A method for one-pot synthesis of D-p-hydroxyphenylglycine

Abstract

The application relates to the technical field of drug synthesis, in particular to a one-pot synthesis method of D-p-hydroxyphenylglycine, which comprises the following steps: dissolving a mixture of 4-(1-chlorovinyl) phenol and D-p-hydroxyphenylglycine in a solvent, and stirring and reacting under pressure of ammonia gas and carbon dioxide in the presence of a specific catalyst to obtain D-p-hydroxyphenylglycine. A brand-new reaction route is designed, raw material cost is low, reaction conversion rate is high, purity is high, selectivity is good, kettle efficiency is high, reaction time is short, operation is convenient, three wastes are controllable, and the method is suitable for large-scale industrial production. Compared with a traditional phenol chemical synthesis method and a phenylglycidine enzyme method, a brand-new substrate is used, and the whole reaction process meets green chemistry, is pollution-free and harmless.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and specifically to a one-pot method for synthesizing D-p-hydroxyphenylglycine. Background Technology

[0002] p-Hydroxyphenylglycine is an important intermediate in the synthesis of β-lactam semi-synthetic broad-spectrum antibiotics (such as amoxicillin and cefadroxil), and also an important intermediate in the synthesis of antibacterial and antiviral drugs and artificial sweeteners. In addition to the continued growth in the amoxicillin raw material market driving the expansion of the L-p-hydroxyphenylglycine market, the rapid growth in demand for raw materials such as cefoperazone, cefadroxil, and cefprozil will also boost global market demand for D-p-hydroxyphenylglycine products.

[0003] Chinese invention patent CN202110023648.0 discloses a batch reaction method for obtaining D-p-hydroxyphenylglycine using phenol, glyoxylic acid, and aminosulfonic acid as raw materials, with a yield of 89.4%. However, this method requires a specific reactor, resulting in high reaction temperatures and low reactor efficiency. Chinese invention patent CN200710054926.9 discloses a one-pot reaction method for obtaining D-p-hydroxyphenylglycine using phenol, glyoxylic acid, and aminosulfonic acid as raw materials, but its yield is very low, only 65%. Existing methods for synthesizing D-p-hydroxyphenylglycine are costly, have low yields, poor selectivity, require specific equipment, and have low reactor efficiency, making them unsuitable for large-scale production. In recent years, with the increasing demand for D-p-hydroxyphenylglycine, raw material prices have risen sharply.

[0004] In view of the above-mentioned defects, the inventors of this invention have finally obtained this invention after a long period of research and practice. Summary of the Invention

[0005] The purpose of this invention is to solve the problems of high cost, low yield, poor selectivity, requirement for specific equipment, and low reactor efficiency in the existing methods for synthesizing D-p-hydroxyphenylglycine, which make it difficult to use for large-scale production. The invention provides a one-pot method for synthesizing D-p-hydroxyphenylglycine.

[0006] To achieve the above objectives, this invention discloses a one-pot synthesis method for D-p-hydroxyphenylglycine, comprising the following steps:

[0007] S1, a mixture of 4-(1-chlorovinyl)phenol and D-p-hydroxyphenylglycine is dissolved in a solvent to obtain a mixed solution, wherein the mass percentage of D-p-hydroxyphenylglycine in the mixture is 1.4%;

[0008] S2, add a catalyst to the mixed solution obtained in step S1, and react with ammonia and carbon dioxide under pressure and stirring to obtain D-p-hydroxyphenylglycine.

[0009] In step S1, the solvent is any one or a combination of methanol, ethanol, and isopropanol.

[0010] In step S1, the solvent is methanol.

[0011] In step S2, the catalyst is any one or a combination of several of nickel chloride, sodium carbonate, cesium carbonate, and tetraphenylphosphine palladium.

[0012] In step S2, the catalyst is a combination of nickel chloride and sodium carbonate, and the amount of catalyst used is 1-4% of the mass of 4-(1-chlorovinyl)phenol.

[0013] In step S2, the reaction pressure is 0.1-3 MPa.

[0014] In step S2, the reaction pressure is 0.5 MPa.

[0015] In step S2, the reaction temperature is 30-80℃.

[0016] In step S2, the reaction temperature is 50-60℃.

[0017] In step S2, the reaction is stirred using an anchor-type stirring paddle at a speed of 200-250 r / min.

[0018] The reaction mechanism of this invention is as follows: 1. In a weakly alkaline system composed of sodium carbonate, ammonia, and carbon dioxide, the phenolic hydroxyl group is protected; 2. The catalyst nickel chloride coordinates and activates the carbon-carbon double bond of the olefin, free ammonia attacks the activated double bond, and chloride ions leave, generating a nickel-coordinated enamine intermediate; 3. Carbon dioxide inserts into the NH bond to generate carbamate, while simultaneously preventing the bimolecular coupling reaction; 4. Under the induction of added D-p-hydroxyphenylglycine, trace amounts of water in the system undergo trans-addition with the enamine double bond to generate an amino alcohol metal complex; 5. Trace amounts of air and nickel in the system undergo a single-electron oxidation cycle, i.e., hydroxymethyl group becomes aldehyde group, while nickel is reduced to generate water to continue the previous cycle; 6. Heating causes the carbamate to decompose and release carbon dioxide, while the aldehyde group hydrates to synthesize geminal glycol. Nickel ion coordination promotes the migration and rearrangement of 1,2-hydrogens, and the geminal glycol dehydrogenates to generate a carboxyl group. After dissociation of the nickel catalyst, a chiral product (D-p-hydroxyphenylglycine) is generated.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention designs a completely new reaction route, uses low-cost raw materials, has a high reaction conversion rate, high purity, good selectivity, high reactor efficiency, short reaction time, convenient operation and controllable waste, and is suitable for large-scale industrial production. Attached Figure Description

[0020] Figure 1 The 1H NMR spectrum of D-p-hydroxyphenylglycine obtained in Example 1;

[0021] Figure 2 The liquid phase spectrum of D-p-hydroxyphenylglycine obtained in Example 1 is shown. Detailed Implementation

[0022] The above-mentioned and other technical features and advantages of the present invention will be described in more detail below with reference to the accompanying drawings.

[0023] Example 1

[0024] The synthesis route is shown below:

[0025]

[0026] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant concentration was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 50.8 g of the target product. The HPLC purity was 99.17%, the selectivity was 98.5%, and the yield was 94%. The 1H NMR spectrum is shown below. Figure 1 As shown; using a chiral column with a normal-phase system, racemic p-hydroxyphenylglycine, L-p-hydroxyphenylglycine, and D-p-hydroxyphenylglycine were separated, and the resulting liquid chromatography chromatogram is shown below. Figure 2 As shown, by Figure 2 It can be seen that racemic p-hydroxyphenylglycine and L-p-hydroxyphenylglycine account for very small proportions in the product, with peak area percentages of 0.72% and 0.11%, respectively, while the rest are D-p-hydroxyphenylglycine, with a peak area percentage of 99.17%.

[0027] Example 2

[0028] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.5 MPa. Carbon dioxide was then introduced until the system pressure reached 1 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.74 g of the target product with an HPLC purity of 98.6%, a selectivity of 97%, and a yield of 92%.

[0029] Example 3

[0030] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of tetrakis(triphenylphosphine)palladium, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 rpm for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49 g of the target product with an HPLC purity of 98%, a selectivity of 97.2%, and a yield of 90.7%.

[0031] Example 4

[0032] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of isopropanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.2 g of the target product with an HPLC purity of 98.7%, a selectivity of 98%, and a yield of 91%.

[0033] Example 5

[0034] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.25 g of nickel chloride, 0.25 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 48.6 g of the target product with an HPLC purity of 97.5%, a selectivity of 96%, and a yield of 90%.

[0035] Example 6

[0036] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 1 g of nickel chloride, 1 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 50.3 g of the target product with an HPLC purity of 98%, a selectivity of 97.2%, and a yield of 93%.

[0037] Example 7

[0038] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.1 MPa. Carbon dioxide was then introduced until the system pressure reached 0.2 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 48.6 g of the target product with an HPLC purity of 97%, a selectivity of 96.5%, and a yield of 90%.

[0039] Example 8

[0040] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of ethanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.2 g of the target product with an HPLC purity of 98.5%, a selectivity of 97.5%, and a yield of 91%.

[0041] Example 9

[0042] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, 75 mL of ethanol, and 75 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.7 g of the target product with an HPLC purity of 98.8%, a selectivity of 98%, and a yield of 92%.

[0043] Example 10

[0044] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of cesium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.2 g of the target product with an HPLC purity of 98.2%, a selectivity of 97.6%, and a yield of 91%.

[0045] Example 11

[0046] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of tetrakis(triphenylphosphine)palladium, 0.5 g of cesium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 rpm for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.5 g of the target product with an HPLC purity of 98.5%, a selectivity of 97%, and a yield of 91.5%.

[0047] Example 12

[0048] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 1.5 MPa. Carbon dioxide was then introduced until the system pressure reached 3 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 48.6 g of the target product with an HPLC purity of 96.8%, a selectivity of 95%, and a yield of 90%.

[0049] Example 13

[0050] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.05 MPa. Carbon dioxide was then introduced until the system pressure reached 0.05 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 48.6 g of the target product with an HPLC purity of 92%, a selectivity of 90%, and a yield of 90%.

[0051] Example 14

[0052] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.4 MPa. Carbon dioxide was then introduced until the system pressure reached 0.8 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.1 g of the target product with an HPLC purity of 95%, a selectivity of 90%, and a yield of 91%.

[0053] Example 15

[0054] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of cesium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the vessel was stirred with a paddle at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.4 g of the target product with an HPLC purity of 96.8%, a selectivity of 95%, and a yield of 91.5%.

[0055] Example 16

[0056] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.75 g of nickel chloride, 0.75 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.7 g of the target product with an HPLC purity of 97%, a selectivity of 95.5%, and a yield of 92%.

[0057] Example 17

[0058] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.625 g of nickel chloride, 0.625 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.5 g of the target product with an HPLC purity of 96.5%, a selectivity of 95.3%, and a yield of 91.6%.

[0059] Example 18

[0060] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, 75 mL of isopropanol, and 75 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.7 g of the target product with an HPLC purity of 98.2%, a selectivity of 97.8%, and a yield of 92%.

[0061] Example 19

[0062] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, 75 mL of ethanol, and 75 mL of isopropanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.7 g of the target product with an HPLC purity of 98.5%, a selectivity of 97.3%, and a yield of 92%.

[0063] Example 20

[0064] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 50.8 g of the target product with an HPLC purity of 99.1%, a selectivity of 98%, and a yield of 94%.

[0065] Example 21

[0066] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 40-50 °C, and the vessel was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 50.2 g of the target product with an HPLC purity of 98.8%, a selectivity of 97.7%, and a yield of 92.9%.

[0067] Example 22

[0068] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 30-40 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.7 g of the target product with an HPLC purity of 98.2%, a selectivity of 97.6%, and a yield of 92%.

[0069] Example 23

[0070] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 60-70 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 50.5 g of the target product with an HPLC purity of 98.9%, a selectivity of 97.8%, and a yield of 93.5%.

[0071] Example 24

[0072] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of nickel chloride, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 70-80 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 48.6 g of the target product with an HPLC purity of 95.8%, a selectivity of 96%, and a yield of 90%.

[0073] Example 25

[0074] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of tetrakis(triphenylphosphine)palladium, 0.5 g of sodium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 rpm for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 49.8 g of the target product with an HPLC purity of 98%, a selectivity of 97.1%, and a yield of 92.2%.

[0075] Example 26

[0076] At room temperature, a mixture of 49.3 g of 4-(1-chlorovinyl)phenol and 0.7 g of D-p-hydroxyphenylglycine, 0.5 g of sodium carbonate, 0.5 g of cesium carbonate, and 150 mL of methanol were sequentially added to a 500 mL pressure vessel. After purging with nitrogen, ammonia was introduced, and the pressure was increased to 0.25 MPa. Carbon dioxide was then introduced until the system pressure reached 0.5 MPa. The temperature was gradually increased to 50-60 °C, and the mixture was stirred with an anchor stirrer at 200-250 r / min for 8 hours. The reaction was considered complete when the reactant content was less than 0.2% by HPLC. The mixture was then cooled to 20 °C, the system was vented, and 50 mL of a 5% potassium dihydrogen phosphate aqueous solution was added. The mixture was filtered, and the filter cake was dried at 50 °C for 12 hours to obtain 48.6 g of the target product with an HPLC purity of 95.5%, a selectivity of 95%, and a yield of 90%.

[0077] Table 1 Summary of data under different reaction conditions

[0078]

[0079] In the above embodiments, Examples 1 and 20 are parallel experiments to verify the stability and feasibility of the experiment; Examples 15 and 10 have different stirring methods, which caused the difference in results.

[0080] In all embodiments, the raw materials used were pre-mixed with 1.4% (by mass) of the chiral target product for catalytic induction. Liquid chromatography data of the reaction results were obtained using a chiral column in a normal-phase system, separating the racemic product, L-type product, and target product.

[0081] Table 1 shows the examples where experiments were conducted to verify the optimal process conditions using four variables: reaction pressure, catalyst, solvent, and reaction temperature. The optimal process conditions were determined as follows: 1. Reaction temperature of 50-60℃ was optimal; 2. Reaction pressure was controlled at approximately 0.5 MPa; 3. The optimal catalyst combination was nickel chloride and sodium carbonate, with a dosage of 2%; 4. Methanol was the optimal solvent. Changing the optimal reaction conditions significantly reduced the reaction yield, purity, and selectivity; 5. Anchor-type stirrers were used.

[0082] The above description is merely a preferred embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalents can be made within the spirit and scope defined by the claims of the present invention, all of which will fall within the protection scope of the present invention.

Claims

1. A one-pot method for synthesizing D-p-hydroxyphenylglycine, characterized in that, Includes the following steps: S1, a mixture of 4-(1-chlorovinyl)phenol and D-p-hydroxyphenylglycine is dissolved in a solvent to obtain a mixed solution, wherein the mass percentage of D-p-hydroxyphenylglycine in the mixture is 1.4%; S2, Add a catalyst to the mixed solution obtained in step S1, and react with ammonia and carbon dioxide under pressure and stirring to obtain D-p-hydroxyphenylglycine; In step S2, the catalyst is any one of the combination of nickel chloride and sodium carbonate, or the combination of nickel chloride and cesium carbonate.

2. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 1, characterized in that, In step S1, the solvent is any one or a combination of methanol, ethanol, and isopropanol.

3. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 2, characterized in that, In step S1, the solvent is methanol.

4. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 1, characterized in that, In step S2, the catalyst is a combination of nickel chloride and sodium carbonate, and the amount of catalyst used is 1-4% of the mass of 4-(1-chlorovinyl)phenol.

5. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 1, characterized in that, In step S2, the reaction pressure is 0.1-3 MPa.

6. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 5, characterized in that, In step S2, the reaction pressure is 0.5 MPa.

7. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 1, characterized in that, In step S2, the reaction temperature is 30-80℃.

8. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 7, characterized in that, In step S2, the reaction temperature is 50-60℃.

9. The method for one-pot synthesis of D-p-hydroxyphenylglycine as described in claim 1, characterized in that, In step S2, the reaction is stirred using an anchor-type stirring paddle at a speed of 200-250 r / min.

Images