A method for preparing enantiopure α-methoxyphenylacetic acid
By using (R/S)-mandelic acid as a raw material, O-alkylation reaction and purifying it with organic base into salt, the problems of expensive raw materials and difficult separation are solved, and the industrial production of enantiopure α-methoxyphenylacetic acid with high purity and high yield is achieved.
Patent Information
- Application Number
- CN202310835407.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-10
- Publication Date
- 2025-08-29
- Estimated Expiration
- 2043-07-10
AI Technical Summary
The existing enantiopure α-methoxyphenylacetic acid synthesis method is expensive, the reaction route is complex, and the separation is difficult, making it difficult to meet the needs of industrial production.
Using (R/S)-mandelic acid as the raw material, O-alkylation reaction with iodomethyl iodide under the action of alkali reagent, purified by salting of organic alkali by mixed solvents with tetrahydrofuran and sulfolane to obtain high-purity enantiopure α-methoxyphenylacetic acid.
It reduces raw material costs, simplifies the process flow, improves the yield to 88.6%, is suitable for industrial production, and has a purity of 99.0%.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing enantiopure α-methoxyphenylacetic acid, and belongs to the technical field of organic synthesis. Background Art
[0002] Enantiopure α-methoxyphenylacetic acid includes (R)-(-)-α-methoxyphenylacetic acid and (S)-(+)-α-methoxyphenylacetic acid. Enantiopure α-methoxyphenylacetic acid is primarily used in absolute stereochemistry and as a common reagent in the synthesis of chiral phosphorus ligands, with extensive applications in the pharmaceutical and materials fields. (R)-(-)-α-methoxyphenylacetic acid is a key intermediate in the anti-tumor drug darusetide (PHA-739358), an Aurora kinase inhibitor that inhibits the proliferation of breast cancer T47 cells and induces apoptosis. It also inhibits Aurora A / B / C with IC50 values of 13nM / 79nM / 61nM, respectively, against targets such as Abl, TrkA, c-RET, and FGFR1. (S)-(+)-α-methoxyphenylacetic acid, as a chiral side chain, can be used as a material for metal cation valence state sensors.
[0003] To date, various methods have been reported for synthesizing enantiopure α-methoxyphenylacetic acid. For example, [Synthesis, 1989, #1, 39-40] reported using (2S,3S)-(-)-3-phenylglycidol as a raw material, ring-opening with a Lewis acid in methanol as a solvent, and cleavage of the diol with an oxidizing agent and ruthenium trichloride hydrate to obtain (R)-(-)-α-methoxyphenylacetic acid. The reaction scheme is as follows:
[0004] This method has high raw material prices, poor economic efficiency and is not suitable for industrial-scale production.
[0005] The literature [Bioorganic and Medicinal Chemistry, 2000, 8, 1957-1968] reports using R-mandelic acid as the starting material. This material was first dissolved in a 6M aqueous sodium hydroxide solution, and dimethyl sulfate was added dropwise. The reaction was allowed to proceed at 50°C for 1 hour. After post-treatment, unreacted R-mandelic acid was recovered, and the target product, (R)-(-)-α-methoxyphenylacetic acid, was obtained in a 37% yield. This method results in incomplete reaction of the starting material, making post-processing and separation difficult. The reaction route is as follows:
[0006]
[0007] The literature [Tetrahedron Asymmetry, 2003, 14, 503-510] reports the use of (R)-(-)-2-methoxy-2-phenylethanol as a raw material, 2,2,6,6-tetramethylpiperidinyl oxide as a catalyst, and sodium hypochlorite oxidation to obtain (R)-(-)-α-methoxyphenylacetic acid in a 79% yield. This method, however, lacks readily available raw materials and produces a small amount of aldehyde, making it unsuitable for industrial production. The reaction scheme is as follows:
[0008]
[0009] The literature [Tetrahedron Asymmetry, 2005, 16, 1897-1900] reports that (R)-(-)-2-methoxy-2-phenylacetaldehyde is oxidized with sodium chlorite in a tert-butyl alcohol and sodium dihydrogen phosphate aqueous buffer system to produce (R)-(-)-α-methoxyphenylacetic acid in a 95% yield. The raw materials for this route are not readily available. The reaction scheme is as follows:
[0010]
[0011] Considering the factors of difficult availability, high cost and separation of raw materials in the above-mentioned synthesis route, it is necessary to conduct in-depth research and optimization on the synthesis process of enantiopure α-methoxyphenylacetic acid to provide a more optimal, safe and stable reaction route that is suitable for industrial production to meet the growing market demand. Summary of the Invention
[0012] To overcome these technical limitations, the present invention proposes a method for preparing enantiopure α-methoxyphenylacetic acid. Using (R / S)-mandelic acid as the main raw material, an O-alkylation reaction is carried out with a methylating agent in the presence of an alkaline reagent. Subsequently, salt formation, purification, and dissociation with an organic base are performed to obtain enantiopure α-methoxyphenylacetic acid with a purity of up to 99.0%.
[0013] By screening a methylating agent, nucleophilic agent, and solvent, the optimal reagents and reaction conditions were determined, wherein the methylating agent is iodomethane, the nucleophilic agent is potassium tert-butoxide, and the solvent is a 9:2 mixture of tetrahydrofuran and sulfolane. The present invention achieves a maximum yield of 88.6% in an aprotic mixed solvent. This process reduces the amount of methylating agent used and increases the conversion rate to 99.5%. Salt formation using an organic base provides high purification efficiency, a good crystal form, and easy filtration. The process is simple, safe, and suitable for industrial-scale production.
[0014] The method for preparing enantiopure α-methoxyphenylacetic acid of the present invention is represented by the following reaction equation:
[0015]
[0016] The steps include:
[0017] A. O-alkylation: (R / S)-mandelic acid is mixed with an aprotic mixed solvent, cooled, and then an alkaline reagent is added, followed by a methylating agent to obtain enantiomerically pure crude α-methoxyphenylacetic acid.
[0018] B. Salt Formation / Dissociation: Add an organic base to the crude enantiomerically pure α-methoxyphenylacetic acid to form a salt, filter, and add aqueous sodium hydroxide to the filter cake for dissociation. The organic base is extracted and the aqueous phase is adjusted to acidity to allow the product to precipitate, thereby obtaining enantiomerically pure α-methoxyphenylacetic acid.
[0019] Furthermore, in the above technical solution, the aprotic mixed solvent is selected from tetrahydrofuran / N,N-dimethylformamide, tetrahydrofuran / sulfolane or tetrahydrofuran / dimethyl sulfoxide mixed solvent, preferably tetrahydrofuran / sulfolane mixed solvent.
[0020] Furthermore, in the above technical solution, the methylating agent is selected from dimethyl sulfate, methyl bromide or methyl iodide, preferably methyl iodide.
[0021] Furthermore, in the above technical solution, the alkaline reagent is selected from sodium hydride, potassium tert-butoxide or sodium tert-butoxide, preferably potassium tert-butoxide.
[0022] Furthermore, in the above technical solution, the molar ratio of the (R / S)-mandelic acid, the methylating agent and the alkaline agent is 1:2.3-2.6:2.3-2.6.
[0023] Furthermore, in the above technical solution, the organic base is selected from dicyclohexylamine or diisopropylamine.
[0024] Advantageous Effects of the Invention
[0025] 1. (R / S)-mandelic acid is relatively cheap. Using it as a raw material can greatly reduce costs. The process is simple and clear, easy to operate, and avoids the use of dimethyl sulfate, which is more toxic. Purification is carried out through organic base salt formation, avoiding post-treatment column chromatography, and is suitable for industrial-scale production.
[0026] 2. Aprotic solvents (non-hydrogen bond donors) reduce the nucleophilicity of (R / S)-mandelic acid. By adding sulfolane, the reaction solubility is better and the chemical selectivity is stronger. The alkalinity of the nucleophile does not change the ee value of the product.
[0027] 3. After optimizing the solvent, nucleophilic reagent and methylating reagent, the yield is as high as 88.6%, and the organic base salt formation has the advantages of high purification efficiency, good crystal form and easy filtration. Specific embodiments
[0028] The present invention will be further described below by way of specific examples. These embodiments should be understood to be merely illustrative of the present invention and not intended to limit the scope of protection of the present invention. After reading the contents described herein, those skilled in the art may make various changes or modifications to the present invention, and these equivalent variations and modifications also fall within the scope defined by the claims of the present invention.
[0029] Condition optimization experiment
[0030] 1. Nucleophile screening
[0031] Using tetrahydrofuran as solvent and methyl iodide as methylating agent, different base reagents were selected and the relatively optimal base reagent was selected based on the conversion rate. As shown in Table 1:
[0032] Table 1 Effect of nucleophilic reagents on product conversion
[0033]
[0034] Note: All reactions were carried out at -10 to 0°C, with the nucleophile and methylating agent in equal molar ratios and both in large excess.
[0035] 2. Reaction solvent screening:
[0036] Under the conditions of potassium tert-butoxide as the base reagent and methyl iodide as the methylating reagent, different mixed solvents were selected and the optimal reaction solvent was selected based on the conversion rate. As shown in Table 2:
[0037] Table 2 Effect of mixed solvents on product conversion
[0038]
[0039]
[0040] 3. Methylation reagent screening:
[0041] Using potassium tert-butoxide as the base reagent and tetrahydrofuran / sulfolane (9:2) as the conditions, different methylation reagents were selected, and the optimal methylation reagent was selected based on the reaction conditions of the reaction solution. As shown in Table 3:
[0042] Table 3 Effect of methylation reagent on product purity
[0043]
[0044] Note: Dimethyl sulfate will produce excessive by-product methyl α-methoxyphenylacetate, which is more toxic; methyl bromide has a too low boiling point and is difficult to operate industrially.
[0045] Example 1
[0046]
[0047] Under nitrogen protection, 15.2 g (0.1 mol) of R-mandelic acid, 135 mL of tetrahydrofuran and 30 mL of sulfolane were added to the reaction flask, the temperature was lowered to -5 ° C, 11.2 g (0.1 mol) of potassium tert-butoxide was added, 34.1 g (0.24 mol) of iodomethane was added, and 15.7 g (0.14 mol) of potassium tert-butoxide was added in batches while controlling the temperature at -5 to 0 ° C. The reaction was carried out for 2 hours, the temperature was lowered to -15 ° C, and an aqueous solution of acetic acid was added to adjust the pH to 6.8. The mixture was allowed to stand for stratification, the lower aqueous layer was removed, and the organic layer was concentrated under reduced pressure until it was no longer liquid. 50 mL of dichloromethane was added, and the organic phase was washed with water. 18.1 g (0.1 mol) of dicyclohexylamine was added to the organic phase, and the temperature was lowered to -5 to 0°C. Methyl tert-butyl ether was added, and a white solid precipitated. The mixture was filtered, and the filter cake was returned to the kettle. 70 mL of methyl tert-butyl ether was added, and 5% sodium hydroxide was added to adjust the pH to 12-13. The mixture was allowed to stand and separate into layers. The aqueous layer was retained, and 5% hydrochloric acid was slowly added to the aqueous phase to adjust the pH to 2-3. A white solid precipitated and was filtered to obtain 14.6 g of (R)-(-)-α-methoxyphenylacetic acid. The yield was 87.9%, and the HPLC result was 99.3%. 1 H-NMR(400MHz, CDCl3):8.89(s,1H),7.54-7.41(m,2H),7.39-7.28(m,3H),4.53(s,1H),3.47(s,3H).
[0048] Example 2
[0049]
[0050] Under nitrogen protection, 15.2 g (0.1 mol) of S-mandelic acid, 135 mL of tetrahydrofuran and 30 mL of sulfolane were added to the reaction flask, the temperature was lowered to -5 ° C, 11.2 g (0.1 mol) of potassium tert-butoxide was added, 34.1 g (0.24 mol) of iodomethane was added, and 15.7 g (0.14 mol) of potassium tert-butoxide was added in batches while controlling the temperature at -5 to 0 ° C. The reaction was carried out for 2 hours, the temperature was lowered to -15 ° C, and an aqueous acetic acid solution was added to adjust the pH to 6.8. The mixture was allowed to stand for stratification, the lower aqueous layer was removed, and the organic layer was concentrated under reduced pressure until it was no longer liquid. 50 mL of dichloromethane was added, and the organic phase was washed with water. 10.1 g (0.1 mol) of diisopropylamine was added to the organic phase, and the temperature was lowered to -5 to 0°C. Methyl tert-butyl ether was added, and a white solid precipitated. The mixture was filtered, and the filter cake was returned to the kettle. 70 mL of methyl tert-butyl ether was added, and 5% sodium hydroxide was added to adjust the pH to 12-13. The mixture was allowed to stand and separate into layers. The aqueous layer was retained, and 5% hydrochloric acid was slowly added to the aqueous phase to adjust the pH to 2-3. A white solid precipitated and was filtered to obtain 14.1 g of (S)-(-)-α-methoxyphenylacetic acid. The yield was 84.9%, and the HPLC result was 99.1%. 1H-NMR (400MHz, CDCl3): 8.86 (s, 1H), 7.51-7.42 (m, 2H), 7.40-7.28 (m, 3H), 4.57 (s, 1H), 3.42 (s, 3H).
[0051] Example 3
[0052]
[0053] Under nitrogen protection, 15.2 g (0.1 mol) of R-mandelic acid, 120 mL of tetrahydrofuran and 15 mL of dimethyl sulfoxide were added to the reaction flask, the temperature was lowered to -5 ° C, 11.2 g (0.1 mol) of potassium tert-butoxide was added, 34.1 g (0.24 mol) of iodomethane was added, and 15.7 g (0.14 mol) of potassium tert-butoxide was added in batches while controlling the temperature at -5 to 0 ° C. The reaction was carried out for 2 hours, the temperature was lowered to -15 ° C, and an aqueous solution of acetic acid was added to adjust the pH to 6.8. The mixture was allowed to stand for stratification, the lower aqueous layer was removed, and the organic layer was concentrated under reduced pressure until it was no longer liquid. , 50 mL of dichloromethane was added, the organic phase was washed with water, 10.1 g (0.1 mol) of diisopropylamine was added to the organic phase, the temperature was lowered to -5 to 0°C, methyl tert-butyl ether was added, a white solid precipitated, filtered, the filter cake was put back into the kettle, 70 mL of methyl tert-butyl ether was added, 5% sodium hydroxide was added to adjust the pH to 12-13, the reaction mixture was allowed to stand and separate, the aqueous layer was retained, 5% hydrochloric acid was slowly added to the aqueous phase to adjust the pH to 2-3, a white solid precipitated, and 13.3 g of (R)-(-)-α-methoxyphenylacetic acid was obtained by filtration, with a yield of 80.3% and an HPLC index of 99.6%.
[0054] Example 4
[0055]
[0056] Under nitrogen protection, 15.2 g (0.1 mol) of S-mandelic acid, 150 mL of tetrahydrofuran and 15 mL of dimethyl sulfoxide were added to the reaction flask, the temperature was lowered to -5 ° C, 11.2 g (0.1 mol) of potassium tert-butoxide was added, 34.1 g (0.24 mol) of iodomethane was added, and 15.7 g (0.14 mol) of potassium tert-butoxide was added in batches at a temperature of -5 to 0 ° C. The reaction was carried out for 2 hours, the temperature was lowered to -15 ° C, and an aqueous solution of acetic acid was added to adjust the pH to 6.8. The mixture was allowed to stand for stratification, the lower aqueous layer was removed, and the organic layer was concentrated under reduced pressure until it was no longer liquid. , 50 mL of dichloromethane was added, the organic phase was washed with water, 18.1 g (0.1 mol) of dicyclohexylamine was added to the organic phase, the temperature was lowered to -5 to 0°C, methyl tert-butyl ether was added, a white solid precipitated, filtered, the filter cake was put back into the kettle, 70 mL of methyl tert-butyl ether was added, 5% sodium hydroxide was added to adjust the pH to 12-13, the reaction mixture was allowed to stand and separate, the aqueous layer was retained, 5% hydrochloric acid was slowly added to the aqueous phase to adjust the pH to 2-3, a white solid precipitated, and 13.5 g of (S)-(-)-α-methoxyphenylacetic acid was obtained by filtration, with a yield of 81.1% and an HPLC index of 99.6%.
[0057] Example 5
[0058] Kilogram-level experiment
[0059]
[0060] Under nitrogen protection, 2.0 kg of R-mandelic acid, 8 L of tetrahydrofuran and 4 L of sulfolane were added to a stainless steel autoclave, the temperature was lowered to -8 ° C, 1.606 kg of potassium tert-butoxide was added in batches, 34.1 g (0.24 mol) of iodomethane was added, and the temperature was controlled at -5 to 0 ° C. A solution of 2.065 kg of potassium tert-butoxide dissolved in 10 L of tetrahydrofuran was slowly added dropwise. After the addition was completed, the reaction was allowed to proceed for 2 hours, and then the temperature was lowered to -20 ° C. An aqueous solution of acetic acid was quickly added to adjust the pH to 6.8. The mixture was allowed to stand and the layers were separated. The lower aqueous layer was removed, and the organic layer was concentrated under reduced pressure until it did not flow, and 7 L of dichloromethane was added. The organic phase was washed with water and replaced with dichloromethane by concentrating under reduced pressure to a water content of <0.1%. 2.383 kg of dicyclohexylamine was added and the temperature was lowered to -5 to 0°C. Methyl tert-butyl ether was added to precipitate a white solid, which was filtered. The filter cake was returned to the kettle and 10 L of methyl tert-butyl ether was added. 5% sodium hydroxide was added to adjust the pH to 12-13. The mixture was allowed to stand and separate into layers. The aqueous layer was retained. 5% hydrochloric acid was slowly added to the aqueous phase to adjust the pH to 2-3. A white solid precipitated and was filtered to obtain 1.935 kg of (R)-(-)-α-methoxyphenylacetic acid in a yield of 88.6%. HPLC analysis showed 99.5%.
[0061] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.
Claims
1. A method for preparing enantiomerically pure α-methoxyphenylacetic acid, characterized in that: The steps include: O-alkylation: R-mandelic acid or S-mandelic acid is mixed with an aprotic mixed solvent, cooled, and then an alkaline reagent is added, followed by a methylating agent to obtain an enantiomerically pure crude α-methoxyphenylacetic acid; the aprotic mixed solvent is selected from a tetrahydrofuran / sulfolane mixed solvent; the methylating agent is selected from iodomethane; and the alkaline agent is selected from potassium tert-butoxide; Salt formation / dissociation: Add an organic base to the crude enantiomerically pure α-methoxyphenylacetic acid to form the salt, filter, and add aqueous sodium hydroxide to the filter cake for dissociation. The organic base is extracted and the aqueous phase is adjusted to acidity to precipitate the product to obtain enantiomerically pure α-methoxyphenylacetic acid.
2. The method for preparing enantiomerically pure α-methoxyphenylacetic acid according to claim 1, characterized in that: The molar ratio of R-mandelic acid or S-mandelic acid, methylating agent and alkaline agent is 1: 2.3-2.6: 2.3-2.
6.
3. The method for preparing enantiomerically pure α-methoxyphenylacetic acid according to claim 1, characterized in that: The organic base is selected from dicyclohexylamine or diisopropylamine.