Synthesis method of 2-[4-(hydroxyphenoxy)] propionic acid

Technical Field

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The invention belongs to the technical field of chemosynthesis and pertains to a synthetic method for the compound 2-[4-(hydroxyphenoxy)] propionic acid, which serves as an intermediate for pesticide synthesis.

Background Technology

China, being a large agricultural nation, has significant consumption of agricultural chemicals. Herbicides are an economical and reliable means for weed control in modern agricultural production systems. However, traditional herbicides often possess high toxicity and low efficiency, leading to significant environmental impacts, which has necessitated the development of more effective and less toxic herbicides. Recently, a number of herbicides, including diphenyl ether, phenoxy propionic acid derivatives, sulfonylureas, and imidazolone compounds, have been developed. Phenoxy propionic acid compounds, known for their high efficiency, low toxicity, wide herbicidal spectrum, and high selectivity, have become some of the best-performing herbicides available today.

2-[4-(hydroxyphenoxy)] propionic acid is a crucial intermediate for synthesizing phenoxy and heterocyclic oxy group phenoxy propionic acid herbicides. Current methods for synthesizing 2-[4-(hydroxyphenoxy)] propionic acid include: (1) reacting raw materials with alpha-halogenated propionic esters ([P] US 614 814); (2) using parahydroxyacetophenone as an initiator in reaction with alpha-halogenated propionic esters, followed by oxidation and hydrolysis ([P] EP 0 334 595); (3) employing ethyl lactate as a raw material under acid-binding agent conditions with triethylamine, through acylation and condensation reactions (Jiamusi University's journal, 23 (2), 260-264). These methods often generate large amounts of by-products, complicating purification and reducing product yield. Some methods entail lengthy reaction times, low overall recovery, or involve catalysts, harsh reaction conditions, and high production costs, making them unsuitable for industrial production.

Summary of the Invention

The objective of the invention is to provide a low-cost and efficient synthetic method for the pesticide intermediate 2-[4-(hydroxyphenoxy)] propionic acid to address the shortcomings of prior art methods.

The present synthesis method involves the following steps:

(1) In a dehydrated alcohol solvent, mix mono-benzyl ether of hydroquinone, sodium hydroxide, and 2-bromopropionic acid ethyl ester in a molar ratio of 1:1:1.2 to 1:1:1.5. Stir at room temperature for 4 to 6 hours. Extract, dry, concentrate, and separate to obtain compound 2-(4-(benzyloxy) phenoxy group) ethyl propionate;

(2) Under inert gas protection, add a reducing agent boron trifluoride-ether and NaI to the 2-(4-(benzyloxy) phenoxy group) ethyl propionate. Stir for 1 to 3 hours at 0 to 5 °C, then extract, dry, concentrate, and separate to get 2-(4-hydroxyphenoxy) ethyl propionate.

The boron trifluoride-ether is used in a quantity of 1 to 3 times the molar weight of 2-(4-hydroxyphenoxy) ethyl propionate, and NaI is used in a quantity of 1 to 3 times the molar weight of 2-(4-(benzyloxy) phenoxy group) ethyl propionate.

(3) Stir 2-(4-hydroxyphenoxy) ethyl propionate in a solution of 5% to 10% NaOH at room temperature for 2 to 4 hours. Drip hydrochloric acid until the reaction solution reaches a pH of 1 to 3, then continue stirring for 1 to 2 hours. Extract, dry, and recrystallize to obtain white solid 2-[4-(hydroxyphenoxy)] propionic acid.

The separation technology mentioned above employs silica gel column chromatography.

The mono-benzyl ether of hydroquinone is prepared as follows: under alkaline conditions using DMF as the solvent, mix Resorcinol and Benzyl Chloride in a molar ratio of 1.2:1 to 1.5:1 at microwave irradiation power of 280 to 350 W for 1 to 2 minutes. Cool to room temperature, filter, and crystallize from the acidified filtrate to obtain white solid mono-benzyl ether of hydroquinone. The alkaline condition consists of an aqueous sodium hydroxide solution in equimolar amounts with Resorcinol.

2-Bromopropionic acid ethyl ester is prepared by mixing ethyl lactate and phosphorus tribromide in a molar ratio of 3:1 to 2:1 under inert gas protection. Stir at room temperature for 3 to 6 hours, then extract and purify to obtain colorless liquid 2-bromopropionic acid ethyl ester.

The process is summarized as follows:

Reaction products are analyzed using magnetic resonance detection, confirming the purity of the product.

Compared to prior art, this invention offers several advantages:

Utilizing Resorcinol and ethyl lactate as raw materials helps to minimize the formation of bis ethers. The process facilitates the production of 2-[4-(hydroxyphenoxy)] propionic acid through mild conditions, reducing reaction times and simplifying after-treatment, resulting in high yields and lower production costs. This presents promising prospects for industrial application.

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Embodiment

The following specific embodiments further describe the synthetic method of 2-[4-(hydroxyphenoxy)] propionic acid.

(1) Preparation of 2-bromopropionic acid ethyl ester

In a dried and clean three-necked flask under a nitrogen environment, add 3.54g (0.03mol) ethyl lactate and 3.25g (0.012mol) phosphorus tribromide successively. Stir at room temperature for 5 hours while monitoring the reaction via thin-layer chromatography (TLC). After the reaction, add saturated sodium bicarbonate solution to release gas, then perform ethyl acetate extraction three times the volume and another two times saturated sodium bicarbonate solution. The collected solution is dried over MgSO4, filtered, and concentrated with a RE-52AA Rotary Evaporator, resulting in a colorless liquid, 2-bromopropionic acid ethyl ester, with a yield of 88%.

(2) Preparation of mono-benzyl ether of hydroquinone

In a 100 mL flask, add 3.08g (0.028mol) Resorcinol.

Weigh 1.12g (0.028mol) sodium hydroxide, dissolve in 8mL of water, and mix with Resorcinol previously added into the flask. Add 15mL DMF and 2.52g (0.02mol) Benzyl Chloride under microwave irradiation at 320W for 60 seconds. Upon completion of the reaction, allow to cool to room temperature. Adjust pH with 10% sodium hydroxide, filter, and wash the filter cake, yielding a colorless solution. Acidify the solution with HCl to obtain mono-benzyl ether of hydroquinone, followed by filtration and recrystallization with activated carbon decolorization, leading to 2.56g of white solid, yielding 64%.

(3) Preparation of 2-(4-(benzyloxy) phenoxy group) ethyl propionate

In a 100 mL flask, weigh 2.50g (0.mol) mono-benzyl ether of hydroquinone, 0.5g (0.mol) sodium hydroxide, and 2.90g (0.016mol) 2-bromopropionic acid ethyl ester, then add 15mL dehydrated alcohol. Stir at room temperature for 5 hours while monitoring with TLC. Upon completion, remove ethanol via rotary evaporation, then add 10mL saturated ammonium chloride solution. Extract with ethyl acetate. The resulting liquid is dried over MgSO4, filtered, and concentrated, then mixed with silica gel (2-3 times the concentrated solution quality) for column chromatography. Collect the eluent, resulting in 2-(4-(benzyloxy) phenoxy group) ethyl propionate, 2.1g, with a transformation efficiency of 58% and a reaction yield of 56%.

The resulting product is confirmed by 1H NMR and 13C NMR as being pure, characterized by the following data:
1H NMR (400MHz, CDCl3): δ=7.40-7.29 (m, 4H), 6.88-6.80 (m, 4H), 4.97 (s, 2H), 4.64 (dd, J1=1.6Hz, J2=6.8Hz, 1H), 4.21 (m, 2H), 1.56 (d, J=1.6Hz, 3H), 1.24-1.19 (m, 3H);
13C NMR (100MHz, CDCl3): δ=172.45, 153.96, 150.25, 142.21, 130.19, 128.57, 128.21, 116.69, 115.78, 70.56, 69.38, 61.53, 16.35, 14.98.

(4) Preparation of 2-(4-hydroxyphenoxy) ethyl propionate

Under nitrogen conditions, mix 2-(4-(benzyloxy) phenoxy group) ethyl propionate 2.0g (0.mol), boron trifluoride-ether 2.82g (0.02mol), and NaI 1.5g (0.01mol) in a 100 mL flask. Stir for 1.5 hours in an ice-water bath. After the reaction, drip saturated sodium bicarbonate into the mixture. Stir at room temperature until no bubbles form, followed by ethyl acetate extraction. The product is dried over MgSO4, filtered, concentrated, and subjected to column chromatography, yielding compound 2-(4-hydroxyphenoxy) ethyl propionate, 1.2g, with a yield of 86%.

The product is confirmed as pure via 1H NMR and 13C NMR, presenting the following characteristics:
1H NMR (400MHz, CDCl3): δ=6.78-6.71 (m, 4H), 5.62 (s, 1H), 4.65 (q, J=6.8Hz, 1H), 4.22 (dd, J1=0.8Hz, J2=7.2Hz, 2H), 1.59 (d, J=6.8Hz, 3H), 1.25 (t, J=7.6Hz, 3H);
13C NMR (100MHz, CDCl3): δ=172.48, 153.69, 151.28, 118.67, 117.53, 70.36, 59.66, 16.27, 14.86.

(5) Preparation of 2-[4-(hydroxyphenoxy)] propionic acid

Dissolve 1.05g (0.005mol) 2-(4-hydroxyphenoxy) ethyl propionate in 8mL of 10% NaOH solution and stir at room temperature for 3 hours. Cool in an ice-water bath while dripping 2mol/L hydrochloric acid, then continue stirring for 1 hour until the reaction solution reaches pH=1. Extract using ethyl acetate; the filtered liquid is further concentrated with a rotary evaporator to obtain the crude product. The crude product is recrystallized with ethanol to yield 0.85g of white solid 2-[4-(hydroxyphenoxy)] propionic acid, achieving a reaction yield of 93%.

The product is confirmed as pure through 1H NMR and 13C NMR, with the following characterization data:
1H NMR (400MHz, DMSO-d6): δ=11.6 (s, 1H), 6.68-6.61 (m, 4H), 4.65 (m, 1H), 1.36 (d, J=6.8Hz, 3H);
13C NMR (100MHz, DMSO-d6): δ=174.26, 153.22, 151.76, 120.35, 119.55, 72.36, 16.84.