A process for the asymmetric synthesis of (s)-3-(4-hydroxyphenyl)pentanoic acid

Abstract

The application relates to the technical field of drug intermediate synthesis, in particular to an asymmetric synthesis method of (S)-3-(4-hydroxyphenyl) pentanoic acid, which comprises the following steps: S1, obtaining (E)-3-(4-acetyloxyphenyl) acrylic acid; S2, obtaining (S, E)-4-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl) phenyl acetate; S3, obtaining 4-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-oxopentan-3-yl) phenyl acetate; and S4, obtaining (S)-3-(4-hydroxyphenyl) pentanoic acid. The synthesis method is safe in reaction, small in pollution, easy to industrialized production, and high in yield, and provides a good synthesis path for synthesizing (S)-3-(4-hydroxyphenyl) pentanoic acid.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and more specifically, to an asymmetric synthesis method for (S)-3-(4-hydroxyphenyl)valerate. Background Technology

[0002] (S)-3-(4-hydroxyphenyl)valerate is a possible key intermediate structure that may be used in novel drug structures, and its structural formula is shown in formula (I).

[0003] (I) Furthermore, in the prior art, for example EP2963027, potential drugs containing this structure have been reported for the intervention and treatment of GPR40-related diseases, and their structural formula is shown in formula (II) below.

[0004] (II) Furthermore, WO2008130514 also reported a potential drug containing this structure, which may be used for diabetes-related diseases, and its structural formula is shown in formula (III) below.

[0005] (III) Currently, the reported synthetic methods for (S)-3-(4-hydroxyphenyl)valerate are primarily achiral synthetic methods. After synthesizing the racemic product, the optically synthesized compound is obtained through chiral preparative chromatography or chemical resolution. For example, Bioorganic & Medicinal Chemistry Letters 22 (2012) 1267–1270 discloses a method for synthesizing racemic 3-(4-hydroxyphenyl)valerate (synthetic route 1).

[0006] While these methods are suitable for small-scale synthesis, their synthetic mechanisms limit yields to no more than 50%. This means that more than half of the materials are wasted, resulting in low production costs and efficiency, making them unsuitable for industrial-scale preparation. Furthermore, existing methods also generate waste. These drawbacks prevent this method from being used for the large-scale, economical synthesis of optically pure 3-(4-hydroxyphenyl)valerate compounds. Summary of the Invention

[0007] The purpose of this invention is to provide a synthetic process route that is high-yield, safe, low-polluting, and easy to industrialize. This method introduces chiral building blocks to induce an increase in the proportion of the desired chiral molecules, providing a promising approach for the synthesis of this compound and similar compounds.

[0008] To achieve the above objectives, the present invention provides the following technical solution: An asymmetric synthesis method for (S)-3-(4-hydroxyphenyl)valerate, the synthesis method comprising the following steps: S1. (E)-3-(4-hydroxyphenyl)acrylic acid, 4-dimethylaminopyridine, pyridine and dichloromethane solution were added sequentially to the reaction flask. After cooling, acetic anhydride was added dropwise. After the reaction, the solvent was removed by vacuum distillation. Deionized water was added and the reaction was cooled. Then hydrochloric acid was added to precipitate the solid. After filtration and drying, (E)-3-(4-acetoxyphenyl)acrylic acid was obtained. S2. (E)-3-(4-acetoxyphenyl)acrylic acid, N,N-dimethylformamide and dichloromethane solution are added sequentially to the reaction flask. After cooling, oxaloyl chloride is added dropwise. After the reaction, the solvent is removed by vacuum evaporation to obtain intermediate acyl chloride. The intermediate acyl chloride is dissolved in dichloromethane solution to form acyl chloride reaction solution. Triethylamine and (S)-4-benzyl-2-oxazolidinone were dissolved in dichloromethane solution, and then acyl chloride reaction solution was added dropwise. After the reaction, the mixture was washed with water to separate the layers, the solvent was evaporated from the obtained organic phase, ethanol was added, the mixture was slurried, filtered, and dried to obtain (S,E)-4-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate; S3. In a reaction flask, add ultra-dry tetrahydrofuran solution and cuprous dimethyl sulfide bromide in sequence. After cooling, add ethyl magnesium bromide solution to the reaction flask to carry out the reaction. Dissolve (S,E)-4-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate in ultra-dry tetrahydrofuran and add it dropwise to the reaction flask. Adjust the pH value with citric acid monohydrate. After the reaction solution returns to room temperature, add ethyl acetate. After filtration, wash the filtrate with deionized water. After removing the solvent from the obtained organic phase under reduced pressure, the crude product is obtained. The crude product is purified by column chromatography with ethyl acetate and n-heptane to obtain 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenyl acetate. S4. Tetrahydrofuran solution, deionized water, lithium hydroxide monohydrate, and hydrogen peroxide were added sequentially to the reaction flask. After the reaction was cooled, a tetrahydrofuran solution containing 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenylacetic acid ester was added to the reaction flask. After stirring the reaction, the pH was adjusted, and the reaction solution was extracted until no product residue was found in the aqueous layer. The combined organic layers were washed with sodium chloride aqueous solution, concentrated, and dried to obtain the crude product. The crude product was purified by column chromatography using a mixed solvent of ethyl acetate and n-heptane to obtain (S)-3-(4-hydroxyphenyl)pentanoic acid.

[0009] Preferably, in step S1, the mass ratio of (E)-3-(4-hydroxyphenyl)acrylic acid, 4-dimethylaminopyridine, pyridine, and acetic anhydride is 1:(0.05~0.08):(0.4~0.5):(0.6~0.7).

[0010] Preferably, the mass-to-volume ratio of (E)-3-(4-hydroxyphenyl)acrylic acid, dichloromethane solution to deionized water is 1:(8~12):(0.4~0.6).

[0011] Preferably, in step S2, the mass ratio of (E)-3-(4-acetoxyphenyl)acrylic acid, N,N-dimethylformamide, and oxaloyl chloride is 1:(0.002~0.004):(0.6~0.7).

[0012] Preferably, the mass-to-volume ratio of (E)-3-(4-acetoxyphenyl)acrylic acid to dichloromethane solution is 1:(8~12).

[0013] Preferably, in step S2, the mass-to-volume ratio of triethylamine, (S)-4-benzyl-2-oxazolidinone, and dichloromethane solution is 1:(1.5~2.0):(9~10).

[0014] Preferably, in step S3, the mass-to-volume ratio of cuprous dimethyl sulfide bromide, ultra-dry tetrahydrofuran solution, and ethyl magnesium bromide solution is 1:(5~6):(9~10).

[0015] Preferably, the mass-to-volume ratio of (S,E)-4-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)acetic acid phenyl ester to ultra-dry tetrahydrofuran is 1:(4~6).

[0016] Preferably, in step S4, the mass-volume ratio of lithium hydroxide monohydrate, hydrogen peroxide, tetrahydrofuran solution, and deionized water is 1:(2.5~3):(12~16):(4~5).

[0017] Compared with the prior art, the beneficial effects of the present invention are: This invention uses inexpensive (E)-3-(4-hydroxyphenyl)acrylic acid (compound 1), which is supplied in large quantities and stably, as a raw material. After protection of the phenolic hydroxyl group, (E)-3-(4-acetoxyphenyl)acrylic acid (compound 2) is obtained. Compound 2 undergoes an oxalyl chloride reaction to generate an acyl chloride intermediate, which is then reacted with (S)-4-benzyl-3-acetyl-2-oxazolidinone to obtain (S,E)-4-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate (compound 3); (S,E)-4-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate (compound 3) and ethyl... Magnesium bromide undergoes an asymmetric addition reaction to yield 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenylacetate (compound 4); 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenylacetate (compound 4) is completely hydrolyzed and protected to give the final product, which is then reacted with ethyl magnesium bromide via an asymmetric addition reaction to yield (S)-3-(4-hydroxyphenyl)valerate (compound 5). This synthetic method is safe, low-polluting, easy to industrialize, and has a high yield, providing a good synthetic route for the synthesis of (S)-3-(4-hydroxyphenyl)valerate. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the synthesis path 1 of the existing synthesis method; Figure 2 This is a schematic diagram of the synthesis route 2 of the synthesis method of the present invention (subscripts 1-5 in the figure represent compounds 1-5 respectively); Figure 3 The hydrogen nuclear magnetic resonance spectrum of the product (compound 3) generated in the embodiments of the present invention; Figure 4 The hydrogen nuclear magnetic resonance spectrum of the product (compound 4) generated in the embodiments of the present invention; Figure 5 The image shows the hydrogen nuclear magnetic resonance spectrum of the product (compound 5) generated in the embodiments of the present invention. Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] Please see Figures 1-5 The present invention provides a technical solution: Example: An asymmetric synthesis method for (S)-3-(4-hydroxyphenyl)valerate. 1. Preparation of (E)-3-(4-acetoxyphenyl)acrylic acid (compound 2) In a 1000 ml reaction flask, 50.33 g of (E)-3-(4-hydroxyphenyl)acrylic acid (compound 1), 500 ml of dichloromethane, 3.72 g of 4-dimethylaminopyridine, and 25.30 g of pyridine were added. The mixture was cooled to 10 °C, and 34.20 g of acetic anhydride was added dropwise. After reacting at room temperature for 16 hours, the solvent was removed by vacuum distillation, and 250 mL of water was added. The mixture was stirred at room temperature for half an hour, then cooled to 0 °C, and 50 mL of hydrochloric acid was added. Subsequently, a large amount of solid precipitated. The solid was filtered and washed with 50 mL of water to obtain a white solid powder. This powder was dried at 55 °C for 16 hours to obtain 55 g of product (E)-3-(4-acetoxyphenyl)acrylic acid (compound 2), with a yield of 87% and a purity of 98%.

[0021] 1 H-NMR (400MHz, CDOD): 7.68 (d, 1H), 7.64 (d, 2H), 7.16 (d, 2H), 6.47 (d, 1H), 2.27 (s, 3H).

[0022] 2. Preparation of (S, E)-4-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate (compound 3) In a 250 mL reaction flask, 9.0 g of (E)-3-(4-acetoxyphenyl)acrylic acid, 90 mL of dichloromethane, and 0.032 g of N,N-dimethylformamide were added. The mixture was cooled to 0 °C, and 5.82 g of oxaloyl chloride was added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 hour. The solvent was evaporated to obtain the intermediate acyl chloride, which was then dissolved in 90 mL of dichloromethane for later use.

[0023] 4.64 g of triethylamine and 8.12 g of (S)-4-benzyl-2-oxazolidinone were dissolved in 45 mL of dichloromethane. The reaction mixture was stirred at 0 °C, and then the acyl chloride reaction solution prepared in the previous step was added dropwise. After stirring at 0 °C for 1 hour, the mixture was heated to room temperature. The reaction mixture was washed with 90 mL of water to separate the layers. The solvent in the obtained organic phase was evaporated, and 22.5 mL of ethanol was added. The mixture was stirred at 10 °C for 1 hour and filtered to obtain a white solid powder. The powder was dried at 50 °C for 16 hours to obtain 10.8 g of product (S, E)-4-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)acetic acid phenyl ester (compound 3), with a yield of 67.7% and a purity of 96%.

[0024] 1 H-NMR (400MHz, d-DMSO): 7.82 (m, 4H), 7.75 (m, 7H), 4.80 (m, 1H), 4.39 (t, 1H). 4.25 (dd, 1H). 3.08 (m, 2H). 2.29 (s, 3H).

[0025] Preparation of 3,4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenylacetate (compound 4) In a 100 mL reaction flask, add 10 mL of ultra-dry tetrahydrofuran and 1.69 g of cuprous dimethyl sulfide bromide. Cool the reaction solution to -30°C. At -30°C, slowly add 16.42 mL of 1M ethyl magnesium bromide to the reaction flask. After stirring the reaction solution at -30°C for half an hour, dissolve 2.0 g of (S,E)-4-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate in 10 mL of ultra-dry tetrahydrofuran and then add it dropwise to the reaction flask. After stirring the reaction solution at -30°C for one hour, the pH of the reaction solution was adjusted to 5 with 10% citric acid monohydrate aqueous solution. The reaction solution was brought back to room temperature, 20 mL of ethyl acetate was added, and the solid impurities were removed by filtration. The filtrate was washed with 20 mL of water, and the solvent was removed by vacuum distillation of the obtained organic phase to obtain the crude product. The crude product was purified by column chromatography with ethyl acetate and n-heptane to obtain 1.65 g of the off-white solid product 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenylacetate (compound 4).

[0026] Yield 76%, purity 98%, diastereomer ratio 70:30.

[0027] 1 H-NMR (400MHz, CDCl3): 7.25 (m, 6H), 7.05 (m, 3H), 4.60 (m, 1H), 4.13(m, 1H) 3.50 (m, 1H) 3.20 (m, 3H) 2.60 (m,1H) 2.27 (s, 3H). 1.6 (m, 3H), 0.84 (m, 3H).

[0028] 4. Preparation of (S)-3-(4-hydroxyphenyl)valeric acid (compound 5) In a 250 mL reaction flask, 100 mL of tetrahydrofuran, 30 mL of water, 6.4 g of lithium hydroxide monohydrate, and 18 g of 30% hydrogen peroxide were added. The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 10°C. Next, 10 g of a tetrahydrofuran solution of 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenylacetate (compound 4) was slowly added to the flask. After stirring the reaction mixture at room temperature for 2 hours, sodium sulfite aqueous solution was added to quench the peroxide until the starch-potassium iodide test paper showed no color change. The pH was adjusted to 3 with 0.5 M dilute hydrochloric acid aqueous solution. The reaction mixture was then extracted three times with ethyl acetate until no product residue remained in the aqueous layer. The combined organic layers were washed twice with sodium chloride aqueous solution and then concentrated to dryness under reduced pressure to obtain crude compound 5. The crude compound was purified by column chromatography with a mixture of ethyl acetate and n-heptane to give 4.3 g of the compound. Class g white solid product (S)-3-(4-hydroxyphenyl)valerate (compound 5).

[0029] Yield 89%, purity 96%, diastereomer ratio 70:30.

[0030] The chiral purity of the product can be further improved by salting (1S,2R)-(-)-1-amino-2-indanol in acetonitrile, removing unwanted isomers and obtaining (S)-3-(4-hydroxyphenyl)valerate (compound 5) with optical purity greater than 99%.

[0031] 1 H-NMR (400MHz, CDCl3): 11.90 (bs, 1H), 9.12 (s, 1H), 6.98-6.96 (d,2H), 6.67-6.65 (d, 2H), 2.76 (m, 1H), 2.67 (m, 1H), 2.34 (m, 1H), 1.58 (m,1H), 1.46 (m, 1H), 0.69 (t, 3H).

[0032] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. An asymmetric synthesis method for (S)-3-(4-hydroxyphenyl)pentanoic acid, characterized in that, The synthesis method includes the following steps: S1. (E)-3-(4-hydroxyphenyl)acrylic acid, 4-dimethylaminopyridine, pyridine and dichloromethane solution were added sequentially to the reaction flask. After cooling, acetic anhydride was added dropwise. After the reaction, the solvent was removed by vacuum distillation. Deionized water was added and the reaction was cooled. Then hydrochloric acid was added to precipitate the solid. After filtration and drying, (E)-3-(4-acetoxyphenyl)acrylic acid was obtained. S2. (E)-3-(4-acetoxyphenyl)acrylic acid, N,N-dimethylformamide and dichloromethane solution are added sequentially to the reaction flask. After cooling, oxaloyl chloride is added dropwise. After the reaction, the solvent is removed by vacuum evaporation to obtain intermediate acyl chloride. The intermediate acyl chloride is dissolved in dichloromethane solution to form acyl chloride reaction solution. Triethylamine and (S)-4-benzyl-2-oxazolidinone were dissolved in dichloromethane solution, and then acyl chloride reaction solution was added dropwise. After the reaction, the mixture was washed with water to separate the layers, the solvent was evaporated from the obtained organic phase, ethanol was added, the mixture was slurried, filtered, and dried to obtain (S,E)-4-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate; S3. In a reaction flask, add ultra-dry tetrahydrofuran solution and cuprous dimethyl sulfide bromide in sequence. After cooling, add ethyl magnesium bromide solution to the reaction flask to carry out the reaction. Dissolve (S,E)-4-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)phenyl acetate in ultra-dry tetrahydrofuran and add it dropwise to the reaction flask. Adjust the pH value with citric acid monohydrate. After the reaction solution returns to room temperature, add ethyl acetate. After filtration, wash the filtrate with deionized water. After removing the solvent from the obtained organic phase under reduced pressure, the crude product is obtained. The crude product is purified by column chromatography with ethyl acetate and n-heptane to obtain 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenyl acetate. S4. Tetrahydrofuran solution, deionized water, lithium hydroxide monohydrate, and hydrogen peroxide were added sequentially to the reaction flask. After the reaction was cooled, a tetrahydrofuran solution containing 4-((S)-1-((S)-4-benzyl-2-oxooxazolidine-3-yl)-1-oxopentane-3-yl)phenylacetic acid ester was added to the reaction flask. After stirring the reaction, the pH was adjusted, and the reaction solution was extracted until no product residue was found in the aqueous layer. The combined organic layers were washed with sodium chloride aqueous solution, concentrated, and dried to obtain the crude product. The crude product was purified by column chromatography using a mixed solvent of ethyl acetate and n-heptane to obtain (S)-3-(4-hydroxyphenyl)pentanoic acid.

2. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, In step S1, the mass ratio of (E)-3-(4-hydroxyphenyl)acrylic acid, 4-dimethylaminopyridine, pyridine, and acetic anhydride is 1:(0.05~0.08):(0.4~0.5):(0.6~0.7).

3. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, The mass-to-volume ratio of the (E)-3-(4-hydroxyphenyl)acrylic acid, dichloromethane solution to deionized water is 1:(8~12):(0.4~0.6).

4. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, In step S2, the mass ratio of (E)-3-(4-acetoxyphenyl)acrylic acid, N,N-dimethylformamide, and oxaloyl chloride is 1:(0.002~0.004):(0.6~0.7).

5. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, The mass-to-volume ratio of the (E)-3-(4-acetoxyphenyl)acrylic acid to dichloromethane solution is 1:(8~12).

6. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, In step S2, the mass-to-volume ratio of triethylamine, (S)-4-benzyl-2-oxazolidinone, and dichloromethane solution is 1:(1.5~2.0):(9~10).

7. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, In step S3, the mass-volume ratio of cuprous dimethyl sulfide bromide, ultra-dry tetrahydrofuran solution, and ethyl magnesium bromide solution is 1:(5~6):(9~10).

8. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, The mass-to-volume ratio of (S,E)-4-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)acetic acid phenyl ester to ultra-dry tetrahydrofuran is 1:(4~6).

9. The asymmetric synthesis method of (S)-3-(4-hydroxyphenyl)pentanoic acid according to claim 1, characterized in that, In step S4, the mass-volume ratio of lithium hydroxide monohydrate, hydrogen peroxide, tetrahydrofuran solution, and deionized water is 1:(2.5~3):(12~16):(4~5).

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