A method for preparing a phenylacetic acid compound

Abstract

The application discloses a preparation method of a phenylacetic acid compound, and particularly, the application uses a substituted or unsubstituted aromatic hydrocarbon as a starting material, and under the action of a palladium catalyst (such as palladium acetate, palladium on carbon, palladium chloride, tetra-triphenyl palladium, etc.), the starting material is reacted with formaldehyde, HCl (aq) and CO to efficiently generate the phenylacetic acid compound. The method disclosed by the application only needs to start from the aromatic hydrocarbon, greatly reduces the difficulty and cost of obtaining the raw material, and avoids stimulating, sensitizing or toxic raw materials. Compared with the prior art, the method disclosed by the application has the advantages of simplicity and efficiency, cheap and easy-to-obtain raw materials, high atomic economy, high yield, green and pollution-free, easy industrialization and the like.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically to a method for preparing phenylacetic acid compounds. Background Technology

[0002] Phenylacetic acid and its derivatives (collectively referred to as phenylacetic acid compounds) are an important class of aromatic carboxylic acid compounds, characterized by a benzene ring linked to a carboxyl group via a methylene group. These compounds have irreplaceable and wide-ranging applications in the fields of medicine, pesticides, fragrances, and chemical intermediates, and their preparation methods are constantly evolving with the requirements of green chemistry and process economy. They can be used in multiple fields, for example, (1) Pharmaceutical industry: This is the most important application area for phenylacetic acid compounds. Phenylacetic acid itself is a key precursor for the synthesis of penicillin G and V, and is also an important intermediate for the preparation of sedative-hypnotic drugs such as phenobarbital, nonsteroidal anti-inflammatory drugs such as ibuprofen and ketoprofen. Its α-substituted or benzene ring-modified derivatives (such as p-hydroxyphenylacetic acid and p-aminophenylacetic acid) are widely used in the synthesis of cardiovascular drugs, antibiotics, and hormone drugs. (2) Pesticide industry: Phenylacetic acid is a core intermediate for the synthesis of highly effective and low-toxicity pyrethroid insecticides (such as cypermethrin). Some derivatives can also be used in the preparation of plant growth regulators and herbicides. (3) Fragrances and daily chemicals: Phenylacetic acid has a sweet honey aroma and can be used directly as a fixative. Its esters (such as ethyl phenylacetate and phenylethyl phenylacetate) are important fragrances for blending rose, honey, and chocolate scents, and are widely used in cosmetics, detergents, and food flavorings. (4) Chemical intermediates: As a basic organic synthesis building block, phenylacetic acid can be used to produce dyes, resin modifiers, ultraviolet absorbers, and monomers for liquid crystal materials. In summary, phenylacetic acid compounds have important industrial applications. Their synthesis and preparation methods mainly fall into the following categories.

[0003] 1. Benzyl chloride carbonylation method (classic industrial route): Using toluene as a raw material, benzyl chloride is generated through side-chain photochlorination, and then reacted with carbon monoxide and water in the presence of a cobalt carbonyl or palladium catalyst to produce phenylacetic acid. This method is mature and uses inexpensive raw materials, but it involves chlorine gas and photochlorination steps, which poses risks of equipment corrosion and environmental impact. Furthermore, benzyl chloride is irritating and sensitizing, making large-scale industrial protection difficult.

[0004] 2. Styrene Process: Styrene is synthesized into phenylacetic acid in a one-step carbonylation-oxidation process in the presence of a catalyst (such as PdCl2-CuCl2). This route has high atom economy and simple steps, making it a current research focus in green processes. The key lies in developing efficient and inexpensive catalyst systems to control side reactions. However, the high cost of raw materials limits its application.

[0005] 3. Phenylacetonitrile hydrolysis method: Benzyl chloride reacts with sodium cyanide to produce phenylacetonitrile, which is then hydrolyzed under acidic or alkaline conditions to obtain phenylacetic acid. This method has a high yield, but it uses highly toxic cyanide and irritating benzyl chloride derivatives, resulting in high waste treatment costs. It has been gradually phased out or strictly restricted.

[0006] 4. Benzaldehyde condensation conversion method (Perkin reaction and related improvements): Benzaldehyde reacts with acetic anhydride under the catalysis of sodium acetate in a Perkin reaction to produce cinnamic acid, which can then be converted to phenylacetic acid through hydrogenation and oxidation. This method still has value in laboratory synthesis and the preparation of certain derivatives, but the steps are lengthy and not conducive to industrial production.

[0007] In summary, the preparation of phenylacetic acid compounds is currently developing towards "green, continuous, and catalytically efficient" methods, with environmentally friendly processes, represented by cyanide-free and halogen-free routes, being a research hotspot. In terms of applications, with the increasing demand for new drug development and high-end fine chemicals, the customized synthesis of functionalized phenylacetic acid derivatives with specific functional group modifications will become increasingly important.

[0008] This invention, resulting from an accidental experimental result, discovered a one-step, highly efficient method for synthesizing phenylacetic acid from substituted aromatic hydrocarbons. This invention offers advantages such as simple operation, environmental friendliness, and low cost, making it suitable for large-scale industrial production. Summary of the Invention

[0009] To overcome the aforementioned problems in existing technologies, this invention uses substituted or unsubstituted aromatic hydrocarbons as starting materials. Under the action of a palladium catalyst (such as palladium acetate, palladium on carbon, palladium chloride, tetraphenylpalladium, etc.), the hydrocarbons react with formaldehyde, HCl(aq), and CO to efficiently generate phenylacetic acid compounds. This method only requires aromatic hydrocarbons as starting materials, greatly reducing the difficulty and cost of obtaining raw materials, while avoiding irritating, sensitizing, or toxic raw materials. Compared with existing technologies, this invention has advantages such as simplicity and efficiency, inexpensive and readily available raw materials, high atom economy, high yield, green and pollution-free operation, and ease of industrialization.

[0010] The method of this invention was discovered accidentally in an experiment. The inventors employed the following strategy in the carbonylation-amination reaction of olefins: formaldehyde was used instead of syngas, and methylamine hydrochloride was used as the amine source. The expected reaction equation is as follows: Analysis of the products after the reaction revealed that the expected reaction products were not obtained. Instead, the inventors unexpectedly discovered and isolated substituted phenylacetic acid derivatives. After analyzing the possible reaction mechanism (as shown in equation (1)), the inventors believe that the solvent anisole and formaldehyde underwent a chloromethylation reaction catalyzed by p-toluenesulfonic acid (TsOH) and hydrochloric acid. Then, some formaldehyde was decomposed into carbon monoxide. In the same system, carbonylation and amination occurred, and the substituted phenylacetic acid derivatives were obtained in one step (the actual reaction equation is shown in equation (2)).

[0011] Equation (1) Equation (2) Although the yield of this reaction is low under these conditions (mainly because most of the formaldehyde is consumed and very little carbon monoxide is produced), with reaction optimization, it could be a relatively ideal method for preparing phenylacetic acid compounds. The inventors subsequently optimized the reaction, primarily by adding carbon monoxide and replacing methylamine hydrochloride with hydrochloric acid, discovering the following highly efficient reaction for preparing phenylacetic acid compounds. It is worth noting that this type of method, starting only from aromatic hydrocarbons, greatly reduces the difficulty and cost of obtaining raw materials, while avoiding irritating, sensitizing, or toxic raw materials, making it an ideal preparation method.

[0012] On one hand, the present invention provides a method for preparing a phenylacetic acid compound of formula (I), comprising: reacting the compound of formula (II) with formaldehyde, hydrochloric acid, and CO in a solvent under the action of a palladium catalyst to obtain the phenylacetic acid compound of formula (I): in, R 1 and R 2 Independently H, C1-C 12 Alkyl, C1-C 12 Alkyl group.

[0013] In some implementations, R 1 and R 2 Independently H, C1-C6 alkyl, C1-C6 alkoxy.

[0014] In other implementations, R 1 and R 2 Independently H, C1-C4 alkyl, C1-C4 alkoxy.

[0015] In some embodiments, the palladium catalyst is one or any combination of palladium acetate, palladium on carbon, palladium chloride, tetraphenylpalladium, bis(dibenzylacetone)palladium, and palladium dichloroacetonitrile.

[0016] In some embodiments, the solvent is one or a mixture in any proportion of acetic acid, cyclopentane, cyclohexane, n-hexane, n-heptane, tetrahydrofuran, methyl tert-butyl ether, sulfolane, and cyclopentylmethyl ether.

[0017] In some embodiments, the reaction temperature is 80-120 degrees Celsius, preferably 90-120 degrees Celsius, and more preferably 100-120 degrees Celsius.

[0018] In some embodiments, the reaction pressure is 0.1-10 MPa, preferably 1-10 MPa, and more preferably 1-5 MPa.

[0019] In some embodiments, the reaction time is 8-20 hours, preferably 8-18 hours, and more preferably 8-15 hours.

[0020] In some embodiments, the amount of formaldehyde used is 1 to 10 times, preferably 1 to 5 times, and more preferably 1 to 3 times, the molar amount of the compound represented by formula (II).

[0021] In some embodiments, the amount of hydrochloric acid used is 1-100 times, preferably 1-50 times, more preferably 1-25 times, particularly preferably 1-13 times, and most preferably 1-6 times, of the molar amount of the compound represented by formula (II).

[0022] In some embodiments, the amount of the palladium catalyst is 0.01%-5% of the molar amount of the compound represented by formula (II), preferably 0.1%-5%.

[0023] In some embodiments, the amount of solvent used is 3-10 times the mass of the compound represented by formula (II), preferably 3-5 times.

[0024] Among them, monosubstituted aromatic hydrocarbons mainly yield para-substituted phenylacetic acid, 1,2-disubstituted aromatic hydrocarbons mainly yield 3,4-disubstituted phenylacetic acid, 1,3-disubstituted aromatic hydrocarbons mainly yield 2,4-disubstituted phenylacetic acid, and 1,4-disubstituted aromatic hydrocarbons mainly yield 2,5-disubstituted phenylacetic acid.

[0025] Beneficial technical effects of the present invention: The method of this invention, due to its ingenious design, only requires aromatic hydrocarbons as raw materials, greatly reducing the difficulty and cost of obtaining them, while avoiding allergenic raw materials. Compared with existing technologies, the method of this invention has the advantages of being simple and efficient, using inexpensive and readily available raw materials, having high atom economy, high yield, being green and pollution-free, and being easy to industrialize.

[0026] The present invention will be further described in detail below through specific embodiments, but the present invention is not limited to the embodiments. Detailed Implementation

[0027] Example 1: 2,4-Dimethoxyphenylacetic acid 13.8 g of 1,3-dimethoxybenzene (0.1 mol), 6 g of paraformaldehyde (0.2 mol), 50 mL of concentrated hydrochloric acid (0.6 mol), 50 g of cyclohexane, and 30 mg of palladium acetate (0.13 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.5 MPa, then twice with carbon monoxide at 0.5 MPa, and finally pressurized to 1 MPa with carbon monoxide. The temperature was raised to 100°C, and the reaction was carried out for 15 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 15.7 g of white crystalline solid 2,4-dimethoxyphenylacetic acid with a purity of 99.4% and a yield of 80.2%.

[0028] 1 H NMR (CDCl3, 300 MHz) δ (ppm): 7.05-7.15 (m, 1H), 6.42-6.49 (m, 2H), 3.78 (s, 6H), 3.52 (s, 2H). Example 2: 2,4-Dimethylphenylacetic acid 10.6 g of 1,3-dimethylbenzene (0.1 mol), 3 g of paraformaldehyde (0.1 mol), 8.3 mL of concentrated hydrochloric acid (0.1 mol), 32 g of n-heptane, and 18 mg of palladium chloride (0.1 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.1 MPa, then twice with carbon monoxide at 0.1 MPa, and finally pressurized to 0.11 MPa with carbon monoxide. The temperature was raised to 80°C, and the reaction was allowed to proceed for 20 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 13.2 g of white crystalline 2,4-dimethylphenylacetic acid with a purity of 99.1% and a yield of 80.1%.

[0029] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 7.67-7.73 (m, 1H), 6.98-7.01 (m, 2H), 3.65 (s, 2H), 2.33 (s, 3H), 2.30 (s, 3H). Example 3: 4-n-hexylphenylacetic acid 16.2 g of n-hexylbenzene (0.1 mol), 30 g of paraformaldehyde (1 mol), 100 mL of concentrated hydrochloric acid (1.2 mol), 162 g of acetic acid, and 11.6 mg of tetrakis(triphenylphosphine)palladium (0.01 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.5 MPa, then twice with carbon monoxide at 0.5 MPa, and finally pressurized to 5 MPa with carbon monoxide. The temperature was raised to 100°C, and the reaction was carried out for 8 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 18.1 g of pale yellow solid 4-n-hexylphenylacetic acid with a purity of 99.3% and a yield of 82.2%.

[0030] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 7.05-7.24 (m, 4H), 3.66 (s, 2H), 2.51-2.61 (m, 2H), 1.50-1.64 (m, 2H), 1.18-1.47 (m, 6H), 0.84-0.92 (m, 3H). Example 4: 4-n-dodecylphenylacetic acid 24.6 g of n-dodecylbenzene (0.1 mol), 6 g of paraformaldehyde (0.2 mol), 208 mL of concentrated hydrochloric acid (2.5 mol), 100 g of cyclohexane, and 0.885 g of palladium chloride (5 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.5 MPa, then twice with carbon monoxide at 0.5 MPa, and finally pressurized to 10 MPa with carbon monoxide. The temperature was raised to 80°C, and the reaction was carried out for 12 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 24.7 g of oily solid 4-n-dodecylphenylacetic acid with a purity of 99.2% and a yield of 81.3%.

[0031] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 7.42-7.45 (m, 2H), 7.02-7.07 (m, 2H), 3.69 (s, 2H), 2.53-2.61 (m, 2H), 1.57-1.64 (m, 2H), 1.18-1.47 (m, 18H), 0.88(t, 3H). Example 5: 4-n-dodecyloxyphenylacetic acid 24.8 g of dodecyloxyphenylene (0.1 mol), 9 g of paraformaldehyde (0.3 mol), 108 mL of concentrated hydrochloric acid (1.3 mol), 100 g of methyl tert-butyl ether, and 0.53 g of 10% palladium on carbon (0.5 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.5 MPa, then twice with carbon monoxide at 0.5 MPa, and finally pressurized to 5 MPa with carbon monoxide. The temperature was raised to 90°C, and the reaction was carried out for 15 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 26.1 g of light gray flaky solid 4-dodecyloxyphenylacetic acid with a purity of 99.1% and a yield of 81.6%.

[0032] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 10.23 (br, 1H), 6.42-7.05 (m, 4H), 3.89 (t, 2H), 3.47 (s, 2H), 0.84-1.86 (m, 23H). Example 6 2,4-Diisopropoxyphenylacetic acid 19.4 g of 1,3-diisopropoxyphenylene (0.1 mol), 6 g of paraformaldehyde (0.2 mol), 50 mL of concentrated hydrochloric acid (0.6 mol), 60 g of n-heptane, and 0.89 g of palladium chloride (5 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.5 MPa, then twice with carbon monoxide at 0.5 MPa, and finally pressurized to 3 MPa with carbon monoxide. The temperature was raised to 120°C, and the reaction was carried out for 8 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 21.7 g of colorless granular solid 2,4-diisopropoxyphenylacetic acid with a purity of 99.6% and a yield of 86.1%.

[0033] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 7.01-7.07 (m, 1H), 6.42-6.47 (m, 2H), 4.49-4.54 (m, 2H), 3.59 (s, 2H), 1.30-1.35 (m, 12H). Example 7 4-tert-butoxyphenylacetic acid 15 g of tert-butoxyphenylene (0.1 mol), 6 g of paraformaldehyde (0.2 mol), 50 mL of concentrated hydrochloric acid (0.6 mol), 30 g of n-heptane, 30 g of acetic acid, and 0.12 g of tetraphenylphosphine palladium (0.1 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.5 MPa, then twice with carbon monoxide at 0.5 MPa, and finally pressurized to 2 MPa with carbon monoxide. The temperature was raised to 110 °C, and the reaction was carried out for 11 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 17.5 g of white solid 4-tert-butoxyphenylacetic acid with a purity of 99.5% and a yield of 84.1%.

[0034] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 9.46 (br, 1H), 7.27 (d, 2H), 6.97 (d,2H), 3.63 (s, 2H), 1.31 (s, 9H). Example 8: 4-tert-Butylphenylacetic acid 13.4 g tert-butylbenzene (0.1 mol), 9 g paraformaldehyde (0.3 mol), 70 mL concentrated hydrochloric acid (0.84 mol), 37 g cyclopentane, 30 g methyl tert-butyl ether, and 1.8 mg palladium chloride (0.01 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.3 MPa, then twice with carbon monoxide at 0.3 MPa, and finally pressurized to 4 MPa with carbon monoxide. The temperature was raised to 100°C, and the reaction was allowed to proceed for 16 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by rotary evaporation, and the product was filtered to obtain 15.7 g of a white solid, 4-tert-butylphenylacetic acid, with a purity of 99.2% and a yield of 81.9%.

[0035] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 7.35 (d, 2H), 7.22 (d, 2H), 3.13 (s,2H), 1.31 (s, 9H). Example 9: 2,5-Dimethylphenylacetic acid 10.6 g of 1,4-xylene (0.1 mol), 5 g of paraformaldehyde (0.17 mol), 20 mL of concentrated hydrochloric acid (0.24 mol), 106 g of n-heptane, and 18 mg of palladium chloride (0.1 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.3 MPa, then twice with carbon monoxide at 0.3 MPa, and finally pressurized to 5 MPa with carbon monoxide. The temperature was raised to 105°C, and the reaction was allowed to proceed for 18 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 13.7 g of a pale yellow solid, 2,5-dimethylphenylacetic acid, with a purity of 99.3% and a yield of 83.8%.

[0036] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 7.05-7.09 (m, 1H), 7.00-7.03 (m, 2H), 3.53 (s, 2H), 2.31 (s, 3H), 2.27 (s, 3H). Example 10 3,4-Dimethylphenylacetic acid 10.6 g of 1,2-xylene (0.1 mol), 7 g of paraformaldehyde (0.23 mol), 40 mL of concentrated hydrochloric acid (0.48 mol), 106 g of n-heptane, and 18 mg of palladium chloride (0.1 mmol) were added to a pressure-resistant reactor. The system was first purged three times with nitrogen at 0.3 MPa, then twice with carbon monoxide at 0.3 MPa, and finally pressurized to 5 MPa with carbon monoxide. The temperature was raised to 105 °C, and the reaction was allowed to proceed for 18 hours. After natural cooling to room temperature, carbon monoxide was carefully released, and the reaction solution was filtered through diatomaceous earth. Most of the organic solvent was removed by vortexing, and the product was filtered to obtain 13.5 g of a pale yellow solid, 3,4-dimethylphenylacetic acid, with a purity of 99.4% and a yield of 82.1%.

[0037] 1 H NMR (CDCl 3， 300 MHz) δ (ppm): 7.28-7.31 (m, 2H), 7.11-7.13 (m, 1H), 3.63 (s, 2H), 2.30 (s, 3H), 2.25 (s, 3H).

Claims

1. A method for preparing a phenylacetic acid compound of formula (I), comprising: In a solvent, the compound represented by formula (II) reacts with formaldehyde, hydrochloric acid, and CO in the presence of a palladium catalyst to yield the phenylacetic acid compound represented by formula (I): in, R 1 and R 2 Independent of H, C1-C 12 Alkyl, C1-C 12 Alkyl group.

2. The preparation method according to claim 1, wherein, The palladium catalyst is one or any combination of palladium acetate, palladium on carbon, palladium chloride, tetraphenylpalladium, bis(diphenylacetone)palladium, and palladium dichloroacetonitrile.

3. The preparation method according to claim 1, wherein, The solvent is one or a mixture in any proportion of acetic acid, cyclopentane, cyclohexane, n-hexane, n-heptane, tetrahydrofuran, methyl tert-butyl ether, sulfolane, and cyclopentylmethyl ether.

4. The preparation method according to claim 1, wherein, The reaction temperature is 80-120 degrees Celsius.

5. The preparation method according to claim 1, wherein, The reaction pressure is 0.1-10 MPa.

6. The preparation method according to claim 1, wherein, The reaction time is 8-20 hours.

7. The preparation method according to claim 1, wherein, The amount of formaldehyde used is 1 to 10 times the molar amount of the compound shown in formula (II).

8. The preparation method according to claim 1, wherein, The amount of hydrochloric acid used is 1-100 times the molar amount of the compound shown in formula (II).

9. The preparation method according to claim 1, wherein, The amount of palladium catalyst used is 0.01%-5% of the molar amount of the compound shown in formula (II).

10. The preparation method according to claim 1, wherein, The amount of solvent used is 3-10 times the mass of the compound shown in formula (II).

Images