Industrial preparation method of p-hydroxyphenylacetic acid

Abstract

The invention relates to an industrial preparation method for synthesizing p-hydroxyphenylacetic acid through copper / ligand catalysis. Specifically, the invention discloses a preparation method for preparing p-hydroxyphenylacetic acid by taking p-chlorobenzyl cyanide as a raw material in an inert solvent and carrying out carbon-oxygen bond coupling reaction under the action of a catalyst and alkali, the method is simple to operate and high in product yield and purity, the production cost is greatly reduced, and the method is very easy for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical intermediate preparation, and in particular relates to an industrial preparation method of p-hydroxyphenylacetic acid. Background Art

[0002] p-Hydroxyphenylacetic acid is an important fine chemical intermediate widely used in a variety of fields, including pharmaceuticals, pesticides, dyes, and liquid crystal materials. In the pharmaceutical field, p-Hydroxyphenylacetic acid can be used to synthesize the important antihypertensive drugs atenolol and metoprolol, as well as the cardiovascular drug 4,7-dihydroxyisoflavone, the anti-inflammatory and analgesic drug benoxaprofen, and the antibiotic latamoxef sodium. It is also used in the synthesis of anticancer drugs, antidiabetic drugs, and antiallergic drugs. Furthermore, p-Hydroxyphenylacetic acid can be aminated to produce p-hydroxyphenylacetamide, etherified to produce p-methoxyphenylacetic acid, esterified to produce p-hydroxyphenylacetic acid methyl ester, and reduced to produce p-hydroxyphenylethanol, thereby deriving a series of important intermediates. In the pesticide field, p-Hydroxyphenylacetic acid can be used to synthesize the insecticide cyanidin.

[0003] At present, there are three main routes reported for the synthesis of p-hydroxyphenylacetic acid at home and abroad:

[0004] Route 1: The route reported in CN103408501B has long synthesis steps, multiple hazardous reactions, large amounts of three wastes, low yields, and high pollution, making it unsuitable for industrial production.

[0005]

[0006] Route 2: In the route reported in CN105777569, the ortho-para regioselectivity of the condensation step of phenol and glyoxylic acid is not high. In addition, the reduction step requires the use of a precious metal catalyst and a special pressure reactor, resulting in high costs.

[0007]

[0008] Route 3: The routes described in US4390723A and US4537988A have stringent reaction conditions, requiring high temperatures (180-200°C) and high pressures (3.0-5.0 MPa) to achieve a good conversion rate. This places high demands on equipment and poses significant safety risks, limiting its application.

[0009]

[0010] Therefore, there is an urgent need in the art to develop a method for preparing p-hydroxyphenylacetic acid that has cheap raw materials, simple operation, can react under normal pressure, has relatively mild conditions, is safe and environmentally friendly, and is easy to industrialize. Summary of the Invention

[0011] An object of the present invention is to provide a method for preparing p-hydroxyphenylacetic acid that is more economical, efficient, safe, environmentally friendly, has relatively mild reaction conditions, and is easy to industrialize.

[0012] In a first aspect of the present invention, a method for preparing p-hydroxyphenylacetic acid is provided, comprising the following steps:

[0013] In an inert solvent, in the presence of a catalyst and a base, the compound of formula II undergoes a CO bond coupling reaction to prepare a compound of formula I;

[0014]

[0015] Where,

[0016] M is an alkali metal (such as Na, K, Cs) or an alkaline earth metal (such as Ca), or an ammonium ion (NH4);

[0017] The catalyst is selected from the group consisting of a combination of copper and a ligand, and a combination of a copper compound and a ligand.

[0018] In another preferred embodiment, the copper or copper compound is selected from the following group: Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(acac)2, 8-hydroxyquinoline copper, or a combination thereof.

[0019] In another preferred embodiment, the copper or copper compound is Cu(OAc)2 and CuSO4.

[0020] In another preferred embodiment, the ligand is selected from the following structures:

[0021]

[0022] in,

[0023] Ra is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0024] Rb is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;

[0025] Rc is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0026] Rd is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;

[0027] Re is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0028] Rf is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;

[0029] Wherein, the "optionally substituted" refers to a group that is unsubstituted or substituted by one or more (especially one, two or three) identical or different substituents; the substituents are independently selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy and C6-C10 aryl.

[0030] In another preferred embodiment, the ligand is selected from one or more of the ligands (L1-L12) shown in Table 1:

[0031] Table 1

[0032]

[0033]

[0034] In another preferred embodiment, the ligand is selected from one or more of the following groups:

[0035]

[0036] In another preferred embodiment, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, tetrabutylammonium hydroxide, or a combination thereof.

[0037] In another preferred embodiment, the base is sodium hydroxide.

[0038] In another preferred embodiment, the inert solvent is selected from the following group: water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, ester solvents, or a combination thereof.

[0039] In another preferred embodiment, the inert solvent is water.

[0040] In another preferred embodiment, the amount of copper or copper compound is 0.1-20 mol% of the compound of formula II.

[0041] In another preferred embodiment, the amount of copper or copper compound is 0.1-10 mol% of the compound of formula II.

[0042] In another preferred embodiment, the amount of copper or copper compound is 0.1-2 mol% of the compound of formula II.

[0043] In another preferred embodiment, the amount of the ligand used is 0.1-20 mol% of the compound of formula II.

[0044] In another preferred embodiment, the amount of the ligand used is 0.1-10 mol% of the compound of formula II.

[0045] In another preferred embodiment, the amount of the ligand used is 0.1-2 mol% of the compound of formula II.

[0046] In another preferred embodiment, the amount of the base used is 1 to 20 times the molar equivalent of the compound of formula II.

[0047] In another preferred embodiment, the amount of the base used is 1 to 10 times the molar equivalent of the compound of formula II.

[0048] In another preferred embodiment, the amount of the base used is 1 to 5 times the molar equivalent of the compound of formula II.

[0049] In another preferred embodiment, the volume of the inert solvent is 1 to 20 times the volume of the compound of formula II.

[0050] In another preferred embodiment, the volume of the inert solvent is 1 to 10 times the volume of the compound of formula II.

[0051] In another preferred embodiment, the volume of the inert solvent is 1 to 5 times the volume of the compound of formula II.

[0052] In another preferred embodiment, the reaction temperature of the coupling reaction is 90-120°C, preferably 95-110°C, and more preferably 100-110°C.

[0053] In another preferred embodiment, the reaction time of the coupling reaction is 2-24 hours, preferably 8-10 hours.

[0054] In another preferred embodiment, the method of the present invention is carried out under normal pressure.

[0055] In another preferred embodiment, the method of the present invention is carried out at 1±0.1 atm.

[0056] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0057] After extensive and in-depth research, the inventors unexpectedly discovered that p-chlorophenylacetonitrile can produce a high-purity p-hydroxybenzoic acid product in high yield in an inert solvent under alkaline conditions using a specific catalyst (copper or a copper compound and a ligand). The method of the present invention is carried out under relatively mild conditions at atmospheric pressure, with a low catalyst price, high catalytic efficiency, and few impurities, offering significant cost advantages, safety, environmental protection, and low production safety risks. Based on this, the inventors completed the present invention.

[0058] the term

[0059] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0060] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0061] The structural formula of "p-hydroxyphenylacetic acid" of the present invention is as follows:

[0062]

[0063] The "p-chlorophenylacetonitrile" described in the present invention is a reaction raw material, and its structural formula is as follows:

[0064]

[0065] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.

[0066] The "C1-C6 alkyl" mentioned in the present invention refers to a straight-chain or branched hydrocarbon group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, etc.

[0067] The term "C6-C14 aryl" as used herein refers to a monovalent aromatic carbocyclic group containing 6 to 14 carbon atoms, preferably an aromatic group containing 6 to 10 (especially 6) ring carbon atoms, such as phenyl, naphthyl, biphenyl, 2,6-dimethylphenyl, and the like.

[0068] The "5-6 membered heteroaryl" of the present invention refers to an aromatic group containing one or more rings and 5-14 ring atoms, preferably 5-10 (especially 5 or 6) ring atoms, which contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Examples include pyridyl, imidazolyl, furyl, thiazolyl, isothiazolyl, and the like.

[0069] The "5-7 membered heterocycloalkyl" of the present invention refers to a saturated or partially unsaturated cyclic group containing one or more rings (preferably 1-2) and 5-7 ring atoms, including one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Examples include tetrahydropyrrolidinyl, piperidinyl, piperazinyl, and the like.

[0070] The term "optionally substituted" as used herein refers to a group that is unsubstituted or substituted by one or more (particularly one, two or three; preferably one or two) substituents.

[0071] If a group contains more than one substituent, these substituents are independently selected, ie they may be the same or different.

[0072] Method of the present invention

[0073] As used herein, the terms "the method of the present invention", "the preparation method of the present invention" and "the industrial preparation method of the present invention" can be used interchangeably to refer to the method described in the first aspect of the present invention.

[0074] Preparation method of p-hydroxyphenylacetic acid

[0075] The present invention provides a method for preparing p-hydroxyphenylacetic acid that is more economical, efficient, safe, environmentally friendly, has relatively mild reaction conditions, and is easy to industrialize. The method comprises the following steps:

[0076] In an inert solvent, in the presence of a catalyst and a base, the compound of formula II undergoes a CO bond coupling reaction to prepare a compound of formula I;

[0077]

[0078] Where,

[0079] M is an alkali metal (such as Na, K, Cs) or an alkaline earth metal (such as Ca), or an ammonium ion (NH4);

[0080] The catalyst is selected from the group consisting of a combination of copper and a ligand, and a combination of a copper compound and a ligand.

[0081] The copper or copper compound includes but is not limited to Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(acac)2, 8-hydroxyquinoline copper, or a combination thereof;

[0082] Preferably, the copper or copper compound is Cu(OAc)2 and CuSO4.

[0083] The ligand is selected from the following structures:

[0084]

[0085] in,

[0086] Ra is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0087] Rb is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;

[0088] Rc is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0089] Rd is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;

[0090] Re is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0091] Rf is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S;

[0092] Wherein, the "optionally substituted" refers to a group that is unsubstituted or substituted by one or more (especially one, two or three) identical or different substituents; the substituents are independently selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy and C6-C10 aryl.

[0093] Preferably, the ligand is selected from one or more of the ligands L1-L12 shown in Table 1:

[0094] More preferably, the ligand is selected from one or more of the following groups:

[0095]

[0096] The base includes, but is not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, tetrabutylammonium hydroxide, or a combination thereof.

[0097] Preferably, the base is sodium hydroxide.

[0098] The inert solvent includes, but is not limited to, water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, ester solvents, or combinations thereof.

[0099] Preferably, the inert solvent is water.

[0100] The amount of copper or copper compound used is 0.1-20 mol% of the compound of formula II.

[0101] Preferably, the amount of copper or copper compound is 0.1-10 mol% of the compound of formula II.

[0102] More preferably, the amount of copper or copper compound is 0.1-2 mol% of the compound of formula II.

[0103] The amount of the ligand used is 0.1-20 mol% of the compound of formula II.

[0104] Preferably, the amount of the ligand used is 0.1-10 mol% of the compound of formula II.

[0105] More preferably, the amount of the ligand used is 0.1-2 mol% of the compound of formula II.

[0106] The amount of the base used is 1 to 20 times the molar equivalent of the compound of formula II.

[0107] Preferably, the amount of the base used is 1 to 10 times the molar equivalent of the compound of formula II.

[0108] More preferably, the amount of the base used is 1 to 5 times the molar equivalent of the compound of formula II.

[0109] The volume of the inert solvent is 1 to 20 times the volume of the compound of formula II.

[0110] Preferably, the volume of the inert solvent is 1 to 10 times the volume of the compound of formula II.

[0111] More preferably, the volume of the inert solvent is 1 to 5 times the volume of the compound of formula II.

[0112] The reaction temperature of the coupling reaction is 90-120°C, preferably 95-110°C, and more preferably 100-110°C.

[0113] The reaction time of the coupling reaction is 2-24 hours, preferably 8-10 hours.

[0114] In another preferred embodiment, the method of the present invention is carried out under normal pressure.

[0115] In another preferred embodiment, the method of the present invention is carried out at 1±0.1 atm.

[0116] The main advantages of the present invention are:

[0117] 1. The present invention provides a method for preparing p-hydroxyphenylacetic acid using p-chlorophenylacetonitrile as a raw material, catalyzed by copper or a copper compound / ligand in an inert solvent and alkaline conditions. The method does not involve hazardous reactions and does not require experiments to be conducted under high temperature or high pressure, thereby avoiding significant safety risks.

[0118] 2. The raw materials of the present invention are cheap, the operation is simple, and no precious metal catalysts are used, which has a great cost advantage.

[0119] 3. The catalyst dosage of the present invention is small, the catalytic efficiency is high, the reaction yield is high, the impurities are small, and the product purity is good.

[0120] 4. The present invention is carried out under normal pressure, the reaction conditions are relatively mild, and it is suitable for industrial production.

[0121] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0122] Unless otherwise stated, the following examples were carried out under normal pressure.

[0123] Example 1:

[0124] To a 2L reaction flask, add 200g of p-chlorophenylacetonitrile, 211g of sodium hydroxide, 2.4g of Cu(OAc)2, 4.8g of ligand L1, and 1kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC confirms completion. Cool to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 193kg of the product, with a yield of 96% and a purity of 99.3%.

[0125] Example 2:

[0126] To a 2L reaction flask, add 200g of p-chlorophenylacetonitrile, 296g of potassium hydroxide, 2.4g of Cu(OAc)2, 4.8g of ligand L1, and 1kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC confirms completion. Cool to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 187g of the product, with a yield of 93% and a purity of 99.1%.

[0127] Example 3:

[0128] To a 25L reaction flask, add 200g of p-chlorophenylacetonitrile, 211g of sodium hydroxide, 2.1g of CuSO4, 4.8g of ligand L1, and 1kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC confirms completion. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes and is filtered, rinsed with water, and dried to yield 177g of the product, with a yield of 88% and a purity of 99.3%.

[0129] Example 4:

[0130] To a 2L reaction flask, add 200g of p-chlorophenylacetonitrile, 316g of sodium hydroxide, 2.4g of Cu(OAc)2, 24.06g of ligand L, and 1.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes, which is then filtered, rinsed with water, and dried to yield 191g of the product, with a yield of 95% and a purity of 99.6%.

[0131] Example 5:

[0132] To a 2L reaction flask, add 200g of p-chlorophenylacetonitrile, 211g of sodium hydroxide, 2.4g of Cu(OAc)2, 4.8g of ligand L1, and 1kg of water. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100-110°C. The reaction was allowed to react for 16 hours, and the reaction was completed by HPLC. The temperature was then lowered to 20-30°C, and the pH was adjusted to 2-3 with concentrated hydrochloric acid. The product crystallized, filtered, rinsed with water, and dried to obtain 181g of the product, with a yield of 90% and a purity of 99.0%.

[0133] Example 6:

[0134] To a 2L reaction flask, add 200g of p-chlorophenylacetonitrile, 211g of sodium hydroxide, 2.4g of Cu(OAc)2, 4.8g of ligand L1, and 1kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC confirms completion. Cool to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 171g of the product, with a yield of 85% and a purity of 98.8%.

[0135] Example 7:

[0136] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 1.97g of ligand L3, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes, which is then filtered, rinsed with water, and dried to yield 65g of the product, with a yield of 65% and a purity of 98.4%.

[0137] Example 8:

[0138] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 2.06g of ligand L4, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 85g of the product, with a yield of 85% and a purity of 99.1%.

[0139] Example 9:

[0140] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 1.59g of ligand L5, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes, which is then filtered, rinsed with water, and dried to yield 48g of the product, with a yield of 48% and a purity of 98.1%.

[0141] Example 10:

[0142] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 1.55g of ligand L6, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes, which is then filtered, rinsed with water, and dried to yield 69g of the product, with a yield of 69% and a purity of 98.0%.

[0143] Example 11:

[0144] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 1.60g of ligand L7, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes, which is then filtered, rinsed with water, and dried to yield 83g of the product, with a yield of 83% and a purity of 98.3%.

[0145] Example 12:

[0146] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 1.42g of ligand L8, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool the temperature to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 90g of the product, with a yield of 90% and a purity of 98.1%.

[0147] Example 13:

[0148] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 92.07g of ligand L, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 68g of the product, with a yield of 68% and a purity of 98.7%.

[0149] Example 14:

[0150] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 1.60g of ligand L10, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms completion. Cool the temperature to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 80g of the product, with a yield of 80% and a purity of 98.0%.

[0151] Example 15:

[0152] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 11.60g of ligand L1, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms the completion of the reaction. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes, which is then filtered, rinsed with water, and dried to yield 50g of the product, with a yield of 50% and a purity of 97.0%.

[0153] Example 16:

[0154] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.2g of Cu(OAc)2, 1.60g of ligand L12, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms the reaction is complete. Cool the temperature to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 65g of the product, with a yield of 65% and a purity of 99.4%.

[0155] Example 17:

[0156] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 148g of potassium hydroxide, 1.05g of CuSO4, 2.4g of ligand L1, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC confirms completion. Cool to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 86g of the product, with a yield of 86% and a purity of 97.2%.

[0157] Example 18:

[0158] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 0.65g of CuCl, 12.4g of ligand L, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC analysis confirms the completion of the reaction. Cool the temperature to 20-30°C and adjust the pH to 2-3 with concentrated hydrochloric acid. The product crystallizes and is filtered, rinsed with water, and dried to obtain 55g of the product, with a yield of 55% and a purity of 98.0%.

[0159] Example 19:

[0160] To a 2L reaction flask, add 100g of p-chlorophenylacetonitrile, 105g of sodium hydroxide, 1.05g of CuSO4, 2.03g of ligand L2, and 0.5kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10 hours. HPLC confirms completion. Cool to 20-30°C, adjust the pH to 2-3 with concentrated hydrochloric acid, and the product crystallizes. Filter, rinse with water, and dry to obtain 87g of the product, with a yield of 87% and a purity of 98.5%.

[0161] Comparative Example 1

[0162] To a 2L reaction flask, add 200g of p-chlorophenylacetonitrile, 211g of sodium hydroxide, 2.4g of Cu(OAc)2, 1.6g of the ligand oxalyl diamide and 1kg of water. Replace the atmosphere with nitrogen three times, raise the temperature to 100-110°C, and react for 8-10h. No product is generated by HPLC.

[0163] The results of all examples are summarized in Table 2:

[0164] Table 2

[0165]

[0166] The results of the screening studies of different ligands of the present invention are summarized in Table 3:

[0167] Table 3

[0168]

[0169]

[0170]

[0171] discuss

[0172] The present inventors repeated the reaction conditions of some patent applications, such as the conditions described in US4390723A and US4537988A using copper or copper salt or a combination of the two, and using 8-hydroxyquinoline copper as a catalyst. The results showed that when the compound of formula II was used as the substrate, the reaction did not occur even when the temperature was raised to reflux at normal pressure.

[0173] In addition, oxalyl diamide was used as a ligand in combination with ketone and / or copper salt to form a catalyst. Experiments were carried out in an inert solvent and under normal pressure, and no product was generated by HPLC detection.

[0174] Unexpectedly, when the specific catalyst (copper or copper compound + specific ligand) of the present invention is used, the preparation of p-hydroxyphenylacetic acid using the compound of formula II as the raw material can be carried out efficiently under normal pressure and mild conditions.

[0175] Compared with the existing technology (which requires high temperature and high pressure conditions to achieve a good conversion rate), in the present invention, the catalytic efficiency of the specific catalyst is very high, and the reaction is carried out under normal pressure and relatively mild conditions, thereby significantly reducing or avoiding production safety risks.

[0176] In addition, the p-hydroxyphenylacetic acid product prepared by the method of the present invention has high yield and purity, is simple to operate, has cost advantages, and is very easy to industrialize.

[0177] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing p-hydroxyphenylacetic acid, characterized in that: The method comprises the following steps: In an inert solvent, in the presence of a catalyst and a base, the compound of formula II undergoes a CO bond coupling reaction to prepare a compound of formula I; Where, M is an alkali metal (such as Na, K, Cs) or an alkaline earth metal (such as Ca), or an ammonium ion (NH4); The catalyst is selected from the group consisting of a combination of copper and a ligand, and a combination of a copper compound and a ligand.

2. The preparation method according to claim 1, wherein The copper or copper compound is selected from the following group: Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(acac)2, 8-hydroxyquinoline copper or a combination thereof; preferably Cu(OAc)2 and CuSO4.

3. The preparation method according to claim 1, wherein The ligand is selected from the following structures: in, Ra is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; Rb is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; Rc is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; Rd is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; Re is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or optionally substituted 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; Rf is selected from the group consisting of an optionally substituted C6-C14 aryl group, an optionally substituted 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; Wherein, the "optionally substituted" refers to a group that is unsubstituted or substituted by one or more (particularly one, two or three) identical or different substituents; the substituents are independently selected from the following group: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy and C6-C10 aryl.

4. The preparation method according to claim 1, wherein The ligand is selected from one or more of the following groups:

5. The preparation method according to claim 1, wherein The ligand is selected from one or more of the following groups:

6. The preparation method according to claim 1, wherein The base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, tetrabutylammonium hydroxide, or a combination thereof; preferably sodium hydroxide.

7. The preparation method according to claim 1, wherein The inert solvent is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, ester solvents, or combinations thereof; preferably water.

8. The preparation method according to claim 1, wherein The amount of copper or copper compound is 0.1-20 mol%, preferably 0.1-10 mol%, more preferably 0.1-2 mol% of the compound of formula II; and / or The amount of the ligand used is 0.1-20 mol%, preferably 0.1-10 mol%, more preferably 0.1-2 mol% of the compound of formula II.

9. The preparation method according to claim 1, wherein The amount of the base used is 1 to 20 times the molar equivalent of the compound represented by formula II, preferably 1 to 10 times the molar equivalent, more preferably 1 to 5 times the molar equivalent; and / or The volume of the inert solvent is 1 to 20 times the volume of the compound of formula II, preferably 1 to 10 times the volume, and more preferably 1 to 5 times the volume.

10. The preparation method according to claim 1, wherein The reaction temperature of the coupling reaction is 90-120°C, preferably 95-110°C, more preferably 100-110°C; and / or The reaction time of the coupling reaction is 2-24 hours, preferably 8-10 hours.

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