A process for the preparation of (S)-2-(4-bromophenyl)propionic acid

Abstract

The application discloses a preparation method of (S)-2-(4-bromophenyl)propionic acid. In the presence of an organic solvent and a buffer solution, a substrate is subjected to asymmetric hydrolysis reaction under the catalysis of a hydrolytic enzyme to generate product (S)-2-(4-bromophenyl)propionic acid. Compared with the prior art, the method provided by the application can adapt to industrial scale production under the premise of maintaining high enantioselectivity, and can ensure the safety of the reaction, reduce the cycle and cost, and achieve green environmental protection.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical synthesis technology, and in particular to a method for preparing (S)-2-(4-bromophenyl)propionic acid. Background Technology

[0002] (S)-2-(4-bromophenyl)propionic acid is an important chemical intermediate widely used in various pharmaceutical synthesis processes (such as cyclin-dependent kinases CDK 12 / 13 or cathepsin K inhibitors). The structure of (S)-2-(4-bromophenyl)propionic acid is as follows:

[0003]

[0004] Currently, there are four main methods for preparing (S)-2-(4-bromophenyl)propionic acid in existing technologies:

[0005] (1) A single chiral isomer can be synthesized asymmetrically with chiral phosphine ligands via metal catalysts (such as Pd, Ni), but there is heavy metal pollution and the enantioselectivity is not high (85%~91% ee).

[0006] (2) The disproportionation reaction of aldehydes is catalyzed by horse liver dehydrogenase, but the reaction volume is large and it is not suitable for large-scale production. Moreover, the enantioselectivity excess value is only 84%.

[0007] (3) For example, the invention patent with application number CN202080026783.4 entitled “Substituted 5-cyclopropyl-1H-pyrazole-3-yl-amine derivative as a selective CDK12 / 13 inhibitor” uses chiral oxazolidinone (Evans cofactor) or chiral alcohol to induce the synthesis of a single configuration amide or ester. However, this method requires the use of the dangerous reagent hydrogen peroxide when removing the product, which can easily pose a great threat to laboratory safety or production safety.

[0008] (4) For example, in the US invention patent with application number US7312353 entitled “Sandwich Cysteine ​​Protease Inhibitor”, a chemical resolution method is used. This method requires first reacting with a chiral amine to synthesize a salt, and then alkalizing the free side to finally obtain a single configuration. However, the overall reaction cycle of this method is long, and it may require multiple resolutions to obtain a qualified chiral isomer.

[0009] Therefore, there is a need in the field for a method to prepare (S)-2-(4-bromophenyl)propionic acid that can be adapted to industrial scale-up production while maintaining high enantioselectivity, ensuring reaction safety, reducing cycle time and cost, and being green and environmentally friendly. Summary of the Invention

[0010] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0011] A method for preparing (S)-2-(4-bromophenyl)propionic acid involves an asymmetric hydrolysis reaction of a substrate under the catalysis of a hydrolytic enzyme in the presence of an organic solvent and a buffer solution to generate the product (S)-2-(4-bromophenyl)propionic acid. The steps of the preparation method are as follows:

[0012] S1. Add organic solvent, buffer solution, substrate and hydrolytic enzyme to the reactor, adjust the pH of the reaction system and keep it at 6.0-8.0, and carry out the asymmetric hydrolysis reaction at 20℃-35℃ for 20-33 hours.

[0013] S2. Adjust the pH value to 9, filter and extract the reaction solution, then adjust the pH of the aqueous phase to 3 and extract again. Combine the organic phases, remove water and concentrate to obtain the crude product.

[0014] S3. The crude product is pulped, filtered and dried to obtain the pure product;

[0015] S4. Methyl (R)-2-(4-bromophenyl)propionate is recovered from the reaction solution and racemized;

[0016] S5. Using racemic (R)-2-(4-bromophenyl)propionate methyl ester as a substrate, repeat steps S1, S2, and S3 to obtain the pure product (S)-2-(4-bromophenyl)propionate.

[0017] Specifically, the substrate is selected from methyl 2-(4-bromophenyl)propionate or its ester derivatives.

[0018] Specifically, the hydrolytic enzyme is selected from lipases, esterases, or proteases.

[0019] Specifically, the organic solvent is selected from one or more of dimethyl sulfoxide, dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, 1,4-dioxane, tetrahydrofuran, isopropyl ether, methyl tertiary ether, n-hexane, and n-heptane, or a mixture thereof.

[0020] Preferably, the organic solvent is selected from one or a mixture of isopropyl ether, n-hexane, and n-heptane.

[0021] Specifically, the buffer solution is a buffer solution that can buffer within the pH range of 6.0-8.0.

[0022] Preferably, the buffer solution is a phosphate buffer solution.

[0023] Specifically, the phosphate buffer solution has a molar concentration of 0.1-0.3 mol / L and a pH value of 6.0-8.0.

[0024] Specifically, the pH value of the asymmetric hydrolysis reaction is adjusted using a sodium hydroxide solution with a concentration of 0.5 mol / L or 1.0 mol / L.

[0025] Specifically, in S2, the filtration refers to using diatomaceous earth to filter the reaction solution to remove enzyme proteins, the extractant for extraction is ethyl acetate, and the dehydrating agent is anhydrous sodium sulfate.

[0026] Specifically, in step S3, the solvent for pulping is methyl ether, and the volume of the methyl ether is 0.5 times that of the crude product.

[0027] The beneficial effects of this invention include:

[0028] (1) The reaction process of the present invention is reasonably designed and uses a hydrolytic enzyme catalysis method to efficiently prepare (S)-2-(4-bromophenyl)propionic acid. Compared with the prior art, the preparation method provided by the present invention can prepare a single configuration of carboxylic acid from a racemic mixture in one step, achieving a higher substrate concentration (100 g / L) and a larger reaction scale (greater than 50 kg), and obtaining (S)-2-(4-bromophenyl)propionic acid with higher enantioselectivity.

[0029] (2) The reaction method provided by the present invention increases the overall reaction yield to 68% by recovering methyl (R)-2-(4-bromophenyl)propionate, racing it, and then enzymatically hydrolyzing it again, thus avoiding the waste of chemical raw materials. In addition, the method provided by the present invention uses inexpensive and readily available raw materials, thereby reducing the reaction cost.

[0030] (3) Compared with the asymmetric synthesis method, the preparation method provided by the present invention has mild reaction conditions, is green and environmentally friendly, avoids the use of dangerous reagents H2O2 and metal catalysts, and ensures safety in the laboratory or production.

[0031] (4) Compared with chemical resolution, the preparation method provided by the present invention significantly improves the product yield and shortens the reaction cycle.

[0032] (5) Compared with the disproportionation reaction of aldehydes catalyzed by horse liver alcohol dehydrogenase, the preparation method of the present invention can adapt to a larger concentration of reaction substrates, is more suitable for industrial scale-up production, and has significantly improved practicality. Attached Figure Description

[0033] Figure 1 The synthetic route of (S)-2-(4-bromophenyl)propionic acid of the present invention is shown below;

[0034] In the figure, LDA is lithium diisopropylamino, MeI is iodomethane, and MeONa is sodium methoxide. Detailed Implementation

[0035] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. 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.

[0036] In all the following embodiments, the correspondence between the English abbreviations and Chinese names of the relevant chemical reagents is as follows:

[0037] THF stands for tetrahydrofuran, LDA stands for lithium diisopropylaminodimethylamine, MeI stands for methyl iodoform, and NaOH stands for sodium hydroxide.

[0038] Example 1 Synthesis of the reaction substrate methyl 2-(4-bromophenyl)propionate

[0039] The preparation method provided by this invention, the synthesis process of the reaction substrate methyl 2-(4-bromophenyl)propionate is as follows:

[0040]

[0041] The method for obtaining the substrate methyl 2-(4-bromophenyl)propionate in this invention is as follows: THF (232 L) was added to a 1000 L reactor, and compound 1 (58 kg) was added to the reactor. The mixture was cooled to -78°C, and under nitrogen protection, LDA (2.00 M, 143 L) was added dropwise to the 1000 L reactor. After the addition was complete, the reaction was carried out at -60 to -78°C for 0.5 hours. MeI (40.9 kg) was added dropwise to the reaction system. After the addition was complete, the temperature was raised to 25°C, and the reaction was continued at this temperature for 12 hours. The reaction was quenched with 60 L of ammonium chloride aqueous solution, and the temperature was maintained below 25°C while stirring was continued for 0.5 hours. The mixture was extracted with ethyl acetate (60 L*2), the organic phases were combined, and the mixture was evaporated to dryness to obtain crude compound 2 (58 kg), which was directly used for the synthesis of the next product (S)-2-(4-bromophenyl)propionic acid.

[0042] Example 2: Synthesis of (S)-2-(4-bromophenyl)propionic acid using n-hexane as an organic solvent

[0043] like Figure 1The synthetic route shown involves adding 80 mL of 0.1 mol / L phosphate buffer to a clean 250 mL glass-jacketed reaction flask, weighing 0.5 g of lipase, and stirring until homogeneous. The reaction system is maintained at 30°C. A 20 mL solution of n-hexane is added dropwise to initiate the reaction. During the reaction, the pH is maintained at approximately 7 using 0.5 mol / L NaOH solution. The reaction is terminated after 20 hours, and the pH is adjusted to 9. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, and the filtrate is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 3 and extracted with ethyl acetate. The resulting organic phases are combined, anhydrous sodium sulfate is added to remove water, and the mixture is filtered again to obtain the organic phase. The organic phase is then concentrated under reduced pressure to obtain 4.9 g of crude (S)-2-(4-bromophenyl)propionic acid. The crude product was then pulped and filtered with 0.5 times its volume of methyl ether, and the filter cake was dried to obtain 4.7 g of pure (S)-2-(4-bromophenyl)propionic acid.

[0044] Example 3: Synthesis of (S)-2-(4-bromophenyl)propionic acid using n-heptane as an organic solvent.

[0045] like Figure 1 The synthetic route shown involves adding 80 mL of 0.1 mol / L phosphate buffer to a clean 250 mL glass-jacketed reaction flask, weighing 0.5 g of lipase, and stirring until homogeneous. The reaction system is maintained at 30°C. A 20 mL solution of n-heptane is added dropwise to initiate the reaction. During the reaction, the pH is maintained at approximately 7 using 0.5 mol / L NaOH solution. The reaction is terminated after 22 hours, and the pH is adjusted to 9. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, and the filtrate is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 3 and extracted with ethyl acetate. The resulting organic phases are combined, anhydrous sodium sulfate is added to remove water, and the mixture is filtered to obtain the organic phase. The organic phase is then concentrated under reduced pressure to obtain 4.85 g of crude (S)-2-(4-bromophenyl)propionic acid. The crude product was then pulped and filtered with 0.5 times its volume of methyl ether, and the filter cake was dried to obtain 4.75 g of pure (S)-2-(4-bromophenyl)propionic acid.

[0046] Example 4: Synthesis of (S)-2-(4-bromophenyl)propionic acid using isopropyl ether as an organic solvent.

[0047] like Figure 1The synthetic route shown involves adding 80 mL of 0.1 mol / L phosphate buffer to a clean 250 mL glass-jacketed reaction flask, weighing 0.5 g of lipase, and stirring until homogeneous. The reaction system is maintained at 30°C. A solution of 10 g of substrate in 20 mL of isopropyl ether is added dropwise to initiate the reaction. During the reaction, the pH is maintained at approximately 7 using 0.5 mol / L NaOH solution. The reaction is terminated after 30 hours, and the pH is adjusted to 9. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, and the filtrate is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 3 and extracted with ethyl acetate. The resulting organic phases are combined, anhydrous sodium sulfate is added to remove water, and the mixture is filtered again to obtain the organic phase. The organic phase is then concentrated under reduced pressure to obtain 4.7 g of crude (S)-2-(4-bromophenyl)propionic acid. The crude product was then pulped and filtered with 0.5 times its volume of methyl ether, and the filter cake was dried to obtain 4.5 g of pure (S)-2-(4-bromophenyl)propionic acid.

[0048] Example 5: Shortening the synthesis cycle of (S)-2-(4-bromophenyl)propionic acid by adjusting the pH value.

[0049] like Figure 1 The synthetic route shown involves adding 80 mL of 0.1 mol / L phosphate buffer to a clean 250 mL glass-jacketed reaction flask, weighing 0.5 g of lipase, and stirring until homogeneous. The reaction system is maintained at 30°C. A 20 mL solution of n-hexane is added dropwise to initiate the reaction. During the reaction, the pH is maintained at approximately 6 using 0.5 mol / L NaOH solution. The reaction is terminated after 20 hours, and the pH is adjusted to 9. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, and the filtrate is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 3 and extracted with ethyl acetate. The resulting organic phases are combined, anhydrous sodium sulfate is added to remove water, and the mixture is filtered again to obtain the organic phase. The organic phase is then concentrated under reduced pressure to obtain 4.6 g of crude (S)-2-(4-bromophenyl)propionic acid. The crude product was then pulped and filtered with 0.5 times its volume of methyl ether, and the filter cake was dried to obtain 4.4 g of pure (S)-2-(4-bromophenyl)propionic acid.

[0050] Example 6: Shortening the synthesis cycle of (S)-2-(4-bromophenyl)propionic acid by adjusting the pH value

[0051] like Figure 1The synthetic route shown involves adding 80 mL of 0.1 mol / L phosphate buffer to a clean 250 mL glass-jacketed reaction flask, weighing 0.5 g of lipase, and stirring until homogeneous. The reaction system is maintained at 30°C. A 20 mL solution of n-hexane is added dropwise to initiate the reaction. During the reaction, the pH is maintained at approximately 8 using 0.5 mol / L NaOH solution. The reaction is terminated after 20 hours, and the pH is adjusted to 9. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, and the filtrate is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 3 and extracted with ethyl acetate. The resulting organic phases are combined, anhydrous sodium sulfate is added to remove water, and the mixture is filtered again to obtain the organic phase. The organic phase is then concentrated under reduced pressure to obtain 4.9 g of crude (S)-2-(4-bromophenyl)propionic acid. The crude product was then pulped and filtered with 0.5 times its volume of methyl ether, and the filter cake was dried to obtain 4.76 g of pure (S)-2-(4-bromophenyl)propionic acid.

[0052] As can be seen from Examples 5 and 6, adjusting the pH can shorten the synthesis cycle of the product and accelerate the reaction rate. In addition, the preparation method provided by the present invention can add a certain amount of enzyme in a timely manner according to the pH change, which can further reduce the total reaction time and shorten the cycle.

[0053] Example 7 Recovery of methyl (R)-2-(4-bromophenyl)propionate

[0054] like Figure 1 The synthetic route shown involves adding 100 mL of methanol to a clean 250 mL glass reaction flask, weighing 50 g of methyl (R)-2-(4-bromophenyl)propionate, and stirring until dissolved. MeONa (100 g) is then added to the reaction mixture, and the reaction is terminated by heating under reflux for 15 hours. The mixture is filtered, and the filtrate is evaporated to dryness to obtain 50 g of methyl 2-(4-bromophenyl)propionate.

[0055] Example 8: Using hexane as an organic solvent, (S)-2-(4-bromophenyl)propionate was synthesized from ethyl 2-(4-bromophenyl)propionate to produce (S)-2-(4-bromophenyl)propionic acid.

[0056] 100 mL of 0.1 mol / L phosphate buffer was added to a clean 250 mL glass-jacketed reaction flask. Lipase (0.5 g) was weighed and added to the phosphate buffer, and the mixture was stirred until homogeneous. The reaction system was kept at 30 °C. A 20 mL solution of n-hexane was added dropwise to the substrate (10 g) to initiate the reaction. During the reaction, the pH was maintained at approximately 7 using 0.5 mol / L NaOH solution. The reaction was terminated after 20 hours, and the pH was adjusted to 9. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The aqueous phase was then adjusted to pH 3 and extracted with ethyl acetate. The resulting organic phases were combined, anhydrous sodium sulfate was added to remove water, and the mixture was filtered again to obtain the organic phase. The organic phase was concentrated under reduced pressure to obtain 4.3 g of crude (S)-2-(4-bromophenyl)propionic acid. The crude product was then slurried and filtered with 0.5 times its volume of methyl ether, and the filter cake was dried to obtain 4.08 g of pure (S)-2-(4-bromophenyl)propionic acid.

[0057] Example 9: Using n-hexane as an organic solvent, (S)-2-(4-bromophenyl)propionate was synthesized from benzyl 2-(bromophenyl)propionate to produce (S)-2-(4-bromophenyl)propionic acid.

[0058] 200 mL of 0.1 mol / L phosphate buffer was added to a clean 250 mL glass-jacketed reaction flask. Lipase (2 g) was weighed and added to the phosphate buffer, and the mixture was stirred thoroughly. The reaction system was kept at 30 °C. A 20 mL solution of n-hexane was added dropwise to the substrate (10 g) to initiate the reaction. During the reaction, the pH was maintained at approximately 7 using 0.5 mol / L NaOH solution. The reaction was terminated after 24 hours. The pH was adjusted to 9, and the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The aqueous phase was then adjusted to pH 3 and extracted with ethyl acetate. The resulting organic phases were combined, anhydrous sodium sulfate was added to remove water, and the mixture was filtered again to obtain the organic phase. The organic phase was concentrated under reduced pressure to obtain 3.6 g of crude (S)-2-(4-bromophenyl)propionic acid. This was then purified by column chromatography to obtain 3.3 g of pure (S)-2-(4-bromophenyl)propionic acid.

[0059] In summary, the above embodiments are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing (S)-2-(4-bromophenyl)propionic acid, characterized in that, In the presence of an organic solvent and a buffer solution, the substrate undergoes an asymmetric hydrolysis reaction catalyzed by a hydrolytic enzyme to generate the product (S)-2-(4-bromophenyl)propionic acid. The preparation method comprises the following steps: S1. Add organic solvent, buffer solution, substrate and hydrolytic enzyme to the reactor, adjust the pH of the reaction system and keep it at 6.0-8.0, and carry out the asymmetric hydrolysis reaction at 20℃-35℃ for 20-33 hours. S2. Adjust the pH value to 9, filter and extract the reaction solution, then adjust the pH of the aqueous phase to 3 and extract again. Combine the organic phases and remove water and concentrate to obtain the crude product. S3. The crude product is pulped, filtered and dried to obtain the pure product; S4. Methyl (R)-2-(4-bromophenyl)propionate is recovered from the reaction solution and racemized. S5. Using the racemic (R)-2-(4-bromophenyl)propionate methyl ester as a substrate, repeat steps S1, S2 and S3 to obtain the pure product (S)-2-(4-bromophenyl)propionate. The substrate is selected from methyl 2-(4-bromophenyl)propionate or its ester derivatives; the ester derivatives of methyl 2-(4-bromophenyl)propionate are selected from ethyl 2-(4-bromophenyl)propionate or benzyl 2-(4-bromophenyl)propionate. The organic solvent is one or a mixture of isopropyl ether, n-hexane, and n-heptane; The hydrolytic enzyme is selected from lipases; The buffer solution is a phosphate buffer solution.

2. The method for preparing (S)-2-(4-bromophenyl)propionic acid as described in claim 1, characterized in that, The phosphate buffer solution has a molar concentration of 0.1-0.3 mol / L and a pH value of 6.0-8.

0.

3. The method for preparing (S)-2-(4-bromophenyl)propionic acid as described in claim 1, characterized in that, The pH value of the asymmetric hydrolysis reaction is adjusted using a sodium hydroxide solution with a concentration of 0.5 mol / L or 1.0 mol / L.

4. The method for preparing (S)-2-(4-bromophenyl)propionic acid as described in claim 1, characterized in that, In step S2, the filtration refers to using diatomaceous earth to filter the reaction solution to remove enzyme proteins, the extractant for extraction is ethyl acetate, and the dehydrating agent is anhydrous sodium sulfate.

5. The method for preparing (S)-2-(4-bromophenyl)propionic acid as described in claim 1, characterized in that, In step S3, the solvent for pulping is methyl ether, and the volume of methyl ether is 0.5 times that of the crude product.

Images