature was further increased to 93 °C, and the mixture was acidified with 10 wt% dilute sulfuric acid until the pH reached 3.5. The mixture was cooled to 55 °C, centrifuged to dry, rinsed with water and centrifuged again, and dried under reduced pressure at 85 °C to obtain 62 kg of p-isopropylbenzoic acid (HPLC detection results: 1.8 min 0.1%, 3.8 min 0.08%, 4.4 min 99.75%, 6.2 min 0.07%).

[0028] Example 4 A method for purifying p-isopropylbenzoic acid includes the following steps: S1, Esterification reaction 80 kg of p-isopropylbenzoic acid (HPLC results: 1.6 min 0.8%, 1.8 min 4%, 3.8 min 0.2%, 4.4 min 91%, 6.2 min 4%) and 240 kg of methanol were added to a 1000 L glass-lined reactor equipped with a condenser. 58 kg of concentrated sulfuric acid was added dropwise (dropping time was 35 min). The mixture was heated to reflux and subjected to esterification reaction for 3 hours. Then, it was cooled to 50 °C, and 400 L of water and 65 kg of sodium chloride were added. The mixture was stirred for half an hour and then transferred to a layered reactor. The lower water layer containing methanol was separated and the methanol was recovered for reuse. The waste sulfuric acid was neutralized with 30% liquid alkali to pH=8. The upper oil layer was separated and subjected to atmospheric distillation. The first fraction, methyl p-isopropylbenzoate, and the last fraction were collected to obtain 70 kg of methyl p-isopropylbenzoate (purity 99.7%) at 244~246 °C.

[0029] S2, hydrolysis reaction 70 kg of methyl p-isopropylbenzoate obtained in step S1 and 700 L of 10% sodium hydroxide aqueous solution were added to a 1000 L glass-lined reactor. The pH was adjusted to 9, and the mixture was heated to (68±2) °C for hydrolysis for 8 hours. The temperature was further increased to 95 °C, and the mixture was acidified with 15 wt% dilute sulfuric acid until the pH reached 3.2. The mixture was cooled to 50 °C, centrifuged to dry, rinsed with water and centrifuged again, and dried under reduced pressure at 80 °C to obtain 61.5 kg of p-isopropylbenzoic acid (HPLC detection results: 1.8 min 0.14%, 3.8 min 0.09%, 4.4 min 99.6%, 6.2 min 0.17%).

[0030] Example 5 A method for purifying p-isopropylbenzoic acid includes the following steps: S1, Esterification reaction 80 kg of p-isopropylbenzoic acid (HPLC results: 1.6 min 0.8%, 1.8 min 4%, 3.8 min 0.2%, 4.4 min 91%, 6.2 min 4%) and 80 kg of methanol were added to a 1000 L glass-lined reactor equipped with a condenser. 65 kg of concentrated sulfuric acid was added dropwise (dropping time was 45 min). The mixture was heated to reflux and subjected to esterification reaction for 8 hours. Then, it was cooled to 30 °C, and 400 L of water, 44 kg of sodium chloride, and 44 kg of potassium chloride were added. The mixture was stirred for half an hour and then transferred to a layered reactor. The lower water layer containing methanol was separated and the methanol was recovered for reuse. The waste sulfuric acid was neutralized with 30% liquid alkali to pH=7. The upper oil layer was separated and subjected to atmospheric distillation. The fore fraction, methyl p-isopropylbenzoate, and the back fraction were collected to obtain 71 kg of methyl p-isopropylbenzoate (purity 99.65%) at 244~246 °C.

[0031] S2, hydrolysis reaction 71 kg of methyl p-isopropylbenzoate obtained in step S1 and 360 L of 10% sodium hydroxide aqueous solution were added to a 1000 L glass-lined reactor to adjust the pH to 11. The reactor was then heated to (73±2) °C for 3 hours for hydrolysis. The temperature was further increased to 95 °C, and the mixture was acidified with 12 wt% dilute sulfuric acid until the pH reached 3.7. The mixture was then cooled to 70 °C, centrifuged to dry, rinsed with water and centrifuged again, and dried under reduced pressure at 83 °C to obtain 63 kg of p-isopropylbenzoic acid (HPLC results: 1.8 min 0.09%, 3.8 min 0.06%, 4.4 min 99.69%, 6.2 min 0.16%).

[0032] Comparative Example 1 A method for purifying p-isopropylbenzoic acid includes the following steps: Add 80 kg of p-isopropylbenzoic acid (HPLC results: 1.6 min 0.8%, 1.8 min 4%, 3.8 min 0.2%, 4.4 min 91%, 6.2 min 4%), 240 kg of water, and 400 kg of 95 wt% ethanol to a 1000 L glass-lined reactor equipped with a condenser. Start stirring and heat to reflux until all raw materials are dissolved. Cool to crystallize at room temperature, centrifuge to dry, and then dry under reduced pressure at 80 °C to obtain 70 kg of p-isopropylbenzoic acid (HPLC results: 1.6 min 0.6%, 1.8 min 3%, 3.8 min 0.1%, 4.4 min 93.3%, 6.2 min 3%).

[0033] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Various modifications and variations can be made to the present invention by any person skilled in the art. Any simple equivalent changes and modifications made based on the scope of protection of this invention and the content of the specification should be included within the scope of protection of the present invention.

Claims

1. A method for purifying p-isopropylbenzoic acid, characterized in that, Includes the following steps: S1. P-isopropylbenzoic acid with a content of ≤93% is esterified with methanol in the presence of a catalyst to obtain methyl p-isopropylbenzoate. S2. The methyl p-isopropylbenzoate obtained in step S1 is subjected to a hydrolysis reaction to obtain p-isopropylbenzoic acid with a content of ≥99.5%.

2. The purification method according to claim 1, characterized in that, In step S1, the mass ratio of p-isopropylbenzoic acid to methanol is 1:(1~3).

3. The purification method according to claim 1, characterized in that, In step S1, the catalyst is a strong acid.

4. The purification method according to claim 1, characterized in that, In step S1, the esterification reaction conditions are as follows: the mixture of p-isopropylbenzoic acid, methanol and catalyst is heated to reflux and maintained at reflux for 3 to 8 hours.

5. The purification method according to claim 1, characterized in that, Step S1 includes the following steps: After the esterification reaction is completed, the reaction system is cooled to 30~50℃, brine is added, mixed evenly, the organic phase is separated, the organic phase is distilled under normal pressure, and the fraction at 244℃~246℃ is collected.

6. The purification method according to claim 1, characterized in that, In step S2, the hydrolysis reaction is carried out under conditions of pH 9 to 14.

7. The purification method according to claim 6, characterized in that, In step S2, the mass ratio of methyl p-isopropylbenzoate to water in the alkaline compound aqueous solution is 1:(4~10).

8. The purification method according to claim 1, characterized in that, In step S2, the hydrolysis reaction conditions are: 65℃~75℃, maintained for 3~8 hours.

9. The purification method according to claim 1, characterized in that, Step S2 includes the following steps: after the hydrolysis reaction is completed, the reaction system is heated to 90~95℃, the pH is adjusted to 3.2~3.8, the temperature is lowered to 50~70℃, centrifuged, the solid is rinsed with water, centrifuged again, and dried to obtain purified p-isopropylbenzoic acid.

10. The purification method according to claim 9, characterized in that, In step S2, the pH is adjusted to 3.2~3.8 using 7.5wt%~15wt% sulfuric acid.